Harlan Pinto

All Publications

• Head and Neck Cancers, Version 1.2015 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Spencer, S., Brizel, D. M., Burtness, B., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Foote, R. L., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Jimeno, A., Kies, M. S., Lydiatt, W. M., Maghami, E., McCaffrey, T., Mell, L. K., Mittal, B. B., Pinto, H. A., Ridge, J. A., Rodriguez, C. R., Samant, S., Shah, J. R., Weber, R. S., Wolf, G. T., Worden, F., Yom, S. S., McMillian, N., Hughes, M. 2015; 13 (7): 847-856

  Abstract

  These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (H&N) Cancers. These Insights describe the different types of particle therapy that may be used to treat H&N cancers, in contrast to traditional radiation therapy (RT) with photons (x-ray). Research is ongoing regarding the different types of particle therapy, including protons and carbon ions, with the goals of reducing the long-term side effects from RT and improving the therapeutic index. For the 2015 update, the NCCN H&N Cancers Panel agreed to delete recommendations for neutron therapy for salivary gland cancers, because of its limited availability, which has decreased over the past 2 decades; the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

  View details for Web of Science ID 000357901600005

• Head and Neck Cancers, Version 1.2015. Journal of the National Comprehensive Cancer Network Pfister, D. G., Spencer, S., Brizel, D. M., Burtness, B., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Foote, R. L., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Jimeno, A., Kies, M. S., Lydiatt, W. M., Maghami, E., McCaffrey, T., Mell, L. K., Mittal, B. B., Pinto, H. A., Ridge, J. A., Rodriguez, C. P., Samant, S., Shah, J. P., Weber, R. S., Wolf, G. T., Worden, F., Yom, S. S., McMillian, N., Hughes, M. 2015; 13 (7): 847-856

  Abstract

  These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (H&N) Cancers. These Insights describe the different types of particle therapy that may be used to treat H&N cancers, in contrast to traditional radiation therapy (RT) with photons (x-ray). Research is ongoing regarding the different types of particle therapy, including protons and carbon ions, with the goals of reducing the long-term side effects from RT and improving the therapeutic index. For the 2015 update, the NCCN H&N Cancers Panel agreed to delete recommendations for neutron therapy for salivary gland cancers, because of its limited availability, which has decreased over the past 2 decades; the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

  View details for PubMedID 26150579

• Concurrent cetuximab versus platinum-based chemoradiation for the definitive treatment of locoregionally advanced head and neck cancer. Head & neck Tang, C., Chan, C., Jiang, W., Murphy, J. D., von Eyben, R., Colevas, A. D., Pinto, H., Lee-Enriquez, N., Kong, C., Le, Q. 2015; 37 (3): 386-392

  Abstract

  The purpose of this study was to present our experience utilizing cetuximab and platinum-based concurrent chemoradiotherapy for the definitive treatment of head and neck squamous cell carcinoma (HNSCC).Patients (n = 177) who received definitive concurrent chemoradiotherapy for HNSCC were stratified into 3 groups: receiving cetuximab monotherapy (n = 24), cetuximab and chemotherapy combination (n = 33), or platinum-based chemotherapy without cetuximab (n = 120). Primary endpoints were freedom from relapse, event-free survival, and overall survival (OS).Patients receiving cetuximab monotherapy were older with lower Karnofsky performance status (KPS) and higher Charlson comorbidity scores compared with those treated with combination cetuximab and chemotherapy or platinum-based concurrent chemoradiotherapy. Patients treated with platinum-based concurrent chemoradiotherapy exhibited significantly better freedom from relapse, event-free survival, and OS compared with those receiving cetuximab monotherapy or cetuximab and chemotherapy combination therapies (all p < .05). Differences between patients receiving cetuximab monotherapy and platinum-based concurrent chemoradiotherapy held on multivariate Cox regression.This study suggests that platinum-based concurrent chemoradiotherapy is superior to cetuximab-based monotherapy for the definitive treatment of HNSCC. © 2014 Wiley Periodicals, Inc. Head Neck 37: 386-392, 2015.

  View details for DOI 10.1002/hed.23609

  View details for PubMedID 24431011

• Head and Neck Cancers, Version 2.2014 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Spencer, S., Brizel, D. M., Burtness, B., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Jimeno, A., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mell, L. K., Mittal, B. B., Pinto, H. A., Ridge, J. A., Rodriguez, C. P., Samant, S., Schuller, D. E., Shah, J. P., Weber, R. S., Wolf, G. T., Worden, F., Yom, S. S., McMillian, N. R., Hughes, M. 2014; 12 (10): 1454-1487

  Abstract

  This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers focuses on glottic laryngeal cancer, which is the most common type of laryngeal cancer and has an excellent cure rate. The lymphatic drainage of the glottis is sparse, and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic laryngeal cancer is early stage at diagnosis. Updates to these guidelines for 2014 include revisions to "Principles of Radiation Therapy" for each site and "Principles of Surgery," and the addition of a new section on "Principles of Dental Evaluation and Management."

  View details for Web of Science ID 000343275600010

• Head and Neck Cancers, Version 2.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Ang, K., Brizel, D. M., Burtness, B. A., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mittal, B. B., Pinto, H. A., Ridge, J. A., Samant, S., Schuller, D. E., Shah, J. P., Spencer, S., Weber, R. S., Wolf, G. T., Worden, F., Yom, S. S., McMillian, N. R., Hughes, M. 2013; 11 (8): 917-923

  Abstract

  These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).

  View details for Web of Science ID 000323156900003

• Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence. Cancer Ho, A. S., Tsao, G. J., Chen, F. W., Shen, T., Kaplan, M. J., Colevas, A. D., Fischbein, N. J., Quon, A., Le, Q., Pinto, H. A., Fee, W. E., Sunwoo, J. B., Sirjani, D., Hara, W., Yao, M. 2013; 119 (7): 1349-1356

  Abstract

  In head and neck cancer (HNC), 3-month post-treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post-treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months.A 10-year retrospective analysis of HNC patients was carried out with long-term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3-month scans, 175 had 3- and 12-month scans, and 77 had 3-, 12-, and 24-month scans.PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT-detected and clinically detected recurrences, with similar 3-year disease-free survival (41% vs 46%, P = .91) and 3-year overall survival (60% vs 54%, P = .70) rates. Compared with 3-month PET/CT, 12-month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive.HNC patients with negative 3-month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT-detected and clinically detected recurrences, although larger prospective studies are needed for further investigation.

  View details for DOI 10.1002/cncr.27892

  View details for PubMedID 23225544

• A Planned Neck Dissection Is Not Necessary in All Patients With N2-3 Head-and-Neck Cancer After Sequential Chemoradiotherapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Soltys, S. G., Choi, C. Y., Fee, W. E., Pinto, H. A., Le, Q. 2012; 83 (3): 994-999

  Abstract

  To assess the role of a planned neck dissection (PND) after sequential chemoradiotherapy for patients with head-and-neck cancer with N2-N3 nodal disease.We reviewed 90 patients with N2-N3 head-and-neck squamous cell carcinoma treated between 1991 and 2001 on two sequential chemoradiotherapy protocols. All patients received induction and concurrent chemotherapy with cisplatin and 5-fluorocuracil, with or without tirapazamine. Patients with less than a clinical complete response (cCR) in the neck proceeded to a PND after chemoradiation. The primary endpoint was nodal response. Clinical outcomes and patterns of failure were analyzed.The median follow-up durations for living and all patients were 8.3 years (range, 1.5-16.3 year) and 5.4 years (range, 0.6-16.3 years), respectively. Of the 48 patients with nodal cCR whose necks were observed, 5 patients had neck failures as a component of their recurrence [neck and primary (n = 2); neck, primary, and distant (n = 1); neck only (n = 1); neck and distant (n = 1)]. Therefore, PND may have benefited only 2 patients (4%) [neck only failure (n = 1); neck and distant failure (n = 1)]. The pathologic complete response (pCR) rate for those with a clinical partial response (cPR) undergoing PND (n = 30) was 53%. The 5-year neck control rates after cCR, cPR→pCR, and cPR→pPR were 90%, 93%, and 78%, respectively (p = 0.36). The 5-year disease-free survival rates for the cCR, cPR→pCR, and cPR→pPR groups were 53%, 75%, and 42%, respectively (p = 0.04).In our series, patients with N2-N3 neck disease achieving a cCR in the neck, PND would have benefited only 4% and, therefore, is not recommended. Patients with a cPR should be treated with PND. Residual tumor in the PND specimens was associated with poor outcomes; therefore, aggressive therapy is recommended. Studies using novel imaging modalities are needed to better assess treatment response.

  View details for DOI 10.1016/j.ijrobp.2011.07.042

  View details for Web of Science ID 000305256000055

  View details for PubMedID 22137026

• Phase I evaluation of TNFerade biologic plus chemoradiotherapy before esophagectomy for locally advanced resectable esophageal cancer GASTROINTESTINAL ENDOSCOPY Chang, K. J., Reid, T., Senzer, N., Swisher, S., Pinto, H., Hanna, N., Chak, A., Soetikno, R. 2012; 75 (6): 1139-?

  Abstract

  Neoadjuvant chemoradiotherapy followed by surgery is the primary treatment option for patients with locally advanced esophageal cancer. This multicenter phase I trial examined intratumoral injection of TNFerade biologic, an adenoviral vector that expresses the human tumor necrosis factor-α gene, with chemoradiotherapy in locally advanced esophageal cancer.To assess pathologic complete response (pCR), time to disease progression, progression-free survival, survival, and safety and tolerance in patients treated with preoperative chemoradiation combined with endoscopy or EUS-guided intratumoral injection of TNFerade biologic.Five weekly injections of TNFerade biologic, dose-escalated logarithmically from 4 × 10(8) to 4 × 10(11) particle units (PU), were given in combination with cisplatin 75 mg/m(2) and intravenous 5-fluorouracil 1000 mg/m(2)/d for 96 hours on days 1 and 29, and concurrent radiation therapy to 45 Gy. Surgery was performed 9 to 15 weeks after treatment.U.S. multicenter study.Patients with stage II and III esophageal cancer were enrolled.Primary outcome measures were safety, feasibility, tolerability, and rate of pCR. Secondary outcome measures were overall survival (OS) and disease-free survival.Twenty-four patients with a median age of 61 years were enrolled; 88% of the patients were men, 21% were stage II, and 79% were stage III. Six (29%) had a pCR, observed among 21 patients (20 who underwent esophagectomy and 1 at autopsy). Dose-limiting toxicities were not observed. The most frequent potentially related adverse events were fatigue (54%), fever (38%), nausea (29%), vomiting (21%), esophagitis (21%), and chills (21%). At the top dose of 4 × 10(11) PU, thromboembolic events developed in 5 of 8 patients. The median OS was 47.8 months. The 3- and 5-year OS rates and disease-free survival rates were 54% and 41% and 38% and 38%, respectively.We included primarily adenocarcinoma.Preoperative TNFerade, in combination with chemoradiotherapy, is active and safe at doses up to 4 × 10(10) PU and is associated with long survival. This regimen warrants additional studies.

  View details for DOI 10.1016/j.gie.2012.01.042

  View details for Web of Science ID 000305453700003

  View details for PubMedID 22520270

• Head and Neck Cancers JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pfister, D. G., Ang, K., Brizel, D. M., Burtness, B. A., Cmelak, A. J., Colevas, D., Dunphy, F., Eisele, D. W., Gilbert, J., Gillison, M. L., Haddad, R. I., Haughey, B. H., Hicks, W. L., Hitchcock, Y. J., Kies, M. S., Lydiatt, W. M., Maghami, E., Martins, R., McCaffrey, T., Mittal, B. B., Pinto, H. A., Ridge, J. A., Samant, S., Sanguineti, G., Schuller, D. E., Shah, J. P., Spencer, S., Trotti, A., Weber, R. S., Wolf, G. T., Worden, F. 2011; 9 (6): 596-649

  View details for Web of Science ID 000291282100002

  View details for PubMedID 21636536

• INTENSITY-MODULATED RADIOTHERAPY FOR LOCALLY ADVANCED CANCERS OF THE LARYNX AND HYPOPHARYNX HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Daly, M. E., Le, Q., Jain, A. K., Maxim, P. G., Hsu, A., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Colevas, A. D., Pinto, H., Chang, D. T. 2011; 33 (1): 103-111

  Abstract

  Limited data evaluate intensity-modulated radiotherapy (IMRT) for cancers of the hypopharynx and larynx. We report clinical outcomes and failure patterns for these patients.Between September 2001 and December 2007, 42 patients with squamous cell carcinoma (SCC) of the hypopharynx (n = 23) and larynx (n = 19) underwent IMRT, 11 postoperatively and 31 definitively. Thirty-six received systemic therapy. Median follow-up was 30 months among surviving patients.Three local failures occurred within the high-dose region and 3 occurred in regional nodes. Seven patients developed distant metastasis as the initial failure. Three-year actuarial estimates of locoregional control, freedom from distant metastasis, and overall survival rates were, respectively, 80%, 72%, and 46%.IMRT provides good locoregional control for SCC of the hypopharynx and larynx compared with historical controls. Locoregional relapses occurred in the high-dose volumes, suggesting adequate target volume delineation. Hypopharyngeal tumors, which fare worse than laryngeal tumors, warrant investigation of more aggressive treatment.

  View details for DOI 10.1002/hed.21406

  View details for Web of Science ID 000286290400017

  View details for PubMedID 20848427

• INTENSITY-MODULATED RADIOTHERAPY IN THE TREATMENT OF OROPHARYNGEAL CANCER: CLINICAL OUTCOMES AND PATTERNS OF FAILURE INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Daly, M. E., Le, Q., Maxim, P. G., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Pinto, H., Chang, D. T. 2010; 76 (5): 1339-1346

  Abstract

  To report outcomes, failures, and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma of the oropharynx.Between Aug 2001 and Oct 2007, 107 patients were treated with IMRT with curative intent at Stanford University. Twenty-two patients were treated postoperatively, and 85 were treated definitively. Concurrent platinum-based chemotherapy was administered to 86 patients (80%) and cetuximab to 8 patients (7%). The prescribed dose was 66 Gy at 2.2 Gy/fraction for definitively treated cases and 60 Gy at 2 Gy/fraction for postoperative cases. Median follow-up was 29 months among surviving patients (range, 4-105 months).Eight patients had persistent disease or local-regional failure at a median of 6.5 months (range, 0-9.9 months). Six local failures occurred entirely within the high-risk clinical target volume (CTV) (one with simultaneous distant metastasis). One patient relapsed within the high- and intermediate-risk CTV. One patient had a recurrence at the junction between the IMRT and low-neck fields. Seven patients developed distant metastasis as the first site of failure. The 3-year local-regional control (LRC), freedom from distant metastasis, overall survival, and disease-free survival rates were 92%, 92%, 83%, and 81%, respectively. T stage (T4 vs. T1-T3) was predictive of poorer LRC (p = 0.001), overall survival (p = 0.001), and disease-free survival (p < 0.001) rates. Acute toxicity consisted of 58% grade 3 mucosal and 5% grade 3 skin reactions. Six patients (6%) developed grade >or=3 late complications.IMRT provides excellent LRC for oropharyngeal squamous cell carcinoma. Distant metastases are a major failure pattern. No marginal failures were observed.

  View details for DOI 10.1016/j.ijrobp.2009.04.006

  View details for Web of Science ID 000276675300012

  View details for PubMedID 19540068

• In vivo H-1 magnetic resonance spectroscopy of lactate in patients with Stage IV head and neck squamous cell carcinoma 49th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Le, Q., Koong, A., Lieskovsky, Y. Y., Narasimhan, B., Graves, E., Pinto, H., Brown, J. M., Spielman, D. ELSEVIER SCIENCE INC. 2008: 1151–57

  Abstract

  To investigate in vivo(1)H magnetic resonance spectroscopy imaging of lactate for assessing tumor hypoxia in head and neck cancers and to determine its utility in predicting the response and outcomes.Volume-localized lactate-edited (1)H magnetic resonance spectroscopy at 1.5 T was performed in vivo on involved neck nodes and control subcutaneous tissues in 36 patients with Stage IV head and neck cancer. The signal intensities (SIs) of lactate, choline, and creatine and the choline/creatine ratio were measured. The tumor partial pressure of oxygen (pO(2)) was obtained in the same lymph node before MRS. Patients were treated with either two cycles of induction chemotherapy (tirapazamine, cisplatin, 5-fluorouracil) followed by simultaneous chemoradiotherapy or the same regimen without tirapazamine. The lactate SI and the choline/creatine ratio correlated with the tumor pO(2), nodal response, and locoregional control.The lactate SI was greater for the involved nodes (median, 0.25) than for the subcutaneous tissue (median, 0.04; p = 0.07). No significant correlation was found between the lactate SI and tumor pO(2) (mean, 0.46 +/- 0.10 for hypoxic nodes [pO(2) < or =10 mm Hg, n = 15] vs. 0.36 +/- 0.07 for nonhypoxic nodes [pO(2) >10 mm Hg, n = 21], p = 0.44). A significant correlation was found between the choline/creatine ratios and tumor pO(2) (mean, 2.74 +/- 0.34 for hypoxic nodes vs. 1.78 +/- 0.31 for nonhypoxic nodes, p = 0.02). No correlation was found between the lactate SI and the complete nodal response (p = 0.52) or locoregional control rates.The lactate SI did not correlate with tumor pO(2), treatment response, or locoregional control. Additional research is needed to refine this technique.

  View details for DOI 10.1016/j.ijrobp.2007.11.030

  View details for Web of Science ID 000257299200025

  View details for PubMedID 18258377

  View details for PubMedCentralID PMC2601688

• Excellent local control with stereotactic radiotherapy boost after external beam radiotherapy in patients with nasopharyngeal carcinoma 87th Annual Meeting of the American-Radium-Society Hara, W., Loo, B. W., Goffinet, D. R., Chang, S. D., Adler, J. R., Pinto, H. A., Fee, W. E., Kaplan, M. J., Fischbein, N. J., Le, Q. ELSEVIER SCIENCE INC. 2008: 393–400

  Abstract

  To determine long-term outcomes in patients receiving stereotactic radiotherapy (SRT) as a boost after external beam radiotherapy (EBRT) for locally advanced nasopharyngeal carcinoma (NPC).Eight-two patients received an SRT boost after EBRT between September 1992 and July 2006. Nine patients had T1, 30 had T2, 12 had T3, and 31 had T4 tumors. Sixteen patients had Stage II, 19 had Stage III, and 47 had Stage IV disease. Patients received 66 Gy of EBRT followed by a single-fraction SRT boost of 7-15 Gy, delivered 2-6 weeks after EBRT. Seventy patients also received cisplatin-based chemotherapy delivered concurrently with and adjuvant to radiotherapy.At a median follow-up of 40.7 months (range, 6.5-144.2 months) for living patients, there was only 1 local failure in a patient with a T4 tumor. At 5 years, the freedom from local relapse rate was 98%, freedom from nodal relapse 83%, freedom from distant metastasis 68%, freedom from any relapse 67%, and overall survival 69%. Late toxicity included radiation-related retinopathy in 3, carotid aneurysm in 1, and radiographic temporal lobe necrosis in 10 patients, of whom 2 patients were symptomatic with seizures. Of 10 patients with temporal lobe necrosis, 9 had T4 tumors.Stereotactic radiotherapy boost after EBRT provides excellent local control for patients with NPC. Improved target delineation and dose homogeneity of radiation delivery for both EBRT and SRT is important to avoid long-term complications. Better systemic therapies for distant control are needed.

  View details for DOI 10.1016/j.ijrobp.2007.10.027

  View details for Web of Science ID 000255971100013

  View details for PubMedID 18164839

• Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial JOURNAL OF THE NATIONAL CANCER INSTITUTE Fakhry, C., Westra, W. H., Cmelak, S. L., Ridge, J. A., Pinto, H., Forastiere, A., Gillison, M. L. 2008; 100 (4): 261-269

  Abstract

  The improved prognosis for patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) relative to HPV-negative HNSCC observed in retrospective analyses remains to be confirmed in a prospective clinical trial.We prospectively evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV HNSCC of the oropharynx or larynx who participated in an Eastern Cooperative Oncology Group (ECOG) phase II trial and who received two cycles of induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and standard fractionation radiation therapy. The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction (PCR) and in situ hybridization. Two-year overall and progression-free survival for HPV-positive and HPV-negative patients were estimated by Kaplan-Meier analysis. The relative hazard of mortality and progression for HPV-positive vs HPV-negative patients after adjustment for age, ECOG performance status, stage, and other covariables was estimated by use of a multivariable Cox proportional hazards model. All statistical tests were two-sided.Genomic DNA of oncogenic HPV types 16, 33, or 35 was located within tumor cell nuclei of 40% (95% confidence interval [CI] = 30% to 50%) of patients with HNSCC of the oropharynx or larynx by in situ hybridization and PCR. Compared with patients with HPV-negative tumors, patients with HPV-positive tumors had higher response rates after induction chemotherapy (82% vs 55%, difference = 27%, 95% CI = 9.3% to 44.7%, P = .01) and after chemoradiation treatment (84% vs 57%, difference = 27%, 95% CI = 9.7% to 44.3%, P = .007). After a median follow-up of 39.1 months, patients with HPV-positive tumors had improved overall survival (2-year overall survival = 95% [95% CI = 87% to 100%] vs 62% [95% CI = 49% to 74%], difference = 33%, 95% CI = 18.6% to 47.4%, P = .005, log-rank test) and, after adjustment for age, tumor stage, and ECOG performance status, lower risks of progression (hazard ratio [HR] = 0.27, 95% CI = 0.10 to 0.75), and death from any cause (HR = 0.36, 95% CI = 0.15 to 0.85) than those with HPV-negative tumors.For patients with HNSCC of the oropharynx, tumor HPV status is strongly associated with therapeutic response and survival.

  View details for DOI 10.1093/jnci/djn011

  View details for Web of Science ID 000253796600009

  View details for PubMedID 18270337

• Phase II trial of chemoradiation for organ preservation in resectable stage III or IV squamous cell carcinomas of the larynx or oropharynx: Results of Eastern Cooperative Oncology Group study E2399 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Cmelak, A. J., Li, S., Goldwasser, M. A., Murphy, B., Cannon, M., Pinto, H., Rosenthal, D. I., Gillison, M., Forastiere, A. A. AMER SOC CLINICAL ONCOLOGY. 2007: 3971–77

  Abstract

  Taxane-based concurrent chemoradiotherapy (CCR) for head and neck cancers has proven to have a favorable toxicity profile compared with cisplatin and radiation. This phase II multi-institutional trial evaluates taxane-based induction chemotherapy followed by CCR for organ preservation in resectable stage III/IVA and IVB larynx and oropharynx (OP) cancer patients.Eligibility required resectable stage T2N+, or T3-T4N0-3M0 biopsy-proven squamous carcinoma, age at least 18 years, PS 0 to 2, good organ function, and no prior chemotherapy or radiation. Treatment was induction paclitaxel 175 mg/m(2) and carboplatin area under the concentration-time curve (AUC) 6 for two cycles every 21 days followed by concurrent paclitaxel 30 mg/m(2) every 7 days with 70 Gy if no evidence of tumor progression. Weekly erythropoietin alpha 40 kU was used for suboptimal hemoglobin (< 14 gm/dL men, < 13 gm/dL women). The primary end point was organ preservation (freedom from primary site salvage surgery or primary tumor recurrence).One hundred five of 111 patients (36 larynx, 69 OP) were eligible. Median follow-up was 36.7 months. Ninety-four percent received full-dose radiotherapy and 91% received at least five cycles of concurrent paclitaxel. No patient progressed while receiving chemotherapy. Organ preservation was 81% at 2 years after completion of therapy (larynx 74%, OP 84%). Thirteen patients required primary-site salvage surgery (seven larynx, six OP), and six of these have progressed and died (three larynx, three OP). Thirteen patients developed distant metastases (seven larynx, six OP; P = .02) and 10 of 36 larynx and 11 of 69 OP patients have died as a result of their disease. Two-year survival is 76% (63% larynx v 83% OP).A high organ preservation rate was obtained with this regimen for OP but not for larynx patients. Toxicity was low, and induction chemotherapy did not preclude delivery of concurrent chemoradiotherapy.

  View details for DOI 10.1200/JCO.2007.10.8951

  View details for Web of Science ID 000249416000029

  View details for PubMedID 17761982

• Evaluation of patterns of failure and subjective salivary function in patients treated with intensity modulated radiotherapy for head and neck squamous cell carcinoma 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Daly, M. E., Lieskovsky, Y., Pawlicki, T., Yau, J., Pinto, H., Kaplan, M., Fee, W. E., Koong, A., Goffinet, D. R., Xing, L., Le, Q. JOHN WILEY & SONS INC. 2007: 211–20

  Abstract

  Our aim was to correlate patterns of failure with target volume delineations in patients with head and neck squamous cell carcinoma (HNSCC) treated with intensity-modulated radiation therapy (IMRT) and to report subjective xerostomia outcomes after IMRT as compared with conventional radiation therapy (CRT).Between January 2000 and April 2005, 69 patients with newly diagnosed nonmetastatic HNSCC underwent curative parotid-sparing IMRT at Stanford University. Sites included were oropharynx (n = 39), oral cavity (n = 8), larynx (n = 8), hypopharynx (n = 8), and unknown primary (n = 6). Forty-six patients received definitive IMRT (66 Gy, 2.2 Gy/fraction), and 23 patients received postoperative IMRT (60.2 Gy, 2.15 Gy/fraction). Fifty-one patients also received concomitant chemotherapy. Posttreatment salivary gland function was evaluated by a validated xerostomia questionnaire in 29 IMRT and 75 matched CRT patients >6 months after completing radiation treatment.At a median follow-up of 25 months for living patients (range, 10-60), 7 locoregional failures were observed, 5 in the gross target or high-risk postoperative volume, 1 in the clinical target volume, and 1 at the junction of the IMRT and supraclavicular fields. The 2-year Kaplan-Meier estimates for locoregional control and overall survival were 92% and 74% for definitive IMRT and 87% and 87% for postoperative IMRT patients, respectively. The mean total xerostomia questionnaire score was significantly better for IMRT than for CRT patients (p = .006).The predominant pattern of failure in IMRT-treated patients is in the gross tumor volume. Parotid sparing with IMRT resulted in less subjective xerostomia and may improve quality of life in irradiated HNSCC patients.

  View details for DOI 10.1002/hed.20505

  View details for Web of Science ID 000244459100002

  View details for PubMedID 17111429

• Clinical role of F-18-FDG PET/CT in the management of squamous cell carcinoma of the head and neck and thyroid carcinoma JOURNAL OF NUCLEAR MEDICINE Quon, A., Fischbein, N. J., McDougall, I. R., Le, Q., Loo, B. W., Pinto, H., Kaplan, M. J. 2007; 48: 58S-67S

  Abstract

  18F-FDG PET/CT has rapidly become a widely used imaging modality for evaluating a variety of malignancies, including squamous cell carcinoma of the head and neck and thyroid cancer. Using both published data and the multidisciplinary experience at our institution, we provide a practical set of guidelines and algorithms for the use of 18F-FDG PET/CT in the evaluation and management of head and neck cancer and thyroid cancer.

  View details for Web of Science ID 000243420900008

  View details for PubMedID 17204721

• Plasma osteopontin is an independent prognostic marker for head and neck cancers 41st Annual Meeting of the American-Society-of-Clinical-Oncology Petrik, D., Lavori, P. W., Cao, H., Zhu, Y., Wong, P., Christofferson, E., Kaplan, M. J., Pinto, H. A., Sutphin, P., Koong, A. C., Giaccia, A. J., Le, Q. AMER SOC CLINICAL ONCOLOGY. 2006: 5291–97

  Abstract

  To confirm the relationship between plasma osteopontin (OPN) levels and treatment outcomes in head and neck squamous cell carcinoma (HNSCC) patients in an expanded study.One hundred forty patients with newly diagnosed HNSCC were enrolled onto this study, 54 previously reported and 86 new patients. Pretreatment plasma OPN levels were assessed in all patients by an enzyme-linked immunosorbent assay method. OPN levels were correlated to treatment outcomes in the new group of patients. Detailed analyses were also performed on the relationship between OPN and tumor control rate, event-free survival (EFS), and postrelapse survival for the entire group.Using a previously defined cut off point of 450 ng/mL, there was a significant correlation between OPN and freedom-from-relapse (P = .047), overall survival (P = .019), and EFS (P = .023) in the new, independent patient cohort (n = 86). Sequence of event analyses using the entire group (N = 140) revealed that OPN was an independent prognostic factor for initial tumor control, EFS in those who have achieved tumor control, and postrelapse survival.In this expanded study, we were able to replicate the prognostic significance of OPN using a predefined cut off point in an independent patient group and demonstrated that plasma OPN is an independent prognostic marker for HNSCC.

  View details for DOI 10.1200/JCO.2006.06.8627

  View details for Web of Science ID 000242342800017

  View details for PubMedID 17114663

• Advanced-staged tonsillar squamous carcinoma: Organ preservation versus surgical management of the primary site 90th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America Shirazi, H. A., Sivanandan, R., Goode, R., Fee, W. E., Kaplan, M. J., Pinto, H. A., Goffinet, D. R., Le, Q. JOHN WILEY & SONS INC. 2006: 587–94

  Abstract

  Our aim was to review our experience in the management of advanced tonsillar squamous cell carcinoma (SCC) and to compare treatment outcomes between patients treated with and without surgery to the primary site.The records of 74 patients with advanced-stage tonsillar SCC were reviewed. The median age at diagnosis was 58 years. Thirty-eight patients received definitive surgery to the primary site, and 36 were treated with an organ-preservation approach (OP) using radiotherapy +/- chemotherapy.No significant difference in overall survival (OS) or freedom from relapse (FFR) by treatment was found. T classification and N status were significant independent predictors on multivariate analysis for OS and FFR. Major late toxicity was noted in 10 patients in the surgical group and nine in the OP group.Patients treated with OP and primary surgery had comparable OS and FFR. T classification and N status were significant independent predictors for tumor relapse and survival. On the basis of these results, we favor organ-preservation therapy for patients with advanced-stage tonsillar SCC.

  View details for DOI 10.1002/hed.20372

  View details for Web of Science ID 000238690100003

  View details for PubMedID 16475199

• Mature results from a randomized phase II trial of cisplatin plus 5-fluorouracil and radiotherapy with or without tirapazamine in patients with resectable stage IV head and neck squamous cell carcinomas CANCER Le, Q. T., Taira, A. I., Budenz, S., Dorie, M. J., Goffinet, D. R., Fee, W. E., Goode, R., Bloch, D., Koong, A., Brown, J. M., Pinto, H. A. 2006; 106 (9): 1940-1949

  Abstract

  The objective of this article was to report the results from a randomized trial that evaluated the efficacy and toxicity of adding tirapazamine (TPZ) to chemoradiotherapy in the treatment of patients with head and neck squamous cell carcinomas (HNSCC).Sixty-two patients with lymph node-positive, resectable, TNM Stage IV HNSCC were randomized to receive either 2 cycles of induction chemotherapy (TPZ, cisplatin, and 5-fluorouracil [5-FU]) followed by simultaneous chemoradiotherapy (TPZ, cisplatin, and 5-FU) or to receive the same regimen without TPZ. Patients who did not achieve a complete response at 50 Grays underwent surgical treatment. Stratification factors for randomization included tumor site, TNM stage, and median tumor oxygen tension. The primary endpoint was complete lymph node response.The addition of TPZ resulted in increased hematologic toxicity. There was 1 treatment-related death from induction chemotherapy. The complete clinical and pathologic response rate in the lymph nodes was 90% and 74% for the standard treatment arm and the TPZ arm, respectively (P = .08) and 89% and 90% at the primary site in the respective treatment arms (P = .71). The 5-year overall survival rate was 59%, the cause-specific survival rate was 68%, the rate of freedom from recurrence was 69%, and the locoregional control rate was 77% for the entire group. There was no difference with regard to any of the outcome parameters between the 2 treatment arms. The significant long-term toxicity rate also was found to be similar between the 2 arms.The addition of TPZ increased hematologic toxicity but did not improve outcomes in patients with resectable, Stage IV HNSCC using the protocol administered this small randomized study. The combination of induction and simultaneous chemoradiotherapy resulted in excellent survival in these patients.

  View details for DOI 10.1002/cncr.21785

  View details for Web of Science ID 000237187400010

  View details for PubMedID 16532436

• Phase II trial of taxol in salivary gland malignancies (E1394): A trial of the Eastern Cooperative Oncology Group HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Gilbert, J., Li, Y., Pinto, H. A., JENNINGS, T., Kies, M. S., Silverman, P., Forastiere, A. A. 2006; 28 (3): 197-204

  Abstract

  Malignant tumors of the salivary glands make up approximately 5% of head and neck cancers. The Eastern Cooperative Oncology Group (ECOG) initiated a phase II evaluation of paclitaxel in patients with locally recurrent or metastatic salivary gland malignancies.Chemo-naive patients with histologically confirmed recurrent or metastatic carcinoma of salivary gland origin (mucoepidermoid, adenocarcinoma, or adenoid cystic) were eligible. Patients were treated with paclitaxel, 200 mg/m(2) IV, every 21 days for a minimum of four cycles.Forty-five patients were treated. Eight partial responses were seen among the 31 patients with mucoepidermoid or adenocarcinoma histologic findings for a response rate of 26%. No responses were seen in the adenoid cystic carcinoma group. No significant difference in overall survival was found among these three histologic subgroups.Paclitaxel demonstrates moderate activity in salivary gland tumors of mucoepidermoid and adenocarcinoma histology. The poor response rate in adenoid cystic carcinoma is consistent with prior reports in this chemoresistant histologic subtype.

  View details for DOI 10.1002/hed.20327

  View details for Web of Science ID 000235599600002

  View details for PubMedID 16470745

• Positron-emission tomography for surveillance of head and neck cancer LARYNGOSCOPE Ryan, W. R., Fee, W. E., Le, Q. T., Pinto, H. A. 2005; 115 (4): 645-650

  Abstract

  To determine the diagnostic accuracy and the ideal timing of fluoro-fluorodeoxyglucose positron-emission tomography (PET) in the posttreatment surveillance of head and neck mucosal squamous cell carcinoma (HNSCC).Retrospective chart review.Our sample includes 103 adult patients with 118 posttreatment PET scans who had undergone treatment for HNSCC. We correlated PET results with surgical pathology and clinical outcome in the subsequent 6 months.For the detection of locoregional persistent or recurrent HNSCC, PET scans had a sensitivity of 82%, specificity of 92%, positive predictive value (PPV) of 64%, negative predictive value (NPV) of 97%, and overall accuracy of 90%. For the detection of distant metastases, PET scans had a sensitivity of 89%, specificity of 97%, PPV of 85%, NPV of 98%, and overall accuracy of 96%. PET scans of the head and neck region performed greater than 1 month after the completion of radiation compared with scans performed within 1 month had a significantly higher sensitivity of 95% versus 55% (P < .01) and NPV of 99% versus 90% (P < .01).PET is effective in detecting distant metastases in the posttreatment surveillance for HNSCC patients. A negative PET is highly reliable for all sites. However, a positive PET in the head and neck region is unreliable because of a high false-positivity rate. PET of the head and neck region has a statistically significant risk of a false-negative reading when performed within 1 month of radiation.

  View details for DOI 10.1097/01.mlg.0000161345.23128.d4

  View details for PubMedID 15805874

• Long-term results of 100 consecutive comprehensive neck dissections - Implications for selective neck dissections ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Sivanandan, R., Kaplan, M. J., Lee, K. J., Lebl, D., PINTO, H., Le, Q. T., Goffinet, D. R., Fee, W. E. 2004; 130 (12): 1369-1373

  Abstract

  The optimal surgical procedure for the neck in patients with squamous head and neck cancers is controversial. Selective neck dissections have replaced modified radical neck dissections as the procedure of choice for the clinically negative (N0) neck and are now being considered for patients with early-stage neck disease. We report the long-term local recurrence rates in 100 consecutive patients undergoing a radical or modified radical neck dissection for clinically positive (N+) and N0 neck disease and review comprehensively the literature reporting and comparing regional control rates for both neck dissection types.The clinical records of 100 consecutive patients who underwent a comprehensive neck dissection (levels I-V) for squamous head and neck cancers with a minimum of a 2-year follow-up were retrospectively reviewed for primary site of disease, clinical and pathologic neck status, histopathologic grade, neck dissection type, and the site and time of recurrence.Complete data were available for 97 patients on whom 99 neck dissections were performed. Three patients died from unknown causes. Seventy-six patients with N+ disease underwent a therapeutic neck dissection, while 24 patients with clinically N0 disease underwent an elective dissection. The overall neck recurrence rate in patients with controlled primary disease was 7%. The neck or regional failure rate for patients completing the recommended adjuvant radiotherapy was 4%. Six (25%) of 24 patients with clinically N0 disease had occult metastases. The recurrence rate for this group was 4%.Further study is needed to determine the optimal surgical management of the N0 and limited N+ neck.

  View details for PubMedID 15611394

• Phase II double-blind randomized study comparing oral aloe vera versus placebo to prevent radiation-related mucositis in patients with head-and-neck neoplasms 39th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Su, C. K., Mehta, V., Ravikumar, L., Shah, R., PINTO, H., Halpern, J., Koong, A., Goffinet, D., Le, Q. T. ELSEVIER SCIENCE INC. 2004: 171–77

  Abstract

  In a single-institution, double-blind, prospective, randomized trial, we determined whether oral aloe vera gel can reduce radiation-induced mucositis in head-and-neck cancer patients.We randomized 58 head-and-neck cancer patients between oral aloe vera and placebo. To be included in this Phase II protocol, patients had to be treated with radiotherapy with curative intent at Stanford University between February 1999 and March 2002. We examined patients biweekly for mucositis at 15 head-and-neck subsites and administered quality-of-life questionnaires.Patients in the aloe and placebo groups were statistically identical in baseline characteristics. By the end of treatment, the two groups were also statistically identical in maximal grade of toxicity, duration of Grade 2 or worse mucositis, quality-of-life scores, percentage of weight loss, use of pain medications, hydration requirement, oral infections, and prolonged radiation breaks.In our randomized study, oral aloe vera was not a beneficial adjunct to head-and-neck radiotherapy. The mean quality-of-life scores were greater in the aloe vera group, but the differences were not statistically significant. Oral aloe vera did not improve tolerance to head-and-neck radiotherapy, decrease mucositis, reduce soreness, or otherwise improve patient well-being.

  View details for DOI 10.1016/j.ijrobp.2004.02.012

  View details for Web of Science ID 000223854500022

  View details for PubMedID 15337553

• Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma 44th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q. T., Tate, D., Koong, A., Gibbs, I. C., Chang, S. D., Adler, J. R., Pinto, H. A., Terris, D. J., Fee, W. E., Goffinet, D. R. ELSEVIER SCIENCE INC. 2003: 1046–54

  Abstract

  Treatment of nasopharyngeal carcinoma using conventional external beam radiotherapy (EBRT) alone is associated with a significant risk of local recurrence. Stereotactic radiosurgery (STR) was used to boost the tumor site after EBRT to improve local control.Forty-five nasopharyngeal carcinoma patients received a STR boost after EBRT at Stanford University. Seven had T1, 16 had T2, 4 had T3, and 18 had T4 tumors (1997 American Joint Commission on Cancer staging). Ten had Stage II, 8 had Stage III, and 27 had Stage IV neoplasms. Most patients received 66 Gy of EBRT delivered at 2 Gy/fraction. Thirty-six received concurrent cisplatin-based chemotherapy. STR was delivered to the primary site 4-6 weeks after EBRT in one fraction of 7-15 Gy.At a medium follow-up of 31 months, no local failures had occurred. The 3-year local control rate was 100%, the freedom from distant metastasis rate was 69%, the progression-free survival rate was 71%, and the overall survival rate was 75%. Univariate and multivariate analyses revealed N stage (favoring N0-N1, p = 0.02, hazard ratio HR 4.2) and World Health Organization histologic type (favoring type III, p = 0.002, HR 13) as significant factors for freedom from distant metastasis. World Health Organization histologic type (p = 0.004, HR 10.5) and age (p = 0.01, HR 1.07/y) were significant factors for survival. Late toxicity included transient cranial nerve weakness in 4, radiation-related retinopathy in 1, and asymptomatic temporal lobe necrosis in 3 patients who originally had intracranial tumor extension.STR boost after EBRT provided excellent local control in nasopharyngeal carcinoma patients. The incidence of late toxicity was acceptable. More effective systemic treatment is needed to achieve improved survival.

  View details for DOI 10.1016/S0360-3016(03)00117-2

  View details for Web of Science ID 000183937500018

  View details for PubMedID 12829140

• Comparison of the comet assay and the oxygen microelectrode for measuring tumor oxygenation in head-and-neck cancer patients Annual Meeting on Radiation Research Le, Q. T., Kovacs, M. S., Dorie, M. J., Koong, A., Terris, D. J., Pinto, H. A., Goffinet, D. R., Nowels, K., Bloch, D., Brown, J. M. ELSEVIER SCIENCE INC. 2003: 375–83

  Abstract

  To compare the Eppendorf PO2 histograph and the alkaline comet assay as methods of measuring tumor hypoxia in patients with head-and-neck squamous cell carcinomas.As part of a larger clinical trial, 65 patients with head-and-neck squamous cell carcinoma nodal metastasis underwent tumor oxygenation measurements with Eppendorf PO2 histographs and comet assays, performed on fine-needle aspirates at 1 and 2 min after 5 Gy. Fifty-four patients had sufficient tumor cells for comet analysis at 1 min and 26 at both 1 and 2 min. Individual cells were examined for DNA single-strand breaks by alkaline gel electrophoresis, and the distribution of values was quantified using median tail moment (MTM). Nonirradiated tumor cells from pretreatment fine-needle aspirates received 5 Gy in vitro to establish the oxygenated response.There was a significant correlation between the 1- and 2-min MTM (slope = 0.77 +/- 0.03). There was no relationship between DNA damage in tumor cells irradiated in vitro and in vivo. No correlation was found between Eppendorf PO2 measurements and comet MTM. There was a statistically significant correlation between the treatment response in the node studied and comet MTMs, whereas no correlation was observed between treatment response and Eppendorf measurements.Comet assays are reproducible, as shown by biopsies at 1 and 2 min. Intertumor variation in the MTM is not a result of intrinsic radiosensitivity but of tumor hypoxia. There was no correlation between Eppendorf PO2 measurements and comet MTM. Comet assays were better than Eppendorf in predicting treatment response as an end point for short-term outcome. Longer follow-up is needed to determine the role of the comet assay as a predictor for locoregional tumor control and survivals.

  View details for DOI 10.1016/S0360-3016(02)04503-0

  View details for Web of Science ID 000182861500010

  View details for PubMedID 12738312

• Identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas CLINICAL CANCER RESEARCH Le, Q. T., Sutphin, P. D., Raychaudhuri, S., Yu, S. C., Terris, D. J., Lin, H. S., Lum, B., Pinto, H. A., Koong, A. C., Giaccia, A. J. 2003; 9 (1): 59-67

  Abstract

  Tumor hypoxia modifies treatment efficacy and promotes tumor progression. Here, we investigated the relationship between osteopontin (OPN), tumor pO(2), and prognosis in patients with head and neck squamous cell carcinomas (HNSCC).We performed linear discriminant analysis, a machine learning algorithm, on the NCI-60 cancer cell line microarray expression database to identify a gene profile that best distinguish cell lines with high Von-Hippel Lindau (VHL) gene expression, an important regulator of hypoxia-related genes, from those with low expression. Plasma OPN levels in 15 volunteers, 31 VHL patients, and 54 HNSCC patients were quantitatively measured by ELISA. The relationships between plasma OPN levels, tumor pO(2) as measured by the Eppendorf microelectrode, freedom from relapse (FFR), and survival in HNSCC patients were evaluated.Microarray analysis indicated that OPN gene expression inversely correlated with that of VHL. These findings were confirmed by Northern blot analysis. ELISA studies and Western blot in a HNSCC cell line demonstrated that hypoxia exposure resulted in increased OPN secretion. Patients with VHL syndrome had significantly higher plasma OPN levels than healthy volunteers. Plasma OPN level inversely correlated with tumor pO(2) (P = 0.003, r = -0.42). OPN levels correlated with clinical outcomes. The 1-year FFR and survival rates were 80 and 100%, respectively, for patients with OPN levels 450 ng/ml (P = 0.002 and 0.0005). Multivariate analysis revealed that OPN was an independent predictor for FFR and survival.Plasma OPN levels appeared to correlate with tumor hypoxia in HNSCC patients and may serve as noninvasive tests to identify patients at high risk for tumor recurrence.

  View details for Web of Science ID 000180430600008

  View details for PubMedID 12538452

• Estimating DNA repair by sequential evaluation of head and neck tumor radiation sensitivity using the comet assay 5th International Conference on Head and Neck Cancer of the International-Society-of-Head-Neck-Cancer Terris, D. J., Ho, E. Y., Ibrahim, H. Z., Dorie, M. J., Kovacs, M. S., Le, Q. T., Koong, A. C., Pinto, H. A., Brown, J. M. AMER MEDICAL ASSOC. 2002: 698–702

  Abstract

  The alkaline comet assay is a microelectrophoretic technique for detecting single-strand DNA breaks, and may be used as an indirect measure of hypoxia by determining the radiation sensitivity of individual cells.To assess the ability of the comet assay to estimate the rate of DNA repair after irradiation in patients with head and neck cancer.The comet assay was used to evaluate DNA damage in fine-needle aspirates of lymph nodes containing metastatic squamous cell carcinoma in patients with head and neck cancer 1, 2, and 3 minutes after treatment with 500 rad (5 Gy) of irradiation. The amount of DNA damage (measured as the "tail moment" of the comet) is proportional to the number of DNA single-strand breaks after irradiation, which in turn depends on the oxygen concentration in each cell.The mean +/- SD of the median tail moment of the 1-minute postirradiation comets was 29.4 +/- 14.2 (n = 27). After 2 minutes, the mean median tail moment decreased to 25.4 +/- 13.6 (n = 25), representing a mean decrease of 11.9% in those patients with both 1- and 2-minute comet assays. Assuming a linear rate of repair, this decrease in DNA damage corresponds to a repair half-life of 4.2 minutes. A 3-minute assay was also performed on samples from a smaller number of patients (n = 9), with a mean value not significantly different from that of the 2-minute assay of the samples from this group.The comet assay is a promising tool for evaluating radiation sensitivity in individual cells. The rate of DNA repair early after irradiation is consistent with data in the literature.

  View details for PubMedID 12049567

• Physician perspectives on increasing minorities in cancer clinical trials: An Eastern Cooperative Oncology Group (ECOG) initiative Workshop on Participation of Minorities and Women in Clinical Cancer Research Pinto, H. A., McCaskill-Stevens, W., Wolfe, P., Marcus, A. C. ELSEVIER SCIENCE INC. 2000: S78–S84

  Abstract

  This paper describes the ECOG-NMA Minority Accrual Initiative to assure minority participation in cancer clinical trials.Focus groups were held to identify physician-reported barriers to the enrollment of minority patients in Cleveland, OH, Indianapolis, IN, Santa Clara County, CA, and Philadelphia, PA. Community physicians affiliated with the National Medical Association (NMA), and Eastern Cooperative Oncology Group (ECOG) investigators participated in the focus groups. A four-step process consisting of focus group workshops were conducted to (i) identify barriers, (ii) develop potential solutions to the barriers, (iii) define solutions to barriers involving specific clinical trials, and (iv) implement the solutions.Focus group participants identified physician lack of information, patient fears and suspicion, the fear of losing patients, and distrust of the health care system as the major barriers to enrollment of African Americans. We found significant differences between community physicians and cancer program physicians in several areas. Community physicians emphasized personal contacts to address the lack of information and to overcome patient fears and suspicions, while the cancer program physicians emphasized printed materials. There was no difference by region in the barriers identified in the focus group workshops; however, the proposed solutions to overcoming the barriers were specific to each site.The four-step process developed by the ECOG and the NMA used the focus group methodology to identify and overcome barriers to participation of African Americans in cancer clinical trials. Outreach efforts to educate patients, their families, and community physicians about cancer clinical trials should be directed at overcoming patient suspicions and providing practical information to physicians about specific trials and how to enroll patients.

  View details for Web of Science ID 000165950000010

  View details for PubMedID 11189096

• In vivo H-1 MR spectroscopy of human head and neck lymph node metastasis and comparison with oxygen tension measurements AMERICAN JOURNAL OF NEURORADIOLOGY Star-Lack, J. M., Adalsteinsson, E., Adam, M. F., Terris, D. J., Pinto, H. A., Brown, J. M., Spielman, D. M. 2000; 21 (1): 183-193

  Abstract

  Current diagnostic methods for head and neck metastasis are limited for monitoring recurrence and assessing oxygenation. 1H MR spectroscopy (1H MRS) provides a noninvasive means of determining the chemical composition of tissue and thus has a unique potential as a method for localizing and characterizing cancer. The purposes of this investigation were to measure 1H spectral intensities of total choline (Cho), creatine (Cr), and lactate (Lac) in vivo in human lymph node metastases of head and neck cancer for comparison with normal muscle tissue and to examine relationships between metabolite signal intensities and tissue oxygenation status.Volume-localized Lac-edited MRS at 1.5 T was performed in vivo on the lymph node metastases of 14 patients whose conditions were untreated and who had primary occurrences of squamous cell carcinoma. MRS measurements were acquired also from the neck muscle tissue of six healthy volunteers and a subset of the patients. Peak areas of Cho, Cr, and Lac were calculated. Tissue oxygenation (pO2) within the abnormal lymph nodes was measured independently using an Eppendorf polarographic oxygen electrode.Cho:Cr ratios were significantly higher in the nodes than in muscle tissue (node Cho:Cr = 2.9 +/- 1.6, muscle Cho:Cr = 0.55 +/- 0.21, P = .0006). Lac was significantly higher in cancer tissue than in muscle (P = .01) and, in the nodes, showed a moderately negative correlation with median pO2 (r = -.76) over a range of approximately 0 to 30 mm Hg. Nodes with oxygenation values less than 10 mm Hg had approximately twice the Lac signal intensity as did nodes with oxygenation values greater than 10 mm Hg (P = .01). Cho signal intensity was not well correlated with pO2 (r = -.46) but seemed to decrease at higher oxygenation levels (>20 mm Hg).1H MRS may be useful for differentiating metastatic head and neck cancer from normal muscular tissue and may allow for the possibility of assessing oxygenation. Potential clinical applications include the staging and monitoring of treatment.

  View details for PubMedID 10669248

• DNA damage measured by the comet assay in head and neck cancer patients treated with tirapazamine. Neoplasia Dorie, M. J., Kovacs, M. S., Gabalski, E. C., Adam, M., Le, Q. T., Bloch, D. A., Pinto, H. A., Terris, D. J., Brown, J. M. 1999; 1 (5): 461-467

  Abstract

  Tirapazamine (TPZ) [3-amino-1,2,4-benzotriazine 1,4-dioxide, SR4233, WIN 59075, and Tirazone] is a novel anticancer drug that is selectively activated by the low oxygen environment in solid tumors. By killing the radioresistant hypoxic cells, TPZ potentiates the antitumor efficacy of fractionated irradiation of transplanted tumors in mice. As this cell kill is closely correlated with TPZ-induced DNA damage, we investigated whether human head and neck cancers would show DNA damage similar to that seen in mouse tumors following TPZ administration. TPZ-induced DNA damage in both transplanted tumors in mice and in neck nodes of 13 patients with head and neck cancer was assessed using the alkaline comet assay on cells obtained from fine-needle aspirates. The oxygen levels of the patients' tumors were also measured using a polarographic oxygen electrode. Cells from the patients' tumors showed DNA damage immediately following TPZ administration that was comparable to, or greater than, that seen with transplanted mouse tumors. The heterogeneity of DNA damage in the patients' tumors was greater than that of individual mouse tumors and correlated with tumor hypoxia. The similarity of TPZ-induced DNA damage in human and rodent tumors suggests that tirapazamine should be effective when added to radiotherapy or to cisplatin-based chemotherapy in head and neck cancers.

  View details for PubMedID 10933062

• Stereotactic radiosurgical boost following radiotherapy in primary nasopharyngeal carcinoma: Impact on local control 39th Annual Meeting of ASTRO Tate, D. J., Adler, J. R., Chang, S. D., Marquez, S., Eulau, S. M., Fee, W. E., PINTO, H., Goffinet, D. R. ELSEVIER SCIENCE INC. 1999: 915–21

  Abstract

  Treatment of patients with nasopharyngeal carcinoma using external beam radiation therapy (EBRT) alone results in significant local recurrence. Although intracavitary brachytherapy can be used as a component of management, it may be inadequate if there is extension of disease to the skull base. To improve local control, stereotactic radiosurgery was used to boost the primary tumor site following fractionated radiotherapy in patients with nasopharyngeal carcinoma.Twenty-three consecutive patients were treated with radiosurgery following radiotherapy for nasopharyngeal carcinoma from 10/92 to 5/98. All patients had biopsy confirmation of disease prior to radiation therapy; Stage III disease (1 patient), Stage IV disease (22 patients). Fifteen patients received cisplatinum-based chemotherapy in addition to radiotherapy. Radiosurgery was delivered using a frame-based LINAC as a boost (range 7 to 15 Gy, median 12 Gy) following fractionated radiation therapy (range 64.8 to 70 Gy, median 66 Gy).All 23 patients (100%) receiving radiosurgery as a boost following fractionated radiation therapy are locally controlled at a mean follow-up of 21 months (range 2 to 64 months). There have been no complications of treatment caused by radiosurgery. However, eight patients (35%) have subsequently developed regional or distant metastases.Stereotactic radiosurgical boost following fractionated EBRT provides excellent local control in advanced stage nasopharynx cancer and should be considered for all patients with this disease. The treatment is safe and effective and may be combined with cisplatinum-based chemotherapy.

  View details for Web of Science ID 000083624000013

  View details for PubMedID 10571198

• Tissue oxygen distribution in head and neck cancer patients HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Adam, M. F., Gabalski, E. C., Bloch, D. A., Oehlert, J. W., Brown, J. M., Elsaid, A. A., Pinto, H. A., Terris, D. J. 1999; 21 (2): 146-153

  Abstract

  The importance of hypoxia in limiting the sensitivity of tumor cells to ionizing radiation has long been known.We evaluated the tissue oxygenation status with a polarographic needle electrode system in 37 patients with malignancies of the head and neck and correlated the pO2 of 25 patients with treatment outcome.Sixteen tumors contained areas of severe hypoxia, defined by pO2 values below 2.5 mm Hg. Tumor oxygenation parameters were not correlated with hemoglobin, age, and history of tobacco use. There were no subcutaneous PO2 values below 10 mm Hg (ie, no areas of moderate or severe hypoxia), whereas this degree of hypoxia was commonly found in the tumors. Though not statistically significant, hypoxic tumors showed trends for poorer treatment outcome.Our data demonstrate a great interindividual variability in the oxygenation of head and neck cancers and appears unassociated with clinical parameters. The method is capable of identifying patients with poorly oxygenated tumors, thereby providing important information for selecting patients who might need customized therapy designed to kill hypoxic tumor cells. Hypoxic tumors show a consistent trend for poor treatment outcome.

  View details for PubMedID 10091983

• Recruiting minority cancer patients into cancer clinical trials: A pilot project involving the Eastern Cooperative Oncology Group and the National Medical Association JOURNAL OF CLINICAL ONCOLOGY McCaskill-Stevens, W., PINTO, H., Marcus, A. C., Comis, R., Morgan, R., Plomer, K., Schoentgen, S. 1999; 17 (3): 1029-1039

  Abstract

  Minority accrual onto clinical trials is of significant interest to cooperative oncology study groups. The Eastern Cooperative Oncology Group (ECOG) conducted a study to identify barriers and solutions to African American accrual onto clinical trials.We hypothesize that the National Medical Association (NMA) might provide insight into ways to increase minority participation and that ECOG might facilitate that participation. Four sites were selected in which NMA chapters existed and ECOG main institutions with less than half of the corresponding percentage of minorities in their communities entered trials for 1992. Fifteen workshops were conducted using discussions and open-ended, self-administered questionnaires.Seventy percent of NMA physicians cited mistrust of the research centers, fear of losing patients, and a lack of respect from ECOG institutions as the most important barriers to minority cancer patient referrals, compared with 30% for ECOG physicians. Sixty-nine percent of NMA and 43% of ECOG physicians cited a lack of information about specific trials. Nearly half of NMA physicians (47%) cited a lack of minority investigators as a barrier, compared with 4% of ECOG physicians. Solutions by both groups were improved communication (73%) and culturally relevant educational materials (40%). ECOG physicians cited more minority outreach staff as a potential solution (22% v 6%). NMA physicians cited increased involvement of referring physicians (44% v4%).NMA physicians who serve a significant sector of the African American population demonstrated a willingness to participate and work with a cooperative group effort to increase participation of minority patients and investigators.

  View details for Web of Science ID 000078972800039

  View details for PubMedID 10071298

• Pretreatment and midtreatment measurement of oxygen tension levels in head and neck cancers LARYNGOSCOPE Gabalski, E. C., Adam, M., PINTO, H., Brown, J. M., Bloch, D. A., Terris, D. J. 1998; 108 (12): 1856-1860

  Abstract

  Considerable evidence exists to suggest that tumor hypoxia results in radioresistance. Historically, it has been difficult to assess tumor oxygen tension levels reliably. These levels can now be assessed in head and neck malignancies using the Eppendorf pO2 histograph, which uses a fine-needle electrode and a computerized micromanipulator. This technology was used to compare the pretreatment tumor oxygen tension level in lymph node metastases of patients with head and neck cancer to measurements taken during nonsurgical treatment after a partial response had been achieved.Prospective study.Oxygen tension levels were measured in the cervical lymph nodes of 10 patients with biopsy-proven head and neck squamous cell carcinoma and cervical metastases who were being treated with nonsurgical management. These levels were obtained using the Eppendorf pO2 histograph system. Measurements were taken before the start of treatment and were repeated when the size of the cervical metastatic node had decreased by 50%. Normal subcutaneous tissue was measured during the same session. The mean and median pO2 levels, as well as the percentage of measurements with pO2 less than 5 mm Hg were determined.A mean of 72.6 measurements per session was taken from each lymph node. The median tumor pO2 measurement fell from a mean (+/-SD) of 13.9+/-8.0 mm Hg to 7.3+/-9.9 mm Hg. Even more dramatic, however, was the substantial increase in the percentage of values less than 5 mm Hg, a rise from 29% to 52%.While there is variability both in the pretreatment oxygenation of head and neck cervical metastases and in the change in tumor oxygen tension during treatment, there appears to be a decrease in the overall oxygenation of the tumors. The dramatic increase in very low oxygen measurements may reflect selective survival of radioresistant or chemoresistant hypoxic tumor cells. Cells at the very low level would be expected to be radiobiologically hypoxic (resistant to radiation-induced cell kill).

  View details for PubMedID 9851504

• Management of the clinically positive neck in organ preservation for advanced head and neck cancer 44th Annual Meeting of the Society-of-Head-and-Neck-Surgeons Dagum, P., Pinto, H. A., Newman, J. P., Higgins, J. P., Terris, D. J., Goffinet, D. R., Fee, W. E. EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC. 1998: 448–52

  Abstract

  To investigate clinicopathologic predictive criteria for the optimal management of neck metastases in patients with advanced head and neck cancers treated with combined chemoradiotherapy.Prospective study, 48 patients. Mean length follow-up, 23 months.Neck stage predicted neck response to chemoradiotherapy; N3 necks showed more partial responses (P = 0.04), and N1 necks showed more complete responses (P = 0.12). Primary tumor site strongly predicted the pathologic response found on neck dissection in patients with a clinical partial response (cPR) following chemoradiotherapy. There was no difference in survival between patients with a clinical complete response (cCR) after chemoradiotherapy, and patients with a pathologic complete response (pCR) after neck dissection (P = 0.20); however, when grouped together, these patients survived longer than did patients with a pPR at neck dissection (P = 0.06).Clinical response to induction chemotherapy is a poor predictor of ultimate neck control. Induction chemotherapy followed by chemoradiotherapy, and planned neck dissection for patients with persistent cervical lymphadenopathy, provides good regional control.

  View details for Web of Science ID 000077441400013

  View details for PubMedID 9874431

• Surgical morbidity of neck dissection after chemoradiotherapy in advanced head and neck cancer Western Section Meeting of the American-Laryngological-Rhinological-and-Otological-Society Newman, J. P., Terris, D. J., Pinto, H. A., Fee, W. E., Goode, R. L., Goffinet, D. R. ANNALS PUBL CO. 1997: 117–22

  Abstract

  The use of chemotherapy and irradiation for organ preservation attempts to eliminate the need for extensive surgery in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). We sought to characterize the morbidity of surgery in patients who needed surgery after treatment with induction chemotherapy followed by simultaneous chemotherapy and radiotherapy (chemoradiotherapy). The surgical morbidity within the first 30 postoperative days of 17 patients treated in an organ preservation approach between July 1991 and December 1994 was compared with a control group of patients undergoing similar surgical procedures during the same period. The organ preservation study patients underwent surgical procedures consisting of 18 neck dissections and 5 resections of the primary site. Six patients in the organ preservation study group experienced 8 surgical complications within the first 30 postoperative days, and most complications were minor. There was no significant difference in the duration of surgery or length of hospitalization between study patients and matched controls. Our surgical complication rate (35.3%) was higher but not statistically different from that of the control group, and compared favorably to reports of surgical morbidity (44% to 61%) in the literature on patients treated with chemoradiotherapy. The lower complication rate seen in this study may be a reflection of early surgical intervention as part of our organ preservation study scheme, the preponderance of neck dissections performed, and the limited number of pharyngeal procedures performed.

  View details for Web of Science ID A1997WH40500005

  View details for PubMedID 9041815

• Adjuvant and neoadjuvant treatment of head and neck cancers: The next chapter SEMINARS IN ONCOLOGY Jacobs, C., PINTO, H. 1995; 22 (6): 540-552

  View details for Web of Science ID A1995TL81500005

  View details for PubMedID 8539631

• Distant metastases from head and neck squamous cancer: the role of adjuvant chemotherapy. Cancer treatment and research Pinto, H. A., Jacobs, C. 1995; 74: 243-262

  View details for PubMedID 7779619

• Head and neck cancers. Macdonald JS, Haller DG, Mayer RJ (eds), Manual of Oncologic Therapeutics Third Edition. J.B. Lippincott, Philadelphia Jacobs C, Pinto HA. 1995: 162-169.
• Head and neck cancer - combined modality therapy and chemotherapy. : Brian MC and Carbone PP (eds), Current Therapy in Hematology-Oncology. Mosby, St. Louis Pinto HA, Jacobs C. 1995
• CHEMOTHERAPY FOR RECURRENT AND METASTATIC HEAD AND NECK-CANCER HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Pinto, H. A., Jacobs, C. 1991; 5 (4): 667-686

  Abstract

  At the present time, the treatment of recurrent and metastatic head and neck squamous and salivary gland cancers with chemotherapy is palliative. Pain relief, improvement in functional parameters, and improved survival are important goals. Although survival benefits are small, palliation can be significant. For squamous cancers, the median duration of response to chemotherapy is 2 to 4 months, and overall survival is about 6 months. Responses can be achieved with acceptable toxicity for good palliation in approximately 30% of patients treated with the standard regimens. Although more intensive chemotherapy regimens often result in higher response rates in pilot trials, they do not offer significant gains in effectiveness or survival. In salivary gland malignancies, results are substantially better, but this may only reflect the different natural history of this heterogeneous group of tumors. A small number of patients will have excellent and very durable responses to chemotherapy. Unfortunately, at this time we are unable to select these patients or determine which regimen will produce this desired result. The optimal use of currently available drugs is in the process of refinement. The timing of palliative chemotherapy represents a major challenge to oncologists and patients. Chemotherapy may in the future have a role in the cure of patients with recurrent disease, but innovative therapy, combined modality approaches, and new drug development will all need to be investigated. We look forward toward a new understanding of tumor biology and the development of agents that may substantially improve the control of these tumors.

  View details for Web of Science ID A1991FY45400006

  View details for PubMedID 1890059