Publications by authors named "Jay O Boyle"

50 Publications

Any day, split halfway: Flexibility in scheduling high-dose cisplatin-A large retrospective review from a high-volume cancer center.

Int J Cancer 2021 Feb 14. Epub 2021 Feb 14.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

High-dose (HD) cisplatin remains the standard of care with chemoradiation for locally advanced oropharyngeal cancer (OPC). Cooperative group trials mandate bolus-HD (100 mg/m  × 1 day, every 3 weeks) cisplatin administration at the beginning of the week to optimize radiosensitization-a requirement which may be unnecessary. This analysis evaluates the impact of chemotherapy administration day of week (DOW) on outcomes. We also report our institutional experience with an alternate dosing schedule, split-HD (50 mg/m  × 2 days, every 3 weeks). We retrospectively reviewed 435 definitive chemoradiation OPC patients from 10 December 2001 to 23 December 2014. Those receiving non-HD cisplatin regimens or induction chemotherapy were excluded. Data collected included DOW, dosing schedule (bolus-HD vs split-HD), smoking, total cumulative dose (TCD), stage, Karnofsky Performance Status, human papillomavirus status and creatinine (baseline, peak and posttreatment baseline). Local failure (LF), regional failure (RF), locoregional failure (LRF), distant metastasis (DM), any failure (AF, either LRF or DM) and overall survival (OS) were calculated from radiation therapy start. Median follow-up was 8.0 years (1.8 months-17.0 years). DOW, dosing schedule and TCD were not associated with any outcomes in univariable or multivariable regression models. There was no statistically significant difference in creatinine or association with TCD in split-HD vs bolus-HD. There was no statistically significant association between DOW and outcomes, suggesting that cisplatin could be administered any day. Split-HD had no observed differences in outcomes, renal toxicity or TCD compared to bolus-HD cisplatin. Our data suggest that there is some flexibility of when and how to give HD cisplatin compared to clinical trial mandates.
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http://dx.doi.org/10.1002/ijc.33518DOI Listing
February 2021

A novel surgeon credentialing and quality assurance process using transoral surgery for oropharyngeal cancer in ECOG-ACRIN Cancer Research Group Trial E3311.

Oral Oncol 2020 11 14;110:104797. Epub 2020 Jul 14.

Yale School of Medicine and Yale Cancer Center, New Haven, CT, United States.

Purpose: Understanding the role of transoral surgery in oropharyngeal cancer (OPC) requires prospective, randomized multi-institutional data. Meticulous evaluation of surgeon expertise and surgical quality assurance (QA) will be critical to the validity of such trials. We describe a novel surgeon credentialing and QA process developed to support the ECOG-ACRIN Cancer Research Group E3311 (E3311) and report outcomes related to QA.

Patients And Methods: E3311 was a phase II randomized clinical trial of transoral surgery followed by low- or standard-dose, risk-adjusted post-operative therapy with stage III-IVa (AJCC 7th edition) HPV-associated OPC. In order to be credentialed to accrue to this trial, surgeons were required to demonstrate active hospital credentials and technique-specific surgical expertise with ≥20 cases of transoral resection for OPC. In addition, 10 paired operative and surgical pathology reports from the preceding 24 months were reviewed by an expert panel. Ongoing QA required <10% rate of positive margins, low oropharyngeal bleeding rates, and accrual of at least one patient per 12 months. Otherwise surgeons were placed on hold and not permitted to accrue until re-credentialed using a new series of transoral resections.

Results: 120 surgeons trained in transoral minimally invasive surgery applied for credentialing for E3311 and after peer-review, 87 (73%) were approved from 59 centers. During QA on E3311, positive final pathologic margins were reported in 19 (3.8%) patients. Grade III/IV and grade V oropharyngeal bleeding was reported in 29 (5.9%) and 1 (0.2%) of patients.

Conclusions: We provide proof of concept that a comprehensive credentialing process can support multicenter transoral head and neck surgical oncology trials, with low incidence of positive margins and *grade III/V oropharyngeal bleeding.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771718PMC
November 2020

The 3 Bs of cancer care amid the COVID-19 pandemic crisis: "Be safe, be smart, be kind"-A multidisciplinary approach increasing the use of radiation and embracing telemedicine for head and neck cancer.

Cancer 2020 09 8;126(18):4092-4104. Epub 2020 Jul 8.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Because of the national emergency triggered by the coronavirus disease 2019 (COVID-19) pandemic, government-mandated public health directives have drastically changed not only social norms but also the practice of oncologic medicine. Timely head and neck cancer (HNC) treatment must be prioritized, even during emergencies. Because severe acute respiratory syndrome coronavirus 2 predominantly resides in the sinonasal/oral/oropharyngeal tracts, nonessential mucosal procedures are restricted, and HNCs are being triaged toward nonsurgical treatments when cures are comparable. Consequently, radiation utilization will likely increase during this pandemic. Even in radiation oncology, standard in-person and endoscopic evaluations are being restrained to limit exposure risks and preserve personal protective equipment for other frontline workers. The authors have implemented telemedicine and multidisciplinary conferences to continue to offer standard-of-care HNC treatments during this uniquely challenging time. Because of the lack of feasibility data on telemedicine for HNC, they report their early experience at a high-volume cancer center at the domestic epicenter of the COVID-19 crisis.
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http://dx.doi.org/10.1002/cncr.33031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361524PMC
September 2020

Temporal Lobe Necrosis in Head and Neck Cancer Patients after Proton Therapy to the Skull Base.

Int J Part Ther 2020 28;6(4):17-28. Epub 2020 May 28.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naïve patients with head and neck cancer treated with proton therapy where the field of radiation involved the skull base.

Materials And Methods: Medical records and dosimetric data for radiation-naïve patients with head and neck cancer receiving proton therapy to the skull base were retrospectively reviewed. Patients with <3 months of follow-up, receiving <45 GyRBE or nonconventional fractionation, and/or no follow-up magnetic resonance imaging (MRI) were excluded. TLN was determined using MRI and graded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Clinical (gender, age, comorbidities, concurrent chemotherapy, smoking, radiation techniques) and dose-volume parameters were analyzed for TLN correlation. The receiver operating characteristic curve and area under the curve (AUC) were performed to determine the cutoff points of significant dose-volume parameters.

Results: Between 2013 and 2019, 234 patients were included. The median follow-up time was 22.5 months (range = 3.2-69.3). Overall TLN rates of any grade, ≥ grade 2, and ≥ grade 3 were 5.6% (N = 13), 2.1%, and 0.9%, respectively. The estimated 2-year TLN rate was 4.6%, and the 2-year rate of any brain necrosis was 6.8%. The median time to TLN was 20.9 months from proton completion. Absolute volume receiving 40, 50, 60, and 70 GyRBE (absolute volume [aV]); mean and maximum dose received by the temporal lobe; and dose to the 0.5, 1, and 2 cm volume receiving the maximum dose (D0.5cm, D1cm, and D2cm, respectively) of the temporal lobe were associated with greater TLN risk while clinical parameters showed no correlation. Among volume parameters, aV50 gave maximum AUC (0.921), and D2cm gave the highest AUC (0.935) among dose parameters. The 11-cm cutoff value for aV50 and 62 GyRBE for D2cm showed maximum specificity and sensitivity.

Conclusion: The estimated 2-year TLN rate was 4.6% with a low rate of toxicities ≥grade 3; aV50 ≤11 cm, D2cm ≤62 GyRBE and other cutoff values are suggested as constraints in proton therapy planning to minimize the risk of any grade TLN. Patients whose temporal lobe(s) unavoidably receive higher doses than these thresholds should be carefully followed with MRI after proton therapy.
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http://dx.doi.org/10.14338/IJPT-20-00014.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302730PMC
May 2020

Dental Implant Survival in Vascularized Bone Flaps: A Systematic Review and Meta-Analysis.

Plast Reconstr Surg 2020 09;146(3):637-648

From the Plastic and Reconstructive Surgery Service, the Dental Service, and the Head and Neck Surgery Service, Department of Surgery, and Medical Library, Memorial Sloan Kettering Cancer Center.

Background: Maxillofacial reconstruction with vascularized bone restores facial contour and provides structural support and a foundation for dental rehabilitation. Routine implant placement in such cases, however, remains uncommon. This study aims to determine dental implant survival in patients undergoing vascularized maxillary or mandibular reconstruction through a systematic review of the literature.

Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the literature was queried for implant placement in reconstructed jaws using Medical Subject Headings terms on PubMed, Embase, and Cochrane platforms. Weighted implant survivals were calculated for the entire cohort and subcohorts stratified by radiotherapy. Meta-analyses were performed to estimate effect of radiation on implant osseointegration.

Results: Of 3965 publications identified, 42 were reviewed, including 1084 patients with 3636 dental implants. Weighted implant survival was 92.2 percent at a median follow-up of 36 months. Survival was 97.0 percent in 269 implants placed immediately in 60 patients versus 89.9 percent in 1897 delayed implants placed in 597 patients, with follow-up of 14 and 40 months, respectively. Dental implants without radiotherapy exposure had better survival than those exposed to radiation (95.3 versus 84.6 percent; p < 0.01) at a median follow-up of 36 months. Meta-analyses showed that radiation significantly increased the risk of implant failure (risk ratio, 4.74; p < 0.01) and suggested that implants placed before radiotherapy trended toward better survival (88.9 percent versus 83.4 percent, p = 0.07; risk ratio, 0.52; p = 0.14).

Conclusions: Overall implant survival was 92.2 percent; however, radiotherapy adversely impacted outcomes. Implants placed before radiotherapy may demonstrate superior survival than implants placed after.
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http://dx.doi.org/10.1097/PRS.0000000000007077DOI Listing
September 2020

Last-line local treatment with the Quad Shot regimen for previously irradiated head and neck cancers.

Oral Oncol 2020 05 14;104:104641. Epub 2020 Mar 14.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Objectives: Patients with prior irradiated head and neck cancer (HNC) who are ineligible for definitive retreatment have limited local palliative options. We report the largest series of the use of the Quad Shot (QS) regimen as a last-line local palliative therapy.

Materials And Methods: We identified 166 patients with prior HN radiation therapy (RT) treated with QS regimen (3.7 Gy twice daily over 2 consecutive days at 4 weeks intervals per cycle, up to 4 cycles). Palliative response defined by symptom(s) relief or radiographic tumor reduction, locoregional progression free survival (LPFS), overall survival (OS) and radiation-related toxicity were assessed.

Results: Median age was 66 years. Median follow-up for all patients was 6.0 months and 9.7 months for living patients. Overall palliative response rate was 66% and symptoms improved in 60% of all patients. Predictors of palliative response were > 2 year interval from prior RT and 3-4 QS cycles. Median LPFS was 5.1 months with 1-year LPFS 17.7%, and median OS was 6.4 months with 1-year OS 25.3%. On multivariate analysis, proton RT, KPS > 70, presence of palliative response and 3-4 QS cycles were associated with improved LPFS and improved OS. The overall Grade 3 toxicity rate was 10.8% (n = 18). No Grade 4-5 toxicities were observed.

Conclusion: Palliative QS is an effective last-line local therapy with minimal toxicity in patients with previously irradiated HNC. The administration of 3-4 QS cycles predicts palliative response, improved PFS, and improved OS. KPS > 70 and proton therapy are associated with survival improvements.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104641DOI Listing
May 2020

Outcomes and toxicities of definitive radiotherapy and reirradiation using 3-dimensional conformal or intensity-modulated (pencil beam) proton therapy for patients with nasal cavity and paranasal sinus malignancies.

Cancer 2020 01 25;126(9):1905-1916. Epub 2020 Feb 25.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Proton therapy (PT) improves outcomes in patients with nasal cavity (NC) and paranasal sinus (PNS) cancers. Herein, the authors have reported to their knowledge the largest series to date using intensity-modulated proton therapy (IMPT) in the treatment of these patients.

Methods: Between 2013 and 2018, a total of 86 consecutive patients (68 of whom were radiation-naive and 18 of whom were reirradiated) received PT to median doses of 70 grays and 67 grays relative biological effectiveness, respectively. Approximately 53% received IMPT.

Results: The median follow-up was 23.4 months (range, 1.7-69.3 months) for all patients and 28.1 months (range, 2.3-69.3 months) for surviving patients. The 2-year local control (LC), distant control, disease-free survival, and overall survival rates were 83%, 84%, 74%, and 81%, respectively, for radiation-naive patients and 77%, 80%, 54%, and 66%, respectively for reirradiated patients. Among radiation-naive patients, when compared with 3-dimensional conformal proton technique, IMPT significantly improved LC (91% vs 72%; P < .01) and independently predicted LC (hazard ratio, 0.14; P = .01). Sixteen radiation-naive patients (24%) experienced acute grade 3 toxicities; 4 (6%) experienced late grade 3 toxicities (osteoradionecrosis, vision loss, soft-tissue necrosis, and soft tissue fibrosis) (grading was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 5.0]). Slightly inferior LC was noted for patients undergoing reirradiation with higher complications: 11% experienced late grade 3 toxicities (facial pain and brain necrosis). Patients treated with reirradiation had more grade 1 to 2 radionecrosis than radiation-naive patients (brain: 33% vs 7% and osteoradionecrosis: 17% vs 3%).

Conclusions: PT achieved remarkable LC for patients with nasal cavity and paranasal sinus cancers with lower grade 3 toxicities relative to historical reports. IMPT has the potential to improve the therapeutic ratio in these malignancies and is worthy of further investigation.
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http://dx.doi.org/10.1002/cncr.32776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304541PMC
January 2020

Patterns of Radiotherapy Use and Outcomes in Head and Neck Soft-Tissue Sarcoma in a National Cohort.

Laryngoscope 2020 01 20;130(1):120-127. Epub 2019 Mar 20.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, U.S.A.

Objectives/hypothesis: We used the National Cancer Database to identify the patterns of care and prognostic factors in adult patients with head and neck soft-tissue sarcoma (HNSTS).

Study Design: Retrospective cohort analysis.

Methods: Using the National Cancer Database, we identified patients age ≥ 18 years who were diagnosed with HNSTS between 2004 and 2013. Both χ and multivariate logistic regression were used to identify factors associated with radiation therapy (RT) utilization. Kaplan-Meier methods were used to estimate overall survival (OS) and Cox proportional regression was used to determine significant contributors to OS.

Results: Our final cohort included 1,282 patients (682 treated with surgery only, 199 treated with RT only, and 401 treated with surgery and RT). Patients with younger age, poor tumor grade, rhabdomyosarcoma histology, and chemotherapy treatment were more likely to receive RT alone without surgery. Among the 1,083 surgical patients, RT utilization was associated with positive margins (odds ratio [OR]: 2.18, 95% confidence interval [CI]: 1.36-3.48), poor grade (OR: 2.92, 95% CI: 1.95-4.38), and chemotherapy use (OR: 1.78, 95% CI: 1.15-2.76). Radiotherapy utilization among surgical patients was not affected by demographic factors (age, sex, or ethnicity) or treatment institution (academic or community). For surgical patients, poor grade, large tumor size, and rhabdomyosarcoma histology were associated with worse OS on multivariate analysis.

Conclusions: In this analysis of HNSTS, younger patients with poor tumor grade and rhabdomyosarcoma histology were more likely to receive RT without surgery. Among surgical patients, adjuvant RT was more likely to be used for positive margins and poor grade, with no demographic disparities identified. Poor grade and rhabdomyosarcoma histology were negative prognostic factors for surgical patients.

Level Of Evidence: NA Laryngoscope, 130:120-127, 2020.
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http://dx.doi.org/10.1002/lary.27901DOI Listing
January 2020

Immediate Dental Implantation in Oncologic Jaw Reconstruction: Workflow Optimization to Decrease Time to Full Dental Rehabilitation.

Plast Reconstr Surg Glob Open 2019 Jan 14;7(1):e2100. Epub 2019 Jan 14.

Department of Surgery, Plastic & Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York City, N.Y.

Full dental rehabilitation following segmental mandibulectomy or maxillectomy for oncologic tumor ablation should be the goal for every patient. But despite advances in technology and reconstructive techniques, many patients do not achieve timely or complete oral rehabilitation. Recognizing this fault, we recently adopted an innovative workflow to increase the number of patients undergoing dental restoration, irrespective of tumor pathology or need for adjuvant radiotherapy. Preoperatively, every osseous jaw reconstruction undergoes virtual surgical planning to incorporate the placement of endosseous implants into the fibula osteocutaneous free flap. The dental implants are then placed intraoperatively at the time of tumor ablation and reconstruction. Four-to-six weeks following the initial surgery, the patient returns to the operating room for vestibuloplasty and exposure of the dental implants. Within 3 days of the vestibuloplasty, a temporary dental prosthesis is placed in the dental clinic, and the patient can then begin radiation therapy if needed. Following adjuvant radiation therapy, the temporary prosthesis can be replaced with a permanent one. At our institution, this innovative workflow has allowed for earlier aesthetic restoration of the jaw and greatly expanded the number of patients able to achieve oral rehabilitation. Herein, we describe this innovative workflow and provide technical pearls for successful execution.
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http://dx.doi.org/10.1097/GOX.0000000000002100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382230PMC
January 2019

A Virtual Surgical Planning Algorithm for Delayed Maxillomandibular Reconstruction.

Plast Reconstr Surg 2019 Apr;143(4):1197-1206

From the Hansjörg Wyss Department of Plastic Surgery, New York University Langone Medical Center; the Department of Surgery, Head and Neck Service, and the Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center; the Division of Plastic and Reconstructive Surgery, Department of Surgery, Montefiore Medical Center/Albert Einstein College of Medicine; and 3D Systems.

Background: The absence of a tumor specimen from which to obtain measurements at the time of delayed maxillomandibular reconstruction introduces degrees of uncertainty, creating the need for substantial intraoperative guesswork by the surgeon. Using the virtual surgical planning environment, the size and shape of missing bony elements is determined, effectively "recreating the defect" in advance of the surgery. Three virtual surgical planning techniques assist the reconstructive surgeon: patient-specific modeling, mirroring the normal contralateral side, and scaled normative data. To facilitate delayed reconstruction a hierarchical algorithm using virtual surgical planning techniques was developed.

Methods: Delayed maxillomandibular virtual surgical planning reconstructions were identified from 2009 to 2016. Demographics, modeling techniques, and surgical characteristics were analyzed.

Results: Sixteen reconstructions were performed for osteoradionecrosis with displacement (50.0 percent) or oncologic defects (37.5 percent). Most patients had prior surgery (81.3 percent) and preoperative radiation therapy (81.3 percent); four had failed prior reconstructions. The following delayed virtual surgical planning techniques were used: patient-specific modeling based on previous imaging (43.8 percent), mirroring normal contralateral anatomy (37.5 percent), and scaled normative data (18.8 percent). Normative and mirrored reconstructions were designed to restore normal anatomy; however, most patient-specific virtual surgical planning designs (71.4 percent) required nonanatomical reconstructions to accommodate soft-tissue limitations and to avoid the need for a second flap. One partial flap loss required a second free flap, and one total flap failure occurred. Hardware exposure was the most common minor complication, followed by infection, dehiscence, and sinus tract formation.

Conclusions: Virtual surgical planning has inherent advantages in delayed reconstruction when compared to traditional flap shaping techniques. An algorithmic approach based on available imaging and remaining native anatomy enables accurate reconstructive planning followed by flap transfer without the need for intraoperative guesswork.

Clinical Question/level Of Evidence: Therapeutic, IV.
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http://dx.doi.org/10.1097/PRS.0000000000005452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438755PMC
April 2019

Patterns of Treatment Failure and Postrecurrence Outcomes Among Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma After Chemoradiotherapy Using Modern Radiation Techniques.

JAMA Oncol 2017 Nov;3(11):1487-1494

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Even though 15% to 50% of patients with head and neck squamous cell carcinoma (HNSCC) experience recurrence, relatively little is known regarding patterns of treatment failure and postrecurrence outcomes after chemoradiotherapy using modern radiation techniques (intensity-modulated radiotherapy [IMRT]). Recurrence patterns are significantly affected by variations in the quality of radiotherapy, which may confound findings from multicenter trials.

Objective: To assess patterns of treatment failure and postrecurrence outcomes for patients with HNSCC treated with contemporary radiotherapy techniques.

Design, Setting, And Participants: This large single-institution cohort study reviewed the outcomes of 1000 consecutive patients with stage III to IVB oropharyngeal carcinoma (n = 703), laryngeal carcinoma (n = 126), or hypopharyngeal carcinoma (n = 46) treated with definitive IMRT with or without concurrent chemotherapy, as well as patients with oral cavity carcinoma (n = 125) treated with postoperative IMRT with or without concurrent systemic therapy, from December 1, 2001, to December 31, 2013, with a median follow-up of 65.1 months among surviving patients. Data analysis was performed from January 31, 2016, to February 17, 2017.

Main Outcomes And Measures: Patterns of treatment failure and overall survival following locoregional failure or distant metastasis.

Results: Among the 1000 patients (186 women and 814 men; mean [SD] age, 59.3 [10.8] years), there were no marginal or isolated out-of-radiation-field failures. Among subsites, the cumulative incidence of local failure was highest among patients with oral cavity carcinoma vs those with oropharyngeal carcinoma (hazard ratio, 5.2; 95% CI, 3.1-8.6; P < .001). Furthermore, patients with oral cavity carcinoma experienced significantly shorter survival following distant metastasis (hazard ratio, 3.66; 95% CI, 1.98-6.80; P < .001). Patients with oropharyngeal carcinoma positive for human papillomavirus or p16 lived longer after locoregional failure compared with patents with oropharyngeal carcinoma negative for human papillomavirus or p16 (median survival, 36.5 vs 13.6 months; P = .007) but not after distant metastasis. Salvage surgery was associated with improved overall survival following locoregional failure (hazard ratio, 0.51; 95% CI, 0.34-0.77; P = .001); oligometastatic disease (1 vs ≥2 lesions: hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001) was associated with improved overall survival following distant metastasis.

Conclusions And Relevance: Overall survival after recurrence of HNSCC is influenced by the HNSCC subsite and human papillomavirus or p16 status, as well surgical and systemic interventions. An oligometastatic phenotype characterizes patients with solitary metastasis after chemoradiotherapy. These findings have important implications for clinical trial designs for HNSCC in the recurrent and oligometastatic setting.
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http://dx.doi.org/10.1001/jamaoncol.2017.0973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710194PMC
November 2017

Complications following transoral robotic surgery (TORS): A detailed institutional review of complications.

Oral Oncol 2017 04 28;67:160-166. Epub 2017 Feb 28.

Department of Surgery Head and Neck Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address:

Objectives: To report the complications occurring following TORS and to identify the factors predictive of complications.

Methods: Following IRB approval a retrospective analysis of all TORS operations at our institution was performed. Postoperative complications within 45days were collected and graded with the Clavien-Dindo system. Complications were categorized into groups: all complications, not related to TORS and TORS related. Unadjusted odds ratios were calculated to test association between patients with and without a complication.

Results: 122 TORS operations were carried out between June 2010 and August 2015. 77% were male, with a median age of 57. There were 92 primary tumor resections, 10second head and neck primary resections, 13 salvage procedures and 7 other indications. Surgical resection involved 1, 2 or >3 sub-sites in 36%, 28% and 36% patients, respectively. Overall, there were 107 complications (66 TORS related, 41 non-TORS related) that occurred in 57 patients (47%). A major complication occurred in 23 patients (18%). 19 patients had a TORS related major complication and 6 patients experienced a non-TORS related major complication. There was a temporal trend in TORS related major complication rate decreasing from 33% in 2010 to 10% in 2015. Statistical analysis showed that the odds of having any complication were 3 times greater in patients over 60years old (p=0.017), and 2.5 times greater when there were more than 2 subsites resected (p=0.022).

Conclusions: Age over 60years and a larger extent of resection were the significant factors predictive of major complications.
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http://dx.doi.org/10.1016/j.oraloncology.2017.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407467PMC
April 2017

White adipose tissue inflammation and cancer-specific survival in patients with squamous cell carcinoma of the oral tongue.

Cancer 2016 Dec 10;122(24):3794-3802. Epub 2016 Aug 10.

Department of Medicine, Weill Cornell Medical College, New York, New York.

Background: Obesity is associated with increased adipose tissue in the tongue. Chronic white adipose tissue (WAT) inflammation commonly occurs in the obese. We investigated whether WAT inflammation in the tongue impacts survival in patients with squamous cell carcinoma (SCC) of the oral tongue.

Methods: In a retrospective cohort study, patients with T1 and T2 SCC of the oral tongue who underwent curative-intent resection were included. Tongue WAT inflammation was defined by the presence of dead or dying adipocytes surrounded by macrophages forming crown-like structures. The primary and secondary endpoints were disease-specific survival (DSS) and overall survival (OS), respectively. Subgroup analyses were carried out in patients without lymph node involvement for whom adjuvant therapies were not indicated.

Results: Archived tissue was available from 125 patients. The median follow-up was 55 months (range, 3-156 months). Overall, 49 of 125 patients (39%) had tongue WAT inflammation, which was associated with higher body mass index, increased tumor thickness, and vascular invasion (P < .05). The 3-year DSS rate for patients with tongue WAT inflammation was 59% (95% confidence interval [CI], 46%-76%) versus 82% (95% CI, 73%-92%) for those without inflammation. For patients without lymph node involvement for whom adjuvant therapy was not indicated (N = 70), tongue WAT inflammation was associated with shortened DSS and OS (P < .05). When adjusted for body mass index and potential prognostic covariates, the hazard ratio for DSS and OS was 5.40 (95% CI, 1.20-24.26) and 2.97 (95% CI, 1.02-8.65), respectively.

Conclusions: Tongue WAT inflammation is associated with worse DSS and OS in patients who have early stage SCC of the oral tongue. Cancer 2016;122:3794-3802. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5138111PMC
December 2016

The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers: Insights From a Precision Oncology Sequencing Platform.

JAMA Oncol 2017 Feb;3(2):244-255

Head and Neck Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies.

Objective: To illuminate the distinct biology of recurrent and metastatic head and neck cancers and review implementation of precision oncology for patients with advanced disease.

Design, Setting, And Participants: After exclusions, 151 patients with advanced, treatment-resistant head and neck tumors, including squamous cell carcinoma (HNSCC), adenoid cystic carcinoma (ACC), and other salivary and cutaneous cancers, whose tumors were sequenced between January 2014 and July 2015 at Memorial Sloan Kettering were recruited. Next-generation sequencing of tumors as part of clinical care included high-depth (median 600×) exonic coverage of 410 cancer genes and whole-genome copy number analysis.

Interventions: Next-generation sequencing of tumors and matched normal DNA.

Main Outcomes And Measures: Feasibility, the frequency of actionable molecular alterations, the effect on decision making, and identification of alterations associated with recurrent and metastatic disease.

Results: Overall, 151 patients (95 men and 56 women; mean [range] age, 61.8 [17-100] years) were included in the study. Next-generation sequencing ultimately guided therapy in 21 of 151 patients (14%) (13 of 53 [25%] of patients with HNSCC) by refining diagnoses and matching patients to specific therapies, in some cases with dramatic responses on basket studies. Molecular alterations were potentially actionable in 28 of 135 patients (21%). The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors. Compared to primary human papillomavirus (HPV)-positive tumors, many recurrent and metastatic HPV-positive tumors exhibited a molecular profile more similar to HPV-negative tumors, including enriched frequencies of TP53 mutation (3 of 20 tumors [15%]), whole genome duplication (5 of 20 tumors [25%]), and 3p deletion (11 of 20 tumors [55%]). There were high rates of TERT promoter mutation in recurrent and metastatic HPV-negative HNSCC (13 of 30 tumors [43%]), cutaneous SCC (11 of 21 tumors [52%]), basal cell carcinoma (3 of 4 tumors [75%]), and ACC (5 of 36 tumors [14%]). Activating NOTCH1 mutations were enriched in metastatic ACCs (8 of 36 tumors [22%]).

Conclusions And Relevance: These findings reveal the molecular landscape of advanced disease and rare cancer subtypes, both predominant challenges in head and neck oncology. To understand the repertoire of targetable alterations in advanced cancers, it is necessary to sequence recurrent and metastatic tumors. These data are important first steps toward implementation of precision head and neck oncology.
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http://dx.doi.org/10.1001/jamaoncol.2016.1790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253129PMC
February 2017

Erlotinib and the Risk of Oral Cancer: The Erlotinib Prevention of Oral Cancer (EPOC) Randomized Clinical Trial.

JAMA Oncol 2016 Feb;2(2):209-16

Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston5Moores Cancer Center, University of California San Diego, La Jolla.

Importance: Standard molecularly based strategies to predict and/or prevent oral cancer development in patients with oral premalignant lesions (OPLs) are lacking.

Objective: To test if the epidermal growth factor receptor inhibitor erlotinib would reduce oral cancer development in patients with high-risk OPLs defined by specific loss of heterozygosity (LOH) profiles. Secondary objectives included prospective determination of LOH as a prognostic marker in OPLs.

Design: The Erlotinib Prevention of Oral Cancer (EPOC) study was a randomized, placebo-controlled, double-bind trial. Accrual occurred from November 2006 through July 2012, with a median follow-up time of 35 months in an ambulatory care setting in 5 US academic referral institutions. Patients with OPLs were enrolled in the protocol, and each underwent LOH profiling (N = 379); they were classified as high-risk (LOH-positive) or low-risk (LOH-negative) patients based on their LOH profiles and oral cancer history. The randomized sample consisted of 150 LOH-positive patients.

Interventions: Oral erlotinib treatment (150 mg/d) or placebo for 12 months.

Main Outcomes And Measures: Oral cancer-free survival (CFS).

Results: A total of 395 participants were classified with LOH profiles, and 254 were classified LOH positive. Of these, 150 (59%) were randomized, 75 each to the placebo and erlotinib groups. The 3-year CFS rates in placebo- and erlotinib-treated patients were 74% and 70%, respectively (hazard ratio [HR], 1.27; 95% CI, 0.68-2.38; P = .45). The 3-year CFS was significantly lower for LOH-positive compared with LOH-negative groups (74% vs 87%, HR, 2.19; 95% CI, 1.25-3.83; P = .01). Increased EGFR gene copy number correlated with LOH-positive status (P < .001) and lower CFS (P = .01). The EGFR gene copy number was not predictive of erlotinib efficacy. Erlotinib-induced skin rash was associated with improved CFS (P = .01).

Conclusions And Relevance: In this trial, LOH was validated as a marker of oral cancer risk and found to be associated with increased EGFR copy number (the target of the intervention). Erlotinib did not, however, improve CFS in high-risk patients with LOH-positive or high-EGFR-gene-copy-number OPLs. These results support incorporation of LOH testing as a prognostic tool in routine clinical practice but do not support erlotinib use in this setting.

Trial Registration: clinicaltrials.gov Identifier: NCT00402779.
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http://dx.doi.org/10.1001/jamaoncol.2015.4364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771491PMC
February 2016

Impact of obesity on the survival of patients with early-stage squamous cell carcinoma of the oral tongue.

Cancer 2014 Apr 21;120(7):983-91. Epub 2014 Jan 21.

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.

Background: Although obesity increases risk and negatively affects survival for many malignancies, the prognostic implications in squamous cell carcinoma (SCC) of the oral tongue, a disease often associated with prediagnosis weight loss, are unknown.

Methods: Patients with T1-T2 oral tongue SCC underwent curative-intent resection in this single-institution study. All patients underwent nutritional assessment prior to surgery. Body mass index (BMI) was calculated from measured height and weight and categorized as obese (≥ 30 kg/m(2) ), overweight (25-29.9 kg/m(2) ), or normal (18.5-24.9 kg/m(2) ). Clinical outcomes, including disease-specific survival, recurrence-free survival, and overall survival, were compared by BMI group using Cox regression.

Results: From 2000 to 2009, 155 patients (90 men, 65 women) of median age 57 years (range, 18-86 years) were included. Baseline characteristics were similar by BMI group. Obesity was significantly associated with adverse disease-specific survival compared with normal weight in univariable (hazard ratio [HR] = 2.65, 95% confidence interval [CI] = 1.07-6.59; P = .04) and multivariable analyses (HR = 5.01; 95% CI = 1.69-14.81; P = .004). A consistent association was seen between obesity and worse recurrence-free survival (HR = 1.87; 95% CI = 0.90-3.88) and between obesity and worse overall survival (HR = 2.03; 95% CI = 0.88-4.65) though without reaching statistical significance (P = .09 and P = .10, respectively) in multivariable analyses.

Conclusions: In this retrospective study, obesity was an adverse independent prognostic variable. This association may not have been previously appreciated due to confounding by multiple factors including prediagnosis weight loss.
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http://dx.doi.org/10.1002/cncr.28532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961521PMC
April 2014

Nomograms for preoperative prediction of prognosis in patients with oral cavity squamous cell carcinoma.

Cancer 2014 Jan 25;120(2):214-21. Epub 2013 Oct 25.

Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.

Background: This study sought to develop prognostic tools that will accurately predict overall and cancer-related mortality and risk of recurrence in individual patients with oral cancer based on host and tumor characteristics. These tools would take into account numerous prognosticators beyond those covered by the traditional TNM (tumor-node-metastasis) staging system.

Methods: Demographic, host, and tumor characteristics of 1617 patients with cancer of the oral cavity, who were treated primarily with surgery at a single-institution tertiary care cancer center between 1985 and 2009, were reviewed from a preexisting database. Recurrent disease was recorded in 509 patients (456 locoregional and 116 distant); 328 patients died of cancer-related causes, and 542 died of other causes. The median follow-up was 42 months (range, 1-300 months). The following variables were analyzed as predictors of prognosis: age, sex, race, alcohol and tobacco use, oral cavity subsite, invasion of other structures, comorbidity, tumor size, and clinical nodal status. The stepdown method was used to select the statistically most influential predictors for inclusion in the final nomogram for each outcome of interest.

Results: The most influential predictors of both recurrence and cancer-specific mortality probability (CSMP) were tumor size, nodal status, subsite, and bone invasion. Nomograms were generated for prediction of overall survival (OS), CSMP, and locoregional recurrence-free probability (LRRFP). The nomograms were internally validated with an overfit-corrected predictive discrimination metric (concordance index) for OS of 67%, CSMP of 66%, and LRRFP of 60%.

Conclusions: Nomograms have been developed that can reasonably estimate OS, CSMP, and LRRFP based on specific tumor and host characteristics in patients with oral cancer.
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http://dx.doi.org/10.1002/cncr.28407DOI Listing
January 2014

A novel tumor: specimen index for assessing adequacy of resection in early stage oral tongue cancer.

Oral Oncol 2014 Mar 12;50(3):213-20. Epub 2013 Dec 12.

Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address:

Purpose: Surgical margin status frequently affects decisions regarding adjuvant treatment; however, reporting and interpretation of surgical margins is subject to considerable subjectivity because of many factors including the adequacy of resection. We developed a novel measure of the adequacy of surgical resection, the tumor: specimen index (TSI), and tested its utility at predicting clinical outcomes in a retrospective cohort study.

Patients And Methods: An institutional database was queried to identify previously untreated patients with T1 and T2 oral tongue cancer who underwent surgery during 1985-2009 (n=433). The TSI, a geometric mean representing the percentage of the surgical specimen that is occupied by the tumor in average single dimension, was calculated from the largest measured lengths, widths, and heights of the tumor in relation to the entire surgical specimen. Multivariate analyses of locoregional recurrence-free probability (LRRFP) and disease-specific survival (DSS) were performed with commonly accepted prognosticators in addition to TSI and surgical margins status.

Results: The mean TSI was 41 (range 11-90; SD 14). Surgical margin status was associated with TSI; margins were negative in 84% of patients with TSI<45 and in 63% of patients with TSI⩾45 (p<0.001). TSI⩾45 was associated with worse LRRFP (57% vs. 76%, p<0.001) and worse DSS (68% vs. 85%, p<0.001). In a multivariate analysis that did not include TSI, surgical margin status independently predicted LRRFP (p=0.014) but not DSS. When TSI was included, only TSI, and not surgical margin status, was an independent predictor of both LRRFP (p=0.002) and DSS (p=0.011).

Conclusion: The tumor: specimen index is an easily-calculated metric for estimating the adequacy of 3-dimensional resection in T1 and T2 oral tongue cancer that independently predicts oncologic outcomes.
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http://dx.doi.org/10.1016/j.oraloncology.2013.11.009DOI Listing
March 2014

Outcomes of a head and neck cancer screening clinic.

Oral Oncol 2013 Dec 29;49(12):1136-40. Epub 2013 Sep 29.

Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA. Electronic address:

Objective: To describe an institutional experience conducting an annual free head and neck (H&N) cancer screening clinic. Specific aims included: (1) identifying factors predicting which individuals will have findings suspicious for malignancy; and (2) evaluating potential barriers to subsequent follow-up among patients with suspicious findings.

Materials And Methods: This retrospective cohort study involved individuals presenting to an annual H&N cancer screening clinic (2001-2012). Original screening clinic data and electronic medical records were reviewed. Descriptive and comparative statistics were utilized in order to address the study aims.

Results: Of 1573 participants, 325 (21%) had abnormal findings on screening, of which 183 (12%) had findings suspicious for cancer. No demographic factors predicted a suspicion for cancer. The presence of patient-reported symptoms (16% vs. 8%; p<0.001) were significantly associated with a suspicion for cancer. Only 20% of individuals with a suspicion for cancer returned to our institution for recommended follow-up. Patients who did not complain of symptoms were less likely to return for follow-up (2% vs. 36%; p<0.001). Of the patients who returned for follow-up evaluation, malignancies were diagnosed in three patients.

Conclusion: Few individuals presenting to a H&N cancer screening clinic will have a malignancy detected, and barriers may influence patients' likelihood to present for subsequent evaluation. Due to self-selection among patients presenting for screening, traditional risk factors may not be associated with the likelihood of detecting a suspicion for H&N cancer. Head and neck cancer screening clinics should thus target patients at high risk, and attempt to ensure appropriate follow-up thereafter.
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http://dx.doi.org/10.1016/j.oraloncology.2013.09.007DOI Listing
December 2013

Effect of zileuton and celecoxib on urinary LTE4 and PGE-M levels in smokers.

Cancer Prev Res (Phila) 2013 Jul 16;6(7):646-55. Epub 2013 May 16.

Department of Surgery (Head and Neck Service), Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.

COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6 ± 1 days on urinary PGE-M and LTE4 levels in smokers. Treatment with zileuton led to an 18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by 61% in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P = 0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4.
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http://dx.doi.org/10.1158/1940-6207.CAPR-13-0083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707304PMC
July 2013

Selective neck dissection in node-positive squamous cell carcinoma of the head and neck.

Otolaryngol Head Neck Surg 2012 Oct 18;147(4):707-15. Epub 2012 Apr 18.

Department of Otolaryngology-Head and Surgery, University of Toronto, Toronto, Ontario, Canada.

Objective: The optimal type of neck dissection in head and neck squamous cell carcinoma (SCC) with clinical cervical metastases has not been determined. The following study was performed to determine the rate of regional control with selective neck dissection (SND) in these patients.

Study Design: Case series with planned data collection.

Setting: Single institution, cancer center.

Methods And Subjects: Patients with cervical lymph node metastases from mucosal cancers of the head and neck who were treated with SND from 2000 to 2010 were selected. Demographics, tumor characteristics, extent of neck dissection, adjuvant treatments, locoregional control, and survival were recorded. Recurrence in the neck and disease-specific survival (DSS) were primary and secondary end points.

Results: One hundred eight patients underwent SND. Sixty-nine (64%) were male. Median age was 62 (20-89) years. The most common primary site was the oral cavity (71.3%). Ninety-five (88%) received adjuvant treatment. Median follow-up was 21 months. Six patients (5.5%) had isolated recurrence in the dissected neck. Patients with N2C disease had poorer neck recurrence-free survival. At the end of study, 64 (59.3%) patients had no evidence of disease, and 23 (21.3%) had died of disease. Two-year DSS was 76.9%. Number of positive nodes (P = .026) and positive surgical margins (P = .001), among others, were predictors of poorer DSS.

Conclusion: In a highly selected group of patients with cervical lymph node metastases from head and neck SCC, selective neck dissection is effective in controlling the disease in the neck when performed in the setting of a multimodality treatment, including adjuvant radiotherapy or radiochemotherapy.
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http://dx.doi.org/10.1177/0194599812444852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787853PMC
October 2012

Prognostic implication of sentinel lymph node biopsy in cutaneous head and neck melanoma.

Head Neck 2010 Dec;32(12):1686-92

Department of Otolaryngology, Division of Head and Neck Surgery, Long Island Jewish Medical Center, New Hyde Park, NY, USA.

Background: Current therapy for intermediate thickness melanoma involves wide local excision with sentinel lymph node biopsy (SLNB). SLNB provides important prognostic information and immediate regional lymphadenectomy for a positive sentinel lymph node (SLN) may improve survival and identifies patients who are candidates for adjuvant therapy and/or clinical trials. The head and neck site is unique because of its complex lymphatic drainage pattern to multiple nodal basins and because of the risk of site-specific morbidity associated with regional lymphadenectomy when compared to other body sites. The goal of this study is to report the results of SLNB for head and neck cutaneous melanoma in locating the sentinel node and to report on the prognostic implications of SLNB for this cohort of patients.

Methods: A prospectively entered melanoma database was used to review consecutive patients with head and neck cutaneous melanoma undergoing SLNB at Memorial Sloan-Kettering Cancer Center between 1996 and 2007. The database, along with a retrospective chart review, was used to evaluate the success of SLNB at locating an SLN and the success rate of frozen section and permanent section analysis at diagnosing metastatic disease. Recurrence at all sites including the nodal basin and status at last follow-up was recorded. Characteristics of the patients' primary melanoma were included. Descriptive statistics along with univariate and multivariate survival analysis were performed.

Results: Between 1996 and 2007, 234 patients with a diagnosis of head and neck cutaneous melanoma underwent SLNB and had at least 1 month of follow-up. At least 1 SLN was identified in 218 of these patients (93%) by lymphoscintigraphy. In 16 patients, no SLN was found. These patients had a much shorter time to recurrence (4.75 months) than either the SLN-positive group (10.7 months) or the SLN-negative group (26.0 months). They had a disease-specific survival (DSS) in between the SLN-positive and SLN-negative group. Of the patients in whom an SLN was identified, 28 patients (12%) had at least 1 positive SLN. Of these, the SLNs of 14 patients (50%) were identified on frozen section; 14 (50%) could only be identified after further sectioning or immunohistochemical analysis postoperatively. Among 190 patients with a negative SLNB, 12 patients had recurrences in the nodal basin. This resulted in a sensitivity of 70%, a negative predictive value of 94%, and a false-negative rate of 30%. The 3-year disease-free survival for SLN-negative and SLN-positive patients was 84% (p < .031) and 58% (p < .102), respectively. The 3-year melanoma-specific survival was 98% (p < .012) and 75% (p < .201), respectively.

Conclusion: The SLN status is an important predictor of survival. The technique, performed in the head and neck is complex and associated with a high false-negative rate.
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http://dx.doi.org/10.1002/hed.21390DOI Listing
December 2010

UV radiation inhibits 15-hydroxyprostaglandin dehydrogenase levels in human skin: evidence of transcriptional suppression.

Cancer Prev Res (Phila) 2010 Sep 19;3(9):1104-11. Epub 2010 Jul 19.

Department of Medicine and Weill Cornell Cancer Center, 525 East 68th Street, Room F-206, New York, NY 10065, USA.

Elevated levels of prostaglandins (PG) have been detected in the skin following UV radiation (UVR). PGs play an important role in mediating both the acute and the chronic consequences of UVR exposure. UVR-mediated induction of cyclooxygenase-2 (COX-2) contributes to increased PG synthesis. In theory, reduced catabolism might also contribute to increased PG levels. 15-Hydroxyprostaglandin deyhdrogenase (15-PGDH), a tumor suppressor gene, plays a major role in PG catabolism. In this study, we investigated whether UVR exposure suppressed 15-PGDH while inducing COX-2 in keratinocytes and in human skin. UVR exposure caused dose-dependent induction of COX-2, suppression of 15-PGDH, and increased prostaglandin E(2) (PGE(2)) production in HaCaT cells. Exposure to UVR suppressed the transcription of 15-PGDH, resulting in reduced 15-PGDH mRNA, protein, and enzyme activities. UVR exposure induced Slug, a repressive transcription factor that bound to the 15-PGDH promoter. Silencing Slug blocked UVR-mediated downregulation of 15-PGDH. The effects of UVR were also evaluated in the EpiDerm skin model, a three-dimensional model of human epidermis. Here too, COX-2 levels were induced and 15-PGDH levels suppressed following UVR exposure. Next, the effects of UVR were evaluated in human subjects. UVR treatment induced COX-2 while suppressing 15-PGDH mRNA in the skin of 9 of 10 subjects. Collectively, these data suggest that reduced expression of 15-PGDH contributes to the elevated levels of PGs found in the skin following UVR exposure. Possibly, agents that prevent UVR-mediated downregulation of 15-PGDH will affect the acute or the long-term consequences of UVR exposure, including nonmelanoma skin cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-10-0089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933319PMC
September 2010

Effects of cigarette smoke on the human oral mucosal transcriptome.

Cancer Prev Res (Phila) 2010 Mar 23;3(3):266-78. Epub 2010 Feb 23.

Department of Surgery (Head and Neck Service),Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Use of tobacco is responsible for approximately 30% of all cancer-related deaths in the United States, including cancers of the upper aerodigestive tract. In the current study, 40 current and 40 age- and gender-matched never smokers underwent buccal biopsies to evaluate the effects of smoking on the transcriptome. Microarray analyses were carried out using Affymetrix HGU133 Plus 2 arrays. Smoking altered the expression of numerous genes: 32 genes showed increased expression and 9 genes showed reduced expression in the oral mucosa of smokers versus never smokers. Increases were found in genes involved in xenobiotic metabolism, oxidant stress, eicosanoid synthesis, nicotine signaling, and cell adhesion. Increased numbers of Langerhans cells were found in the oral mucosa of smokers. Interestingly, smoking caused greater induction of aldo-keto reductases, enzymes linked to polycyclic aromatic hydrocarbon-induced genotoxicity, in the oral mucosa of women than men. Striking similarities in expression changes were found in oral compared with the bronchial mucosa. The observed changes in gene expression were compared with known chemical signatures using the Connectivity Map database and suggested that geldanamycin, a heat shock protein 90 inhibitor, might be an antimimetic of tobacco smoke. Consistent with this prediction, geldanamycin caused dose-dependent suppression of tobacco smoke extract-mediated induction of CYP1A1 and CYP1B1 in vitro. Collectively, these results provide new insights into the carcinogenic effects of tobacco smoke, support the potential use of oral epithelium as a surrogate tissue in future lung cancer chemoprevention trials, and illustrate the potential of computational biology to identify chemopreventive agents.
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http://dx.doi.org/10.1158/1940-6207.CAPR-09-0192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833216PMC
March 2010

Elevated levels of urinary prostaglandin e metabolite indicate a poor prognosis in ever smoker head and neck squamous cell carcinoma patients.

Cancer Prev Res (Phila) 2009 Nov 20;2(11):957-65. Epub 2009 Oct 20.

Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.

Cyclooxygenase (COX)-derived prostaglandin E(2) (PGE(2)) plays a role in the development and progression of several tumor types including head and neck squamous cell carcinoma (HNSCC). Measurements of urinary PGE metabolite (PGE-M) can be used as an index of systemic PGE(2) production. In ever smokers, increased levels of urinary PGE-M reflect increased COX-2 activity. In this study, we determined whether baseline levels of urinary PGE-M were prognostic for ever smoker HNSCC patients. A retrospective chart review of ever smoker HNSCC patients treated with curative intent was done. Fifteen of 31 evaluable patients developed progressive disease (recurrence or a second primary tumor) after a median follow-up of 38 months. There were no statistically significant differences between patients with (n = 15) or without disease progression (n = 16) with regard to stage, site, treatment received, smoking status, and aspirin use during follow-up. Median urinary PGE-M levels were significantly higher in HNSCC patients with disease progression (21.7 ng/mg creatinine) compared with patients without (13.35 ng/mg creatinine; P = 0.03). Importantly, patients with high baseline levels of urinary PGE-M had a significantly greater risk of disease progression (hazard ratio, 4.76, 95% CI, 1.31-17.30; P < 0.01) and death (hazard ratio, 9.54; 95% CI, 1.17-77.7; P = 0.01) than patients with low baseline levels of urinary PGE-M. These differences were most evident among patients with early-stage disease. Taken together, our findings suggest that high baseline levels of urinary PGE-M indicate a poor prognosis in HNSCC patients. Possibly, HNSCC patients with high COX-2 activity manifested by elevated urinary PGE-M will benefit from treatment with a COX-2 inhibitor.
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http://dx.doi.org/10.1158/1940-6207.CAPR-09-0093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784194PMC
November 2009

UVR exposure sensitizes keratinocytes to DNA adduct formation.

Cancer Prev Res (Phila) 2009 Oct 29;2(10):895-902. Epub 2009 Sep 29.

Department of Medicine and Weill Cornell Cancer Center, 525 East 68th Street, Room F-206, New York, NY 10065, USA.

UV radiation (UVR) and exposure to tobacco smoke, a source of polycyclic aromatic hydrocarbons (PAH), have been linked to skin carcinogenesis. UVR-mediated activation of the aryl hydrocarbon receptor (AhR) stimulates the transcription of CYP1A1 and CYP1B1, which encode proteins that convert PAH to genotoxic metabolites. We determined whether UVR exposure sensitized human keratinocytes to PAH-induced DNA adduct formation. UVR exposure induced CYP1A1 and CYP1B1 in HaCaT cells, an effect that was mimicked by photooxidized tryptophan (aTRP) and FICZ, a component of aTRP. UVR exposure or pretreatment with aTRP or FICZ also sensitized cells to benzo(a)pyrene (B[a]P)-induced DNA adduct formation. alphaNF, an AhR antagonist, suppressed UVR-, aTRP-, and FICZ-mediated induction of CYP1A1 and CYP1B1 and inhibited B[a]P-induced DNA adduct formation. Treatment with 17-AAG, an Hsp90 inhibitor, caused a marked decrease in levels of AhR; inhibited UVR-, aTRP-, and FICZ-mediated induction of CYP1A1 and CYP1B1; and blocked the sensitization of HaCaT cells to B[a]P-induced DNA adduct formation. FICZ has been suggested to be a physiologic ligand of the AhR that may have systemic effects. Hence, studies of FICZ were also carried out in MSK-Leuk1 cells, a model of oral leukoplakia. Pretreatment with alpha-naphthoflavone or 17-AAG blocked FICZ-mediated induction of CYP1A1 and CYP1B1, and suppressed the increased B[a]P-induced DNA adduct formation. Collectively, these results suggest that sunlight may activate AhR signaling and thereby sensitize cells to PAH-mediated DNA adduct formation. Antagonists of AhR signaling may have a role in the chemoprevention of photocarcinogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758323PMC
http://dx.doi.org/10.1158/1940-6207.CAPR-09-0125DOI Listing
October 2009

Lymph node density is a significant predictor of outcome in patients with oral cancer.

Cancer 2009 Dec;115(24):5700-10

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Background: The impact of lymph node metastases on prognosis in patients with oral cavity squamous cell carcinoma (OSCC) has been well recognized. However, accurate stratification of risk for recurrence among patients with lymph node metastases is difficult based on the existing staging systems. In the current study, the utility of lymph node density (LND) was evaluated as an alternative method for predicting survival.

Methods: Three hundred eighty-six patients who underwent neck dissection were included. The median follow-up was 67 months. Five-year overall survival (OS), disease-specific survival (DSS), and locoregional failure (LRF) rates were calculated using the Kaplan-Meier method. LND (number of positive lymph nodes/total number of excised lymph nodes) and tumor-node-metastasis (TNM) staging variables were subjected to multivariate analysis.

Results: Using the median (LND=0.06) as the cutoff point, LND was found to be significantly associated with outcome. For patients with LND0.06 (P<.001). Similarly, the DSS for patients with LND0.06 (P<.001). On univariate analysis, pathologic T and N classification, extracapsular spread, and LND were found to be significant predictors of outcome (P<.001). However, on multivariate analysis, LND remained the only independent predictor of OS (P=.02; hazards ratio, 2.0), DSS (P=.02; hazards ratio, 2.3), and LRF (P=.005; hazards ratio, 4.1). LND was also found to be the only significant predictor of outcome in patients receiving adjuvant radiotherapy (P<.05). Within individual subgroups of pN1 or pN2 patients, LND reliably stratified patients according to their risk of failure (P<.05).

Conclusions: After surgery for OSCC, pathologic evaluation of the neck using LND was found to reliably stratify the risk of disease recurrence and survival.
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http://dx.doi.org/10.1002/cncr.24631DOI Listing
December 2009

Levels of prostaglandin E metabolite and leukotriene E(4) are increased in the urine of smokers: evidence that celecoxib shunts arachidonic acid into the 5-lipoxygenase pathway.

Cancer Prev Res (Phila) 2009 Apr 31;2(4):322-9. Epub 2009 Mar 31.

Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.

Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) play a role in inflammation and carcinogenesis. Biomarkers that reflect tobacco smoke-induced tissue injury are needed. In this study, levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E(4) (LTE(4)), biomarkers of the COX and 5-LO pathways, were compared in never smokers, former smokers, and current smokers. The effects of celecoxib, a selective COX-2 inhibitor, on levels of PGE-M and LTE(4) were determined. Baseline levels of PGE-M and LTE(4) were positively associated with smoking status; levels of PGE-M and LTE(4) were higher in current versus never smokers. Treatment with 200 mg celecoxib twice daily for 6 +/- 1 days led to a reduction in urinary PGE-M levels in all groups but exhibited the greatest effect among subjects with high baseline PGE-M levels. Thus, high baseline PGE-M levels in smokers reflected increased COX-2 activity. In individuals with high baseline PGE-M levels, treatment with celecoxib led to a significant increase in levels of urinary LTE(4), an effect that was not found in individuals with low baseline PGE-M levels. In conclusion, increased levels of urinary PGE-M and LTE(4) were found in human smokers, a result that may reflect subclinical lung inflammation. In individuals with high baseline levels of PGE-M (elevated COX-2 activity), celecoxib administration shunted arachidonic acid into the proinflammatory 5-LO pathway. Because 5-LO activity and LTE(4) have been suggested to play a role in cardiovascular disease, these results may help to explain the link between use of COX-2 inhibitors and cardiovascular complications.
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http://dx.doi.org/10.1158/1940-6207.CAPR-09-0005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745265PMC
April 2009

Effects of tobacco smoke on gene expression and cellular pathways in a cellular model of oral leukoplakia.

Cancer Prev Res (Phila) 2008 Jul 31;1(2):100-11. Epub 2008 Mar 31.

Department of Physiology and Biophysics, Weill Medical College of Cornell University, Box 75, Room E-509, 1300 York Avenue, New York, NY 10065, USA.

In addition to being causally linked to the formation of multiple tumor types, tobacco use has been associated with decreased efficacy of anticancer treatment and reduced survival time. A detailed understanding of the cellular mechanisms that are affected by tobacco smoke (TS) should facilitate the development of improved preventive and therapeutic strategies. We have investigated the effects of a TS extract on the transcriptome of MSK-Leuk1 cells, a cellular model of oral leukoplakia. Using Affymetrix HGU133 Plus 2 arrays, 411 differentially expressed probe sets were identified. The observed transcriptome changes were grouped according to functional information and translated into molecular interaction network maps and signaling pathways. Pathways related to cellular proliferation, inflammation, apoptosis, and tissue injury seemed to be perturbed. Analysis of networks connecting the affected genes identified specific modulated molecular interactions, hubs, and key transcription regulators. Thus, TS was found to induce several epidermal growth factor receptor (EGFR) ligands forming an EGFR-centered molecular interaction network, as well as several aryl hydrocarbon receptor-dependent genes, including the xenobiotic metabolizing enzymes CYP1A1 and CYP1B1. Notably, the latter findings in vitro are consistent with our parallel finding that CYP1A1 and CYP1B1 levels were increased in oral mucosa of smokers. Collectively, these results offer insights into the mechanisms underlying the procarcinogenic effects of TS and raise the possibility that inhibitors of EGFR or aryl hydrocarbon receptor signaling will prevent or delay the development of TS-related tumors. Moreover, the inductive effects of TS on xenobiotic metabolizing enzymes may help explain the reduced efficacy of chemotherapy, and suggest targets for chemopreventive agents in smokers.
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http://dx.doi.org/10.1158/1940-6207.CAPR-08-0007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773527PMC
July 2008

Oral tongue cancer gene expression profiling: Identification of novel potential prognosticators by oligonucleotide microarray analysis.

BMC Cancer 2009 Jan 12;9:11. Epub 2009 Jan 12.

Dental Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, NY, USA.

Background: The present study is aimed at identifying potential candidate genes as prognostic markers in human oral tongue squamous cell carcinoma (SCC) by large scale gene expression profiling.

Methods: The gene expression profile of patients (n=37) with oral tongue SCC were analyzed using Affymetrix HG_U95Av2 high-density oligonucleotide arrays. Patients (n=20) from which there were available tumor and matched normal mucosa were grouped into stage (early vs. late) and nodal disease (node positive vs. node negative) subgroups and genes differentially expressed in tumor vs. normal and between the subgroups were identified. Three genes, GLUT3, HSAL2, and PACE4, were selected for their potential biological significance in a larger cohort of 49 patients via quantitative real-time RT-PCR.

Results: Hierarchical clustering analyses failed to show significant segregation of patients. In patients (n=20) with available tumor and matched normal mucosa, 77 genes were found to be differentially expressed (P< 0.05) in the tongue tumor samples compared to their matched normal controls. Among the 45 over-expressed genes, MMP-1 encoding interstitial collagenase showed the highest level of increase (average: 34.18 folds). Using the criterion of two-fold or greater as overexpression, 30.6%, 24.5% and 26.5% of patients showed high levels of GLUT3, HSAL2 and PACE4, respectively. Univariate analyses demonstrated that GLUT3 over-expression correlated with depth of invasion (P<0.0001), tumor size (P=0.024), pathological stage (P=0.009) and recurrence (P=0.038). HSAL2 was positively associated with depth of invasion (P=0.015) and advanced T stage (P=0.047). In survival studies, only GLUT3 showed a prognostic value with disease-free (P=0.049), relapse-free (P=0.002) and overall survival (P=0.003). PACE4 mRNA expression failed to show correlation with any of the relevant parameters.

Conclusion: The characterization of genes identified to be significant predictors of prognosis by oligonucleotide microarray and further validation by real-time RT-PCR offers a powerful strategy for identification of novel targets for prognostication and treatment of oral tongue carcinoma.
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http://dx.doi.org/10.1186/1471-2407-9-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649155PMC
January 2009