Bio

Clinical Focus


  • Robotics
  • Cancer > GI Oncology
  • global surgery
  • Surgical Procedures, Minimally Invasive
  • General Surgery
  • Surgical Oncology
  • Colorectal Surgery

Academic Appointments


Administrative Appointments


  • Associate Dean, Academic Affairs, Stanford University School of Medicine (2008 - Present)
  • Govenor, American College of Surgeons (2008 - 2014)
  • President, American College of Surgeons, Northern CA Chapter (2008 - 2009)
  • Chief of General Surgery, Palo Alto Veterans Health Care System (1997 - Present)
  • Chair, Faculty Senate, Stanford University Medical School Faculty Senate (2006 - 2008)
  • Chair, Committee on Student Promotion, Professionalism, and Performance, Stanford University School of Medicine (2007 - 2011)
  • Residency Site Director, Stanford University, PAVAHCS (2003 - Present)
  • Surgical Clerkship Director, Stanford University School of Medicine (2000 - 2008)
  • Cancer Liaison Program Physician, American College of Surgeons Commission on Cancer Program (1997 - 2011)

Honors & Awards


  • Alumni of the Year, Loyola Stritch School of Medicine (2009)
  • Cancer Liaison Physician Outstanding Performance Award, Commission on Cancer (2008)
  • John Austin Collins Memorial Award for Outstanding Dedication to Resident Teaching, Stanford University Department of Surgery (2007)
  • Kaiser Foundation Award for Excellence in Clinical Teaching, Stanford University School of Medicine (2006)
  • Outstandng Teacher Award, Association of Surgical Education (2005)
  • Editorial Board, Journal of Laparoendoscopic and Advanced Surgical Techniques (2000)
  • Editorial Board, Surgical Endoscopy (2000)
  • The Arthur L. Bloomfield Award for Excellence in Teaching of Clinical Medicine, Stanford University School of Medicine (2003)
  • The Henry J. Kaiser Award for Excellence in Clinical Teaching, Stanford University School of Medicine (2002)
  • The Franklin G. Ebaugh Award for Outstanding Dedication to Medical Student Advising, Stanford University School of Medicine (2002)
  • The Arthur L. Bloomfield Award for Excellence in Teaching of Clinical Medicine, The Franklin G. Ebaugh Award for Outstanding Dedication to Medical Student Advising (1999)

Professional Education


  • Fellowship:LAC and USC Medical Center (1995) CA
  • Residency:University of Pittsburgh Medical Center (1994) PA
  • Medical Education:LOYOLA UNIVERSITY CHICAGO Marcella Niehoff School of Nursing (1986) IL
  • Residency:Yale - New Haven Hospital (1989) CT
  • Fellowship:University of Pittsburgh School of Medicine (1992) PA
  • Board Certification: General Surgery, American Board of Surgery (1996)
  • Internship:Yale - New Haven Hospital (1987) CT
  • MD, Loyola University, MD (1986)
  • B.A., Carleton College, Biology (1981)

Community and International Work


  • California Coalition for Colrectal Cancer/C4

    Topic

    Colorectal cancer

    Populations Served

    all

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

  • Doctors Without Borders/MSF

    Topic

    Suregry

    Partnering Organization(s)

    Medecins Sans Frontieres/Doctors Without Borders

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Cancer Site Committee, CA State American Cancer Society Cancer Team

    Topic

    cancer screening prevention

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

  • Co-Chair Regional Council, American Cancer Society Central Coast Division

    Topic

    Cancer

    Location

    California

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

  • American Cancer Society Member, Chair of the Silicon Valley Unit Board of Directors

    Topic

    Cancer

    Populations Served

    all

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

  • Colon and Rectal Cancer Initiative

    Topic

    Screening and Prevention

    Partnering Organization(s)

    American Cancer Society

    Populations Served

    all

    Location

    California

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

Research & Scholarship

Current Research and Scholarly Interests


Our research interests are primarily in global surgery, quality improvement and surgical oncology, especially gastrointestinal cancers.We have ongoing studies in medical management trials for post operative ileus, robotics, pneumonia prevention, telehealth, and care delivery in low income settings.

Teaching

2013-14 Courses


Publications

Journal Articles


  • The evolving application of single-port robotic surgery in general surgery JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES Qadan, M., Curet, M. J., Wren, S. M. 2014; 21 (1): 26-33

    Abstract

    Advances in the field of minimally invasive surgery have grown since the original advent of conventional multiport laparoscopic surgery. The recent development of single incision laparoscopic surgery remains a relatively novel technique, and has had mixed reviews as to whether it has been associated with lower pain scores, shorter hospital stays, and higher satisfaction levels among patients undergoing procedures through cosmetically-appeasing single incisions. However, due to technical difficulties that arise from the clustering of laparoscopic instruments through a confined working space, such as loss of instrument triangulation, poor surgical exposure, and instrument clashing, uptake by surgeons without a specific interest and expertise in cutting-edge minimally invasive approaches has been limited. The parallel use of robotic surgery with single-port platforms, however, appears to counteract technical issues associated with single incision laparoscopic surgery through significant ergonomic improvements, including enhanced instrument triangulation, organ retraction, and camera localization within the surgical field. By combining the use of the robot with the single incision platform, the recognized challenges of single incision laparoscopic surgery are simplified, while maintaining potential advantages of the single-incision minimally invasive approach. This review provides a comprehensive report of the evolving application single-port robotic surgery in the field of general surgery today.

    View details for DOI 10.1002/jhbp.37

    View details for Web of Science ID 000328792500007

    View details for PubMedID 24124130

  • Traumatic injuries in developing countries: report from a nationwide cross-sectional survey of sierra leone. JAMA surgery Stewart, K. A., Groen, R. S., Kamara, T. B., Farahzad, M. M., Samai, M., Cassidy, L. D., Kushner, A. L., Wren, S. M. 2013; 148 (5): 463-469

    Abstract

    OBJECTIVE To use a nationwide household survey tool to provide an estimate of injury prevalence, mechanisms of traumatic injuries, and number of injury-related deaths in a low-income country. DESIGN A randomized, cross-sectional nationwide survey using the Surgeons OverSeas Assessment of Surgical Need tool was conducted in 2012. SETTING Sierra Leone, Africa. PARTICIPANTS Three thousand seven hundred fifty randomly selected participants throughout Sierra Leone. MAIN OUTCOME MEASURES Mechanisms of injury based on age, sex, anatomic location, cause, and sociodemographic factors as well as mechanisms of injury-related deaths in the previous year were the primary outcome measures. RESULTS Data were collected and analyzed from 1843 households and 3645 respondents (98% response rate). Four hundred fifty-two respondents (12%) reported at least 1 traumatic injury in the preceding year. Falls were the most common cause of nonfatal injuries (40%). The extremities were the most common injury site regardless of age or sex. Traffic injuries were the leading cause of injury-related deaths (32% of fatal injuries). CONCLUSIONS This study provides baseline data on the mechanisms of traumatic injuries as well as the sociodemographic factors affecting injury prevalence in one of the world's poorest nations. It is anticipated that these data will provide an impetus for further studies to determine injury severity, associated disability, and barriers to accessing care in these resource-poor areas.

    View details for DOI 10.1001/jamasurg.2013.1341

    View details for PubMedID 23325317

  • The influence of intern home call on objectively measured perioperative outcomes. JAMA surgery Kastenberg, Z. J., Rhoads, K. F., Melcher, M. L., Wren, S. M. 2013; 148 (4): 347-351

    Abstract

    HYPOTHESIS In July 2011, surgical interns were prohibited from being on call from home by the new residency review committee guidelines on work hours. In support of the new Accreditation Council for Graduate Medical Education work-hour restrictions, we expected that a period of intern home call would correlate with increased rates of postoperative morbidity and mortality. DESIGN Prospective cohort. SETTING University-affiliated tertiary Veterans Affairs Medical Center. PATIENTS All patients identified in the Veterans Affairs National Surgical Quality Improvement Program database who underwent an operation performed by general, vascular, urologic, or cardiac surgery services between fiscal years (FYs) 1999 and 2010 were included. MAIN OUTCOME MEASURES During FYs 1999-2003, the first call for all patients went to an in-hospital intern. In the subsequent period (FYs 2004-2010), the first call went to an intern on home call. Thirty-day unadjusted morbidity and mortality rates and risk-adjusted observed to expected ratios were analyzed by univariate analysis and joinpoint regression, respectively. RESULTS Unadjusted overall morbidity rates decreased between 1999-2003 and 2004-2010 (12.14% to 10.19%, P= .003). The risk-adjusted morbidity observed to expected ratios decreased at a uniform annual percentage change of -6.03% (P<.001). Unadjusted overall mortality rates also decreased between the 2 periods (1.76% to 1.26%; P= .05). There was no significant change in the risk-adjusted mortality observed to expected ratios during the study. CONCLUSIONS The institution of an intern home call schedule was not associated with increased rates of postoperative morbidity or mortality.

    View details for DOI 10.1001/jamasurg.2013.1063

    View details for PubMedID 23715944

  • An estimate of hernia prevalence in Sierra Leone from a nationwide community survey. Hernia : the journal of hernias and abdominal wall surgery Patel, H. D., Groen, R. S., Kamara, T. B., Samai, M., Farahzad, M. M., Cassidy, L. D., Kushner, A. L., Wren, S. M. 2013

    Abstract

    A large number of unrepaired inguinal hernias is expected in sub-Saharan Africa where late presentation often results in incarceration, strangulation, or giant scrotal hernias. However, no representative population-based data are available to quantify the prevalence of hernias. We present data on groin masses in Sierra Leone to estimate prevalence, barriers to care, and associated disability.A cluster randomized, cross-sectional household survey of 75 clusters of 25 households with 2 respondents each was designed to calculate the prevalence of and disability caused by groin hernias in Sierra Leone using a verbal head-to-toe examination. Barriers to hernia repairs were assessed by asking participants the main reason for delay in surgical care.Information was obtained from 3,645 respondents in 1,843 households, of which 1,669 (46%) were male and included in the study. In total, 117 males or 7.01% (95% CI 5.64-8.38) reported a soft or reducible swelling likely representing a hernia with four men having two masses. Of the 93.2% who indicated the need for health care, only 22.2% underwent a procedure, citing limited funds (59.0%) as the major barrier to care. On disability assessment, 20.2% were not able to work secondary to the groin swelling.The results indicate groin masses represent a major burden for the male population in Sierra Leone. Improving access to surgical care for adult patients with hernias and early intervention for children will be vital to address the burden of disease and prevent complications or limitations of daily activity.

    View details for DOI 10.1007/s10029-013-1179-3

    View details for PubMedID 24241327

  • Telehealth Follow-up in Lieu of Postoperative Clinic Visit for Ambulatory Surgery: Results of a Pilot Program. JAMA surgery Hwa, K., Wren, S. M. 2013: 1-5

    Abstract

    IMPORTANCE Telehealth encounters can safely substitute for routine postoperative clinic visits in selected ambulatory surgical procedures. OBJECTIVE To examine whether an allied health professional telephone visit could safely substitute for an in-person clinic visit. DESIGN Prospective case series during a 10-month study period from October 2011 to October 2012 (excluding July and August 2012). SETTING University-affiliated veterans hospital. PATIENTS Ambulatory surgery patients who underwent elective open hernia repair or laparoscopic cholecystectomy during the 10-month study period. INTERVENTIONS Patients were called 2 weeks after surgery by a physician assistant and assessed using a scripted template. Assessment variables included overall health, pain, fever, incision appearance, activity level, and any patient concerns. If the telephone assessment was consistent with absence of infection and return to baseline activities, the patient was discharged from follow-up. Patients who preferred a clinic visit were seen accordingly. MAIN OUTCOMES AND MEASURES Percentage of patients who accepted telehealth follow-up and complications that presented in telehealth patients within 30 days of surgery. RESULTS One hundred fifteen open herniorrhaphy and 26 laparoscopic cholecystectomy patients had attempted telehealth follow-up. Seventy-eight percent (110) of all patients were successfully contacted; of those, 70.8% (63) of hernia patients and 90.5% (19) of cholecystectomy patients accepted telehealth as the sole means of follow-up. Complications in the telehealth patients were zero for cholecystectomy and 4.8% (3) for herniorrhaphy. Nearly all patients expressed great satisfaction with the telephone follow-up method. CONCLUSIONS Telehealth can be safely used in selected ambulatory patients as a substitute for the standard postoperative clinic visit with a high degree of patient satisfaction. Time and expense for travel (7-866 miles) were reduced and the freed clinic time was used to schedule new patients.

    View details for PubMedID 23842982

  • Prevention of VTE in Nonorthopedic Surgical Patients Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines CHEST Gould, M. K., Garcia, D. A., Wren, S. M., Karanicolas, P. J., Arcelus, J. I., Heit, J. A., Samama, C. M. 2012; 141 (2): E227S-E277S
  • Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest Gould, M. K., Garcia, D. A., Wren, S. M., Karanicolas, P. J., Arcelus, J. I., Heit, J. A., Samama, C. M. 2012; 141 (2): e227S-77S

    Abstract

    VTE is a common cause of preventable death in surgical patients.We developed recommendations for thromboprophylaxis in nonorthopedic surgical patients by using systematic methods as described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.We describe several alternatives for stratifying the risk of VTE in general and abdominal-pelvic surgical patients. When the risk for VTE is very low (< 0.5%), we recommend that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation. For patients at low risk for VTE (?1.5%), we suggest mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no prophylaxis (Grade 2C). For patients at moderate risk for VTE (?3%) who are not at high risk for major bleeding complications, we suggest low-molecular-weight heparin (LMWH) (Grade 2B), low-dose unfractionated heparin (Grade 2B), or mechanical prophylaxis with IPC (Grade 2C) over no prophylaxis. For patients at high risk for VTE (?6%) who are not at high risk for major bleeding complications, we recommend pharmacologic prophylaxis with LMWH (Grade 1B) or low-dose unfractionated heparin (Grade 1B) over no prophylaxis. In these patients, we suggest adding mechanical prophylaxis with elastic stockings or IPC to pharmacologic prophylaxis (Grade 2C). For patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer, we recommend extended-duration, postoperative, pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B). For patients at moderate to high risk for VTE who are at high risk for major bleeding complications or those in whom the consequences of bleeding are believed to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). For patients in all risk groups, we suggest that an inferior vena cava filter not be used for primary VTE prevention (Grade 2C) and that surveillance with venous compression ultrasonography should not be performed (Grade 2C). We developed similar recommendations for other nonorthopedic surgical populations.Optimal thromboprophylaxis in nonorthopedic surgical patients will consider the risks of VTE and bleeding complications as well as the values and preferences of individual patients.

    View details for DOI 10.1378/chest.11-2297

    View details for PubMedID 22315263

  • The Role of Unconscious Bias in Surgical Safety and Outcomes SURGICAL CLINICS OF NORTH AMERICA Santry, H. P., Wren, S. M. 2012; 92 (1): 137-?

    Abstract

    Racial, ethnic, and gender disparities in health outcomes are a major challenge for the US health care system. Although the causes of these disparities are multifactorial, unconscious bias on the part of health care providers plays a role. Unconscious bias occurs when subconscious prejudicial beliefs about stereotypical individual attributes result in an automatic and unconscious reaction and/or behavior based on those beliefs. This article reviews the evidence in support of unconscious bias and resultant disparate health outcomes. Although unconscious bias cannot be entirely eliminated, acknowledging it, encouraging empathy, and understanding patients' sociocultural context promotes just, equitable, and compassionate care to all patients.

    View details for DOI 10.1016/j.suc.2011.11.006

    View details for Web of Science ID 000301157800014

    View details for PubMedID 22269267

  • Racial and ethnic differences in lymph node examination after colon cancer resection do not completely explain disparities in mortality CANCER Rhoads, K. F., Cullen, J., Ngo, J. V., Wren, S. M. 2012; 118 (2): 469-477

    Abstract

    In 1999, a multidisciplinary panel of experts in colorectal cancer reviewed the relevant medical literature and issued a consensus recommendation for a 12-lymph node (LN) minimum examination after resection for colon cancer. Some authors have shown racial/ethnic differences in receipt of this evidence-based care. To date, however, none has investigated the correlation between disparities in LN examination and disparities in outcomes after colon cancer treatment.This retrospective analysis used California Cancer Registry linked to California Office of Statewide Health Planning and Development discharge data (1996-2006). Chi-square analysis, logistic regression, and Cox proportional hazard models predicted disparities in receipt of an adequate examination and the effect of an inadequate exam on mortality and disparities. Patients with stage I and II colon cancers undergoing surgery in California were included; patients with stage III and IV disease were excluded.A total of 37,911 records were analyzed. Adequate staging occurred in fewer than half of cases. An inadequate examination (<12 LNs) was associated with higher mortality rates. Hispanics had the lowest odds of receiving an adequate exam; however, blacks, not Hispanics, had the highest risk of mortality compared with whites. This disparity was not completely explained by inadequate LN examination.Inadequate LN exam occurs often and is associated with increased mortality. There are disparities in receipt of the minimum exam, but this only explains a small part of the observed disparity in mortality. Improving the quality of LN examination alone is unlikely to correct colon cancer disparities.

    View details for DOI 10.1002/cncr.26316

    View details for Web of Science ID 000298846600025

    View details for PubMedID 21751191

  • Single-Port Robotic Cholecystectomy Results From a First Human Use Clinical Study of the New da Vinci Single-Site Surgical Platform ARCHIVES OF SURGERY Wren, S. M., Curet, M. J. 2011; 146 (10): 1122-1127

    Abstract

    To report our results from a first human use clinical study with the da Vinci Surgical single-site instrumentation in patients with gallbladder disease and to perform a retrospective comparison with traditional multiport laparoscopic cholecystectomy.Ten patients underwent robotic single-port cholecystectomy performed with the da Vinci Si robot and novel da Vinci single-site instrumentation. Outcomes and operative times were compared with patients undergoing traditional multiport laparoscopic cholecystectomy during the same period.Tertiary care Veterans Administration hospital.Outpatients older than 18 years with an American Society of Anesthesiologists class of 1 to 3, no prior upper abdominal surgery, and diagnosis of noninflammatory biliary disease.Single-site robotic cholecystectomy.Operative time, complications up to 30 days, pain scores, and overall satisfaction.Nine of 10 patients had completion of robotic single-site cholecystectomy. Average operating room time was 105.3 minutes compared with an average of 106.1 minutes in the standard laparoscopic group. There were no serious adverse events in the robotic surgery group, with an average follow-up of 3 or more months.Robotic single-port cholecystectomy is feasible and comparable with standard laparoscopic cholecystectomy in the Veterans Administration medical center setting.

    View details for DOI 10.1001/archsurg.2011.143

    View details for Web of Science ID 000295942300002

    View details for PubMedID 21690436

  • Innovation in Safety, and Safety in Innovation JAMA SURGERY Eisenberg, D., Wren, S. M. 2014; 149 (1): 7-9

    View details for DOI 10.1001/jamasurg.2013.5112

    View details for Web of Science ID 000330117300002

    View details for PubMedID 24352512

  • Long-Term Comparison of Endovascular and Open Repair of Abdominal Aortic Aneurysm NEW ENGLAND JOURNAL OF MEDICINE Lederle, F. A., Freischlag, J. A., Kyriakides, T. C., Matsumura, J. S., Padberg, F. T., Kohler, T. R., Kougias, P., Jean-Claude, J. M., Cikrit, D. F., Swanson, K. M. 2012; 367 (21): 1988-1997

    Abstract

    Whether elective endovascular repair of abdominal aortic aneurysm reduces long-term morbidity and mortality, as compared with traditional open repair, remains uncertain.We randomly assigned 881 patients with asymptomatic abdominal aortic aneurysms who were candidates for both procedures to either endovascular repair (444) or open repair (437) and followed them for up to 9 years (mean, 5.2). Patients were selected from 42 Veterans Affairs medical centers and were 49 years of age or older at the time of registration.More than 95% of the patients underwent the assigned repair. For the primary outcome of all-cause mortality, 146 deaths occurred in each group (hazard ratio with endovascular repair versus open repair, 0.97; 95% confidence interval [CI], 0.77 to 1.22; P=0.81). The previously reported reduction in perioperative mortality with endovascular repair was sustained at 2 years (hazard ratio, 0.63; 95% CI, 0.40 to 0.98; P=0.04) and at 3 years (hazard ratio, 0.72; 95% CI, 0.51 to 1.00; P=0.05) but not thereafter. There were 10 aneurysm-related deaths in the endovascular-repair group (2.3%) versus 16 in the open-repair group (3.7%) (P=0.22). Six aneurysm ruptures were confirmed in the endovascular-repair group versus none in the open-repair group (P=0.03). A significant interaction was observed between age and type of treatment (P=0.006); survival was increased among patients under 70 years of age in the endovascular-repair group but tended to be better among those 70 years of age or older in the open-repair group.Endovascular repair and open repair resulted in similar long-term survival. The perioperative survival advantage with endovascular repair was sustained for several years, but rupture after repair remained a concern. Endovascular repair led to increased long-term survival among younger patients but not among older patients, for whom a greater benefit from the endovascular approach had been expected. (Funded by the Department of Veterans Affairs Office of Research and Development; OVER ClinicalTrials.gov number, NCT00094575.).

    View details for DOI 10.1056/NEJMoa1207481

    View details for Web of Science ID 000311340200006

    View details for PubMedID 23171095

  • Cost-effectiveness of open versus endovascular repair of abdominal aortic aneurysm in the OVER trial JOURNAL OF VASCULAR SURGERY Stroupe, K. T., Lederle, F. A., Matsumura, J. S., Kyriakides, T. C., Jonk, Y. C., Ge, L., Freischlag, J. A. 2012; 56 (4): 901-?

    Abstract

    This study was conducted to determine the costs and comparative cost-effectiveness of two methods of abdominal aortic aneurysm (AAA) repair in the Open Versus Endovascular Repair (OVER) Veterans Affairs (VA) Cooperative Study, a multicenter randomized trial of 881 patients.The primary outcomes of this analysis were mean total health care cost per life-year and per quality-adjusted life-year (QALY) from randomization to 2 years after. QALYs were calculated from EuroQol (EQ)-5D questionnaires collected at baseline and annually. Health care utilization data were obtained directly from patients and from national VA and Medicare data sources. VA costs were obtained from national VA sources using methods previously developed by the VA Health Economics Resource Center. Costs for non-VA care were determined from Medicare claims data or billing data from the patient's health care providers.After 2 years of follow-up, mean life-years were 1.78 in the endovascular repair group and 1.74 in the open repair group (difference, 0.04; 95% confidence interval [CI], -0.03 to 0.09; P = .29). Mean QALYs were 1.462 in the endovascular group and 1.461 in the open group (difference adjusting for baseline EQ-5D score, 0.006; 95% CI, -0.038 to 0.052; P = .78). Mean graft costs were higher in the endovascular group ($14,052 vs $1363; P < .001), but length of stay was shorter (5.0 vs 10.5 days; P < .001), resulting in a lower mean cost of the hospital admission for the AAA procedure in the endovascular repair group of $37,068 vs $42,970 (difference, -$5901; 95% CI, -$12,135 to -$821; P = .04). After 2 years, total health care costs remained lower in the endovascular group, but the difference was no longer significant (-$5019; 95% CI, -$16,720 to $4928; P = .35). The probability of endovascular repair being less costly and more effective was 70.9% for life-years and 51.4% for QALYs.In this multicenter randomized trial, endovascular AAA repair resulted in lower cost and better survival than open repair after the initial hospitalization for repair; but after 2 years, survival, quality of life, and costs were not significantly different between the two treatments.

    View details for DOI 10.1016/j.jvs.2012.01.086

    View details for Web of Science ID 000309512300001

    View details for PubMedID 22640466

  • Innovative leadership of casualty care: comment on "Eliminating preventable death on the battlefield". Archives of surgery Wren, S. M. 2011; 146 (12): 1358-?

    View details for DOI 10.1001/archsurg.2011.282

    View details for PubMedID 22184292

  • Solitary metastatic clear cell carcinoma to the spleen. Rare tumors Zayed, M. A., Kosek, J., Wren, S. M. 2011; 3 (4)

    Abstract

    A 57-year-old with a 9-year history of increased abdominal girth, presented with increased abdominal pain, anemia, and acute renal failure. His past medical history was only remarkable for a previous lung cancer 21 years ago that was treated with a right upper lung lobectomy. A computed tomography (CT) scan of the patient's abdomen showed a solitary 202025cm cystic splenic mass. The patient underwent an urgent splenectomy. Intra-operatively a large splenic cystic cavity was found with a solid inferior splenic mass. An exhaustive histological analysis of the splenic mass confirmed a clear cell carcinoma with low malignant potential that likely represented a metastatic lesion from the patient's previous distant lung cancer. Postoperatively the patient recovered well and at 1-year followup the patient demonstrated no further evidence of metastatic disease. This case is extremely unique and provides a very rare example of a metastatic solitary clear cell carcinoma to the spleen, with a presumed latency period of more than 20 years.

    View details for DOI 10.4081/rt.2011.e43

    View details for PubMedID 22355498

  • Endoscopic clipping of a post-whipple pancreatic bleed SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES Kaltenbach, T., Wren, S., Schumacher, L., Soetikno, R. 2009; 23 (9): 2159-2160

    Abstract

    Bleeding after pancreaticoduodenectomy most often occurs from the gastro- or duodeno-jejunal anastomosis. Bleeding at the pancreatic surface would be the most difficult to treat because it typically requires surgical resection of the pancreatic remnant-a surgery that has significant morbidity and mortality. Data that describe the role of endoscopy in the management of pancreaticojejunostomy bleeding are limited.We present the case of a 69-year-old man who had massive upper gastrointestinal bleeding on postoperative day 2 after a pyloric sparing Whipple procedure for cholangiocarcinoma. We endoscopically approached this massive upper gastrointestinal bleed by understanding the postsurgical anatomy to consider all of the potential bleeding sources: duodenojejunostomy, hepaticojejunstomy, and the pancreaticojejunostomy. Using a pediatric colonoscope with water jet capabilities, active bleeding could be seen originating from the cut pancreatic surface. Complete hemostasis was achieved after placement of two clips. We clipped again two clays later due to a minor rebleeding episode. We repeated endoscopy on postoperative day 6 for surveillance of the site. All clips were in place and there was no evidence of bleeding. The patient did well without recurrent bleeding and was discharged home on postoperative day 7. Six-month follow-up showed no recurrent bleeding episodes or development of fistulas.Endoscopic treatment of a bleeding site on the pancreatic surface of a pancreaticojejunostomy can be successful during the immediate postoperative period. Such an attempt at endoscopic hemostasis may prevent the need for completion pancreatectomy.

    View details for DOI 10.1007/s00464-009-0357-y

    View details for Web of Science ID 000269209700035

  • Male Patients Above Age 60 have as Good Outcomes as Male Patients 50-59 Years Old at 1-Year Follow-up After Bariatric Surgery OBESITY SURGERY Wool, D., Bellatorre, N., Wren, S., Eisenberg, D. 2009; 19 (1): 18-21

    Abstract

    It is estimated that 25% of Americans older than 60 years are obese. Male gender and advanced age are indicators of increased risk for bariatric surgery. Good results have been shown in patients older than 50, but nearly all published studies include a large majority of females, and few include patients >60 years old. In this study, we examined the results of males over 60 years old.We reviewed a prospective database of 107 consecutive patients who underwent bariatric surgery between April 2002 and June 2007 at the Palo Alto VA. Of these, 60 patients were males older than 50 and available for follow-up 12 months postoperatively. There were 47 males 50-59 years old (group I) and 13 males older than 60 years (group II). Data were analyzed using Student's t test.Mean preoperative body mass index was similar in both groups (49.4 vs. 47.5 kg/m(2); p = 0.468). Length of hospital stay was similar (3.2 vs. 3.5 days; p = 0.678), but early morbidity was higher in group II patients (30.8% vs. 8.5%; p = 0.037). Morbidity included urinary tract infection, cardiac arrhythmias, and early bowel obstruction. Excess weight loss after 1 year was not significantly different (63.6% vs. 60.6%; p = 0.565). Diabetes resolution or improvement was seen in 87% of group I patients and 90% of group II patients.Despite a higher early morbidity rate, obese males >/=60 years old perform as well as male patients 50-59 years old with respect to excess weight loss, mortality, length of stay, and improvement of diabetes, at 1 year postoperatively.

    View details for DOI 10.1007/s11695-008-9734-1

    View details for Web of Science ID 000262281700004

    View details for PubMedID 18855082

  • Metastatic colon adenocarcinoma mimicking herpes zoster JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Goodwin, T. L., Wren, S. M. 2007; 205 (4): 625-625
  • Care within a Veterans Hospital - Earlier detection of colon cancer SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES van Roessel, P., Rouse, R. V., Wren, S. M. 2007; 21 (8): 1434-1440

    Abstract

    In 1998 the Veterans Administration mandated an externally monitored targeted colon cancer screening rate that was expected to result in earlier cancer detection and improved patient survival. The effectiveness of the protocol was evaluated in a retrospective case series at a tertiary care Veterans Administration Hospital that included all patients with the diagnosis of colon cancer between 1991 and 2003.Tumor stage, tumor location, and patient survival data were recorded and compared to National Cancer Data Base (NCDB) benchmarks.The study facility had a greater percentage of early cancers and fewer later stage cancers than the NCDB benchmark. Overall survival was better for the VA cohort compared to NCDB (all-cause 5-year survival: VA, 0.72; NCDB, 0.47. p < or = .001).The VA facility had a significantly greater percentage of early cancers and fewer stage III or IV cancers compared to a national benchmark and significantly improved survival compared to the national benchmark.

    View details for DOI 10.1007/s00464-006-9184-6

    View details for Web of Science ID 000248737700035

    View details for PubMedID 17294311

  • Transnasal small-caliber esophagogastroduodenoscopy for preoperative evaluation of the high-risk morbidly obese patient SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES Alami, R. S., Schuster, R., Friedland, S., Curet, M. J., Wren, S. M., Soetikno, R., Morton, J. M., Safadi, B. Y. 2007; 21 (5): 758-760

    Abstract

    Esophagogastroduodenoscopy (EGD) is an important facet of the preoperative evaluation for bariatric surgery. Morbidly obese patients are at high risk for airway complications during this procedure, and an attractive alternative is transnasal EGD. This report describes a series of patients evaluated successfully using this technique.All patients undergoing preoperative transnasal small-caliber EGD for morbid obesity surgery between September 2004 and June 2005 at a Veterans Affairs Hospital were included in the analysis. The variables assessed were the adequacy of the examination, patient tolerance, the need for sedation, and the ability to perform interventions.The study enrolled 25 patients (17 men and 8 women) with an average age of 55 years (range, 44-63 years) and an average body mass index (BMI) of 47 kg/m2 (range, 38-69 kg/m2). All the patients met the 1991 National Institutes of Health (NIH) Consensus Conference Criteria for bariatric surgery and were undergoing preoperative evaluation. The most common comorbidities were hypertension (82%), diabetes mellitus (80%), and obstructive sleep apnea (68%). All 25 patients had successful cannulation of the duodenum's second portion with excellent tolerance. There were no sedation requirements for 23 (92%) of the 25 patients. Significant pathology was found in 14 (56%) of the 25 patients, including hiatal hernia (28%), gastritis (16%), esophageal intestinal metaplasia (16%), esophagitis (12%), gastric polyps (8%), gastric ulcer (4%) and esophageal varices (4%). Biopsies were indicated for 12 patients and successful for all 12 (100%).Transnasal small-caliber EGD is a feasible and safe alternative to conventional EGD for the preoperative evaluation of patients undergoing bariatric surgery. It requires minimal to no sedation in a population at high risk for complications in this setting. In addition, this technique is effective in identifying pathology that requires preoperative treatment and offers a complete examination with biopsy capabilities. This technique should be considered for all morbidly obese patients at high risk for airway compromise during EGD.

    View details for DOI 10.1007/s00464-006-9101-z

    View details for Web of Science ID 000246351800013

    View details for PubMedID 17235723

  • Short- and long-term outcomes of standardized EMR of nonpolypoid (flat and depressed) colorectal lesions >= 1 cm (with video) GASTROINTESTINAL ENDOSCOPY Kaltenbach, T., Friedland, S., Maheshwari, A., Ouyang, D., Rouse, R. V., Wren, S., Soetikno, R. 2007; 65 (6): 857-865

    Abstract

    Nonpolypoid (flat and depressed) colorectal lesions are increasingly recognized. Their endoscopic removal requires specialized EMR techniques, which are more complex to perform. Outcomes data on EMR of nonpolypoid neoplasms in the United States is needed.To determine the safety and efficacy of EMR in the resection of nonpolypoid colorectal neoplasms > or = 1 cm.Retrospective analysis.Veterans Affairs Palo Alto Health Care System.Over a 5-year period, patients who underwent EMR for nonpolypoid colorectal lesions > or = 1 cm.A standardized approach that included lesion assessment, classification, inject-and-cut EMR technique, reassessment, and treatment of residual tissue.Complete resection, bleeding, perforation, development of advanced cancer, and death.A total of 100 patients (125 lesions: 117 flat and 8 depressed) met inclusion criteria. Mean size was 16.7 +/- 7 mm (range, 10-50 mm). Histology included 5 submucosal invasive cancers, 5 carcinomas in situ, and 91 adenomas. Thirty-eight patients (48 lesions) did not receive surveillance colonoscopy: 8 had surgery, 16 had hyperplastic pathology, and 14 did not undergo repeat examination. Surveillance colonoscopy was performed on 62 patients (77 lesions). Complete resection was achieved in 100% of these patients after 1 to 3 surveillance colonoscopies. All patients received follow-up (mean [standard deviation] = 4.5 +/- 1.4 years); none developed colorectal cancer or metastasis.Single endoscopist, retrospective study.A standardized EMR (inject-and-cut) technique is a safe and curative treatment option in nonpolypoid colorectal neoplasms (> or = 1 cm) in the United States.

    View details for DOI 10.1016/j.gie.2006.11.035

    View details for Web of Science ID 000246217300017

    View details for PubMedID 17466205

  • The use of acellular dermal matrix for contaminated abdominal wall defects: wound status predicts success AMERICAN JOURNAL OF SURGERY Schuster, R., Singh, J., Safadi, B. Y., Wren, S. M. 2006; 192 (5): 594-597

    Abstract

    Contaminated abdominal wall fascial defects present a challenging problem. The use of human acellular dermal matrix (AlloDerm; LifeCell Corp., Branchburg, NJ) provides a novel method of primary closure of abdominal wall defects in this setting. The aim of the current study was to determine what factors predicted fascial wall failure as determined by the presence of hernia on follow-up exam after AlloDerm placement.All patients who underwent surgery for contaminated abdominal wall fascial defects with placement of AlloDerm from June 2003 to September 2005 at a tertiary care Veterans Affairs hospital were included in the analysis. Patients were followed until hernia recurrence or last clinic visit.Eighteen patients had AlloDerm placed for contaminated fascial defects and all were included in the analysis. Primary wound closure was performed on 12/18 (67%) patients, with 6/18 (33%) patients initially left with open wounds. Patients with open wounds were treated with wound vacuum-assisted closure (VAC) devices (4/6) or saline dressings (2/6). Overall ventral hernia recurrence rate was 50% (9/18) with an average follow up of 9.1 months. Patients who had primary wound closure at the completion of the operation had a 33% (4/12) recurrence rate. Patients who did not have primary wound closure had an 83.3% (5/6) recurrence rate. The significant difference shows (P = .03) that open wound status predicts recurrence. The average size of AlloDerm sheets used was 164.0 cm2 in the closed group and 146.2 cm2 in the primary open wound group (P = .64). Average cost per patient was 4680 dollars for AlloDerm.These data suggest that an open wound in the postoperative period after AlloDerm placement for treatment of contaminated fascial defects is associated with a high probability of hernia recurrence. Our data do not support the use of this expensive material unless there is a good chance of having a closed wound.

    View details for DOI 10.1016/j.amjsurg.2006.08.017

    View details for Web of Science ID 000241820000007

    View details for PubMedID 17071190

  • Concurrent gastric bypass and repair of anterior abdominal wall hernias OBESITY SURGERY Schuster, R., Curet, M. J., Alami, R. S., Morton, J. M., Wren, S. M., Safadi, B. Y. 2006; 16 (9): 1205-1208

    Abstract

    Many patients seeking surgical treatment for morbid obesity present with anterior abdominal wall hernias. Although principles of hernia repair involve a tension-free repair with the use of prosthetic mesh, there is concern about the use of mesh in gastric bypass surgery due to potential contamination with the contents of the gastrointestinal tract and resultant mesh infection. We report our series of patients undergoing Roux-en-Y gastric bypass (RYGBP) and simultaneous anterior abdominal wall hernia repair.All patients who underwent simultaneous RYGBP surgery and anterior abdominal wall hernia repair were reviewed.12 patients underwent concurrent RYGBP and anterior wall hernia repair. There were 5 women and 7 men with average age 54.9 +/- 8.5 years (range 35 to 64) and average body mass index (BMI) 50.4 +/- 10.3 kg/m(2) (range 38 to 70). Two open and 10 laparoscopic RYGBP operations were performed. Nine patients (75%) underwent incisional hernia repairs and 3 patients (25%) underwent umbilical hernia repair concurrent with gastric bypass. Average size of defect was 14.7 +/- 13.4 cm(2). One patient had primary repair and 11 patients had prosthetic mesh repair: polypropylene in 3 patients (25%) and polyester in 8 patients (67%). With a 14.1 +/- 9.3 month follow-up, there have been no mesh infections and 2 recurrences, one in the patient who underwent primary repair and one in a patient repaired with polyester mesh but with two previous failed incisional hernia repairs.Concurrent RYGBP and repair of anterior abdominal wall hernias is safe and feasible. In order to optimize success, tension-free principles of hernia repair with the use of prosthetic mesh should be followed since no mesh infections occurred in our series.

    View details for Web of Science ID 000240355400015

    View details for PubMedID 16989705

  • Laparoscopic Roux-en-Y gastric bypass at a Veterans Affairs and high-volume academic facilities: a comparison of institutional outcomes AMERICAN JOURNAL OF SURGERY Alami, R. S., Morton, J. M., Sanchez, B. R., Curet, M. J., Wren, S. M., Safadi, B. Y. 2005; 190 (5): 821-825

    Abstract

    Outcomes of bariatric surgery have been linked to institutional case volume. The objective of our study was to compare outcome of laparoscopic Roux-en-y gastric bypass (RYGB) in 2 settings: a low-volume Veterans Affairs (VA) and a high-volume university hospital (UH).Over a period of 27 months, 140 patients underwent RYGB (137 laparoscopic, 3 open) performed by 1 surgeon. Fifty-five were performed at a VA and 85 at a UH with an annual caseload close to 300.The body mass index in both groups was similar, but patients at the VA were older, mostly men, and more likely to have hypertension (HTN), obstructive sleep apnea, and diabetes mellitus (DM). Operative and anesthesia times were significantly longer at the VA. There were no differences in 30-day mortality (none), major morbidity, conversion rates, or reoperation rates.Laparoscopic RYGB can be performed safely at a VA facility despite a higher risk population and low annual volume.

    View details for DOI 10.1016/j.amjsurg.2005.07.027

    View details for Web of Science ID 000232935200030

    View details for PubMedID 16226965

  • Preoperative oral antibiotics in colorectal surgery increase the rate of Clostridium difficile colitis ARCHIVES OF SURGERY Wren, S. M., Ahmed, N., Jamal, A., Safadi, B. Y. 2005; 140 (8): 752-755

    Abstract

    Bowel preparation traditionally consists of cathartics, oral antibiotics, and intravenous antibiotics. We hypothesize that the use of oral antibiotics in bowel preparation results in a higher rate of postoperative Clostridium difficile colitis.Retrospective case-controlled study of elective colon surgery patients; January 1997 to June 2003.Tertiary care veterans administration hospital.Records of patients who underwent elective colorectal surgery (n = 304) were reviewed. Patients with bowel obstruction or emergent operation were excluded.Detection of C difficile toxin A/B by enzyme-linked immunosorbent assay in a stool specimen within 30 days of surgery.All 304 patients received both cathartics and intravenous antibiotics. Of 304 patients, 107 (35.1%) received oral antibiotics. The rate of postoperative C difficile colitis was 4.2% in the entire study population. The rate of C difficile infection was higher in patients who received oral antibiotics (7.4%) compared with patients who did not receive oral antibiotics (2.6%; P = .03). There were no C difficile-related mortalities.Oral nonabsorbable antibiotics in bowel preparation resulted in a higher rate of C difficile infection. This may be due to the additional effect of oral antibiotics on normal bowel flora. We recommend that oral nonabsorbable antibiotics not be used in preoperative bowel preparation regimens since postoperative C difficile infection can lead to additional morbidity, length of stay, and hospital costs.

    View details for Web of Science ID 000230948300009

    View details for PubMedID 16103284

  • Comparison of training on two laparoscopic simulators and assessment of skills transfer to surgical performance JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Youngblood, P. L., Srivastava, S., Curet, M., Heinrichs, W. L., Dev, P., Wren, S. M. 2005; 200 (4): 546-551

    Abstract

    Several studies have investigated the transfer of surgical trainees' skills acquired on surgical simulators to the operating room setting. The purpose of this study was to compare the effectiveness of two laparoscopic surgery simulators by assessing the transfer of skills learned on simulators to closely matched surgical tasks in the animal laboratory.In this post-test-only Control group study design, 46 surgically naive medical student volunteers were randomly assigned to one of three groups: Tower Trainer group (n = 16), LapSim group (n = 17), and Control group (n = 13). Outcomes measures included both time and accuracy scores on three laparoscopic tasks (Task 1: Grasp and Place; Task 2: Run the Bowel; Task 3: Clip and Cut) performed on live anesthetized pigs, and a global rating of overall performance as judged by four experienced surgeons.The Tower Trainer group performed significantly better than the Control group on 1 of 7 outcomes measures-Task 3: Time (p < 0.032), although the LapSim group performed significantly better than the Control group on 2 of 7 measures-Task 3: Time (p < 0.008) and Global score (p < 0.005). In comparing the two simulators, the LapSim group performed significantly better than the Tower Trainer group on 3 of 7 outcomes measures-Task 2: Time (p < 0.032), Task 2: Accuracy (p < 0.030) and Global score (p < 0.005), although the Tower Trainer group did not perform significantly better than the LapSim group on any measure.This study demonstrated that naive subjects trained on a virtual-reality part-task trainer performed better on live surgical tasks in a porcine model as compared with those trained with a traditional box trainer. These findings could aid in selection of appropriate training methodologies.

    View details for DOI 10.1016/j.jamcollsurg.2004.11.011

    View details for Web of Science ID 000228085200007

    View details for PubMedID 15804468

  • Introducing laparoscopic Roux-en-Y gastric bypass at a Veterans Affairs medical facility AMERICAN JOURNAL OF SURGERY Safadi, B. Y., Kieran, J. A., Hall, R. G., Morton, J. M., Bellatorre, N., Shinoda, E., Johnson, P. J., Curet, M. J., Wren, S. M. 2004; 188 (5): 606-610

    Abstract

    Previous studies have shown that advanced age, diabetes, and male gender are associated with higher morbidity and mortality after bariatric surgery. Those risk factors are characteristic of patients in the Veterans Affairs (VA) health care system. Laparoscopic Roux-en-Y gastric bypass (RYGB) has become an established treatment modality for morbid obesity. Our objective was to review the initial experience with laparoscopic (RYGB) for morbid obesity at our VA facility.A retrospective review was used.Between May of 2002 and April of 2004, 40 patients underwent laparoscopic RYGB. All patients met National Institutes of Health consensus statement guidelines for bariatric surgery. There were 30 (75%) male and 10 (25%) female patients, with an average age of 49.9 +/- 8.7 years and an average body mass index (BMI) of 48.1 +/- 8.5 kg/m(2). Preoperative comorbidities included diabetes mellitus (DM) in 59%, hypertension in 79%, and obstructive sleep apnea in 74.4%. The procedure was converted to an open procedure in 3 patients (7.5%). There were no mortalities. Immediate (within 30 days) complications developed in 9 (22.5%) patients, necessitating abdominal re-operation in 3 patients (7.5%). The median length of hospital stay was 3 days. Late complications (>30 days) developed in 8 (20%) patients. Percent excess weight loss at 3, 6, and 12 months was 44% (n = 34), 59% (n = 29), and 70.0% (n = 22), respectively. In 23 patients who were followed-up for more than 3 months, DM resolved in 79% and improved in 21% at a mean follow-up evaluation of 13 months.Laparoscopic RYGB can be performed with acceptable morbidity and with good short-term results in a VA hospital setting. Morbid obesity is prevalent in the VA patient population and access to bariatric surgery should be an available alternative.

    View details for DOI 10.1016/j.amjsurg.2004.07.021

    View details for Web of Science ID 000225208600032

    View details for PubMedID 15546580

  • Institutional commitment to rectal cancer screening results in earlier-stage cancers on diagnosis ANNALS OF SURGICAL ONCOLOGY Battat, A. C., Rouse, R. V., Dempsey, L., Safadi, B. Y., Wren, S. M. 2004; 11 (11): 970-976

    Abstract

    The Veterans Administration hospitals underwent an institutional directive in 1998 to meet a colorectal cancer screening (CRCS) standard. This intervention should result in an increase in the hospital's screening rate and percentage of early-stage rectal cancers diagnosed.A retrospective review, from 1991 to 2002, of our institution's pathology and cancer registry databases for rectal cancers. CRCS data were obtained from the Veterans Administration Prevention Disease Index. Cancer stage at diagnosis was compared before and after the directive and was compared with the National Cancer Data Base and the Surveillance, Epidemiology, and End Results data.The rate of CRCS was 55% in 1998 and increased to 75% in 2003. During the 11 years studied, a total of 147 rectal cancers were diagnosed. After the Veterans Administration directive, there was a significant increase in stage 0 cancers (P < .02) and an overall migration to earlier-stage cancers. Our Veterans Administration hospital had a significantly greater percentage of stage 0 cancers both before (P < .007) and after the directive (P < .00) and had fewer stage 3 cancers after the directive (P < .03) compared with National Cancer Data Base data. Compared with Surveillance, Epidemiology, and End Results data, the Palo Alto Veterans Affairs Health Care System had more local disease (P < .03) and less regional disease (P < .006).These data suggest that a monitored institutional directive may significantly increase early detection of rectal cancers. This should result in a greater survival rate and lower local recurrence rate, because survival is predicated on stage at presentation. This may serve as a model for other health-care systems.

    View details for DOI 10.1245/ASO.2004.03.047

    View details for Web of Science ID 000224781300006

    View details for PubMedID 15525825

  • Utilization of laparoscopic antireflux surgery at a single Veterans Affairs facility compared with the Veterans Affairs national trend AMERICAN JOURNAL OF SURGERY Safadi, B. Y., Kown, M., Wren, S. 2003; 186 (5): 505-508

    Abstract

    The widespread use of laparoscopy in the early 1990s has led to an increase in the utilization of antireflux procedures for the treatment of gastroesophageal reflux disease (GERD). This trend has been observed in the private sector, but not within the Department of Veterans Affairs (VA) health care system. Published data suggest that among patients undergoing antireflux surgical procedures, those in the VA were less likely than those in the private sector to undergo laparoscopic surgery. The objective of this study was to determine the trend in the use of laparoscopic antireflux surgical procedures at our VA facility and compare it with the national VA trend.All antireflux operations performed at our VA facility from 1991 to 2002 were recorded along with techniques used. National VA data on the utilization of antireflux procedures from 1991 to 1999 was extracted from a recent publication by Finlayson et al.In contrast to the trend observed nationally across VA hospitals, the rate of utilization of antireflux surgery at our VA facility has increased compared with baseline in 1991. Of 83 fundoplications performed from 1991 to 2002, 76 (92%) were attempted or completed laparoscopically. The conversion rate from laparoscopic to open approach was 6.6%.We have observed an increase in the utilization of antireflux surgery since 1991 at our VA facility. In addition, most fundoplications were performed laparoscopically. These findings are in contrast to published national VA data. The presence of surgeons with interest in laparoscopy, institutional support, and a dedicated esophageal function laboratory may explain these findings.

    View details for DOI 10.1016/j.amjsurg.2003.07.025

    View details for Web of Science ID 000186307300017

    View details for PubMedID 14599615

  • A novel technique to treat ruptured umbilical hernias in patients with liver cirrhosis and severe ascites JOURNAL OF LAPAROENDOSCOPIC & ADVANCED SURGICAL TECHNIQUES-PART A Melcher, M. L., Lobato, R. L., Wren, S. M. 2003; 13 (5): 331-332

    Abstract

    The full-thickness skin erosion (rupture) of an umbilical hernia in a patient with end-stage liver disease can lead to significant morbidity and mortality. Here, we present a case report of the use of a novel technique to treat a patient with this condition. The use of a fibrin-based tissue adhesive provides a means of managing such patients medically.

    View details for Web of Science ID 000185762400011

    View details for PubMedID 14617394

  • Positron emission tomography in the initial staging of esophageal cancer ARCHIVES OF SURGERY Wren, S. M., Stijns, P., Srinivas, S. 2002; 137 (9): 1001-1006

    Abstract

    To assess the value of positron emission tomography (PET) compared with computed tomography (CT) in the initial staging of esophageal cancer.Case series.Tertiary care veterans hospital.Patients with newly diagnosed esophageal cancers from January 1996 through May 2001 who underwent both CT and PET scanning within 4 weeks were included in the study (n = 24). Only patients who underwent pathological or radiographic follow-up were included.The sensitivity, specificity, and negative and positive predictive values of CT and PET were determined based on a criterion standard of pathological staging in 16 patients (67%) and follow-up imaging in 8 patients (33%).For staging regional lymph node involvement, CT and PET scans showed no statistically significant difference in sensitivity (57% and 71%, respectively) and specificity (71% and 86%, respectively). For detection of metastatic disease, CT and PET showed no significant difference in sensitivity (83% and 67%, respectively) and specificity (75% and 92%, respectively). There was no significant difference in clinical decision making when the results of both tests were discordant.There was no significant difference between the 2 imaging modalities in the initial staging of esophageal cancer. The CT scan was a sensitive indicator of distant metastases, whereas PET was more specific. It is unclear what additional role PET scanning should have in the initial screening of patients.

    View details for Web of Science ID 000177920800004

    View details for PubMedID 12215149

  • Effective management of bleeding during tumor resection with a collagen-based hemostatic agent AMERICAN SURGEON Chapman, W. C., Wren, S. M., LEBOVIC, G. S., Malawer, M., Sherman, R., Block, J. E. 2002; 68 (9): 802-807

    Abstract

    In a prospective controlled trial hemostatic effectiveness of a novel collagen-based composite (CoStasis) was compared with a collagen sponge applied with manual pressure at diffusely bleeding sites after surgical tumor resection. The proportion of subjects achieving complete cessation of bleeding within 10 minutes (i.e., hemostatic success) and the time to "complete hemostasis" were determined at raw surgical sites after tumor resection among 23 experimental and 30 control subjects. There was a similar distribution in tumor types (e.g., benign vs malignant) evaluated between treatment groups. A significantly greater proportion of experimental subjects achieved complete hemostasis within 10 minutes of observation compared with controls [23 of 23 (100%) vs 21 of 30 (70%); P = 0.003]. The median time required to achieve complete hemostasis was more than three times longer for subjects treated with the collagen sponge compared with subjects treated with CoStasis (243 vs 78 seconds; P = 0.0001). Approximately 80 per cent of experimental subjects achieved complete hemostasis within 2 minutes compared with only 35 per cent of controls. There were no adverse events related to the experimental treatment in this study. These results support the use of this novel hemostatic agent to control diffuse surgical site bleeding after tumor resection at diverse anatomical locations.

    View details for Web of Science ID 000181916500015

    View details for PubMedID 12356154

  • Intravascular hemolysis from a Clostridium perfringens liver abscess JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Kreidl, K. O., Green, G. R., Wren, S. M. 2002; 194 (3): 387-387

    View details for Web of Science ID 000174231900014

    View details for PubMedID 11893140

  • Decompressive colonoscopy with intracolonic vancomycin administration for the treatment of severe pseudomembranous colitis SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES Shetler, K., Nieuwenhuis, R., Wren, S. M., Triadafilopoulos, G. 2001; 15 (7): 653-659

    Abstract

    We explored the potential of early decompressive colonoscopy with intracolonic vancomycin administration as an adjunctive therapy for severe pseudomembranous Clostridium difficile colitis with ileus and toxic megacolon.We reviewed the symptoms, signs, laboratory tests, radiographic findings, and outcomes from the medical records of seven patients who experienced eight episodes of severe pseudomembranous colitis with ileus and toxic megacolon. All seven patients underwent decompressive colonoscopy with intracolonic perfusion of vancomycin.Fever, abdominal pain, diarrhea, abdominal distention, and tenderness were present in all patients. Five of seven patients were comatose, obtunded, or confused, and six of the seven required ventilatory support. The white blood cell count was greater than 16,000 in seven cases (six patients). Colonoscopy showed left-side pseudomembranous colitis in one patient, right-side colitis in one patient, and diffuse pseudomembranous pancolitis in five patients. Two patients were discharged with improvement. Five patients had numerous medical problems leading to their death. Complete resolution of pseudomembranous colitis occurred in four patients. One patient had a partial response, and two patients failed therapy.Colonoscopic decompression and intracolonic vancomycin administration in the management of severe, acute, pseudomembranous colitis associated with ileus and toxic megacolon is feasible, safe, and effective in approximately 57% to 71% of cases.

    View details for Web of Science ID 000169664100006

    View details for PubMedID 11591962

  • Results of a screening program for prostate cancer in patients scheduled for abdominoperineal resection for colorectal pathologic findings UROLOGY Terris, M. K., Wren, S. M. 2001; 57 (5): 943-945

    Abstract

    Because of the difficulty of accessing the prostate for tissue sampling after surgical removal of the rectum and obliteration of the anus, we started an early detection program for prostate cancer in all men scheduled for abdominoperineal resection.Twenty consecutive men were screened for prostatic adenocarcinoma before planned abdominoperineal resection for colorectal pathologic findings. Patients were 48 to 77 years old (mean 66.9). Screening included serum prostate-specific antigen determination and digital rectal examination. Those patients with suspicious findings underwent transrectal ultrasound-guided sextant biopsies of the prostate.One patient was excluded because of a prior history of prostate cancer. Six (31.6%) of the remaining 19 patients demonstrated elevated prostate-specific antigen levels (greater than 4.0 ng/mL); two of these patients also had an abnormal digital rectal examination. Transrectal ultrasound and prostate biopsies in these 6 patients revealed prostatic adenocarcinoma in 3 patients (50% of those undergoing biopsies or 15.8% of those screened). The 13 patients who did not undergo prostate biopsies had prostate-specific antigen levels from 0.4 to 2.4 ng/mL (mean 0.9) and normal prostate glands according to the digital rectal examinations.Screening for prostate cancer in men 50 years old or older with 10 years or longer life expectancy before they undergo abdominoperineal resection detects a significant number of prostatic malignancies and should be encouraged.

    View details for Web of Science ID 000168644300021

    View details for PubMedID 11337299

  • A novel collagen-based composite offers effective hemostasis for multiple surgical indications: Results of a randomized controlled trial SURGERY Chapman, W. C., Sherman, R., Boyce, S., Malawer, M., Hill, A., Buncke, G., Block, J. E., Fung, C. J., Clavien, P., Lee, K. F., LEBOVIC, G. S., Wren, S. M., Diethrich, E., Goldstein, R. 2001; 129 (4): 445-450

    Abstract

    Intraoperative bleeding is ubiquitous during open surgical procedures and uniformly effective hemostasis remains elusive. We conducted a randomized controlled trial to determine the effectiveness of a novel collagen-based composite (CoStasis Surgical Hemostat) compared with standard methods of hemostasis during general, hepatic, cardiac, and orthopedic operations.Hemostatic treatment was assigned randomly to 347 subjects; 318 subjects (167 CoStasis, 151 controls) underwent operation, received treatment, and provided hemostatic success data. CoStasis was applied to the bleeding site without manual pressure as a sprayable liquid composite of bovine microfibrillar collagen, bovine thrombin, and autologous plasma. Manual compression was used as the control hemostat. Hemostatic success was achieved if bleeding had ceased completely within 10 minutes (3 minutes for cardiac subjects). The time to controlled bleeding (ie, slight oozing) and time to complete hemostasis were recorded for all subjects.Hemostatic success was achieved in more than 90% (153/167) of CoStasis subjects compared with 58% (88/151) of control subjects (P =.01). Superior hemostatic effectiveness with CoStasis was realized in every surgical specialty: general (77/79 vs 49/75, P =.01), hepatic (38/39 vs 20/29, P =.01), cardiac (28/37 vs 17/37, P =.02), and orthopedic (10/12 vs 2/10, P =.01). The duration of bleeding was also significantly shorter with CoStasis. The median time to controlled bleeding (42 seconds vs 150 seconds, P =.0001) and time to complete hemostasis (75 seconds vs 252 seconds, P =.0001) were both markedly longer with the control intervention. There were no serious adverse events related to the use of CoStasis.CoStasis is more effective at controlling and stopping diffuse intraoperative bleeding than standard methods of hemostasis in 4 distinct surgical indications representing a wide variety of operative interventions.

    View details for Web of Science ID 000167986600010

    View details for PubMedID 11283536

  • External beam radiotherapy for synchronous rectal and prostatic tumors. Urology Siu, W., Kapp, D. S., Wren, S. M., King, C., Terris, M. K. 2001; 57 (4): 800-?

    Abstract

    Two patients were diagnosed with large rectal tumors and localized prostate cancer. The prostate-specific antigen level at diagnosis was 7.9 ng/mL and 9.0 ng/mL in the 2 patients. Knowledge of the presence of both tumors and their close proximity allowed creation of a modified three-dimensional conformal radiotherapy plan to treat both tumors. The patients had no evidence of rectal tumor recurrence and their prostate-specific antigen level was 0.5 ng/mL and 0.7 ng/mL at 1 and 2 years after therapy, respectively. We conclude that efficient, effective pelvic irradiation can be designed for synchronous rectal and prostate malignancies.

    View details for PubMedID 11306416

  • Does an infected peripancreatic fluid collection or abscess mandate operation? ANNALS OF SURGERY Baril, N. B., Ralls, P. W., Wren, S. M., Selby, R. R., Radin, R., Parekh, D., Jabbour, N., Stain, S. C. 2000; 231 (3): 361-367

    Abstract

    To assess the treatment of peripancreatic fluid collections or abscess with percutaneous catheter drainage (PCD).Surgical intervention has been the mainstay of treatment for infected peripancreatic fluid collections and abscesses. Increasingly, PCD has been used, with mixed results reported in the literature.A retrospective chart review of 1993 to 1997 was performed on 82 patients at a tertiary care public teaching hospital who had computed tomography-guided aspiration for suspected infected pancreatic fluid collection or abscess. Culture results, need for subsequent surgical intervention, length of stay, and death rate were assessed.One hundred thirty-five aspirations were performed in 82 patients (57 male patients, 25 female patients) with a mean age of 40 years (range 17-68). The etiologies were alcohol (41), gallstones (32), and other (9). The mean number of Ranson's criteria was four (range 0-9). All patients received antibiotics. Forty-eight patients had evidence of pancreatic necrosis on computed tomography scan. Cultures were negative in 40 patients and positive in 42. Twenty-five of the 42 culture-positive patients had PCD as primary therapy, and 6 required subsequent surgery. Eleven patients had primary surgical therapy, and five required subsequent surgery. Six patients were treated with only antibiotics. The death rates were 12% for culture-positive patients and 8% for the entire 82 patients.Historically, patients with positive peripancreatic aspirate culture have required operation. This series reports an evolving strategy of reliance on catheter drainage. PCD should be considered as the initial therapy for culture-positive patients, with surgical intervention reserved for patients in whom treatment fails.

    View details for Web of Science ID 000085635500009

    View details for PubMedID 10714629

  • Clinical and pathologic overlap in nonsteroidal anti-inflammatory drug-related small bowel diaphragm disease and the neuromuscular and vascular hamartoma of the small bowel AMERICAN JOURNAL OF SURGICAL PATHOLOGY Cortina, G., Wren, S., Armstrong, B., Lewin, K., Fajardo, L. 1999; 23 (11): 1414-1417

    Abstract

    Diaphragm disease (DD) is a radiographically subtle cause of small bowel obstruction and is part of the spectrum of diseases associated with nonsteroidal anti-inflammatory drug injury. The neuromuscular and vascular hamartoma (NMVH) is a nonepithelial hamartomatous, submucosally based proliferation of mature submucosal elements capable of causing small bowel obstruction. The authors report two patients in whom the clinical setting and gross pathology are that of DD, but the histologic characterization is identical to that described for NMVH. It is probable that in some patients the two diseases overlap so that some patients readily fit the criteria for both entities.

    View details for Web of Science ID 000083467900013

    View details for PubMedID 10555011

  • Antiviral cytotoxic activity across a species barrier in mixed xenogeneic chimeras: Functional restriction to host MHC JOURNAL OF IMMUNOLOGY Colson, Y. L., Tripp, R. A., Doherty, P. C., Wren, S. M., Neipp, M., El-Ezz, A. Y., Ildstad, S. T. 1998; 160 (8): 3790-3796

    Abstract

    Reconstitution of lethally irradiated mice with a mixture of mouse and rat bone marrow cells (mouse + rat-->mouse) results in mixed xenogeneic chimerism and donor-specific tolerance. The current study demonstrates that mouse and rat T lymphocytes that have developed in xenogeneic chimeras are restricted to Ag presentation by mouse, but not rat, APC. Restriction to host Ags results in functional immunocompetence with generation of antiviral cytotoxic activity in vivo, within and across species barriers. These data demonstrate for the first time that the host thymus is sufficient to support development and positive selection of functional cross-species T lymphocytes. The superior immunocompetence, as compared with fully xenogeneic (rat-->mouse) chimeras, may prove to be of significant benefit in the clinical application of xenotransplantation to solid organ transplantation and immune reconstitution for AIDS.

    View details for Web of Science ID 000072970400023

    View details for PubMedID 9558082

  • Color flow sonography in evaluating the resectability of periampullary and pancreatic tumors JOURNAL OF ULTRASOUND IN MEDICINE Ralls, P. W., Wren, S. M., Radin, R., Stain, S. C., Yang, J., Parekh, D. 1997; 16 (2): 131-140

    Abstract

    Over the past several years, we have developed a technique to assess the resectability of periampullary and pancreatic tumors using color flow sonography. This is a feasibility study to determine if sonography with color flow imaging can play a role in evaluating patients with periampullary and pancreatic tumors. This study comprises a retrospective analysis of 51 patients referred for color flow sonographic evaluation of resectability of periampullary and pancreatic neoplasm. Scanning was performed with state-of-the-art color flow sonographic systems. Vessels that were touched or occluded by tumor were categorized according to a Pancreatic Color Doppler Score. Other factors affecting resectability (metastasis, enlarged nodes) were recorded. Sonographic findings were correlated with surgical resectability and pathologic findings regarding tumor margins. The color flow study was complete technically (all index vessels visualized) in 49 of 51 patients (96%). In all, 643 of 647 vessels (99.4%) were imaged. Forty-five patients had sufficient surgical, pathologic, or clinical proof to be included in the resectability analysis. All 18 patients with circumferential tumor or vascular occlusion (Pancreatic Color Doppler Score 4 and 5) were found to have unresectable disease. All 10 patients in whom tumor did not touch (Pancreatic Color Doppler Score 0) had negative margins. All 30 patients considered to have unresectable tumors sonographically could not be resected. Patients in this category had one or more of the following: positive pathologic margins, positive nodes, liver metastasis, or not clinically resectable. Six of 15 considered resectable sonographically (40%) were unresectable for cure. Surgeons believed that color flow sonography influenced management in 10 of 45 patients (22% overall). Color flow sonography, a painless, noninvasive, and relatively inexpensive examination, may be an effective screening tool to evaluate periampullary and pancreatic neoplasms for resectability. Our data show that color flow sonography can correctly predict unresectability of periampullary and pancreatic neoplasms. Any future evaluation of imaging and management of periampullary and pancreatic tumors should include color flow sonography.

    View details for Web of Science ID A1997XT74600009

    View details for PubMedID 9166806

  • A NONLETHAL CONDITIONING APPROACH TO ACHIEVE DURABLE MULTILINEAGE MIXED CHIMERISM AND TOLERANCE ACROSS MAJOR, MINOR, AND HEMATOPOIETIC HISTOCOMPATIBILITY BARRIERS JOURNAL OF IMMUNOLOGY Colson, Y. L., Wren, S. M., Schuchert, M. J., Patrene, K. D., Johnson, P. C., Boggs, S. S., Ildstad, S. T. 1995; 155 (9): 4179-4188

    Abstract

    Reconstitution of lethally irradiated mice with a mixture of syngeneic and allogeneic (A+B-->A) bone marrow results in multilineage mixed allogeneic chimerism, donor-specific transplantation tolerance, superior immunocompetence and resistance to graft-vs-host disease. However, the morbidity and mortality associated with lethal irradiation would be a major limitation to the clinical application of chimerism to induce tolerance for solid organ grafts or treat other nonmalignant hematologic diseases. We report here that durable multilineage mixed allogeneic chimerism and donor-specific transplantation tolerance for skin and primarily vascularized allografts can be achieved across multiple histocompatibility barriers using a nonmyeloablative radiation-based approach. The percentage of B10 mouse recipients that engrafted directly correlated with the degree of disparity between donor and recipient and the dose of total body irradiation administered. Although the occurrence of engraftment following conditioning with doses of total body irradiation of > or = 600 cGy was similar for animals receiving bone marrow disparate at MHC or MHC, minor and hematopoietic (Hh-1) loci (67% vs 78%), the level of donor chimerism was significantly less when multiple histocompatibility barriers were present (94.6 +/- 3.8% vs 37.5 +/- 12.5%). Treatment of the recipient with cyclophosphamide 2 days following allogeneic bone marrow transplantation reduced the dose of radiation sufficient for reliable engraftment to only 500 cGy of total body irradiation, regardless of MHC and Hh-1 disparity. Donor chimerism was stable and present in all lineages, with production of lymphoid (T and B cell), NK, and myeloid (erythrocyte, platelet, granulocyte, and macrophage) cells. Mixed chimeras exhibited donor-specific tolerance in vitro, as assessed by mixed lymphocyte culture (MLR) and cytotoxicity (CML) assays, and in vivo to skin and primarily vascularized cardiac allografts. The observation that engraftment and tolerance can be achieved across multiple histocompatibility barriers using nonmyeloablative recipient conditioning may allow allogeneic bone marrow transplantation to be applied to nonmalignant disease states in which lethal conditioning cannot be justified, including the induction of donor-specific tolerance for solid organ transplantation and the treatment of hemoglobinopathies and enzyme deficiency states.

    View details for Web of Science ID A1995TB46800008

    View details for PubMedID 7594573

  • PHENOTYPIC CHARACTERIZATION OF A NOVEL BONE-MARROW-DERIVED CELL THAT FACILITATES ENGRAFTMENT OF ALLOGENEIC BONE-MARROW STEM-CELLS BLOOD Kaufman, C. L., Colson, Y. L., Wren, S. M., Watkins, S., SIMMONS, R. L., Ildstad, S. T. 1994; 84 (8): 2436-2446

    Abstract

    Bone marrow transplantation is an accepted therapy for hematologic malignancies, aplastic anemia, metabolic disorders, and solid tumors. However, graft-versus-host disease (GVHD) and failure of engraftment have limited the widespread application of this technology to nonmalignant disease states. The use of purified bone marrow stem cells has been suggested as an approach to promote engraftment yet avoid GVHD. Although bone marrow stem cells, purified by cell sorting, engraft and repopulate lethally irradiated genetically identical recipients, they do not engraft in major histocompatibility complex (MHC)-disparate allogeneic recipients. We report for the first time the characterization of a novel cell population of donor bone marrow origin, separate from the hematopoietic stem cell, that facilitates engraftment of purified allogeneic bone marrow stem cells in an MHC-specific fashion without causing GVHD. Although 1,000 purified stem cells (c-kit+/Sca-1+/lineage-) reliably repopulate syngeneic mouse recipients, 10 times that number do not engraft in MHC-disparate allogeneic recipients. The addition of as few as 30,000 facilitating cells (CD8+/CD45R+/TCR-) is sufficient to permit engraftment of purified stem cells in MHC-disparate recipients. The cell surface phenotype of this purified cellular population differs significantly from other characterized lineages of lymphoid or myeloid origin. Based on multiparameter rare-events cell sorting, the facilitating fraction is CD8+, CD3+, CD45R+, Thy 1+, class IIdim/intermediate but alpha beta-TCR- and gamma delta-TCR-. This cellular population comprises approximately 0.4% of the total bone marrow and is separate from the hematopoietic stem cell. The coadministration of purified facilitating cells plus stem cells to optimize engraftment yet avoid GVHD may expand the potential application of bone marrow transplantation to disease states in which the morbidity and mortality associated with conventional BMT cannot be justified.

    View details for Web of Science ID A1994PL35900005

    View details for PubMedID 7919363

  • EVIDENCE FOR EARLY TH2 T-CELL PREDOMINANCE IN XENOREACTIVITY TRANSPLANTATION Wren, S. M., Wang, S. C., Thai, N. L., Conrad, B., Hoffman, R. A., Fung, J. J., SIMMONS, R. L., Ildstad, S. T. 1993; 56 (4): 905-911

    Abstract

    Two distinct subsets of CD4+ Th lymphocytes have been characterized by their cytokine profiles: Th 1 (TH1) and Th 2 (TH2). While TH1 cells predominate in cell-mediated responses, TH2 cells support the humoral response. We have examined the mRNA cytokine profile of normal mouse lymphocytes in response to alloantigen versus xenoantigen (rat) in MLC, and present evidence to suggest that early in proliferative responses, alloreactivity is dominated primarily by TH1-type lymphocytes, while xenoreactivity is predominantly TH2. Normal mouse lymphocyte-responding cells were cultured in a one-way MLR with either allo or xeno antigen and examined for production of mRNA for cytokines characteristically produced by TH1 (IL-2, IFN-gamma) or TH2 (IL-4, IL-10) cells. Semiquantitative reverse transcription-polymerase chain reaction analysis was performed for mouse IL-2, IL-4, IL-10, and IFN-gamma mRNA. In the mouse anti-rat xeno response, mRNA for TH2 gene products were upregulated, with greater levels of IL-4 and IL-10 at 24 and 48 hr when compared with controls. In contrast, upregulation of mRNA for TH1 gene products occurred in the mouse anti-mouse allo response, with higher levels of IL-2 and IFN-gamma at 24 and 48 hr. In the anti-xeno response, upregulation of all 4 cytokines occurred by day 4 and peak levels of mRNA for all cytokines examined were 2-3 times that seen for the peak anti-allogeneic response. These data suggest that early xenorecognition may differ from allorecognition by differential activation of the TH2 subset. A better understanding of the balance between Th subset function and cytokine profile in allo and xeno reactivity may allow a more targeted and specific approach to control the early events in xenograft rejection.

    View details for Web of Science ID A1993MD80500025

    View details for PubMedID 8212215

  • CHARACTERIZATION OF THE IMMUNOSUPPRESSIVE EFFECTS OF NITRIC-OXIDE IN GRAFT-VS-HOST DISEASE JOURNAL OF IMMUNOLOGY Hoffman, R. A., Langrehr, J. M., Wren, S. M., Dull, K. E., Ildstad, S. T., McCarthy, S. A., SIMMONS, R. L. 1993; 151 (3): 1508-1518

    Abstract

    The generation of nitric oxide (.N = O) during in vitro assays involving lymphocyte-macrophage interaction can result in profound inhibition of lymphocyte proliferation. The present study examined whether .N = O synthesis plays a role in the suppression observed in immune function assays during graft vs host disease (GvHD). By using a parent to F1 model to induce GvHD (C57BL/6J to C57BL/6J x DBA 2J F1), a mild but transient increase in serum NO2- plus NO3- levels was observed on day 12 after inoculation. Resident peritoneal macrophages obtained from mice with GvHD demonstrated enhanced .N = O synthesis in response to LPS, compared with control F1 peritoneal macrophages. Similarly, when splenocytes from GvHD mice were cultured with Con A or LPS enhanced supernatant NO2- levels were observed, compared with control F1 mice. Addition of NG-monomethyl-L-arginine (NMA), a competitive inhibitor of .N = O synthesis, resulted in decreased NO2- levels and greatly enhanced proliferation in response to Con A. Addition of NMA to LPS-stimulated cultures did not enhance proliferation, perhaps as the result of the paucity of B cells in the GvHD population. LPS-induced .N = O synthesis by GvHD splenocytes was blocked by anti-IFN-gamma mAb, whereas Con A-induced .N = O synthesis was relatively unaffected by similar concentrations of anti-IFN-gamma mAb, suggesting different mechanisms of induction of .N = O synthesis. A proliferative response of splenocytes from mice with GvHD to third-party alloantigen was not detectable, even in the presence of NMA. The suppression observed when splenocytes from GvHD animals were added to control TNP-modified self cultures was partially reversed in the presence of NMA. These results demonstrate that .N = O synthesis in both splenocyte and peritoneal macrophage populations from GvHD mice is enhanced, revealing that in vivo priming of macrophages for .N = O synthesis occurs during GvHD. Some, but not all, in vitro tests of immune function by using GvHD splenocytes are suppressed by the generation of .N = O.

    View details for Web of Science ID A1993LP72500037

    View details for PubMedID 8335943

  • CD4+ T-CELLS, BUT NOT CD8+ T-CELLS, MEDIATE THE BREAKING OF TOLERANCE IN MIXED ALLOGENEIC CHIMERAS (B10+B10.BR-]B10) TRANSPLANTATION Wren, S. M., HRONAKES, M. L., Ildstad, S. T. 1993; 55 (6): 1382-1389

    Abstract

    Reconstitution of mouse recipients with a mixture of syngeneic plus allogeneic bone marrow (A+B-->A) results in stable mixed lymphohematopoietic chimerism and donor-specific transplantation tolerance. Previously, it was reported that administration of large numbers of unmanipulated host-type splenocytes to neonatal or adult radiation bone marrow chimeras resulted in a loss of chimerism and donor-specific transplantation tolerance. To characterize the phenotype(s) of cells that were responsible for this loss of chimerism, we performed depletion of various subsets of unmanipulated B10 splenocytes prior to infusion into mixed allogeneic chimeras (B10 + B10.BR-->B10). Recipients were followed serially to identify changes in the level of donor chimerism and by in vitro functional assays of tolerance. We report here that CD4+ T cells, but not CD8+ T cells, were sufficient to mediate the loss of donor chimerism. In all recipients in which allogeneic chimerism became undetectable, there was a simultaneous loss of donor-specific transplantation tolerance.

    View details for Web of Science ID A1993LK58900033

    View details for PubMedID 8100092

  • CHARACTERIZATION OF MATURATION AND FUNCTION OF NATURAL-KILLER-CELLS IN XENOGENEIC (RAT -] MOUSE) BONE-MARROW CHIMERAS - EVIDENCE THAT RAT NK CELLS ARE PRESENT AND FUNCTIONAL IN A XENOGENEIC ENVIRONMENT TRANSPLANTATION Vandenbrink, M. R., French, S. W., Beck, T. P., HRONAKES, M. L., Wren, S. M., Ildstad, S. T. 1993; 55 (2): 355-361

    Abstract

    Reconstitution of B10 recipient mice, conditioned with total body irradiation (950 rads), with 40 x 10(6) untreated F344 or WF rat bone marrow cells results in stable rat stem-cell engraftment with multilineage lymphohematopoietic chimerism. We have now characterized NK cell generation, maturation, and function in fully xenogeneic chimeras (WF rat-->B10 mouse; F344-->B10 mouse). Early during xenogeneic reconstitution, rat-derived NK cells predominated in splenic lymphoid tissue, composing 14-18% of total cells at week 1 and increasing to 35.6-59.9% of total cells at week 2. By week 6, levels of rat NK cells had decreased and stabilized to that expected for normal rat (9-14.2%). The NK chimerism was reliably stable for up to 7 months following reconstitution. Most importantly, rat-derived NK cells were functional in both YAC tumor cytolysis and ADCC assays, suggesting that the xenogeneic mouse host environment was sufficient to support the generation, maturation, and function of rat-derived NK cells.

    View details for Web of Science ID A1993KN01500024

    View details for PubMedID 8434388

  • SUBLETHAL IRRADIATION - A NONLETHAL METHOD TO ACHIEVE CROSS-SPECIES CHIMERISM (RAT-]MOUSE) TRANSPLANTATION PROCEEDINGS ABOUELEZZ, A. Y., Wren, S. M., Kaufman, C. L., Ricordi, C., Haluszczak, C., Ildstad, S. T. 1992; 24 (6): 2866-2867

    View details for Web of Science ID A1992KC41300224

    View details for PubMedID 1465976

  • PREFERENTIAL DEVELOPMENT OF NKR-P1-EXPRESSING CELLS IN THE SPLEEN VERSUS THYMUS AND BONE-MARROW OF FULLY XENOGENEIC (RAT-]MOUSE) CHIMERAS TRANSPLANTATION PROCEEDINGS Kaufman, C. L., Chambers, W. H., Wren, S. M., ABOUELEZZ, A. Y., Ildstad, S. T. 1992; 24 (6): 2887-2888

    View details for Web of Science ID A1992KC41300233

    View details for PubMedID 1465984

  • THE REQUIREMENT FOR ALLOGENEIC CHIMERISM FOR 2ND TRANSFER OF TOLERANCE FROM MIXED ALLOGENEIC CHIMERAS (A + B -] A) TO SECONDARY RECIPIENTS TRANSPLANTATION Wren, S. M., HRONAKES, M. L., Ildstad, S. T. 1992; 54 (6): 1031-1040

    Abstract

    We have applied the model of mixed allogeneic chimerism (A+B-->A), in which stem cells from both allogeneic and syngeneic donor engraft, to determine the in vivo cellular requirements for transfer of tolerance from mixed chimeras to secondary recipients. Using two approaches, we have demonstrated that the persistence of donor-specific transplantation tolerance is dependent on the presence of bone-marrow-derived cells. When untreated bone marrow from mixed chimeras was transferred to irradiated secondary recipient mice, most of the secondary recipients were rescued, but only 48% were demonstrably chimeric. This pattern of repopulation, therefore, allowed us to examine whether chimerism was required to maintain transplantation tolerance. In all of our studies, the presence of allogeneic chimerism was required for successful transfer of tolerance from mixed allogeneic chimeras to irradiated secondary recipients. Only those secondary recipients which repopulated with demonstrable allogeneic chimerism exhibited in vivo and in vitro evidence for transfer of donor-specific transplantation tolerance. These results were confirmed by using transfer of bone marrow from mixed chimeras depleted of allogeneic class I elements. In an attempt to identify a putative population of suppressor cells, second transfer of splenic lymphoid cells from mixed allogeneic chimeras, containing approximately 6 times more T-lymphocytes that were functionally tolerant to donor alloantigens, was also performed with similar results. These data suggest that the in vivo maintenance of tolerance to MHC transplantation alloantigens requires persistence of donor bone marrow-derived alloantigens.

    View details for Web of Science ID A1992KD06200017

    View details for PubMedID 1465769

  • EVIDENCE THAT INDEFINITE SURVIVAL OF SMALL-BOWEL ALLOGRAFTS ACHIEVED BY A BRIEF COURSE OF CYCLOSPORINE OR FK506 IS NOT DUE TO SYSTEMIC HYPORESPONSIVENESS TRANSPLANTATION Langrehr, J. M., Hoffman, R. A., Demetris, A. J., Lee, K. K., Neuhaus, P., Wren, S. M., Ildstad, S. T., Schraut, W. H. 1992; 54 (3): 505-510

    Abstract

    The immunological status of Lewis (LEW) recipients of indefinitely surviving (greater than 400 days) orthotopic Brown-Norway (BN) small bowel allografts was investigated 1 to 1 1/2 years after cessation of immunosuppressive therapy with either cyclosporine or FK506 and compared with recipients of syngeneic grafts. A normal proliferative response (as measured by a mixed lymphocyte culture) of recipient peripheral lymph node lymphocytes in response to the donor-specific (BN) and the third-party (ACI) antigen, was observed in all experimental groups. Cytolytic T cell generation (as measured by a standard 51Cr-release cytotoxicity assay) in response to the donor-specific (BN) and the third-party (ACI) antigen was observed also in all groups. A FACS analysis of allograft-recipient splenocytes showed no evidence for systemic lymphoid chimerism. BN or ACI skin grafts transplanted onto recipients of allogeneic and syngeneic small bowel grafts were rejected completely in 12-17 days, while the intestinal grafts remained functional. Immunohistologic evaluation of the allografts, using anti-BN class I and anti-Lewis class II monoclonal antibodies showed anti-BN staining on the epithelial and endothelial structures, whereas the mononuclear cells in the lamina propria stained positively with the anti-LEW monoclonal antibody. However, lymphoid depletion and scarring of Peyer's patches and mesenteric lymph nodes as well as focal obliterative mesenteric arteriopathy, indicative of an indolent chronic rejection, were observed. These data demonstrate that recipients of indefinitely surviving small bowel allografts remain immune competent and do not retain the intestinal graft on the basis of specific hyporesponsiveness to the donor antigens.

    View details for Web of Science ID A1992JP01800022

    View details for PubMedID 1384185

  • LONG-TERM SURVIVAL OF DONOR-SPECIFIC PANCREATIC-ISLET XENOGRAFTS IN FULLY XENOGENEIC CHIMERAS TRANSPLANTATION PROCEEDINGS Zeng, Y., Ildstad, S. T., Wren, S. M., Rilo, H. L., BEREITER, D. R., CARROLL, P. B., Tzakis, A. G., Starzl, T. E., Ricordi, C. 1992; 24 (3): 985-985

    View details for Web of Science ID A1992HY79500106

    View details for PubMedID 1604698

  • MIXED XENOGENEIC CHIMERAS (RAT PLUS MOUSE TO MOUSE) - EVIDENCE OF RAT STEM-CELL ENGRAFTMENT, STRAIN-SPECIFIC TRANSPLANTATION TOLERANCE, AND SKIN-SPECIFIC ANTIGENS TRANSPLANTATION Ildstad, S. T., Boggs, S. S., Vecchini, F., Wren, S. M., HRONAKES, M. L., Johnson, P. C., Vandenbrink, M. R. 1992; 53 (4): 815-822

    Abstract

    We report the induction of stable and reliably detectable mixed xenogeneic chimerism through the coadministration of a mixture of untreated rat bone marrow plus T cell-depleted mouse bone marrow into B10 recipients conditioned with total body irradiation (TCD B10 mouse + untreated F344 rat----B10 mouse). Recipients repopulated as true mixed lymphopoietic chimeras, with from 1-21.6% rat-derived lymphoid cells in peripheral blood and splenic lymphoid tissue. Production of rat platelets was also demonstrated. Rat platelet and lymphoid chimerism was reliably detectable in chimeras from 1 to 7 months following reconstitution, suggesting engraftment of the rat bone marrow stem cell. Production of each stem cell-derived lineage appeared to be under independent regulation since a significantly greater proportion of platelets were rat-derived (24-81%) than were lymphocytes (1-21.6% rat), while erythrocytes were preferentially syngeneic (less than 2% rat). The tolerance induced by this model was highly donor strain-specific: donor-specific rat and mouse skin grafts were accepted while MHC-disparate third-party mouse (C3H; H-2k) and rat (Wistar Furth; Rt1Au) skin grafts were promptly rejected. Although specifically prolonged xenogeneic donor rat skin grafts underwent a slow chronic rejection, and some totally disappeared. In spite of this, chimeras retained their lymphoid chimerism, suggesting the presence of skin-specific antigens. This model for mixed xenogeneic chimerism with reliably detectable rat lymphoid cells may provide a model to study the existence of tissue-specific antigens across a species barrier, as well as mechanisms responsible for the induction and maintenance of this strain-specific transplantation tolerance.

    View details for Web of Science ID A1992HP30600022

    View details for PubMedID 1566347

  • CROSS-SPECIES TRANSPLANTATION TOLERANCE - RAT BONE-MARROW DERIVED CELLS CAN CONTRIBUTE TO THE LIGAND FOR NEGATIVE SELECTION OF MOUSE T-CELL RECEPTOR-V-BETA IN CHIMERAS TOLERANT TO XENOGENEIC ANTIGENS (MOUSE + RAT -] MOUSE) JOURNAL OF EXPERIMENTAL MEDICINE Ildstad, S. T., Vacchio, M. S., Markus, P. M., HRONAKES, M. L., Wren, S. M., Hodes, R. J. 1992; 175 (1): 147-155

    Abstract

    Mixed xenogeneic bone marrow reconstitution (mouse + rat----mouse) results in stable mixed lymphopoietic chimerism (1-48% rat), long-term survival, and the induction of stable functional donor-specific transplantation tolerance to xenoantigens in vivo. To examine the role of negative selection of potentially xenoreactive T lymphocytes during tolerance induction across a species barrier, mixed xenogeneic chimeras (mouse + rat----mouse) were prepared and analyzed using a mixture of mouse and rat bone marrow cells for relative T cell receptor (TCR)-V beta expression on mouse T cells. In mixed xenogeneic chimeras (B10 mouse + rat----B10 mouse), T cell maturation proceeded normally in the presence of rat bone marrow-derived elements, and functional donor-specific tolerance to rat xenoantigens was present when assessed by mixed lymphocyte reactivity in vitro. V beta 5, which is expressed at high (undeleted) levels in normal B10 mice, was consistently deleted in B10 recipients of Wistar Furth (WF), but not F344 rat bone marrow, whereas the coadministration of either F344 rat or WF rat bone marrow with B10 mouse bone marrow cells resulted in a significant decrease in expression of TCR-V beta 11. Taken together, these data demonstrate for the first time that rat bone marrow-derived cells can contribute in a strain-specific manner to the ligand for negative selection of specific mouse TCR-V beta during tolerance induction across a species barrier.

    View details for Web of Science ID A1992GY43600018

    View details for PubMedID 1530958

  • CROSS-SPECIES BONE-MARROW TRANSPLANTATION - EVIDENCE FOR RECOGNITION OF SKIN-SPECIFIC ANTIGENS ACROSS A SPECIES BARRIER (RAT-]MOUSE) JOURNAL OF SURGICAL RESEARCH Ildstad, S. T., Wren, S. M., HRONAKES, M. L. 1991; 51 (5): 372-376

    Abstract

    We have developed a model to study cross-species bone marrow transplantation and the associated donor-specific transplantation tolerance induced using fully xenogeneic chimeras. Reconstitution of lethally irradiated B10 mice with untreated F344 rat bone marrow cells results in fully xenogeneic chimerism (F344 rat----B10 mouse). Survival of recipients is excellent (greater than 80% at 100 days) and stable rat lymphoid and multilineage chimerism are present throughout the life of the chimeras. Recipients are specifically tolerant to donor-type skin xenografts yet are competent to reject major histocompatibility complex (MHC)--disparate third party strain rat xenografts. Although prolonged, donor-specific skin xenografts underwent chronic rejection which had its onset at approximately 40 days following skin graft placement. We have now examined these chimeras by serial flow cytometry typing to determine whether this is due to skin-specific antigens expressed on skin, but not on the bone marrow elements to which the chimeras were rendered tolerant. In all animals examined, lymphopoietic chimerism persisted unchanged even after the onset of inflammation in the grafts, suggesting the presence of skin specific antigens. This model may provide a method to study tissue and organ specific antigens recognized across a species barrier.

    View details for Web of Science ID A1991GK45000003

    View details for PubMedID 1758170

  • CROSS-SPECIES BONE-MARROW TRANSPLANTATION - EVIDENCE FOR TOLERANCE INDUCTION, STEM-CELL ENGRAFTMENT, AND MATURATION OF LYMPHOCYTES-T IN A XENOGENEIC STROMAL ENVIRONMENT (RAT-]MOUSE) JOURNAL OF EXPERIMENTAL MEDICINE Ildstad, S. T., Wren, S. M., Boggs, S. S., HRONAKES, M. L., Vecchini, F., Vandenbrink, M. R. 1991; 174 (2): 467-478

    Abstract

    Transplantation of untreated F344 rat bone marrow into irradiated B10 mouse recipients (non-TCD F344----B10) to produce fully xenogeneic chimeras resulted in stable xenogeneic lymphoid chimerism, ranging from 82% to 97% rat. Survival of animals was excellent, without evidence for GVH disease. The specificity of tolerance which resulted was highly donor-specific; MHC disparate third party mouse and rat skin grafts were promptly rejected while donor-specific F344 grafts were significantly prolonged (MST greater than 130 days). Multi-lineage rat stem cell-derived progeny including lymphoid cells (T- and B-lymphocytes), myeloid cells, erythrocytes, platelets, and natural killer (NK) cells were present in the fully xenogenic chimeras up to 7 months after bone marrow transplantation. Immature rat T-lymphocytes matured and acquired the alpha/beta T-cell receptor in the thymus of chimeras in a pattern similar to normal rat controls, suggesting that immature T-lymphocytes of rat origin could interact with the murine xenogeneic thymic stroma to undergo normal maturation and differentiation. This model may be useful to study the mechanisms responsible for the induction and maintenance of donor-specific transplantation tolerance across a species barrier.

    View details for Web of Science ID A1991FY50200018

    View details for PubMedID 1856629

  • MIXED ALLOGENEIC RECONSTITUTION (A+B-]A) TO INDUCE DONOR-SPECIFIC TRANSPLANTATION TOLERANCE - PERMANENT ACCEPTANCE OF A SIMULTANEOUS DONOR SKIN-GRAFT TRANSPLANTATION Ildstad, S. T., Wren, S. M., Oh, E., HRONAKES, M. L. 1991; 51 (6): 1262-1267

    Abstract

    Mixed allogeneic reconstitution, in which a mixture of T-cell-depleted bone marrow of syngeneic host and allogeneic donor type is transplanted into a lethally irradiated recipient (A+B----A), results in mixed lymphopoietic chimerism with engraftment of a mixture of both host and donor bone marrow elements. Recipients are specifically tolerant to donor both in vitro and in vivo. Donor-specific skin grafts survive indefinitely when they are placed after full bone marrow repopulation at 28 days, while third-party grafts are rapidly rejected. To determine whether a delay of a month or more for full bone marrow repopulation is required before a donor-specific graft can be placed, we have now examined whether tolerance induction can be achieved if a graft is placed at the time of bone marrow transplantation. Permanent acceptance of donor-specific B10.BR skin grafts occurred when mixed allogeneic chimerism (B10+B10.BR----B10) was induced and a simultaneous allogeneic donor graft placed. In vitro, mixed reconstituted recipients were specifically tolerant to the B10.BR donor lymphoid cells but fully reactive to MHC-disparate third-party (BALB/c; H-2dd) when assessed by mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) assays. These data therefore indicate that a donor-specific graft placed at the time of mixed allogeneic reconstitution is permanently accepted without rejection. To determine whether an allogeneic skin graft alone without allogeneic bone marrow would be sufficient to induce tolerance, syngeneic reconstitution (B10----B10) was carried out, and a simultaneous B10.BR allogeneic skin graft placed. Although skin grafts were prolonged in all recipients, all grafts rejected when full lymphopoietic repopulation occurred at 28 days. Taken together, these data suggest that allogeneic donor bone marrow elements are required for the induction and maintenance of donor-specific transplantation tolerance and that allogeneic skin grafts alone are not sufficient for tolerance induction.

    View details for Web of Science ID A1991FR73600022

    View details for PubMedID 1828637

  • EFFECT OF SELECTIVE T-CELL DEPLETIONS IN MIXED XENOGENEIC RECONSTITUTION ON SPECIFIC HYPOREACTIVITY TO TRANSPLANTATION ACROSS A SPECIES BARRIER TRANSPLANTATION Ildstad, S. T., Wren, S. M., Stephany, D., Sachs, D. H. 1986; 41 (3): 372-376

    Abstract

    We have recently reported the induction of long-term specific hyporeactivity to transplantation across a species barrier (rat----mouse) through reconstitution of irradiated recipients with a mixture of T-cell-depleted host-type C57BL/10Sn (B10) bone marrow plus T-cell-depleted F344 rat bone marrow (B10+F344----B10) (1). We report here the influence of selective T cell depletions of host-type and/or donor-type bone marrow on induction of such hyporeactivity. Mice that received mixed bone marrow inocula in which the syngeneic marrow had been T-cell-depleted, whether or not the xenogeneic donor marrow had been treated, showed specific prolongation of F344 donor-type skin grafts. In contrast, F344 rat skin grafts were promptly rejected by animals that had received mixed bone marrow inocula in which the syngeneic component had not been T-cell-depleted. Serologic reactivity against F344 lymphocyte cell surface antigens also differed among the four groups; animals that had received untreated syngeneic bone marrow demonstrated high levels of reactivity to F344 target cells, while animals reconstituted with mixed inocula in which the syngeneic component had been T-cell-depleted exhibited low levels, if any, of serologic reactivity against F344 splenocytes. This model for mixed xenogeneic reconstitution may be helpful to define the conditions required for induction of transplantation tolerance across a species barrier.

    View details for Web of Science ID A1986A511800017

    View details for PubMedID 3513395

  • EFFECT OF SELECTIVE T-CELL DEPLETION OF HOST AND OR DONOR BONE-MARROW ON LYMPHOPOIETIC REPOPULATION, TOLERANCE, AND GRAFT-VS-HOST DISEASE IN MIXED ALLOGENEIC CHIMERAS (B-10 + B10.D2-]B10) JOURNAL OF IMMUNOLOGY Ildstad, S. T., Wren, S. M., Bluestone, J. A., BARBIERI, S. A., Stephany, D., Sachs, D. H. 1986; 136 (1): 28-33

    Abstract

    Reconstitution of lethally irradiated mice with a mixture of T cell-depleted syngeneic plus T cell-depleted allogeneic bone marrow (B10 + B10.D2----B10) leads to the induction of mixed lymphopoietic chimerism, excellent survivals, specific in vivo transplantation tolerance to subsequent donor strain skin grafts, and specific in vitro unresponsiveness to allogeneic donor lymphoid elements as assessed by mixed lymphocyte reaction (MLR) proliferative and cell-mediated lympholysis (CML) cytotoxicity assays. When B10 recipient mice received mixed marrow inocula in which the syngeneic component had not been T cell depleted, whether or not the allogeneic donor marrow was treated, they repopulated exclusively with host-type cells, promptly rejected donor-type skin allografts, and were reactive in vitro to the allogeneic donor by CML and MLR assays. In contrast, T cell depletion of the syngeneic component of the mixed marrow inocula resulted in specific acceptance of allogeneic donor strain skin grafts, whether or not the allogeneic bone marrow was T cell depleted. Such animals were specifically unreactive to allogeneic donor lymphoid elements in vitro by CML and MLR, but were reactive to third party. When both the syngeneic and allogeneic marrow were T cell depleted, variable percentages of host- and donor-type lymphoid elements were detected in the mixed reconstituted host. When only the syngeneic bone marrow was T cell depleted, animals repopulated exclusively with donor-type cells. Although these animals had detectable in vitro anti-host (B10) reactivity by CML and MLR and reconstituted as fully allogeneic chimeras, they exhibited excellent survival and had no in vivo evidence for graft-vs-host disease. In addition, experiments in which untreated donor spleen cells were added to the inocula in this last group suggest that the presence of T cell-depleted syngeneic bone marrow cells diminishes graft-vs-host disease and the mortality from it. This system may be helpful as a model for the study of alloresistance and for the identification of syngeneic cell phenotypes, which when present prevent engraftment of allogeneic marrow.

    View details for Web of Science ID A1986AWM4600006

    View details for PubMedID 2933464

  • CHARACTERIZATION OF MIXED ALLOGENEIC CHIMERAS - IMMUNOCOMPETENCE, INVITRO REACTIVITY, AND GENETIC SPECIFICITY OF TOLERANCE JOURNAL OF EXPERIMENTAL MEDICINE Ildstad, S. T., Wren, S. M., Bluestone, J. A., BARBIERI, S. A., Sachs, D. H. 1985; 162 (1): 231-244

    Abstract

    Mixed allogeneically reconstituted mice (B10 + B10.D2----B10) that specifically accept B10.D2 tail skin allografts were examined for in vivo and in vitro immunocompetence, patterns of hematopoietic repopulation, and in vitro reactivity. In vitro, mixed allogeneic chimeras (B10 + B10.D2----B10) manifested specific tolerance in mixed lymphocyte reactions and cell-mediated lympholysis to B10 and B10.D2 splenocytes, with normal responses to third-party (B10.BR) cells. Such chimeras were immunocompetent in B cell and helper T cell responses, as assessed by their primary plaque forming cell responses to in vivo sheep red blood cell immunization. This is in contrast to fully allogeneic chimeras, which responded less well. In addition, survival of the mixed allogeneic chimeras in a conventional animal facility was superior to that of fully allogeneic chimeras, and similar to syngeneically reconstituted (B10----B10) mice. Specific tolerance to skin grafts, degree of allogeneic engraftment, and persistence of chimerism was also assessed in a noncongenic mixed allogeneic combination (B10 + C3H----B10). Such animals manifested specific hyporeactivity to C3H skin allografts, but eventual chronic rejection of the grafts occurred in spite of stable and persistent mixed chimerism. MHC-congenic (B10.BR) skin grafts were accepted indefinitely in the same animals, suggesting that skin-specific non-major histocompatibility complex antigens were responsible for rejection of the C3H skin allografts.

    View details for Web of Science ID A1985ALW4900017

    View details for PubMedID 3159825

  • INVIVO AND INVITRO CHARACTERIZATION OF SPECIFIC HYPOREACTIVITY TO SKIN XENOGRAFTS IN MIXED XENOGENEICALLY RECONSTITUTED MICE (B10+F344RAT-]B10) JOURNAL OF EXPERIMENTAL MEDICINE Ildstad, S. T., Wren, S. M., Sharrow, S. O., Stephany, D., Sachs, D. H. 1984; 160 (6): 1820-1835

    Abstract

    Mixed xenogeneically reconstituted mice (F344 rat + C57BL/10Sn----C57BL/10Sn), which specifically retain F344 tail skin xenografts, were studied for the specificity of such hyporeactivity and for in vitro reactivity and immunocompetence. Survival of mixed reconstituted animals was excellent, without evidence for graft vs. host disease. Donor-type tail skin grafts were specifically prolonged (mean survival time = 80 d) in comparison with normal controls and syngeneically reconstituted animals. In vitro, such animals manifested specific hyporeactivity by mixed lymphocyte reaction and cell-mediated lympholysis to F344 rat and B10 cells, with normal response to third-party rat (Wistar-Furth) and mouse (B10.BR). Examination of lymphoid tissues with a fluorescence-activated cell sorter revealed low levels, if any, of donor-type cells detectable. This system offers a model for investigation of xenogeneic transplantation tolerance.

    View details for Web of Science ID A1984TX70100015

    View details for PubMedID 6239902

  • INHIBITION OF THE GRAFT-VERSUS-HOST RESPONSE BY BCGCW-INDUCED SUPPRESSOR CELLS OR PROSTAGLANDIN-E1 CELLULAR IMMUNOLOGY Wren, S. M., Wepsic, H. T., Larson, C. H., DESILVA, M. A., Mizushima, Y. 1983; 76 (2): 361-371

    Abstract

    Immunization of C57BL/6 mice with BCGcw stimulated a population of "suppressor cells" which had a decreased capacity to induce the graft-versus-host response. The graft-versus-host response was quantitated using the Simonsen splenomegaly assay. F1 mice (C57BL/6 X CBA) were inoculated intraperitoneally with 1 X 10(8) parental (C57BL/6) or (CBA) spleen cells. The F1 mice were sacrificed 13 days later and the resulting splenomegaly was 3-4 times the normal amount. F1 mice which were injected with parental BCGcw-primed C57BL/6 spleen cells had a 50% inhibition of splenomegaly, whereas BCGcw-primed CBA spleen cells (a strain which does not develop suppressor cells) did not show this inhibition. In vitro results also confirmed that only C57BL/6 mice and not CBA mice developed suppressor cells after BCGcw immunization. A second study showed that X-irradiated (1000 R) BCGcw-primed "suppressor cells" could inhibit splenomegaly caused by the inoculation of normal parental C57BL/6 cells into F1 mice. The mechanism by which BCGcw-primed "suppressor cells" caused this inhibition of splenomegaly was delineated and found to be dependent upon the secretion of prostaglandin (PGE-1). Indomethacin and aspirin, potent inhibitors of prostaglandin synthesis, blocked the activity of C57BL/6 BCGcw "suppressor cells" and splenomegaly resulted. Systemic administration of the prostaglandin (15S)-15-methyl PGE-1 reduced splenomegaly approximately 50% in F1 mice which were injected with C57BL/6 or CBA cells. These results indicated that immunization with BCGcw stimulated a population of "suppressor cells" which could cause a decrease in graft-versus-host response and that the secretion of prostaglandin was responsible for this inhibition.

    View details for Web of Science ID A1983QM43500016

    View details for PubMedID 6220811

Conference Proceedings


  • Is cryosurgical ablation appropriate for treating hepatocellular cancer? Wren, S. M., Coburn, M. M., Tan, M., Daniels, J. R., Yassa, N., Carpenter, C. L., Stain, S. C. AMER MEDICAL ASSOC. 1997: 599-604

    Abstract

    To examine the feasibility and efficacy of cryosurgical ablation as treatment for patients with cirrhosis with unresectable hepatocellular carcinoma.Retrospective case series.A tertiary public hospital and a cancer center.Twelve patients with cirrhosis with hepatocellular carcinoma (stage II, 2; stage III, 1; stage IVA, 7; stage IVB, 2).Cryosurgical ablation of all identifiable tumors. Nine patients treated with curative intent were included in the survival analysis, and 3 were treated for palliation. Five patients were treated with preoperative intra-arterial chemoembolization.Perioperative complications and the effects of tumor stage and chemoembolization were examined. Patient survival and disease-free interval were calculated by life-table analysis.No perioperative deaths occurred and 1 patient had 2 postoperative complications: pneumonia and biloma. The mean survival has been 19 months after cryosurgical ablation and 29 months after diagnosis. Three of the 9 patients treated with curative intent died with recurrence at a mean of 17 months after cryosurgical ablation. Four patients are alive with recurrence at a mean of 19 months after cryosurgical ablation and 38 months after diagnosis. Two patients with stage II disease have no evidence of recurrence 10 and 32 months after cryosurgical ablation.Cryosurgical ablation is feasible and safe for treatment of hepatocellular carcinoma in patients with cirrhosis. The technique is primarily palliative but may provide a possibility of cure in patients with lower-stage disease.

    View details for Web of Science ID A1997XE52600008

    View details for PubMedID 9197851

  • The role of anticoagulation in pylephlebitis Baril, N., Wren, S., Radin, R., Ralls, P., Stain, S. CAHNERS PUBL CO. 1996: 449-453

    Abstract

    Pylephlebitis may complicate any intra-abdominal infection and carries a high mortality rate. Acute cases are usually anticoagulated to prevent thrombus extension and enteric ischemia; however, the role of anticoagulation has not been clearly defined.Over a 3-year period, pylephlebitis was diagnosed in 44 patients with portal vein thrombosis on computed tomography scan with fever, leukocytosis, and/or positive blood cultures. The charts were reviewed for etiology, extent of venous thrombosis, and method and results of treatment.Eighteen patients were hypercoagulable, due to clotting factor deficiencies (6), malignancy (8), or AIDS (4). Fifteen patients had mesenteric vein involvement. Thirty-two patients were not anticoagulated, and 5 died (3 with hypercoagulable states and 2 with normal clotting function). Twelve patients were anticoagulated, and none developed subsequent bowel infarction or died.Patients with pylephlebitis and a hypercoagulable state due to neoplasms or clotting factor deficiencies should be anticoagulated. Patients with normal clotting function and mesenteric vein involvement may also benefit. We believe anticoagulation in patients with thrombus isolated to the portal vein and normal clotting function may be unnecessary.

    View details for Web of Science ID A1996VR81800009

    View details for PubMedID 8942542

  • Selective management of hepatic adenomas Ault, G. T., Wren, S. M., Ralls, P. W., Reynolds, T. B., Stain, S. C. SOUTHEASTERN SURGICAL CONGRESS. 1996: 825-829

    Abstract

    Hepatic adenomas are uncommon hepatic neoplasms that may be identified after life-threatening hemorrhage, or as an incidental radiologic finding. The incidence of malignant transformation is unknown, and the correct treatment strategy is unclear. We examined our 10-year experience in the management of 12 patients with hepatic adenomas. Eleven adults (mean age of 37.6 years) and one 3-month-old were identified. Nine of 10 adult females (90%) were taking a hormonal preparation at the time of diagnosis. Four patients with tumor sizes of 1.0 to 4.0 cm were observed after cessation of oral contraceptives. Four patients with lesions of 5.5 to 13 cm underwent surgical resection. Three had malignant transformation, and two of the three had increased Alpha-fetoprotein levels. Four patients presented with acute hemorrhage and were treated initially by hepatic arterial embolization. We conclude that management of adenomas should be individualized based on their size and mode of presentation. Patients with lesions less than 5 cm and normal alpha-fetoprotein can be safely observed off oral contraceptives and followed by radiologic imaging. Lesions >5 cm should be considered for surgical resection due to the risk of malignancy. Hepatic arterial embolization is a new approach for acute hemorrhage.

    View details for Web of Science ID A1996VJ94300010

    View details for PubMedID 8813164

  • Assessment of resectability of pancreatic head and periampullary tumors by color flow Doppler sonography Wren, S. M., Ralls, P. W., Stain, S. C., Kasiraman, A., Carpenter, C. L., Parekh, D. AMER MEDICAL ASSOC. 1996: 812-817

    Abstract

    To examine the sensitivity of color flow Doppler ultrasonography in assessing resectability of pancreatic head and periampullary tumors.Validation cohort study.Tertiary care public hospital.Thirty-seven patients with pancreatic head or periampullary cancer were studied by color flow Doppler examination of the relevant blood vessels.A pancreatic Doppler score (PDS) was defined as the closest circumferential contact of the tumor to the superior mesenteric vein, superior mesenteric artery, or portal vein. A PDS of 1 indicated no contact (n = 9); PDS 2, less than 50% contact (n = 10); PDS 3, 50% to 99% contact (n = 7); and PDS 4, encasement (n = 11). The PDS was compared with operative and histologic resection margins.The lack of vascular invasion was confirmed operatively in 7 of 7 patients with a PDS of 1, and 6 patients who underwent resection had clear histologic margins. Nine (90%) of 10 patients with a PDS of 2 were confirmed to have no vascular invasion, and 3 (43%) of 7 patients who underwent resection had clear margins. Five (83%) of 6 patients with a PDS of 3 had correct operative findings, and both patients who underwent resection had positive margins. Operative confirmation of encasement was found in all 7 patients with a PDS of 4 who had operative exploration, and none underwent resection.Color flow Doppler sonography and PDS predicted resectability and the histologic margin status (positive predictive value, 97%). Patients with a PDS of 1 are predicted to have clear histologic margins after resection. Patients with a PDS of 4 have unresectable tumors, and nonoperative palliation should be considered. Patients with a PDS of 2 or 3 have a high likelihood of positive histologic margins after resection and may be candidates for neoadjuvant chemotherapy.

    View details for Web of Science ID A1996VA59100005

    View details for PubMedID 8712903

  • INDIVIDUAL ASSESSMENT OF VISUAL-PERCEPTION BY SURGEONS OBSERVING THE SAME LAPAROSCOPIC ORGANS WITH VARIOUS IMAGING-SYSTEMS Berci, G., Wren, S. M., Stain, S. C., Peters, J., PAZPARTLOW, M. SPRINGER VERLAG. 1995: 967-973

    Abstract

    Laparoscopic surgery necessitates that operations be performed via a television screen; therefore, image quality is crucial in determining the final outcome. Electronic imaging systems are constantly undergoing revisions and incorporating new ideas. Recently, we have been confronted with a variety of systems, and we, as operators, have no idea what the differences are between the old and the newer systems. As clinicians, we have no electronic yardstick available to compare the options presented or to check the specifications. This study examines critical aspects of image perception. General surgeons, gynecologists, operating-room nurses, as well as allied health personnel all experienced in laparoscopic surgery participated as test subjects. A blinded study was performed in which various camera systems (single chip, three-chip, digitized and nondigitized) were displayed in random fashion. Porcine abdominal areas were displayed using the various imaging units. Participants graded image perception based on the following characteristics: sharpness, color, contrast, and depth of field. The audience were blinded to the types, brand, and number of cameras utilized. A significant preference was shown for digitized systems (P < 0.0001). Also, digitized single-chip cameras scored higher than three-chip cameras (P < 0.05). We propose thorough testing by surgeons and nursing personnel before deciding what type of equipment to purchase.

    View details for Web of Science ID A1995RT66600003

    View details for PubMedID 7482214

  • XENOREACTIVITY IN MOUSE PLUS RAT-]MOUSE CHIMERAS CONRAD, B. G., Wren, S. M., Thai, N. L., Wang, S. C., Ricordi, C., Fung, J. J., PERRY, F. E., Ildstad, S. T. ELSEVIER SCIENCE INC. 1993: 455-456

    View details for Web of Science ID A1993KN62100177

    View details for PubMedID 8438377

  • T-CELL MITOGENIC RESPONSES IN FULLY XENOGENEIC CHIMERAS (WF RAT--]-B10 MOUSE) ARE RESTORED BY BLOCKING THE L-ARGININE-DEPENDENT NITRIC-OXIDE PATHWAY Wren, S. M., Hoffman, R. A., Billiar, T. R., ABOUELEZZ, A., HRONAKES, M. L., Ildstad, S. T. ELSEVIER SCIENCE INC. 1992: 499-500

    View details for Web of Science ID A1992HN85700033

    View details for PubMedID 1566404

  • EVIDENCE FOR THYMIC MATURATION OF BOTH RAT AND MOUSE T-CELLS IN MIXED XENOGENEIC CHIMERAS (B10 MOUSE + F344 RAT--]-B10 MOUSE) ABOUELEZZ, A. Y., Schuchert, M. J., Wren, S. M., HRONAKES, M. L., Beck, T. P., Ildstad, S. T. ELSEVIER SCIENCE INC. 1992: 501-502

    View details for Web of Science ID A1992HN85700034

    View details for PubMedID 1348886

  • CROSS-SPECIES TRANSPLANTATION - NK CELL NUMBER AND FUNCTION ARE NORMAL IN FULLY XENOGENEIC CHIMERAS (RAT-]MOUSE) French, S. N., Wren, S. M., HRONAKES, M. L., Ildstad, S. T. W B SAUNDERS CO-ELSEVIER INC. 1992: 307-311

    Abstract

    When untreated F344 rat bone marrow is transplanted into B10 mouse recipients conditioned with total body irradiation, stable fully xenogeneic chimerism (rat----mouse) results. Chimeras are specifically tolerant to the donor strain of rat, survival is excellent (greater than 80% at 8 months), and all stem-cell-derived lineages are produced by the rat stem cell. We have previously demonstrated normal function of T-lymphocytes in these chimeras, but have not examined the immune function of natural killer (NK) cells present. Because NK cells play a critical role in immune surveillance, absence of function could result in a serious immunodeficiency state. We present data here to suggest that rat NK cells that have developed in a mouse stromal environment are normal in function as well as number. In all fully xenogeneic chimeras tested from 8 weeks to 8 months following bone marrow transplantation, NK cells were present at a normal level (10% to 16%). NK cells function in these chimeras, as tested by spontaneous lysis of YAC tumor cell targets, was normal or superior to normal F344 rat and B10 mouse NK cells.

    View details for Web of Science ID A1992HJ05700007

    View details for PubMedID 1501002

  • KINETICS OF EARLY T-CELL REPOPULATION IN FULLY XENOGENEIC CHIMERAS (F344 RAT-]B10 MOUSE) - EVIDENCE FOR RAT T-CELL MATURATION IN A XENOGENEIC MOUSE THYMUS Wren, S. M., HRONAKES, M. L., Ildstad, S. T. MOSBY-YEAR BOOK INC. 1991: 238-246

    Abstract

    We recently reported the model of fully xenogeneic chimerism achieved by transplantation of rat bone marrow into mouse recipients (F344 rat----B10 mouse), resulting in stable long-term rat lymphoid chimerism. We have now extended this model to examine whether developing precursor rat T cells from rat bone marrow stem cells can undergo normal differentiation in mature lymphocytes under the influence of a xenogeneic mouse thymus. We examined thymic and splenic lymphoid cells from fully xenogeneic chimeras starting 1 week after bone marrow transplantation to characterize early T-cell repopulation and phenotype. Our data suggest that developing rat precursor T cells are able to undergo normal differentiation in the mouse thymus. The first precursor T cells appeared 2 weeks after reconstitution and by week 10 accounted for more than 90% of thymocytes present in the chimeras. In chimeras, developing rat T lymphocytes in the mouse thymus exhibited an immature pattern (Thy 1.1+, alpha beta-TCRdull, CD4+ plus CD8+) when analyzed by flow cytometry. This pattern was similar to a normal rat. In contrast, splenic T-lymphoid cells showed a mature rat phenotype (Thy 1.1-, alpha beta-TCRhi, CD4+ or CD8+), again similar to a normal rat. This development began 2 weeks after bone marrow transplantation, and both thymus and spleen from chimeras exhibited "normal" rat T-cell staining profiles by 10 weeks after reconstitution. Overall, these data indicate that developing rat T cells are capable of undergoing normal maturation in a xenogeneic mouse thymus of tolerant animals.

    View details for Web of Science ID A1991FZ62800016

    View details for PubMedID 1858033

  • MIXED CHIMERISM TO INDUCE TOLERANCE FOR SOLID ORGAN-TRANSPLANTATION Wren, S. M., Nalesnik, M., HRONAKES, M. L., Oh, E., Ildstad, S. T. W B SAUNDERS CO-ELSEVIER INC. 1991: 439-443

    Abstract

    Chimerism, or the coexistence of tissue elements from more than one genetically different strain or species in an organism, is the only experimental state that results in the induction of donor-specific transplantation tolerance. Transplantation of a mixture of T-cell-depleted syngeneic (host-type) plus T-cell-depleted allogeneic (donor) bone marrow into a normal adult recipient mouse (A + B----A) results in mixed allogeneic chimerism. Recipient mice exhibit donor-specific transplantation tolerance, yet have full immunocompetence to recognize and respond to third-party transplantation antigens. After complete hematolymphopoietic repopulation at 28 days, animals accept a donor-specific skin graft but reject major histocompatibility complex (MHC) locus-disparate third-party grafts. We now report that permanent graft acceptance can also be achieved when the graft is placed at the time of bone marrow transplantation. Histologically, grafts were viable and had only minimal inflammatory changes. This model may have potential future clinical application for the induction of donor-specific transplantation tolerance.

    View details for Web of Science ID A1991FF05500014

    View details for PubMedID 2056405

  • SUCCESSFUL TRANSFER OF DONOR-SPECIFIC TRANSPLANTATION TOLERANCE BY ADOPTIVE TRANSFER OF FULLY ALLOGENEIC CHIMERIC BONE-MARROW Wren, S. M., HRONAKES, M. L., Ildstad, S. T. ELSEVIER SCIENCE INC. 1991: 735-736

    View details for Web of Science ID A1991EV39000289

    View details for PubMedID 1990670

  • CROSS-SPECIES MIXED CHIMERISM (MOUSE + RAT -] MOUSE) - FACILITATED ENGRAFTMENT OF RAT STEM-CELLS WITH UNTREATED RAT BONE-MARROW Vandenbrink, M. R., Wren, S. M., French, S. W., HRONAKES, M. L., Ildstad, S. T. ELSEVIER SCIENCE INC. 1991: 807-808

    View details for Web of Science ID A1991EV39000322

    View details for PubMedID 1671307

Footer Links:

Stanford Medicine Resources: