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Background:Recently, the management of head and neck squamous cell carcinoma (HNSCC) has focused considerable attention on biomarkers, which may influence outcomes. Tests for human papilloma infection, including direct assessment of the virus as well as an associated tumour suppressor gene p16, are considered reproducible. Tumours from familial melanoma syndromes have suggested that nuclear localisation of p16 might have a further role in risk stratification. We hypothesised p16 staining that considered nuclear localisation might be informative for predicting outcomes in a broader set of HNSCC tumours not limited to the oropharynx, human papilloma virus (HPV) status or by smoking status.Methods:Patients treated for HNSCC from 2002 to 2006 at UNC (University of North Carolina at Chapel Hill) hospitals that had banked tissue available were eligible for this study. Tissue microarrays (TMA) were generated in triplicate. Immunohistochemical (IHC) staining for p16 was performed and scored separately for nuclear and cytoplasmic staining. Human papilloma virus staining was also carried out using monoclonal antibody E6H4. p16 expression, HPV status and other clinical features were correlated with progression-free (PFS) and overall survival (OS).Results:A total of 135 patients had sufficient sample for this analysis. Median age at diagnosis was 57 years (range 20-82), with 68.9% males, 8.9% never smokers and 32.6% never drinkers. Three-year OS rate and PFS rate was 63.0% and 54.1%, respectively. Based on the p16 staining score, patients were divided into three groups: high nuclear, high cytoplasmic staining group (HN), low nuclear, low cytoplasmic staining group (LS) and high cytoplasmic, low nuclear staining group (HC). The HN and the LS groups had significantly better OS than the HC group with hazard ratios of 0.10 and 0.37, respectively, after controlling for other factors, including HPV status. These two groups also had significantly better PFS than the HC staining group. This finding was consistent for sites outside the oropharynx and did not require adjustment for smoking status.Conclusion:Different p16 protein localisation suggested different survival outcomes in a manner that does not require limiting the biomarker to the oropharynx and does not require assessment of smoking status. [ABSTRACT FROM AUTHOR]

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia., Competing Interests: Disclosure BK declares grants or contracts from Merck Sharp & Dohme (MSD) Oncology, Ono Pharmaceutical and AstraZeneca, consulting fees from AstraZeneca, MSD Oncology, ABL Bio, Genexine, Cellid, Handok, Celid, Trial Informatics and CBS Bio, payment or honoraria from MSD Oncology and Merck. J-PM declares consulting fees/honoraria from Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boehringer, Bristol Myers Squibb (BMS), Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, iTEOS, TheRNA and NEKTAR, support for attending meetings and/or travel from Amgen, Pfizer and MSD and participation at a Safety or Advisory Board for PsiOxus. LL declares institutional grants or contracts from AstraZeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis Inc, Debiopharm International SA, Hoffman-La Roche Ltd., IRX Therapeutics Inc., Medpace Inc., Merck-Serono, MSD, Novartis, Pfizer, Roche Spa and Buran and receipt of honoraria or fees (for public speaking/teaching in medical meetings and/or for providing expert opinion in Advisory Boards) for AstraZeneca, Bayer, BMS, Eisai, MSD, Merck-Serono, Boehringer Ingelheim, Hoffman La Roche Ltd., Novartis, Roche, Debiopharm International SA, Sobi, Incyte Biosciences Italy SRL, Doxa Pharma, Amgen, Nanobiotics and GlaxoSmithKline (GSK). CB declares payment or honoraria from Merck KGaA, BMS and Roche. MT declares consulting fees from Ono Pharmaceuticals, MSD, BMS and Merck Biopharma, and honoraria from Eisai, Ono Pharmaceuticals, BMS and Merck Biopharma. MA declares consulting fees from MSD, AstraZeneca, Eli Lilly, DKSH, Eisai, Roche, Novartis and Merck, payment or honoraria from MSD, AstraZeneca, Eli Lilly, DKSH, Eisai, Roche, Novartis and Merck, support for attending meetings and/or travel from MSD, Roche, Elekta/Abex and AstraZeneca, and is the president of the Malaysian Oncological Society. MKA declares honoraria for presentations from Pfizer and Boehringer Ingelheim, sponsorship for meetings from AstraZeneca, Boehringer Ingelheim and DKSH. QSNg declares support for attending meetings and or travel from BMS, Boehringer Ingelheim, MSD and Astellas, and participation in Safety or Advisory Boards for MSD and Boehringer Ingelheim. WIWZ declares honoraria for lectures from Amgen Malaysia, DKSH Malaysia, Eisai Malaysia, Eli Lilly Malaysia, Ipsen Malaysia, MSD Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono Malaysia, Pfizer Malaysia and Roche Malaysia, travel grants from Amgen Malaysia, Celgene Malaysia, Eisai Malaysia, Eli Lilly Malaysia, MSD Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche Malaysia, participation on an Advisory Board for Celgene Malaysia, Roche Malaysia, Eli Lilly Malaysia, Eisai Malaysia and MSD Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and is a member of ASCO AP Regional Council and Greater Petaling Cancer City Challenge UICC. NK declares institutional grants or contracts from Ono Pharmaceutical, BMS, AstraZeneca, Pfizer, Chugai Pharmaceutical, Rakuten Medical, Bayer and Adlai Nortye, payment or honoraria from Ono Pharmaceutical, BMS, Merck Biopharma, MSD, Eisai and Bayer, participation on a Data Safety Monitoring Board or Advisory Board for Bayer and Adlai Nortye. GC declares institutional grants from Merck, consulting fees from BMS, Pfizer, MSD, AstraZeneca, Daichii Sankyo, Lilly, Novartis and Seattle Genetics, payment or honoraria from AstraZeneca, Roche and Daichii Sankyo. SP declares fees for consultancy/advisory roles from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Foundation Medicine, Illumina, Imedex, Incyte, Janssen, Medscape, MSD, Merck Serono, Merrimack, Novartis, PharmaMar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, speaker roles for AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Illumina, Imedex, Medscape, MSD, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda and the receipt of grants/research support: (Sub) investigator in trials (institutional financial support for trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, BMS, Clovis, GSK, Illumina, Lilly, MSD, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics, Roche/Genentech. TWK declares institutional grants or contracts from Roche, and sanofi-aventis. TY declares institutional grants or contracts from Taiho Pharmaceutical, Sumitomo Dainippon, Ono Pharmaceutical, Chugai Pharmaceutical, Amgen, Parexel International, MSD, Daiichi-Sankyo and Sanofi. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma., Methods: Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3+3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume., Results: Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%). Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months. Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume., Conclusions: The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)