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Objective: Achieving clear surgical margins is one of the primary surgical goals in treating oral squamous cell carcinoma (OSCC) and thus aiming to improve overall and disease-specific survival. Therefore, we developed the Goal-Oriented Assessment for Intraoperative Margin ('GAIM') protocol, a novel intraoperative approach for margin assessment, and present here our 5-year experience and outcomes., Methods: 'GAIM' is a 7-step procedure comprising systematic ruler-aided resection of labeled tumor-bed margins, frozen section (FS) co-produced by both pathologists and operating surgeons, and immediate extension of resection according to FS findings. Data from all patients operated using the 'GAIM' protocol at a single tertiary center between 2018 to 2022 were analyzed, including margin status on FS and final pathology (FP) records, recurrence, and mortality., Results: A total of 196 patients were included, 56.6% (n = 111) stages I-II, and 43.4% (n = 85) stages III-IV. Using the 'GAIM' protocol, we achieved an overall 94.4% of clean and revised clean surgical margins. Patients with a 2-year and longer follow-up (n = 141) had local recurrence in 3.5% when both FS and final margins were clean, 8.1% when FP margins were clean, and 16.7% with close/positive final margins., Conclusions: The proposed 'GAIM' protocol is a novel, effective, reproducible, and safe approach for margin evaluation that can be systematically applied. It can increase the rate of final clean surgical margins and potentially improve patients' outcomes., Level of Evidence: 3 Laryngoscope, 134:1725-1732, 2024., (© 2023 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: To characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study., Methods: Associations between biomarkers (tumor mutational burden (TMB), neoantigen load (NL), 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP), and PD-L1 combined positive score (CPS)) and clinical outcomes with pembrolizumab were assessed in patients with R/M HNSCC (n=192). Tumor human papillomavirus (HPV) status was also evaluated with the use of p16 immunohistochemistry and whole exome sequencing (WES; HPV + , mapping >20 HPV reads) in pretreatment tumor samples (n=106)., Results: TMB, clonality-weighted TMB, and Tcell inf GEP were significantly associated with objective response (p = 0.0276, p = 0.0201, and p = 0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p = 0.0550 and p = 0.0682, respectively). No correlation was observed between TMB and Tcell inf GEP (Spearman ρ=-0.026) or TMB and PD-L1 (Spearman ρ=0.009); a correlation was observed between Tcell inf GEP and PD-L1 (Spearman ρ=0.511). HPV status by WES and p16 immunohistochemistry showed concordance (84% ҡ=0.573) among patients whose HPV results were available using both methods., Conclusions: TMB and inflammatory biomarkers (Tcell inf GEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC; further study of these relationships in randomized clinical trials is needed., Trial Registration Number: NCT01848834., Competing Interests: Competing interests: RIH: research grant (to institution) from Merck; consultant/ad board member for Merck, BMS, Astra Zeneca, Pfizer, Genentech, Kura, Celgene, Eisai, Loxo, Immunomic, GSK, Gilead, Vaccinex, EMD Serono, BioNTech, Achilles; royalties from Up to Date; data safety monitoring board for Nanobiotix, ISA. TYS: grant (to institution) from Merck, Nanobiotix, Regeneron, Bristol Myers Squibb, AstraZeneca; honorarium from Merck, Nanobiotix, Regeneron, Innate Pharma, AstraZeneca, eTheRNA, Nektar. LQMC: grants from Merck, Lily/Imclone, Bristol Myers Squibb, AstraZeneca/MedImmune, Pfizer, Seattle Genetics, Dynavax, Alkermes, Novartis; personal fees from Merck, Pfizer, Dynavax, Synthrox, Alkermes, Cullinan, Elicio, Genentech, Novartis, Daiichi Sankyo, Gilead, Regeneron/Sanofi Genzyme. SG: consultant to Seattle Genetics. JW: research grant (to institution) from Merck; research grant from Merck, AstraZeneca, Celgene, G1; personal fees from AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1, Jounce, AbbVie, Rakuten. IG: has nothing to disclose. JPE: has nothing to disclose. BB: grants from Merck, Bristol Myers Squibb, Fox Chase Cancer Center; personal fees from Merck, AstraZeneca, Fox Chase Cancer Center. MT: research grant from MSD, Ono Pharmaceutical, Bristol Myers Squibb, Bayer, Eisai, Merck Biopharma, Pfizer, Rakuten Medical, Novartis; personal fees from MSD, Ono Pharmaceutical, Bristol Myers Squibb, Bayer, Eisai, Merck Biopharma, LOXO, Pfizer, Celgene, Rakuten Medical, Amgen, Novartis. BK: grants from Ono Pharmaceutical, MSD Oncology, AstraZeneca; personal fees from MSD Oncology, AstraZeneca, Genexis, Handok. HK: research grant from Merck, Kura Oncology, Lilly, Exelixis, Elevar Therapeutics, Ayala Pharmaceuticals, Novartis; consulting for PIN Therapeutics, Mitoimmune; advisory board for Bayer, GlaxoSmithKline, Prelude Therapeutics, Achilles Therapeutics. KM: research grant from Solasio Pharma, Pfizer, Amgen, Daiichi Sankyo, Parexel International, MSD, Merck Serono; research grant and honorarium from Sanofi, Ono, Taiho, consulting and honorarium from Eli Lilly, Chugai, honorarium from Takeda, Bristol Myers Squibb, Bayer. AA: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. RM: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. MA: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA; patent (US20180327848) issued for RNA Gene Signatures (inventor of 18-gene T-cell inflamed signature). LH: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. JL: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA; patent (US20180327848) issued for RNA Gene Signatures (inventor of 18-gene T-cell inflamed signature). RC: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA; patent pending for angiogenesis and mMDSC gene expression-based biomarker of tumor response to PD-1 antagonists (patent 2020/167619). JC: former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. RM: research grant from AstraZeneca, Merck; consulting/advisory board for Rakuten Medical., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We investigated the findings and pitfalls of FDG-PET/CT scanning after maxillectomy with reconstruction/rehabilitation procedures, in patients with head and neck malignancies treated during nine years at one tertiary medical centre., Methods: Fourteen patients (10 males), aged 22-84 years, underwent 17 reconstruction/rehabilitation maxillectomy surgeries and 35 PET/CT scans. Postoperative PET/CT findings were correlated with clinical and imaging follow-up., Results: Increased FDG uptake, mean SUVmax 2.4 ± 1.4 (range 0.3-4.3), was observed at the postoperative bed following 12 of 17 surgeries (71%; 10 obturators, two mesh reconstructions). Following the remaining 5/17 surgeries (three with a fat flap and two without any reconstructions), abnormal FDG uptake was not observed at the postoperative bed.CT features of postoperative sites included: non-homogeneous mixed iso/hyperdense structures (hollow or filled) with multiple surrounding and/or inside air bubbles ("sponge appearance") and mucosal thickening along the postoperative bed wall (in all cases with obturator implants); rich fat density material in reconstructions with a fat flap and in closures without reconstruction, and radiopaque elongated structures in mesh reconstructions.No correlation was found of the mean SUVmax in initial scans, with the time from the surgery date (10 ± 6 months; r=0.04, P =0.90), or with the mean SUVmax in final scans (at 25± 17 months, P =0.17)., Conclusions:: Increased FDG uptake, together with corresponding non-specific CT features, may persist for a prolonged period after surgery with obturators and mesh implantations, mimicking malignancy or infection. Awareness of variations in postoperative PET-CT appearance can help avoid false interpretations and redundant invasive procedures.

Background: The tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is associated with immune suppression, one of the pathways being the programmed death receptor 1 (PD-1) and its ligands (PD-L1/PD-L2). Checkpoint inhibitors of PD-1/PD-L1, like pembrolizumab, have been recently approved for treatment of OSCC. We described the histologic findings in OSCC following neoadjuvant pembrolizumab, including identification of immune-related cell populations and cancer-associated fibroblasts (CAFs). Materials and Methods: Patients with OSCC clinical stages 3 and 4 and a combined PD-L1 score >1 were randomized either to the standard oncologic protocol or to the pembrolizumab arm of MK-3475-689 study for Head and Neck, Lip, and Oral Cavity. The latter were given two standard doses of 200 mg of pembrolizumab, 3 weeks apart, and then underwent surgical oncologic procedure according to the initial stage. Sections from the resection specimens were analyzed for pathological response to pembrolizumab. Various populations of immune-related cells within the tumor microenvironment were characterized by immunohistochemistry, as were the CAFs. Results: Three patients who were randomized to the pembrolizumab study were described. One patient presented with a tongue SCC, the other two had SCC of the mandibular ridge with bony involvement. Only the patient with tongue SCC showed clinical complete response. Microscopically, the tumor was replaced by a granulomatous type of inflammation. Immunohistochemical stains revealed massive T cell rich (CD3 + ) infiltrate, with approximately equal amounts of CD4 + and CD8 + cells, numerous macrophages of CD68 + and CD163 + phenotypes; no CAFs were identified. The other two patients were regarded as non-responders as at least 50% of the tumor was viable. The tumor microenvironment of these tumors was generally associated with a lesser extent of inflammatory response compared to the tongue tumor, a variable CD4 + /CD8 + ratio and presence of CAFs. Neither T regulatory cells (FOXP3 + ) nor natural killer cells (CD56 + , CD57 + ) were identified in any of the cases. Conclusion: We showed that characterizing the specific populations of immune-related cells and CAFs after treatment with pembrolizumab, may add to our understanding of the tumor-TME interactions in this setting. These findings should be investigated in future studies on a larger number of patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dobriyan, Gluck, Alon, Barshack, Yahalom and Vered.)

Restricted mouth opening or trismus is often encountered in patients with head and neck cancer. The restriction may be the presenting sign of malignancy, a sequela of tumor site or growth, an adverse effect of oncologic treatment, or a first sign of tumoral recurrence. In general, any insult to the temporomandibular joint, masticatory muscles, or their neural innervation may cause limitation in mouth opening. The etiologies leading to trismus are as follows: myospasm secondary to tumor infiltration; reflectory myospasm; radiation-induced myositis and myofibrosis; temporomandibular joint involvement with tumor; unfavorable postsurgical scarring; muscle and joint atrophy secondary to immobilization; pain; jaw fracture and hardware failure; and infection. Preventive measures should be implemented before, during, and after treatment. These measures include identification of high-risk patients, utilization of dose-sculpting radiation techniques whenever possible, performing reconstruction at the same time of resective surgery whenever feasible, and initiating mobilization exercises as early as possible. When trismus develops, treatments are often challenging and disappointing. These include physical therapy, mouth opening appliances, drug therapy, and release surgery. All medical specialties dealing with head and neck cancer should be familiar with the diagnosis and prevention of trismus and make an effort to ensure patients are referred to the appropriate care when needed. Trismus should not be considered a trivial sequela of head and neck cancer.

Immune-checkpoint inhibitor (ICI)-related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non-small cell lung carcinoma, and head and neck squamous cell carcinoma patients ( n = 403) treated with anti-PD-1 ( n = 356) or anti-CTLA-4 ( n = 47) were divided into a case group (radiologic evidence of PA); control group matched by age, gender, and previous lines of treatment; and colitis group (ICI-induced colitis). Quantitative pancreatic volumetry was used for calculation of the decrease in pancreatic volume over time (atrophy rate). Thirty-one patients (7.7%) developed PA compared with 41 matched controls ( P = 0.006). Four patients developed EPI, all from the anti-PD-1-treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI ( P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti-PD-1-induced colitis patients ( n = 22) was presented at a median of 2 months ( P = 0.029). ICI-induced PA is irreversible and can result in EPI. EPI should be suspected in cases of late-onset steroid-resistant diarrhea with features of steatorrhea and treated with oral enzyme supplements., (©2018 American Association for Cancer Research.)

Background: Second-line treatment options for advanced head and neck squamous cell carcinoma (HNSCC) are limited. The phase Ib KEYNOTE-012 study evaluated the safety and the efficacy of pembrolizumab for the treatment of HNSCC after long-term follow-up., Methods: Multi-centre, non-randomised trial included two HNSCC cohorts (initial and expansion) in which 192 patients were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks (initial cohort; N = 60) or 200 mg every 3 weeks (expansion cohort; N = 132). Co-primary endpoints were safety and overall response rate (ORR; RECIST v1.1; central imaging vendor review)., Results: Median follow-up was 9 months (range, 0.2-32). Treatment-related adverse events (AEs) of any grade and grade 3/4 occurred in 123 (64%) and 24 (13%) patients, respectively. No deaths were attributed to treatment-related AEs. ORR was 18% (34/192; 95% CI, 13-24%). Median response duration was not reached (range, 2+ to 30+ months); 85% of responses lasted ≥6 months. Overall survival at 12 months was 38%., Conclusions: Some patients received 2 years of treatment and the responses were ongoing for more than 30 months; the durable anti-tumour activity and tolerable safety profile, observed with long-term follow-up, support the use of pembrolizumab as a treatment for recurrent/metastatic HNSCC.

Purpose: Delayed sinonasal complications of radiation therapy include choanal stenosis, osteoradionecrosis, chronic sinusitis, and intranasal synechiae. Only sporadic cases on their surgical treatment have been reported, with equivocal results., Methods and Materials: We performed a prospective case series of all patients who had been surgically treated for delayed sinonasal complications of radiation therapy in our institution during the past 10 years. The inclusion criteria required ≥6 months of follow-up after surgery. The included patients were asked to complete a Sino-Nasal Outcome Test 16-item questionnaire preoperatively and 6 months after surgery., Results: Nine patients with history of radiation therapy for nasopharyngeal carcinoma were included in our series. In all cases, partial or complete subjective improvement occurred., Conclusions: In select cases, endoscopic sinus surgery could be of benefit in the treatment of delayed sinonasal complications of radiation therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Radiotherapy (RT) plays a key role in the management of head and neck cancer (HNC), especially in locally advanced disease. Patients undergoing head and neck RT, especially elderly ones, are suffering from low and labile blood pressure (BP) during the treatment. They complain of weakness and fatigue and are prone to recurrent falls. The aim of this study was to characterize BP changes during RT period., Methods: Patients with HNC, receiving radiation to the neck, were recruited from Sheba medical center RT unit. Office BP, orthostatic measurements, 24-hour ambulatory BP monitoring, body weight, and metabolic parameters were measured at baseline after 30 days and after 90 days from beginning of therapy., Results: Nineteen patients (17 males), 64 ± 12 years old were recruited. Nine hypertensive patients continued their antihypertensive treatment during the study. Office systolic BP and diastolic BP decreased significantly after 30 days (128 ± 4/80 ± 3 to 122 ± 3/74 ± 3 mm Hg; P < 0.05). Average 24-hour BP values after 30 days of RT decreased from 130 ± 3/76 ± 2 to 123 ± 3/71 ± 2 mm Hg; P < 0.05. A similar trend was observed for day and night BP levels. Decrease in office and ambulatory BP was sustained for several months after RT completion. No orthostasis was observed during the study period. Patient lost weight significantly during the study period. However, BP changes were independent of weight loss., Conclusion: There is a significant and sustained BP reduction after head and neck RT, without orthostatic changes. Clinicians should be aware of this phenomenon and consider treatment adaption accordingly., (© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

To characterize the clinical features of oncology patients presenting with shortness of breath mistakenly diagnosed at first with pulmonary emboli, but later found instead to have extrinsic compression of the pulmonary artery or its tributaries by tumor. Medical charts and computed tomography (CT) angiographies of these patients were reviewed retrospectively. In a 7-year period, 11 patients from a single institute were identified. Five patients were excluded as they had a pleural and pericardial effusion that by itself could result in dyspnea. All had varied solid tumors and none had lymphoma. In three of six patients, an increased ratio between right and left ventricle was detected by CT angiography; however, in contradistinction to patients with pulmonary emboli, this was not found to be associated with short survival. The term 'pseudo pulmonary emboli' is suggested to describe this phenomenon. Anticoagulant treatment to avoid in-situ pulmonary artery thrombosis may be considered; however, misdiagnosis of pulmonary embolism may delay the appropriate treatment with chemotherapy, biological therapy, and radiotherapy.

Objective: There are only sporadic reports of delayed sino-nasal complications associated with nasopharyngeal carcinoma (NPC) treated with radiotherapy. These include choanal stenosis, osteoradionecrosis, chronic sinusitis, and intranasal synechiae. Most likely, these complications are underestimated as in many institutions nasal endoscopies in NPC patients are not performed routinely. The aim of this study was to identify the onset and incidence of delayed sino-nasal complications in NPC patients and their effect on quality of life (QOL)., Study Design: Case series with chart review., Setting: Tertiary medical center., Subjects and Methods: A retrospective chart review was performed on all patients treated for NPC in our institution between 1988 through 2009. The inclusion criteria required at least a 3-year follow-up without recurrence. Included patients were contacted prospectively and asked to fill a SNOT-16 questionnaire., Results: Sixty-two patients were included in our review. There were 42 males and 20 females. The average age at onset was 42 years. The AJCC staging for T1, T2, T3, and T4 tumors was 22 (35%), 11 (18%), 18 (29%), and 11 (18%), respectively. Eleven patients (18%) suffered from chronic sinusitis. Nine patients (15%) developed choanal stenosis. Five patients (8%) developed osteoradionecrosis. Two patients suffered from nasal synechiae. Forty-eight patients completed the SNOT-16 questionnaire. Patients with choanal stenosis had the lowest QOL scores out of the cohort., Conclusion: The incidence of delayed sino-nasal complications after radiation treatment for NPC is not negligible and should be kept in mind when addressing the quality of life of NPC survivors., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.)

Patients diagnosed with head and neck squamous cell cancer (HNSCC) frequently develop dysphagia and odynophagia owing to advancing disease or as a result of medical interventions. Selected patients diagnosed with advanced HNSCC may require the insertion of a percutaneous endoscopic gastrostomy (PEG) tube as part of their management. During the past 2 decades, there have been increasing reports describing tumor seeding at the PEG exit site, which have caused controversy relating to the technique used in PEG insertion. Although PEG placement is considered a safe procedure for patients with advanced head and neck cancer, the method can lead to tumor seeding, probably from direct traumatic tumor shedding. This report describes a case of tumor implantation at the PEG site in a patient with an advanced SCC of the tongue, with a review of the available literature concerning this rare condition and its possible pathogenesis., (Copyright © 2014 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The standard treatment for non-metastatic oral cavity squamous cell carcinoma (OCSCC) is surgical resection followed by post-operative radiotherapy (PORT) with/without chemotherapy in high risk patients. Given the substantial toxicity of PORT we assessed lymph node ratio (LNR) as a predictor of PORT benefit., Design: By using the Surveillance, Epidemiology and End Results (SEER) database, we analyzed all node positive OCSCC patients diagnosed between 1988 and 2007 who underwent neck dissection. LNR was categorized into three groups: < 6%, 6-12.5% and > 12.5%., Results: In 3091 subjects identified, median survival was 32, 25 and 16 months for LNR Groups 1, 2 and 3, respectively. On multivariate analysis, survival was associated with age, race, grade, tumor size, nodal stage, extra-capsular extension, use of PORT and LNR. When stratified by LNR group, PORT was associated with a survival benefit only in Group 3 (LNR > 12.5%): 2 year survival 25% vs 37%. No benefit to PORT was seen when the LNR ≤ 12.5%: 2 year survival 51% vs 54%., Conclusion: A low LNR is associated with extended survival in LN positive OCSCC. The survival benefit associated with PORT in this disease appears to be limited to those with a LNR > 12.5%. Validation is required prior to the clinical implementation of our findings., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To identify high-risk patients with desmoid tumors who could benefit from postoperative radiotherapy (RT) and to determine the efficacy of postoperative and definitive RT., Materials and Methods: Retrospective analysis of clinical data for all patients with desmoid tumors who underwent definitive local therapy at the University of Michigan from 1984 through 2008. Estimates for local control were calculated using the product-limit method of Kaplan and Meier, and associations with patient, tumor, and RT characteristics were explored using Cox proportional hazard regression., Results: Treatment for 95 patients who qualified for the study included surgery, RT, or both in 54, 13, and 28 cases, respectively. With a median follow-up of 38 months, the actuarial 3-year local control (95% confidence interval [CI]) was not significantly different (p = 0.3) among the three treatment groups: 84.6% (70.2-92.4), 92.3% (56.6-98.9), and 69.0% (43.1-84.9), respectively. Tumor site in the head/neck (p = 0.03) and history of previous surgical therapy (p = 0.01) were associated with increased recurrence risk (HR = 2.8, 95% CI 1.1-7.4, and HR = 3.2, 95% CI = 1.3-7.8), whereas gender, age, use of RT, and positive margins were not (p > 0.2)., Conclusions: Our findings suggest equivalent local control rates after surgery, RT, or a combination of both. Although history of previous surgical therapy or site of origin in the head/neck region were found to be associated with increased risk of recurrence after local therapy, there was no clear association between surgical margin status and local control., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Up to 4% of breast cancer cases occur in women younger than 35 years. Studies have suggested an association between breast cancer at a young age, poorer outcome, and adverse clinical and pathologic characteristics. It is unclear whether age is an independent prognostic factor., Objectives: To characterize the prognostic significance of young age at diagnosis through comparison of disease characteristics of "less-young" (born between 1958-1962 and aged 37-44 years) and "very-young" (born after 1967 and aged ≤35 years) premenopausal patients., Methods: Consecutive patients with breast cancer born after 1967 treated at Sheba Medical Centre between January, 1999 and October, 2002 were identified and their files reviewed. This cohort was identified as "very-young" and was compared with a group of "less-young" patients. The clinico-pathologic characteristics and survival data were compared., Results: Sixty-one very young and 94 less-young patients were identified. The mean age at diagnosis was 29.9 (range, 23-34 years) and 40.5 years (range, 37-44 years) for the very young and less young patients, respectively (P < 0.0001). Significantly more very young patients had metastatic disease at presentation (20% vs. 3%, respectively, P = 0.0007). The very young patients were more likely to have high grade, endocrine nonresponsive tumors than the less young patients. After controlling for stage and tumor grade, very-young age was not shown to be an independent risk factor for reduced survival., Conclusions: Very young age among Israeli women with breast cancer is associated with higher stage at diagnosis, adverse pathologic characteristics and adverse outcome but is not an independent prognostic factor for survival.

Purpose: Reporting long-term toxicities in trials of chemoirradiation (CRT) of head-and-neck cancer (HNC) has mostly been limited to observer-rated maximal Grades >or=3. We evaluated this reporting approach for dysphagia by assessing patient-reported dysphagia (PRD) and objective swallowing dysfunction through videofluoroscopy (VF) in patients with various grades of maximal observer-reported dysphagia (ORD)., Methods and Materials: A total of 62 HNC patients completed quality-of-life questionnaires periodically through 12 months post-CRT. Five PRD items were selected: three dysphagia-specific questions, an Eating-Domain, and "Overall Bother." They underwent VF at 3 and 12 months, and ORD (Common Terminology Criteria for Adverse Events) scoring every 2 months. We classified patients into four groups (0-3) according to maximal ORD scores documented 3-12 months post-CRT, and assessed PRD and VF summary scores in each group., Results: Differences in ORD scores among the groups were considerable throughout the observation period. In contrast, PRD scores were similar between Groups 2 and 3, and variable in Group 1. VF scores were worse in Group 3 compared with 2 at 3 months but similar at 12 months. In Group 1, PRD and VF scores from 3 through 12 months were close to Groups 2 and 3 if ORD score 1 persisted, but were similar to Group 0 in patients whose ORD scores improved by 12 months., Conclusions: Patients with lower maximal ORD grades, especially if persistent, had similar rates of PRD and objective dysphagia as patients with highest grades. Lower ORD grades should therefore be reported. These findings may have implications for reporting additional toxicities besides dysphagia., ((c) 2010 Elsevier Inc. All rights reserved.)

p53 is a major tumor suppressor gene, frequently mutated in human cancer, but rarely mutated in malignant melanoma (MM). Mdm2, the major negative regulator of p53, is overexpressed in 50-60% of MM patients, by an unknown mechanism. Single nucleotide polymorphism at position 309 of the Mdm2 promoter correlates with increased Mdm2 levels and reduced p53 activation. We speculated that guanine at position 309 (G309) of the Mdm2 promoter might be a cause of Mdm2 overexpression in MM patients, and associated with increased risk of MM. We aimed to estimate the prevalence of G309 in MM patients. Genomic DNA was collected from a cohort of 28 MM patients of various clinical stages. The relevant DNA stretch was sequenced and thymidine/guanidine polymorphism at position 309 of Mdm2 promoter was examined. We compared the resultant frequencies with the frequencies reported in the literature for the general population. The G allele frequency in the cohort of MM patients was 0.518. This frequency is high compared with the reported frequency of 0.351 in Caucasian healthy populations (odds ratio=1.98, P=0.014). It is also higher than a G allele frequency of 0.464 reported for Ashkenazi Jewish women, although this comparison was not statistically significant (odds ratio=1.14, P=0.76). These results suggest that the single nucleotide polymorphism G309 in the Mdm2 promoter might be an important genetic predisposing factor, and possibly indicate a molecular mechanism of disease regarding MM. These results must be confirmed in a larger cohort of MM patients and controls.

Purpose: Reirradiation (re-RT) of recurrent head and neck cancer (HNC) may achieve long-term disease control in some patients, at the expense of high rates of late sequelae. Limiting the re-RT targets to the recurrent gross tumor volume (rGTV) would reduce the volumes of reirradiated tissues; however, its effect on tumor recurrence pattern is unknown., Methods and Materials: This is a retrospective review of 66 patients who underwent curative-intent re-RT for nonresectable recurrent or second primary mucosal squamous cell HNC. Treatment was delivered with three-dimensional conformal (3D) RT or intensity-modulated RT (IMRT). The targets in all patients consisted of the rGTVs with tight (0.5-cm) margins, with no intent to treat prophylactically lymph nodes or subclinical disease in the vicinity of the rGTVs. The sites of locoregional failures (LRFs) were determined using imaging at the time of failure and were compared with the rGTVs., Results: Median re-RT dose was 68 Gy. Forty-seven patients (71%) received concomitant chemotherapy, and 31 (47%) received hyperfractionated, accelerated RT. At a median follow-up of 42 months, 16 (23%) were alive and disease-free. Fifty patients (77%) had a third recurrence or persistent disease, including 47 LRFs. All LRFs occurred within the rGTVs except for two (4%) (95% confidence interval, 0-11%). Nineteen patients (29%) had Grade > or = 3 late complications, mostly dysphagia (12 patients)., Conclusions: Almost all LRFs occurred within the reirradiated rGTVs despite avoiding prophylactic RT of tissue at risk of subclinical disease. These results support confining the re-RT targets to the rGTVs to reduce reirradiated tissue volumes.

Purpose: To analyze patterns of failure in patients with head-and-neck cutaneous squamous cell carcinoma (HNCSCC) and clinical/radiologic evidence of perineural invasion (CPNI), in order to define neural clinical target volume (CTV) for treatment planning., Methods and Materials: Patients treated with three-dimensional (3D) conformal or intensity-modulated radiotherapy (IMRT) for HNCSCC with CPNI were included in the study. A retrospective review of the clinical charts, radiotherapy (RT) plans and radiologic studies has been conducted., Results: Eleven consecutive patients with HNCSCCs with CPNI were treated from 2000 through 2007. Most patients underwent multiple surgical procedures and RT courses. The most prevalent failure pattern was along cranial nerves (CNs), and multiple CNs were ultimately involved in the majority of cases. In all cases the involved CNs at recurrence were the main nerves innervating the primary tumor sites, as well as their major communicating nerves. We have found several distinct patterns of disease spread along specific CNs depending on the skin regions harboring the primary tumors, including multiple branches of CN V and VII. These patterns and the pertinent anatomy are detailed in the this article., Conclusions: Predictable disease spread patterns along cranial nerves supplying the primary tumor sites were found in this study. Awareness of these patterns, as well as knowledge of the relevant cranial nerve anatomy, should be the basis for CTV definition and delineation for RT treatment planning.

Purpose: To compare dose-volume consequences of the inclusion of various portions of the seminal vesicles (SVs) in the clinical target volume (CTV) in intensity-modulated radiotherapy (IMRT) for patients with prostate cancer., Methods and Materials: For 10 patients with prostate cancer, three matched IMRT plans were generated, including 1 cm, 2 cm, or the entire SVs (SV1, SV2, or SVtotal, respectively) in the CTV. Prescription dose (79.2 Gy) and IMRT planning were according to the high-dose arm of the Radiation Therapy Oncology Group (RTOG) 0126 protocol. We compared plans for percentage of rectal volume receiving minimum doses of 60-80 Gy and for rectal normal tissue complication probability (NTCP[R])., Results: There was a detectable increase in rectal dose in SV2 and SVtotal compared with SV1. The magnitude of difference between plans was modest in the high-dose range. In 2 patients, there was underdosing of the planning target volume (PTV) because of constraints on rectal dose in the SVtotal plans. All other plans were compliant with RTOG 0126 protocol requirements. Mean NTCP increased from 14% to 17% and 18% for SV1, SV2, and SV total, respectively. The NTCP correlated with the size of PTV-rectum volume overlap (Pearson's r = 0.86; p < 0.0001), but not with SV volume., Conclusions: Doubling (1 to 2 cm) or comprehensively increasing (1 cm to full SVs) SV volume included in the CTV for patients with prostate IMRT is achievable in the majority of cases without exceeding RTOG dose-volume limits or underdosing the PTV and results in only a moderate increase in NTCP.

Type 2 diabetes mellitus is associated with increased incidence and inferior outcome of various malignancies. The aim of this study was to explore the impact of type 2 diabetes on breast cancer characteristics at presentation. The study population included 79 diabetic and 158 age-matched non-diabetic patients. Parity, country of birth, co-morbidity other than diabetes, and mode of diagnosis were similar in both groups. Mean body mass index (BMI) was higher among diabetic patients. Tumour stage and size were higher among diabetic patients and the differences remained significant after adjustment for BMI. Moreover, after adjustment for BMI, breast cancer among diabetic patients was more often hormone receptor negative. Our results show that diabetes mellitus is associated with negative prognostic factors at breast cancer presentation.

A novel single base pair deletion in the acid sphingomyelinase (ASM) gene (677delT in the cDNA) was identified in 12 Israeli Arab families with Niemann-Pick disease (NPD) type A. This deletion creates a premature stop codon which explains the complete deficiency of ASM activity in these patients and the severe clinical manifestation. A single mutation in 12 families living in a relatively small geographical region suggests a founder effect and explains the high frequency of this disease in this population. This is in contrast to multiple mutations found in two other lysosomal storage disorders prevalent in this population, namely, Hurler disease (MPSI) and metachromatic leukodystrophy. Mutations analysis is therefore an important tool in characterizing the grounds for the high frequency of inherited diseases as well as a basis for prevention programs for prevalent diseases through carrier identification and the ascertainment of high risk families.