Bio

Clinical Focus


  • Cancer > GI Oncology
  • Adrenal Cancer
  • Carcinoid Tumors
  • Carcinoid Tumors - Endocrinology
  • Carcinoid Tumors - Surgery
  • Endocrine - Surgery
  • Endocrinology Surgery
  • Esophageal Cancer
  • Esophageal Cancer - Thoracic Surgery
  • Gastrointestinal Cancers
  • Gastrointestinal Cancers - Surgical Oncology
  • Gastrointestinal Oncology Surgery
  • General Surgery
  • Liver Cancer
  • Liver Cancer - Surgery
  • Multiple Endocrine Neoplasias
  • Multiple Endocrine Neoplasias - Surgery
  • Osteosarcoma
  • Osteosarcoma - Surgery
  • Pancreas Surgery
  • Pancreatic Cancer
  • Pancreatic Cancer - Surgery
  • Parathyroid Disease
  • Parathyroid Disease - Surgery
  • Sarcomas - Soft Tissue
  • Sarcomas - Soft Tissue - Surgery
  • Sarcomas - Surgical Oncology
  • Stomach Cancer
  • Stomach Cancer - Surgery
  • Thyroid Cancers
  • Thyroid Cancers - Surgery

Academic Appointments


Professional Education


  • Internship:Duke University Medical Center (1974) NC
  • Residency:Duke University Medical Center (1982) NC
  • Board Certification: General Surgery, American Board of Surgery (1983)
  • Fellowship:National Cancer Institute (1979) MD
  • Medical Education:SUNY Upstate Medical University (1973) NY

Research & Scholarship

Current Research and Scholarly Interests


Interleukin-12 is a Th1 cytokine. It is important in the cell mediated immune response. We are investigating its role as an anti-tumor cytokine to augment the immune response against cancer. We are planning a human trial.

Clinical Trials


  • Evaluation of Preexisting Immunity Markers in Human Tumor Tissue Sample Not Recruiting

    The purpose of this study is to evaluate markers of immune response in human tumor samples.

    Stanford is currently not accepting patients for this trial. For more information, please contact Robin Malone Cisco, (650) 724 - 5570.

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  • Phase II Gemcitabine + Fractionated Stereotactic Radiotherapy for Unresectable Pancreatic Adenocarcinoma Not Recruiting

    This multi-institutional trial aims to evaluate the potential benefit and side effects of adding fractionated stereotactic body radiotherapy/surgery (SBRT) before and after chemotherapy with gemcitabine for locally advanced pancreatic cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Laurie Ann Columbo, 650-736-0792.

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  • Permission to Collect Blood Over Time for Research Recruiting

    To determine whether biomarkers assessed in blood samples can be used to detect individuals at risk for developing blood clots or worsening of their underlying disease. The ultimate goal of the study is to identify key biomarkers derived from blood that are most characteristic and informative of individuals who will go on to develop a clotting complication.

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  • Identification of Key Blood Molecular Markers for Immunotherapy Not Recruiting

    To identify unique blood markers in cancer patients so that we can identify patients with evidence of pre-existing immunity who may be a responder to immunotherapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Kangla Tsung, 650-725-8198.

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  • 68Ga DOTA-TATE PET/CT in Somatostatin Receptor Positive Tumors Recruiting

    The primary objective of the study is to evaluate 68Ga-DOTA TATE PET/CT for staging and monitoring response to chemotherapy in patients with carcinoid, neuroendocrine tumors, medullary thyroid cancer and other cancers expressing somatostatin receptors.

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  • Prognostic Value of Baseline Computed Tomography (CT) Perfusion Parameters of Pancreatic Cancer for Patients Undergoing Stereotactic Body Radiotherapy or Surgical Resection Not Recruiting

    The purpose of this study is first, to determine whether baseline perfusion characteristics of pancreatic cancer, as characterized by CT perfusion studies, can predict tumor response to treatment by stereotactic body radiotherapy (SBRT). The second goal of this study is to determine whether baseline perfusion characteristics in those patients with resectable pancreatic cancer correlate with immunohistologic markers of angiogenesis such as microvessel density and vascular endothelial growth factor (VEGF) expression.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lindee Burton, (650) 725 - 4712.

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  • Phase I Dose Escalation of Stereotactic Radiosurgical Boost for Locally Advanced Esophageal Cancer Not Recruiting

    To study the safety and feasibility of stereotactic radiation dose escalation following neoadjuvant chemotherapy with concurrent conventionally fractionated radiation, by evaluating the acute and late toxicity of treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Laurie Ann Columbo, (650) 736 - 0792.

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  • Trilogy Stereotactic Body Radiotherapy for Pancreatic Cancer Not Recruiting

    This study will assess the efficacy of treating locally advanced pancreatic cancer using Stereotactic Body Radiotherapy (using Trilogy) and Gemcitabine

    Stanford is currently not accepting patients for this trial. For more information, please contact Jeff Kim, (650) 498 - 7703.

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  • Cyberknife Radiosurgery for Locally Advanced Pancreatic Cancer Not Recruiting

    The purpose of the trial is to test the efficacy of combining conventional chemoradiotherapy with radiosurgery for locally advanced pancreas cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Stanford Cancer Clinical Trials Office, (650) 498 - 7061.

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  • Phase 1-2 Vatalanib and Gemcitabine in Advanced Pancreatic Cancer Not Recruiting

    The purpose of the study is to determine the optimal safe and tolerable dose of gemcitabine in combination with once daily or twice daily dose of PTK/ZK in patients with unresectable pancreatic cancer. The Phase II part of this study planned to determine the antitumor activity of this regimen and its effectiveness of preventing tumor growth and spread.

    Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Kaiser, (650) 724 - 0079.

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Teaching

2014-15 Courses


Publications

All Publications


  • Prognostic relevance of lymph node ratio and total lymph node count for small bowel adenocarcinoma. Surgery Tran, T. B., Qadan, M., Dua, M. M., Norton, J. A., Poultsides, G. A., Visser, B. C. 2015; 158 (2): 486-493

    Abstract

    Nodal metastasis is a known prognostic factor for small bowel adenocarcinoma. The goals of this study were to evaluate the number of lymph nodes (LNs) that should be retrieved and the impact of lymph node ratio (LNR) on survival.Surveillance, Epidemiology, and End Results was queried to identify patients with small bowel adenocarcinoma who underwent resection from 1988 to 2010. Survival was calculated with the Kaplan-Meier method. Multivariate analysis identified predictors of survival.A total of 2,772 patients underwent resection with at least one node retrieved, and this sample included equal numbers of duodenal (n = 1,387) and jejunoileal (n = 1,386) adenocarcinomas. There were 1,371 patients with no nodal metastasis (N0, 49.4%), 928 N1 (33.5%), and 474 N2 (17.1%). The median numbers of LNs examined for duodenal and jejunoileal cancers were 9 and 8, respectively. Cut-point analysis demonstrated that harvesting at least 9 for jejunoileal and 5 LN for duodenal cancers resulted in the greatest survival difference. Increasing LNR at both sites was associated with decreased overall median survival (LNR = 0, 71 months; LNR 0-0.02, 35 months; LNR 0.21-0.4, 25 months; and LNR >0.4, 16 months; P < .001). Multivariate analysis confirmed number of LNs examined, T-stage, LN positivity, and LNR were independent predictors of survival.LNR has a profound impact on survival in patients with small bowel adenocarcinoma. To achieve adequate staging, we recommend retrieving a minimum of 5 LN for duodenal and 9 LN for jejunoileal adenocarcinomas.

    View details for DOI 10.1016/j.surg.2015.03.048

    View details for PubMedID 26013988

  • Number of Lymph Nodes Removed and Survival after Gastric Cancer Resection: An Analysis from the US Gastric Cancer Collaborative. Journal of the American College of Surgeons Gholami, S., Janson, L., Worhunsky, D. J., Tran, T. B., Squires, M. H., Jin, L. X., Spolverato, G., Votanopoulos, K. I., Schmidt, C., Weber, S. M., Bloomston, M., Cho, C. S., Levine, E. A., Fields, R. C., Pawlik, T. M., Maithel, S. K., Efron, B., Norton, J. A., Poultsides, G. A. 2015; 221 (2): 291-299

    Abstract

    Examination of at least 16 lymph nodes (LNs) has been traditionally recommended during gastric adenocarcinoma resection to optimize staging, but the impact of this strategy on survival is uncertain. Because recent randomized trials have demonstrated a therapeutic benefit from extended lymphadenectomy, we sought to investigate the impact of the number of LNs removed on prognosis after gastric adenocarcinoma resection.We analyzed patients who underwent gastrectomy for gastric adenocarcinoma from 2000 to 2012, at 7 US academic institutions. Patients with M1 disease or R2 resections were excluded. Disease-specific survival (DSS) was calculated using the Kaplan-Meier method and compared using log-rank and Cox regression analyses.Of 742 patients, 257 (35%) had 7 to 15 LNs removed and 485 (65%) had ≥16 LNs removed. Disease-specific survival was not significantly longer after removal of ≥16 vs 7 to 15 LNs (10-year survival, 55% vs 47%, respectively; p = 0.53) for the entire cohort, but was significantly improved in the subset of patients with stage IA to IIIA (10-year survival, 74% vs 57%, respectively; p = 0.018) or N0-2 disease (72% vs 55%, respectively; p = 0.023). Similarly, for patients who were classified to more likely be "true N0-2," based on frequentist analysis incorporating both the number of positive and of total LNs removed, the hazard ratio for disease-related death (adjusted for T stage, R status, grade, receipt of neoadjuvant and adjuvant therapy, and institution) significantly decreased as the number of LNs removed increased.The number of LNs removed during gastrectomy for adenocarcinoma appears itself to have prognostic implications for long-term survival.

    View details for DOI 10.1016/j.jamcollsurg.2015.04.024

    View details for PubMedID 26206635

  • Cyst Fluid Glucose is Rapidly Feasible and Accurate in Diagnosing Mucinous Pancreatic Cysts. American journal of gastroenterology Zikos, T., Pham, K., Bowen, R., Chen, A. M., Banerjee, S., Friedland, S., Dua, M. M., Norton, J. A., Poultsides, G. A., Visser, B. C., Park, W. G. 2015; 110 (6): 909-914

    Abstract

    Better diagnostic tools are needed to differentiate pancreatic cyst subtypes. A previous metabolomic study showed cyst fluid glucose as a potential marker to differentiate mucinous from non-mucinous pancreatic cysts. This study seeks to validate these earlier findings using a standard laboratory glucose assay, a glucometer, and a glucose reagent strip.Using an IRB-approved prospectively collected bio-repository, 65 pancreatic cyst fluid samples (42 mucinous and 23 non-mucinous) with histological correlation were analyzed.Median laboratory glucose, glucometer glucose, and percent reagent strip positive were lower in mucinous vs. non-mucinous cysts (P<0.0001 for all comparisons). Laboratory glucose<50 mg/dl had a sensitivity of 95% and a specificity of 57% (LR+ 2.19, LR- 0.08). Glucometer glucose<50 mg/dl had a sensitivity of 88% and a specificity of 78% (LR+ 4.05, LR- 0.15). Reagent strip glucose had a sensitivity of 81% and a specificity of 74% (LR+ 3.10, LR- 0.26). CEA had a sensitivity of 77% and a specificity of 83% (LR+ 4.67, LR- 0.27). The combination of having either a glucometer glucose<50 mg/dl or a CEA level>192 had a sensitivity of 100% but a low specificity of 33% (LR+ 1.50, LR- 0.00).Glucose, whether measured by a laboratory assay, a glucometer, or a reagent strip, is significantly lower in mucinous cysts compared with non-mucinous pancreatic cysts.

    View details for DOI 10.1038/ajg.2015.148

    View details for PubMedID 25986360

  • Predictive Factors for Surgery Among Patients with Pancreatic Cysts in the Absence of High-Risk Features for Malignancy JOURNAL OF GASTROINTESTINAL SURGERY Quan, S. Y., Visser, B. C., Poultsides, G. A., Norton, J. A., Chen, A. M., Banerjee, S., Friedland, S., Park, W. G. 2015; 19 (6): 1101-1105

    Abstract

    Without a reliable biopsy technique for pancreatic cysts, consensus-based guidelines are used to guide surgical utilization. The primary objective of this study was to characterize the proportion of operations performed outside of these guidelines.A 5-year retrospective review between July 1, 2007, and June 30, 2012, was performed of consecutive patients seen at a single tertiary medical center for a pancreatic cyst. Manual chart review for relevant clinical variables and cyst characteristics was performed.During this period, 148 patients underwent surgery, and of these, 23 (16 %) patients had no high-risk criteria by the 2006 Sendai criteria. None of these harbored high-grade dysplastic or cancerous lesions. A high cyst carcinoembryonic antigen (CEA) level (35 %), patient anxiety (26 %), and physician concern (22 %) were explicit reasons to proceed to surgery. An elevated cyst CEA level >192 ng/ml was the most significant predictor (OR 5.14 (95 % confidence interval (CI) 1.47-18.0) for surgery without high-risk criteria.A high cyst CEA level was significantly associated with the decision to operate outside of consensus-based guidelines. The misuse of cyst CEA in the management of pancreatic cysts negatively impacts patient anxiety, increases physician uncertainty, and leads to surgery with minimal benefit.

    View details for DOI 10.1007/s11605-015-2786-3

    View details for Web of Science ID 000355344300016

    View details for PubMedID 25749855

  • Extracorporeal Pringle for laparoscopic liver resection SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES Dua, M. M., Worhunsky, D. J., Hwa, K., Poultsides, G. A., Norton, J. A., Visser, B. C. 2015; 29 (6): 1348-1355

    Abstract

    A primary concern during laparoscopic liver resection (lapLR) is hemorrhage during parenchymal transection. Intermittent pedicle clamping is an effective method to minimize blood loss during open liver surgery; however, inflow occlusion techniques are challenging to reproduce during laparoscopy. The purpose of this study is to describe the safety and efficacy of a facile method for Pringle maneuver during lapLR.154 patients who underwent lapLR from 2007 to 2013 were retrospectively reviewed. For Pringle, the hepatoduodenal ligament is encircled with an umbilical tape which is externalized through a flexible Rumel tourniquet running alongside a port used for the operation. The internal end of the catheter is close to the pedicle and the external end is extracorporeal, allowing for easy external occlusion. Patients who underwent Pringle Maneuver (PM, n = 88) were compared to patients who had "No Occlusion" (NO, n = 66) with respect to patient characteristics, operative outcomes, changes in postoperative liver function, and complications.Annual placement of the tourniquet and vascular occlusion increased from 35.7 to 82.8 % (p = 0.004) and 21.4 to 62.1 % (p = 0.02), respectively. Median occlusion time was 24 min (IQR 15-34.3, min 5, max 70). Peak transaminase levels were comparable between groups (AST 298 ± 32 vs 405 ± 47 U/L, p = 0.15; ALT 272 ± 27 vs 372 ± 34 U/L, p = 0.14, NO and PM, respectively). Postoperative transaminase and bilirubin levels for both groups were not significantly different with similar recovery to baseline. Subgroup analysis of cirrhotic patients who underwent Pringle demonstrated similar transaminase profiles compared to non-cirrhotic patients. There were two conversions (1.3 %) and postoperative 30-day mortality was 0.65 %.Extracorporeal tourniquet placement in lapLR is a quick and safe method of gaining control for inflow occlusion. Routine adoption of laparoscopic Pringle maneuver facilitates low conversion rates without liver injury.

    View details for DOI 10.1007/s00464-014-3801-6

    View details for Web of Science ID 000354130200013

    View details for PubMedID 25159645

  • Leiomyosarcoma: One Disease or Distinct Biologic Entities Based on Site of Origin? JOURNAL OF SURGICAL ONCOLOGY Worhunsky, D. J., Gupta, M., Gholami, S., Tran, T. B., Ganjoo, K. N., van de Rijn, M., Visser, B. C., Norton, J. A., Poultsides, G. A. 2015; 111 (7): 808-812

    Abstract

    Leiomyosarcoma (LMS) can originate from the retroperitoneum, uterus, extremity, and trunk. It is unclear whether tumors of different origin represent discrete entities. We compared clinicopathologic features and outcomes following surgical resection of LMS stratified by site of origin.Patients with LMS undergoing resection at a single institution were retrospectively reviewed. Clinicopathologic variables were compared across sites. Survival was calculated using the Kaplan-Meier method and compared using log-rank and Cox regression analyses.From 1983 to 2011, 138 patients underwent surgical resection for LMS. Retroperitoneal and uterine LMS were larger, higher grade, and more commonly associated with synchronous metastases. However, disease-specific survival, recurrence-free survival, and recurrence patterns were not significantly different across the four sites. Synchronous metastases (HR 3.20, P < 0.001), but not site of origin, size, grade, or margin status, were independently associated with worse DSS. A significant number of recurrences and disease-related deaths were noted beyond 5 years.Although larger and higher grade, retroperitoneal and uterine LMS share similar survival and recurrence patterns with their trunk and extremity counterparts. LMS of various anatomic sites may not represent distinct disease processes based on clinical outcomes. The presence of metastatic disease remains the most important prognostic factor for LMS.

    View details for DOI 10.1002/jso.23904

    View details for Web of Science ID 000353996400003

    View details for PubMedID 25920434

  • IL-12 Augments Antitumor Responses to Cycled Chemotherapy JOURNAL OF IMMUNOTHERAPY Zhang, L., Feng, D., Hu, Y., Tsung, K., Norton, J. A. 2015; 38 (4): 137-144

    Abstract

    Loss of antitumor response to repeated chemotherapy is a major cause of treatment failure in cancer patients. The development of acquired drug resistance is thought to come primarily from changes in tumor cells, and not host response to the tumor. Our recent study shows that antitumor immunity is activated and contributes significantly to the efficacy of chemotherapy. In this study of mouse tumor models, we demonstrate that loss of antitumor response during multiple cycles of chemotherapy is associated with a lack of immune activation, and not intrinsic tumor cell drug resistance. More importantly, we show that adding interleukin-12 (IL-12) to cycled chemotherapy maintains and even increases antitumor immune response in both immunogenic and nonimmunogenic murine tumors and significantly prolongs survival. In some instances, larger tumor burdens that relapse following an initial cycle of cyclophosphamide and IL-12 are eradicated by subsequent cycles of the same treatment at the same doses. Further analysis demonstrates that the initial cycle of the combined therapy increases antitumor immunity of the host. In other mice when tumors are not eradicated by the current cycle of therapy, it serves as a starting point for the subsequent cycles of treatment to generate higher levels of antitumor immunity and greater antitumor response. These results show that the status of host antitumor immunity is a critical factor affecting antitumor efficacy during repeated administration of chemotherapy. Further, IL-12 augments the antitumor immune response under such conditions.

    View details for DOI 10.1097/CJI.0000000000000074

    View details for Web of Science ID 000353058300001

    View details for PubMedID 25839439

  • Compliance With Gastric Cancer Guidelines is Associated With Improved Outcomes. Journal of the National Comprehensive Cancer Network Worhunsky, D. J., Ma, Y., Zak, Y., Poultsides, G. A., Norton, J. A., Rhoads, K. F., Visser, B. C. 2015; 13 (3): 319-325

    Abstract

    Limited data are available on the implementation and effectiveness of NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer.We sought to assess rates of compliance with NCCN Guidelines, specifically stage-specific therapy during the initial episode of care, and to determine its impact on outcomes.The California Cancer Registry was used to identify cases of gastric cancer from 2001 to 2006. Logistic regression and Cox proportional hazard models were used to predict guideline compliance and the adjusted hazard ratio for mortality. Patients with TNM staging or summary stage (SS) were also analyzed separately.Compliance with NCCN Guidelines occurred in just 45.5% of patients overall. Patients older than 55 years were less likely to receive guideline-compliant care, and compliance was associated with a median survival of 20 versus 7 months for noncompliant care (P<.001). Compliant care was also associated with a 55% decreased hazard of mortality (P<.001). Further analysis revealed that 50% of patients had complete TNM staging versus an SS, and TNM-staged patients were more likely to receive compliant care (odds ratio, 1.59; P<.001). TNM-staged patients receiving compliant care had a median survival of 25.3 months compared with 15.1 months for compliant SS patients.Compliance with NCCN Guidelines and stage-specific therapy at presentation for the treatment of patients with gastric cancer was poor, which was a significant finding given that compliant care was associated with a 55% reduction in the hazard of death. Additionally, patients with TNM-staged cancer were more likely to receive compliant care, perhaps a result of having received more intensive therapy. Combined with the improved survival among compliant TNM-staged patients, these differences have meaningful implications for health services research.

    View details for PubMedID 25736009

  • Mutation profiling of tumor DNA from plasma and tumor tissue of colorectal cancer patients with a novel, high-sensitivity multiplexed mutation detection platform ONCOTARGET Kidess, E., Heirich, K., Wiggin, M., Vysotskaia, V., Visser, B. C., Marziali, A., Wiedenmann, B., Norton, J. A., Lee, M., Jeffrey, S. S., Poultsides, G. A. 2015; 6 (4): 2549-2561

    Abstract

    Circulating tumor DNA (ctDNA) holds promise as a non-invasive means for tumor monitoring in solid malignancies. Assays with high sensitivity and multiplexed analysis of mutations are needed to enable broad application.We developed a new assay based on sequence-specific synchronous coefficient of drag alteration (SCODA) technology, which enriches for mutant DNA to achieve high sensitivity and specificity. This assay was applied to plasma and tumor tissue from non-metastatic and metastatic colorectal cancer (CRC) patients, including patients undergoing surgical resection for CRC liver metastases.Across multiple characterization experiments, the assay demonstrated a limit of detection of 0.001% (1 molecule in 100,000) for the majority of the 46 mutations in the panel. In CRC patient samples (n=38), detected mutations were concordant in tissue and plasma for 93% of metastatic patients versus 54% of non-metastatic patients. For three patients, ctDNA identified additional mutations not detected in tumor tissue. In patients undergoing liver metastatectomy, ctDNA anticipated tumor recurrence earlier than carcinoembryonic antigen (CEA) value or imaging.The multiplexed SCODA mutation enrichment and detection method can be applied to mutation profiling and quantitation of ctDNA, and is likely to have particular utility in the metastatic setting, including patients undergoing metastatectomy.

    View details for Web of Science ID 000352691800047

    View details for PubMedID 25575824

  • Does the extent of resection impact survival for duodenal adenocarcinoma? Analysis of 1,611 cases. Annals of surgical oncology Cloyd, J. M., Norton, J. A., Visser, B. C., Poultsides, G. A. 2015; 22 (2): 573-580

    Abstract

    Because duodenal adenocarcinoma (DA) is relatively rare, few studies have investigated the impact of resection type on long-term outcomes.The Surveillance, Epidemiology, and End Results database was used to identify all patients between 1988 and 2010 with DA. Patients were divided into two groups based on the type of surgery received: simple resection (SR), defined as a simple removal of the primary site, and radical resection (RR), defined as removal of the primary site with a resection in continuity with other organs. Differences in disease-specific survival (DSS) and overall survival (OS) were compared.Of the 1,611 patients included, 746 (46.3 %) underwent SR and 865 (53.7 %) underwent RR. As expected, patients undergoing RR were more likely to present with poorly differentiated and large tumors, as well as advanced stage disease. Despite greater lymph node (LN) retrieval (11.0 vs. 6.8; p < 0.0001), RR was not associated with improved survival (5-year DSS and OS rates of 52.8 and 41.3 % for SR vs. 48.8 and 37.6 % for RR; p > 0.05). On univariate Cox proportional hazards regression analysis, the type of surgery was not associated with OS (odds ratio [OR] 0.98; 95 % confidence interval [CI] 0.87-1.11). Increasing TNM stages, tumor grade, fewer LNs removed, LN ratio, and absence of radiation were associated with worse survival. After controlling for confounding factors, type of surgery still did not influence OS (OR 1.11; 95 % CI 0.97-1.27).Radical resection (e.g., in the form of pancreaticoduodenectomy) does not appear to impact survival compared with simple segmental resection for DA.

    View details for DOI 10.1245/s10434-014-4020-z

    View details for PubMedID 25160736

  • Metastatic Lobular Breast Carcinoma Mimicking Primary Signet Ring Adenocarcinoma in a Patient With a Suspected CDH1 Mutation JOURNAL OF CLINICAL ONCOLOGY Mahmud, N., Ford, J. M., Longacre, T. A., Parent, R., Norton, J. A. 2015; 33 (4): E19-E21

    View details for DOI 10.1200/JCO.2013.49.1159

    View details for Web of Science ID 000352422900002

    View details for PubMedID 24590638

  • Impact of histological subtype on long-term outcomes of neuroendocrine carcinoma of the breast BREAST CANCER RESEARCH AND TREATMENT Cloyd, J. M., Yang, R. L., Allison, K. H., Norton, J. A., Hernandez-Boussard, T., Wapnir, I. L. 2014; 148 (3): 637-644
  • Single-versus Multifraction Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma: Outcomes and Toxicity INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Pollom, E. L., Alagappan, M., von Eyben, R., Kunz, P. L., Fisher, G. A., Ford, J. A., Poultsides, G. A., Visser, B. C., Norton, J. A., Kamaya, A., Cox, V. L., Columbo, L. A., Koong, A. C., Chang, D. T. 2014; 90 (4): 918-925
  • Laparoscopic Transgastric Necrosectomy for the Management of Pancreatic Necrosis JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Worhunsky, D. J., Qadan, M., Dua, M. M., Park, W. G., Poultsides, G. A., Norton, J. A., Visser, B. C. 2014; 219 (4): 735-743
  • Laparoscopic spleen-preserving distal pancreatectomy: the technique must suit the lesion. Journal of gastrointestinal surgery Worhunsky, D. J., Zak, Y., Dua, M. M., Poultsides, G. A., Norton, J. A., Visser, B. C. 2014; 18 (8): 1445-1451

    Abstract

    Splenic preservation is currently recommended during minimally invasive surgery for benign tumors of the distal pancreas. The aim of this study was to evaluate the outcomes of patients undergoing laparoscopic spleen-preserving distal pancreatectomy, with particular attention paid to the technique used for spleen preservation (splenic vessel ligation vs preservation). A review of consecutive patients who underwent laparoscopic distal pancreatectomy with the intention of splenic preservation was conducted. Patient demographics, operative data, and outcomes were collected and analyzed. Fifty-five consecutive patients underwent laparoscopic distal pancreatectomy with the intention of splenic preservation; 5 required splenectomy (9 %). Of the remaining 50 patients, 31 (62 %) had splenic vessel ligation, and 19 (38 %) had vessel preservation. Patient demographics and tumor size were similar. The vessel ligation group had significantly more pancreas removed (95 vs 52 mm, P < 0.001) and longer operative times (256 vs 201 min, P = 0.008). Postoperative outcomes, complication rates, and splenic viability were similar between groups. Laparoscopic spleen-preserving distal pancreatectomy is a safe operation with a high rate of success (91 %). Vessel ligation was the chosen technical strategy for lesions that required resection of a greater length of pancreas. We found no advantage to either technique with respect to outcomes and splenic preservation. Operative approach should reflect technical considerations including location in the pancreas.

    View details for DOI 10.1007/s11605-014-2561-x

    View details for PubMedID 24939598

  • RET Gene Mutations (Genotype and Phenotype) of Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma CANCER Krampitz, G. W., Norton, J. A. 2014; 120 (13): 1920-1931

    View details for DOI 10.1002/cncr.28661

    View details for Web of Science ID 000337763300006

  • Pancreatic neuroendocrine tumours: hypoenhancement on arterial phase computed tomography predicts biological aggressiveness HPB Worhunsky, D. J., Krampitz, G. W., Poullos, P. D., Visser, B. C., Kunz, P. L., Fisher, G. A., Norton, J. A., Poultsides, G. A. 2014; 16 (4): 304-311

    Abstract

    Contrary to pancreatic adenocarcinoma, pancreatic neuroendocrine tumours (PNET) are commonly hyperenhancing on arterial phase computed tomography (APCT). However, a subset of these tumours can be hypoenhancing. The prognostic significance of the CT appearance of these tumors remains unclear.From 2001 to 2012, 146 patients with well-differentiated PNET underwent surgical resection. The degree of tumour enhancement on APCT was recorded and correlated with clinicopathological variables and overall survival.APCT images were available for re-review in 118 patients (81%). The majority had hyperenhancing tumours (n = 80, 68%), 12 (10%) were isoenhancing (including cases where no mass was visualized) and 26 (22%) were hypoenhancing. Hypoenhancing PNET were larger, more commonly intermediate grade, and had higher rates of lymph node and synchronous liver metastases. Hypoenhancing PNET were also associated with significantly worse overall survival after a resection as opposed to isoenhancing and hyperenhancing tumours (5-year, 54% versus 89% versus 93%). On multivariate analysis of factors available pre-operatively, only hypoenhancement (HR 2.32, P = 0.02) was independently associated with survival.Hypoenhancement on APCT was noted in 22% of well-differentiated PNET and was an independent predictor of poor outcome. This information can inform pre-operative decisions in the multidisciplinary treatment of these neoplasms.

    View details for DOI 10.1111/hpb.12139

    View details for Web of Science ID 000332989700002

  • Molecular assessment of surgical-resection margins of gastric cancer by mass-spectrometric imaging PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Eberlin, L. S., Tibshirani, R. J., Zhang, J., Longacre, T. A., Berry, G. J., Bingham, D. B., Norton, J. A., Zare, R. N., Poultsides, G. A. 2014; 111 (7): 2436-2441

    Abstract

    Surgical resection is the main curative option for gastrointestinal cancers. The extent of cancer resection is commonly assessed during surgery by pathologic evaluation of (frozen sections of) the tissue at the resected specimen margin(s) to verify whether cancer is present. We compare this method to an alternative procedure, desorption electrospray ionization mass spectrometric imaging (DESI-MSI), for 62 banked human cancerous and normal gastric-tissue samples. In DESI-MSI, microdroplets strike the tissue sample, the resulting splash enters a mass spectrometer, and a statistical analysis, here, the Lasso method (which stands for least absolute shrinkage and selection operator and which is a multiclass logistic regression with L1 penalty), is applied to classify tissues based on the molecular information obtained directly from DESI-MSI. The methodology developed with 28 frozen training samples of clear histopathologic diagnosis showed an overall accuracy value of 98% for the 12,480 pixels evaluated in cross-validation (CV), and 97% when a completely independent set of samples was tested. By applying an additional spatial smoothing technique, the accuracy for both CV and the independent set of samples was 99% compared with histological diagnoses. To test our method for clinical use, we applied it to a total of 21 tissue-margin samples prospectively obtained from nine gastric-cancer patients. The results obtained suggest that DESI-MSI/Lasso may be valuable for routine intraoperative assessment of the specimen margins during gastric-cancer surgery.

    View details for DOI 10.1073/pnas.1400274111

    View details for Web of Science ID 000331396500018

  • Postoperative Serum Amylase Predicts Pancreatic Fistula Formation Following Pancreaticoduodenectomy JOURNAL OF GASTROINTESTINAL SURGERY Cloyd, J. M., Kastenberg, Z. J., Visser, B. C., Poultsides, G. A., Norton, J. A. 2014; 18 (2): 348-353

    Abstract

    Early identification of patients at risk for developing pancreatic fistula (PF) after pancreaticoduodenectomy (PD) may facilitate prevention or treatment strategies aimed at reducing its associated morbidity.A retrospective review of 176 consecutive PD performed between 2006 and 2011 was conducted in order to analyze the association between the serum amylase on postoperative day 1 (POD1) and the development of PF.Serum amylase was recorded on POD1 in 146 of 176 PD cases (83.0 %). Twenty-seven patients (18.5 %) developed a postoperative PF: 6 type A, 19 type B, and 2 type C. Patients with a PF had a mean serum amylase on POD1 of 659 ± 581 compared to 246 ± 368 in those without a fistula (p < 0.001). On logistic regression, a serum amylase >140 U/L on POD1 was strongly associated with developing a PF (OR, 5.48; 95 % CI, 1.94-15.44). Sensitivity and specificity of a postoperative serum amylase >140 U/L was 81.5 and 55.5 %, respectively. Positive and negative predictive values were 29.3 and 93.0 %, respectively.An elevated serum amylase on POD1 may be used, in addition to other prognostic factors, to help stratify risk for developing PF following PD.

    View details for DOI 10.1007/s11605-013-2293-3

    View details for Web of Science ID 000331379100038

    View details for PubMedID 23903930

  • Reassessment of the Current American Joint Committee on Cancer Staging System for Pancreatic Neuroendocrine Tumors JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Qadan, M., Ma, Y., Visser, B. C., Kunz, P. L., Fisher, G. A., Norton, J. A., Poultsides, G. A. 2014; 218 (2): 188-195

    Abstract

    Adopting a unified staging system for pancreatic neuroendocrine tumors (PNETs) has been challenging. Currently, the American Joint Committee on Cancer (AJCC) recommends use of the pancreatic adenocarcinoma staging system for PNETs. We sought to explore the prognostic usefulness of the pancreatic adenocarcinoma staging system for PNETs.The Surveillance, Epidemiology, and End Results program data were used to identify patients with PNETs who underwent curative-intent surgical resection from 1983 to 2008. The discriminatory ability of the AJCC system was examined and a new TNM system was devised using extent of disease variables.In 1,202 patients identified, lymph node metastasis was associated with worse 10-year overall survival after resection (51% vs 63%; p < 0.0001), as was the presence of distant metastatic disease (35% vs 62%; p < 0.0001). The current AJCC system (recorded by the Surveillance, Epidemiology, and End Results program in 412 patients since 2004) distinguished 5-year overall survival only between stages I and II (p = 0.01), but not between stages II and III (p = 0.97), or stages III and IV (p = 0.36). By modifying the T stage to be based on size alone (0.1 to 1.0 cm, 1.1 to 2.0 cm, 2.1 to 4.0 cm, and >4.0 cm) and revising the TNM subgroups, we propose a novel TNM system with improved discriminatory ability between disease stages (stages I vs II; p = 0.16; II vs III; p < 0.0001; and III vs IV; p = 0.008).In this study evaluating the current AJCC staging system for PNETs, there were no significant differences detected between stages II and III or stages III and IV. We propose a novel TNM system that might better discriminate between outcomes after surgical resection of PNETs.

    View details for DOI 10.1016/j.jamcollsurg.2013.11.001

    View details for Web of Science ID 000329763900008

  • Pancreatic neuroendocrine tumors CURRENT PROBLEMS IN SURGERY Krampitz, G. W., NORTON, J. A. 2013; 50 (11): 509-545

    View details for DOI 10.1067/j.cpsurg.2013.08.001

    View details for Web of Science ID 000327104300002

    View details for PubMedID 24206780

  • Long-term Results of Adjuvant Imatinib Mesylate in Localized, High-Risk, Primary Gastrointestinal Stromal Tumor ACOSOG Z9000 (Alliance) Intergroup Phase 2 Trial ANNALS OF SURGERY DeMatteo, R. P., Ballman, K. V., Antonescu, C. R., Corless, C., Kolesnikova, V., von Mehren, M., McCarter, M. D., Norton, J., Maki, R. G., Pisters, P. W., Demetri, G. D., Brennan, M. F., Owzar, K. 2013; 258 (3): 422-429

    Abstract

    To conduct the first adjuvant trial of imatinib mesylate for treatment of gastrointestinal stromal tumor (GIST).GIST is the most common sarcoma. Although surgical resection has been the mainstay of therapy for localized, primary GIST, postoperative tumor recurrence is common. The KIT protooncogene or, less frequently, platelet-derived growth factor receptor alpha is mutated in GIST; the gene products of both are inhibited by imatinib mesylate.This was a phase II, intergroup trial led by the American College of Surgeons Oncology Group, registered at ClinicalTrials.gov as NCT00025246. From September 2001 to September 2003, we accrued 106 patients who had undergone complete gross tumor removal but were deemed at high risk for recurrence. Patients were prescribed imatinib 400 mg per day for 1 year and followed with serial radiologic evaluation. The primary endpoint was overall survival (OS).After a median follow-up of 7.7 years, the 1-, 3-, and 5-year OS rates were 99%, 97%, and 83%, which compared favorably with a historical 5-year OS rate of 35%. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 96%, 60%, and 40%. On univariable analysis, age and mitotic rate were associated with OS. On multivariable analysis, the RFS rate was lower with increasing tumor size, small bowel site, KIT exon 9 mutation, high mitotic rate, and older age.Adjuvant imatinib in patients with primary GIST who are at high risk of recurrence prolongs OS compared with that of historical controls. Optimal duration of adjuvant therapy remains undefined. (NCT00025246).

    View details for DOI 10.1097/SLA.0b013e3182a15eb7

    View details for Web of Science ID 000330463900006

    View details for PubMedID 23860199

  • Metabolomic-derived novel cyst fluid biomarkers for pancreatic cysts: glucose and kynurenine. Gastrointestinal endoscopy Park, W. G., Wu, M., Bowen, R., Zheng, M., Fitch, W. L., Pai, R. K., Wodziak, D., Visser, B. C., Poultsides, G. A., Norton, J. A., Banerjee, S., Chen, A. M., Friedland, S., Scott, B. A., Pasricha, P. J., Lowe, A. W., Peltz, G. 2013; 78 (2): 295-302 e2

    Abstract

    BACKGROUND: Better pancreatic cyst fluid biomarkers are needed. OBJECTIVE: To determine whether metabolomic profiling of pancreatic cyst fluid would yield clinically useful cyst fluid biomarkers. DESIGN: Retrospective study. SETTING: Tertiary-care referral center. PATIENTS: Two independent cohorts of patients (n = 26 and n = 19) with histologically defined pancreatic cysts. INTERVENTION: Exploratory analysis for differentially expressed metabolites between (1) nonmucinous and mucinous cysts and (2) malignant and premalignant cysts was performed in the first cohort. With the second cohort, a validation analysis of promising identified metabolites was performed. MAIN OUTCOME MEASUREMENTS: Identification of differentially expressed metabolites between clinically relevant cyst categories and their diagnostic performance (receiver operating characteristic [ROC] curve). RESULTS: Two metabolites had diagnostic significance-glucose and kynurenine. Metabolomic abundances for both were significantly lower in mucinous cysts compared with nonmucinous cysts in both cohorts (glucose first cohort P = .002, validation P = .006; and kynurenine first cohort P = .002, validation P = .002). The ROC curve for glucose was 0.92 (95% confidence interval [CI], 0.81-1.00) and 0.88 (95% CI, 0.72-1.00) in the first and validation cohorts, respectively. The ROC for kynurenine was 0.94 (95% CI, 0.81-1.00) and 0.92 (95% CI, 0.76-1.00) in the first and validation cohorts, respectively. Neither could differentiate premalignant from malignant cysts. Glucose and kynurenine levels were significantly elevated for serous cystadenomas in both cohorts. LIMITATIONS: Small sample sizes. CONCLUSION: Metabolomic profiling identified glucose and kynurenine to have potential clinical utility for differentiating mucinous from nonmucinous pancreatic cysts. These markers also may diagnose serous cystadenomas.

    View details for DOI 10.1016/j.gie.2013.02.037

    View details for PubMedID 23566642

  • Metabolomic-derived novel cyst fluid biomarkers for pancreatic cysts: glucose and kynurenine GASTROINTESTINAL ENDOSCOPY Park, W. G., Wu, M., Bowen, R., Zheng, M., Fitch, W. L., Pai, R. K., Wodziak, D., Visser, B. C., Poultsides, G. A., Norton, J. A., Banerjee, S., Chen, A. M., Friedland, S., Scott, B. A., Pasricha, P. J., Lowe, A. W., Peltz, G. 2013; 78 (2): 295-?
  • Preexisting antitumor immunity augments the antitumor effects of chemotherapy. Cancer immunology, immunotherapy : CII Zhang, L., Feng, D., Yu, L. X., Tsung, K., Norton, J. A. 2013; 62 (6): 1061-1071

    Abstract

    Efficacy of cancer chemotherapy is generally believed to be the result of direct drug killing of tumor cells. However, increased tumor cell killing does not always lead to improved efficacy. Herein, we demonstrate that the status of antitumor immunity at the time of chemotherapy treatment is a critical factor affecting the therapeutic outcome in that tumor-bearing mice that possess preexisting antitumor immunity respond to chemotherapy much better than those that do not. Enhancing antitumor immunity before or at the time of chemotherapy-induced antigen release increases subsequent response to chemotherapy significantly. By in vitro and in vivo measurements of antitumor immunity, we found a close correlation between the intensity of antitumor immunity activated by chemotherapy and the efficacy of treatment. Immune intervention with interleukin-12 during the early phase of chemotherapy-induced immune activation greatly amplifies the antitumor response, often resulting in complete tumor eradication not only at the chemo-treated local site, but also systemically. These findings provide additional evidence for an immune-mediated antitumor response to chemotherapy. Further, our results show that timely immune modification of chemotherapy-activated antitumor immunity can result in enhanced antitumor-immune response and complete tumor eradication.

    View details for DOI 10.1007/s00262-013-1417-7

    View details for PubMedID 23595208

  • Seventh Edition (2010) of the AJCC/UICC Staging System for Gastric Adenocarcinoma: Is there Room for Improvement? ANNALS OF SURGICAL ONCOLOGY Patel, M. I., Rhoads, K. F., Ma, Y., Ford, J. M., Visser, B. C., Kunz, P. L., Fisher, G. A., Chang, D. T., Koong, A., Norton, J. A., Poultsides, G. A. 2013; 20 (5): 1631-1638

    Abstract

    The gastric cancer AJCC/UICC staging system recently underwent significant revisions, but studies on Asian patients have reported a lack of adequate discrimination between various consecutive stages. We sought to validate the new system on a U.S. population database.California Cancer Registry data linked to the Office of Statewide Health Planning and Development discharge abstracts were used to identify patients with gastric adenocarcinoma (esophagogastric junction and gastric cardia tumors excluded) who underwent curative-intent surgical resection in California from 2002 to 2006. AJCC/UICC stage was recalculated based on the latest seventh edition. Overall survival probabilities were calculated using the Kaplan-Meier method.Of 1905 patients analyzed, 54 % were males with a median age of 70 years. Median number of pathologically examined lymph nodes was 12 (range, 1-90); 40 % of patients received adjuvant chemotherapy, and 31 % received adjuvant radiotherapy. The seventh edition AJCC/UICC system did not distinguish outcome adequately between stages IB and IIA (P = 0.40), or IIB and IIIA (P = 0.34). By merging stage II into 1 category and moving T2N1 to stage IB and T2N2, T1N3 to stage IIIA, we propose a new grouping system with improved discriminatory abilityIn this first study validating the new seventh edition AJCC/UICC staging system for gastric cancer on a U.S. population with a relatively limited number of lymph nodes examined, we found stages IB and IIA, as well as IIB and IIIA to perform similarly. We propose a revised stage grouping for the AJCC/UICC staging system that better discriminates between outcomes.

    View details for DOI 10.1245/s10434-012-2724-5

    View details for Web of Science ID 000317308200032

    View details for PubMedID 23149854

  • Hospital readmission after a pancreaticoduodenectomy: an emerging quality metric? HPB Kastenberg, Z. J., Morton, J. M., Visser, B. C., Norton, J. A., Poultsides, G. A. 2013; 15 (2): 142-148

    Abstract

    Hospital readmission has attracted attention from policymakers as a measure of quality and a target for cost reduction. The aim of the study was to evaluate the frequency and patterns of rehospitalization after a pancreaticoduodenectomy (PD).The records of all patients undergoing a PD at an academic medical centre for malignant or benign diagnoses between January 2006 and September 2011 were retrospectively reviewed. The incidence, aetiology and predictors of subsequent readmission(s) were analysed.Of 257 consecutive patients who underwent a PD, 50 (19.7%) were readmitted within 30 days from discharge. Both the presence of any post-operative complication (P = 0.049) and discharge to a nursing/rehabilitation facility or to home with health care services (P = 0.018) were associated with readmission. The most common reasons for readmission were diet intolerance (36.0%), pancreatic fistula/abscess (26.0%) and superficial wound infection (8.0%). Nine (18.0%) readmissions had lengths of stay of 2 days or less and in four of those (8.0%) diagnostic evaluation was eventually negative.Approximately one-fifth of patients require hospital readmission within 30 days of discharge after a PD. A small fraction of these readmissions are short (2 days or less) and may be preventable or manageable in the outpatient setting.

    View details for DOI 10.1111/j.1477-2574.2012.00563.x

    View details for Web of Science ID 000313548400009

    View details for PubMedID 23297725

  • Current management of the Zollinger-Ellison syndrome. Advances in surgery Krampitz, G. W., Norton, J. A. 2013; 47: 59-79

    Abstract

    In summary, ZES is a syndrome caused by gastrinoma, usually located within the gastrinoma triangle and associated with symptoms of peptic ulcer disease, GERD, and diarrhea. The diagnosis of ZES is made by measuring fasting levels of serum gastrin, BAO, and the secretin stimulation test. Because of the high association of ZES and MEN1, HPT must be excluded by obtaining a serum calcium and parathyroid hormone level. Treatment of ZES consists of medical control of symptoms with PPIs and evaluation for potentially curative surgical intervention. Noninvasive imaging studies including SRS, CT, and MRI should be performed initially to evaluate for metastases and identify resectable disease. Invasive imaging modalities such as EUS may be performed to further evaluate primary tumors. IOUS, palpation, and duodenotomy are used for intraoperative localization of gastrinomas. In patients with MEN1, surgical resection should be pursued only if there is an identifiable tumor larger than 2 cm and after surgery for the primary hyperparathyroidism (3 1/2-gland parathyroidectomy). All patients with resectable localized sporadic gastrinoma should undergo surgical exploration, even those with biochemical evidence but negative imaging studies. Tumor is most commonly found in the duodenum, and the cure rate is high. In patients with liver metastases, surgery should be considered if all identifiable tumor can be safely removed. A multidisciplinary approach including surgical and nonsurgical therapies should be taken in patients with advanced disease.

    View details for PubMedID 24298844

  • Current management of the zollinger-ellison syndrome. Advances in surgery Krampitz, G. W., Norton, J. A. 2013; 47 (1): 59-79

    View details for DOI 10.1016/j.yasu.2013.02.004

    View details for PubMedID 25293453

  • Diagnostic Utility of Metabolomic-Derived Biomarkers for Pancreatic Cysts Park, W. G., Wu, M., Bowen, R., Zheng, M., Fitch, W. L., Pai, R. K., Wodziak, D., Visser, B. C., Poultsides, G. A., NORTON, J. A., Banerjee, S., Chen, A. M., Friedland, S., Pasricha, P. J., Lowe, A. W., Peltz, G. LIPPINCOTT WILLIAMS & WILKINS. 2012: 1394-1394
  • Recurrent Duodenal Stricture Secondary to Untreated Crohn's Disease DIGESTIVE DISEASES AND SCIENCES Plerhoples, T. A., Norton, J. A. 2012; 57 (10): 2516-2518

    View details for DOI 10.1007/s10620-012-2080-0

    View details for Web of Science ID 000309227300008

    View details for PubMedID 22526582

  • Value of Surgery in Patients With Negative Imaging and Sporadic Zollinger-Ellison Syndrome ANNALS OF SURGERY Norton, J. A., Fraker, D. L., Alexander, H. r., Jensen, R. T. 2012; 256 (3): 509-517

    Abstract

    To address the value of surgery in patients with sporadic Zollinger-Ellison syndrome (ZES) with negative imaging studies.Medical control of acid hypersecretion in patients with sporadic ZES is highly effective. This has led to these patients frequently not being sent to surgery, especially if preoperative imaging studies are negative, due, in large part, to existence of almost no data on the success of surgery in this group.Fifty-eight prospectively studied patients with sporadic ZES (17% of total studied) had negative imaging studies, and their surgical outcome was compared with 117 patients with positive imaging results.Thirty-five patients had negative imaging studies in the pre-somatostatin receptor scintigraphy (SRS) era, and 23 patients in the post-SRS era. Patients with negative imaging studies had long disease histories before surgery [mean ± SEM (from onset) = 7.9 ± 1 [range, -0.25 to 35 years]) and 25% were followed for 2 or more years from diagnosis. At surgery, gastrinoma was found in 57 of 58 patients (98%). Tumors were small (mean = 0.8 cm, 60% <1 cm). The most common primary sites were duodenal 64%, pancreatic 17%, and lymph node (10%). Fifty percent had a primary-only, 41% primary + lymph node, and 7% had liver metastases. Thirty-five of 58 patients (60%) were cured immediately postoperatively, and at last follow-up [mean = -9.4 years; range, 0.2-22 years], 27 patients (46%) remained cured. During follow-up, 3 patients died, each had liver metastases at surgery. In comparison to positive imaging patients, those with negative imaging studies had lower preoperative fasting gastrin levels; had a longer delay before surgery; more frequently had a small duodenal tumor; less frequently had a pancreatic tumor, multiple tumors, or developed a new lesion postoperatively; and had a longer survival.Sporadic ZES patients with negative imaging studies are not rare even in the post-SRS period. An experienced surgeon can find gastrinoma in almost every patient (98%) and nearly one half (46%) are cured, a rate similar to patients with positive imaging findings. Because liver metastases were found in 7%, which may have been caused by a long delay in surgery and all the disease-related deaths occurred in this group, surgery should be routinely undertaken early in ZES patients despite negative imaging studies.

    View details for DOI 10.1097/SLA.0b013e318265f08d

    View details for Web of Science ID 000308670900023

    View details for PubMedID 22868363

  • Lymph Nodes and Survival in Pancreatic Neuroendocrine Tumors ARCHIVES OF SURGERY Krampitz, G. W., Norton, J. A., Poultsides, G. A., Visser, B. C., Sun, L., Jensen, R. T. 2012; 147 (9): 820-827

    Abstract

    Lymph node metastases decrease survival in patients with pancreatic neuroendocrine tumors (pNETs).Prospective database searches.National Institutes of Health (NIH) and Stanford University Hospital (SUH).A total of 326 patients underwent surgical exploration for pNETs at the NIH (n = 216) and SUH (n = 110).Overall survival, disease-related survival, and time to development of liver metastases.Forty patients (12.3%) underwent enucleation and 305 (93.6%) underwent resection. Of the patients who underwent resection, 117 (35.9%) had partial pancreatectomy and 30 (9.2%) had a Whipple procedure. Forty-one patients also had liver resections, 21 had wedge resections, and 20 had lobectomies. Mean follow-up was 8.1 years (range, 0.3-28.6 years). The 10-year overall survival for patients with no metastases or lymph node metastases only was similar at 80%. As expected, patients with liver metastases had a significantly decreased 10-year survival of 30% (P < .001). The time to development of liver metastases was significantly reduced for patients with lymph node metastases alone compared with those with none (P < .001). For the NIH cohort with longer follow-up, disease-related survival was significantly different for those patients with no metastases, lymph node metastases alone, and liver metastases (P < .001). Extent of lymph node involvement in this subgroup showed that disease-related survival decreased as a function of the number of lymph nodes involved (P = .004).As expected, liver metastases decrease survival of patients with pNETs. Patients with lymph node metastases alone have a shorter time to the development of liver metastases that is dependent on the number of lymph nodes involved. With sufficient long-term follow-up, lymph node metastases decrease disease-related survival. Careful evaluation of number and extent of lymph node involvement is warranted in all surgical procedures for pNETs.

    View details for Web of Science ID 000308883700011

    View details for PubMedID 22987171

  • Failure to comply with NCCN guidelines for the management of pancreatic cancer compromises outcomes HPB Visser, B. C., Ma, Y., Zak, Y., Poultsides, G. A., Norton, J. A., Rhoads, K. F. 2012; 14 (8): 539-547

    Abstract

    There are little data available regarding compliance with the National Comprehensive Cancer Network (NCCN) guidelines. We investigated variation in the management of pancreatic cancer (PC) among large hospitals in California, USA, specifically to evaluate whether compliance with NCCN guidelines correlates with patient outcomes.The California Cancer Registry was used to identify patients treated for PC from 2001 to 2006. Only hospitals with ? 400 beds were included to limit evaluation to centres possessing resources to provide multimodality care (n= 50). Risk-adjusted multivariable models evaluated predictors of adherence to stage-specific NCCN guidelines for PC and mortality.In all, 3706 patients were treated for PC in large hospitals during the study period. Compliance with NCCN guidelines was only 34.5%. Patients were less likely to get recommended therapy with advanced age and low socioeconomic status (SES). Using multilevel analysis, controlling for patient factors (including demographics and comorbidities), hospital factors (e.g. size, academic affiliation and case volume), compliance with NCCN guidelines was associated with a reduced risk of mortality [odds ratio (OR) for death 0.64 (0.53-0.77, P < 0.0001)].There is relatively poor overall compliance with the NCCN PC guidelines in California's large hospitals. Higher compliance rates are correlated with improved survival. Compliance is an important potential measure of the quality of care.

    View details for DOI 10.1111/j.1477-2574.2012.00496.x

    View details for Web of Science ID 000305993800007

    View details for PubMedID 22762402

  • Pancreatic Neuroendocrine Tumors: Radiographic Calcifications Correlate with Grade and Metastasis ANNALS OF SURGICAL ONCOLOGY Poultsides, G. A., Huang, L. C., Chen, Y., Visser, B. C., Pai, R. K., Jeffrey, R. B., Park, W. G., Chen, A. M., Kunz, P. L., Fisher, G. A., Norton, J. A. 2012; 19 (7): 2295-2303

    Abstract

    Studies to identify preoperative prognostic variables for pancreatic neuroendocrine tumor (PNET) have been inconclusive. Specifically, the prevalence and prognostic significance of radiographic calcifications in these tumors remains unclear.From 1998 to 2009, a total of 110 patients with well-differentiated PNET underwent surgical resection at our institution. Synchronous liver metastases present in 31 patients (28%) were addressed surgically with curative intent. Patients with high-grade PNET were excluded. The presence of calcifications in the primary tumor on preoperative computed tomography was recorded and correlated with clinicopathologic variables and overall survival.Calcifications were present in 16% of patients and were more common in gastrinomas and glucagonomas (50%), but never encountered in insulinomas. Calcified tumors were larger (median size 4.5 vs. 2.3 cm, P=0.04) and more commonly associated with lymph node metastasis (75 vs. 35%, P=0.01), synchronous liver metastasis (62 vs. 21%, P<0.01), and intermediate tumor grade (80 vs. 31%, P<0.01). On multivariate analysis of factors available preoperatively, calcifications (P=0.01) and size (P<0.01) remained independent predictors of lymph node metastasis. Overall survival after resection was significantly worse in the presence of synchronous liver metastasis (5-year, 64 vs. 86%, P=0.04), but not in the presence of radiographic calcifications.Calcifications on preoperative computed tomography correlate with intermediate grade and lymph node metastasis in well-differentiated PNET. This information is available preoperatively and supports the routine dissection of regional lymph nodes through formal pancreatectomy rather than enucleation in calcified PNET.

    View details for DOI 10.1245/s10434-012-2305-7

    View details for Web of Science ID 000305558000030

    View details for PubMedID 22396008

  • Intensity-Modulated Radiotherapy for Pancreatic Adenocarcinoma Abelson, J. A., Murphy, J. D., Minn, A. Y., Chung, M., Fisher, G. A., Ford, J. M., Kunz, P., Norton, J. A., Visser, B. C., Poultsides, G. A., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2012: E595-E601

    Abstract

    To report the outcomes and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for pancreatic adenocarcinoma.Forty-seven patients with pancreatic adenocarcinoma were treated with IMRT between 2003 and 2008. Of these 47 patients, 29 were treated adjuvantly and 18 definitively. All received concurrent 5-fluorouracil chemotherapy. The treatment plans were optimized such that 95% of the planning target volume received the prescription dose. The median delivered dose for the adjuvant and definitive patients was 50.4 and 54.0 Gy, respectively.The median age at diagnosis was 63.9 years. For adjuvant patients, the 1- and 2-year overall survival rate was 79% and 40%, respectively. The 1- and 2-year recurrence-free survival rate was 58% and 17%, respectively. The local-regional control rate at 1 and 2 years was 92% and 80%, respectively. For definitive patients, the 1-year overall survival, recurrence-free survival, and local-regional control rate was 24%, 16%, and 64%, respectively. Four patients developed Grade 3 or greater acute toxicity (9%) and four developed Grade 3 late toxicity (9%).Survival for patients with pancreatic cancer remains poor. A small percentage of adjuvant patients have durable disease control, and with improved therapies, this proportion will increase. Systemic therapy offers the greatest opportunity. The present results have demonstrated that IMRT is well tolerated. Compared with those who received three-dimensional conformal radiotherapy in previously reported prospective clinical trials, patients with pancreatic adenocarcinoma treated with IMRT in our series had improved acute toxicity.

    View details for DOI 10.1016/j.ijrobp.2011.09.035

    View details for Web of Science ID 000300980300003

    View details for PubMedID 22197234

  • Diagnostic accuracy of cyst fluid amphiregulin in pancreatic cysts BMC GASTROENTEROLOGY Tun, M. T., Pai, R. K., Kwok, S., Dong, A., Gupta, A., Visser, B. C., Norton, J. A., Poultsides, G. A., Banerjee, S., Van Dam, J., Chen, A. M., Friedland, S., Scott, B. A., Verma, R., Lowe, A. W., Park, W. G. 2012; 12

    Abstract

    Accurate tests to diagnose adenocarcinoma and high-grade dysplasia among mucinous pancreatic cysts are clinically needed. This study evaluated the diagnostic utility of amphiregulin (AREG) as a pancreatic cyst fluid biomarker to differentiate non-mucinous, benign mucinous, and malignant mucinous cysts.A single-center retrospective study to evaluate AREG levels in pancreatic cyst fluid by ELISA from 33 patients with a histological gold standard was performed.Among the cyst fluid samples, the median (IQR) AREG levels for non-mucinous (n = 6), benign mucinous (n = 15), and cancerous cysts (n = 15) were 85 pg/ml (47-168), 63 pg/ml (30-847), and 986 pg/ml (417-3160), respectively. A significant difference between benign mucinous and malignant mucinous cysts was observed (p = 0.025). AREG levels greater than 300 pg/ml possessed a diagnostic accuracy for cancer or high-grade dysplasia of 78% (sensitivity 83%, specificity 73%).Cyst fluid AREG levels are significantly higher in cancerous and high-grade dysplastic cysts compared to benign mucinous cysts. Thus AREG exhibits potential clinical utility in the evaluation of pancreatic cysts.

    View details for DOI 10.1186/1471-230X-12-15

    View details for Web of Science ID 000301923400002

    View details for PubMedID 22333441

  • A Prospective Study of Total Gastrectomy for CDH1-Positive Hereditary Diffuse Gastric Cancer ANNALS OF SURGICAL ONCOLOGY Chen, Y., Kingham, K., Ford, J. M., Rosing, J., Van Dam, J., Jeffrey, R. B., Longacre, T. A., Chun, N., Kurian, A., Norton, J. A. 2011; 18 (9): 2594-2598

    Abstract

    Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome. Up to 30% of families with HDGC have mutations in the E-cadherin gene, CDH1. The role of prophylactic versus therapeutic gastrectomy for HDGC was studied prospectively.Eighteen consecutive patients with CDH1 mutations and positive family history were studied prospectively, including 13 without and 5 with symptoms. Proportions were compared by Fisher's exact test, and survival by the Breslow modification of the Wilcoxon rank-sum test.Each patient underwent total gastrectomy (TG), and 17 (94%) were found to have signet ring cell adenocarcinoma. Twelve of 13 asymptomatic patients had T1, N0 cancer, and only 2/12 (16%) had it diagnosed preoperatively despite state-of-the-art screening methods. Each asymptomatic patient did well postoperatively, and no patient has recurred. For five symptomatic patients, each (100%) was found to have signet ring cell adenocarcinoma (P = 0.002 versus asymptomatic) by preoperative endoscopy; three (60%) had lymph node involvement and two (40%) had distant metastases at time of operation. Two-year survival was 100% for asymptomatic and 40% for symptomatic patients (P < 0.01).The data show that asymptomatic patients with family history of HDGC and CDH1 mutation have high probability of having signet ring cell adenocarcinoma of the stomach that is not able to be diagnosed on endoscopy; when symptoms arise, the diagnosis can be made by endoscopy, but they have metastases and decreased survival. Surveillance endoscopy is of limited value, and prophylactic gastrectomy (PG) is recommended for patients with family history of HDGC and CDH1 mutations.

    View details for DOI 10.1245/s10434-011-1648-9

    View details for Web of Science ID 000294346700027

    View details for PubMedID 21424370

  • SINGLE-FRACTION STEREOTACTIC BODY RADIATION THERAPY AND SEQUENTIAL GEMCITABINE FOR THE TREATMENT OF LOCALLY ADVANCED PANCREATIC CANCER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Schellenberg, D., Kim, J., Ciristman-Skieller, C., Chun, C. L., Columbo, L. A., Ford, J. M., Fisher, G. A., Kunz, P. L., Van Dam, J., Quon, A., Desser, T. S., Norton, J., Hsu, A., Maxim, P. G., Xing, L., Goodman, K. A., Chang, D. T., Koong, A. C. 2011; 81 (1): 181-188

    Abstract

    This Phase II trial evaluated the toxicity, local control, and overall survival in patients treated with sequential gemcitabine and linear accelerator-based single-fraction stereotactic body radiotherapy (SBRT).Twenty patients with locally advanced, nonmetastatic pancreatic adenocarcinoma were enrolled on this prospective single-institution, institutional review board-approved study. Gemcitabine was administered on Days 1, 8, and 15, and SBRT on Day 29. Gemcitabine was restarted on Day 43 and continued for 3-5 cycles. SBRT of 25 Gy in a single fraction was delivered to the internal target volume with a 2- 3-mm margin using a nine-field intensity-modulated radiotherapy technique. Respiratory gating was used to account for breathing motion. Follow-up evaluations occurred at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT.All patients completed SBRT and a median of five cycles of chemotherapy. Follow-up for the 2 remaining alive patients was 25.1 and 36.4 months. No acute Grade 3 or greater nonhematologic toxicity was observed. Late Grade 3 or greater toxicities occurred in 1 patient (5%) and consisted of a duodenal perforation (G4). Three patients (15%) developed ulcers (G2) that were medically managed. Overall, median survival was 11.8 months, with 1-year survival of 50% and 2-year survival of 20%. Using serial computed tomography, the freedom from local progression was 94% at 1 year.Linear accelerator-delivered SBRT with sequential gemcitabine resulted in excellent local control of locally advanced pancreatic cancer. Future studies will address strategies for reducing long-term duodenal toxicity associated with SBRT.

    View details for DOI 10.1016/j.ijrobp.2010.05.006

    View details for Web of Science ID 000294093300025

    View details for PubMedID 21549517

  • Surgical Management of Neuroendocrine Tumors of the Gastrointestinal Tract ONCOLOGY-NEW YORK Huang, L. C., Poultsides, G. A., Norton, J. A. 2011; 25 (9): 794-803

    Abstract

    Neuroendocrine tumors of the pancreas (islet cell tumors) and of the luminal gastrointestinal tract (carcinoids) are a heterogeneous group of epithelial neoplasms that share certain common characteristics. First, they are similar histologically and are difficult to distinguish under light microscopy. Second, they can be associated with hypersecretory syndromes. Third, they are generally slow-growing and have a better prognosis than adenocarcinomas at the same site; however, they do become incurable when they progress to unresectable metastatic disease. Surgery is the only curative treatment and is recommended for most patients for whom cross-sectional imaging suggests that complete resection is possible. This article reviews the surgical management of gastrointestinal neuroendocrine tumors, including the preoperative control of hormonal symptoms, extent of resection required, postoperative outcomes, and differing management strategies as determined by whether the tumor has arisen sporadically or as part of a familial disorder, such as multiple endocrine neoplasia type 1 (MEN1).

    View details for Web of Science ID 000293651000002

    View details for PubMedID 21936439

  • Ruptured Biliary Cystadenoma Managed by Angiographic Embolization and Interval Partial Hepatectomy DIGESTIVE DISEASES AND SCIENCES Ghole, S. A., Bakhtary, S., Staudenmayer, K., Sze, D. Y., Pai, R. K., Visser, B. C., Norton, J. A., Poultsides, G. A. 2011; 56 (7): 1949-1953

    View details for DOI 10.1007/s10620-011-1677-z

    View details for Web of Science ID 000291481800006

    View details for PubMedID 21445579

  • Pancreatic Endocrine Tumors With Major Vascular Abutment, Involvement, or Encasement and Indication for Resection ARCHIVES OF SURGERY Norton, J. A., Harris, E. J., Chen, Y., Visser, B. C., Poultsides, G. A., Kunz, P. C., Fisher, G. A., Jensen, R. T. 2011; 146 (6): 724-732

    Abstract

    Surgery for pancreatic endocrine tumors (PETs) with blood vessel involvement is controversial.Resection of PETs with major blood vessel involvement can be beneficial.The combined databases of the National Institutes of Health and Stanford University hospitals were queried.Operation, pathologic condition, complications, and disease-free and overall survival.Of 273 patients with PETs, 46 (17%) had preoperative computed tomography evidence of major vascular involvement. The mean size for the primary PET was 5.0 cm. The involved major vessel was as follows: portal vein (n = 20), superior mesenteric vein or superior mesenteric artery (n = 16), inferior vena cava (n = 4), splenic vein (n = 4), and heart (n = 2). Forty-two of 46 patients had a PET removed: 12 (27%) primary only, 30 (68%) with lymph nodes, and 18 (41%) with liver metastases. PETs were removed by either enucleation (n = 7) or resection (n = 35). Resections included distal or subtotal pancreatectomy in 23, Whipple in 10, and total in 2. Eighteen patients had concomitant liver resection: 10 wedge resection and 8 anatomic resections. Nine patients had vascular reconstruction: each had reconstruction of the superior mesenteric vein and portal vein, and 1 had concomitant reconstruction of the superior mesenteric artery. There were no deaths, but 12 patients had complications. Eighteen patients (41%) were immediately disease free, and 5 recurred with follow-up, leaving 13 (30%) disease-free long term. The 10-year overall survival was 60%. Functional tumors were associated with a better overall survival (P < .001), and liver metastases decreased overall survival (P < .001).These findings suggest that surgical resection of PETs with vascular abutment/invasion and nodal or distant metastases is indicated.

    View details for Web of Science ID 000291851500018

    View details for PubMedID 21690450

  • Pattern of Lymph Node Involvement and Prognosis in Pancreatic Adenocarcinoma: Direct Lymph Node Invasion Has Similar Survival to Node-Negative Disease AMERICAN JOURNAL OF SURGICAL PATHOLOGY Pai, R. K., Beck, A. H., Mitchem, J., Linehan, D. C., Chang, D. T., Norton, J. A., Pai, R. K. 2011; 35 (2): 228-234

    Abstract

    Lymph node status is one of the most important predictors of survival in pancreatic ductal adenocarcinoma. Surgically resected pancreatic adenocarcinoma is often locally invasive and may invade directly into peripancreatic lymph nodes. The significance of direct invasion into lymph nodes in the absence of true lymphatic metastases is unclear. The purpose of this study was to retrospectively compare clinical outcome in patients with pancreatic ductal adenocarcinoma with direct invasion into peripancreatic lymph nodes with patients with node-negative adenocarcinomas and patients with true lymphatic lymph node metastasis. A total of 380 patients with invasive pancreatic ductal adenocarcinoma classified as pT3, were evaluated: ductal adenocarcinoma with true lymphatic metastasis to regional lymph nodes (248 cases), ductal adenocarcinoma without lymph node involvement (97 cases), and ductal adenocarcinoma with regional lymph nodes involved only by direct invasion from the main tumor mass (35 cases). Isolated lymph node involvement by direct invasion occurred in 35 of 380 (9%) patients. Overall survival for patients with direct invasion of lymph nodes (median survival, 21 mo; 5-year overall survival, 36%) was not statistically different from patients with node-negative adenocarcinomas (median survival, 30 mo; 5-year overall survival, 31%) (P=0.609). Patients with node-negative adenocarcinomas had an improved survival compared with patients with lymph node involvement by true lymphatic metastasis (median survival, 15 mo; 5-year overall survival, 8%) (P<0.001) regardless of the number of lymph nodes involved by adenocarcinoma. There was a trend toward decreased overall survival for patients with 1 or 2 lymph nodes involved by true lymphatic metastasis compared with patients with direct invasion of tumor into lymph nodes (P=0.056). However, this did not reach statistical significance. Our results indicate that patients with isolated direct lymph node invasion have a comparable overall survival with patients with node-negative adenocarcinomas as opposed to true lymphatic lymph node metastasis.

    View details for DOI 10.1097/PAS.0b013e318206c37a

    View details for Web of Science ID 000286581700007

    View details for PubMedID 21263243

  • Supercharged Jejunum Flap for Total Esophageal Reconstruction: Single-Surgeon 3-Year Experience and Outcomes Analysis PLASTIC AND RECONSTRUCTIVE SURGERY Barzin, A., Norton, J. A., Whyte, R., Lee, G. K. 2011; 127 (1): 173-180

    Abstract

    Esophageal reconstruction after total esophagectomy remains a formidable task irrespective of the conduit chosen. Historically, the gastric pull-up and colonic interposition have served as primary choices for such defects. However, where the stomach and colon are unavailable or unsuitable, the jejunum serves as a reliable alternative for the reconstruction of total esophageal defects.The authors performed an outcomes analysis of a single surgeon's surgical technique and experience. Patients who received supercharged pedicled jejunum flaps for reconstruction of total esophageal defects over a 3-year period were included in this study. Data were collected prospectively evaluating operative technique, length of hospital stay, operative time, complications, postoperative diet, and quality-of-life outcomes analysis.Five patients underwent supercharged pedicled jejunal flap surgery during this study period. All flaps had complete viability and no microvascular complications. One patient had a radiographic anastomotic leak detected by barium swallow that was reexplored and closed primarily and reinforced with a pectoralis advancement flap with subsequent resolution. All patients are currently tolerating a regular diet and there are no symptoms of reflux or dumping. No conduit strictures or redundancy has been found to date, and there has been no need for reoperation in the long term.The supercharged jejunum flap is a reliable alternative to the gastric pull-up and colonic interposition for total esophageal reconstruction. In our experience, the key maneuver in this technique is a substernal tunnel for the jejunal conduit and exposure of recipient vessels and the esophageal stump by means of a manubriectomy, clavicle resection, partial first rib resection and, occasionally, a second rib resection.

    View details for DOI 10.1097/PRS.0b013e3181f95a36

    View details for Web of Science ID 000285992100023

    View details for PubMedID 21200211

  • Expression of p16(INK4A) But Not Hypoxia Markers or Poly Adenosine Diphosphate-Ribose Polymerase Is Associated With Improved Survival in Patients With Pancreatic Adenocarcinoma Chang, D. T., Chapman, C. H., Norton, J. A., Visser, B., Fisher, G. A., Kunz, P., Ford, J. M., Koong, A. C., Pai, R. K. WILEY-BLACKWELL. 2010: 5179-5187

    Abstract

    Pancreatic cancer is associated with mutations in the tumor suppressor gene cyclin-dependent kinase inhibitor 2A (p16(INK4A) ), a regulator of the cell cycle and apoptosis. This study investigates whether immunohistochemical expression of p16(INK4A) as well as hypoxia markers and poly adenosine diphosphate-ribose polymerase (PARP) correlates with survival in patients with resected pancreatic adenocarcinoma.Seventy-three patients with pancreatic adenocarcinoma who underwent curative resection at Stanford University were included. From the surgical specimens, a tissue microarray was constructed using triplicate tissue cores from the primary tumor and used for immunohistochemical staining for the following markers: carbonic anhydrase IX, dihydrofolate reductase, p16(INK4A) , and PARP1/2. Staining was scored as either positive or negative and percentage positive staining. Staining score was correlated with overall survival (OS) and progression-free survival (PFS).Of the markers tested, only immunohistochemical expression of p16(INK4A) correlated with clinical outcome. On univariate analysis, p16(INK4A) expression in the tumor was associated with improved OS (P = .038) but not PFS (P = .28). The median survival for patients with positive versus negative p16(INK4A) staining was 28.8 months versus 18 months. On multivariate analysis, p16(INK4A) expression was associated with improved OS (P = .026) but not PFS (P = .25). Age (P = .0019) and number of nodes involved (P = .025) were also significant for OS. Adjuvant chemotherapy and margin status did not correlate with OS or PFS.Expression of p16(INK4A) is associated with improved OS in patients with resected pancreatic adenocarcinoma. Further investigation is needed for validation, given conflicting data in the published literature. .

    View details for DOI 10.1002/cncr.25481

    View details for Web of Science ID 000284047400009

    View details for PubMedID 20665497

  • Comparison of Intensity-Modulated Radiotherapy and 3-Dimensional Conformal Radiotherapy as Adjuvant Therapy for Gastric Cancer Minn, A. Y., Hsu, A., La, T., Kunz, P., Fisher, G. A., Ford, J. M., Norton, J. A., Visser, B., Goodman, K. A., Koong, A. C., Chang, D. T. JOHN WILEY & SONS INC. 2010: 3943-3952

    Abstract

    The current study was performed to compare the clinical outcomes and toxicity in patients treated with postoperative chemoradiotherapy for gastric cancer using intensity-modulated radiotherapy (IMRT) versus 3-dimensional conformal radiotherapy (3D CRT).Fifty-seven patients with gastric or gastroesophageal junction cancer were treated postoperatively: 26 with 3D CRT and 31 with IMRT. Concurrent chemotherapy was capecitabine (n=31), 5-fluorouracil (5-FU) (n=25), or none (n=1). The median radiation dose was 45 Gy. Dose volume histogram parameters for kidney and liver were compared between treatment groups.The 2-year overall survival rates for 3D CRT versus IMRT were 51% and 65%, respectively (P=.5). Four locoregional failures occurred each in the 3D CRT (15%) and the IMRT (13%) patients. Grade>or=2 acute gastrointestinal toxicity was found to be similar between the 3D CRT and IMRT patients (61.5% vs 61.2%, respectively) but more treatment breaks were needed (3 vs 0, respectively). The median serum creatinine from before radiotherapy to most recent creatinine was unchanged in the IMRT group (0.80 mg/dL) but increased in the 3D CRT group from 0.80 mg/dL to 1.0 mg/dL (P=.02). The median kidney mean dose was higher in the IMRT versus the 3D CRT group (13.9 Gy vs 11.1 Gy; P=.05). The median kidney V20 was lower for the IMRT versus the 3D CRT group (17.5% vs 22%; P=.17). The median liver mean dose for IMRT and 3D CRT was 13.6 Gy and 18.6 Gy, respectively (P=.19). The median liver V30 was 16.1% and 28%, respectively (P<.001).Adjuvant chemoradiotherapy was well tolerated. IMRT was found to provide sparing to the liver and possibly renal function.

    View details for DOI 10.1002/cncr.25246

    View details for Web of Science ID 000280677100025

    View details for PubMedID 20564136

  • Role of Factor VII in Correcting Dilutional Coagulopathy and Reducing Re-operations for Bleeding Following Non-traumatic Major Gastrointestinal and Abdominal Surgery JOURNAL OF GASTROINTESTINAL SURGERY Tsai, T. C., Rosing, J. H., Norton, J. A. 2010; 14 (8): 1311-1318

    Abstract

    The objective of this study is to evaluate the effectiveness of rfVIIa in reducing blood product requirements and re-operation for postoperative bleeding after major abdominal surgery.Hemorrhage is a significant complication after major gastrointestinal and abdominal surgery. Clinically significant bleeding can lead to shock, transfusion of blood products, and re-operation. Recent reports suggest that activated rfVIIa may be effective in correcting coagulopathy and decreasing the need for re-operation.This study was a retrospective review over a 4-year period of 17 consecutive bleeding postoperative patients who received rfVIIa to control hemorrhage and avoid re-operation. Outcome measures were blood and clotting factor transfusions, deaths, thromboembolic complications, and number of re-operations for bleeding.Seventeen patients with postoperative hemorrhage following major abdominal gastrointestinal surgery (nine pancreas, four sarcoma, two gastric, one carcinoid, and one fistula) were treated with rfVIIa. In these 17 patients, rfVIIa was administered for 18 episodes of bleeding (dose 2,400-9,600 mcg, 29.8-100.8 mcg/kg). Transfusion requirement of pRBC and FFP were each significantly less than pre-rfVIIa. Out of the 18 episodes, bleeding was controlled in 17 (94%) without surgery, and only one patient returned to the operating room for hemorrhage. There were no deaths and two thrombotic complications. Coagulopathy was corrected by rfVIIa from 1.37 to 0.96 (p < 0.0001).Use of rfVIIa in resuscitation for hemorrhage after non-traumatic major abdominal and gastrointestinal surgery can correct dilutional coagulopathy, reducing blood product requirements and need for re-operation.

    View details for DOI 10.1007/s11605-010-1227-6

    View details for Web of Science ID 000280260700017

    View details for PubMedID 20517651

  • Hyperparathyroidism with hypercalcaemia in chronic kidney disease: primary or tertiary? NDT plus Lunn, M. R., Muñoz Mendoza, J., Pasche, L. J., Norton, J. A., Ayco, A. L., Chertow, G. M. 2010; 3 (4): 366-371

    Abstract

    Objective . This study aims to highlight the challenges in the diagnosis of hyperparathyroidism (HPT) in patients with advanced chronic kidney disease (CKD). Methods . In this report, we describe a middle-aged Filipino gentleman with underlying CKD who presented with intractable nausea, vomiting, severe and medically refractory hypercalcaemia and parathyroid hormone (PTH) concentrations in excess of 2400 pg/mL. The underlying pathophysiology as well as the aetiologies and current relevant literature are discussed. We also suggest an appropriate diagnostic approach to identify and promptly treat patients with CKD, HPT and hypercalcaemia. Results . Evaluation confirmed the presence of a large parathyroid adenoma; HPT and hypercalcaemia resolved rapidly following resection. Conclusion . This case report is remarkable for its severe hypercalcaemia requiring haemodialysis, large adenoma size, acute-on-chronic kidney injury and markedly elevated PTH concentration in association with primary HPT in CKD.

    View details for DOI 10.1093/ndtplus/sfq077

    View details for PubMedID 25949433

  • Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research JOURNAL OF MEDICAL GENETICS Fitzgerald, R. C., Hardwick, R., Huntsman, D., Carneiro, F., Guilford, P., Blair, V., Chung, D. C., Norton, J., Ragunath, K., Van Krieken, J. H., Dwerryhouse, S., Caldas, C. 2010; 47 (7): 436-444

    Abstract

    25-30% of families fulfilling the criteria for hereditary diffuse gastric cancer have germline mutations of the CDH1 (E-cadherin) gene. In light of new data and advancement of technologies, a multidisciplinary workshop was convened to discuss genetic testing, surgery, endoscopy and pathology reporting. The updated recommendations include broadening of CDH1 testing criteria such that: histological confirmation of diffuse gastric criteria is only required for one family member; inclusion of individuals with diffuse gastric cancer before the age of 40 years without a family history; and inclusion of individuals and families with diagnoses of both diffuse gastric cancer (including one before the age of 50 years) and lobular breast cancer. Testing is considered appropriate from the age of consent following counselling and discussion with a multidisciplinary team. In addition to direct sequencing, large genomic rearrangements should be sought. Annual mammography and breast MRI from the age of 35 years is recommended for women due to the increased risk for lobular breast cancer. In mutation positive individuals prophylactic total gastrectomy at a centre of excellence should be strongly considered. Protocolised endoscopic surveillance in centres with endoscopists and pathologists experienced with these patients is recommended for: those opting not to have gastrectomy, those with mutations of undetermined significance, and in those families for whom no germline mutation is yet identified. The systematic histological study of prophylactic gastrectomies almost universally shows pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. Expert histopathological confirmation of these early lesions is recommended.

    View details for DOI 10.1136/jmg.2009.074237

    View details for Web of Science ID 000279326400002

    View details for PubMedID 20591882

  • A NOVEL PRKAR1A MUTATION ASSOCIATED WITH PRIMARY PIGMENTED NODULAR ADRENOCORTICAL DISEASE AND THE CARNEY COMPLEX ENDOCRINE PRACTICE Peck, M. C., Visser, B. C., Norton, J. A., Pasche, L., Katznelson, L. 2010; 16 (2): 198-204

    Abstract

    To delineate the genetic and phenotypic features of Carney complex in a family with multiple cases of primary pigmented nodular adrenocortical disease (PPNAD).Detailed clinical, laboratory, genetic, radiologic, and pathologic findings are presented, and the pertinent literature is reviewed.A 17-year-old girl presented with symptoms and physical findings suggestive of hypercortisolemia, in addition to facial lentigines. She was found to have adrenocorticotropic hormone (ACTH)-independent Cushing syndrome. The adrenal glands appeared normal on computed tomographic scanning. Bilateral surgical adrenalectomy revealed PPNAD. Evaluation of her 14-year-old sister revealed ACTH-independent Cushing syndrome as well as facial lentigines, and adrenalectomy revealed PPNAD as well. Genetic testing of the 2 sisters and their mother (who also had multiple facial lentigines but did not have Cushing syndrome) revealed a novel mutation in the PRKAR1A gene.We describe a novel mutation in the PRKAR1A gene in a family with Carney complex and multiple members with PPNAD. PPNAD should be suspected in cases of ACTH-independent Cushing syndrome, and screening for Carney complex and its complications is recommended in all cases of PPNAD, including first-degree relatives.

    View details for DOI 10.4158/EP09245.OR

    View details for Web of Science ID 000277497400011

    View details for PubMedID 19833579

  • Solid Pseudopapillary Tumor of the Pancreas: An Unexpected Finding After Minor Abdominal Trauma DIGESTIVE DISEASES AND SCIENCES Cisco, R., Jeffrey, R. B., Norton, J. A. 2010; 55 (2): 240-241

    View details for DOI 10.1007/s10620-009-1030-y

    View details for Web of Science ID 000273520900004

    View details for PubMedID 19890713

  • INTERFRACTIONAL UNCERTAINTY IN THE TREATMENT OF PANCREATIC CANCER WITH RADIATION INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Jayachandran, P., Minn, A. Y., Van Dam, J., Norton, J. A., Koong, A. C., Chang, D. T. 2010; 76 (2): 603-607

    Abstract

    To compare the interfractional variation in pancreatic tumor position using bony anatomy and implanted fiducial markers.Five consecutively treated patients with pancreatic adenocarcinoma who received definitive intensity-modulated radiation therapy at Stanford University (Stanford, CA) underwent fiducial seed placement and treatment on the Varian Trilogy system (Varian, Palo Alto, CA) with respiratory gating. Daily orthogonal kilovoltage imaging was performed to verify patient positioning, and isocenter shifts were made initially to match bony anatomy. Next, a final shift to the fiducial seeds was made under fluoroscopic guidance to confirm the location of the pancreatic tumor during the respiratory gated phase. All shifts were measured along three axes, left (+)-right (-), anterior (-)-posterior (+), and superior (+)-inferior (-), and the overall interfractional tumor movement was calculated based on these values.A total of 140 fractions were analyzed. The mean absolute shift to fiducial markers after shifting to bony anatomy was 1.6 mm (95th percentile, 7 mm; range, 0-9 mm), 1.8 mm (95th percentile, 7 mm; range, 0-13 mm), and 4.1 mm (95th percentile, 12 mm; range, 0-19 mm) in the anterior-posterior, left-right, and superior-inferior directions, respectively. The mean interfractional vector shift distance was 5.5 mm (95th percentile, 14.5 mm; range, 0-19.3 mm). In 28 of 140 fractions (20%) no fiducial shift was required after alignment to bony anatomy.There is substantial residual uncertainty after alignment to bony anatomy when radiating pancreatic tumors using respiratory gating. Bony anatomy matched tumor position in only 20% of the radiation treatments. If bony alignment is used in conjunction with respiratory gating without implanted fiducials, treatment margins need to account for this uncertainty.

    View details for DOI 10.1016/j.ijrobp.2009.06.029

    View details for Web of Science ID 000274121500040

    View details for PubMedID 19879062

  • Surgical Management of Zollinger-Ellison Syndrome; State of the Art SURGICAL CLINICS OF NORTH AMERICA Morrow, E. H., Norton, J. A. 2009; 89 (5): 1091-?

    Abstract

    Much has been learned about the diagnosis and treatment of Zollinger-Ellison Syndrome (ZES), and certain questions require further investigation. Delay in diagnosis of ZES is still a significant problem, and clinical suspicion should be elevated. The single best imaging modality for localization and staging of ZES is somatostatin receptor scintigraphy. Goals of surgical treatment for ZES differ between sporadic and MEN-1-related cases. All sporadic cases of ZES should be surgically explored (including duodenotomy) even with negative imaging results, because of the high likelihood of finding and removing a tumor for potential cure. Surgery for MEN-1-related cases should be focused on prevention of metastatic disease, with surgery being recommended when pancreatic tumors are greater than 2 cm. The role of Whipple procedure, especially for MEN-1 cases, should be explored further. Laparoscopic and endoscopic treatments are more experimental, but may have a role.

    View details for DOI 10.1016/j.suc.2009.06.018

    View details for Web of Science ID 000271782300005

    View details for PubMedID 19836486

  • Appendiceal Mucinous Neoplasms Clinicopathologic Study of 116 Cases With Analysis of Factors Predicting Recurrence AMERICAN JOURNAL OF SURGICAL PATHOLOGY Pai, R. K., Beck, A. H., Norton, J. A., Longacre, T. A. 2009; 33 (10): 1425-1439

    Abstract

    The classification and nomenclature of appendiceal mucinous neoplasms are controversial. To determine the outcome for patients with appendiceal mucinous neoplasms and further evaluate whether they can be stratified into groups that provide prognostic information, the clinicopathologic features of 116 patients (66 with clinical follow-up) with appendiceal mucinous neoplasms were studied. From a wide variety of histopathologic features assessed, the important predictors that emerged on univariate statistical analysis were presence of extra-appendiceal neoplastic epithelium (P=0.01), high-grade cytology (P<0.0001), architectural complexity (P<0.001), and invasion (P<0.001). Stratification using a combination of these predictors resulted in a 4-tiered classification scheme. All 16 patients with mucinous neoplasms confined to the appendix and lacking high-grade cytology, architectural complexity, and invasion were alive with no recurrences at median 59 months follow-up (=mucinous adenoma). One of 14 patients with low-grade cytology and acellular peritoneal mucin deposits developed recurrent tumor within the peritoneum at 45 months with no patient deaths to date (median, 48-mo follow-up) (=low-grade mucinous neoplasm with low risk of recurrence). None of the 2 patients with acellular peritoneal mucinous deposits outside of the right lower quadrant developed recurrence at 163 and 206 months. Twenty-seven patients with low-grade mucinous neoplasms with extra-appendiceal neoplastic epithelium had 1-year, 3-year, 5-year, and 10-year overall survival rates of 96%, 91%, 79%, and 46%, respectively, at median 53 months follow-up (=low-grade mucinous neoplasm with high risk of recurrence). Three of the 4 patients with extra-appendiceal epithelium limited to the right lower quadrant developed full-blown peritoneal disease at 6, 41, and 99 months follow-up and 1 patient eventually died of disease. Nine patients with appendiceal neoplasms with invasion or high-grade cytology and follow-up showed 1-year, 3-year, and 5-year overall survival rates of 86%, 57%, and 28% (=mucinous adenocarcinoma). At 10 years, all patients with mucinous adenocarcinoma were either dead or lost to follow-up. Appendiceal mucinous neoplasms can be stratified into 4 distinct risk groups on the basis of a careful histopathologic assessment of cytoarchitectural features and extent of disease at presentation.

    View details for Web of Science ID 000270399700001

    View details for PubMedID 19641451

  • Major Blood Vessel Reconstruction During Sarcoma Surgery ARCHIVES OF SURGERY Song, T. K., Harris, E. J., Raghavan, S., Norton, J. A. 2009; 144 (9): 817-822

    Abstract

    To evaluate the outcomes of major vessel reconstruction as part of surgery to remove sarcomas.Retrospective review.Tertiary academic medical center.Fourteen patients (10 female) with retroperitoneal or extremity sarcomas and major blood vessel involvement who underwent surgery to remove the tumor and had blood vessel reconstruction between 2003 and 2008. Each patient underwent computed tomography angiography.Early (<30 days) and late (>30 days) operative morbidity and mortality, freedom from disease, and graft patency.Seven patients had retroperitoneal sarcomas and 7, extremity sarcomas. Thirteen tumors were malignant (7 high grade and 6 low grade) and 1, benign (leiomyoma). Seven patients had replacement of artery and vein; 5, artery only; and 2, vein only. In all, 16 arteries were reconstructed (2 common femoral; 5 iliac; 2 superficial femoral; 1 brachial; 1 popliteal; and 2 aorta, one with implantation of both iliac arteries and the other with implantation of the left renal, superior mesenteric, and hepatic arteries). Eight patients (57%) had 9 veins reconstructed (3 external iliac, 3 superficial femoral, 2 vena cava, and 1 popliteal). Primary arterial patency was 58% and primary-assisted patency was 83%. Venous patency was 78%. Local recurrence occurred in 3 patients (21%). Five-year disease-free and overall survival were 52% and 68%, respectively. Limb salvage was achieved in 93%.Involvement of vascular structures is not a contraindication for resection of sarcomas, but appropriate planning is necessary to optimize outcome.

    View details for Web of Science ID 000269833500004

    View details for PubMedID 19797105

  • The value of surgery for retroperitoneal sarcoma. Sarcoma Gholami, S., Jacobs, C. D., Kapp, D. S., Parast, L. M., Norton, J. A. 2009; 2009: 605840-?

    Abstract

    Introduction. Retroperitoneal sarcomas are uncommon large malignant tumors. Methods. Forty-one consecutive patients with localized retroperitoneal sarcoma were retrospectively studied. Results. Median age was 58 years (range 20-91 years). Median tumor size was 17.5 cm (range 4-41 cm). Only 2 tumors were <5 cm. Most were liposarcoma (44%) and high-grade (59%). 59% were stage 3 and the rest was stage 1. Median followup was 10 months (range 1-106 months). Thirty-eight patients had an initial complete resection; 15 (37%) developed recurrent sarcoma and 12 (80%) had a second complete resection. Patients with an initial complete resection had a 5-year survival of 46%. For all patients, tumor grade affected overall survival (P = .006). Complete surgical resection improved overall survival for high-grade tumors (P = .03). Conclusions. Tumor grade/stage and complete surgical resection for high-grade tumors are important prognostic variables. Radiation therapy or chemotherapy had no significant impact on overall or recurrence-free survival. Complete surgical resection is the treatment of choice for patients with initial and locally recurrent retroperitoneal sarcoma.

    View details for DOI 10.1155/2009/605840

    View details for PubMedID 19826633

  • INTRAOPERATIVE RADIATION THERAPY FOR LOCALLY ADVANCED AND RECURRENT SOFT-TISSUE SARCOMAS IN ADULTS INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Tran, P. T., Hara, W., Su, Z., Lin, H. J., Bendapudi, P. K., Norton, J., Teng, N., King, C. R., Kapp, D. S. 2008; 72 (4): 1146-1153

    Abstract

    To analyze the outcomes of and identify prognostic factors for patients treated with surgery and intraoperative radiotherapy (IORT) for locally advanced and recurrent soft-tissue sarcoma in adults from a single institution.We retrospectively reviewed 50 consecutive patients treated with IORT to 62 sites of disease. Primary sites included retroperitoneum-pelvis (78%), extremity (8%), and other (14%). Seventy percent of patients had recurrent disease failing prior surgery (70%) and/or radiation (32%). Mean disease-free interval (DFI) before IORT was 1.9 years (range, 2 weeks-5.4 years). The IORT was delivered with orthovoltage X-rays using individually sized beveled cone applicators. Clinical characteristics were as follows: mean tumor size, 10 cm (range, 1-25 cm); high-grade histologic subtype (72%); and mean dose, 1,159 cGy (range, 600-1,600 cGy). Postoperative radiation or chemotherapy was administered to 37% of IORT Sites and 32% of patients, respectively. Outcomes measured were infield control (IFC), locoregional control (LRC), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and treatment-related complications. Mean and median follow-up of alive patients were 59 and 35 months, respectively.Kaplan-Meier 5-year IFC, LRC, DMFS, and DSS probabilities for the entire group were 55%, 26%, 51%, and 25%, respectively. Prognostic factors found to be significant (p < 0.05) on multivariate analysis were prior DFI and tumor size for LRC, extremity location and leiomyosarcoma histologic subtype for DMFS, and prior DFI for DSS. Our cohort had five Grade 3/4 complications associated with treatment or a 5-year Kaplan-Meier Grade 3/4 complication-free survival rate of 85%.IORT after tumor reductive surgery is well tolerated and seems to confer IFC in carefully selected patients.

    View details for DOI 10.1016/j.ijrobp.2008.02.012

    View details for Web of Science ID 000260592600026

    View details for PubMedID 18394818

  • Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Schellenberg, D., Goodman, K. A., Lee, F., Chang, S., Kuo, T., Ford, J. M., Fisher, G. A., Quon, A., Desser, T. S., Norton, J., Greco, R., Yang, G. P., Koong, A. C. 2008; 72 (3): 678-686

    Abstract

    Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy.A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife. Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT.All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13).SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.

    View details for DOI 10.1016/j.ijrobp.2008.01.051

    View details for Web of Science ID 000259894300008

    View details for PubMedID 18395362

  • Hereditary diffuse gastric cancer - Implications of genetic testing for screening and prophylactic surgery CANCER Cisco, R. M., Ford, J. M., Norton, J. A. 2008; 113 (7): 1850-1856

    Abstract

    Approximately 10% of patients with gastric cancer show familial clustering, and 3% show autosomal dominance and high penetrance. Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant, inherited cancer syndrome in which affected individuals develop diffuse-type gastric cancer at a young age. Inactivating mutations in the E-cadherin gene CDH1 have been identified in 30% to 50% of patients. CDH1 mutation carriers have an approximately 70% lifetime risk of developing DGC, and affected women carry an additional 20% to 40% risk of developing lobular breast cancer. Because endoscopic surveillance is ineffective in identifying early HDGC, gene-directed prophylactic total gastrectomy currently is offered for CDH1 mutation carriers. In series of asymptomatic individuals undergoing total gastrectomy for CDH1 mutations, the removed stomachs usually contain small foci of early DGC, making surgery not prophylactic but curative. The authors of this review recommend consideration of total gastrectomy in CDH1 mutation carriers at an age 5 years younger than the youngest family member who developed gastric cancer. Individuals who choose not to undergo prophylactic gastrectomy should be followed with biannual chromoendoscopy, and women with CDH1 mutations also should undergo regular surveillance with magnetic resonance imaging studies of the breast. Because of the emergence of gene-directed gastrectomy for HDGC, today, a previously lethal disease is detected by molecular techniques, allowing curative surgery at an early stage.

    View details for DOI 10.1002/cncr.23650

    View details for Web of Science ID 000259661800013

    View details for PubMedID 18798546

  • Inherited pancreatic endocrine tumor syndromes: Advances in molecular pathogenesis, diagnosis, management, and controversies CANCER Jensen, R. I., Berna, M. J., Bingham, D. B., Norton, J. A. 2008; 113 (7): 1807-1843

    Abstract

    Pancreatic endocrine tumors (PETs) can occur as part of 4 inherited disorders, including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1) (von Recklinghausen disease), and the tuberous sclerosis complex (TSC). The relative frequency with which patients who have these disorders develop PETs is MEN1>VHL>NF-1>TSC. Over the last few years, there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization and the medical and surgical treatment of PETs in such patients. The study of PETs in these disorders not only has provided insights into the possible pathogenesis of sporadic PETs but also has presented several unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore, the study of PETs in these uncommon disorders has provided valuable insights that, in many cases, are applicable to the general group of patients with sporadic PETs. In this article, these areas are reviewed briefly along with the current state of knowledge of the PETs in these disorders, and the controversies that exist in their management are summarized briefly and discussed.

    View details for DOI 10.1002/cncr.23648

    View details for Web of Science ID 000259661800011

    View details for PubMedID 18798544

  • Hereditary diffuse gastric cancer: surgery, surveillance and unanswered questions FUTURE ONCOLOGY Cisco, R. M., Norton, J. A. 2008; 4 (4): 553-559

    Abstract

    Hereditary diffuse gastric cancer (HDGC) is an inherited cancer-susceptibility syndrome characterized by autosomal dominance and high penetrance. In 30-50% of cases, a causative germline mutation in CDH1, the E-cadherin gene, may be identified. Female carriers of CDH1 mutations also have an increased (20-40%) risk of lobular breast cancer. Endoscopic surveillance of patients with CDH1 mutations is ineffective because early foci of HDGC are typically small and underlie normal mucosa. CDH1 mutation carriers are therefore offered the option of prophylactic gastrectomy, which commonly reveals early foci of invasive signet-ring cell cancer. We review recommendations for genetic testing, surveillance and prophylactic surgery in HDGC. Areas for future research are discussed, including development of new screening modalities, optimal timing of prophylactic gastrectomy, identification of additional causative mutations in HDGC, management of patients with CDH1 missense mutations and prevention/early detection of lobular breast cancer in CDH1 mutation carriers.

    View details for DOI 10.2217/14796694.4.4.553

    View details for Web of Science ID 000261774900013

    View details for PubMedID 18684065

  • Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. American journal of surgical pathology Rogers, W. M., Dobo, E., Norton, J. A., Van Dam, J., Jeffrey, R. B., Huntsman, D. G., Kingham, K., Chun, N., Ford, J. M., Longacre, T. A. 2008; 32 (6): 799-809

    Abstract

    Hereditary diffuse gastric cancer is a rare autosomal dominant cancer susceptibility syndrome caused by germline E-cadherin (CDH1) mutations in 40% of cases with a high degree of penetrance. Screening endoscopy has not been useful in identifying early cancer, in part owing to conflicting data concerning site(s) of involvement in the stomach and the lack of endoscopically detectable pathology. Risk-reducing total gastrectomy specimens from 8 asymptomatic adults with germline mutations in the CDH1 gene (3 different pedigrees) were studied using a sequential serial sectioning protocol with submission of the entire stomach for histologic analysis. The presence, size, and distribution of signet ring cell clusters were determined for each section and geographic maps of the invasive foci were constructed and compared with gastrectomy specimens from patients with germline E-cadherin mutation and symptomatic gastric cancer. All but 1 of the asymptomatic patients with germline mutations in the CDH1 gene had negative endoscopic screening. All risk-reducing gastrectomy specimens were macroscopically normal. All contained multiple foci (mean, 10.9) of microscopic intramucosal signet ring cell carcinoma confined to the superficial gastric mucosa; no invasion of submucosa was identified. In situ carcinoma was present in 6/8 cases. The majority of signet ring foci were located in the proximal one third of the stomach, most within oxyntic-type mucosa. The number and size of foci were not related to age, but there was a trend toward more severe disease burden in women. Stomachs from the symptomatic group of patients with germline CDH1 mutations exhibited infiltrative foci with higher Ki-67 labeling that extended well beyond the superficial mucosa. In addition, while superficial signet ring cancer exhibited decreased or absent E-cadherin and beta-catenin protein expression in all cases studied, deeply invasive signet ring cancer showed reversion to E-cadherin and beta-catenin protein expression in a subset of mutation carriers. Our study indicates that superficial intramucosal signet ring carcinoma, although widespread, is predominantly located in the proximal one third of the stomach in patients with E-cadherin gene mutations. The observed site predilection suggests a possible role for geographically targeted endoscopic surveillance biopsy in patients who elect to delay surgical intervention.

    View details for DOI 10.1097/PAS.0b013e31815e7f1a

    View details for PubMedID 18391748

  • An update of a phase I/II study of the VEGF receptor tyrosine kinase inhibitor vatalanib and gemcitabine in patients with advanced pancreatic cancer Kuo, T., Cabebe, E. C., Koong, A., NORTON, J. A., Kunz, P. L., Ford, J. M., KAISER, H. L., Rogers, J., Sikic, B. I., Fisher, G. A. AMER SOC CLINICAL ONCOLOGY. 2008
  • Prospective study of surgery for primary hyperparathyroidism (HPT) in multiple endocrine neoplasia-type 1 and Zollinger-Ellison syndrome - Long-term outcome of 6 more virulent form of HPT ANNALS OF SURGERY Norton, J. A., Venzon, D. J., Berna, M. J., Alexander, H. R., Fraker, D. L., Libutti, S. K., Marx, S. J., Gibril, F., Jensen, R. T. 2008; 247 (3): 501-510

    Abstract

    Primary hyperparathyroidism (HPT) in multiple endocrine neoplasia type 1 (MEN1) patients with Zollinger-Ellison syndrome (ZES) is caused by parathyroid hyperplasia. Surgery for parathyroid hyperplasia is tricky and difficult. Long-term outcome in ZES/MEN1/HPT is not well known.Eighty-four consecutive patients (49 F/35 M) with ZES/MEN1/HPT underwent initial parathyroidectomy (PTX) and were followed at 1- to 3-year intervals.Age at PTX was 36 +/- 2 years. Mean follow-up was 17 +/- 1 years. Before PTX, mean Ca = 2.8 mmol/L (normal level (nl <2.5), PTH i = 243 pg/mL (nl <65), and gastrin = 6950 pg/mL (nl < 100). Sixty-one percent had nephrolithiasis. Each patient had parathyroid hyperplasia. Fifty-eight percent of patients had 4 parathyroid glands identified. Nine of 84 (11%) had 4 glands removed with immediate autograft, 40/84 (47%) 3 to 3.5 glands, whereas 35/84 (42%) <3 glands removed. Persistent/recurrent HPT occurred in 42%/48% of patients with <3 glands, 12%/44% with 3 to 3.5 glands, and 0%/55% with 4 glands removed. Hypoparathyroidism occurred in 3%, 10%, and 22%, respectively. The disease-free interval after surgery was significantly longer if >3 glands were removed. After surgery to correct the HPT, each biochemical parameter of ZES was improved and 20% of patients no longer had laboratory evidence of ZES.HPT/MEN1/ZES is a severe form of parathyroid hyperplasia with a high rate of nephrolithiasis, persistent and recurrent HPT. Surgery to correct the hypercalcemia significantly ameliorates the ZES. Removal of less than 3.5 glands has an unacceptably high incidence of persistent HPT (42%), whereas 4-gland resection and transplant has a high rate of permanent hypoparathyroidism (22%). More than 3-gland resection has a longer disease-free interval. The surgical procedure of choice for patients with HPT/MEN1/ZES is 3.5-gland parathyroidectomy. Careful long-term follow-up is necessary as a significant proportion will develop recurrent HPT.

    View details for DOI 10.1097/SLA.0b013e31815efda5

    View details for Web of Science ID 000253436200016

    View details for PubMedID 18376196

  • Tissue effects after stereotactic body radiotherapy using cyberknife for patients with abdominal malignancies CLINICAL ONCOLOGY Cupp, J. S., Koong, A. C., Fisher, G. A., NORTON, J. A., Goodman, K. A. 2008; 20 (1): 69-75

    Abstract

    To report the tissue effects of treatment with single fraction stereotactic body radiotherapy (SBRT) using Cyberknife on malignant tumours of the abdomen and adjacent normal organs.The data from four autopsies with unresectable pancreatic carcinoma and one lymph node excision from a case of recurrent neuroblastoma were reviewed for radiation-related tissue effects within the primary cancer and the normal organs within the radiation field.Cases of unresectable pancreatic carcinoma consistently showed radiation-induced changes in both the primary tumour and the adjacent, non-malignant colorectal tissue. An additional case of lymph nodes exposed to stereotactic radiation showed typical radiation-related changes, including lymphocyte depletion and capsular fibrosis.A myriad of radiation-related tissue effects are seen after SBRT with Cyberknife. The changes parallel those reported after conventionally fractionated radiotherapy and suggest that the pathophysiological mechanisms of radiation-induced normal tissue damage are similar for biologically equivalent single and fractionated doses of radiotherapy.

    View details for DOI 10.1016/j.clon.2007.08.009

    View details for Web of Science ID 000253281700013

    View details for PubMedID 17900882

  • High predictive value of pancreatic protocol CT as the only preoperative staging in pancreatic cancer Cisco, R. M., Jeffrey, R. B., Greco, R. S., NORTON, J. A. SPRINGER. 2008: 88-88
  • A carrier of both MEN1 and BRCA2 mutations: case report a-lid review of the literature CANCER GENETICS AND CYTOGENETICS Ghataorhe, P., Kurian, A. W., Pickart, A., Trapane, P., Norton, J. A., Kingham, K., Ford, J. M. 2007; 179 (2): 89-92

    Abstract

    High-penetrance autosomal dominant cancer susceptibility genes such as BRCA2 and MEN1 result in specific patterns of cancers in individuals who inherit germline mutations. Their incidence in the population is relatively low, however, and it is highly unusual to identify individuals with two or more inherited cancer gene mutations. We describe a family with multiple cases of MEN1-associated cancers as well as pancreatic adenocarcinoma, ovarian cancer, and male breast cancer, in which we identified germline mutations in both MEN1 and BRCA2. To our knowledge, this is the first report of a patient with both MEN1 and BRCA2 mutations and with a personal history of hyperparathyroidism and pancreatic neuroendocrine tumors.

    View details for DOI 10.1016/j.cancergencyto.2007.08.009

    View details for Web of Science ID 000251478000001

    View details for PubMedID 18036394

  • Role of surgery in Zollinger-Ellison syndrome JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Norton, J. A., Jensen, R. T. 2007; 205 (4): S34-S37
  • CDH1 truncating mutations in the E-cadherin gene - An indication for total gastrectomy to treat hereditary diffuse gastric cancer ANNALS OF SURGERY Norton, J. A., Ham, C. M., Van Dam, J., Jeffrey, R. B., Longacre, T. A., Huntsman, D. G., Chun, N., Kurian, A. W., Ford, J. M. 2007; 245 (6): 873-879

    Abstract

    Approximately 1% to 3% of all gastric cancers are associated with families exhibiting an autosomal dominant pattern of susceptibility. E-cadherin (CDH1) truncating mutations have been shown to be present in approximately 30% of families with hereditary diffuse gastric cancer (HDGC) and are associated with a significantly increased risk of gastric cancer and lobular breast cancer.Individuals from a large kindred with HDGC who were identified to have a CDH1 mutation prospectively underwent comprehensive screening with stool occult blood testing, standard upper gastrointestinal endoscopy with random gastric biopsies, high-magnification endoscopy with random gastric biopsies, endoscopic ultrasonography, CT, and PET scans to evaluate the stomach for occult cancer. Subsequently, they each underwent total gastrectomy with D-2 node dissection and Roux-en-Y esophagojejunostomy. The stomach and resected lymph nodes were evaluated pathologically.Six patients were identified as CDH1 carriers from a single family. There were 2 men and 4 women. The mean age was 54 years (range, 51-57 years). No patient had any signs or symptoms of gastric cancer. Exhaustive preoperative stomach evaluation was normal in each case, and the stomach and adjacent lymph nodes appeared normal at surgery. However, each patient (6 of 6, 100%) was found to have multiple foci of T1 invasive diffuse gastric adenocarcinoma (pure signet-ring cell type). No patient had lymph node or distant metastases. Each was staged as T1N0M0. Each patient recovered uneventfully without morbidity or mortality.CDH1 mutations in individuals from families with HDGC are associated with gastric cancer in a highly penetrant fashion. CDH1 mutations are an indication for total gastrectomy in these patients. This mutation will identify patients with cancer before other detectable symptoms or signs of the disease.

    View details for DOI 10.1097/01.sla.0000254370.29893.e4

    View details for Web of Science ID 000246873000007

    View details for PubMedID 17522512

  • Surgery for gastrinoma. Advances in surgery Cisco, R. M., Norton, J. A. 2007; 41: 165-176

    Abstract

    Surgery has been demonstrated to offer potential for cure in patients who have sporadic ZES and improved tumor-related survival in all patients who have ZES with gastrinomas larger than 2.5 cm. Techniques such as preoperative localization with SRS and intraoperative localization with duodenotomy have improved the effectiveness of surgical intervention for ZES. Future directions for investigation should include better defining the role of preoperative EUS and developing new, more sensitive techniques for preoperative localization. More research also is needed to define the appropriate indications for pancreaticoduodenectomy in ZES and to determine whether proximal vagotomy should be performed at the time of surgical exploration.

    View details for PubMedID 17972563

  • Intraoperative radiation therapy for soft tissue sarcomas Hara, W., Tran, P., Su, Z., Lin, J., Norton, J., King, C., Goffinet, D., Kapp, D. S. ELSEVIER SCIENCE INC. 2007: S754-S754
  • Surgery increases survival in patients with gastrinoma ANNALS OF SURGERY Norton, J. A., Fraker, D. L., Alexander, H. R., Gibril, F., Liewehr, D. J., Venzon, D. J., Jensen, R. T. 2006; 244 (3): 410-419

    Abstract

    To determine whether the routine use of surgical exploration for gastrinoma resection/cure in 160 patients with Zollinger-Ellison syndrome (ZES) altered survival compared with 35 ZES patients who did not undergo surgery.The role of routine surgical exploration for resection/cure in patients with ZES has been controversial since the original description of this disease in 1955. This controversy continues today, not only because medical therapy for acid hypersecretion is so effective, but also in large part because no studies have shown an effect of tumor resection on survival.Long-term follow-up of 160 ZES patients who underwent routine surgery for gastrinoma/resection/cure was compared with 35 patients who had similar disease but did not undergo surgery for a variety of reasons. All patients had preoperative CT, MRI, ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994 to determine resectability. At surgery, all had the same standard ZES operation. All patients were evaluated yearly with imaging studies and disease activity studies.The 35 nonsurgical patients did not differ from the 160 operated in clinical, laboratory, or tumor imaging results. The 2 groups did not differ in follow-up time since initial evaluation (range, 11.8-12 years). At surgery, 94% had a tumor removed, 51% were cured immediately, and 41% at last follow-up. Significantly more unoperated patients developed liver metastases (29% vs. 5%, P = 0.0002), died of any cause (54 vs. 21%, P = 0.0002), or died a disease-related death (23 vs. 1%, P < 0.00001). Survival plots showed operated patients had a better disease-related survival (P = 0.0012); however, there was no difference in non-disease-related survival. Fifteen-year disease-related survival was 98% for operated and 74% for unoperated (P = 0.0002).These results demonstrate that routine surgical exploration increases survival in patients with ZES by increasing disease-related survival and decreasing the development of advanced disease. Routine surgical exploration should be performed in ZES patients.

    View details for DOI 10.1097/01.sla.0000234802.44320.a5

    View details for Web of Science ID 000240261500009

    View details for PubMedID 16926567

  • Lessons from Coley's Toxin SURGICAL ONCOLOGY-OXFORD Tsung, K., Norton, J. A. 2006; 15 (1): 25-28

    Abstract

    The active molecule in Coley's Toxin is not tumor necrosis factor (TNF) or endotoxin (LPS), but interleukin-12 (IL-12). IL-12 holds the key to improved anti-tumor immuns response.

    View details for DOI 10.1016/j.suronc.2006.05.002

    View details for Web of Science ID 000240759000003

    View details for PubMedID 16814541

  • Surgery for primary pancreatic neuroendocrine tumors JOURNAL OF GASTROINTESTINAL SURGERY Norton, J. A. 2006; 10 (3): 327-331

    View details for DOI 10.1016/j.gassur.2005.08.023

    View details for Web of Science ID 000236010200003

    View details for PubMedID 16504877

  • Surgery for gastrinoma and insulinoma in multiple endocrine neoplasia type 1. Journal of the National Comprehensive Cancer Network Norton, J. A., Fang, T. D., Jensen, R. T. 2006; 4 (2): 148-153

    Abstract

    The surgical management of pancreatic endocrine tumors in patients with multiple endocrine neoplasia type 1 remains controversial. Gastrinoma and insulinoma are the 2 most common functional pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. Gastrinomas cause gastric acid hypersecretion and peptic ulcer disease that are best managed using proton pump inhibitors. Surgery to remove the gastrinoma in patients with multiple endocrine neoplasia type 1 is seldom curative unless a more extensive Whipple pancreaticoduodenectomy is performed. Because the prognosis is excellent, aggressive resections such as a Whipple procedure are only indicated for large, locally metastatic, advanced tumors. Furthermore, surgery to remove imageable tumors that are 2 cm in diameter is associated with excellent outcomes and decreased probability of liver metastases. Because gastrinomas are commonly multiple and most originate in the duodenum and develop lymph node metastases, the duodenum should be opened and all tumors and lymph nodes excised. Insulinomas cause hypoglycemia that results in neuroglycopenic symptoms. Medical management of the hypoglycemia is less effective than that of the gastric acid hypersecretion. Fortunately, the insulinoma is usually clearly identified using routine pancreatic imaging studies. There is a high likelihood of cure when the insulinoma is excised surgically. However, recurrent hypoglycemia may occur, and careful follow-up is indicated.

    View details for PubMedID 16451771

  • Inhibition of host signal transducer and activator of transcription factor 6 results in cure with cyclophosphamide and interleukin 12 immunotherapy ANNALS OF SURGICAL ONCOLOGY Norton, J. A., Li, M., Lee, N. C., Tsung, K. 2006; 13 (1): 118-124

    Abstract

    Interleukin (IL)-12 immunotherapy is highly effective against established immunogenic tumors. However, nonimmunogenic tumors fail to respond to IL-12 therapy. Analysis of tumor rejection of the immunogenic tumors shows that a preexisting antitumor immune response is required for an effective IL-12 response. It is not known whether this lack of a preexisting host antitumor immune response is a limiting factor for the lack of response to IL-12 therapy by nonimmunogenic tumors.Experiments were done using the spontaneously arising nonimmunogenic metastatic murine breast 4T1 carcinoma in normal and STAT6 knockout BALB/c mice.4T1 is nonimmunogenic in normal mice, and established subcutaneous tumors are resistant to immunotherapy with cyclophosphamide (Cy) plus IL-12. However, in STAT6 knockout mice, 4T1 becomes immunogenic, and established 4T1 tumors are eradicated by Cy plus IL-12. Adoptive transfer of spleen cells from normal mice into STAT6 knockout mice before tumor inoculation reduces both the immunogenicity and response to Cy plus IL-12 immunotherapy of 4T1 in the recipient mice.Cy plus IL-12 immunotherapy can eradicate nonimmunogenic tumors as long as a preexisting immunity is established in the tumor-bearing host. Furthermore, the STAT6 pathway is likely involved in the suppression of the development of host antitumor immunity.

    View details for DOI 10.1245/ASO.2006.03.514

    View details for Web of Science ID 000234752000018

    View details for PubMedID 16372153

  • Long-term functionality of cryopreserved parathyroid autografts: A 13-year prospective analysis SURGERY Cohen, M. S., Dilley, W. G., Wells, S. A., Moley, J. F., Doherty, G. M., Sicard, G. A., Skinner, M. A., NORTON, J. A., DeBenedetti, M. K., Lairmore, T. C. 2005; 138 (6): 1033-1040

    Abstract

    The functional results of cryopreserved heterotopic parathyroid autotransplantation (CHPA) are not well defined. The authors evaluated the outcomes of delayed CHPA for the treatment of surgically induced hypoparathyroidism.Since November 1991, 448 parathyroid samples from 436 patients were cryopreserved at our institution. Of these, 29 patients underwent 34 CHPA procedures, with placement of 20 to 25 pieces of parathyroid tissue (approximately 50 to 75 mg) into the forearm. Outcomes were determined based on peripheral parathyroid hormone (PTH) levels and, where available, PTH gradients between grafted and nongrafted arms. Graft function results were defined as completely functional (patients with normal PTH and calcium levels off all calcium/vitamin D supplementation), partially functional (normal PTH levels and mild hypocalcemia on calcium supplementation), or nonfunctional (low PTH levels and dependent on calcium/vitamin D supplementation).Of the 29 patients with CHPA, prospective data were available for 26 patients undergoing 30 CHPA procedures (9 patients with MEN 1, 4 with MEN 2A, 1 with MEN 2B, and 12 with sporadic hyperparathyroidism). The mean follow-up interval was 2 years. Twelve of 26 patients (46%) had completely functional grafts, 6 patients (23%) had partially functional grafts, and the remaining 8 patients (31%) had nonfunctional grafts. No patient with CHPA had graft-dependent recurrent hyperparathyroidism. Of the 14 patients (15 autografts) with MEN, 7 patients (50%) had fully functional grafts, and 2 patients (14%) had partially functional grafts. The mean cryopreservation period was 7.9 months (range, 1 week to 22 months) for functional autografts and 15.3 months (range, 2 weeks to 106 months) for nonfunctional autografts (P < .01).Based on these data and those in previous studies, approximately 60% of delayed, cryopreserved parathyroid autografts are functional. In this study 40% autografts (46% of patients) achieved full competency off supplements. Some patients have evidence of graft function with normal PTH levels but are not normocalcemic. Results were similar for patients with MEN and nonhereditary hyperparathyroidism. The duration of cryopreservation was a significant indicator of graft failure, and no functional autograft was observed beyond 22 months of preservation. CHPA is a useful treatment modality for patients with postoperative hypocalcemia after thyroid or parathyroid surgery, who do not respond to immediate parathyroid autotransplantation.

    View details for DOI 10.1016/j.surg.2005.09.029

    View details for Web of Science ID 000234319000018

    View details for PubMedID 16360388

  • Surgical treatment and prognosis of gastrinoma BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY NORTON, J. A. 2005; 19 (5): 799-805

    Abstract

    Zollinger-Ellison syndrome (ZES) is a clinical syndrome with severe peptic ulcer disease and diarrhea caused by gastric acid hypersecretion secondary to a neuroendocrine tumour that secretes excessive amounts of the hormone gastrin (gastrinoma). Gastrinomas occur in a familial and a sporadic form. Patients with gastrinoma in the familial setting of Multiple Endocrine Neoplasia type 1 (MEN-1) are seldom, if ever, cured of Zollinger-Ellison syndrome by the current non-Whipple operations to remove duodenal and pancreatic gastrinoma. Surgery is currently used in these patients to deal with the malignant nature of pancreatic or duodenal neuroendocrine tumours. Malignant potential is best determined by tumour size. Tumours that are greater than 2 cm in size should be excised. In the sporadic setting, cure occurs in a significant proportion of patients (50%) by surgical resection of gastrinoma. Duodenotomy has improved both the tumour detection rate and the cure rate and should be routinely done. Whipple pancreaticoduodenectomy results in the highest probability of cure in both sporadic and MEN-1 gastrinoma patients as it removes the entire gastrinoma triangle. However, the excellent long-term survival of these patients with lesser operations and the increased operative mortality and long-term morbidity of Whipple make its current role unclear until further studies are done.

    View details for DOI 10.1016/j.bpg.2005.05.003

    View details for Web of Science ID 000233664500010

    View details for PubMedID 16253901

  • Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Koong, A. C., Christofferson, E., Le, Q. T., Goodman, K. A., Ho, A., Kuo, T., Ford, J. M., Fisher, G. A., Greco, R., Norton, J., Yang, G. P. 2005; 63 (2): 320-323

    Abstract

    To determine the efficacy of concurrent 5-fluorouracil (5-FU) and intensity-modulated radiotherapy (IMRT) followed by body stereotactic radiosurgery (SRS) in patients with locally advanced pancreatic cancer.In this prospective study, all patients (19) had pathologically confirmed adenocarcinoma and were uniformly staged. Our treatment protocol consisted of 45 Gy IMRT with concurrent 5-FU followed by a 25 Gy SRS boost to the primary tumor.Sixteen patients completed the planned therapy. Two patients experienced Grade 3 toxicity (none had more than Grade 3 toxicity). Fifteen of these 16 patients were free from local progression until death. Median overall survival was 33 weeks.Concurrent IMRT and 5-FU followed by SRS in patients with locally advanced pancreatic cancer results in excellent local control, but does not improve overall survival and is associated with more toxicity than SRS, alone.

    View details for DOI 10.1016/j.ijrobp.2005.07.002

    View details for Web of Science ID 000232083700002

    View details for PubMedID 16168826

  • Surgery and prognosis of duodenal gastrinoma as a duodenal neuroendocrine tumor BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY Norton, J. A. 2005; 19 (5): 699-704

    Abstract

    It has become increasingly clear that duodenal gastrinomas are the most common cause of Zollinger-Ellison syndrome (ZES). However, attempts to find these tumors before and during surgery for ZES have had limited success until duodenotomy (opening the duodenum) was described. The routine use of duodenotomy in patients with non-familial gastrinoma increases the number of duodenal tumors found, and the immediate and long-term cure-rate. The increase in cure-rate appears to be secondary to increased detection of small, previously undetectable duodenal gastrinomas. Duodenotomy detects small tumors (<1 cm) in the proximal duodenum. It does not detect more duodenal gastrinomas per patient, nor does it detect tumors in unusual duodenal locations. Duodenotomy decreases the death-rate associated with these tumors. However, it has not affected the rate of development of liver metastases. Duodenotomy is a critical method to find duodenal gastrinomas. It should be routinely performed in all surgery to find and remove gastrinoma for cure of ZES.

    View details for DOI 10.1016/j.bpg.2005.05.001

    View details for Web of Science ID 000233664500003

    View details for PubMedID 16253894

  • Computed tomography, endoscopic, laparoscopic, and intra-operative sonography for assessing resectability of pancreatic cancer SURGICAL ONCOLOGY-OXFORD Long, E. E., Van Dam, J., Weinstein, S., Jeffrey, B., Desser, T., Norton, J. A. 2005; 14 (2): 105-113

    Abstract

    Pancreas cancer is the fourth leading cancer killer in adults. Cure of pancreas cancer is dependent on the complete surgical removal of localized tumor. A complete surgical resection is dependent on accurate preoperative and intra-operative imaging of tumor and its relationship to vital structures. Imaging of pancreatic tumors preoperatively and intra-operatively is achieved by pancreatic protocol computed tomography (CT), endoscopic ultrasound (EUS), laparoscopic ultrasound (LUS), and intra-operative ultrasound (IOUS). Multi-detector CT with three-dimensional (3-D) reconstruction of images is the most useful preoperative modality to assess resectability. It has a sensitivity and specificity of 90 and 99%, respectively. It is not observer dependent. The images predict operative findings. EUS and LUS have sensitivities of 77 and 78%, respectively. They both have a very high specificity. Further, EUS has the ability to biopsy tumor and obtain a definitive tissue diagnosis. IOUS is a very sensitive (93%) method to assess tumor resectability during surgery. It adds little time and no morbidity to the operation. It greatly facilitates the intra-operative decision-making. In reality, each of these methods adds some information to help in determining the extent of tumor and the surgeon's ability to remove it. We rely on pancreatic protocol CT with 3-D reconstruction and either EUS or IOUS depending on the tumor location and operability of the tumor and patient. With these modern imaging modalities, it is now possible to avoid major operations that only determine an inoperable tumor. With proper preoperative selection, surgery is able to remove tumor in the majority of patients.

    View details for DOI 10.1016/j.suronc.2005.07.001

    View details for Web of Science ID 000231899500005

    View details for PubMedID 16125619

  • Characterization of a recurrent germ line mutation of the E-cadherin gene: Implications for genetic testing and clinical management CLINICAL CANCER RESEARCH Suriano, G., Yew, S., Ferreira, P., Senz, J., Kaurah, P., Ford, J. M., Longacre, T. A., NORTON, J. A., Chun, N., Young, S., Oliveira, M. J., MacGillivray, B., Rao, A., Sears, D., Jackson, C. E., Boyd, J., Yee, C., Deters, C., Pai, G. S., Hammond, L. S., McGivern, B. J., Medgyesy, D., Sartz, D., Arun, B., Oelschlager, B. K., Upton, M. P., Neufeld-Kaiser, W., Silva, O. E., Donenberg, T. R., Kooby, D. A., Sharma, S., Jonsson, B. A., Gronberg, H., Gallinger, S., Seruca, R., Lynch, H., Huntsman, D. G. 2005; 11 (15): 5401-5409

    Abstract

    To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals.We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing.We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers.In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.

    View details for Web of Science ID 000230878900012

    View details for PubMedID 16061854

  • Endocrine tumours of the gastrointestinal tract. Surgical treatment of neuroendocrine metastases. Best practice & research. Clinical gastroenterology Norton, J. A. 2005; 19 (4): 577-583

    Abstract

    Neuroendocrine tumors of the intestinal tract have low malignant potential but can result in decreased survival if they spread to the liver. The estimated 5-year survival of patients with liver metastases from neuroendocrine tumor is only 20%. Further, morbidity related to the Carcinoid Syndrome and other endocrine symptoms may also greatly reduce the quality of life. Treatment options for liver neuroendocrine tumor include long-acting somatostatin receptor antagonists (LAR), inteferon-alpha, chemotherapy and hepatic artery embolisation with and without chemotherapy. Surgical resection is feasible in select patients, but it may result in major morbidity and even mortality. In our series of 18 patients with liver neuroendocrine tumors, there was no operative mortality and acceptable morbidity. All 10 patients with the Carcinoid syndrome had complete amelioration of symptoms and the 5-year actuarial survival was 80%. Aggressive major surgery for liver neuroendocrine tumor metastases can be performed safely with acceptable mortality by experienced surgeons. Results have been similar for patients with gastrinoma and pancreatic neuroendocrine tumors. Surgical resection appears to result in outstanding long-term survival and amelioration of symptoms. It should be the first-line therapy for patients with liver neuroendocrine tumors in whom the tumor can be completely removed.

    View details for PubMedID 16183528

  • A national comparison of surgical versus percutaneous drainage of pancreatic pseudocysts: 1997-2001 JOURNAL OF GASTROINTESTINAL SURGERY Morton, J. M., Brown, A., Galanko, J. A., NORTON, J. A., Grimm, I. S., Behrns, K. E. 2005; 9 (1): 15-20

    Abstract

    Case series results indicate that a surgical approach is superior to percutaneous drainage of pancreatic pseudocysts. To determine if this surgical advantage is persistent, national outcomes for both approaches were compared from 1997 through 2001. The National Inpatient Sample, a 20% sample of all nonfederal hospital discharges, was searched for patients who had a pancreatic pseudocyst diagnosis, an ICD-9 diagnosis code 577.2, and an ICD-9 procedure code of 52.01 for percutaneous drainage (PD) or 52.4 and 52.96 for the surgical approaches. Variables were compared by using either t test or chi2 analysis. Confounding variables were controlled for by linear or logistic regression models. No clinically significant demographic, comorbidity, and disease-specific severity-of-illness differences existed between the two groups. Significant differences in complications, length of stay (15+/-15 versus 21+/-22 days, P<0.0001), and inpatient mortality (5.9% versus 2.8%, P<0.0001) favored the surgical approach. In addition, endoscopic retrograde cholangiopancreatography use had a protective effect on mortality (odds ratio, 0.7), whereas percutaneous drainage had an increased risk of mortality (odds ratio, 1.4). This population-based study suggests that surgical drainage of pancreatic pseudocysts, particularly when coupled with use of endoscopic retrograde cholangiopancreatography, leads to decreased complications, length of stay, and mortality in comparison with percutaneous drainage.

    View details for DOI 10.1016/j.gassur.2004.10.005

    View details for Web of Science ID 000226973200005

    View details for PubMedID 15623440

  • Gastric carcinoid tumors in multiple endocrine neoplasia-1 patients with Zollinger-Ellison syndrome can be symptomatic, demonstrate aggressive growth, and require surgical treatment SURGERY NORTON, J. A., Melcher, M. L., Gibril, F., Jensen, R. T. 2004; 136 (6): 1267-1273

    Abstract

    Gastric carcinoid tumors occur in 15% to 50% of patients with multiple endocrine neoplasia-1/Zollinger-Ellison syndrome (MEN-1/ZES) but are thought to be benign. We report 5 patients with MEN-1/ZES with symptomatic, aggressive gastric carcinoid tumors that required surgical procedures.This was a retrospective chart review.Each patient had MEN-1/ZES. Each patient had innumerable gastric carcinoid tumors with symptoms. The fasting gastrin level was 47,000 pg/mL (normal, <200 pg/mL); the basal acid output was 79 mEq/hr (n = 3), and the age at surgical exploration was 47 +/- 6 years, with a duration of MEN-1 of 21 +/- 3 years and of ZES of 15 +/- 2 years. All patients had elevated 5-HIAA or serotonin levels. Somatostatin receptor scintigraphy showed increased stomach uptake in 4 patients (80%). Four patients had a total gastrectomy; 4 patients had lymph node metastases removed, and 3 patients had liver metastases resected. One patient who did not have a total gastrectomy had liver carcinoid metastases.These results demonstrate that gastric carcinoid tumors in patients with longstanding MEN-1/ZES may be symptomatic, aggressive, and metastasize to the liver. With increased long-term medical treatment and life expectancy, these tumors will become an important determinant of survival.

    View details for DOI 10.1016/j.surg.2004.06.057

    View details for Web of Science ID 000225874800046

    View details for PubMedID 15657586

  • Resolved and unresolved controversies in the surgical management of patients with Zollinger-Ellison syndrome ANNALS OF SURGERY Norton, J. A., Jensen, R. T. 2004; 240 (5): 757-773

    Abstract

    Highlight unresolved controversies in the management of Zollinger-Ellison syndrome (ZES).Recent studies have resolved some of the previous controversies including the surgical cure rate in patients with and without Multiple Endocrine Neoplasia-type1 (MEN1), the biological behavior of duodenal and pancreatic gastrinomas, role of imaging studies to localize tumor, and gastrectomy to manage acid output.Review of the literature based on computer searches in Index Medicus, Pubmed and Ovid.Current controversies as identified in the literature include the role of endoscopic ultrasound (EUS), surgery in ZES patients with MEN1, pancreaticoduodenectomy (Whipple procedure), lymph node primary gastrinoma, parietal cell vagotomy, reoperation and surgery for metastatic tumor, and the use of minimally invasive surgical techniques to localize and remove gastrinoma.It is hoped that future studies will focus on these issues to improve the surgical management of ZES patients.

    View details for DOI 10.1097/01.sla.0000143252.02142.3e

    View details for Web of Science ID 000224739200005

    View details for PubMedID 15492556

  • Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in patients with Zollinger-Ellison syndrome? ANNALS OF SURGERY Norton, J. A., Alexander, H. R., FRAKER, D. L., VENZON, D. J., Gibril, F., Jensen, R. T. 2004; 239 (5): 617-625

    Abstract

    To determine whether routine use of duodenotomy (DUODX) alters cure rate, survival, or development of liver metastases in 143 patients (162 operations) with Zollinger-Ellison syndrome (ZES) without MEN1.DUODX has been shown to increase the detection of duodenal gastrinomas, but it is unknown if it alters rate of cure, liver metastases, or survival. Data from our prospective studies of surgery in ZES allow us to address this issue because DUODX was not performed before 1987, whereas it was routinely done after 1987.All patients with sporadic ZES (non-MEN1) undergoing surgery for possible cure without a prior DUODX from November 1980 to June 2003 were included. Patients had preoperative computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994. At surgery, all had the same standard ZES operation and were assessed immediately postoperatively, at 3 to 6 months, and yearly for cure (fasting gastrin, secretin test. and imaging studies).A DUODX was performed in 79 patients (94 operations), and no DUODX was performed in 64 patients (68 operations), with 10 patients having both (no DUODX, then a DUODX later). Gastrinoma was found in 98% with DUODX compared with 76% with no DUODX (P < 0.00001). Duodenal gastrinomas were found more frequently with DUODX (62% vs. 18%; P < 0.00001), whereas pancreatic, lymph node, and other primary gastrinomas occurred similarly. Six of the 10 patients with 2 operations had a duodenal tumor found with DUODX during a second operation that was missed in the first operation without DUODX. Both the immediate postoperative cure rate (65% vs. 44%; P = 0.010) and long-term cure rate at last follow-up (8.8 +/- 0.4 years; range, 0.1 to 21.5) (52% vs. 26%; P = 0.0012) were significantly greater with a DUODX than without. In patients without pancreatic tumors or liver metastases at surgery, both the rate of developing liver metastases (6% vs. 9.5%) and the disease-related death rate (0% vs. 2%) were low and not significantly different in patients with or without a DUODX.These results demonstrate that routine use of DUODX increases the short-term and long-term cure rate due to the detection of more duodenal gastrinomas. The rate of development of hepatic metastases and/or disease-related mortality in patients without pancreatic tumors is low, and no effect of DUODX on these parameters was seen. Duodenotomy (DUODX) should be routinely performed during all operations for cure of sporadic ZES.

    View details for DOI 10.1097/01.sla.0000124290.05524.5e

    View details for Web of Science ID 000221023600008

    View details for PubMedID 15082965

  • Antitumor immunity induced by dendritic cell-based vaccination is dependent on interferon-gamma and interleukin-12 JOURNAL OF SURGICAL RESEARCH Hiramoto, J. S., Tsung, K., Bedolli, M., NORTON, J. A., Hirose, R. 2004; 116 (1): 64-69

    Abstract

    This study was conducted to determine whether dendritic cells (DCs) pulsed with a tumor cell lysate can effectively vaccinate against tumor cells and to establish which cytokines are necessary.Each wild-type mouse received two subcutaneous immunizations (days 14 and 7) with either saline, tumor lysate, DCs, or tumor-lysate-pulsed DCs. Gamma-interferon (gamma-IFN), knock-out (KO), and interleukin-12 (IL-12) KO mice were also used in immunizations. A tumor challenge was given at day 0. Splenocytes were assayed for gamma-IFN production.All saline-injected mice (n = 19) and all mice injected with tumor lysate (n = 9) developed tumors. Six of nine mice immunized with DCs alone and 6/24 mice treated with lysate-pulsed DCs developed a tumor. Splenocytes from both the saline- and lysate-immunized groups produced undetectable levels of gamma-IFN, while those from mice immunized with either DCs or pulsed DCs produced high levels of gamma-IFN. Four of five gamma-IFN KO mice developed tumors after immunization with tumor-lysate-pulsed DCs. None of four IL-12 KO mice developed a tumor after immunization with wild-type pulsed DCs and 1/10 wild-type mice developed tumor after immunization with IL-12 KO pulsed DCs. Three of four IL-12 KO mice developed tumors after immunization with IL-12 KO pulsed DCs.Tumor-lysate-pulsed DCs can initiate an effective antitumor immune response. The presence of gamma-IFN in the host is essential for antitumor protection. In contrast, tumor protection is observed if IL-12 is present in either the host or the DCs.

    View details for DOI 10.1016/j.jss.2003.09.006

    View details for Web of Science ID 000188368900009

    View details for PubMedID 14732350

  • Results of initial operation for hyperparathyroidism in patients with multiple endocrine neoplasia type 1 SURGERY Elaraj, D. M., SKARULIS, M. C., Libutti, S. K., NORTON, J. A., Bartlett, D. L., Pingpank, J. F., Gibril, F., Weinstein, L. S., Jensen, R. T., Marx, S. J., Alexander, H. R. 2003; 134 (6): 858-864

    Abstract

    Hyperparathyroidism in patients with multiple endocrine neoplasia type 1 (MEN1) is characterized by multiglandular disease and a propensity for recurrence after parathyroidectomy (PTx). This study analyzes outcomes of a cohort of MEN1 patients undergoing initial PTx at one institution.Between April 1960 and September 2002, 92 patients with MEN1 underwent initial PTx. Outcomes were analyzed based on extent of parathyroid resection.Fourteen percent had 2.5 or fewer glands resected, 69% had subtotal PTx, and 17% had total PTx (88% with immediate autotransplantation). The initial surgical cure rate was 98%. Excluding 6 patients lost to follow-up, 33% have developed recurrent hyperparathyroidism (in 46% after < or =2.5 PTx, in 33% after subtotal, and in 23% after total PTx). Median recurrence-free survival was not statistically significantly different between subtotal versus total PTx, but it was longer for subtotal and total PTx compared with lesser resection (16.5 vs 7.0 years, respectively, P=.03). The incidence of severe hypoparathyroidism was 46% after total versus 26% after subtotal PTx.Subtotal and total PTx result in durable control of MEN1-associated hyperparathyroidism and have longer recurrence-free intervals compared with lesser resection. The high incidence of severe hypoparathyroidism after total PTx suggests that subtotal PTx is the initial operation of choice in this setting.

    View details for DOI 10.1016/S0039-6060(03)00406-9

    View details for Web of Science ID 000187389100002

    View details for PubMedID 14668715

  • Aggressive surgery for metastatic liver neuroendocrine tumors SURGERY NORTON, J. A., Warren, R. S., Kelly, M. G., Zuraek, M. B., Jensen, R. T. 2003; 134 (6): 1057-1063

    Abstract

    Neuroendocrine tumors of the gastrointestinal tract (carcinoids, pancreatic endocrine tumors) have low malignant potential but can decrease survival rates if they spread to the liver (LNET).The records of 16 patients with LNET primarily from gastrointestinal carcinoids treated surgically were retrospectively reviewed.There were 12 women and 4 men. Median age was 56 years (range 25 to 75). Thirteen (81%) had a carcinoid tumor and 5 had gastrinoma. Two patients with multiple endocrine neoplasia type 1 had both a gastric carcinoid and a jejunal gastrinoma. Eight patients (50%) had the carcinoid syndrome. Each patient had all identifiable LNET either resected or ablated. Ten patients had liver wedge resections, 1 right trisegmentectomy, 5 left hepatic lobectomies, and 2 radiofrequency ablations. Thirteen (81%) patients had concomitant bowel resections. Two patients had concomitant total gastrectomies to remove stomach primaries. The final patient had an extraintestinal pelvic primary or a liver primary. There were no operative deaths, and all 8 (100%) patients with the carcinoid syndrome had amelioration of symptoms. The 5-year actuarial survival rate was 82% with a median follow-up of 32 months.This study demonstrates that liver and concomitant extrahepatic surgery can be performed safely in patients with liver metastases because of carcinoids or pancreatic endocrine tumors. It results in excellent long-term survival and amelioration of symptoms. Surgery should be the first-line therapy for patients with LNET.

    View details for DOI 10.1016/S0039-6060(03)00496-3

    View details for Web of Science ID 000187389100052

    View details for PubMedID 14668741

  • Current surgical management of Zollinger-Ellison syndrome (ZES) in patients without multiple endocrine neoplasia-type 1 (MEN1) SURGICAL ONCOLOGY-OXFORD NORTON, J. A., Jensen, R. T. 2003; 12 (2): 145-151

    Abstract

    The role of surgery in the management of patients with sporadic (not part of multiple endocrine neoplasia type 1) Zollinger-Ellison syndrome (ZES) is controversial. In this setting, 60-90% of gastrinomas are malignant and medical therapy can control the gastric acid hypersecretion in virtually every patient. Therefore, the progression of tumor is the major determinant of survival. Surgery will cure approximately one-third of patients with sporadic ZES. It will decrease the development of liver metastases and may improve survival. Somatostatin receptor scintigraphy is the best preoperative localization study. Its results are as good as all other imaging studies combined. Operative techniques should always include duodenotomy (opening the duodenum) and meticulous dissection of lymph nodes in the gastrinoma triangle, because duodenal primary tumors are often missed and lymph node primary tumors or metastases are common. Postoperative evaluation should include secretin test because it is the most sensitive method to document cure and detect tumor recurrence.

    View details for DOI 10.1016/S0960-7404(03)00035-5

    View details for Web of Science ID 000185260800008

    View details for PubMedID 12946485

  • Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors ARCHIVES OF SURGERY Norton, J. A., Kivlen, M., Li, M., Schneider, D., Chuter, T., Jensen, R. T. 2003; 138 (8): 859-865

    Abstract

    There is considerable controversy about the treatment of patients with malignant advanced neuroendocrine tumors of the pancreas and duodenum. Aggressive surgery remains a potentially efficacious antitumor therapy but is rarely performed because of its possible morbidity and mortality.Aggressive resection of advanced neuroendocrine tumors can be performed with acceptable morbidity and mortality rates and may lead to extended survival.The medical records of patients with advanced neuroendocrine tumors who underwent surgery between 1997 and 2002 by a single surgeon at the University of California, San Francisco, were reviewed in an institutional review board-approved protocol.Surgical procedure, pathologic characteristics, complications, mortality rates, and disease-free and overall survival rates were recorded. Disease-free survival was defined as no tumor identified on radiological imaging studies and no detectable abnormal hormone levels. Proportions were compared statistically using the Fisher exact test. Kaplan-Meier curves were used to estimate survival rates.Twenty patients were identified (11 men and 9 women). Of these, 10 (50%) had gastrinoma, 1 had insulinoma, and the remainder had nonfunctional tumors; 2 had multiple endocrine neoplasia type 1, and 1 had von Hippel-Lindau disease. The mean age was 55 years (range, 34-72 years). In 10 patients (50%), tumors were thought to be unresectable according to radiological imaging studies because of multiple bilobar liver metastases (n = 6), superior mesenteric vein invasion (n = 3), and extensive nodal metastases (n = 1). Tumors were completely removed in 15 patients (75%). Surgical procedures included 8 proximal pancreatectomies (pancreatoduodenectomy or whipple procedure), 3 total pancreatectomies, 9 distal pancreatectomies, and 3 tumor enucleations from the pancreatic head. Superior mesenteric vein reconstruction was done in 3 patients. Liver resections were done in 6 patients, and an extended periaortic node dissection was performed in 1. The spleen was removed in 11 patients, and the left kidney was removed as a result of tumor metastases in 2. Eighteen patients had primary pancreatic tumors, and 2 had duodenal tumors; 2 patients with multiple endocrine neoplasia type 1 had both pancreatic and duodenal tumors. The mean tumor size was 8 cm (range, 0.5-23 cm). Of the patients, 14 (70%) had lymph node metastases and 8 (40%) had liver metastases. The mean postoperative hospital stay was 11.5 days (range, 6-26 days). Six patients (30%) had postoperative complications. There was a significantly greater incidence of pancreatic fistulas with enucleations compared with resections (P =.04). There were no operative deaths. The mean follow-up period was 19 months (range, 1-96 months); 18 patients (90%) are alive, 2 died of progressive tumor, and 12 (60%) are disease-free. The actuarial overall survival rate is 80% at 5 years, and disease-free survival rates indicate that all tumors will recur by the 7-year follow-up visit.Aggressive surgery including pancreatectomy, splenectomy, superior mesenteric vein reconstruction, and liver resection can be done with acceptable morbidity and low mortality rates for patients with advanced neuroendocrine tumors. Although survival rates following surgery are excellent, most patients will develop a recurrent tumor. These findings suggest that conventional contraindications to surgical resection, such as superior mesenteric vein invasion and nodal or distant metastases, should be reconsidered in patients with advanced neuroendocrine tumors.

    View details for Web of Science ID 000184618800011

    View details for PubMedID 12912744

  • Management and outcome of patients with sporadic gastrinoma arising in the duodenum ANNALS OF SURGERY Zogakis, T. G., Gibril, F., Libutti, S. K., NORTON, J. A., White, D. E., Jensen, R. T., Alexander, H. R. 2003; 238 (1): 42-48

    Abstract

    Primary duodenal gastrinomas are now recognized as a common etiology for patients with sporadic Zollinger Ellison Syndrome (ZES); however, the clinical and pathologic features of this condition and long-term outcome after operation are not well characterized.Between November 1982 and September 2000, 63 patients diagnosed with sporadic ZES underwent resection of a primary duodenal gastrinoma and regional nodal metastases with curative intent. Data from a prospectively maintained database were reviewed for clinical and pathologic parameters relating to primary tumor size, location, frequency of lymph node metastases, and disease-specific and disease-free survival.There were 41 males and 22 females (mean age, 48.6 years). The majority of duodenal gastrinomas were in the first or second portions of the duodenum (83%). Tumor size ranged from 0.2 to 2.0 cm with 62% measuring less than 1.0 cm. Sixty percent of individuals had regional lymph node metastases identified primarily in proximity to the primary tumor. At a median 10-year follow-up, the overall disease-specific and disease-free survivals were 100% and 60%, respectively. Actuarial 10-year disease-free survival was significantly higher for patients without lymph node metastases versus those with lymph node metastases (78% versus 48%, P = 0.0137).Duodenal gastrinomas in patients with sporadic ZES are frequently small, most commonly located in the proximal duodenum, and associated with regional lymph node metastases in 60%. Disease-free survival is lower for patients with regional lymph node metastases suggesting that a more systematic lymphadenectomy to extirpate occult disease may be indicated in this group.

    View details for DOI 10.1097/01.SLA.0000074963.87688.31

    View details for Web of Science ID 000185834900006

    View details for PubMedID 12832964

  • Evidence-based analysis: postoperative gastric bleeding: etiology and prevention SURGICAL ONCOLOGY-OXFORD Hiramoto, J. S., Terdiman, J. P., NORTON, J. A. 2003; 12 (1): 9-19

    Abstract

    Although the incidence of stomach hemorrhage is declining, stress-related gastric bleeding remains an important source of morbidity and mortality in cancer patients undergoing major surgical procedures to remove tumor. Prevention of stress-related bleeding is desirable; however, the optimal use of drugs to prevent gastric bleeding is unclear. Prophylaxis is recommended for surgical patients who require prolonged mechanical ventilation or have a coaguloathy. Histamine-2 receptor antagonists and sucralfate will reduce the likelihood of clinically important gastric-bleeding. Sucralfate appears to be less effective than H-2 blockers, but it is associated with fewer side effects such as nosocomial pneumonia. Preliminary studies show that proton pump inhibitors are most effective, have few side effects, but are most expensive. Intravenous proton pump inhibitors may be the drugs of choice for stress ulcer prophylaxis (SUP) in high-risk patients.

    View details for DOI 10.1016/S0960-7404(02)00073-7

    View details for Web of Science ID 000182503800002

    View details for PubMedID 12689666

  • Cure of an established nonimmunogenic tumor, SCCVII with a novel interleukin 12-based immunotherapy regimen in C3H mice ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Mandpe, A. H., Tsung, K., NORTON, J. A. 2003; 129 (7): 786-792

    Abstract

    To develop a murine model of effective treatment with immunotherapy for established head and neck squamous cell carcinoma.Prospective animal study. Subjects Female C3H mice, 8 to 12 weeks old.A subcutaneous inoculation of 2 x 10(5) SCC VII cells in C3H mice was established for 7 to 12 days. Tests for concomitant immunity were performed, with and without interleukin 12 modification. Tumors were also tested for responsiveness to interleukin 12 (5 mice) and to cyclophosphamide followed by interleukin 12 (5 mice). SCC VII tumors in 24 mice were treated with interleukin 12 followed by cyclophosphamide and interleukin 12. Five mice with tumors treated with isotonic sodium chloride solution served as controls. Tumors were measured 3 to 4 times weekly, and cure was defined as complete regression of the tumor for at least 60 days. Cured mice were rechallenged with 2 x 10(5) SCC VII cells to verify antitumor immunity. Immunohistochemistry of regressing tumors was performed for CD4+ and CD8+ T cells.Tumor-bearing mice easily developed second tumors when challenged with 2 x 10(5) tumor cells in the opposite flank. However, interleukin 12 treatment provided immunity to second tumors in 8 (100%) of 8 mice when started at day 4 and in 2 (40%) of 5 when treated from day 7. SCC VII did not respond to standard interleukin 12 or cyclophosphamide plus interleukin 12 therapy. Seventy-five percent of animals (18/24) treated with interleukin 12 followed by cyclophosphamide plus interleukin 12 were successfully cured, and all cured mice resisted subsequent challenge with SCC VII. Immunohistochemistry of regressed tumors showed an intense CD4+ and CD8+ infiltrate that was absent in the untreated and nonresponding tumors.Nonimmunogenic SCC VII is a nonimmunogenic tumor that can be converted into an immunogenic tumor with interleukin 12 treatment. Additional treatment with cyclophosphamide plus interleukin 12 leads to complete regression in 75% of mice.

    View details for Web of Science ID 000184104400018

    View details for PubMedID 12874083

  • Possible primary lymph node gastrinoma: Occurrence, natural history, and predictive factors a prospective study ANNALS OF SURGERY Norton, J. A., Alexander, H. R., FRAKER, D. L., VENZON, D. J., Gibril, F., Jensen, R. T. 2003; 237 (5): 650-657

    Abstract

    To analyze the results of a prospective study of 176 patients with Zollinger-Ellison syndrome (ZES) (138 sporadic, 38 MEN1) undergoing 207 operations over a 17-year period.The existence of lymph node (LN) primary gastrinoma causing ZES is controversial.Three groups of patients were compared: LN only resected, cured, and no relapse (likely LN primary); same criteria but relapse (unlikely LN primary); and duodenal primary and LN metastases (Duo-LN).Forty-five (26%) had only LN(s) as the initial tumor found. Twenty-six of the 45 (58%) fit the definition of a likely LN primary because they were apparently cured postresection. At 10.4 +/- 1.2 years, 69% of the 26 patients with likely LN primary tumors have remained cured and have LN primaries. In the 8 of 26 with recurrent ZES, it occurred at 5 +/- 1 years, and 3 had duodenal gastrinoma that had been missed. Ten percent (13/138) of all patients with sporadic ZES and 0% (0/38) with ZES and MEN1 remained cured with only a LN tumor removed. In patients with sporadic gastrinomas no clinical, laboratory, or radiographic localization feature differed among patients with likely LN primary (n = 16) and those with unlikely LN primary (n = 6) or those with Duo-LN (n = 37). In the likely LN primary group, the largest LN was 2.2 +/- 0.2 cm, the number of LNs removed was 1.3 +/- 0.1 (25% > or =1 LN), and 78% were in the gastrinoma triangle, which also did not differ from the other 2 groups. Disease-free survival was similar in the likely LN primary group, patients with Duo-LN, and those with pancreatic primaries.These results support the conclusion that primary LN gastrinomas occur and are not rare (approximately 10% of sporadic cases). These results suggest that a proportion (25%) of these tumors are either multiple or malignant. Because no clinical, laboratory, or tumoral characteristic distinguishes patients with LN primary tumors, all patients with ZES undergoing surgery should have an extensive exploration to exclude duodenal or pancreatic tumors and routine removal of lymph nodes in the gastrinoma triangle.

    View details for Web of Science ID 000185834700012

    View details for PubMedID 12724631

  • Macrophages as effector cells in interleukin 12-induced T cell-dependent tumor rejection CANCER RESEARCH Tsung, K., Dolan, J. P., Tsung, Y. L., NORTON, J. A. 2002; 62 (17): 5069-5075

    Abstract

    Interleukin (IL)-12 activates a T-cell-dependent antitumor immune response that is able to eradicate established large tumors in a number of immunogenic tumor models. The effector mechanisms in these dramatic antitumor responses have not yet been identified. In this report, we show that the effector mechanism of IL-12-induced rejection of established MCA207 tumors is unique in that it is not dependent on perforin, Fas/Fas ligand, and nitric oxide. Study of cyclophosphamide plus IL-12 (Cy + IL-12)-induced rejection of ascites Sa1 tumor demonstrates that macrophages are the predominant immune cell infiltration in the ascites. These macrophages possess nonspecific tumoricidal activity in vivo as immune distinct MCA207 tumor cells inoculated i.p., but not s.c., in mice bearing regressing Sa1 ascites tumors after Cy + IL-12 therapy are rejected. Furthermore, Cy + IL-12-treated Sa1 ascites cells or macrophages, but not spleen macrophages from the same mouse or inflammatory macrophages induced by thioglycollate, are able to suppress the development of immune-irrelevant s.c. tumors in a Winn assay. These macrophages kill various tumor cells in a contact-dependent manner in vitro, and the cytotoxicity is preserved after fixation with paraformaldehyde. These results demonstrate that activated macrophages function as effector cells in an IL-12-induced, T-cell-dependent eradication of established tumors through a novel contact-dependent, paraformaldehyde fixation-resistant, apoptosis-inducing mechanism.

    View details for Web of Science ID 000177897200036

    View details for PubMedID 12208763

  • The role of IFN-gamma in rejection of established tumors by IL-12: Source of production and target CANCER RESEARCH Segal, J. G., Lee, N. C., Tsung, Y. L., NORTON, J. A., Tsung, K. 2002; 62 (16): 4696-4703

    Abstract

    We have demonstrated previously that established small and large murine MCA207 sarcomas can be completely eradicated by treatment with interleukin (IL) 12 alone and cyclophosphamide plus IL-12 (Cy+IL-12), respectively. The antitumor effect of IL-12/Cy+IL-12 has been found to be dependent on IFN-gamma and T cells. The role of IFN-gamma in IL-12-induced tumor rejection is unclear, because after IL-12 administration IFN-gamma is produced by multiple cell types, and it acts on most cell types because of the ubiquitous expression of its receptor. Using a T-cell-adoptive transfer model, we show that after IL-12 treatment, tumor-specific T-cell production of IFN-gamma is necessary and sufficient for rejection of established tumors. Furthermore, by testing tumors using IFN-gamma-unresponsive tumor cells, we show that tumor cell expression of MHC class I molecules in vivo is abrogated by blocking the response to IFN-gamma. However, tumor response to IFN-gamma is not essential for rejection of established small and large tumors by IL-12 and Cy+IL-12, respectively; neither is it essential for expression of tumor immunogenicity. Our results indicate that the rejection of established tumors by IL-12/Cy+IL-12 is dependent on the induction of a Th1 response producing IFN-gamma that acts on host cells.

    View details for Web of Science ID 000177496600029

    View details for PubMedID 12183428

  • Multiple-gland disease in primary hyperparathyroidism - A function of operative approach? ARCHIVES OF SURGERY Lee, N. C., Norton, J. A. 2002; 137 (8): 896-899

    Abstract

    The approach to surgery for primary hyperparathyroidism (PHPT) is controversial. To determine whether routine bilateral neck exploration increases the detection of multiple-gland disease compared with a focused unilateral approach, we compared the incidence of single vs multiple-gland disease in patients undergoing surgical treatment for PHPT as a function of unilateral or bilateral exploration.From 1993 through 1997, 214 consecutive patients underwent initial bilateral neck exploration for PHPT by a single surgeon. Each patient underwent the surgical procedure without prior localizing studies. Four parathyroid glands were identified, and abnormal glands were excised. The results were compared with published studies of patients who underwent either bilateral neck exploration or focused unilateral neck exploration for PHPT.All reported studies from 1995 through 2001 in a MEDLINE search using the terms "parathyroidectomy" or "primary hyperparathyroidism and surgery" and either "bilateral" or "conventional" or "minimally invasive," "selective," or "unilateral."The studies were analyzed for numbers of patients and a final diagnosis of either a single adenoma or multiple-gland disease (double adenoma or hyperplasia). Proportions were compared statistically with a chi(2) test.In our series of 214 patients who underwent bilateral neck exploration, 79.4% had a single adenoma, and 20.6% had multiple-gland disease. Of 2166 patients in 14 studies who underwent bilateral neck exploration, 79.7% had a single adenoma, and 19.3% had multiple-gland disease. Of 2095 patients in 31 studies with a focused unilateral approach, 92.5% had a single adenoma, whereas only 5.3% had multiple-gland disease. The incidence of multiple-gland disease was significantly lower among patients treated with a focused unilateral approach compared with a bilateral approach as used in our series and the literature (P<.001).The data suggest that a focused unilateral surgical approach for PHPT may underestimate the incidence of multiple-gland disease.

    View details for Web of Science ID 000177326900004

    View details for PubMedID 12146987

  • Production of interferon-gamma by tumor-sensitized T cells is essential for interleukin-12-induced complete tumor eradication SURGERY Lee, N. C., Tsung, K., NORTON, J. A. 2002; 132 (2): 365-368

    Abstract

    Interferon-gamma (IFN-gamma) is essential for eradication of established large tumors by interleukin-12 (IL-12), but the critical source of IFN-gamma has not been defined. Adoptive transfer of T cells into T cell-deficient mice allows for evaluation of the role of T cells and T cell production of IFN-gamma in the antitumor immune response.Wild-type C57BL/6, IL-12 receptor-beta1 knockout (IL-12Rbeta1 KO), IFN-gamma knockout (IFN-gamma KO), and IFN-gamma receptor-alpha knockout (IFN-gammaRalpha KO) mice were immunized and used as donors for adoptive transfer. Transfer of either splenocytes or CD90(+) T cells was performed into recipient T cell receptor-beta knockout (TCRbeta KO) and IFN-gamma/TCRbeta double knockout mice bearing 14-day subcutaneous MCA207 tumors. Half of the mice were treated with IL-12, and cure rates were compared.Transfer of either 1/4 immunized spleen equivalent or 10(7) immunized T cells into both TCRbeta KO and IFN-gamma/TCRbeta KO mice resulted in 80% to 100% cure when given with IL-12. However, transfer of 10(7) immunized T cells from IFN-gamma KO mice into TCRbeta KO mice was ineffective with or without IL-12. T cell response to IL-12, but not IFN-gamma, was required for tumor regression.Production of IFN-gamma by IL-12-responsive tumor-sensitized T cells is both necessary and sufficient for complete tumor eradication induced by IL-12. T cells are the source, but not the target, of IFN-gamma during tumor regression.

    View details for DOI 10.1067/msy.2002.125352

    View details for Web of Science ID 000177851900037

    View details for PubMedID 12219036

  • Pre-existing tumor-sensitized T cells are essential for eradication of established tumors by IL-12 and cyclophosphamide plus IL-12 JOURNAL OF IMMUNOLOGY Le, H. N., Lee, N. C., Tsung, K., NORTON, J. A. 2001; 167 (12): 6765-6772

    Abstract

    The antitumor immune response activated by IL-12, especially by a combination of cyclophosphamide and IL-12 (Cy+IL-12), is clinically significant in certain experimental tumor models, in that a number of well-established (10-20 mm in diameter) s.c. tumors are completely eradicated. Furthermore, Cy+IL-12 treatment is also able to eradicate well-established grossly detectable experimental lung metastases and advanced ascites tumors. Despite the dramatic antitumor effects seen in some tumor models, Cy+IL-12 fails to induce regression of other established tumors. Characterization of tumor immunogenicity shows that all tumors responding to IL-12 and Cy+IL-12 treatments are immunogenic tumors, in that an antitumor immune response is detectable in tumor-bearing hosts upon tumor establishment. In contrast, none of the nonimmunogenic tumor responds to IL-12 and Cy+IL-12 treatments. Analysis of cellular requirements for successful tumor rejection through an adoptive cell transfer approach reveals that the presence of tumor-sensitized, but not naive, T cells is essential for tumor rejection by IL-12 and Cy+IL-12. Transfer of these tumor-sensitized T cells must be conducted before, but not after, IL-12 treatment in order for tumor rejection to occur. The requirement of sensitized T cells is also tumor specific. In mice bearing immunogenic tumors, the presence of pre-existing tumor-sensitized T cells is demonstrated by adoptive cell transfer experiments using purified spleen T cells from these mice. Results from our study show that Cy+IL-12-based immunotherapy of cancer may be highly effective and that pre-existing tumor-sensitized T cells are essential for the success of the therapy.

    View details for Web of Science ID 000172613400010

    View details for PubMedID 11739491

  • Iatrogenic pheochromocytomatosis: A previously unreported result of laparoscopic adrenalectomy SURGERY Li, M. L., Fitzgerald, P. A., Price, D. C., NORTON, J. A. 2001; 130 (6): 1072-1077

    Abstract

    Laparoscopic adrenalectomy is now regarded as the procedure of choice for treatment of small or benign adrenal tumors, including pheochromocytoma. However, long-term outcomes have not been critically assessed. We report here 3 cases of pheochromocytomatosis recurring 3 to 4 years after laparoscopic adrenalectomy. We postulate laparoscopic-induced seeding of tumor as the mechanism of recurrence.We retrospectively reviewed the cases of 3 patients with documented biochemical and radiolabeled metaiodobenzylguanidine evidence of recurrent pheochromocytoma after prior presumed curative laparoscopic adrenalectomy.Original pheochromocytomas were 5.5 to 6.5 cm in diameter. At the time of laparoscopic adrenalectomy, tumors were not believed to be malignant, based on clinical or histopathologic data. However, on 3- to 4-year follow-up, each patient developed symptoms, elevated urinary catecholamine levels, and metaiodobenzylguanidine imaging consistent with recurrence. At reoperation, multiple small tumor nodules were found in the adrenal bed near the site of the initial laparoscopic resection. The original operative notes suggested some possible method of local seeding: tumor fragmentation and spillage or excessive tumor manipulation.Pheochromocytoma recurrence may occur as a result of local spillage of tumor during laparoscopic adrenalectomy. The relative risk of recurrence between open and laparoscopic resection needs to be assessed. Long-term follow-up will continue to be important, regardless of operative approach.

    View details for DOI 10.1067/msy.2001.118373

    View details for Web of Science ID 000173015300052

    View details for PubMedID 11742341

  • Reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1 SURGERY Kivlen, M. H., Bartlett, D. L., Libutti, S. F., SKARULIS, M. C., Marx, S. J., Simonds, W. F., Weinstein, L. S., Jensen, R. T., McCart, J. A., Naik, A. M., Kranda, K. C., Brennan, M. F., NORTON, J. A., FRAKER, D. L., Alexander, H. R. 2001; 130 (6): 991-998

    Abstract

    Patients with multiple endocrine neoplasia type 1 and hyperparathyroidism often undergo multiple operations because of inadequate initial surgery, presence of supernumerary and ectopic glands, regrowth of remnant glands, or autograft hyperfunction. Management of this patient population is complex.From January 1975 to December 2000 we performed 94 reoperative parathyroidectomies consisting of 79 neck reexplorations, 12 autograft removals, and 3 median sternotomies in 75 patients. Data were gathered by retrospective chart review and follow-up telephone interviews.Excluding autograft excision, reoperative surgery was successful (normocalcemia longer than 6 months) in 91%; autograft removal was successful in only 58%. With a median follow-up of 59 months, 64% of patients are currently free from hypercalcemia, and this outcome was not influenced by the total number of glands resected. The median time to recurrent hypercalcemia was 125 months. Thirty patients received an autograft after reoperation. The complication rate for all reoperations was 12%, including permanent recurrent laryngeal nerve injury in 2 patients (2.1%).Reoperative parathyroidectomy in patients with multiple endocrine neoplasia type 1 was safe and successful in the majority of patients; however, recurrent hyperparathyroidism is likely to develop in most individuals beyond 10 years of follow-up. The total number of glands accounted for after reoperation is not associated with successful outcome.

    View details for DOI 10.1067/msy.2001.118379

    View details for Web of Science ID 000173015300026

    View details for PubMedID 11742328

  • Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome ANNALS OF SURGERY NORTON, J. A., Alexander, H. R., FRAKER, D. L., VENZON, D. J., Gibril, F., Jensen, R. T. 2001; 234 (4): 495-505

    Abstract

    To determine the role of surgery in patients with Zollinger-Ellison syndrome (ZES) and multiple endocrine neoplasia type 1 (MEN1) with either limited or advanced pancreatic endocrine tumors (PETs).The role of surgery in patients with MEN1 and ZES is controversial. There have been numerous previous studies of surgery in patients with PETs; however, there are no prospective studies on the results of surgery in patients with advanced disease.Eighty-one consecutive patients with MEN1 and ZES were assigned to one of four groups depending on the results of imaging studies. Group 1 (n = 17) (all PETs smaller than 2.5 cm) and group 3 (n = 8) (diffuse liver metastases) did not undergo surgery. All patients in group 2A (n = 17; single PET 2.5-6 cm [limited disease]) and group 2B (n = 31; two or more lesions, 2.5 cm in diameter or larger, or one lesion larger than 6 cm) underwent laparotomy. Tumors were preferably removed by simple enucleation, or if not feasible resection. Patients were reevaluated yearly.Pancreatic endocrine tumors were found in all patients at surgery, with groups 2A and 2B having 1.7 +/- 0.4 and 4.8 +/- 1 PETs, respectively. Further, 35% of the patients in group 2A and 88% of the patients in group 2B had multiple PETs, 53% and 84% had a pancreatic PET, 53% and 68% had a duodenal gastrinoma, 65% and 71% had lymph node metastases, and 0% and 12% had liver metastases. Of the patients in groups 2A and 2B, 24% and 58% had a distal pancreatectomy, 0% and 13% had a hepatic resection, 0% and 6% had a Whipple operation, and 53% and 68% had a duodenal resection. No patient was cured at 5 years. There were no deaths. The early complication rate, 29%, was similar for groups 2A and 2B. Mean follow-up from surgery was 6.9 +/- 0.8 years, and during follow-up liver metastases developed in 6% of the patients in groups 2A and 2B. Groups 1, 2A, and 2B had similar 15-year survival rates (89-100%); they were significantly better than the survival rate for group 3 (52%).Almost 40% of patients with MEN1 and ZES have advanced disease without diffuse distant metastases. Despite multiple primaries and a 70% incidence of lymph node metastases, tumor can be removed with no deaths and complication rates similar to those in patients with limited disease. Further, despite previous studies showing that patients with advanced disease have decreased survival rates, in this study the patients with advanced tumor who underwent surgical resection had the same survival as patients with limited disease and patients without identifiable tumor. This suggests that surgical resection should be performed in patients with MEN1 who have ZES and advanced localized PET.

    View details for Web of Science ID 000171502900016

    View details for PubMedID 11573043

  • Intraoperative ultrasound and preoperative localization detects all occult insulinomas ARCHIVES OF SURGERY Hiramoto, J. S., Feldstein, V. A., LaBerg, J. M., NORTON, J. A. 2001; 136 (9): 1020-1025

    Abstract

    Preoperative invasive localization procedures with intraoperative ultrasound (IOUS) can result in successful surgical treatment of occult insulinomas when noninvasive imaging study results are equivocal or negative.Prospective study.Tertiary care university hospital.Thirty-seven consecutive patients with a biochemical diagnosis of insulinoma without multiple endocrine neoplasia (MEN).All patients underwent portal venous sampling (PVS) (n = 22) or calcium angiogram (n = 15) followed by surgery with palpation and IOUS (n = 37).Portal venous sampling, calcium angiogram, palpation, and IOUS were compared for accurate localization of insulinoma.All patients were cured of hypoglycemia after surgery. Portal venous sampling correctly localized tumors in 17 (77%) of 22 patients. Calcium angiogram was correct in 13 (87%) of 15 patients. Palpation identified 24 (65%) of 37 tumors, and IOUS found 35 (95%) of 37 tumors. The 2 tumors missed by IOUS were located in the tail of the pancreas and were resected based on regional localization alone.Intraoperative ultrasound is the single best localization study, but it will miss some tumors that regional localization can identify. Combining both modalities allowed surgical cure of all insulinomas in our study. Therefore, we recommend both IOUS and regional localization for insulinoma when preoperative imaging studies are equivocal.

    View details for Web of Science ID 000170895600012

    View details for PubMedID 11529824

  • Prognostic value of initial pasting serum gastrin levels in patients with Zollinger-Ellison syndrome JOURNAL OF CLINICAL ONCOLOGY Berger, A. C., Gibril, F., VENZON, D. J., DOPPMAN, J. L., NORTON, J. A., Bartlett, D. L., Libutti, S. K., Jensen, R. T., Alexander, H. R. 2001; 19 (12): 3051-3057

    Abstract

    To assess the value of the initial fasting serum gastrin (FSG) at presentation in patients with Zollinger-Ellison Syndrome (ZES) in predicting primary tumor characteristics and survival.A total of 239 patients were treated for ZES between December 1981 and September 1998, with a mean follow-up of 9.1 +/- 0.6 years. At initial evaluation, 86 patients (36%) had mild (0 to 499 pg/mL), 61 (25.5%) had moderate (500 to 1,000 pg/mL), and 92 (38.5%) had severe (> 1,000 pg/mL) elevations in FSG. Primary tumor location and size, presence of lymph node or hepatic metastases, and survival were analyzed based on the level of initial FSG.In patients with sporadic ZES, but not in those with multiple endocrine neoplasia type 1 (MEN-1) and ZES, there was a significant relationship between the level of initial FSG and tumor size and location of primary tumor, frequency of lymph node and liver metastases, and survival. The median 5- and 10-year survival decreased with increasing initial FSG (P <.001) in patients with sporadic ZES; MEN-1 patients lived longer than sporadic ZES patients (P =.012), and survival in this group was not associated with the level of initial FSG. Multivariate analysis showed that factors independently associated with death from disease in patients with sporadic ZES were liver metastases (P =.0001), a pancreatic site (P =.0027), and primary tumor size (P =.011) but not initial FSG (P >.30).The severity of FSG at presentation is associated with size and site of tumor and the presence of hepatic metastases, factors that are significant independent predictors of outcome. The level of FSG at presentation may be useful in planning the nature and extent of the initial evaluation and management in patients with sporadic ZES.

    View details for Web of Science ID 000169303900010

    View details for PubMedID 11408501

  • A high-resolution radiation hybrid map of the human genome draft sequence SCIENCE Olivier, M., Aggarwal, A., Allen, J., Almendras, A. A., Bajorek, E. S., Beasley, E. M., Brady, S. D., Bushard, J. M., Bustos, V. I., Chu, A., Chung, T. R., de Witte, A., Denys, M. E., Dominguez, R., Fang, N. Y., Foster, B. D., Freudenberg, R. W., Hadley, D., Hamilton, L. R., Jeffrey, T. J., Kelly, L., Lazzeroni, L., Levy, M. R., Lewis, S. C., Liu, X., Lopez, F. J., Louie, B., Marquis, J. P., Martinez, R. A., Matsuura, M. K., Misherghi, N. S., NORTON, J. A., Olshen, A., Perkins, S. M., Perou, A. J., Piercy, C., Piercy, M., Qin, F., Reif, T., Sheppard, K., Shokoohi, V., Smick, G. A., Sun, W. L., Stewart, E. A., Tejeda, J. F., Tran, N. M., Trejo, T., Vo, N. T., Yan, S. C., Zierten, D. L., Zhao, S. Y., Sachidanandam, R., Trask, B. J., Myers, R. M., Cox, D. R. 2001; 291 (5507): 1298-?

    Abstract

    We have constructed a physical map of the human genome by using a panel of 90 whole-genome radiation hybrids (the TNG panel) in conjunction with 40,322 sequence-tagged sites (STSs) derived from random genomic sequences as well as expressed sequences. Of 36,678 STSs on the TNG radiation hybrid map, only 3604 (9.8%) were absent from the unassembled draft sequence of the human genome. Of 20,030 STSs ordered on the TNG map as well as the assembled human genome draft sequence and the Celera assembled human genome sequence, 36% of the STSs had a discrepant order between the working draft sequence and the Celera sequence. The TNG map order was identical to one of the two sequence orders in 60% of these discrepant cases.

    View details for Web of Science ID 000166993400040

    View details for PubMedID 11181994

  • Recent advances in carcinoid pathogenesis, diagnosis and management SURGICAL ONCOLOGY-OXFORD Ganim, R. B., NORTON, J. A. 2000; 9 (4): 173-179

    Abstract

    Carcinoid tumors usually present as diagnostic dilemmas due to obscure or nonspecific symptomatology. Advances in molecular biology are allowing the investigation of molecular markers of aggressiveness, better serum tumor markers, as well as the molecular pathogenesis of carcinoid heart disease. Somatostatin receptor scintigraphy (SRS) and whole body positron emission tomography (PET) are providing much improved sensitivity in localization of both primary and metastatic tumors. Long acting depot somatostatin analogues are combining effectiveness and ease of use for medical management of carcinoid syndrome. An additional benefit may be tumor growth suppression.

    View details for Web of Science ID 000170073800002

    View details for PubMedID 11476988

  • Multiple endocrine neoplasia type 2B - genetic basis and clinical expression SURGICAL ONCOLOGY-OXFORD Lee, N. C., Norton, J. A. 2000; 9 (3): 111-118

    Abstract

    Multiple endocrine neoplasia (MEN) type 2B is a heritable endocrine disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, multiple mucosal neuromas, and a marfanoid habitus. Intestinal ganglioneuromatosis, corneal nerve thickening and skeletal abnormalities are also often present. The disease is inherited in an autosomal dominant fashion and is caused by a single mutation in the RET proto-oncogene, with a methionine to threonine substitution at codon 918. The MTC in MEN 2B presents at an earlier age and tends to be more aggressive than the MTC in MEN 2A. It is multicentric and bilateral and occurs as young as age 3, with early lymph node metastases. Pheochromocytoma is also often bilateral but is rarely malignant. If pheochromocytoma is detected, adrenalectomy should precede thyroidectomy to avoid intraoperative catecholamine crisis. Patients at risk for MEN 2B should undergo genetic screening in infancy. Total thyroidectomy should be performed on all patients positive for RET mutations even prior to the onset of clinical symptoms.

    View details for Web of Science ID 000168912100003

    View details for PubMedID 11356339

  • Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1 ANNALS OF SURGERY Lairmore, T. C., Chen, V. Y., DeBenedetti, M. K., Gillanders, W. E., NORTON, J. A., Doherty, G. M. 2000; 231 (6): 909-916

    Abstract

    To review the authors' 7-year experience with a surgical approach for pancreatic and duodenal neuroendocrine tumors (NETs) in patients with multiple endocrine neoplasia type 1 (MEN 1) designed to remove all gross tumor with limited complications, preserving pancreatic function.MEN 1 is an autosomal dominant familial neoplasia syndrome characterized by the development of NETs of the duodenum and pancreas. Some tumors are clinically insignificant or follow a benign course, although a subset pursues a malignant, lethal natural history; the risk of surgical management must be appropriate to the disease course.The clinical, biochemical, genetic, and pathologic data were retrospectively reviewed for 21 consecutive MEN 1 patients undergoing pancreatic resection for NETs between 1993 and 1999 at one institution. Age at operation, presenting symptoms, results of preoperative and intraoperative localization studies, major and minor complications, and pathology, including metastases, were analyzed.The surgical approach was selected based on the location and size of the tumors. Five patients required pancreaticoduodenectomy, 11 patients underwent non-Whipple pancreatic resections, and 5 underwent simple enucleation of benign NETs. The incidence of regional lymph node metastases was 33%.Major pancreatic procedures can be performed safely in most patients with MEN 1 and NETs. Because NETs are the most common MEN 1-related cause of death in the authors' kindreds, an aggressive surgical approach, including early intervention before malignant spread and major pancreatic resection where indicated, appears justified.

    View details for Web of Science ID 000087472500031

    View details for PubMedID 10816635

  • Results of heterotopic parathyroid autotransplantation: A 13-year experience SURGERY Feldman, A. L., Sharaf, R. N., SKARULIS, M. C., Bartlett, D. L., Libutti, S. K., Weinstein, L. S., Marx, S. J., NORTON, J. A., FRAKER, D. L., Alexander, H. R. 1999; 126 (6): 1042-1048

    Abstract

    The reported success of heterotopic parathyroid autotransplantation (HPA) in patients with primary hyperparathyroidism varies from 20% to 60%. The purpose of this study was to evaluate our results with HPA to help define its role in this patient group.Between July 1985 and June 1998, 44 patients underwent 51 HPA procedures at our institution. Twenty to 25 fragments of parathyroid tissue measuring 1 to 3 mm3 each were placed into the forearm musculature. HPA results were scored as nonfunctional (requiring calcium and vitamin D), partially functional (normocalcemia on calcium alone), fully functional (normocalcemia without supplementation), or hyperfunctional (hypercalcemia without supplementation).Follow-up data were available for 39 patients who underwent 46 autografts (20 immediate and 26 cryopreserved). With a median follow-up of 35 months, 19 autografts (41%) were nonfunctional; 9 autografts (20%) were partially functional; 15 autografts (33%) were fully functional, and 3 autografts (7%) were hyperfunctional. Full function was observed in 35% of immediate and 31% of delayed autografts.One third of parathyroid autografts develop full function, and an additional one fifth develop partial function. Recurrent hyperparathyroidism is uncommon. No benefit was observed from immediate versus delayed HPA, and the modest success rate of HPA suggests that improvements in technique are warranted.

    View details for Web of Science ID 000084064500016

    View details for PubMedID 10598186

  • Surgery to cure the Zollinger-Ellison syndrome NEW ENGLAND JOURNAL OF MEDICINE NORTON, J. A., FRAKER, D. L., Alexander, H. R., VENZON, D. J., DOPPMAN, J. L., Serrano, J., Goebel, S. U., Peghini, P. L., Roy, P. K., Gibril, F., Jensen, R. T. 1999; 341 (9): 635-644

    Abstract

    The role of surgery in patients with the Zollinger-Ellison syndrome is controversial. To determine the efficacy of surgery in patients with this syndrome, we followed 151 consecutive patients who underwent laparotomy between 1981 and 1998. Of these patients, 123 had sporadic gastrinomas and 28 had multiple endocrine neoplasia type 1 with an imaged tumor of at least 3 cm in diameter. Tumor-localization studies and functional localization studies were performed routinely. All patients underwent surgery according to a similar operative protocol, and all patients who had surgery after 1986 underwent duodenotomy.The 151 patients underwent 180 exploratory operations. The mean (+/-SD) follow-up after the first operation was 8+/-4 years. Gastrinomas were found in 141 of the patients (93 percent), including all of the last 81 patients to undergo surgery. The tumors were located in the duodenum in 74 patients (49 percent) and in the pancreas in 36 patients (24 percent); however, primary tumors were found in lymph nodes in 17 patients (11 percent) and in another location in 13 patients (9 percent). The primary location was unknown in 24 patients (16 percent). Among the patients with sporadic gastrinomas, 34 percent were free of disease at 10 years, as compared with none of the patients with multiple endocrine neoplasia type 1. The overall 10-year survival rate was 94 percent.All patients with the Zollinger-Ellison syndrome who do not have multiple endocrine neoplasia type 1 or metastatic disease should be offered surgical exploration for possible cure.

    View details for Web of Science ID 000082192500002

    View details for PubMedID 10460814

  • Analysis of factors associated with longterm (five or more years) cure in patients undergoing operation for Zollinger-Ellison syndrome SURGERY Alexander, H. R., Bartlett, D. L., VENZON, D. J., Libutti, S. K., DOPPMAN, J. L., FRAKER, D. L., NORTON, J. A., Gibril, F., Jensen, R. T. 1998; 124 (6): 1160-1166

    Abstract

    Only 30% to 40% of patients with Zollinger-Ellison syndrome (ZES) undergoing operation with curative intent have biochemical cures. The purpose of this analysis was to identify perioperative factors associated with long-term (> or = 5 years) biochemical cures.From December 1981 to September 1997, 128 patients with potentially curable ZES underwent 152 abdominal explorations with resection of all identifiable disease. Of these, 31 outcomes were identified with documented cures at > or = 5 years from operation and were compared with outcomes of 110 patients who were not cured. Univariate and multivariate statistical analyses were performed.The results of a normal immediate postoperative fasting serum gastrin and secretin stimulation test were significantly and independently correlated with 5-year cure (P2 = .005 and .0099, respectively). A diagnosis of multiple endocrine neoplasia type 1 was significantly inversely correlated with cure on univariate analysis (P2 = .027). Gender, age, duration of symptoms, results of diagnostic tests, or results of imaging studies did not correlate with outcome.All patients with sporadic potentially curable ZES should undergo exploration because outcome is not associated with preoperative tests. Only 5% of patients with ZES and multiple endocrine neoplasia type 1 were cured at 5 years. A normal fasting serum gastrin or secretin stimulation value value immediately postoperatively provides important prognostic information.

    View details for Web of Science ID 000077388700060

    View details for PubMedID 9854598

  • Operative management of islet-cell tumors arising in the head of the pancreas SURGERY Park, B. J., Alexander, H. R., Libutti, S. K., Huang, J., Royalty, D., SKARULIS, M. C., Jensen, R. T., GORDEN, P., DOPPMAN, J. L., Shawker, T. H., FRAKER, D. L., NORTON, J. A., Bartlett, D. L. 1998; 124 (6): 1056-1061

    Abstract

    Pancreatic islet cell tumors (ICTs) can be treated by enucleation or pancreatic resection. We reviewed our experience with ICTs in the head of the pancreas to define indications for enucleation versus pancreaticoduodenectomy.Between January 1982 and December 1997, 48 patients underwent surgical resection for presumed ICTs of the pancreatic head. Of these, 18 were found on pathologic examination to be disease in a lymph node. Thirty patients had 32 true pancreatic head ICTs. We reviewed the operative results and postoperative courses in these patients.Mean diameter of the ICTs was 15 mm. Twenty-seven patients (90%) underwent successful enucleations. Three patients failed enucleation and underwent pancreaticoduodenectomy. There was no operative mortality. The median time to regular diet was 7 days. The median time to removal of all drains was 22 days. The most common complication was pancreatic fistula (15%). No patient required reoperation for treatment of a fistula.Most ICTs of the pancreatic head can be removed with enucleation, preserving pancreatic tissue and avoiding the morbidity of pancreaticoduodenectomy. The primary indication for pancreaticoduodenectomy is not the size of the lesion but its proximity to the pancreatic duct.

    View details for Web of Science ID 000077388700029

    View details for PubMedID 9854583

  • Surgical treatment of localized gastrinoma within the liver: A prospective study SURGERY NORTON, J. A., Doherty, G. M., FRAKER, D. L., Alexander, R., DOPPMAN, J. L., VENZON, D. J., Gibril, F., Jensen, R. T. 1998; 124 (6): 1145-1152

    Abstract

    Studies demonstrate that liver metastases of gastrinoma significantly reduce survival.Since 1982 we have prospectively studied 213 patients with Zollinger-Ellison syndrome. For this report the results of surgery for localized liver gastrinoma were analyzed.Zollinger-Ellison syndrome was diagnosed biochemically in all patients and acid output was controlled with medications. Imaging studies demonstrated liver gastrinoma in 69 patients (32%). Fifty-two had diffuse unresectable disease, whereas 17 (10%) had localized disease. All patients with localized liver gastrinoma and 2 patients with diffuse disease who needed surgery are the subject of this report. Major hepatic lobectomy was performed in 10 patients and wedge resections in 9. Three patients had apparent liver primary gastrinomas and 16 had metastatic disease. Seventeen of 19 patients were able to have all identifiable gastrinoma resected. Extrahepatic tumor was also removed at the same procedure. Extirpation of liver gastrinoma required hepatic lobectomy in 10 patients and wedge resections in the others. Five-year survival was 85%. Five of 17 completely resected patients (29%) remained disease free.Resectable localized liver gastrinoma is rare. Primary liver gastrinomas can occur. Surgical resection of localized liver gastrinoma provides a cure rate similar to that of extrahepatic gastrinoma and an excellent long-term survival.

    View details for Web of Science ID 000077388700056

    View details for PubMedID 9854596

  • Prospective study of somatostatin receptor scintigraphy and its effect on operative outcome in patients with Zolinger-Ellison syndrome ANNALS OF SURGERY Alexander, H. R., FRAKER, D. L., NORTON, J. A., Bartlett, D. L., Tio, L., Benjamin, S. B., DOPPMAN, J. L., Goebel, S. U., Serrano, J., Gibril, F., Jensen, R. T. 1998; 228 (2): 228-238

    Abstract

    To determine the relative abilities of somatostatin receptor scintigraphy (SRS) and conventional imaging studies (computed tomography, magnetic resonance imaging, ultrasound, angiography) to localize gastrinomas before surgery in patients with Zollinger-Ellison syndrome (ZES) subsequently found at surgery, and to determine the effect of SRS on the disease-free rate.Recent studies demonstrate that SRS is the most sensitive imaging modality for localizing neuroendocrine tumors such as gastrinomas. Because of conflicting results in small series, it is unclear in ZES whether SRS will alter the disease-free rate, which gastrinomas are not detected, what factors contribute to failure to detect a gastrinoma, or whether the SRS result should be used to determine operability in patients without hepatic metastases, as recently recommended by some investigators.Thirty-five consecutive patients with ZES undergoing 37 exploratory laparotomies for possible cure were prospectively studied. All had SRS and conventional imaging studies before surgery. Imaging results were determined by an independent investigator depending on surgical findings. All patients underwent an identical surgical protocol (palpation after an extensive Kocher maneuver, ultrasound during surgery, duodenal transillumination, and 3 cm duodenotomy) and postoperative assessment of disease status (fasting gastrin, secretin test imaging within 2 weeks, at 3 to 6 months, and yearly), as used in pre-SRS studies previously.Gastrinomas were detected in all patients at each surgery. Seventy-four gastrinomas were found: 22 duodenal, 8 pancreatic, 3 primaries in other sites, and 41 lymph node metastases. The relative detection order on a per-patient or per-lesion basis was SRS > angiography, magnetic resonance imaging, computed tomography > ultrasound. On a per-lesion basis, SRS had greater sensitivity than all conventional studies combined. SRS missed one third of all lesions found at surgery. SRS detected 30% of gastrinomas < or =1.1 cm, 64% of those 1.1 to 2 cm, and 96% of those >2 cm and missed primarily small duodenal tumors. Tumor size correlated closely with SRS rate of detection. SRS did not increase the disease-free rate immediately after surgery or at 2 years mean follow-up.SRS is the most sensitive preoperative imaging study for extrahepatic gastrinomas in patients with ZES and should replace conventional imaging studies as the preoperative study of choice. Negative results of SRS for localizing extrahepatic gastrinomas should not be used to decide operability, because a surgical procedure will detect 33% more gastrinomas than SRS. SRS does not increase the disease-free rate. In the future, more sensitive methods to detect small gastrinomas, especially in the duodenum and in periduodenal lymph nodes, or more extensive surgery will be needed to improve the postoperative disease-free rate in ZES.

    View details for Web of Science ID 000075297600013

    View details for PubMedID 9712569

  • Lethality of multiple endocrine neoplasia type I WORLD JOURNAL OF SURGERY Doherty, G. M., Olson, J. A., Frisella, M. M., Lairmore, T. C., Wells, S. A., NORTON, J. A. 1998; 22 (6): 581-587

    Abstract

    The lethality of the endocrine tumors associated with multiple endocrine neoplasia type I (MEN-I), particularly the pancreatic islet cell tumors, has been controversial. We evaluated the cause and age of death in MEN-I kindreds. Our database contains 34 distinct kindreds with 1838 members. Reliable death data are available for 103 people (excluding accidents and age < 18 years). We compared survival curves of MEN-I patients who died from causes related to MEN-I with those from MEN-I carriers who died from a nonendocrine cause and unaffected kindred members. We also compared ages of death between affected and unaffected members of MEN-I kindreds. Of 59 MEN-I-affected patients, 27 died directly of MEN-I-specific illness and 32 of non-MEN-I causes. The MEN-I-specific deaths occurred at a younger age (median 47 years) than either MEN-I patients whose death was from some nonendocrine cause (median 60 years, p < 0.02) or than all kindred members who did not die of MEN-I disease (median 55 years, p < 0.05). The causes of death of the MEN-I patients included islet cell tumor (n = 12), ulcer disease (n = 6), hypercalcemia/uremia (n = 3), carcinoid tumor (n = 6), and nonendocrine malignancies (n = 9). There was no difference in survival between MEN-I carriers and unaffected kindred members. Of our MEN-I patients, 46% died from causes related to their endocrine tumors after a median age of 47 years, which was younger than family members who did not die from these tumors. Pancreatic islet cell tumors were the most common cause of death of MEN-I patients. Management of kindreds with MEN-I should include an aggressive screening program with early therapeutic intervention when a tumor is identified.

    View details for Web of Science ID 000073528400013

    View details for PubMedID 9597932

  • A prospective analysis of the frequency, location, and curability of ectopic (nonpancreaticoduodenal, nonnodal) gastrinoma SURGERY Wu, P. C., Alexander, H. R., Bartlett, D. L., DOPPMAN, J. L., FRAKER, D. L., NORTON, J. A., Gibril, F., Fogt, F., Jensen, R. T. 1997; 122 (6): 1176-1182

    Abstract

    Extrapancreatic, extraduodenal and extralymphatic (ectopic) gastrinomas have been reported only rarely. The frequency, locations, and surgical outcome of these lesions are unknown.From 1982 to 1997, 215 patients with Zollinger-Ellison syndrome were evaluated prospectively at the National Institutes of Health and 142 patients (66%) underwent standardized surgical exploration and resection. Eight patients (5.6%) (six men and two women; mean age, 41 years) had primary gastrinoma located in ectopic sites. Long-term follow-up was derived from a prospective database.Ectopic gastrinoma tissue was identified and resected in the liver (three patients), common bile duct (one patient), jejunum (one patient), omentum (one patient), pylorus (one patient), and ovary (one patient). Seven patients (88%) were cured biochemically after resection and five patients (63%) have sustained cures, with a mean follow-up of 7.5 years (range, 0.4 to 11.7 years). One patient with a jejunal primary gastrinoma had a biochemical recurrence at 2 years, and another with a primary hepatic gastrinoma had a recurrence 6 years after resection. A patient with a pyloric primary gastrinoma was not cured.Extraduodenal, extrapancreatic, and extranodal gastrinomas are encountered in 5.6% of patients who undergo exploration with curative intent. If no gastrinoma is found in the usual locations, other ectopic sites should be examined carefully. Resection of these primary ectopic tumors can lead to durable biochemical cures.

    View details for Web of Science ID 000071089200049

    View details for PubMedID 9426435

  • Pancreatic polypeptide is a useful plasma marker for radiographically evident pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1 SURGERY Mutch, M. G., Frisella, M. M., DeBenedetti, M. K., Doherty, G. M., NORTON, J. A., Wells, S. A., Lairmore, T. C. 1997; 122 (6): 1012-1019

    Abstract

    The usefulness of human pancreatic polypeptide (hPP) as a plasma marker for islet cell neoplasms is controversial. We sought to determine the relation between fasting plasma hPP levels and radiographically detectable pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1 (MEN 1).Fasting plasma hPP levels were measured prospectively in 202 individuals from 31 independent kindreds with MEN 1. Plasma levels greater than 3.0 times the normal age-specific values were defined as elevated. Patients with elevated plasma hPP levels were evaluated with computed tomographic scanning and magnetic resonance imaging, octreotide scanning, or selective angiography.Twenty-two patients had elevated fasting plasma hPP levels, and 20 of these patients were evaluated radiographically. Pancreatic lesions were detected in 19 patients. A group of eight patients with normal basal fasting plasma hPP levels were evaluated with computed tomography, magnetic resonance imaging, octreotide scanning, or selective angiography based on clinical presentation. One patient in this group had an imaging study that was positive for a pancreatic lesion.The presence of a markedly elevated fasting plasma hPP level in patients with MEN 1 is 95% sensitive and 88% specific for the presence of radiographically detectable pancreatic islet cell tumors.

    View details for Web of Science ID 000071089200008

    View details for PubMedID 9426414

  • Heterotopic autotransplantation of parathyroid tissue in children undergoing total thyroidectomy JOURNAL OF PEDIATRIC SURGERY Skinner, M. A., NORTON, J. A., Moley, J. F., DeBenedetti, M. K., Wells, S. A. 1997; 32 (3): 510-513

    Abstract

    The purpose of this study was to examine the efficacy of parathyroid autotransplantation in children undergoing total thyroidectomy.We have prospectively evaluated 32 cases of total thyroidectomy in children. The ages ranged from 1 year to 15.7 years, and the mean was 8.9 years. In 31 cases, the indication for surgery was a diagnosis of MEN2A or 2B based on direct DNA testing. One child had suspected sporadic medullary thyroid carcinoma. All of the patients underwent heterotopic autotransplantation of parathyroid gland tissue. In 26 cases, the parathyroid tissue was placed in the nondominant forearm, while in 6 children it was autotransplanted into the sternocleidomastoid muscle.In 31 of 32 children (97%), the serum calcium level transiently decreased in the immediate postoperative period. All of the patients were placed on oral calcium carbonate and vitamin D supplementation, and the serum calcium levels became normal within several days. The supplemental medications were then weaned as tolerated. Within 3 months of their procedure, 30 patients (94%) had adequate parathyroid tissue engraftment, and the calcium and vitamin D medications were discontinued. One child required 9 months of calcium and vitamin D medications before she could be weaned from the medications. One child has been treated more recently, and is currently being weaned from supplemental calcium and vitamin D. Serum PTH levels in 22 patients who had placement of the tissue into their forearms were measured, and in each there was increased PTH in the grafted arm compared with the nongrafted arm. In five children who had parathyroid tissue grafted into the sternocleidomastoid muscle, the peripheral serum PTH levels were in the normal range.The heterotopic autotransplantation of resected parathyroid tissue is safe and effective in preventing permanent hypoparathyroidism.

    View details for Web of Science ID A1997WP14100033

    View details for PubMedID 9094030

  • Advances in molecular genetics AMERICAN JOURNAL OF SURGERY Lairmore, T. C., NORTON, J. A. 1997; 173 (1): 37-41

    Abstract

    The three known mechanisms of cellular transformation and oncogenesis include mutations in proto-oncogenes, inactivation of both copies of a tumor suppressor gene, and defects in DNA mismatch repair genes. Examples of each are included to substantiate the importance of understanding these mechanisms. RET is a proto-oncogene that is fundamental to the pathogenesis, and in the current era, molecular diagnosis of MEN 2 syndromes. TP53 is a tumor suppressor gene that is mutated in individuals with Li-Fraumeni syndrome. CDKN2 is a tumor suppressor gene that is mutated in pancreatic cancers and is associated with a poorer prognosis and the development of melanoma. MSH2 is a mismatch repair gene that is important in the pathogenesis of HNPCC and Muir-Torre syndrome. Altered gene function such as loss of DCC in colon cancers may affect cell adhesion properties and promote metastases. As we begin to better define and understand the mechanisms of neoplasia, we will be able to improve current diagnosis and treatment.

    View details for Web of Science ID A1997WJ12700013

    View details for PubMedID 9046882

  • Is reoperation for gastrinoma excision indicated in Zollinger-Ellison syndrome? SURGERY Jaskowiak, N. T., FRAKER, D. L., Alexander, H. R., NORTON, J. A., DOPPMAN, J. L., Jensen, R. T. 1996; 120 (6): 1055-1062

    Abstract

    Surgical excision of gastrinomas in patients with Zollinger-Ellison syndrome (ZES) decreases the incidence of hepatic metastases, but long-term biochemical cures are achieved in fewer than 30% of cases. A growing number of patients have persistent or recurrent disease after initial operation. The effect of reoperation in these patients has not been previously reported.From December 1982 to August 1995, 120 patients with ZES underwent operation for gastrinoma resection. Seventy-eight patients had recurrent or persistent ZES after operation; 17 patients underwent 18 reoperations. After initial operation all patients underwent yearly functional and imaging studies. If a tumor was unequivocally imaged, reexploration was done.Five patients, all with sporadic disease, were disease free after operation, with a median follow-up of 28 months. Tumor was found in all 18 reoperations and resected in 17. In patients with continuing disease-free intervals, locations of gastrinomas included pancreatic head lymph nodes (three), liver metastasis (one), and pancreatic tail lymph node (one). There were no deaths in the cured group; two patients in the group with persistent disease have died (median follow-up, 34 months).Reoperation for gastrinoma excision resulted in elimination of disease in 30% of patients and should be considered for patients with imageable disease.

    View details for Web of Science ID A1996VW99200046

    View details for PubMedID 8957495

  • Evaluation of somatostatin-receptor scintigraphy for detecting neuroendocrine tumors SURGERY Meko, J. B., Doherty, G. M., Siegel, B. A., NORTON, J. A. 1996; 120 (6): 975-983

    Abstract

    Somatostatin-receptor scintigraphy (SRS) has gained attention as an imaging modality for neuroendocrine tumors (NETs). The purpose of this study was to present one of the first American series evaluating the ability of SRS to detect local and distant disease caused by NETs.Medical records were reviewed from 35 patients who underwent a total of 38 studies using 111In-pentetreotide between 1993 and 1995. Twenty-two patients had islet cell tumors, seven had carcinoid tumors, and six had other NETs.The overall sensitivity of SRS was 74% for detecting local disease (primary tumor +/- regional lymph node metastases) in all NETs, excluding insulinoma, 75% in gastrinoma, 0% in insulinoma, 78% in other islet cell tumors, and 50% in carcinoids. For detecting distant disease, the overall sensitivity of SRS was 67% for all NETs, excluding insulinoma, 100% for gastrinoma, 50% for other islet cell tumors, and 80% for carcinoids. Specificity and positive predictive value were 100% for all tumors. Negative predictive value ranged from 33% to 100%.A positive SRS study strongly predicts the presence of tumor (100% positive predictive value in our study). However, unlike the European reports of very high sensitivity (80% to 88%), we found that SRS had a lower sensitivity (67% for all NETs excluding insulinoma and 71% for noninsulinoma gastroenteropancreatic NETs). Thus negative SRS in patients with NETs must be viewed cautiously, because the false-negative rate is high, and this limits the use of this method in the most difficult patients.

    View details for Web of Science ID A1996VW99200022

    View details for PubMedID 8957483

  • Expression of secreted platelet-derived growth factor-B by recombinant nonreplicating and noncytopathic vaccinia virus ANNALS OF SURGERY NORTON, J. A., Peplinski, G. R., Tsung, K. 1996; 224 (4): 555-560

    Abstract

    The purpose of this study was to develop a noncytopathic vector for transient delivery of biologically active platelet-derived growth factor (PDGF) to wounds.Topical application of the protein PDGF-B has improved wound healing in experimental studies of healing-impaired wounds. However, use of PDGF-B has been limited by availability of recombinant protein, short half-life, and inability to reliably apply to the wounded area. One approach to supply local PDGF-B is through transient gene transfer and expression.Treatment of vaccinia virus with psoralen and long-wave ultraviolet irradiation makes it noncytopathic and nonreplicative. The authors inserted various transgenes encoding different forms of PDGF into recombinant vaccinia virus at the hemaglutinin locus by homologous recombination. Because the PDGF-B expressed from full length cDNA is not secreted because of the membrane retention sequence at the C-terminal end of the polypeptide, the authors inserted a 3'-truncated form of human PDGF-B cDNA in recombinant vaccinia virus to achieve secretion. To avoid interference in bioassays by a virally encoded epidermal growth factor homologue called vaccinia growth factor (VGF) in wild type vaccinia virus (CR-19), we used a VGF-negative strain to express PDGF-B (vSC20PDGF-B). Biologic activity of PDGF was tested by measuring proliferation of a 3T3 fibroblast cell line.Supernatant from CR-19-infected cells (VGF+) and from truncated vSC20PDGF infected cells caused mild and marked proliferation of 3T3 cells, respectively, whereas supernatant from full-length vSC20PDGF virally infected cells did not. Furthermore, in vitro infection of a confluent 3T3 monolayer with noncytopathic and nonreplicative vaccinia encoding either VGF or truncated PDGF also caused similar proliferation.These results provide important preliminary evidence for the ability to treat nonhealing wounds with nonreplicating and noncytopathic recombinant vaccinia viruses encoding cytokine growth factors.

    View details for Web of Science ID A1996VL76000080

    View details for PubMedID 8857859

  • A prospective trial evaluating a standard approach to reoperation for missed parathyroid adenoma ANNALS OF SURGERY Jaskowiak, N., NORTON, J. A., Alexander, H. R., DOPPMAN, J. L., Shawker, T., Skarulis, M., Marx, S., Spiegel, A., FRAKER, D. L. 1996; 224 (3): 308-320

    Abstract

    The authors evaluate the results of preoperative imaging protocols and surgical re-exploration in a series of patients with missed parathyroid adenomas after failed procedures for primary hyperparathyroidism.The success rate is lower and the complication rate is increased in patients undergoing reoperation for primary hyperparathyroidism compared with initial procedures. Scarring and distortion of tissue planes plus the potential for ectopic gland location leads to this worsened outcome.Two hundred eighty-eight consecutive patients with persistent/recurrent hyperparathyroidism were treated at a single institution after a failed procedure or procedures at outside institutions. Two hundred twenty-two of these patients (77%) were believed to have a missed single adenoma, and these patients underwent 228 operations and 227 preoperative work-ups. Preoperative evaluation consisted of a combination of four noninvasive imaging studies--neck ultrasound, nuclear medicine scan, neck and mediastinal computed tomography scan, and neck and mediastinal magnetic resonance imaging. Based on the noninvasive testing alone, 27% patients underwent surgery whereas the other patients underwent invasive studies, including selective angiography (58%), selective venous sampling for parathyroid hormone (43%), or percutaneous aspiration of suspicious lesions (15%).Abnormal parathyroid adenomas were found in 209 of 222 initial procedures and 6 of 6 second procedures, with an overall success rate in terms of resolution of hypercalcemia in 97% (215/222) of patients. The single most common site of missed adenoma glands was in the tracheal-esophageal groove in the posterior superior mediastinum (27%). The most common ectopic sites for parathyroid adenomas are thymus (17%), intrathyroidal (10%), undescended glands (8.6%), carotid sheath (3.6%), and the retroesophageal space (3.2%). The most sensitive and specific noninvasive imaging test is the sestamibi subtraction scan, with 67% true-positive and no false-positive results. The rate of true-positive and false-positive results for ultrasound, computed tomography, magnetic resonance imaging, and technetium thallium scans were 48%/21%, 52%/16%, 48%/14% and 42%/8%, respectively. The incidence of injury to the recurrent laryngeal nerve was 1.3%.A single missed parathyroid adenoma is the most common cause for a failed initial parathyroid operation. Appropriate use of preoperative imaging tests and knowledge of the potential location or parathyroid adenomas can lead to very high cure rates with minimal morbidity.

    View details for Web of Science ID A1996VG49400012

    View details for PubMedID 8813259

  • Cytokine production and antitumor effect of a nonreplicating, noncytopathic recombinant vaccinia virus expressing interleukin-12 SURGERY Meko, J. B., Tsung, K., NORTON, J. A. 1996; 120 (2): 274-283

    Abstract

    Cancer gene therapy with interleukin-12 (IL-12) has generated much interest because of the potent antitumor effects of this cytokine. The purpose of this study was to construct a nonreplicating, noncytopathic recombinant vaccinia virus (irecVV) encoding murine IL-12 (ivKT0327mIL-12) and to assess its biologic activity and antitumor effects.ivKT0327mIL-12 was constructed by inserting the genes encoding mIL-12 into the VV genome by homologous recombination. Psoralen and long-wave ultraviolet light were used to render the virus incapable of replication or cell lysis. Cytokine production was assessed by infecting tumor cell lines and measuring mIL-12 in the culture supernatants by using a bioassay. C57BL/6 mice were injected subcutaneously in a randomized, blinded fashion with 5 x 10(5) MCA 101 fibrosarcoma cells or 5 x 10(5) PAN 02 pancreatic tumor cells infected in vitro with either ivKT0327mIL-12 or ivKT033, a control irecVV containing no cytokine genes. Emergence of tumor and tumor size were measured.Tumor cells infected with ivKT0327mIL-12 produced large amounts of biologically active mIL-12 (up to 793 ng/10(6) cells/24 hr) but continued to proliferate in vitro with no cytopathic effect. Mice injected with MCA 101 infected with ivKT0327mIL-12 had significantly delayed tumor emergence (p < 0.03) and decreased tumor size (p < 0.003) compared with mice injected with ivKT033-infected MCA 101. Tumor growth was also significantly smaller in a similar experiment with PAN 02 (p < 0.01).Tumor cells infected with irecVV encoding mIL-12 express high levels of biologically active mIL-12 in vitro and exhibit delayed tumor establishment, significant tumor growth inhibition, or both, in vivo.

    View details for Web of Science ID A1996VK88600021

    View details for PubMedID 8751593

  • Laparoscopic adrenalectomy compared to open adrenalectomy for benign adrenal neoplasms JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Brunt, L. R., Doherty, G. M., NORTON, J. A., Soper, N. J., Quasebarth, M. A., Moley, J. F. 1996; 183 (1): 1-10

    Abstract

    Laparoscopic adrenalectomy has recently been used for removing a variety of adrenal neoplasms. The purpose of the present study was to compare results and outcomes in patients who underwent either laparoscopic or open adrenalectomy at our institution from 1988 to the present.The records of 66 consecutive patients with benign adrenal neoplasms who underwent adrenalectomy from 1988 through 1995 were retrospectively reviewed. Patients were divided into three groups based on the operative approach: group I (n = 25), open anterior transabdominal approach; group II (n = 17), open posterior retroperitoneal approach; and group III (n = 24), laparoscopic transabdominal flank approach. Various parameters were compared and statistical analyses were performed.The three groups were similar in age, gender, American Society of Anesthesiologists class, and distribution of unilateral compared with bilateral adrenalectomy. Mean tumor size was slightly larger in group I (3.4 +/- 1.4 cm) than in group II (2.4 +/- 1.4 cm) or group III (2.7 +/- 1.4 cm) (p = NS). Mean operative times for unilateral adrenalectomy were 142 +/- 38 minutes in group I, 136 +/- 34 minutes in group II, and 183 +/- 35 minutes in group III (p < 0.001, groups I and II compared with group III). For bilateral adrenalectomy, mean operative times were 205 +/- 71 minutes (group I), 328 +/- 11 minutes (group II), and 422 +/- 77 minutes (group III). Patients who underwent laparoscopic adrenalectomy had significantly less operative blood loss (mean, 104 mL compared to 408 mL in group I and 366 mL in group II, p < 0.001) and a lower incidence of perioperative blood transfusion. Laparoscopic adrenalectomy was also associated with significantly reduced parenteral pain medication requirements (p < or = 0.001) and more rapid resumption of a regular diet (p < or = 0.01) compared to open adrenalectomy. Postoperative length of stay was significantly longer in group I (8.7 +/- 4.5 days) and in group II (6.2 +/- 3.9 days) after open adrenalectomy than after laparoscopic adrenalectomy (3.2 +/- 0.9 days) (p < 0.01). Total hospital charges were similar for groups II and III but somewhat higher for group I. Patients were able to resume 100 percent activity an average of 10.6 +/- 4.9 days after laparoscopic adrenalectomy and returned to work a mean of 16.0 +/- 6.1 days postoperatively.Laparoscopic adrenalectomy is a safe and effective procedure and has several advantages over open adrenalectomy. Laparoscopic adrenalectomy should become the preferred operative approach for the treatment of patients with small, benign adrenal neoplasms.

    View details for Web of Science ID A1996UV69700001

    View details for PubMedID 8673301

  • Mammographically detected breast cancer - Benefits of stereotactic core versus wire localization biopsy ANNALS OF SURGERY Yim, J. H., Barton, P., Weber, B., Radford, D., Levy, J., Monsees, B., Flanagan, F., NORTON, J. A., Doherty, G. M. 1996; 223 (6): 688-697

    Abstract

    The authors evaluated the differences between stereotactic core needle biopsy (SCNBx) and needle localization surgical biopsy (NLBx) in cost and treatment course for patients with mammographically detected breast cancer.Stereotactic core needle breast biopsy is a reproducible and reliable alternative to surgical biopsy for histologic diagnosis of mammographic lesions.Records from 52 consecutive patients with invasive breast cancer diagnosed by SCNBx (n = 21) or NLBx (n = 31) over 2 years were reviewed. Episode-of-care costs were extracted from the Barnes Hospital billing system database.At the time of excision, surgical margins were statistically more frequently positive in patients treated with NLBx (55%) than patients treated with SCNBx (0%, p < 0.0001). Furthermore, patients in the NLBx group undergoing breast conservation surgery required re-excision more frequently (74%) than those in the SCNBx group (0%, p = 0.001). There were no complications in either group after the diagnostic procedure. All SCNBx results were correct in the diagnosis of invasive breast cancer. The median cost of SCNBx was approximately $1000 less than the median cost of NLBx. This cost difference was carried through the definitive procedure, whether it was breast conservation or mastectomy.This study shows the advantage of SCNBx to diagnose breast cancer and definitive operative care at a single procedure. The preoperative diagnosis of breast cancer eliminated positive operative margins and procedures to re-excise breast tissue. The use of SCNBx also saved approximately $1000 per patient compared with the use of NLBx. Our data suggest that SCNBx is the diagnostic procedure of choice for mammographically detected cancers.

    View details for Web of Science ID A1996UQ46900013

    View details for PubMedID 8645042

  • Role of endogenous interferon gamma in murine tumor growth and tumor necrosis factor alpha antitumor efficacy ANNALS OF SURGICAL ONCOLOGY Doherty, G. M., Alexander, H. R., MERINO, M. J., VENZON, D. J., NORTON, J. A. 1996; 3 (2): 198-203

    Abstract

    The anticancer role of tumor necrosis factor-alpha (TNF-alpha) has been limited by toxicity. These experiments evaluate blocking endogenous interferon-gamma (IFN-gamma) activity to abrogate TNF-alpha toxicity.C57B1/6 mice bearing MCA 105 tumor were treated with TNF-alpha and anti-IFN-gamma antibody (Ab) to evaluate the effect on the acute lethality of TNF-alpha and their efficacy as evaluated by tumor growth rate, tumor histology, and survival.Anti-IFN-gamma Ab decreased TNF-alpha lethality. Anti-IFN-gamma Ab alone increased tumor growth significantly more than did nonimmune IgG (p2 < 0.0001). Tumor-bearing mice that received nonimmune IgG and TNF-alpha had slower tumor growth (p2 < 0.02) and a trend toward improved survival (p = 0.07) compared with saline-treated controls. Anti-IFN-gamma Ab abrogated the antitumor effect of TNF-alpha, prevented acute tumor necrosis histologically, and resulted in tumor growth rate and host survival similar to that of controls. The findings in mice that received anti-IFN-gamma Ab and high-dose TNF-alpha were comparable with those in mice that received a lower, equitoxic dose of TNF-alpha alone.Blocking endogenous IFN-gamma accelerates tumor growth in this model and partially abrogates the toxic and antitumor activity of exogenous TNF-alpha equally. This suggests that blocking endogenous IFN-gamma activity is not a useful strategy for limiting TNF-alpha treatment toxicity.

    View details for Web of Science ID A1996TX81500015

    View details for PubMedID 8646522

  • Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B JOURNAL OF PEDIATRIC SURGERY Skinner, M. A., DeBenedetti, M. K., Moley, J. F., NORTON, J. A., Wells, S. A. 1996; 31 (1): 177-182

    Abstract

    Recently it has become possible to identify persons who have multiple endocrine neoplasia (MEN) syndrome types 2A and 2B based on the presence of missense mutations in the RET protooncogene. Kindred members who have inherited these syndromes can be identified before clinical or biochemical evidence of medullary thyroid carcinoma (MTC) develops, the malignancy that occurs in all affected patients. It is not known whether prophylactic removal of the thyroid gland early in childhood, based on a positive genetic test result, has a better clinical outcome than that associated with thyroidectomy after MTC is diagnosed clinically or biochemically. The authors' goal was to determine the long-term outcome for patients with MEN 2A and 2B who had thyroidectomy for MTC during childhood. These results were compared with those of patients who had prophylactic removal of the thyroid gland after the genetic diagnosis of MEN 2A was established. The hospital records of 49 children with MEN 2A or 2B were reviewed. Each patient had thyroidectomy for MTC before 16 years of age. The mean age at the time of operation was 10 years, and the mean follow-up period for those who had surgery before the availability of direct DNA genetic testing was 9.8 years. The indications for surgery included an elevated basal or stimulated plasma calcitonin level, a positive genetic test result, a thyroid mass, family history of MTC, or a phenotype diagnostic of MEN 2B. All children for whom the diagnosis of MEN 2A was established by direct genetic testing had thyroidectomy within the last 2 years. Of the 11 patients with MEN 2B who underwent thyroidectomy during childhood, 10 had MTC, and only 3 (27%) remain free of disease after the mean follow-up period of 11 years. One patient died, and seven are alive with persistent MTC. Among the 24 patients with MEN 2A who had their thyroid glands removed because of a family history of MTC or because of biochemical evidence of the disease, 5 (21%) have persistent or recurrent MTC after the mean follow-up period of 9.3 years. In four of these, the MTC was confined to the thyroid gland at the time of thyroidectomy. Of the 14 children who had thyroidectomy based on direct DNA testing, MTC was present in 11. Only four had elevated levels of stimulated plasma calcitonin before surgery. None had lymph node metastasis or surgical complications. The authors conclude that a significant number of patients with MEN 2A or 2B who undergo thyroidectomy in childhood for MTC have persistent or recurrent disease long-term. The genetic diagnosis of patients with these syndromes may allow for prophylactic surgery before the development of biochemical or clinical evidence of MTC. This approach is safe, but longer clinical follow-up will be necessary to confirm that MTC has been cured.

    View details for Web of Science ID A1996TR13500034

    View details for PubMedID 8632274

  • PROSPECTIVE-STUDY OF SURGICAL RESECTION OF DUODENAL AND PANCREATIC GASTRINOMAS IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-1 SURGERY MacFarlane, M. P., FRAKER, D. L., Alexander, H. R., NORTON, J. A., Lubensky, I., Jensen, R. T. 1995; 118 (6): 973-980

    Abstract

    The role of surgical resection of gastrinoma in multiple endocrine neoplasia type 1 (MEN 1) is controversial because of low biochemical cure rates, but with adequate duodenal exploration higher cure rates may be possible.We have prospectively evaluated this proposal in ten consecutive patients with MEN 1 and Zollinger-Ellison syndrome who underwent surgical exploration for gastrinoma resection including a detailed evaluation of the duodenum by palpation, intraoperative endoscopy with transillumination, and duodenotomy.Duodenal tumors were present in seven patients. Six of seven patients had metastatic deposits in lymph nodes, and two of seven had synchronous pancreatic tumors. Three patients had a single duodenal tumor, one patient had two tumors, and three patients had more than 20 duodenal tumors. Positive gastrin staining by use of immunohistochemistry was seen in all duodenal tumors. None of these seven patients were biochemically cured. Of three patients with negative duodenal explorations, two had single pancreatic tumors removed and one had only lymph node gastrinoma. No patients were biochemically cured.Not all patients with MEN 1 and Zollinger-Ellison syndrome have duodenal gastrinomas. In the 70% of patients with duodenal tumors, even extensive duodenal exploration with removal of positive lymph nodes does not result in cures because 86% of tumors had metastasized to lymph nodes and 43% of patients had large numbers of tumors.

    View details for Web of Science ID A1995TH94700009

    View details for PubMedID 7491542

  • PLASMA PROINSULIN-LIKE COMPONENT IN INSULINOMA - A 25-YEAR EXPERIENCE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM GORDEN, P., SKARULIS, M. C., Roach, P., Comi, R. J., FRAKER, D. L., NORTON, J. A., Alexander, H. R., DOPPMAN, J. L. 1995; 80 (10): 2884-2887

    View details for Web of Science ID A1995RZ37700010

    View details for PubMedID 7559869

  • LOCALIZATION OF INSULINOMAS TO REGIONS OF THE PANCREAS BY INTRAARTERIAL STIMULATION WITH CALCIUM ANNALS OF INTERNAL MEDICINE DOPPMAN, J. L., Chang, R., FRAKER, D. L., NORTON, J. A., Alexander, H. R., MILLER, D. L., COLLIER, E., SKARULIS, M. C., GORDEN, P. 1995; 123 (4): 269-273

    Abstract

    To determine the sensitivity of calcium injected into pancreatic arteries in localizing insulin-secreting tumors to regions of the pancreas.To stimulate the release of insulin, 25 patients with surgically proven insulinomas (average diameter, 15 mm) had calcium gluconate (0.025 mEq Ca++/kg body weight) injected before surgery into the arteries supplying the pancreatic head (gastroduodenal and superior mesenteric arteries) and the body and tail (splenic artery) of the pancreas.Tertiary referral hospital.Insulin levels were measured in samples taken from the right and left hepatic veins before and 30, 60, and 120 seconds after calcium injection. A twofold increase in insulin level in the sample taken from the right hepatic vein 30 or 60 seconds after injection localized the insulinoma to the segment of the pancreas supplied by the selectively injected artery. Localization done using calcium stimulation was compared with localization done using transcutaneous ultrasonography (n = 22), computed tomography (n = 23), magnetic resonance imaging (n = 21), arteriography (n = 25), and portal venous sampling (n = 9).Calcium stimulation localized 22 of 25 insulinomas (sensitivity, 88% [95% CI, 68% to 97%]) to the correct region of the pancreas. The sensitivities of the other imaging methods were 9% for ultrasonography (CI, 1% to 23%), 17% for computed tomography (CI, 5% to 39%), 43% for magnetic resonance imaging (CI, 22% to 66%), 36% for arteriography (CI, 18% to 57%), and 67% for portal venous sampling (CI, 30% to 93%). Calcium stimulation added only a few minutes to the time needed for pancreatic arteriography and caused no morbid conditions.Intra-arterial calcium stimulation with right hepatic vein sampling for insulin gradients is the most sensitive preoperative test for localizing insulinomas.

    View details for Web of Science ID A1995RN66500004

    View details for PubMedID 7611592

  • IN-VIVO GENE-THERAPY OF A MURINE PANCREAS TUMOR WITH RECOMBINANT VACCINIA VIRUS ENCODING HUMAN INTERLEUKIN-1BETA SURGERY Peplinski, G. R., Tsung, K., Meko, J. B., NORTON, J. A. 1995; 118 (2): 185-191

    Abstract

    Recombinant vaccinia virus (VV) encoding human interleukin-1 beta (vMJ601hIL-1 beta) given intravenously persists in tumor tissue and expresses hIL-1 beta for at least 9 days after treatment and is associated with significant retardation of tumor growth. To document the significance of this approach and to further elucidate the mechanism, this study compares the antitumor effect of vMJ601hIL-1 beta administered either intravenously or intratumorally and intravenous recombinant hIL-1 beta protein.C57BL/6 mice with established subcutaneous pancreatic tumors were randomized to treatment with intravenous or intratumoral vMJ601hIL-1 beta, wild-type VV, saline solution, or intravenous recombinant hIL-1 beta protein in a blinded fashion. Toxicity and tumor size were measured. Data were analyzed with the Kruskal-Wallis and Wilcoxon tests.Treatment with intratumoral vMJ601hIL-1 beta repeatedly resulted in significant reduction in tumor size as compared with saline treated controls (p < 0.001). Tumor growth inhibition was consistently similar after intravenous or intratumoral vMJ601hIL-1 beta administration (p > 0.52). Wild-type VV given intratumorally or intravenously had no antitumor effect versus saline controls (p > 0.30). No significant toxicity or deaths resulted from vMJ601hIL-1 beta treatment. Recombinant hIL-1 beta protein administered intravenously caused severe toxicity (median lethal dose approximately 100 micrograms/kg), and no significant antitumor effect was observed at sublethal doses versus saline controls (p = 0.19).Direct, in vivo hIL-1 beta gene delivery and expression by recombinant VV given intravenously or intratumorally results in significant tumor growth inhibition, which appears to be a consequence of local, intratumoral vaccinia infection and production of hIL-1 beta.

    View details for Web of Science ID A1995RM96500009

    View details for PubMedID 7638732

  • PALLIATIVE OPERATIONS FOR PATIENTS WITH UNRESECTABLE ENDOCRINE NEOPLASIA SURGICAL CLINICS OF NORTH AMERICA Zogakis, T. G., NORTON, J. A. 1995; 75 (3): 525-538

    Abstract

    No good randomized studies exist for many types of endocrine tumors to prove that surgery increases the survival of patients with these tumors. However, many case reports and our own experience suggest that it does. Therefore, surgery may be performed to potentially increase the survival of patients with metastatic and localized malignant endocrine tumors. Subsequently, these tumors may still recur locally or distantly. Therefore, surgery is usually a palliative procedure but is occasionally curative. Because endocrine tumors secrete hormonal substances resulting in particular syndromes, debulking surgery may be necessary to control hormonal syndromes. The location of a tumor may cause mass symptoms that can also be relieved by surgery. Thus, many patients with malignant endocrine neoplasia benefit from aggressive surgery. The surgeon must determine the resectability of the tumor as well as the operative morbidity and benefit to the patient before proceeding.

    View details for Web of Science ID A1995QY63500014

    View details for PubMedID 7538230

  • PROLONGATION OF SKIN ALLOGRAFTS BY RECOMBINANT TUMOR-NECROSIS-FACTOR AND INTERLEUKIN-1 ANNALS OF SURGERY Parenteau, G. L., Doherty, G. M., Peplinski, G. R., Tsung, K., NORTON, J. A. 1995; 221 (5): 572-578

    Abstract

    The hypothesis is that systemic administration of recombinant tumor necrosis factor-alpha (TNF-alpha) and/or recombinant interleukin-1 alpha (IL-1 alpha) can decrease the rejection of a skin allograft.Tumor necrosis factor and IL-1 are pluripotent cytokine hormones that are central to the host immunologic response to foreign substances. Cytokine effects and toxicity may be reduced by systemic administration of recombinant cytokines. The authors previously have demonstrated that pretreatment with cytokines such as IL-1 or TNF can reduce the lethality of endotoxin (lipopolysaccharide), gram-negative sepsis, cancer cachexia, and oxygen toxicity.Skin grafts from the tails of Balb/c mice were placed on the backs of C57Bl/6 mice. Mice were treated with daily intraperitoneal saline, recombinant m-TNF (Genentech, South San Francisco, CA) or h-IL-1 (Hoffman LaRoche, Nutley, NJ) from postgraft day 1 to postgraft day 28. Tumor necrosis factor and IL-1 high doses were chosen because they protected mice from the lethality of lipopolysaccharide. Animals were examined daily for toxicity and graft rejection. Graft survival was plotted in a Kaplan-Meier plot and analyzed by the log-rank test. Comparison of proportions was done using the Fisher's exact test.Either TNF or IL-1 alone significantly prolonged skin graft survival compared with saline control. Furthermore, the combination of TNF and IL-1 prolonged skin graft survival longer than either cytokine alone. Mice on the highest dose TNF and IL-1 combination did not reject skin grafts during the 28-day treatment period. Significant toxicity was associated with cytokine treatment. Similar significant proportions of death occurred with IL-1 alone and the highest combination of TNF and IL-1.Both TNF and IL-1 can be effective as suppressors of skin allograft rejection in mice.

    View details for Web of Science ID A1995QX81000015

    View details for PubMedID 7748039

  • CONSTRUCTION AND EXPRESSION IN TUMOR-CELLS OF A RECOMBINANT VACCINIA VIRUS ENCODING HUMAN INTERLEUKIN-1-BETA ANNALS OF SURGICAL ONCOLOGY Peplinski, G. R., Tsung, K., Whitman, E. D., Meko, J. B., NORTON, J. A. 1995; 2 (2): 151-159

    Abstract

    Human interleukin-1 beta (hIL-1 beta) injected intratumorally has demonstrated growth inhibition of transplanted subcutaneous tumors in mice, regression of metastatic lesions, resistance to tumor rechallenge, and increased survival. Vaccinia virus (VV) can be genetically engineered to produce cytokines and may be an effective vector for gene therapy of cancer. This study was designed to (a) construct a VV expressing hIL-1 beta, (b) assess tumor cell infection in vitro with this construct, (c) measure hIL-1 beta production, and (d) assess the bioactivity of the secreted cytokine.The hIL-1 beta gene was amplified from a plasmid clone using polymerase chain reaction (PCR) and then cloned into a homologous recombination (HR) and expression vector, which was used to insert the hIL-1 beta gene into the VV genome. Selection of the recombinant VV (vMJ601hIL-1 beta) was based on inactivation of viral TK and expression of beta-galactosidase. vMJ601hIL-1 beta infectivity and cytokine production was assessed by infecting tumor cell lines and analyzing culture supernatants for hIL-1 beta. Bioactivity of the hIL-1 beta produced was demonstrated using an IL-1 dependent T helper cell line.The hIL-1 beta gene was successfully cloned into the VV genome by HR, which was confirmed by PCR. vMJ601hIL-1 beta efficiently infected tumor cells, as shown by increased hIL-1 beta secretion (0 to > 500 ng/ml) and morphologic evidence of viral cytopathic effect. vMJ601hIL-1 beta-infected cells secreted large amounts of hIL-1 beta (mean 772 ng/10(6) cells/24 h). The secreted hIL-1 beta was bioactive (mean bioactivity 6.8 x 10(8) U/mg of hIL-1 beta).(a) hIL-1 beta can be cloned into VV, (b) vMJ601hIL-1 beta retains its infectivity, (c) a large amount of hIL-1 beta is secreted, and (d) the secreted hIL-1 beta is bioactive. Recombinant VV may allow in situ cytokine gene delivery and expression in established tumors.

    View details for Web of Science ID A1995QH86800011

    View details for PubMedID 7728569

  • LOCALIZATION AND OPERATIVE MANAGEMENT OF UNDESCENDED PARATHYROID ADENOMAS IN PATIENTS WITH PERSISTENT PRIMARY HYPERPARATHYROIDISM SURGERY Billingsley, K. G., FRAKER, D. L., DOPPMAN, J. L., NORTON, J. A., Shawker, T. H., SKARULIS, M. C., Marx, S. J., Spiegel, A. M., Alexander, H. R. 1994; 116 (6): 982-990

    Abstract

    Between 5% and 10% of patients who undergo cervical exploration for primary hyperparathyroidism will have persistent or recurrent hyperparathyroidism. Many of these patients have parathyroid tumors in unusual locations. One such site of ectopic parathyroid tissue is an undescended parathyroid adenoma at or superior to the carotid bifurcation. We describe our experience with the preoperative localization and surgical management of undescended parathyroid adenomas.From 1982 to 1993 a consecutive series of 255 patients have undergone localization studies and surgical exploration for persistent or recurrent hyperparathyroidism at the Clinical Center of the National Institutes of Health. Operative strategy was determined by review of the patient's surgical history, disease reports, and data from localizing studies. Patients with an undescended parathyroid adenoma identified before the operation were examined with a direct approach high in the neck. Patients who did not have definitive preoperative localization were explored with the previous transverse cervical incision.Seventeen undescended parathyroid adenomas were identified in 255 patients. Thirteen (76%) of 17 patients had an undescended parathyroid adenoma precisely localized before the operation and were examined via a limited, oblique incision high in the neck anterior to the sternocleidomastoid muscle. In the 13 patients who had undergone accurate localization before the operation, the median operative time was 75 minutes compared with 235 minutes for four patients who did not have an undescended parathyroid adenoma identified before the operation and were examined via a previous transverse cervical incision. All patients were cured of their hyperparathyroidism.Undescended parathyroid adenomas were the cause of failed cervical exploration in 17 (7%) of 255 patients. Accurate preoperative localization of these lesions is possible in most cases with a combination of noninvasive and invasive modalities. Successful preoperative localization can convert a prolonged exploration of the neck and mediastinum into a brief, curative procedure with minimal morbidity.

    View details for Web of Science ID A1994PW09000006

    View details for PubMedID 7985106

  • APPARENT LYMPH-NODE PRIMARY GASTRINOMA SURGERY Arnold, W. S., FRAKER, D. L., Alexander, H. R., Weber, H. C., NORTON, J. A., Jensen, R. T. 1994; 116 (6): 1123-1130

    Abstract

    The existence of lymph node (LN) primary gastrinoma as a cause of Zollinger-Ellison syndrome is controversial. We reviewed our experience with patients in whom gastrinomas were identified and excised only from LNs.From 1982 to 1992, 110 patients with ZES underwent exploration for gastrinoma and 21 (19%) had disease limited to one or more LNs. Standardized exploration included intraoperative ultrasonography, intraoperative endoscopy with transillumination and exploratory duodenotomy in 86%, 67%, and 24% of patients, respectively. Each patient underwent yearly biochemical and radiologic follow-up.Thirteen patients (62%) with a median follow-up period of 5.8 years had an initial biochemical cure, whereas eight patients (38%) with a median follow-up period of 3.6 years had persistent disease. Of the 13 patients whose condition initially returned to normal, four have had biochemical recurrence, with a median time to recurrence of 4.2 years and a median follow-up period of 7.4 years. Nine patients (43%) remain biochemically cured, with a median follow-up period of 5.3 years.Resection of apparent LN primary gastrinoma is warranted, because 43% of those who underwent resection had no evidence of disease, with a median follow-up period of 5.3 years.

    View details for Web of Science ID A1994PW09000027

    View details for PubMedID 7985097

  • COST OF UNSUCCESSFUL SURGERY FOR PRIMARY HYPERPARATHYROIDISM SURGERY Doherty, G. M., Weber, B., NORTON, J. A. 1994; 116 (6): 954-958

    Abstract

    Surgery for primary hyperparathyroidism demands skill and experience. The monetary and personal costs of unsuccessful surgery are investigated here.We reviewed 47 consecutive patients operated on by one surgeon during a period of 16 months, including their clinical data and medical costs of their treatment.All 39 patients without previous operation were normocalcemic after operation, with no recurrent nerve injury nor hypoparathyroidism. Of the eight who had undergone previous operation elsewhere, seven had abnormal glands that should have been resected at the initial operation, and hypoparathyroidism developed in two patients. Total costs of reoperative parathyroid surgery were more than twice the cost of an initial operation (median, $8383 versus $3948, p < 0.001) because of the cost of radiologic studies (median, $3378 versus $43, p < 0.001).(1) An experienced parathyroid surgeon can consistently cure hyperparathyroidism at the initial operation. (2) The majority of patients referred for hyperparathyroidism not cured by previous operation have glands in usual anatomic locations. (3) The cost to the patient of an inadequate initial operation includes the physical effects of remaining hyperparathyroid, additional time off work, potentially invasive localization testing, reoperative surgery with increased risk of complications, and substantial expense. Initial parathyroid surgery should be performed by surgeons experienced and proficient in its practice.

    View details for Web of Science ID A1994PW09000002

    View details for PubMedID 7985102

  • SURGERY IN ZOLLINGER-ELLISON SYNDROME ALTERS THE NATURAL-HISTORY OF GASTRINOMA ANNALS OF SURGERY FRAKER, D. L., NORTON, J. A., Alexander, H. R., VENZON, D. J., Jensen, R. T. 1994; 220 (3): 320-330

    Abstract

    The authors assessed the impact of gastrinoma resection on the subsequent development of hepatic metastases in Zollinger-Ellison syndrome.The symptoms of acid hypersecretion can be controlled medically in Zollinger-Ellison syndrome with high-dose pharmacologic therapy. The current role of surgery is curative excision of the gastrinoma. Because biochemical cure is obtained only in a portion of the patients and the neoplastic disease may be indolent in this syndrome, the ability of surgical resection of gastrinoma to alter or improve the subsequent development of hepatic metastases and mortality has not been defined.One hundred twenty-four patients with the biochemical diagnosis of Zollinger-Ellison syndrome and no hepatic metastases on initial imaging studies were evaluated. Ninety-eight patients underwent surgical exploration for curative gastrinoma resections while 26 patients were managed medically. Long-term follow-up regarding development of hepatic metastases and survival were evaluated.Surgical exploration with gastrinoma excision resulted in a significantly decreased incidence of hepatic metastases 3% (3/98) compared with patients managed medically 23% (6/26) with comparable follow-up (p < 0.003). Two deaths due to metastatic gastrinoma occurred in the nonoperative group compared with no disease-specific deaths in the surgical group (p = 0.085).For the patient with Zollinger-Ellison syndrome without metastatic disease, surgical exploration with attempted curative gastrinoma resection is recommended because it may alter the natural history of this syndrome.

    View details for Web of Science ID A1994PH67000008

    View details for PubMedID 7916560

  • PREDICTIVE DNA TESTING AND PROPHYLACTIC THYROIDECTOMY IN PATIENTS AT RISK FOR MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A ANNALS OF SURGERY Wells, S. A., Chi, D. D., Toshima, K., DEHNER, L. P., Coffin, C. M., DOWTON, B., Ivanovich, J. L., DeBenedetti, M. K., Dilley, W. G., Moley, J. F., NORTON, J. A., DONISKELLER, H. 1994; 220 (3): 237-250

    Abstract

    Missense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy.A polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing.Direct DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal.The PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.

    View details for Web of Science ID A1994PH67000002

    View details for PubMedID 7916559

  • REOPERATION FOR RECURRENT OR PERSISTENT MEDULLARY-THYROID CANCER SURGERY Moley, J. F., Wells, S. A., Dilley, W. G., Tisell, L. E., NORTON, J. A., Grant, C., Pasieka, J. L., Merrell, R. C., Talpos, G. B., Rosen, I. B., Carty, S. E. 1993; 114 (6): 1090-1096

    Abstract

    Initial operations for medullary thyroid cancer (MTC) frequently do not eradicate all disease, as evidenced by persistently elevated levels of stimulated plasma calcitonin.Thirty-two patients with MTC and elevated stimulated plasma calcitonin levels after thyroidectomy were studied between 1990 and 1993. Thirty-five repeat neck explorations and microdissections were performed. Four patients also underwent a median sternotomy and mediastinal dissection.In nine patients (group 1), stimulated plasma calcitonin levels were undetectable after reoperation, whereas in 13 cases (group 2) the calcitonin levels decreased by 40% or more. In 10 cases (group 3) the CT levels did not decrease. Primary tumors that exhibited invasive features (invasion of adjacent structures or extranodal or extracapsular spread) were found more often in patients from group 3 than in patients from groups 1 or 2 (p < 0.05, Fisher's exact test).Reoperation resulted in normalization of calcitonin levels in 28% of patients and a decrease in calcitonin levels by 40% or more in another 42% of patients. The data also suggest that patients whose primary MTC has invaded tissues beyond the thyroid gland or a lymph node capsule are less likely to benefit from repeat operation.

    View details for Web of Science ID A1993MK90000015

    View details for PubMedID 8256212

  • EFFECTIVE REVERSIBILITY OF THE SIGNS AND SYMPTOMS OF HYPERCORTISOLISM BY BILATERAL ADRENALECTOMY SURGERY ZEIGER, M. A., FRAKER, D. L., PASS, H. I., NIEMAN, L. K., Cutler, G. B., Chrousos, G. P., NORTON, J. A., Merrell, R. C., Pasieka, J. L., Kaplan, E., Clark, O. H., Andersen, D., Thompson, N. W. 1993; 114 (6): 1138-1143

    Abstract

    The long-term outcome of bilateral adrenalectomy in the management of patients with Cushing's syndrome has not been previously well studied.We reviewed our long-term results in 34 patients treated with bilateral adrenalectomy between 1983 and the present. Fourteen presented with occult or metastatic ectopic adrenocorticotropic hormone (ACTH) syndrome, 10 with failed treatment of Cushing's disease, five with primary micronodular and four with massive macronodular adrenocortical disease and one with indeterminate cause of Cushing's syndrome.All patients underwent bilateral adrenalectomy. Of 19 patients who required antihypertensive medications before operation, 15 (79%) had significant improvement and were either off all antihypertensive medication or required less medication after operation. Of 7 patients who required medications for diabetes mellitus, after operation 6 (86%) required no medication or changed from injections to oral hypoglycemic agents. Of 9 patients with mood changes or depression, the symptoms of 8 (88%) resolved. Of 29 patients with documented weight gain, 23 (79%) showed marked weight loss. Of 13 hirsute patients, 10 (77%) had resolutions of symptoms. Of 21 patients with complaints of fatigue, the symptoms of 16 (76%) resolved. Of 8 women with amenorrhea, 6 (75%) had resolution of symptoms. Each patient in the primary adrenocortical disease group, except one with residual fatigue, had complete resolution of his or her symptoms. There was no difference in resolution of symptoms between the ectopic ACTH and Cushing's disease groups. Six patients died: in the ectopic ACTH group one died of suicide at 1 month, and four of metastatic tumor at 9, 24, 25, and 48 months, and the patient with macronodular adrenocortical hyperplasia died of a myocardial infarction at 30 months. The remainder of the patients have been followed for a mean of 32 months (3 to 67 months). None of the patients had any evidence of recurrent hypercortisolism.We conclude that bilateral adrenalectomy is a safe, effective, and long-lasting method to ameliorate the devastating signs and symptoms of hypercortisolism in patients with Cushing's syndrome.

    View details for Web of Science ID A1993MK90000023

    View details for PubMedID 8256220

  • PREVALENCE OF PHEOCHROMOCYTOMA AND HYPERPARATHYROIDISM IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-2A - RESULTS OF LONG-TERM FOLLOW-UP SURGERY Howe, J. R., NORTON, J. A., Wells, S. A., Proye, C., Talpos, G. B., Carty, S. E. 1993; 114 (6): 1070-1077

    Abstract

    Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant condition in which virtually all affected kindred members have medullary thyroid carcinoma (MTC). However, the penetrance of pheochromocytoma and hyperparathyroidism in affected kindred members is variable, and the true prevalence of these neoplasms is unclear from previous studies.Members of MEN 2A kindreds with more than 10 years of follow-up screening for MTC, pheochromocytoma, or hyperparathyroidism were studied. The diagnosis of pheochromocytoma was based on histologic examination and hyperparathyroidism on both parathyroid hyperplasia plus preoperative elevation of serum calcium levels.Eighty-six patients operated on for MTC from 12 different MEN 2A kindreds were studied, with a mean follow-up of 12.9 years of screening for pheochromocytoma (79 patients) and 15.0 years for hyperparathyroidism (78 patients). Pheochromocytomas developed in 42% of patients with MTC, with a range of 6% to 100% in different kindreds. The prevalence of hyperparathyroidism was 35%, ranging from 0% to 53% between kindreds. The average age at diagnosis of MTC, pheochromocytoma, and hyperparathyroidism was 29, 37, and 36 years, respectively.We conclude that the penetrance of pheochromocytoma and hyperparathyroidism is variable in different kindreds with MEN 2A but that the overall prevalence of pheochromocytoma approximates 40% and that of hyperparathyroidism 35%.

    View details for Web of Science ID A1993MK90000012

    View details for PubMedID 7903003

  • EXPRESSION OF PAPILLARY THYROID-CARCINOMA IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-2A SURGERY Decker, R. A., Numann, P. J., NORTON, J. A., Moley, J. F., Talpos, G. B. 1993; 114 (6): 1059-1063

    Abstract

    The ret protooncogene (RET), shown to be rearranged in human papillary thyroid cancers (PTC), has been mapped by in situ hybridization to 10q11.2 near the predisposition locus for the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). To date PTC has not been an observed characteristic of MEN 2; however, linkage studies in affected families have shown no meiotic recombinants between the MEN 2A gene and RET suggesting tight linkage between loci. Furthermore, RET appears to be expressed in medullary thyroid carcinoma (MTC) and pheochromocytoma and for these reasons has emerged as a candidate gene for MEN 2.Two patients from a single kindred with MEN 2A (18 affected) are presented in which expression of PTC appeared to cosegregate with the MEN2 gene. In both patients the diagnosis of occult C-cell disease was suspected by an elevation in the basal and pentagastrin-stimulated peak calcitonin levels. Histologic examination of the thyroid gland after operation for MTC revealed tumor nodules consistent with PTC. There was no history of radiation exposure. Characteristics of MEN 2A syndrome in the kindred in addition to MTC and PTC include hyperparathyroidism and Hirschsprung's disease in three and two patients, respectively.Two-point linkage analysis with a new highly polymorphic DNA marker, LGfd01, derived from a cosmid clone mapping to 10q11.2 assigns the MEN 2 predisposition locus in this kindred to chromosome 10q11.2 (0 = 0.00; maximum LOD, 4.78). Recombination between MEN 2A and a polymorphic microsatellite from the RET locus could not be shown among informative meioses.The observed association of MEN 2A and PTC is intriguing and suggests that the variation in expression of the syndrome may be due to the presence of a structural alteration affecting several contiguous genes spanning the putative MEN 2 region.

    View details for Web of Science ID A1993MK90000010

    View details for PubMedID 7903002

  • AN EVALUATION OF HUMAN RECOMBINANT ALPHA-INTERFERON IN PATIENTS WITH METASTATIC GASTRINOMA GASTROENTEROLOGY Pisegna, J. R., SLIMAK, G. G., DOPPMAN, J. L., Strader, D. B., Metz, D. C., Benya, R. V., ORBUCH, M., FISHBEYN, V. A., FRAKER, D. L., NORTON, J. A., Maton, P. N., Jensen, R. T. 1993; 105 (4): 1179-1183

    Abstract

    Metastatic gastrinoma is becoming increasingly recognized in patients with Zollinger-Ellison Syndrome. The mean 5-year survival of these patients is < 20%. Chemotherapeutic regimens are of limited benefit. The aim of this study was to evaluate the use of interferon in these patients because a preliminary report suggested it might be effective.The efficacy and toxicity of interferon was assessed in 13 consecutive Zollinger-Ellison syndrome patients with liver metastases. Patients were treated with human recombinant alpha interferon (5 million IU, subcutaneously [SC]) daily and followed up at 3-month intervals with multiple imaging studies. At each follow-up, toxicity of therapy was assessed and fasting serum gastrin concentrations were obtained.No patient showed a reduction in tumor size at any follow-up. One patient died after 2 months. At 6 months, six patients (46%) had stable tumor size in the liver, although new bone metastases developed in one patient. Three patients showed stable disease for up to 21 months. Changes in serum gastrin correlated with tumor response at 6 months. All patients developed some side effects of therapy. Thirty-one percent required dose reduction, and one patient (8%) had to have interferon therapy interrupted briefly.These results fail to define a therapeutic role for interferon in the treatment of metastatic gastrinoma.

    View details for Web of Science ID A1993LZ24600029

    View details for PubMedID 8405864

  • PARENTERAL CONTROL OF GASTRIC-ACID HYPERSECRETION IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME DIGESTIVE DISEASES AND SCIENCES Vinayek, R., Hahne, W. F., Euler, A. R., NORTON, J. A., Jensen, R. T. 1993; 38 (10): 1857-1865

    Abstract

    Parenteral control of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome is increasingly required; however, existing methods of determining the required dose are cumbersome and not applicable in all centers. A previous study suggested that the required parenteral dose of histamine H2-receptor antagonists correlated with the previous oral dose. In the present study, in 31 patients with Zollinger-Ellison syndrome we evaluated the hypothesis that an effective parenteral histamine H2-receptor antagonist dose could be predicted from the previous oral dose. Twenty-three patients were taking oral ranitidine (mean 1.3 g/day), six patients famotidine (152 mg/day), and two patients cimetidine (1.8 g/day). Each patient was treated with a continuous intravenous infusion of the equivalent dose of ranitidine (mean dose 1 mg/kg/hr with 35% requiring 0.5 mg/kg/hr, 49% 1 mg/kg/hr, 3% 1.5 mg/kg/hr, 10% 2 mg/kg/hr, and 3% 2.5 mg/kg/hr. This dose of ranitidine acutely controlled acid secretion (< 10 meq/hr) in all patients. To evaluate long-term efficacy and safety, 20 patients were maintained on this dose through the peri- and postoperative periods. Mean duration was 7.1 days with 25% treated 3-5 days, 40% 6-8 days, 30% 8-10 days, and 5% > 10 days. The predicted dose continued to control acid secretion in 95% of patients with one patient requiring one dose adjustment. No biochemical, clinical, or hematological toxicity was seen, although ranitidine was stopped in one patient because of skin rash. These results demonstrate that the parenteral dose of ranitidine required to control acid secretion in patients with Zollinger-Ellison syndrome can be predicted from the oral dose.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993MB72700014

    View details for PubMedID 8104773

  • CONTROVERSIES IN SURGICAL THERAPY FOR APUDOMAS SEMINARS IN SURGICAL ONCOLOGY FRAKER, D. L., NORTON, J. A. 1993; 9 (5): 437-442

    Abstract

    Location of gastrinomas by means of portal venous sampling is a technique in which venous blood from various sites in the portal system around the pancreas and duodenum is obtained and assayed for gastrin levels. A gradient of 50% or greater compared to systemic gastrin levels from a given location regionally identifies the site of gastrin overproduction, thereby locating the tumor. The only area in which venous sampling may help, in the authors' opinion, is in the small subset of patients who have occult gastrinoma not imaged with any other modality, in the body or tail of the pancreas that cannot be found with intraoperative ultrasound or palpation. It is considered that a secretin angiogram is equally effective and is a simpler procedure. Similarly, in insulinoma regional location of the tumor by means of a calcium angiogram has eliminated the usefulness of portal venous sampling. Controversial areas of surgical treatment of APUDomas often reflect a balance between the risks and benefits of aggressive surgery, as data to support an aggressive surgical approach to obtain improved survival often do not exist. For example, if patients with occult MTC can undergo cervical reexploration with minimal or no morbidity the potential benefit of removing malignant disease, warrants this approach. Similarly, if patients with MEN-1 can be explored safely with resection of pancreatic and duodenal tumors, then this position can be defended. On the other hand, if a subgroup of patients with MEN-2 and pheochromocytomas can be spared bilateral adrenalectomy without compromising their long-term outcome in terms of disease-free survival, then this conservative approach is warranted.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993LZ54500010

    View details for PubMedID 7902610

  • T-CELL RECOGNITION OF OVARIAN-CANCER SURGERY Peoples, G. E., Schoof, D. D., ANDREWS, J. V., NORTON, J. A., Kim, B., Alexander, H. R., Goedegebuure, P. S., Eberlein, T. J. 1993; 114 (2): 227-234

    Abstract

    The existence of a tumor-specific T-cell immune response to human malignant melanoma has been well documented. In contrast, the existence of tumor-specific cytotoxic T lymphocyte to ovarian cancer remains controversial despite the abundant lymphocytic infiltrates in the malignant ascites and solid tumor of these patients.Tumor-associated lymphocytes (TAL) from the malignant ascites and tumor-infiltrating lymphocytes (TIL) from the solid tumors were isolated from six untreated patients with ovarian cancer. TAL and TIL were grown with initial anti-cluster of differentiation of T cells (CD3), low-dose interleukin-2, and tumor stimulation. T-cell lines were analyzed in functional studies.At 5 weeks, TAL and TIL from five of six patients were > 50% CD8+, and one of six was > 70% CD4+. In all five pairs of CD8 positive cultures, both TAL and TIL exhibited high levels of tumor-specific cytotoxicity for ascite and solid tumor, respectively. T-cell recognition of tumor was mediated through the T-cell receptor-CD3 complex and was human leukocyte antigen class I restricted. TAL and TIL lysed autologous ascitic tumor equally well; however, TAL-mediated tumoricidal activity against autologous solid tumor was consistently and significantly poorer than TIL-mediated killing.Tumor-specific cytotoxic T lymphocytes can be expanded from both TAL and TIL. However, TAL do not kill solid tumor as efficiently as TIL. This suggests the requirement of TIL, or a combination of TIL and TAL, for effective immunotherapy.

    View details for Web of Science ID A1993LQ38400013

    View details for PubMedID 8342128

  • USE OF INTRAOPERATIVE ULTRASONOGRAPHY TO LOCALIZE ISLET-CELL TUMORS WORLD JOURNAL OF SURGERY ZEIGER, M. A., Shawker, T. H., NORTON, J. A. 1993; 17 (4): 448-454

    Abstract

    Because approximately 50% of insulinomas and a similar proportion of gastrinomas are not evident on preoperative imaging studies, precise intraoperative localization of these small tumors is imperative. Recently the use of high-resolution real-time B-mode ultrasonography has dramatically facilitated the operative detection of pancreatic islet cell tumors. The tumor appears sonolucent compared to the more echo-dense surrounding pancreas. This operative technique has been especially useful in patients with insulinoma because these tumors are generally located within the pancreas. In fact, it is so helpful during explorations for insulinoma some suggest that extensive preoperative localization studies are no longer indicated--that the patient can simply be explored with intraoperative ultrasonography (IOUS). It has not been as useful for gastrinomas because of their common extrapancreatic location. Accumulating evidence suggests that IOUS is an effective tool to aid in the operative localization and resection of pancreatic islet cell tumors. Not only can it precisely localize the tumor, it can accurately document the relation of the tumor to other vital pancreatic structures including ducts, veins, and arteries.

    View details for Web of Science ID A1993LP53500006

    View details for PubMedID 8395749

  • INTRAARTERIAL CALCIUM STIMULATION TEST FOR DETECTION OF INSULINOMAS WORLD JOURNAL OF SURGERY DOPPMAN, J. L., MILLER, D. L., Chang, R., GORDEN, P., Eastman, R. C., NORTON, J. A. 1993; 17 (4): 439-443

    Abstract

    Occult insulinomas are adenomas not visualized by routine preoperative imaging studies, including ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), and arteriography. Reliance for detecting occult insulinomas has been placed on portal venous sampling (PVS), a sensitive (> 75%) but invasive procedure that requires considerable experience to enable sampling of small veins about the pancreatic head. For the past 2 years we have attempted to localize insulinomas by stimulating the release of insulin with a selective intraarterial injection of calcium gluconate and sampling for insulin gradients in the hepatic veins. This study replaces PVS by indicating the region of the pancreas within which the tumor lies, although, like PVS, it does not directly visualize the tumor. Our experience in 9 patients with surgically proved insulinomas is reviewed, comparing the results with PVS as well as with US, CT, MRI, and arteriography.

    View details for Web of Science ID A1993LP53500004

    View details for PubMedID 8362527

  • IL-1 RECEPTOR ANTAGONIST (IL-1RA) AUGMENTS IL-2-INDUCED PULMONARY VASCULAR LEAK JOURNAL OF SURGICAL RESEARCH THOM, A. K., FRAKER, D. L., NORTON, J. A. 1993; 54 (4): 336-341

    Abstract

    Interleukin-2 (IL-2) therapy is dose limited by a severe vascular leak with resulting systemic and pulmonary toxicity. Although recognized as a mediator of septic shock and vascular leak, the relative role of IL-1 in IL-2 toxicity is unclear. We evaluated the effect of IL-1 receptor antagonist (IL-1ra) on IL-2 lethality, pulmonary vascular leak, and treatment of pulmonary metastases in a murine model. In vivo induction of mRNA for IL-1 alpha was evaluated in liver by Northern blots after 0, 5, 8, and 11 doses of IL-2 in C3H/HEN mice. The expression index for the IL-1 alpha gene increased from 0.16 to 0.74 after 5 doses of IL-2, and further increased to 1.04 after 11 doses of IL-2. C3H/HEN mice (n = 56) were randomized to receive phosphate-buffered saline (PBS), IL-1ra high dose (HD), or IL-1ra low dose (LD) by continuous subcutaneous infusion via Alzet mini-pumps. The biologic effectiveness of the dose and administration of IL-1ra was determined by the ability to block IL-1-induced IL-6 production in vivo. Mean serum IL-6 levels 3 hr after intraperitoneal IL-1 alpha (10 micrograms/kg) were: PBS, 3730 +/- 526 (mean +/- SEM pg/ml); IL-1ra (LD), 1156 +/- 398; and IL-1ra (HD), 594 +/- 30 (P < 0.01, IL-1ra HD or LD vs PBS). Pulmonary vascular leak was measured by iv I125 albumin after 8 doses of IL-2 (100,000 U ip q 8 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993LM66700013

    View details for PubMedID 8331927

  • INTERLEUKIN-1 RECEPTOR ANTIBODY (IL-1RAB) PROTECTION AND TREATMENT AGAINST LETHAL ENDOTOXEMIA IN MICE JOURNAL OF SURGICAL RESEARCH McNamara, M. J., NORTON, J. A., Nauta, R. J., Alexander, H. R. 1993; 54 (4): 316-321

    Abstract

    Interleukin-1 (IL-1) is a mediator of endotoxin shock and IL-1 receptor blockade has been shown to have therapeutic efficacy against endotoxic shock and sepsis in laboratory models. The current studies were designed to characterize the efficacy of a murine monoclonal IL-1 receptor antibody (IL-1rab) against endotoxin (LPS) lethality and to investigate whether combined anticytokine therapy using the IL-1rab and a highly specific polyclonal rabbit anti-mouse TNF antibody (TNF Ab) could provide additive or synergistic efficacy against LPS lethality in C57B1/6 female mice. A single intraperitoneal (ip) dose of IL-1rab, 0.1 or 0.2 mg, significantly reduced lethality from LPS, 30 to 40 mg/kg ip, compared to nonimmune IgG, 0.1 or 0.2 mg, in control mice (P2 < 0.05). Treatment with IL-1rab was effective when administered from 6 hr before to 1 hr after LPS. After LPS, circulating levels of IL-6 were significantly lower in IL-1rab-treated mice [IL-6 (ng/ml) 2 h after LPS: IgG, 100 +/- 25, IL-1rab, 41 +/- 8; 4 h after LPS: IgG, 46 +/- 13, IL-1rab, 8 +/- 1; P2 < 0.05 and 0.03, respectively]. Northern blot analysis showed that IL-1rab markedly lowered IL-6 gene expression after LPS. Combined treatment with IL-1rab and TNF Ab did not result in any improvement in survival after LPS compared to either agent alone. These results indicate that an IL-1 receptor antibody has therapeutic efficacy against LPS and significantly decreases IL-6 production.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993LM66700009

    View details for PubMedID 8331925

  • THE ROLE OF TUMOR-NECROSIS-FACTOR IN THE TOXICITY AND THE ANTINEOPLASTIC ACTIVITY OF INTERLEUKIN-2 IMMUNOTHERAPY TUMOR NECROSIS FACTOR : MOLECULAR AND CELLULAR BIOLOGY AND CLINICAL RELEVANCE FRAKER, D. L., NORTON, J. A. 1993: 221-225
  • AN 11-YEAR EXPERIENCE WITH ADRENOCORTICAL CARCINOMA SURGERY Pommier, R. F., Brennan, M. F., Grant, C. S., Woltering, E., Newsome, H. H., Norton, J., Hickey, R., Rastad, J. 1992; 112 (6): 963-971
  • SURGICAL STRATEGY IN THE MANAGEMENT OF NON-SMALL-CELL ECTOPIC ADRENOCORTICOTROPIC HORMONE SYNDROME SURGERY ZEIGER, M. A., PASS, H. I., DOPPMAN, J. D., NIEMAN, L. K., Chrousos, G. P., Cutler, G. B., Jensen, R. T., NORTON, J. A., Udelsman, R., Prinz, R., Aun, F., Kinder, B., Thompson, N., Clark, O. 1992; 112 (6): 994-1001

    Abstract

    Non-small cell ectopic adrenocorticotropic hormone (ACTH) syndrome is a rare cause of hypercortisolism that may require surgery for either curative resection or palliative adrenalectomy.We report our surgical experience with 41 patients with ectopic ACTH syndrome and no evidence of small cell lung cancer at initial evaluation.All 41 patients had documented hypercortisolism secondary to ectopic production of ACTH. Based on imaging study results, we determined that 21 patients had localized/resectable disease; eight patients had metastatic disease, and 12 patients had occult disease at examination. Of the 21 patients with localized disease, 16 (76%) were cured of ectopic ACTH by surgery (15 bronchial carcinoid, one pheochromocytoma). Patients with bronchial carcinoid had the greatest probability for cure of ectopic ACTH syndrome, and patients with thoracic primary tumor were more likely to be cured than patients with abdominal primaries. Of the eight patients who had metastatic disease, none were cured of the disease; five patients underwent bilateral adrenalectomy, and three patients were given medical therapy. Only one patient was alive after 5 years. Of the 12 patients who had occult disease, four patients were eventually cured of the disease (three bronchial carcinoid, one thymic carcinoid); one patient died of disease (small cell lung cancer), and seven patients still have occult disease. Nine of 12 patients with occult disease underwent bilateral adrenalectomy for surgical management of hypercortisolism.This study suggests that the most common primary focus of ectopic ACTH production is within the thorax with 25 of 34 (74%) identifiable tumors originating within either the thymus or bronchus. Adrenalectomy offers excellent palliation of hypercortisolism secondary to either occult or metastatic disease. Patients who initially have localized disease usually have bronchial carcinoids and have a high probability of cure with surgical resection (81%).

    View details for Web of Science ID A1992KB29300005

    View details for PubMedID 1333646

  • PROSPECTIVE-STUDY OF THE USE OF INTRAARTERIAL SECRETIN INJECTION AND PORTAL VENOUS SAMPLING TO LOCALIZE DUODENAL GASTRINOMAS SURGERY THOM, A. K., NORTON, J. A., DOPPMAN, J. L., MILLER, D. L., Chang, R., Jensen, R. T., VANHEERDEN, J., Woltering, E., Saxe, A., Thompson, N., Prinz, R. A. 1992; 112 (6): 1002-1009

    Abstract

    Duodenal gastrinomas producing Zollinger-Ellison syndrome (ZES) are rarely imaged on preoperative studies. Measurement of serum gastrin levels by transhepatic portal venous sampling (PVS) or by sampling from hepatic veins after intraarterial secretin injection have been advocated as useful tests to identify these tumors before operation.As part of a prospective study, selective intraarterial secretin injection has been performed in 36 consecutive patients with ZES, PVS has been performed in 30 of these patients, and the results have been compared.Gastrinomas were found at laparotomy in 33 of 36 patients (92%). Duodenal tumors were found in 18 patients (50%). The remaining patients had liver, pancreatic, or nodal disease (n = 15). Thirty-two of 36 patients (89%) had positive results with intraarterial secretin injection study, whereas 18 of 30 (60%) had a positive PVS gradient (p = 0.02, Fisher's exact test). The most common positive gradient with intraarterial secretin injection was found with injections of the gastroduodenal artery, and the most common positive gradient with PVS was found in the inferior pancreaticoduodenal (IPDV) or superior pancreaticoduodenal vein (SPDV). Fourteen of 18 (78%) patients with duodenal gastrinomas had a positive GDA injection, whereas five of 18 (28%) without duodenal tumors had a positive GDA injection (p = 0.006). Five of 16 patients with duodenal gastrinomas had a positive gradient in the IPDV or SPDV, whereas four of 14 without duodenal tumors had a positive gradient in the IPDV or SPDV (not significant).Intraarterial secretin injection is more sensitive than PVS at localizing duodenal gastrinomas and should replace PVS in patients with ZES and occult tumors.

    View details for Web of Science ID A1992KB29300006

    View details for PubMedID 1455303

  • A RANDOMIZED, PROSPECTIVE TRIAL OF POSTOPERATIVE SOMATOSTATIN ANALOG IN PATIENTS WITH NEUROENDOCRINE TUMORS OF THE PANCREAS SURGERY Lange, J. R., STEINBERG, S. M., Doherty, G. M., Langstein, H. N., White, D. E., Shawker, T. H., Eastman, R. C., Jensen, R. T., NORTON, J. A., Andersen, D. K., Proye, C., Rastad, J., PUARTE, B., Clark, O., Weber, C. 1992; 112 (6): 1033-1038
  • PROSPECTIVE-STUDY OF AGGRESSIVE RESECTION OF METASTATIC PANCREATIC ENDOCRINE TUMORS SURGERY Carty, S. E., Jensen, R. T., NORTON, J. A., Ellison, C., Talpos, G., Kaplan, E. L., Modlin, I. 1992; 112 (6): 1024-1032

    Abstract

    Because metastatic pancreatic endocrine tumors (MPET) have a poor prognosis, 17 patients with potentially resectable MPET were prospectively studied to define the efficacy of aggressive resection.Patients underwent resection when the full extent of MPET was deemed operable after imaging studies were obtained. Two patients underwent three reoperations for recurrent tumor.MPET were completely excised in 16 of 20 cases by major resections of liver, viscera, and nodes, with no operative mortality. Survival was 87% at 2 years and 79% at 5 years with mean follow-up of 3.2 years. Median imaging disease-free interval was 1.8 years, and four of 17 patients remain biochemically cured. After aggressive resection patients with MPET limited in extent had higher survival than patients with extensive MPET (p < 0.019). In a nonrandomized cohort of 25 patients with inoperable tumor, survival was 60% at 2 years and 28% at 5 years.In select patients MPET can be resected safely with a favorable outcome; most patients will experience recurrence, but some may be cured. Resection of extensive MPET does not appear to improve survival. Resection of limited MPET should be considered as life-extending and potentially curative therapy.

    View details for Web of Science ID A1992KB29300009

    View details for PubMedID 1455305

  • CYTOKINES AND THEIR ROLE IN THE PATHOPHYSIOLOGY OF CANCER CACHEXIA JOURNAL OF PARENTERAL AND ENTERAL NUTRITION McNamara, M. J., Alexander, H. R., NORTON, J. A. 1992; 16 (6): S50-S55
  • CHOLERA-TOXIN PRETREATMENT PROTECTS AGAINST TUMOR-NECROSIS-FACTOR LETHALITY WITHOUT COMPROMISING TUMOR RESPONSE TO THERAPY ARCHIVES OF SURGERY Block, M. I., Alexander, H. R., NORTON, J. A. 1992; 127 (11): 1330-1334

    Abstract

    Antitumor therapy with tumor necrosis factor is limited by systemic toxic effects. We studied whether cholera toxin, a bacterial exotoxin that adenosine diphosphate-ribosylates the alpha-subunit of Gs proteins, could separate the lethal from the antitumor effects of tumor necrosis factor. A single dose of intravenous cholera toxin protected non-tumor-bearing mice from a lethal dose of Escherichia coli endotoxin administered 6 or 24 hours later. On the basis of these results, tumor-bearing mice were randomized to receive either cholera toxin or saline, followed 6 hours later by either human tumor necrosis factor (400 micrograms/kg) or saline. Tumor-bearing mice pretreated with cholera toxin had (1) reduced treatment-related mortality (0/11 vs 5/11 for saline controls) and (2) tumor regression similar to that of controls. In a separate experiment in tumor-bearing mice, intravenous human tumor necrosis factor treatment induced an increase in serum levels of murine tumor necrosis factor to a peak of 500 pg/mL at 1 hour in saline-pretreated controls, while a similar increase could not be detected in those mice pretreated with cholera toxin. These results suggest that pretreatment with cholera toxin can reduce the endogenous tumor necrosis factor response to administered tumor necrosis factor and separate the lethal from the antitumor effects. Cholera toxin may prove to be a useful tool for investigating the mechanisms underlying the varied effects of tumor necrosis factor.

    View details for Web of Science ID A1992JW88400015

    View details for PubMedID 1444796

  • RECOMBINANT INTERLEUKIN-1 RECEPTOR ANTAGONIST (IL-1RA) - EFFECTIVE THERAPY AGAINST GRAM-NEGATIVE SEPSIS IN RATS SURGERY Alexander, H. R., Doherty, G. M., VENZON, D. J., MERINO, M. J., FRAKER, D. L., NORTON, J. A. 1992; 112 (2): 188-194

    Abstract

    Morbidity and mortality from bacterial sepsis remain high despite aggressive diagnostic and therapeutic intervention. Interleukin-1 has been implicated as mediator of the lethal effects of endotoxemia or bacterial sepsis. The current experiments were designed to evaluate the therapeutic efficacy of a human recombinant interleukin-1 receptor antagonist (IL-1ra) against polymicrobial gram-negative septicemia in rats.Male rats underwent placement of indwelling carotid arterial and superior vena caval catheters followed by cecal ligation and puncture (CLP). After 3 hours rats received either IL-1ra (10 mg/kg intravenous bolus followed by 5 mg/kg/hr) or an equal volume of vehicle intravenously for 24 hours. Heart rate, respirations, mean arterial blood pressure, and temperature were recorded at frequent intervals, and survival was assessed for 30 hours after CLP.There were no differences in vital signs between groups at baseline or before treatment, and all animals appeared ill with huddled posture, piloerection, and hyperventilation. Twenty-four hours after CLP, IL-1ra significantly ameliorated bradycardia (p = 0.01), hypothermia (p = 0.001), and hypotension (p = 0.05), and 30-hour survival was significantly improved (71% vs 20%, p less than 0.05).IL-1ra lessens the acute hemodynamic, hypothermic, and mortal effects of gram-negative sepsis induced by CLP in rats. These data suggest that IL-1 receptor blockade may be an important new treatment strategy against overwhelming bacterial sepsis.

    View details for Web of Science ID A1992JG45100009

    View details for PubMedID 1386478

  • INTERLEUKIN-1-ALPHA PREVENTION OF THE LETHALITY OF ESCHERICHIA-COLI PERITONITIS JOURNAL OF SURGICAL RESEARCH Lange, J. R., Alexander, H. R., MERINO, M. J., Doherty, G. M., NORTON, J. A. 1992; 52 (6): 555-559

    Abstract

    Interleukin-1 (IL-1) is an inflammatory mediator with a variety of described physiologic functions. IL-1 alpha has been shown to confer a survival advantage to experimental animals when administered before a lethal bacterial challenge. The experiments reported here were performed to define the effective pretreatment interval of a single intravenous dose of IL-1 alpha in a murine model of bacterial peritonitis, to examine the differential induction of cytokines in animals with and without IL-1 alpha pretreatment, and to assess differences in histologic evidence of end organ damage. IL-1 alpha (27 micrograms/kg iv) conferred a survival advantage to mice given a lethal challenge of live Escherichia coli (2 x 10(8) CFU/mouse ip) when the pretreatment was given 2 to 24 hr before the bacterial inoculum. Longer pretreatment intervals were not significantly protective. Treatment with IL-1 alpha at 1 hr after bacterial inoculum also did not improve survival. Mice pretreated with IL-1 alpha developed significantly lower peak serum levels of TNF-alpha after E. coli injection than did control mice. Pretreated and control mice had similar peak serum levels of IL-6 after bacterial challenge; however, IL-1 alpha-pretreated mice had a less prolonged elevation of serum levels of IL-6. IL-1 alpha-pretreated animals were protected from the histologic evidence of end organ damage seen in control animals. Thus, in this model of E. coli peritonitis pretreatment with a single intravenous dose of IL-1 alpha confers a significant protective effect when given within a limited time range. Treatment outside this interval has no apparent beneficial effect.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1992JN40500004

    View details for PubMedID 1528030

  • CURATIVE RESECTION IN ZOLLINGER-ELLISON SYNDROME - RESULTS OF A 10-YEAR PROSPECTIVE-STUDY ANNALS OF SURGERY NORTON, J. A., DOPPMAN, J. L., Jensen, R. T. 1992; 215 (1): 8-18

    Abstract

    Since 1980, 73 patients with Zollinger-Ellison syndrome (ZES) without radiographic evidence of liver metastases were studied on a prospective protocol including medical management of gastric acid hypersecretion, extensive radiographic tumor localization, and exploratory surgery to find and resect gastrinoma for potential cure. Each patient had gastric acid hypersecretion effectively controlled with either H2-blockers or omeprazole. Patients were divided prospectively into two groups, with all patients undergoing the same preoperative localization studies and extensive laparotomy. In contrast to group 1 (1980-1986) (36 patients), group 2 (1987-Oct. 1990) (37 patients) also underwent additional procedures (transillumination and duodenotomy) at surgery to find duodenal gastrinomas. Preoperative imaging studies localized tumor in 38 (52%) patients, and portal venous sampling for gastrin determinations was positive in 49 (67%) patients. Gastrinomas were found and resected in 57 (78%) patients. Significantly more gastrinomas (92% of patients) were found in group 2 than in group 1 patients (64%) (p less than 0.01). This increase was due to increased numbers of duodenal gastrinomas in group 2 than in group 1 patients (43% versus 11%; p less than 0.01). The increased ability to find duodenal gastrinomas did not significantly improve the immediate disease-free rate, which was 58% for all patients. Duodenal primary gastrinomas were found to have a significantly greater incidence of metastases (55%) and a significantly shorter disease-free interval (12 months) than pancreatic gastrinomas (22% and 84 months, respectively) suggesting that duodenal gastrinomas may be more malignant and not more frequently curable than pancreatic gastrinomas. Operations were performed with no deaths and 11% morbidity rate. Long-term follow-up showed that 50% of patients initially rendered disease free would develop recurrent disease by 5 years. Survival was excellent for all patients, and none died of malignant spread of the tumor or uncontrolled peptic ulcer disease, with a mean follow-up of 5 years. This finding is in contrast to patients who presented with metastatic disease on imaging studies and had a 20% 5-year survival rate. This study suggests that all patients with localized sporadic ZES can have the gastric acid hypersecretion managed medically, that overall survival of these patients is excellent, most (78%) can have all gastrinoma found and resected, and some (30%) will be cured (long-term disease-free survival).

    View details for Web of Science ID A1992GY75700003

    View details for PubMedID 1531004

  • The use of intraoperative ultrasound during cancer surgery. Important advances in oncology Shawker, T. H., NORTON, J. A., Oldfield, E. H. 1992: 167-187

    View details for PubMedID 1582672

  • RESULTS OF A PROSPECTIVE STRATEGY TO DIAGNOSE, LOCALIZE, AND RESECT INSULINOMAS SURGERY Doherty, G. M., DOPPMAN, J. L., Shawker, T. H., MILLER, D. L., Eastman, R. C., GORDEN, P., NORTON, J. A. 1991; 110 (6): 989-997

    Abstract

    Since 1982, 25 consecutive patients with benign sporadic (non-multiple endocrine neoplasia type I) insulinomas have been studied. Most were referred because either the tumor was not identified at the referring institution or the diagnosis was unclear. Each patient suffered severe neuroglycopenic symptoms for a median of 24 months before diagnosis of insulinoma, and 32% had hypoglycemic seizures. Eighteen patients (72%) had a confirmed weight gain. Each patient underwent a supervised fast until 72 hours or the onset of significant neuroglycopenic symptoms (median duration 16 hours), with serum levels of glucose (median 35 mg/dl; range 24 to 46 mg/dl), insulin (median 21 microU/ml; range 11 to 230 microU/ml), C-peptide (median 2.5 ng/ml; range 1.0 to 7.2 ng/ml), and proinsulin fraction (median 55%; range 14% to 86%) measured at the termination of the fast. Preoperative imaging with ultrasonography, computed tomography, magnetic resonance, and angiography visualized tumor in a minority of patients (26%, 17%, 25%, and 35%, respectively); in 48% of patients one or more imaging study results was positive. Selective portal venous sampling for insulin was the most informative localizing test (77% positive; no false-positive results). Tumor was resected for cure in 24 of 25 patients. Intraoperative ultrasonography identified nonpalpable tumor in seven patients and was crucial to the achievement of this high rate of surgical cure. We conclude that the diagnosis of insulinoma can be made by the results of a supervised fast, portal venous sampling is the most sensitive preoperative test for localizing insulinomas, and intraoperative ultrasonography is essential for intraoperative detection of insulinomas.

    View details for Web of Science ID A1991GU13000010

    View details for PubMedID 1745987

  • LOCATION, INCIDENCE, AND MALIGNANT POTENTIAL OF DUODENAL GASTRINOMAS SURGERY THOM, A. K., NORTON, J. A., Axiotis, C. A., Jensen, R. T. 1991; 110 (6): 1086-1093

    Abstract

    Duodenal gastrinomas are increasingly found at surgery, yet information about their location and characteristics is based on the results of either pooled series or retrospective reviews of small numbers of selected cases. To address these issues we have analyzed the location, incidence, and malignant potential of duodenal gastrinomas in 65 consecutive patients who underwent removal of all tumor as part of a 10-year prospective study to resect gastrinomas in patients with sporadic Zollinger-Ellison syndrome. The primary gastrinoma was located in the duodenum in 24 patients (37%). There were 19 men and five women aged 32 to 69 years (mean 49.4 years), with symptoms for 0.6 to 35 years (mean 7.9 years). Preoperative studies included serum gastrin levels of 114 to 35,798 pg/ml (mean 2060 pg/ml), basal acid output of 7 to 95 mEq/hr (mean 37.6 mEq/hr), and a positive secretin test result in 22 patients. Preoperative imaging studies identified tumor in the duodenal area in 11 patients (46%), but most positive imaging findings were metastatic gastrinoma in lymph nodes, and the primary duodenal tumor itself was identified in only two patients. Portal venous sampling had a localizing gastrin gradient in the inferior or superior pancreaticoduodenal vein in 17 of 23 patients (74%). Each of the 24 patients had a single, small duodenal wall tumor of 2.8 to 10.1 mm diameter (mean 6 mm). Each tumor stained positive for gastrin by immunohistochemistry. Seventeen tumors (71%) were located in the first portion of the duodenum, five (21%) in the second, and two (8%) in the third. Each tumor originated in the submucosa, and 13 (54%) were limited to the submucosa, whereas 11 (46%) were locally invasive, four (16%) extending into the muscularis mucosa and seven (29%) into the muscularis propria. Thirteen patients (54%) had spread to regional lymph nodes, whereas two (8%) had liver metastases. Lymph node metastases were seen with larger duodenal tumors (mean 7.1 vs 5.4 mm; p less than 0.01). The data suggest that a single duodenal wall gastrinoma is a common cause of Zollinger-Ellison syndrome (37%). These small (less than 1 cm) tumors are located in the submucosal layer of the proximal duodenum (92%) and are malignant more often than previously thought (54%).

    View details for Web of Science ID A1991GU13000023

    View details for PubMedID 1745977

  • PRIMARY BILATERAL ADRENOCORTICAL CAUSES OF CUSHINGS-SYNDROME SURGERY ZEIGER, M. A., NIEMAN, L. K., Cutler, G. B., Chrousos, G. P., DOPPMAN, J. L., TRAVIS, W. D., NORTON, J. A. 1991; 110 (6): 1106-1115

    Abstract

    Nontumorous primary adrenal causes of Cushing's syndrome are exceedingly rare. Herein we review our results with seven patients in whom there is biochemical evidence of a primary (adrenocorticotropin independent) bilateral adrenal cause of endogenous hypercortisolism. Each patient had low plasma adrenocorticotropin levels. All patients had elevated 24-hour urinary free cortisol levels and 17-hydroxycorticosteroids that were not suppressed by high-dose dexamethasone. Plasma levels of adrenocorticotropin and cortisol were not elevated by ovine corticotropin-releasing factor. No patient had a gradient between petrosal and peripheral adrenocorticotropin levels. No pituitary tumors were detected by magnetic resonance imaging or computed tomography. Five of six patients who underwent iodocholesterol scanning showed bilateral adrenal activity. Computed tomographic and magnetic resonance imaging of the abdomen demonstrated bilateral small adrenal glands in three patients, an adrenal mass in one patient with Carney's complex, and massively enlarged glands in three patients. Each patient underwent bilateral adrenalectomy and was given glucocorticoid and mineralocorticoid replacement. Pathologic examination of four of these bilateral adrenal specimens revealed primary pigmented micronodular adrenocortical disease, with adrenal gland weights between 2.5 and 13.4 gm (mean 5.2 gm). However, the remaining three patients had primary adrenocorticotropin-independent bilateral macronodular adrenocortical disease with adrenal gland weights between 32 and 81 gm (mean 52 gm). Although each of the patients with primary pigmented micronodular adrenocortical disease was cured by bilateral adrenalectomy through a posterior approach, two of the three patients required an anterior approach. We conclude that Cushing's syndrome can arise through two distinct forms of primary bilateral adrenal cortical disease. Computed tomography is important in evaluation of these patients because the size of the adrenal glands influences the surgical approach.

    View details for Web of Science ID A1991GU13000026

    View details for PubMedID 1745978

  • CT AND MR IMAGING OF MASSIVE MACRONODULAR ADRENOCORTICAL DISEASE - A RARE CAUSE OF AUTONOMOUS PRIMARY ADRENAL HYPERCORTISOLISM JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY DOPPMAN, J. L., NIEMAN, L. K., TRAVIS, W. D., MILLER, D. L., Cutler, G. B., Chrousos, G. P., NORTON, J. A. 1991; 15 (5): 773-779

    Abstract

    We studied four patients with adrenocorticotropic hormone (ACTH)-independent hypercortisolism due to bilateral massive enlargement of the adrenal glands. The combined weight of the adrenal glands ranged from 69 to 149 g and the adrenal cortex was replaced in three of four patients by multiple nodules ranging from microscopic to 4 cm in diameter. One patient had massive diffuse enlargement. All patients had low or undetectable levels of serum ACTH, absence of petrosal sinus to peripheral gradients of ACTH in bilateral samples from the inferior petrosal sinuses before and after stimulation by corticotropin releasing hormone, and absence of an adenoma on MR imaging of the pituitary gland. The marked degree of adrenocortical enlargement and absence of ACTH dependency separates this massive macronodular disease from the more common ACTH-dependent macronodular hyperplasia encountered in older patients with pituitary-dependent Cushing disease. All patients required bilateral adrenalectomy to control hypercortisolism. We present the spectrum of nodular adrenal disease associated with hypercortisolism and a differential diagnosis based on morphologic criteria.

    View details for Web of Science ID A1991GF35400009

    View details for PubMedID 1653280

  • PENTOXIFYLLINE SUPPRESSION OF TUMOR-NECROSIS-FACTOR GENE-TRANSCRIPTION SURGERY Doherty, G. M., Jensen, J. C., Alexander, H. R., Buresh, C. M., NORTON, J. A. 1991; 110 (2): 192-198

    Abstract

    Pentoxifylline decreases lung injury after intravenous endotoxin; the mechanism is unknown. Tumor necrosis factor-alpha (TNF) is secreted by macrophages in response to endotoxin and mediates some of the toxicity of endotoxin. This study investigates the effects of pentoxifylline on endotoxin-stimulated TNF production in vitro and in vivo. Pentoxifylline concentrations of 100 and 1000 micrograms/ml inhibited TNF production by murine adherent peritoneal exudate cells incubated with endotoxin 1 microgram/ml. Similarly, pentoxifylline at 100 and 1000 micrograms/ml decreased the number of available TNF messenger RNA transcripts in peritoneal exudate cells assessed by Northern blot. Pentoxifylline had no effect on TNF mRNA stability, but appeared to act by inhibiting the rate of TNF mRNA production (transcription). In murine in vivo experiments at each dose of endotoxin administered from 0.01 to 30 mg/kg, pentoxifylline treatment significantly reduced serum TNF levels, suggesting a favorable shift of the endotoxin dose-response curve. Expression of murine TNF gene in the livers of these animals showed fewer TNF transcripts in the pentoxifylline-treated animals compared to controls. Pentoxifylline inhibited endotoxin-induced TNF production both in vivo and in vitro and exerted this control by inhibiting endotoxin-induced transcription of the TNF gene. This study suggests that pentoxifylline may ameliorate endotoxic shock by decreasing macrophage TNF production.

    View details for Web of Science ID A1991FZ62800010

    View details for PubMedID 1858029

  • HUMAN RECOMBINANT INTERLEUKIN-1-ALPHA PROTECTION AGAINST THE LETHALITY OF ENDOTOXIN AND EXPERIMENTAL SEPSIS IN MICE JOURNAL OF SURGICAL RESEARCH Alexander, H. R., Doherty, G. M., FRAKER, D. L., Block, M. I., SWEDENBORG, J. E., NORTON, J. A. 1991; 50 (5): 421-424

    Abstract

    Human recombinant interleukin-1 alpha (IL-1) has a diverse range of physiological activities which may be beneficial or deleterious to the host. Pretreatment with doses of IL-1 has been shown to protect mice against a subsequent lethal bacterial injection; however, the protective effects of a single intravenous (iv) dose of IL-1 have not been well characterized. The current experiments were performed to determine the best dose, timing, and duration of action of a single iv dose of IL-1 against a subsequent lethal challenge with intraperitoneal endotoxin (LPS) or experimental sepsis induced by cecal ligation and puncture (CLP). Female C57B1/6 mice treated with iv IL-1 24 hr prior to 30 mg/kg LPS ip had improved survival compared to saline-treated controls (P less than 0.01). IL-1 was also protective when given 6 to 72 hr, but not 2 or 96 hr, prior to LPS. IL-1 protection against LPS lethality was similar to protection seen with an iv dose of tumor necrosis factor (TNF). After CLP, survival was improved with IL-1 versus saline pretreatment (P = 0.02). Unlike previous work with TNF, no toxicity or lethality was observed at any dose of IL-1 administered. A single iv dose of IL-1 protects against the lethality of LPS and CLP in mice. IL-1 may be a useful treatment strategy in patients at risk for the development of life-threatening sepsis.

    View details for Web of Science ID A1991FM48300002

    View details for PubMedID 2038179

  • INSULINOMAS - LOCALIZATION WITH SELECTIVE INTRAARTERIAL INJECTION OF CALCIUM RADIOLOGY DOPPMAN, J. L., MILLER, D. L., Chang, R., Shawker, T. H., GORDEN, P., NORTON, J. A. 1991; 178 (1): 237-241

    Abstract

    To facilitate the noninvasive preoperative localization of islet cell tumors less than 15 mm in diameter, the authors examined the use of calcium as an insulin secretagogue in an arterial stimulation venous sampling (ASVS) technique. In four patients with episodic hypoglycemia, calcium gluconate (0.01-0.025 mEq Ca2+/kg) was injected directly into branches of the celiac plexus (gastroduodenal, splenic, and hepatic arteries) and the superior mesenteric artery. In all patients, serum levels of insulin rose abruptly in blood samples taken from the right hepatic vein 30 and 60 seconds after the infusion of calcium into the artery supplying the tumor; injection into an artery not supplying the tumor did not result in a similar rise. Accurate localization of the insulinomas was verified at surgery in three patients. In the fourth patient, who did not undergo surgery, arteriographic results were positive for insulinoma at the predicted site. On the basis of these results, the authors believe noninvasive ASVS may replace invasive portal venous sampling as the most effective method for the localization of occult insulinomas.

    View details for Web of Science ID A1991EP11700044

    View details for PubMedID 1984311

  • ULTRASTRUCTURAL PATHOLOGY EXPLAINS RESULTS OF TL-201/TC-99M PARATHYROID SUBTRACTION SCINTIGRAPHY RADIOACTIVE ISOTOPES IN CLINICAL MEDICINE AND RESEARCH Sandrock, D., MERINO, M. J., NORTON, J. A., MILLER, D. L., Neumann, R. D. 1991: 328-332
  • THE UTILITY OF CIRCULATING LEVELS OF HUMAN PANCREATIC-POLYPEPTIDE AS A MARKER FOR ISLET CELL TUMORS SURGERY Langstein, H. N., NORTON, J. A., CHIANG, H. C., Odorisio, T. M., Maton, P. N., Marx, S. J., Jensen, R. T. 1990; 108 (6): 1109-1116

    Abstract

    The measurement of plasma levels of human pancreatic polypeptide (hPP) has been reported to be clinically useful in predicting the existence of pancreatic islet cell neoplasms in patients with familial multiple endocrine neoplasia type 1 (FMEN-I) and the possible presence of metastatic disease in patients with islet cell tumors. However, these studies have not been prospective and involve small numbers of patients. In this study, fasting plasma samples from 36 patients with biopsy-proved islet cell tumors were analyzed for hPP by radioimmunoassay and compared with age-matched control subjects. Of 13 patients with FMEN-I who had islet cell tumors, 7 (54%) had elevated plasma hPP levels before surgery. After resection of all islet cell tumors, 4 of 12 patients evaluated after surgery still had elevated levels. Fifteen patients had islet cell tumors that were localized (seven insulinomas and eight gastrinomas), but none of these patients had elevated hPP levels, either before or after surgery. Nine patients, including one with FMEN-I, with metastatic islet cell tumors to the liver were studied; three with more advanced disease had elevated hPP levels before surgery. Each of the nine patients underwent resection of all gross disease and the three patients with elevated preoperative levels had normal postoperative hPP levels. Our results indicate that basal plasma levels of hPP were not clinically useful. The hPP levels did not reliably predict the presence of islet cell tumors in patients with FMEN-I, because 46% of patients with tumors did not have elevated plasma levels, and in those with elevated values hPP levels did not reliably predict the resection of all tumor. Plasma levels of hPP have no utility in patients with localized sporadically occurring islet cell tumors and limited utility (33%) in predicting the presence of metastatic islet cell tumors to the liver.

    View details for Web of Science ID A1990EL87300026

    View details for PubMedID 2174193

  • TIME TO RECOVERY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AFTER CURATIVE RESECTION OF ADRENAL-TUMORS IN PATIENTS WITH CUSHINGS-SYNDROME SURGERY Doherty, G. M., NIEMAN, L. K., Cutler, G. B., Chrousos, G. P., NORTON, J. A. 1990; 108 (6): 1085-1090

    Abstract

    The recovery time of the hypothalamic-pituitary-adrenal (HPA) axis after curative resection of adrenal tumors in patients with Cushing's syndrome is poorly documented. Eight consecutive patients were treated with a standardized hydrocortisone replacement strategy after curative resection of a cortisol-secreting tumor and the time to recovery of the HPA axis was determined. Hypercortisolism was documented by elevated 24-hour urinary free cortisol levels. Cure was documented by undetectable postoperative morning serum cortisol levels. Each patient received replacement hydrocortisone after surgery and was reevaluated every 3 to 6 months with an adrenocorticotrophic hormone (ACTH) stimulation test. Each patient was also monitored carefully for symptoms and signs of adrenal insufficiency, which was defined as symptoms consistent with this diagnosis that responded to increases in hydrocortisone levels. After surgical resection, each patient was cured of hypercortisolism. Subsequently, despite replacement hydrocortisone, each patient had symptoms of hypocortisolism, and in four of eight patients the dose of hydrocortisone was increased to relieve the symptoms. Patients required a median time of 15 months (range, 9 to 22 months) to recover a normal ACTH stimulation test and 19 months (range, 12 to 24 months) to allow discontinuation of replacement doses of hydrocortisone. The results suggest that surgical resection of a cortisol-secreting adrenal tumor will result in rapid cure of hypercortisolism, but complete recovery of the HPA axis and discontinuation of replacement steroids will require between 1 and 2 years. Normal adrenal function, as assessed by the cortisol response to ACTH, returns despite replacement doses of hydrocortisone, and replacement doses of hydrocortisone can be tapered rapidly or discontinued after a normal ACTH stimulation test.

    View details for Web of Science ID A1990EL87300022

    View details for PubMedID 2247834

  • LOCALIZATION AND SURGICAL-TREATMENT OF OCCULT INSULINOMAS ANNALS OF SURGERY NORTON, J. A., Shawker, T. H., DOPPMAN, J. L., MILLER, D. L., FRAKER, D. L., CROMACK, D. T., GORDEN, P., Jensen, R. T. 1990; 212 (5): 615-620

    Abstract

    Management of patients with biochemical evidence of insulinoma and negative preoperative imaging studies (occult) tumors is controversial, varying from primarily medical management to aggressive, blind nearly total pancreatectomy to extirpate the tumor. Since 1982, 12 consecutive patients with occult insulinoma underwent preoperative portal venous sampling (PVS) for insulin followed by surgical exploration with intraoperative ultrasound (IOUS). Eleven of twelve patients (92%) had insulinoma removed and were cured. Portal venous sampling correctly predicted the location of the insulinoma in 9 patients (75%) and that no tumor would be found in another patient. A fourfold insulin gradient in the pancreatic tail of one patient correctly predicted that a distal pancreatectomy would remove the insulinoma despite the fact that neither palpation nor IOUS identified any tumor. Intraoperative ultrasound was the single best method to identify occult tumors because it correctly identified 10 of 11 insulinomas that were found, including five pancreatic head tumors that were not palpable. Palpation identified five insulinomas. Of the 10 tumors that were identified during operation by palpation or ultrasound, IOUS identified significantly more (100% versus 50%, p = 0.03) and guided the successful enucleation of each. The results support the strategy of preoperative PVS and operation with IOUS to localize and remove insulinoma in patients with occult tumors. Most tumors (75%) will be correctly localized to a specific pancreatic region by preoperative PVS and identified by IOUS (83%), allowing simple enucleation and biochemical correction of hypoglycemia. Morbid blind pancreatic resections are no longer indicated and long-term medical management of hypoglycemia should be reserved for the occasional patient (8%) who fails preoperative PVS and operation guided by IOUS.

    View details for Web of Science ID A1990EG93000009

    View details for PubMedID 2241318

  • INTRAVENOUS OMEPRAZOLE IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME UNDERGOING SURGERY GASTROENTEROLOGY Vinayek, R., Frucht, H., London, J. F., Miller, L. S., Stark, H. A., NORTON, J. A., Cederberg, C., Jensen, R. T., Gardner, J. D., Maton, P. N. 1990; 99 (1): 10-16

    Abstract

    Twenty patients with Zollinger-Ellison syndrome who were undergoing surgery were studied prospectively to assess the efficacy and safety of IV omeprazole. During the preoperative period, in 19 of 20 patients, omeprazole 60 mg administered as an IV bolus every 12 hours inhibited acid output to less than 5 mEq/h measured in the last hour before the next dose of drug. In one patient, acid output was 25 mEq/h 12 hours after omeprazole, 60 mg, and increasing the dose to 100 mg every 12 hours reduced acid output to less than 5 mEq/h. During the operative and postoperative periods, IV omeprazole controlled gastric acid hypersecretion in all patients for up to 15 days. During this time, all patients received the dose determined preoperatively. No patient developed any clinical, hematological, or biochemical toxicity that could be attributed to omeprazole therapy during the preoperative or postoperative period. The present study demonstrates that omeprazole administered by IV bolus is safe and effective for controlling gastric acid hypersecretion. In contrast to IV histamine H2-receptor antagonists, IV omeprazole has the advantages of not requiring continuous infusion or postoperative dose adjustments. Intravenous omeprazole will become the drug of choice in patients with Zollinger-Ellison syndrome undergoing surgery.

    View details for Web of Science ID A1990DH80400002

    View details for PubMedID 1971604

  • UNDESCENDED PARATHYROID ADENOMA - AN IMPORTANT ETIOLOGY FOR FAILED OPERATIONS FOR PRIMARY HYPERPARATHYROIDISM WORLD JOURNAL OF SURGERY FRAKER, D. L., DOPPMAN, J. L., Shawker, T. H., Marx, S. J., Spiegel, A. M., NORTON, J. A. 1990; 14 (3): 342-348

    Abstract

    From July, 1982 to April, 1989, a total of 145 patients with persistent or recurrent primary hyperparathyroidism (HPT) were explored; 105 patients had an adenoma as the cause of HPT, and in 9 patients (9%), the abnormal gland was located at or superior to the carotid bifurcation (undescended parathyroid gland). These 9 patients had 14 prior explorations for HPT including 4 median sternotomies and 5 thyroidectomies. Each of the 9 patients was symptomatic of HPT, including bone disease in 8 of 9 patients and renal stones in 4 of 9 patients. Seven patients had an undescended parathyroid adenoma correctly localized preoperatively by ultrasound (n = 5), angiography (n = 5), venous sampling (n = 1), or computed tomography scan (n = 4). These 7 patients with accurate preoperative localization were explored by an incision anterior to the sternocleidomastoid muscle high in the neck that avoided the previous operative field and allowed rapid resection of the parathyroid adenoma. In the 2 patients who did not have accurate preoperative localization, the undescended adenoma was found after long tedious exploration including median sternotomy in 1 patient. Each patient (n = 9) who had an undescended parathyroid adenoma removed was cured of hypercalcemia, and 5 patients required postoperative 1,25-dihydroxy vitamin D3 for hypocalcemia. We conclude that undescended parathyroid adenomas comprise a significant proportion (9%) of adenomas during reoperations for persistent HPT.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1990DD83600010

    View details for PubMedID 2368436

  • IMPACT OF TOLERANCE ON ANTITUMOR EFFICACY OF TUMOR-NECROSIS-FACTOR IN MICE CANCER RESEARCH FRAKER, D. L., Sheppard, B. C., NORTON, J. A. 1990; 50 (8): 2261-2267

    Abstract

    Repetitive sublethal doses of tumor necrosis factor (TNF) can induce tolerance or tachyphylaxis to the toxic effects of TNF. Because tumor-bearing (TB) mice are more sensitive to the toxic effects of TNF, this study investigates whether similar tolerance occurs in TB mice and whether it affects the antitumor response of TNF. Nontumor-bearing C3H/Hen mice were treated with twice daily i.p. sublethal escalating doses of human recombinant TNF (2, 2, 3, 3, 4, and 4 micrograms i.p. every 12 h for 6 days) and were challenged 2 days later with a lethal i.v. dose (40 micrograms) of TNF. TNF-pretreated mice had 100% survival as compared to 0% survival in control mice previously treated with saline (P less than 0.01). Tumor-bearing C57BL/6 mice bearing an MCA-106 or MCA-102 sarcoma were treated with an identical TNF-tolerizing regimen (2, 2, 3, 3, 4, and 4 micrograms i.p. every 12 h for 6 days) beginning 3 days following tumor inoculation and were similarly more resistant to a subsequent 100% lethal i.v. treatment dose of TNF than control TB mice. A significantly greater percentage of TNF-pretreated mice bearing the MCA-106 sarcoma survived treatment doses of 8, 12, and 16 micrograms of TNF i.v. than control TB mice. Similarly, a significantly greater percentage of TNF-pretreated mice bearing the MCA-102 sarcoma survived treatment doses of 6 and 9 micrograms of TNF i.v. than control TB mice. However, the ability to administer higher doses of TNF i.v. to TNF-pretreated TB mice did not improve therapeutic efficacy. In mice bearing the MCA-106 tumor the most efficacious treatment responses were seen in animals that were previously naive to TNF, and treatment toxicity (lethality) correlated directly with antitumor efficacy such that larger treatment doses of TNF in tolerant mice resulted in similar antitumor effects as smaller treatment doses in control TB mice. In mice bearing the MCA-102 tumor, equitoxic treatment doses of TNF produced similar antitumor effects in both control and tolerant TB mice. There were no differences in cure rate for TNF-tolerant or control TB mice bearing either tumor. The results suggest that TNF tolerance occurs in TB mice and reduces the toxicity as well as the therapeutic efficacy of TNF.

    View details for Web of Science ID A1990CZ34900009

    View details for PubMedID 2317813

  • THE ROLE OF SURGERY IN THE MANAGEMENT OF ISLET CELL TUMORS GASTROENTEROLOGY CLINICS OF NORTH AMERICA FRAKER, D. L., NORTON, J. A. 1989; 18 (4): 805-830

    Abstract

    Endocrine tumors of the pancreas are rare disorders that can cause life-threatening symptoms related to the excessive hormonal secretion and the malignant nature of the neoplasm. In addition, these neoplasms can present as part of familial endocrinopathy syndromes, especially multiple endocrine neoplasia type 1 (MEN-1). The initial step in evaluation of a patient with an islet cell tumor is definitive diagnosis of the hormonal syndrome that usually can be achieved biochemically. The next step is to reverse the life-threatening hormonal syndrome medically to allow radiographic localization of the islet cell neoplasm and to prepare the patient for elective surgery. In general, the goal of surgery is to accurately stage the extent of disease and to totally resect the tumor resulting in complete correction of the excessive hormonal condition and freedom from malignant progression of the tumor. Resection of the neoplasm should encompass metastatic disease in select individuals in whom complete or nearly complete resection can be achieved. Surgery must be performed with acceptable morbidity and mortality because the medical management of the excessive hormonal secretion in most patients is adequate and the progression rate of malignant islet cell carcinomas is usually slow. Patients with MEN-1 should be identified during evaluation by careful history and should be managed differently. These patients always have multiple islet cell tumors and may have malignant islet cell carcinomas. Large (3 cm) imageable pancreatic neoplasms in patients with MEN-1 should be resected because nearly 50 per cent are malignant. Zollinger-Ellison syndrome in patients with MEN-1 and primary hyperparathyroidism is best managed initially by surgery directed at the hyperparathyroidism. It may be impossible to correct the biochemical abnormalities of Zollinger-Ellison syndrome by islet cell tumor resection in patients with MEN-1. However, insulinoma or VIPoma syndromes can often be corrected by islet cell tumor resection. Portal venous sampling for hormones may be helpful in determining what hormone a specific tumor is secreting.

    View details for Web of Science ID A1989CE88900009

    View details for PubMedID 2559034

  • PREVENTION AND TREATMENT OF ENDOTOXIN AND SEPSIS LETHALITY WITH RECOMBINANT HUMAN-TUMOR NECROSIS FACTOR SURGERY Sheppard, B. C., FRAKER, D. L., NORTON, J. A. 1989; 106 (2): 156-162

    Abstract

    Tumor necrosis factor (TNF) is a macrophage product released in response to endotoxin that has been implicated as a cause of the toxicity and lethality seen in septic shock. Previous work suggests that tolerance to nutritional and lethal effects of TNF occur after repeated exposure to recombinant tumor necrosis factor (rTNF). In this study pretreatment of rats with a single low intravenous dose of rTNF prevented subsequent death when a lethal dose of rTNF was administered 24 hours later (tolerance or tachyphylaxis). Pretreatment with rTNF also afforded protection against the lethal effects of either endotoxin or cecal ligation and puncture when rats were challenged 24 hours later. Recombinant TNF injected 6 hours after cecal ligation and puncture initially resulted in a significant survival advantage for treated animals. When this experiment was repeated with a different lot of rTNF, however, the therapeutic benefit of rTNF was not obtained until the dose was decreased by a factor of 10. Protection against the lethal effects of cecal ligation and puncture did not occur when rTNF was given 24 hours after the insult. A single low dose of rTNF can result in tolerance or tachyphylaxis to the lethal effects of TNF. The results suggest that the early administration of low-dose rTNF may be useful in the prevention and treatment of the lethality of sepsis.

    View details for Web of Science ID A1989AJ36500007

    View details for PubMedID 2669193

  • REVERSAL OF THE TOXIC EFFECTS OF CACHECTIN BY CONCURRENT INSULIN ADMINISTRATION AMERICAN JOURNAL OF PHYSIOLOGY FRAKER, D. L., MERINO, M. J., NORTON, J. A. 1989; 256 (6): E725-E731

    Abstract

    Rats treated with recombinant human tumor necrosis factor-cachectin, 100 micrograms/kg ip twice daily for 5 consecutive days, had a 56% decrease in food intake, a 54% decrease in nitrogen balance, and a 23-g decrease in body weight gain vs. saline-treated controls. Concurrent neutral protamine hagedorn insulin administration of 2 U/100 g sc twice daily reversed all of these changes to control levels without causing any treatment deaths. The improvement seen with insulin was dose independent. Five days of cachectin treatment caused a severe interstitial pneumonitis, periportal inflammation in the liver, and an increase in wet organ weight in the heart, lungs, kidney, and spleen. Concurrent insulin treatment led to near total reversal of these histopathologic changes. Cachectin treatment did not significantly change blood glucose levels from control values of 130-140 mg/dl, but insulin plus cachectin caused a significant decrease in blood glucose from 1 through 12 h after injection. Administration of high-dose insulin can near totally reverse the nutritional and histopathologic toxicity of sublethal doses of cachectin in rats.

    View details for Web of Science ID A1989AC79200027

    View details for PubMedID 2660586

  • GASTRINOMAS - COMPARISON OF MR IMAGING WITH CT, ANGIOGRAPHY, AND US RADIOLOGY Frucht, H., DOPPMAN, J. L., NORTON, J. A., MILLER, D. L., Dwyer, A. J., Frank, J. A., Vinayek, R., Maton, P. N., Jensen, R. T. 1989; 171 (3): 713-717

    Abstract

    In this prospective study, magnetic resonance (MR) imaging was used to localize gastrinoma in 24 patients with Zollinger-Ellison syndrome. The results were confirmed by means of either surgery or percutaneous liver biopsy and compared with results of computed tomographic (CT) scanning, selective abdominal angiography, and abdominal ultrasound (US). For primary extrahepatic gastrinoma (intra-or extrapancreatic), MR imaging had a sensitivity of 20% and a specificity of 100%, with a positive predictive value of 100% and a negative predictive value of 11%. For metastatic gastrinoma in the liver, MR imaging had a sensitivity of 43% and a specificity of 100%, with a positive predictive value of 100% and a negative predictive value of 81%. The ability of MR imaging to depict extrahepatic gastrinomas was directly related to tumor size; no tumors smaller than 1 cm were detected, and 50% of tumors 3 cm or larger were detected. MR imaging was as effective as abdominal US but less effective than either CT scanning or selective abdominal angiography for the detection of extrahepatic gastrinoma. In seven patients with hepatic gastrinoma, three gastrinomas were detected with MR imaging and with abdominal US, while five were detected with CT scanning and with selective abdominal angiography. These results indicate that, at the present time, MR imaging is generally not useful in the initial attempt to localize gastrinomas.

    View details for Web of Science ID A1989U594000026

    View details for PubMedID 2655004

  • TOLERANCE TO TUMOR NECROSIS FACTOR NUTRITION NORTON, J. A., FRAKER, D. L. 1989; 5 (2): 131-135

    View details for Web of Science ID A1989AP18300015

    View details for PubMedID 2520273

  • CACHECTIN ACTIVITY IN THE SERUM OF CACHECTIC, TUMOR-BEARING RATS ARCHIVES OF SURGERY STOVROFF, M. C., FRAKER, D. L., NORTON, J. A. 1989; 124 (1): 94-99

    Abstract

    Cachectin/tumor necrosis factor has been postulated to be a possible mediator of cancer cachexia. Using a sensitive bioassay, we attempted to detect circulating cachectin activity in the serum of sarcoma-bearing rats and to correlate levels with measurements of cachexia and the extent of disease. In addition, we resected the tumor to determine the time course of reversal of cachexia and the disappearance of cachectin activity in the serum. Circulating cachectin activity was not detectable in the serum of non-tumor-bearing rats or in tumor-bearing rats until 28 days after implantation. With evidence of food intake and body weight decline, cachectin activity became detectable in the serum and levels increased as cachexia and tumor burden increased. Serum cachectin activity levels correlated directly with tumor burden and inversely with food intake and body weight change. After resection of the tumor, food intake and body weight increased and serum cachectin activity became undetectable. Serum triglyceride levels were higher in cachectic tumor-bearing rats than in pair-fed non-tumor-bearing controls, and levels decreased after tumor resection as cachectin activity decreased. The results suggest that cachectin is a humoral mediator of cachexia in this rat-tumor model.

    View details for Web of Science ID A1989R703100018

    View details for PubMedID 2910253

  • LOCALIZATION AND RESECTION OF INSULINOMAS AND GASTRINOMAS JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION FRAKER, D. L., NORTON, J. A. 1988; 259 (24): 3601-3605

    View details for Web of Science ID A1988N776400030

    View details for PubMedID 2836638

  • PROSPECTIVE-STUDY OF CHEMOTHERAPY IN PATIENTS WITH METASTATIC GASTRINOMA GASTROENTEROLOGY VONSCHRENCK, T., Howard, J. M., DOPPMAN, J. L., NORTON, J. A., Maton, P. N., Smith, F. P., Vinayek, R., Frucht, H., Wank, S. A., Gardner, J. D., Jensen, R. T. 1988; 94 (6): 1326-1334

    Abstract

    Ten consecutive patients with metastatic gastrinoma that increased in size over time were studied prospectively during treatment with monthly cycles of streptozotocin (3 g/m2), 5-fluorouracil (1.2 g/m2), and adriamycin (40 mg/m2) to determine the response rate and time-courses of changes during chemotherapy and to assess various methods of evaluating the effect of chemotherapy. Forty percent of patients demonstrated an initial objective response (greater than or equal to 25% decrease in tumor size with no new lesions) and 60% failed chemotherapy (greater than or equal to 25% increase in tumor size or appearance of new lesions). The mean dose of streptozotocin was 27 g/m2 with objective responses occurring at 3.7 +/- 0.7 mo and failures at 4.5 +/- 0.7 mo. Responses lasted 9.7 +/- 2.8 cycles and no complete responses occurred. Survival was not significantly different in responders versus nonresponders (26 +/- 11 vs. 15 +/- 4.8 mo, p greater than 0.1). Changes in serum gastrin concentration, basal acid output, or sensitivity to a given dose of histamine H2-receptor antagonist did not reflect changes in tumor size. Computed tomography and angiography were the best methods to assess changes in tumor size during chemotherapy, whereas liver-spleen scan and ultrasound were relatively insensitive. All patients developed side effects with chemotherapy: 100% had vomiting, 80% alopecia, 40% transient proteinuria, and 20% leukopenia. The present results indicate that chemotherapy with streptozotocin, 5-fluorouracil, and adriamycin is much less effective in patients with extensive metastatic gastrinoma than previously reported. Computed tomography scanning is the method of choice to assess changes in tumor size. Changes in serum gastrin concentration, acid secretion, or tumor size assessed by liver-spleen scan or ultrasound are not sensitive indicators of the tumor response during chemotherapy.

    View details for Web of Science ID A1988N454600011

    View details for PubMedID 2966088

  • INTRAOPERATIVE ULTRASONOGRAPHIC LOCALIZATION OF ISLET CELL TUMORS - A PROSPECTIVE COMPARISON TO PALPATION ANNALS OF SURGERY NORTON, J. A., CROMACK, D. T., Shawker, T. H., DOPPMAN, J. L., Comi, R., GORDEN, P., Maton, P. N., Gardner, J. D., Jensen, R. T. 1988; 207 (2): 160-168

    Abstract

    The purpose of the present study was to evaluate prospectively the value of intraoperative ultrasound scanning (IOUS) in localizing islet cell tumors by comparing results of IOUS to those of palpation during 44 consecutive laparotomies for gastrinoma (36) or insulinoma (8). All patients had preoperative radiographic imaging studies and selective venous sampling for hormones, which guided the subsequent laparotomy. Any suspicious finding by palpation and/or IOUS was resected. Pathologic evidence of islet cell neoplasm served as the reference standard. Five patients were excluded from analysis because neither palpation nor IOUS had suspicious findings and no islet cell tumor was found. Seven pancreatic insulinomas were found in seven patients. IOUS was as sensitive as palpation at localizing insulinomas. Twenty-three pancreatic gastrinomas were found in 19 patients. IOUS was equal to palpation in the ability to localize gastrinomas. Gastrinomas that were successfully imaged by IOUS were significantly larger than gastrinomas that were not imaged. Twelve extrapancreatic gastrinomas were found in nine patients, and palpation was more sensitive than IOUS at localizing these small duodenal wall tumors. Five patients (11%) had their surgical management changed by IOUS. Two patients had pancreatic tumors (one gastrinoma and insulinoma) enucleated that would not have been found without IOUS, and three patients had resections of pathologically proven malignant islet cell tumors based on sonographic findings. All five patients were cured with short follow-up. The present results demonstrate that palpation and IOUS are complementary because IOUS can image tumors that are not palpable and IOUS can provide additional information concerning malignant potential not detected by palpation.

    View details for Web of Science ID A1988L978700008

    View details for PubMedID 2829761

  • EFFECT OF PROSTAGLANDIN-F2ALPHA ON HUMAN PARATHYROID ADENOMAS - EVIDENCE FOR UNCOUPLING OF PARATHYROID-HORMONE SECRETION AND CAMP ACCUMULATION JOURNAL OF BONE AND MINERAL RESEARCH Fitzpatrick, L. A., Norton, J., Martin, C., Sharp, M., AURBACH, G. D. 1988; 3 (1): 81-86

    Abstract

    Human parathyroid adenomas are aberrantly regulated by extracellular calcium. We tested pertussis toxin, which ADP-ribosylates and inactivates several guanine nucleotide regulatory proteins, to test the role of these proteins in the secretory control of adenomatous parathyroid tissue. Pertussis toxin did not affect basal cAMP accumulation in 12 adenomas and enhanced parathyroid hormone (PTH) release in 6 of 10 adenomas. Prostaglandin F2 alpha (PGF2 alpha) inhibited cAMP in three of six adenomas, and pertussis toxin pretreatment did not affect this result. PTH release in 7 of 10 adenomas was inhibited by PGF2 alpha, and pertussis toxin did not significantly alter PTH release. Pertussis toxin catalyzed ADP-ribosylation of a 40-kDa protein in all adenomas tested (n = 8). We conclude that cAMP accumulation was not affected by pertussis toxin but that in 6 of 10 adenomas, the toxin enhanced PTH release. We suggest that cAMP accumulation and PTH release may be uncoupled from negative control by inhibitory ligands in adenomatous tissue or that the G-proteins involved do not couple to regulatory receptors or to effector.

    View details for Web of Science ID A1988M256300011

    View details for PubMedID 2850725

  • STRAIN RATE DEPENDENCY OF WOUND BREAKING STRENGTH FOR THE DERMAL WOUND MODEL PROCEEDINGS OF THE ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, PTS 1-4 Talbot, T. L., CROMACK, D. T., NORTON, J. A., TIPTON, H. W. 1988: 687-687
  • DIFFERENTIATION OF ADRENAL MASSES BY MAGNETIC-RESONANCE-IMAGING SURGERY DOPPMAN, J. L., REINIG, J. W., Dwyer, A. J., Frank, J. P., Norton, J., Loriaux, D. L., KEISER, H. 1987; 102 (6): 1018-1026

    Abstract

    Eighty-one adrenal masses in 68 patients were examined with magnetic resonance imaging (MRI). Masses included nonfunctioning adenomas (17), metastases (25), adrenocortical carcinomas (10), and pheochromocytomas (23). T1-weighted pulse sequences depicted the anatomy with a resolution comparable to that of computed tomography (CT). T2-weighted pulse sequences provided some histologic specificity separating nonfunctioning adenomas with low signal-intensity from metastases with intermediate signal-intensity and pheochromocytomas with high signal-intensity. Pheochromocytomas could always be distinguished from other adrenal masses. In 20% of the cases, metastases with low signal-intensity could not be distinguished from nonfunctioning adenomas.

    View details for Web of Science ID A1987L164600018

    View details for PubMedID 3686342

  • THE USE OF HIGH-RESOLUTION INTRAOPERATIVE ULTRASOUND TO LOCALIZE GASTRINOMAS - AN INITIAL REPORT OF A PROSPECTIVE-STUDY WORLD JOURNAL OF SURGERY CROMACK, D. T., NORTON, J. A., Sigel, B., Shawker, T. H., DOPPMAN, J. L., Maton, P. N., Jensen, R. T. 1987; 11 (5): 648-653

    View details for Web of Science ID A1987K061100015

    View details for PubMedID 3314183

  • THE USE OF HIGH-RESOLUTION ULTRASOUND TO LOCATE PARATHYROID TUMORS DURING REOPERATIONS FOR PRIMARY HYPERPARATHYROIDISM WORLD JOURNAL OF SURGERY Kern, K. A., Shawker, T. H., DOPPMAN, J. L., MILLER, D. L., Marx, S. J., Spiegel, A. M., AURBACH, G. D., NORTON, J. A. 1987; 11 (5): 579-585

    View details for Web of Science ID A1987K061100004

    View details for PubMedID 3314177

  • PREOPERATIVE INSULIN REVERSES CACHEXIA AND DECREASES MORTALITY IN TUMOR-BEARING RATS JOURNAL OF SURGICAL RESEARCH Moley, J. F., Morrison, S. D., NORTON, J. A. 1987; 43 (1): 21-28

    Abstract

    As a model of surgical stress in the cancer-bearing animal, we resected large flank sarcomas from cachectic rats under ether anesthesia and closed wounds primarily. The metabolic cost of tumor resection was measured using a long-term continuous indirect calorimeter. In the immediate postresection period energy balance decreased and host energy expenditure increased significantly (P less than 0.005). In animals with similar tumor weights, mortality following resection was determined by the degree of cachectic depletion. We then considered whether improvement of preoperative host nutritional status with insulin treatment might improve a subsequent surgical outcome. Insulin, when administered exogenously to cachectic tumor-bearing rats, has been shown to stimulate food intake and preserve host weight and does not stimulate tumor growth. When individual rats bearing a cachexia-producing flank sarcoma demonstrated a decline in food intake to less than 75% of predicted (approximately 25 days after tumor implantation), they were randomized to receive either daily injections of NPH insulin (2 units/100 g/day) for 5 days or no treatment for 5 days. Animals then underwent tumor resection and 14-day survival was measured. All resections were performed in an unbiased manner without the surgeon's knowledge of each rat's treatment status. In an experiment using 59 rats, insulin-treated rats had a threefold higher 5-day preoperative food intake and did not lose weight in the preoperative period, while untreated rats lost 17 g (P less than 0.001). Mortality in the insulin-treated group was 10% versus 28% in the untreated group.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1987J255500004

    View details for PubMedID 3599982

  • INFERIOR THYROID ARTERY ARISING FROM COMMON CAROTID-ARTERY WITH ABERRANT RIGHT SUBCLAVIAN ARTERY CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY Simmons, J. T., DOPPMAN, J. L., Norton, J. 1987; 10 (3): 150-152

    Abstract

    We describe an unusual variant in the blood supply to the inferior portion of the right thyroid gland encountered during parathyroid localization studies. A brief review of other possible variants is given.

    View details for Web of Science ID A1987H777900007

    View details for PubMedID 3111696

  • LOCALIZATION OF PARATHYROID ADENOMAS IN PATIENTS WHO HAVE UNDERGONE SURGERY .2. INVASIVE PROCEDURES RADIOLOGY MILLER, D. L., DOPPMAN, J. L., Krudy, A. G., Shawker, T. H., NORTON, J. A., Vucich, J. J., MORRISH, K. A., Marx, S. J., Spiegel, A. M., AURBACH, G. D. 1987; 162 (1): 138-141

    Abstract

    The authors studied intraarterial digital subtraction angiography (DSA), conventional selective angiography, parathyroid venous sampling (PVS), and intraoperative ultrasound (US) as localization procedures for parathyroid adenomas in 53 patients with proved parathyroid adenomas and previous unsuccessful parathyroid surgery. PVS had the highest overall sensitivity as a single study (80%), followed by intraoperative US (78%), angiography (60%), and DSA (49%). Invasive procedures permitted successful localization of adenomas in 41 of 43 patients studied (95%). False-positive studies were uncommon. The optimum sequence of invasive localization procedures is determined by clinical factors and not by the sensitivity of individual tests. The authors recommend DSA be performed first, followed by angiography, PVS, and intraoperative US, in that order.

    View details for Web of Science ID A1987F351700026

    View details for PubMedID 3538146

  • LOCALIZATION OF PARATHYROID ADENOMAS IN PATIENTS WHO HAVE UNDERGONE SURGERY .1. NONINVASIVE IMAGING METHODS RADIOLOGY MILLER, D. L., DOPPMAN, J. L., Shawker, T. H., Krudy, A. G., NORTON, J. A., Vucich, J. J., MORRISH, K. A., Marx, S. J., Spiegel, A. M., AURBACH, G. D. 1987; 162 (1): 133-137

    Abstract

    The authors evaluated computed tomography (CT), ultrasound (US), technetium/thallium scintigraphy, and magnetic resonance (MR) imaging as localization procedures in 53 patients with proved parathyroid adenomas and previous unsuccessful parathyroid surgery. CT had the highest overall sensitivity (47%), followed by US (36%) and scintigraphy (27%). There is still too little data to assess MR imaging. Adenoma size affected the sensitivity of CT, scintigraphy, and MR imaging but not US. When all three studies were used, at least one study depicted a lesion in 78% of patients, but definitive localization (two positive studies) was achieved in only 31%.

    View details for Web of Science ID A1987F351700025

    View details for PubMedID 3538145

  • SELECTIVE VENOUS SAMPLING FOR GASTRIN TO LOCALIZE GASTRINOMAS - A PROSPECTIVE ASSESSMENT ANNALS OF INTERNAL MEDICINE CHERNER, J. A., DOPPMAN, J. L., NORTON, J. A., MILLER, D. L., Krudy, A. G., Raufman, J. P., COLLEN, M. J., Maton, P. N., Gardner, J. D., Jensen, R. T. 1986; 105 (6): 841-847

    Abstract

    In 27 consecutive patients with Zollinger-Ellison syndrome, we prospectively evaluated the ability of selective venous sampling for gastrin to localize gastrinomas, then compared the results with those from imaging studies and with findings at surgery. All patients had a gastrin gradient, but in only 20 patients was it significant. Neither the magnitude of the gastrin gradient nor its presence or absence correlated with the frequency with which gastrinoma was found at surgery. A gastrinoma was found at surgery in 15 patients, of whom 12 had positive imaging studies, 11 had a significant gastrin gradient, 14 had both tests positive, and 1 had both tests negative. A gastrinoma was not found at surgery in 12 patients, of whom 8 had a significant gradient and none had a positive imaging study. Gastrin sampling has equal sensitivity with imaging studies in localizing gastrinoma, but imaging studies have higher positive and negative predictive values and higher specificity. Thus, selective venous sampling for gastrin is much less useful in localizing gastrinoma than has been suggested and should not be routinely done preoperatively in patients with Zollinger-Ellison syndrome.

    View details for Web of Science ID A1986F162500004

    View details for PubMedID 3535602

  • PROSPECTIVE-STUDY OF GASTRINOMA LOCALIZATION AND RESECTION IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME ANNALS OF SURGERY NORTON, J. A., DOPPMAN, J. L., COLLEN, M. J., Harmon, J. W., Maton, P. N., Gardner, J. D., Jensen, R. T. 1986; 204 (4): 468-479

    Abstract

    In 1982, a prospective study was initiated of 52 consecutive patients with proven Zollinger-Ellison syndrome (ZES), involving surgical exploration with the goal of removing the gastrinoma after an extensive protocol to localize the tumor. Each patient underwent ultrasound, computed tomography (CT) with oral/intravenous (IV) contrast, and selective arteriography. Eighteen patients had metastatic disease identified by imaging studies and confirmed by percutaneous biopsies, and two patients had multiple endocrine neoplasia type I (MEN-I) with negative imaging studies; therefore, these 20 patients did not undergo laparotomy. Each of the remaining 32 patients (3 with MEN-I and positive imaging studies) underwent laparotomy, and gastrinomas were removed in 20 patients. Preoperative ultrasound localized tumors in 20% of patients, CT in 40%, arteriography in 60%, and any of the modalities in 70% of patients. Infusion CT and arteriography were 100% specific. In 18 patients with either negative imaging (17) or false-positive imaging (1 ultrasound), gastrinomas were found and removed in six patients (33%). Twenty-four gastrinomas were found in 20 patients at laparotomy: eight in lymph nodes around the pancreatic head, four in the pancreatic head, one in the pancreatic body, three in the pancreatic tail, three in the pyloric channel, one in the duodenal wall, two in the jejunum at the ligament of Treitz, one in the ovary, and multiple liver metastases in one patient. If one excludes patients with MEN-I or liver metastatic disease, 12/28 (43%) of patients were biochemically "cured" immediately after operation. This result decreased to 7/23 (30%) with greater than 6 months follow-up. No patients with gastrinomas resected have developed recurrent gastrinoma on follow-up imaging studies (longest follow-up: 4 years). This study indicates that 95% of metastatic gastrinoma can be diagnosed before operation and that, by a combination of careful imaging studies and thorough exploration at surgery, 30% of patients with gastrinomas may be curable.

    View details for Web of Science ID A1986E249800015

    View details for PubMedID 3532971

  • INTRAOPERATIVE ULTRASOUND AND REOPERATIVE PARATHYROID SURGERY - AN INITIAL EVALUATION WORLD JOURNAL OF SURGERY NORTON, J. A., Shawker, T. H., Jones, B. L., Spiegel, A. M., Marx, S. J., Fitzpatrick, L., AURBACH, G. D., DOPPMAN, J. L. 1986; 10 (4): 631-639

    View details for Web of Science ID A1986D347000013

    View details for PubMedID 3529650

  • DEMONSTRATION OF AN ANGIOGRAPHICALLY HYPOVASCULAR INSULINOMA WITH INTRAARTERIAL DYNAMIC CT AMERICAN JOURNAL OF ROENTGENOLOGY FINK, I. J., Krudy, A. G., Shawker, T. H., NORTON, J. A., GORDEN, P., DOPPMAN, J. L. 1985; 144 (3): 555-556

    View details for Web of Science ID A1985ACG1100021

    View details for PubMedID 2982249

  • INSULIN REVERSAL OF CANCER CACHEXIA IN RATS CANCER RESEARCH Moley, J. F., Morrison, S. D., NORTON, J. A. 1985; 45 (10): 4925-4931

    Abstract

    The anabolic effects of exogenous neutral protamine hagedorn insulin on tumor-bearing (TB) and non-tumor-bearing (NTB) rats were examined. Exogenous insulin (2 units/100 g/day) produced similar hypoglycemia in TB and NTB rats. Food intake and body weight gain were significantly increased by insulin in NTB rats. In TB rats in an early stage of cachexia, insulin increased food intake and host weight (total body weight minus tumor weight). In TB rats with severe cachexia, insulin increased food intake and stabilized host weight when untreated TB controls were not eating and were losing weight. When daily insulin administration was started at an early stage of tumor growth and continued until death, there was again significant enhancement of host weight and food intake. Heart and adrenal weights were significantly reduced in insulin-treated TB animals. Tumor growth was not stimulated by insulin treatment. Survival time was slightly reduced in TB rats treated with long-term insulin. Survival time in TB rats randomized to insulin during late cachectic decline was not different from untreated TB controls. Insulin did not have any measurable effect on energy expenditure or the motor activity compartment of energy expenditure in either TB or NTB rats. Insulin treatment can reverse experimental cancer cachexia. It is a nutritional therapy which preferentially feeds the host over the tumor. As yet, its beneficial effects have not prolonged survival of tumor-bearing animals.

    View details for Web of Science ID A1985ARH6200038

    View details for PubMedID 3896470

  • PARATHYMIC PARATHYROID - CT, US, AND ANGIOGRAPHIC FINDINGS RADIOLOGY DOPPMAN, J. L., Shawker, T. H., Krudy, A. G., MILLER, D. L., Marx, S. J., Spiegel, A. M., NORTON, J. A., Brennan, M. F., Schaaf, M., AURBACH, G. D. 1985; 157 (2): 419-423

    Abstract

    Six patients with primary hyperparathyroidism caused by an undescended parathymic adenoma are described. All glands were anterior to the common carotid artery at the level of the hyoid bone. Blood supply was from the superior thyroid artery, and venous drainage was into the superior thyroid vein. Ultrasound (one of five) and computed tomography (two of six) were rarely positive, but glands can be detected with both modalities if the examination is carried high enough. Glands within the carotid sheath are generally lower in the neck and have a blood supply from the inferior thyroid artery with drainage into the vertebral veins.

    View details for Web of Science ID A1985ASU8200027

    View details for PubMedID 3901107

  • ULTRASONIC PARATHYROID LOCALIZATION IN PREVIOUSLY OPERATED PATIENTS CLINICAL RADIOLOGY Krudy, A. G., Shawker, T. H., DOPPMAN, J. L., Horvath, K., Schneider, P. D., NORTON, J. A., Marx, S. J., Spiegel, A. M. 1984; 35 (2): 113-118

    Abstract

    Sixty-two patients with hyperparathyroidism and failed prior neck surgery were examined by ultrasound before reoperation to localise abnormally enlarged glands. If mediastinal lesions are excluded, a total of 57 glands greater than 5 mm in size were removed from 48 patients. Ultrasound demonstrated only 18 of these for a true positive rate of 32%. There were 39/57 (68%) false negatives. In addition, there were 16 false positives. In our experience, the detection rate of ultrasound for enlarged parathyroid glands in patients with failed surgery is significantly less than that reported in previously unoperated patients (73%), or in the limited number of reported cases of patients with previous operations (75%). Our high false negative rate is probably partially due to the large number of posteriorly located small glands which cannot be adequately visualised by ultrasound. Nevertheless, because of its non-invasive nature, low cost and ready availability, ultrasound should be utilised as an initial screening procedure in patients with failed previous surgery.

    View details for Web of Science ID A1984SL87900005

    View details for PubMedID 6697653

  • CONTRIBUTION OF INERT MASS TO EXPERIMENTAL CANCER CACHEXIA IN RATS JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Morrison, S. D., Moley, J. F., NORTON, J. A. 1984; 73 (4): 991-998

    Abstract

    An inert artificial tumor (AFT) was inflated in male F344 rats to simulate, experimentally, the growth in mass of large transplantable tumors that produce cachexia. The AFT depressed host weight gain and skeletal muscle mass up to 30% and food intake up to 20% of the depression induced by tumors of comparable size. When the growth rate of the AFT was low, there was no depression of food intake. Work-induced hypertrophy of skeletal muscles, as assessed by a gastrocnemius tenotomy model, was approximately equal to that of normal, tumor-bearing, and AFT-bearing animals. The AFT elevated host total energy expenditure by 12.5% and compartment-of-energy expenditure attributable to motor activity by 10.5%. The elevation of energy expenditure accounted for most of the depression of weight gain of AFT-bearing animals below that of intact animals. The large mass of most transplantable tumors leads to an overestimate of the malignant tissue-depletive effects of tumor and an under-estimate of the asthenic effects.

    View details for Web of Science ID A1984TN61800027

    View details for PubMedID 6592392

  • INTRAOPERATIVE URINARY CYCLIC ADENOSINE-MONOPHOSPHATE AS A GUIDE TO SUCCESSFUL REOPERATIVE PARATHYROIDECTOMY ANNALS OF SURGERY NORTON, J. A., Brennan, M. F., Saxe, A. W., Wesley, R. A., DOPPMAN, J. L., Krudy, A. G., Marx, S. J., Santora, A. C., Hicks, M., AURBACH, G. D., Spiegel, A. M. 1984; 200 (4): 389-395

    Abstract

    Sixty patients with persistent or recurrent primary hyperparathyroidism underwent reexploration during which urinary cyclic adenosine monophosphate (UcAMP) levels were determined at half-hour intervals by radioimmunoassay. Retrospective analysis of the data allowed us to develop UcAMP criteria for surgical success. Following removal of parathyroid tissue, if an individual UcAMP level dropped 50% from the median baseline level, or if elevated levels dropped to less than 4.0 nmol/dl glomerular filtrate, surgery was predicted to be successful. Eight unsuccessful procedures in seven patients produced no decline in UcAMP, and the intraoperative results accurately predicted surgical failure. Fifty-three patients underwent successful procedures and in every case UcAMP fell. Ninety-eight per cent of these successful procedures were predicted by our criteria. Levels of UcAMP fell 1.5 +/- 0.5 hours (means +/- SD) following abnormal parathyroidectomy. In 19 of 36 successful cases diagnosed before surgery as adenoma, the operative procedure was terminated before a significant drop in UcAMP. In 16 of 17 successful cases diagnosed before surgery as hyperplasia or uncertain histology, UcAMP fell during the operation. Intraoperative determination of UcAMP is helpful in reoperative parathyroid surgery. The criteria established allow intraoperative prediction of success with remarkable accuracy. Urinary cyclic AMP is especially helpful in reoperation for multigland disease; when enough pathologic tissue has been removed, the criteria will be met and the procedure may be terminated with confidence.

    View details for Web of Science ID A1984TM59200001

    View details for PubMedID 6091573

  • HYPERFUNCTIONING CYSTIC PARATHYROID-GLANDS - CT AND SONOGRAPHIC FINDINGS AMERICAN JOURNAL OF ROENTGENOLOGY Krudy, A. G., DOPPMAN, J. L., Shawker, T. H., Spiegel, A. M., Marx, S. J., Norton, J., Schaaf, M., Moss, M. L., Weiss, M. A., SCHACHNER, S. H. 1984; 142 (1): 175-178

    Abstract

    Four functioning cystic parathyroid glands were evaluated with computed tomography (CT) and sonography in four patients, only one of whom had prior surgery. Sonography demonstrated solid lesions of decreased echogenicity with fluid-filled cavities near the lower thyroid poles or in the posterosuperior mediastinum. On CT the cystic parts of the lesions were of low attenuation (1-44 H), often with a well defined wall that was better demonstrated after intravenous contrast administration. Fine-needle aspiration biopsy of two of the cystic parathyroids revealed elevated parathyroid hormone levels. These lesions probably represent degenerating adenomas rather than true parathyroid cysts. While the CT and sonographic findings are nonspecific, the diagnosis of a cystic parathyroid should be entertained when a fluid-filled lesion is encountered in the neck of a patient with or without hypercalcemia. The diagnosis may be confirmed by assay of parathyroid hormone from the fluid aspirate.

    View details for Web of Science ID A1984RW79400043

    View details for PubMedID 6606954

  • PARATHYROID ASPIRATION DIRECTED BY ANGIOGRAPHY - AN ALTERNATIVE TO VENOUS SAMPLING RADIOLOGY Krudy, A. G., DOPPMAN, J. L., Marx, S. J., NORTON, J. A., Spiegel, A. M., Santora, A. C., AURBACH, G. D. 1984; 152 (1): 207-208

    Abstract

    Not all parathyroid glands can be visualized by CT or ultrasound and, therefore, cannot be aspirated using these techniques. We report the localization of a parathyroid gland by arteriography and needle aspiration under fluoroscopic guidance. This technique can be used to confirm a diagnosis of hypervascular parathyroid tissue that cannot otherwise be confirmed.

    View details for Web of Science ID A1984SW88400041

    View details for PubMedID 6729114

  • REMOVAL OF GASTRINOMAS FOR CONTROL OF ZOLLINGER-ELLISON SYNDROME ANNALS OF SURGERY Harmon, J. W., NORTON, J. A., Collin, M. J., Krudy, A. G., Shawker, T. H., DOPPMAN, J. L., Davis, J., Jensen, R. T. 1984; 200 (4): 396-404

    Abstract

    There are two distinct problems in patients with Zollinger-Ellison Syndrome (ZES): peptic ulcer diathesis and malignant tumors. Antisecretory drugs have allowed us to control the ulcer symptoms and acid output in 45 patients with ZES. We report here the initial seven patients selected for surgical exploration with the goal of removing their gastrinomas. Prior to surgery, an extensive and rigorous protocol to localize the gastrinoma was carried out, including hypotonic duodenography, abdominal ultrasonography, selective arteriography, portal vein sampling for gastrin, and computerized tomography. With this protocol of radiographic localization, gastrinomas were found in two of the seven cases and the syndrome was "cured" in three of the seven patients. The results also demonstrate that preoperative localization is not a substitute for careful surgical exploration as tumors were found in two patients in whom localization failed.

    View details for Web of Science ID A1984TM59200002

    View details for PubMedID 6148919

  • DETECTION OF MEDIASTINAL PARATHYROID-GLANDS BY NONSELECTIVE DIGITAL ARTERIOGRAPHY AMERICAN JOURNAL OF ROENTGENOLOGY Krudy, A. G., DOPPMAN, J. L., MILLER, D. L., NORTON, J. A., Marx, S. J., Spiegel, A. M., Santora, A. C., AURBACH, G. D., Schaaf, M. 1984; 142 (4): 693-695

    Abstract

    Six patients with failed previous operations and anterior mediastinal parathyroid glands were evaluated with selective angiography and nonselective arterial digital arteriography. Selective angiography depicted two of nine mediastinal glands; nonselective arterial digital arteriography depicted only one of nine mediastinal glands and missed a sizable (4.5 cm) gland demonstrated by routine arteriography. Nonselective arterial digital arteriography did not demonstrate any additional mediastinal glands. From this preliminary experience, it was concluded that nonselective arterial digital arteriography is not a sensitive method for detecting mediastinal glands.

    View details for Web of Science ID A1984SH78400007

    View details for PubMedID 6608224

  • LOCALIZATION OF ISLET CELL TUMORS BY DYNAMIC CT - COMPARISON WITH PLAIN CT, ARTERIOGRAPHY, SONOGRAPHY, AND VENOUS SAMPLING AMERICAN JOURNAL OF ROENTGENOLOGY Krudy, A. G., DOPPMAN, J. L., Jensen, R. T., NORTON, J. A., COLLEN, M. J., Shawker, T. H., Gardner, J. D., McArthur, K., GORDEN, P. 1984; 143 (3): 585-589

    Abstract

    Ten patients with suspected islet cell tumors (seven with possible gastrinomas, three with insulinomas) underwent diagnostic evaluation with dynamic CT scanning, routine CT scanning, angiography, and sonography. Venous sampling was also performed in selected instances. Nine sites of gastrinoma and three insulinomas were confirmed surgically in eight patients. Two patients had negative surgical explorations. Routine CT demonstrated five of the nine gastrinomas and one of two insulinomas. Angiography was positive in six of nine gastrinomas and all three insulinomas. Sonography showed only two of the nine gastrinomas and two of the three insulinomas. Dynamic CT scanning demonstrated three additional lesions (two gastrinomas, one insulinoma) not visible on routine CT scanning. Although most of these lesions were visible arteriographically, dynamic CT scans at the appropriate level localized the pathology in the transverse plane and greatly aided in surgical resection of these lesions. Dynamic CT scanning is a useful adjunct to routine angiographic and CT workup of patients with islet cell tumors.

    View details for Web of Science ID A1984TE56200026

    View details for PubMedID 6087646

  • WORK IN PROGRESS - ABNORMAL PARATHYROID-GLANDS - COMPARISON OF NON-SELECTIVE ARTERIAL DIGITAL ARTERIOGRAPHY, SELECTIVE PARATHYROID ARTERIOGRAPHY, AND VENOUS DIGITAL ARTERIOGRAPHY AS METHODS OF DETECTION RADIOLOGY Krudy, A. G., DOPPMAN, J. L., MILLER, D. L., Marx, S. J., NORTON, J. A., Santora, A. C., Lasker, R. D., Downs, R. W., Spiegel, A. M., AURBACH, G. D. 1983; 148 (1): 23-29

    Abstract

    Nonselective arterial digital arteriography (NSADA), selective parathyroid arteriography (SPA), and venous digital arteriography (VDA) were compared as methods of detecting parathyroid enlargement in 14 patients with primary hyperparathyroidism undergoing preoperative localization following unsuccessful neck surgery. All 14 had SPA and NSADA, consisting of contrast injections into the ascending aorta, innominate artery, and left subclavian artery; 7 also had VDA. Surgery was performed in 9 patients, and 2 additional glands were confirmed by fine-needle aspiration and venous sampling. Parathyroid glands could not be located in 3 patients, who were not re-explored. SPA demonstrated 11/13 abnormal glands (85%). NSADA detected 7/13 (54%), and there were 2 false positives. VDA showed 5/6 glands detected by NSADA (83%); the seventh patient did not have VDA. The overall quality of VDA was inferior to NSADA. Although NSADA and VDA are less sensitive than SPA, they are safer and easier to perform and should be the initial vascular screening procedures following unsuccessful parathyroid surgery.

    View details for Web of Science ID A1983QV03900005

    View details for PubMedID 6134300

  • MUSCLE MASS AND ITS RELATIONSHIP TO TUMOR MASS AND ACTIVITY SURGICAL FORUM NORTON, J. A., Moley, J. F., Morrison, S. 1983; 34: 425-427
  • EFFECTS OF EXOGENOUS INSULIN ADMINISTRATION ON FOOD-INTAKE, BODY-WEIGHT CHANGE, AND TUMOR DOUBLING TIME SURGICAL FORUM Moley, J. F., Morrison, S., NORTON, J. A. 1983; 34: 91-93
  • ASPIRATION OF ENLARGED PARATHYROID-GLANDS FOR PARATHYROID-HORMONE ASSAY RADIOLOGY DOPPMAN, J. L., Krudy, A. G., Marx, S. J., Saxe, A., Schneider, P., NORTON, J. A., Spiegel, A. M., Downs, R. W., Schaaf, M., Brennan, M. E., Schneider, A. B., AURBACH, G. D. 1983; 148 (1): 31-35

    Abstract

    Enlarged parathyroid glands were percutaneously aspirated under computed tomographic (CT) control in 7 patients, and levels of parathyroid hormone (PTH) and human thyroglobulin (HTg) were measured. All 7 patients had high levels of PTH in at least 1 specimen. It is concluded that the measurement of high concentrations of PTH in the aspirate from a cervical or mediastinal mass, with CT documentation of needle position, provides absolute localization of parathyroid masses.

    View details for Web of Science ID A1983QV03900006

    View details for PubMedID 6856859

  • THE INFLUENCE OF TUMOR-BEARING ON PROTEIN-METABOLISM IN THE RAT JOURNAL OF SURGICAL RESEARCH NORTON, J. A., Shamberger, R., Stein, T. P., Milne, G. W., Brennan, M. F. 1981; 30 (5): 456-462

    View details for Web of Science ID A1981LW89400006

    View details for PubMedID 7242064

  • LOCALIZATION AND RESECTION OF CLINICALLY INAPPARENT MEDULLARY CARCINOMA OF THE THYROID SURGERY NORTON, J. A., DOPPMAN, J. L., Brennan, M. F. 1980; 87 (6): 616-622

    Abstract

    Seven patients who, following thyroidectomy for medullary carcinoma of the thyroid (MCT) had elevated peripheral basal or stimulated plasma calcitonin (CT) levels but no other evidence of disease, were prospectively studied to determine if disease could be localized by selective venous catheterization with pentagastrin stimulation. Disease was correctly localized to a surgically resectable area of the neck in every case and removed with low morbidity rates. Postoperative CT levels decreased in six of seven patients studied, suggesting reduction in tumor burden. One patient had no detectable CT following repeat selective venous catheterization with pentagastrin stimulation. Preoperative and postoperative carcinoembryonic antigen levels changed in a similar manner to CT levels in four of five patients studied. All patients remain alive 6 months to 3 years following the initial operation.

    View details for Web of Science ID A1980JV08900003

    View details for PubMedID 7376073

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