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The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with biliary tract cancer (BTC), published in late 2022 were adapted in December 2023, according to established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with BTC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with BTC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and the Taiwan Oncology Society (TOS). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different regions of Asia. Drug access and reimbursement in the different regions of Asia are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with BTC across the different countries and regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices and molecular profiling, as well as age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different countries., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [ 177 Lu]Lu-DOTA-TATE ( 177 Lu-Dotatate) treatment., Methods: NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177 Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks ( 177 Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting., Findings: Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177 Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177 Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177 Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period., Interpretation: First-line 177 Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177 Lu-Dotatate should be considered a new standard of care in first-line therapy in this population., Funding: Advanced Accelerator Applications, a Novartis Company., Competing Interests: Declaration of interests SS reports support for the present work from Novartis; grants or contracts from Novartis; consulting fees from Ipsen, Novartis, and Camurus; and meeting attendance support from Ipsen and Novartis. DH reports support for the present work from Novartis; grants or contracts from Novartis, ITM, RayzeBio, Thermo Fisher Scientific, Camurus, and Genentech/Roche; consulting fees from Novartis, TerSera, ITM, Crinetics, Amryt, Camurus, Chimeric Therapeutics, Harpoon Therapeutics, HarbourBioMed, Lantheus, Exelixis, and Ipsen; and participation on a data safety monitoring board for Alphamedix. SM reports advisory board participation for Novartis Oncology and Ipsen. KH reports payment for steering committee participation from Novartis; grants or contracts from Novartis and SOFIE Biosciences; consulting fees from Advanced Accelerator Applications (a Novartis company), Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, ITM, Janssen, Merck, Molecular Partners, NVision, Pfizer, POINT Biopharma, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, SOFIE Biosciences, Telix, Theragnostics, and Y-mAbs; honoraria from PeerVoice; meeting support from Janssen; advisory board participation for Fusion and GE Healthcare; and stock or stock options for SOFIE Biosciences, Pharma15, NVision, Convergent, Aktis Oncology, and AdvanCell. MP reports grants or contracts from Advanced Accelerator Applications (a Novartis company), Novartis, Ipsen, ITM, Camurus, and Boehringer Ingelheim; consulting fees from Advanced Accelerator Applications (a Novartis company), Novartis, Ipsen, Riemser, and HUTCHMED; honoraria from Ipsen, Advanced Accelerator Applications (a Novartis company), Novartis, Boehringer Ingelheim, MSD, Lilly, Recordati, Sanofi, and Serb; advisory board participation for Crinetics and Advanced Accelerator Applications (a Novartis company); and unpaid roles as ENETS committee member and President, on the ESMO education committee, and on the INCA advisory board. PLK reports grants or contracts from RayzeBio and Novartis; honoraria from Natera, ITM, BMS, and Foundation Medicine; steering committee participation (uncompensated) for RayzeBio and Exelixis; and advisory board participation and honoraria from Amgen, Genentech, Crinetics, HUTCHMED, and Ipsen. BC reports advisory board participation and honoraria from Advanced Accelerator Applications (a Novartis company). SL reports advisory board participation for Advanced Accelerator Applications (a Novartis company). JC reports grants or contracts from Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications (a Novartis company), Eisai, Amgen, and Bayer; and consulting fees and honoraria from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications (a Novartis company), Amgen, Sanofi, Lilly, Hutchinson Pharma, ITM, Advanz, Merck, Esteve, and Roche. AG-B reports consulting fees from Advanced Accelerator Applications (a Novartis company), Bayer, and Sanofi; and speaker fees and meeting support from Novartis. D-YO reports grants or contracts from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok; and advisory board participation for AstraZeneca, Novartis, Genentech/Roche, Merck, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD, LG Chem, Astellas, AbbVie, J-Pharma, Mirati Therapeutics, Eutilex, Moderna, and Idience. CY reports grants or contracts from Bayer, Ipsen, AstraZeneca, Boehringer Ingelheim, Servier, and Eisai; and honoraria from Bayer, Ipsen, MSD, Merck, Celgene, AstraZeneca, GSK, Eisai, Roche, Genentech, and Novartis. TRH reports consulting fees from TerSera; advisory board participation and research support from Camurus, ITM, Advanced Accelerator Applications (a Novartis company), Crinetics, and Perspective Therapeutics; research support from Thermo Fisher Scientific; and an unpaid role as President of NANETS. IF, YZ, and PA report employment by Novartis and stock or stock options for Novartis. WWdH reports consulting fees and honoraria from Ipsen, Novartis, and Advanced Accelerator Applications (a Novartis company); and consulting fees from ITM. DF reports grants or contracts from Camurus and Pfizer; honoraria from Novartis and Recordati Rare Diseases; and advisory board participation for Camurus, Ipsen, Novartis, Recordati Rare Diseases, and Pfizer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements are clinically actionable genomic alterations in cholangiocarcinoma (CCA). Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in FIGHT-202 (NCT02924376). We report final outcomes from the extended follow-up period., Patients and Methods: The multicenter, open-label, single-arm, phase II FIGHT-202 study enrolled patients ≥18 years old with previously treated advanced/metastatic CCA with FGFR2 fusions or rearrangements (cohort A), other FGF/FGFR alterations (cohort B), or no FGF/FGFR alterations (cohort C). Patients received once-daily oral pemigatinib 13.5 mg in 21-day cycles (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) in cohort A assessed as per RECIST v1.1 by an independent review committee; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety., Results: FIGHT-202 enrolled 147 patients (cohort A, 108; cohort B, 20; cohort C, 17; unconfirmed FGF/FGFR alterations, 2). By final analysis, 145 (98.6%) had discontinued treatment due to progressive disease (71.4%), withdrawal by patient (8.2%), or adverse events (AEs; 6.8%). Median follow-up was 45.4 months. The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively. Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively. The most common treatment-emergent AEs (TEAEs) were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Overall, 15 (10.2%) patients experienced TEAEs leading to pemigatinib discontinuation; intestinal obstruction and acute kidney injury (n = 2 each) occurred most frequently., Conclusions: Pemigatinib demonstrated durable response and prolonged OS with manageable AEs in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in the extended follow-up period of FIGHT-202., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The selection of superior sires is paramount for enhancing the efficiency of animal production in the livestock industry. However, semen quality assessment still relies on conventional semen analysis techniques in both animals and humans. Despite extensive efforts to develop various biomarkers for more accurate and precise predictions of male fertility potential, more effective physiological indicators and advance potential biomarkers are needed. Herein, we aimed to develop new potential biomarkers related to sperm motion kinematics for male fertility prediction. We first evaluated sperm motion kinematic parameters and expression levels of sperm motility-related proteins of 30 Duroc boars. We then explored the correlation between litter size, sperm motion kinematics parameters, and sperm motility-related proteins. Progressive sperm motility (%), rapid sperm motility (%), slow sperm motility (%), straight-line velocity (μm/s), linearity (%), beat cross frequency (Hz), mean angular displacement (degree), wobble (%) were correlated with litter size. Furthermore, the expression of axonemal dynein light intermediate polypeptide 1 (DNALI1) and radial spoke head protein 9 homolog (RSPH9) correlated with litter size. The overall accuracy exceeded 60% for predicting litter size using these sperm motion parameters and proteins. Notably, our study observed an increase in litter size after predicting litter size using these parameters and proteins. Thus, sperm motion kinematic parameters and protein expression, particularly of DNALI1 and RSPH9, could serve as new biomarkers for male fertility. These results may contribute to improved understanding of the mechanisms underlying sperm motility., Competing Interests: Declaration of competing interest The authors have declared that no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Volume changes in reconstructed flaps, particularly regarding symmetry, are an important consideration to improve long-term esthetic results in patients who undergo breast reconstruction. Asian patients with thin abdominal tissues tend to require bipedicled flaps, which provide a greater volume of abdominal tissue. We investigated volume changes in free abdominal flaps and the factors that may affect flap volume, particularly the number of pedicles., Methods: The study included all consecutive patients who underwent immediate unilateral breast reconstruction using free abdominal flaps between January 2016 and December 2018. The initial flap volume was calculated intraoperatively, and the postoperative flap volume was calculated using computed tomography or magnetic resonance imaging based on the Cavalieri principle., Results: The study included 131 of 249 patients. Compared with the initial inset volume, the mean flap volumes at 1 and 2 years postoperatively decreased to 80.11% and 73.80%, respectively. The multivariable analysis of factors that affect flap volume showed a significant association with the flap inset ratio, radiation (P = .019,.040, respectively). Stratification based on the number of pedicles showed that the flap inset ratio was significantly negatively correlated with the postoperative flap volume change in unipedicled (P < .05) but not in bipedicled flaps., Conclusions: The flap volume decreased over time, and its change had a negative correlation with the flap inset ratio in the unipedicled group. Therefore, prediction of postoperative volume changes in various clinical situations is important before breast reconstruction., Competing Interests: Declaration of Competing Interest None of the authors has any financial interest in relation to the content of this article., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA., Patients and Methods: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR)., Results: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA., Conclusions: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches., Competing Interests: Disclosure DVTC has received personal fees from Archer, Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Five Prime Therapeutics, Foundation Medicine, Guardant Health, Tempus Labs, Genentech/Roche, Gritstone Oncology, Lilly, Merck, Novartis, AstraZeneca, Natera, Pieris Pharmaceuticals, QED Therapeutics, Seattle Genetics, Taiho Pharmaceutical, and Zymeworks. YKK has received consulting fees from ALX Oncology, Amgen, Blueprint Medicines, Bristol Myers Squibb, Daehwa Pharmaceutical, MacroGenics, Merck & Co., Inc., Novartis, Roche, Surface Oncology, and Zymeworks. HHY has received payments to the institution for grants from Bristol Myers Squibb and Merck & Co., Inc.; consulting fees from ALX Oncology, Astellas Pharma, AstraZeneca, BeiGene, Bristol Myers Squibb, MacroGenics, Merck & Co, Inc., Novartis, OncXerna Therapeutics, and Zymeworks; honoraria from BeiGene; and advisory board or data safety monitoring board payments from ALX Oncology, Astellas Pharma, AstraZeneca, BeiGene, Bristol Myers Squibb, MacroGenics, Merck & Co., Inc., Novartis, OncXerna Therapeutics, and Zymeworks. DYO has received grants from Array BioPharma, AstraZeneca, BeiGene, Lilly, HANDOK, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Novartis, and Servier Pharmaceuticals; and participated in advisory boards for ASLAN Pharmaceuticals, AstraZeneca, Basilea Pharmaceutica, Bayer, BeiGene, Celgene, a Bristol-Myers Squibb Company, Genentech/Roche, Halozyme, Merck Serono, Novartis, Taiho Pharmaceutical, Turning Point Therapeutics, and Zymeworks. AIS has received stock payments from Lilly; payments for leadership role from NEXT Oncology; honoraria from Amgen, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Janssen Oncology, Merck, Novartis, and Takeda; and personal and institutional payments for advisory boards from Amgen, Array BioPharma, AstraZeneca, Bristol Myers Squibb, Gritstone Oncology, Incyte, Janssen Research and Development, Merck & Co., Inc., Mirati Therapeutics, Novartis, and Takeda; consulting fees from Amgen, Array BioPharma, AstraZeneca, Bristol Myers Squibb, Gritstone Oncology, Janssen Research and Development, Jazz Pharmaceuticals, Incyte, Merck & Co., Inc., Mirati Therapeutics, Novartis, and Takeda; and grants and other support from AbbVie, ADC Therapeutics, Amgen, Arch Therapeutics, Astellas Pharma, Astex Pharmaceuticals, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Gritstone Oncology, Ignyta, Incyte, Janssen Oncology, LAM Therapeutics, Loxo Oncology, MacroGenics, MedImmune, Mirati Therapeutics, NewLink Genetics, Novartis, Plexxikon, Roche, Rubius Therapeutics, Takeda, and TrovaGene. SVU has participated in advisory boards for Array BioPharma, Bayer, Eisai, Exelixis, Incyte, and Syros Pharmaceuticals; and grants to institution from AbbVie, ArQule, AstraZeneca, Atreca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, a Bristol-Myers Squibb Company, CicloMed, Evelo Biosciences, Exelixis, G1 Therapeutics, GlaxoSmithKline, IGM Biosciences, Incyte, Isofol Medical, KLUS Pharma, MacroGenics, Merck & Co., Inc., Mersana Therapeutics, OncoMed Pharmaceuticals, Pfizer, Regeneron Pharmaceuticals, Revolution Medicines, Synermore Biologics, Takeda, Tarveda Therapeutics, Tesaro, Tempest Therapeutics, and Vigeo Therapeutics. EJA has received research funding from Bristol Myers Squibb, AstraZeneca, Seagen, AbbVie, and Lilly; consulting fees from AstraZeneca, Janssen Biotech, and McKesson. PMB has received consulting fees from Bristol Myers Squibb and Merck; grants/research support to institution from Ipsen, Processa Pharmaceuticals, AbbVie, MacroGenics, Merck, Taiho Pharmaceutical, and Athenex. JC has received consulting fees from Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Foundation Medicine, Lilly, MacroGenics, Merck & Co., Inc., Novartis, Ono Pharmaceutical, Silverback Therapeutics, and Turning Point Therapeutics; speaker’s bureau honorarium from Bristol Myers Squibb and Merck and Co., Inc.; data safety monitoring board member fees from Yiviva; and research payments to the institution from Brooklyn ImmunoTherapeutics, MacroGenics, and Merck & Co., Inc. HCC received grants/research support from Lilly, GlaxoSmithKline, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Merck Serono, Bristol Myers Squibb/Ono Pharmaceutical, Taiho Pharmaceutical, Amgen, BeiGene, Incyte, and Zymeworks; received honoraria from Lilly and Merck Serono; and did consultation for Amgen, BeiGene, Bristol Myers Squibb, Celltrion, Gloria Therapeutics, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Merck Serono, Taiho Pharmaceutical, and Zymeworks. FG has received consulting fees for participating on advisory boards from Janssen, Epizyme, and Regeneron/Sanofi; speaker’s bureau honorarium from Epizyme, Regeneron/Sanofi, and Pfizer. SJK has received consulting fees for participating on advisory boards from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Merck & Co., Inc., Natera, and Pieris Pharmaceuticals; and stock options from Turning Point Therapeutics. KWL has received consulting fees from Bayer, Bristol Myers Squibb, Daiichi Sankyo, and ISU ABXIS; honorarium from Boryung Pharmaceutical and Ono Pharmaceutical; and research grants to the institution from ABL Bio, ALX Oncology, Astellas Pharma, AstraZeneca, BeiGene, Bolt Biotherapeutics, Daiichi Sankyo, Five Prime Therapeutics, Genexine, Green Cross Corp, InventisBio, Leap Therapeutics, LSK BioPharma, MacroGenics, MedPacto, Merck KGaA, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Oncologie, Pharmacyclics, Ono Pharmaceutical, Pfizer, Seagen, Taiho Pharmaceutical, Trishula Therapeutics, Y-Biologics, and Zymeworks for conducting clinical trials. JP has received honoraria from Agendia, Guardant Health, and Tempus; consulting fees from TerSera Therapeutics; research funding for clinical trials from AbbVie, BerGenBio, Calithera Biosciences, Inc, eFFECTOR Therapeutics, EMD Serono, Epizyme, Genentech/Roche, Immunity Bio, Immutep S.A.S., Incyte, Janssen Pharmaceuticals, Jounce Therapeutics, Lilly, KeChow Pharma, Loxo Oncology, MacroGenics, Inc., Merck, Mirati, Natera, Novocure Ltd, Sermonix Pharmaceuticals, TerSera Therapeutics, Turning Point Therapeutics, Salarius Pharmaceuticals, Immunomedics, Pfizer, and Kyowa Kirin; and owns stocks of Oncology Consultants, Zogen, Spectrum Pharmaceuticals, Roche, TerSera Therapeutics. LS has received consulting fees from Boehringer Ingelheim, Haichuang Pharmaceutical, Harbour BioMed, Merck & Co., Inc., Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and Mingji Biopharmaceutical; speaker’s bureau fees from CStone Pharmaceuticals, Jiangsu Hengrui Pharmaceuticals, Hutchison Whampoa, and Zai Lab; participated on advisory boards for Bristol Myers Squibb, CStone Pharmaceuticals, Rongchang Pharmaceuticals, and Zai Lab; and grants to the institution from Beihai Kangcheng (Beijing) Medical Technology, Beijing Xiantong Biomedical Technology, Jacobio Pharmaceuticals, Qilu Pharmaceutical, and Zai Lab. MM has received grants and nonfinancial support from the AIO, BMBF, EORTC, and German Cancer Aid; personal fees from Amgen, Bristol Myers Squibb, Falk Foundation, Lilly, MGI Group, Merck Serono, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Pfizer, Roche, and Taiho Pharmaceutical; grants to the institution from Amgen, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and Pfizer; and nonfinancial support from Amgen and Bristol Myers Squibb paid to the institution. JS, DL, and MKR are/were employees of MacroGenics and hold stock in the company. HP has received grants to institution from Adlai Nortye USA, Alpine Immune Sciences, Ambrx, Amgen, Aprea Therapeutics AB, Array BioPharma, Bayer, BeiGene, BJ Bioscience Inc., Bristol Myers Squibb, Daiichi Sankyo, Lilly, Elicio Therapeutics, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Hoffman-La Roche, Hutchison MediPharma, ImmuneOncia Therapeutics, Incyte, Jounce Therapeutics, MabSpace Biosciences, MacroGenics, MedImmune, Medivation, Merck & Co., Inc., Millennium Pharmaceuticals, Mirati Therapeutics, Novartis, Oncologie, Pfizer, PsiOxus Therapeutics, Puma Biotechnology, Regeneron Pharmaceuticals, Repare Therapeutics, Seattle Genetics, Synermore Biologics, Taiho Pharmaceutical, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, and Xencor; writing support from MacroGenics; and participated in advisory boards for Jacobio Pharmaceuticals. BYS, STK, SCO, and MBS have declared no conflicts of interest. Data sharing The data collected for the study will not be made available to others., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with advanced biliary tract cancer who progress on first-line therapy have limited treatment options. The TreeTopp study assessed varlitinib, a reversible small molecule pan-human epidermal growth factor receptor inhibitor, plus capecitabine in previously treated advanced biliary tract cancer., Patients and Methods: This global, double-blind, randomized, placebo-controlled phase II study enrolled patients with confirmed unresectable or metastatic biliary tract cancer and disease progression after one prior line of gemcitabine-containing chemotherapy. Patients received oral varlitinib 300 mg or placebo twice daily (b.i.d.) for 21 days, plus oral capecitabine 1000 mg/m 2 b.i.d. on days 1-14, in 21-day treatment cycles. Co-primary endpoints were objective response rate and progression-free survival (PFS) according to RECIST v1.1 by Independent Central Review., Results: In total, 127 patients received varlitinib plus capecitabine (n = 64) or placebo plus capecitabine (n = 63). The objective response rate was 9.4% with varlitinib plus capecitabine versus 4.8% with capecitabine alone (odds ratio 2.28; P = 0.42). Median PFS was 2.83 versus 2.79 months [hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.60-1.37; P = 0.63] and overall survival was 7.8 versus 7.5 months (HR, 1.11; 95% CI, 0.69-1.79; P = 0.66), respectively. In a subgroup analysis, the addition of varlitinib appeared to provide a PFS benefit in female patients (median, 4.1 versus 2.8 months; HR, 0.59; 95% CI, 0.28-1.23) and those with gallbladder cancer (median, 2.9 versus 1.6 months; HR, 0.55; 95% CI, 0.26-1.19). Grade ≥3 treatment-emergent adverse events were reported in 65.6% of patients receiving varlitinib plus capecitabine versus 58.7% of those receiving capecitabine alone., Conclusions: In patients with advanced biliary tract cancer, second-line treatment with varlitinib plus capecitabine was well tolerated but did not improve efficacy versus capecitabine alone. A PFS benefit was suggested in female patients and those with gallbladder cancer., Competing Interests: Disclosures MMJ has served as a consultant/steering committee member for Taiho, QED, AstraZeneca, Meclun, TransThera, Bristol Myers Squibb (BMS), EMD Serono, Incyte, Nucana, and PCI, and has received research funding from EMD Serono, Merck, QED, Novartis, AstraZeneca, Basilea, Eli Lilly, ASLAN, Incyte, and Agios, and honoraria/speaker bureau fees from QED, Agios, and Incyte. D-YO has served as a consultant/advisory board member for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, and Turning Point, and has received research grants from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, Merck Sharp & Dohme (MSD), and Handok. MI has served as an advisory board member for Eisai, Eli Lilly Japan, ASLAN, GlaxoSmithKline, Nihon Servier, Chugai, BMS, Novartis, Bayer, and Takeda, has received honoraria from Eisai, MSD, Eli Lilly Japan, Yakult, Teijin Pharma, Astellas, EA Pharma, Sumitomo Dainippon, Otsuka, Yakult, Nihon Servier, Taiho, Chugai, BMS, Novartis, Bayer, and Takeda, and has received research funding from Eisai, Merck Serono, MSD, Eli Lilly Japan, Yakult, Ono, ASLAN, J-Pharma, AstraZeneca, EA Pharma, Pfizer, Merus N.V., Nihon Servier, Delta-Fly Pharma, Chiome Bioscience, Chugai, BMS, Novartis, Bayer, and Takeda. W-PY has served as an advisory board member for ASLAN. NM is a consultant for ASLAN. BL is a former employee (at the time of the study) and current shareholder of ASLAN. CF and KH are employees and shareholders of ASLAN., (Copyright © 2021. Published by Elsevier Ltd.)

Background: First-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated., Patients and Methods: RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m 2 ) and gemcitabine (1000 mg/m 2 ). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed., Results: In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade ≥3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events., Conclusions: Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents., Competing Interests: Disclosure MT: consultancy/advisory role with Advance Medical, AstraZeneca, Bristol-Myers Squibb (BMS), EcoR1 Capital, Elicio Therapeutics, FibroGen, Inc., GlaxoSmithKline, Immunovia, ISPEN, Karyopharm Therapeutics, Merck & Co., Inc., and Swedish Orphan Biovitrum; research funding from Celgene and Halozyme; other relationship(s) with Astellas Pharma Global Development, Inc. (DSMC). D-YO: consultancy/advisory role with ASLAN, AstraZeneca, Bayer, Genentech/Roche, Halozyme, Merck Serono, Novartis, Taiho, and Zymeworks; research funding from Array, AstraZeneca, and Eli Lilly. JT: consultancy/advisory role with Array Biopharma, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Chugai, F. Hoffmann-La Roche Ltd, Foundation Medicine, Genentech, Inc., Genmab A/S, HalioDX SAS, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, Merck Sharp & Dohme (MSD), Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics LLC, an AbbVie Company, ProteoDesign SL, Rafael Pharmaceuticals, Roche Diagnostics, Sanofi, Seagen, Seattle Genetics, Servier, Symphogen, Taiho, and VCN Biosciences. MR: honoraria from Baxalta, Celgene, and Shire; consultancy/advisory role with Baxalta, Celgene, Eli Lilly, Novartis, Novocure, Pfizer, and Shire; research funding to Institution from Celgene; travel expenses from Celgene, AstraZeneca; other relationship(s) with AstraZeneca, Boston Pharmaceuticals, and Celgene. EVC: consultancy/advisory role with AstraZeneca, Bayer, BMS, Celgene, Lilly, MSD, Merck DGaA, Novartis, Roche, and Servier; research funding from Amgen, Bayer, Boehringer Ingelheim, BMS, Celgene, Ipsen, Lilly, Merck, Merck KGaA, Novartis, Roche, and Servier. AH: consultancy/advisory role with AbbVie, Ipsen, Merck, and Novartis; research funding from Ipsen. D-TW: speakers' bureau for AstraZeneca, BMS, Celgene, Eisai, Falk, Ipsen, Novartis, Roche, Servier, Shire Baxalta, and Sirtex; travel expenses from Bayer Health Pharma, Celgene, Ipsen, Novartis, and Sirtex. NS: honoraria from Eli Lilly, Merck Serono, MSD Oncology, and Pierre Fabre; consultancy/advisory role with AstraZeneca, Pfizer, and Servier; research funding from AstraZeneca, BMS, and Pfizer; travel expenses from AstraZeneca, BMS, Eli Lilly, Merck, and Roche. J-BB: honoraria from Amgen, AstraZeneca, Bayer, Celgene, Merck Serono, Mundipharma, Pierre Fabre, Roche, Sanofi, and Servier; consultancy/advisory role with Amgen, AstraZeneca, Bayer, Merck Serono, Pierre Fabre, and Servier; travel expenses from Amgen, Bayer, Celgene, Merck Serono, Roche, Sanofi, and Servier. H-MC: research funding from Astellas, Halozyme, Pharmacyclics LLC, an AbbVie Company, Senhwa Biosciences, Taiho Oncology. JM: consultancy/advisory role with Advance Medical, AstraZeneca, Bayer, Pierre-Fabre, Roche, Sanofi, Servier, Shire, and Sirtex; research funding from Amgen, Biocartis, Incyte, Merck, Nanostring, and Servier; patents, royalties, or other intellectual property with GAIS-42-patent P5020EP00. RG: honoraria from AAA, Amgen, Bayer, BMS, Ipsen, Lilly, Merck, MSD, Novartis, PharmaMar, Pfizer, Roche, and Sanofi; research funding from ARMO Biosciences, AstraZeneca, Pfizer, Novartis, Ipsen, Roche, Pharmacyclics LLC, an AbbVie Company, Boston Biomedicals, Merck, MSD, Amgen, Sanofi, Bayer, BMS, Boehringer, Sysmex, Gilead Sciences, Servier, Adacap, VCN, Lilly, PharmaMar; travel expenses from Ipsen, Merck, Novartis, and Servier. SL: consultancy/advisory role with Amgen, Lilly, Merck Serono, and Servier; research funding from Amgen and Merck Serono; speakers' bureau for BMS, Lilly, Merck Serono, Roche, and Servier. LMC: employment with Oregon Health & Science University; honoraria from Aduro Biotech, AstraZeneca, Carisma Therapeutics, Inc., Cell Signaling Technologies, CytomX Therapeutics, Inc., Jackson Laboratories, Seattle Genetics, Syndax Pharmaceuticals, Inc., Verseau Therapeutics, Inc., and Zymeworks, Inc.; consultancy/advisory role with Carisma Therapeutics Inc., Cell Signaling Technologies, CytomX Therapeutics, Inc., Syndax Pharmaceuticals, Inc., Verseau Therapeutics, Inc., and Zymeworks, Inc.; research funding (for profit) Acerta Pharma, Deciphera Pharmaceuticals, Innate Pharma, Roche Glycart and Parker Institute for Immunotherapy, and Syndax Pharmaceuticals, Inc.; patents, royalties, or other intellectual property with Oregon Health & Science University; other relationship(s) with Reagent from Reagent support from: Acerta Pharma, LLC, Cell Signaling Technologies, Deciphera Pharmaceuticals, Genentech/Roche Glycart AG, NanoString Technologies, Inc., Plexxikon, Inc, and Syndax Pharmaceuticals. LF: research funding from AbbVie, Bavarian Nordic, BMS, Dendreon, Janssen, Merck, Roche/Genentech. GC: employment with Pharmacyclics LLC, an AbbVie Company; stock ownership in AbbVie. DJ: employment with Pharmacyclics LLC, an AbbVie Company; leadership role with Pharmacyclics LLC, an AbbVie Company; stock ownership in AbbVie; patents, royalties, or other intellectual property with Pharmacyclics LLC, an AbbVie Company. TM: consultancy/advisory role with Advance Medical HCMS, Baxter, BioLineRX Ltd, Celgene SLU, Eisai, Genzyme, Incyte, IPSEN Pharma Lab. Menarini, Lab. Servier, Lilly, QED Therapeutics, MSD, Prime Oncology EU, QED Therapeutics Inc., Sanofi-Aventis; research funding from Agios, ASLAN, AstraZeneca, Bayer, Celgene, Genentech, Hallozyme, Immunomedics, Lilly, Merimarck, Millenium, Novartis, Pfizer, Pharmacyclics LLC, an AbbVie Company, and Roche; travel expenses from Servier and Incyte. LCT has declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Biliary tract cancers, including intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder cancer, are low-incidence malignancies in most high-income countries, but represent a major health problem in endemic areas; moreover, the incidence of intrahepatic cholangiocarcinoma is rising globally. Surgery is the cornerstone of cure; the optimal approach depends on the anatomical site of the primary tumour and the best outcomes are achieved through management by specialist multidisciplinary teams. Unfortunately, most patients present with locally advanced or metastatic disease. Most studies in advanced disease have pooled the various subtypes of biliary tract cancer by necessity to achieve adequate sample sizes; however, differences in epidemiology, clinical presentation, natural history, surgical therapy, response to treatment, and prognosis have long been recognised. Additionally, the identification of distinct patient subgroups harbouring unique molecular alterations with corresponding targeted therapies (such as isocitrate dehydrogenase-1 mutations and fibroblast growth factor receptor-2 fusions in intrahepatic cholangiocarcinoma, among others) is changing the treatment paradigm. In this Seminar we present an update of the causes, diagnosis, molecular classification, and treatment of biliary tract cancer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: This study was conducted to identify patients who may benefit from adjuvant chemoradiotherapy (CRT) for positive or close resection margin (RM) after curative resection of pancreatic adenocarcinoma., Methods: From 2004 to 2015, total of 472 patients with pancreatic adenocarcinoma underwent curative resection. After excluding patients with RM > 2 mm or unknown, remaining 217 patients were retrospectively analyzed. Forty-six (21.2%) patients were treated with adjuvant chemotherapy alone (CTx; mainly gemcitabine-based), 142 (65.4%) with adjuvant CRT (mainly upfront), and 29 (13.4%) patients didn't receive any adjuvant therapy (noTx group)., Results: Locoregional recurrence rate was significantly lower in the CRT group (43.7%) than in the CTx group (71.7%) or noTx group (65.5%) (p = 0.001). Significant survival benefits of CRT over CTx (HR 0.602, p = 0.020 for overall survival (OS); HR 0.599, p = 0.016 for time to any recurrence (TTR)) were demonstrated in multivariate analysis. CRT group had more 5-year survivors than other groups. In the subgroup analysis, such benefits of adjuvant CRT over CTx was observed only in patients with head tumor & vascular RM > 0.5 mm, but not in patients with body/tail tumor or vascular RM ≤ 0.5 mm. In the CRT group, radiation dose≥54 Gy was significantly associated with better TTR and OS., Conclusions: Adjuvant CRT could improve TTR and OS compared to adjuvant CTx alone in patients with close RM under 2 mm. Radiation dose escalation may be beneficial when feasible. Modern CRT regimen-based randomized evidence is needed for these high-risk patients., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose: Timely diagnosis and identification of etiology of pediatric mild-to-moderate sensorineural hearing loss (SNHL) are both medically and socioeconomically important. However, the exact etiologic spectrum remains uncertain. We aimed to establish a genetic etiological spectrum, including copy-number variations (CNVs) and efficient genetic testing pipeline, of this defect., Methods: A cohort of prospectively recruited pediatric patients with mild-to-moderate nonsyndromic SNHL from 2014 through 2018 (n = 110) was established. Exome sequencing, multiplex ligation-dependent probe amplification (MLPA), and nested customized polymerase chain reaction (PCR) for exclusion of a pseudogene, STRCP, from a subset (n = 83) of the cohort, were performed. Semen analysis was also performed to determine infertility (n = 2)., Results: Genetic etiology was confirmed in nearly two-thirds (52/83 = 62.7%) of subjects, with STRC-related deafness (n = 29, 34.9%) being the most prevalent, followed by MPZL2-related deafness (n = 9, 10.8%). This strikingly high proportion of Mendelian genetic contribution was due particularly to the frequent detection of CNVs involving STRC in one-third (27/83) of our subjects. We also questioned the association of homozygous continuous gene deletion of STRC and CATSPER2 with deafness-infertility syndrome (MIM61102)., Conclusion: Approximately two-thirds of sporadic pediatric mild-to-moderate SNHL have a clear Mendelian genetic etiology, and one-third is associated with CNVs involving STRC. Based on this, we propose a new guideline for molecular diagnosis of these children.

Combination therapy is an alternative approach to reduce viral shedding and improve clinical outcomes following influenza virus infections. In this study we used oseltamivir (OST), a neuraminidase inhibitor and nitazoxanide (NTZ), a host directed drug, and found in vitro that the combination of these two antivirals have a synergistic relationship. Using the ferret model of (A/Perth/265/2009, (H1N1)pdm09), virus infections, we found that the combination of NTZ and OST was more effective than either NTZ or OST independently in preventing infection and reducing duration of viral shedding. However, these benefits were only seen if treatment was administered prophylactically, as opposed to therapeutically. We also found that if prophylactically treated ferrets that had detectable virus in the upper respiratory tract, no virus was detected in the lower respiratory tract. This benefit was not observed with NTZ or OST alone. The combination of NTZ and OST enhances the antiviral effect of OST, which is the standard of care in most settings., (Copyright © 2020. Published by Elsevier B.V.)

Background: Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here., Patients and Methods: Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test., Results: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [-2.47; 95% confidence interval (CI) -7.27, 2.33; P = 0.31]. Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI -8.75, -0.16; P = 0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [P = 0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P = 0.32; HR 1.38; 95% CI 0.73, 2.63)., Conclusions: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer., Clincaltrials.gov Number: NCT02184195., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: For the management of immune checkpoint inhibitor (ICI)-induced pneumonitis (ICI-pneumonitis), discontinuation of ICIs and high dose corticosteroid based on grade are generally recommended. The purpose of this study is to describe management and outcome of ICI-pneumonitis and explore what to consider when managing ICI-pneumonitis with or without corticosteroids in addition to grade., Methods: We reviewed data of 706 cancer patients who were treated with ICIs and identified radiographically proven pneumonitis. The diagnosis of ICI-pneumonitis was established after excluding alternative aetiologies either by a bronchoscopy or a thorough examination of clinical features. The evaluation of the management and outcome of pneumonitis were evaluated according to the time of corticosteroid administration., Results: ICI-pneumonitis developed in 16 patients (2.3%); nine grade 1, four grade 2 and three grade 3. Initially, 10 patients were spared from corticosteroid administration; fourpatients eventually received corticosteroid after 4 weeks of pneumonitis diagnosis due to clinical, radiographical aggravation and/or clinicians' decision. The other sixpatients never received corticosteroid and improved or remained stable radiographically. When the four and sixpatients were compared, pneumonitis grade was similar, while the latter sixpatients had a later onset from initiation of ICIs (mean 37.48 weeksvs25.45 weeks), more prior lines of chemotherapy (median 2.5 vs 1.0 lines), higher proportion of current/ex-smokers (83.3% vs 50.0%), and fewer other accompanying immune-related adverse events (50% vs 75%). Time to improvement of pneumonitis was similar between the fourpatients who received delayed corticosteroid and fivepatients who received corticosteroid within 4 weeks(3.6 vs 2.5 weeks)., Conclusions: Our analyses provide clinical insights that stratification of the patients is important in managing ICI-pneumonitis. Along with ICI-pneumonitis grade, more factors associated with the outcome need to be unravelled in the future., Competing Interests: Competing interests: None declared., (© Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background: Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors., Patients and Methods: This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival., Results: Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ≥1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n = 84), melanoma (n = 22), non-small-cell lung cancer (NSCLC; n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases., Conclusions: Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study., Clinicaltrials.gov Identifier: NCT01988896 (the investigators in the NCT01988896 study are listed in the supplementary Appendix, available at Annals of Oncology online)., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To evaluate the prognostic value of matrix metalloproteinase-9 (MMP-9) in patients with extrahepatic bile duct (EHBD) cancer undergoing surgical resection and adjuvant radiotherapy., Methods: Between January 2000 and August 2006, patients who underwent complete resection followed by adjuvant radiotherapy for EHBD cancer were enrolled in this study. The expression of MMP-9 was assessed with immunohistochemical staining. The prognostic values of the MMP-9 expression and other clinicopathologic factors were evaluated in univariate and multivariate analyses., Results: Sixty-six patients were included in this study. All received radiotherapy with a median dose of 40 Gy (range, 40-56), and 61 patients received concomitant fluoropyrimidine chemotherapy. MMP-9 was highly expressed in 33 patients (50.0%). MMP-9 expression was significantly associated with locoregional recurrence-free survival (LRRFS) and overall survival (OS) but not with distant metastasis-free survival (DMFS). The 5-year LRRFS and OS rates were 50.8% versus 86.5% (p = .0281), and 23.3% versus 68.1% (p = .0087) in patients with low and high expression of MMP-9, respectively. Among the clinicopathologic factors, tumor location was associated with DMFS and OS (p = .0292 and .0003, respectively). Nodal stage and histologic differentiation showed significant association with DMFS (p = .0277 and .0060, respectively). Based on multivariate analysis for OS, tumor location was the only significant prognostic factor (p = .0021), while MMP-9 expression showed marginal significance (p = .0633)., Conclusion: MMP-9 expression is a useful prognostic factor for predicting LRRFS and OS in patients with EHBD cancer after surgical resection and adjuvant radiotherapy., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens., Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, standard therapy [including two or more previous chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG] performance status of 0-1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2:1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343., Findings: Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8·87 months (IQR 6·57-12·37) in the nivolumab group and 8·59 months (5·65-11·37) in the placebo group. Median overall survival was 5·26 months (95% CI 4·60-6·37) in the nivolumab group and 4·14 months (3·42-4·86) in the placebo group (hazard ratio 0·63, 95% CI 0·51-0·78; p<0·0001). 12-month overall survival rates were 26·2% (95% CI 20·7-32·0) with nivolumab and 10·9% (6·2-17·0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed., Interpretation: In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines., Funding: Ono Pharmaceutical and Bristol-Myers Squibb., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Nitazoxanide is a thiazolide compound that was originally developed as an anti-parasitic agent, but has recently been repurposed for the treatment of influenza virus infections. Thought to exert its anti-influenza activity via the inhibition of hemagglutinin maturation and intracellular trafficking in infected cells, the effectiveness of nitazoxanide in treating patients with non-complicated influenza is currently being assessed in phase III clinical trials. Here, we describe the susceptibility of 210 seasonal influenza viruses to tizoxanide, the active circulating metabolite of nitazoxanide. An optimised cell culture-based focus reduction assay was used to determine the susceptibility of A(H1N1)pdm09, A(H3N2), and influenza B viruses circulating in the southern hemisphere from the period March 2014 to August 2016. Tizoxanide showed potent in vitro antiviral activity against all influenza viruses tested, including neuraminidase inhibitor-resistant viruses, allowing the establishment of a baseline level of susceptibility for each subtype. Median EC 50 values (±IQR) of 0.48 μM (0.33-0.71), 0.62 μM (0.56-0.75), 0.66 μM (0.62-0.69), and 0.60 μM (0.51-0.67) were obtained for A(H1N1)pdm09, A(H3N2), B(Victoria lineage), and B(Yamagata lineage) influenza viruses respectively. There was no significant difference in the median baseline tizoxanide susceptibility for each influenza subtype tested. This is the first report on the susceptibility of circulating viruses to tizoxanide. The focus reduction assay format described is sensitive, robust, and less laborious than traditional cell based antiviral assays, making it highly suitable for the surveillance of tizoxanide susceptibility in circulating seasonal influenza viruses., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Attempts have been made to revise the nodal stage due to simplicity of current N staging system in ampullary adenocarcinoma. However, because of the disease rarity, there have only been a few studies assessing the prognostic impact of lymph node (LN) parameters., Methods: We retrospectively analyzed 120 patients who underwent radical resection followed by adjuvant chemoradiotherapy for ampullary adenocarcinoma. The effect of LN parameters (number of total harvest LNs, number of metastatic LN (MLN), lymph node ratio (LNR), and log odds of positive LNs (LODDS)) on overall survival (OS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival were evaluated. Cutoff points of MLN, LNR and LODDs were determined using maximal χ 2 method., Results: Fifty-seven patients (48%) were staged as pN1 and their survival was not significantly decreased compared with pN0 patients. There was also no significant difference between patients with MLN 0 vs. 1. In univariate analyses, MLN (0-1 vs. ≥2), LNR (≤17% vs. >17%) and perineural invasion were common prognosticators for OS and LRFS. Distant metastasis-free survival was not influenced by LN status. In addition, multivariate analysis revealed that among the LN parameters, LNR was able to independently predict both OS and LRFS., Conclusions: LNR performs better than other LN related parameters for predicting survival. After radical resection followed by adjuvant treatment, survival of patients with one positive LN does not seem to differ from patients without LN metastasis., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Introduction: Response to mesenchymal-epithelial transition (MET) inhibitors in NSCLC with mesenchymal-epithelial transition gene (MET) exon 14 skipping (METex14) has fueled molecular screening efforts and the search for optimal therapies. However, further work is needed to refine the clinicopathologic and prognostic implications of METex14 skipping., Methods: Among 795 East Asian patients who underwent a surgical procedure for NSCLC, we screened 45 patients with quintuple-negative (EGFR-negative/KRAS-negative/anaplastic lymphoma kinase gene [ALK]-negative/ROS1-negative/ret proto-oncogene [RET]-negative) lung adenocarcinomas by using reverse-transcriptase polymerase chain reaction and found 17 patients (37.8%) with METex14 skipping. We also investigated the effect of small interfering RNA (siRNA) targeting skipping junction in cells with METex14 skipping., Results: The median age of the 17 patients was 73 years. The acinar subtype was predominant (52.9%), followed by the solid subtype (35.3%). MET immunohistochemistry demonstrated 100% sensitivity and 70.4% specificity. Multivariate analyses showed that patients with METex14 skipping had a higher recurrence rate than those with ALK fusion (versus METex14 skipping) (hazard ratio = 0.283, 95% confidence interval: 0.119-0.670) in stage I to IIIA disease; however, the differences in overall survival were not significant after adjustment for pathologic stage (p = 0.669). Meanwhile, siRNA decreased MET-driven signaling pathways in Hs746T cells, and combined treatment with siRNA and crizotinib inhibited cell proliferation in crizotinib-resistant H596 cells., Conclusions: The prevalence of METex14 skipping was quite high in East Asian patients without other driver mutations in lung adenocarcinomas. METex14 skipping was associated with old age, the acinar or solid histologic subtype, and high MET immunohistochemical expression. The prognosis of patients with METex14 skipping was similar to that of patients with major driver mutations. siRNA targeting the junction of METex14 skipping could inhibit MET-driven signaling pathways in cells with METex14 skipping., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to investigate post-recurrence overall survival (PROS) in patients with recurrent extrahepatic cholangiocarcinoma (EHC) and to indicate which groups of patients need active salvage treatments., Methods: We retrospectively reviewed the records of 251 consecutive patients who underwent curative surgery followed by adjuvant chemoradiotherapy for EHC. Among these, 144 patients experienced a recurrence and were included for further analysis., Results: The median PROS was 7 months (range, 1-130). In multivariate analysis, poorly differentiated histology, short disease-free survival, poor performance status, and elevated CA 19-9 were identified as significant prognosticators for poor PROS. Based on this, we stratified study patients into three categories by the number of risk factors: group 1 (0 or 1 factors), group 2 (2 factors) and group 3 (3-4 factors). Median PROS for groups 1, 2, and 3 were 13, 7, and 5 months, respectively (p < 0.001). Group 1 patients showed a significant benefit from salvage treatment, but groups 2 and 3 did not demonstrate clear benefit. In addition, we developed a nomogram to specifically identify individual patient's prognosis., Conclusion: Our simple risk stratification as well as proposed nomogram can classify patients into subgroups with different prognosis and will help facilitate personalized strategies after recurrence., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas., Patients and Methods: Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1-6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10-18 mg/kg) (Regimen B)., Results: Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as pyrexia, nausea, anemia, diarrhea, and fatigue. Among 60 response-evaluable patients, confirmed partial responses and stable disease were observed in 7 (12%) and 30 (50%) patients, respectively; 26 (70%) of these patients had received prior HER2-targeted therapy. Tumor reductions were observed in over half (18/23, 78%) of response-evaluable patients with breast cancer including durable (>30 weeks) responders. Ex vivo analyses of patient peripheral blood mononuclear cell samples confirmed the ability of margetuximab to support enhanced ADCC compared with trastuzumab., Conclusions: Margetuximab was well-tolerated and has promising single-agent activity. Further development efforts of margetuximab as single agent and in combination with other therapeutic agents are ongoing., Trial Registration Id: NCT01148849., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Reduced tissue damage is a theoretical advantage of using an ultrasonic harmonic scalpel. We hypothesized that the harmonic scalpel would outperform electrocautery in deep inferior epigastric perforator flap surgery, possibly resulting in a shorter operative time and reduced postoperative drainage and pain. Between January and August 2015, 24 consecutive patients were assigned to immediate deep inferior epigastric perforator flap elevation (12 for bipolar electrocautery and 12 for harmonic scalpel). The main outcome variables were total operative time, flap elevation time (starting from the fascia incision), and drainage volume. We compared the number of perforators isolated and the Moon and Taylor classification of the pedicle. Data were tested for normality using the Kolmogorov-Smirnov test before analysis. Continuous variables were compared by Wilcoxon rank-sum test. Data were analyzed using the statistical software SAS, version 9.3 (SAS Institute, Cary, NC, USA). Both groups were comparable with respect to clinical characteristics (mean age, body mass index, and flap weights). There was a statistically significant difference in the operative time between dissection with the harmonic scalpel and electrocautery (305.2 vs. 380.3 min, respectively, p = 0.002). The flap elevation time was reduced, particularly when using the harmonic scalpel where its usage seems crucial for dissecting deep inferior epigastric perforators (59.8 vs. 145.9 min, respectively, p < 0.0001). No statistical difference was observed in the drainage volume and length of hospital stay between the groups. We conclude that the harmonic scalpel may be more reliable and efficient as an alternative to electrocautery., (Copyright © 2016 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: A wide range of response rates have been reported in HER2-positive gastric cancer (GC) patients treated with trastuzumab. Other HER2-targeted therapies for GC have yet to show efficacy in clinical trials. These findings raise question about the ability of standard HER2 diagnostics to accurately distinguish between GC patients who would and would not benefit from anti-HER2 therapies., Patients and Methods: GC patients (n = 237), including a subset from the Trastuzumab in GC (ToGA) trial were divided into three groups based on HER2 status and history of treatment with standard chemotherapy or chemotherapy plus trastuzumab. We applied mass spectrometry-based proteomic analysis to quantify HER2 protein expression in formalin-fixed tumor samples. Using HER2 expression as a continuous variable, we defined a predictive protein level cutoff to identify which patients would benefit from trastuzumab. We compared quantitated protein level with clinical outcome and HER2 status as determined by conventional HER2 diagnostics., Results: Quantitative proteomics detected a 115-fold range of HER2 protein expression among patients diagnosed as HER2 positive by standard methods. A protein level of 1825 amol/µg was predicted to determine benefit from the addition of trastuzumab to chemotherapy. Trastuzumab treated patients with HER2 protein levels above this cutoff had twice the median overall survival (OS) of their counterparts below the cutoff (35.0 versus 17.5 months, P = 0.011). Conversely, trastuzumab-treated patients with HER2 levels below the cutoff had outcomes similar to HER2-positive patients treated with chemotherapy. (Progression-free survival = 7.0 versus 6.5 months: P = 0.504; OS = 17.5 versus 12.6 months: P = 0.520). HER2 levels were not prognostic for response to chemotherapy., Conclusions: Proteomic analysis of HER2 expression demonstrated a quantitative cutoff that improves selection of GC patients for trastuzumab as compared with current diagnostic methods., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population., Methods: In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783., Findings: Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0)., Interpretation: Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract., Funding: Novartis Pharmaceuticals Corporation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or both (THP), or monoclonal antibodies alone (HP)., Patients and Methods: Immune gene mRNA expression (n = 350, 83.8%), lymphocyte infiltration (TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry (n = 305, 73.1%) were correlated with pCRB. We studied five selected genes (IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells (IGG), T cells (CD8A), antigen-presenting cells (MHC2), and to MHC1 genes (MHC1), STAT1 co-expressed genes (STAT1), and interferon-inducible genes (IF-I). Gene expression data from the NOAH trial were used for validation., Results: TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only., Conclusions: The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In this study, we aimed to identify demographic and clinical variables that correlate with perceived information provision among cancer patients and determine the association of information provision with decisional conflict (DC)., Patients and Methods: We enrolled a total of 625 patients with cancer from two Korean hospitals in 2012. We used the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ-INFO26) to assess patients' perception of the information received from their doctors and the Decisional Conflict Scale (DCS) to assess DC. To identify predictive sociodemographic and clinical variables for adequate information provision, backward selective logistic regression analyses were conducted. In addition, adjusted multivariate logistic regression analyses were carried out to identify clinically meaningful differences of perceived level of information subscales associated with high DC., Results: More than half of patients with cancer showed insufficient satisfaction with medical information about disease (56%), treatment (73%), other services (83%), and global score (80%). In multiple logistic regression analyses, lower income and education, female, unmarried status, type of cancer with good prognosis, and early stage of treatment process were associated with patients' perception of inadequate information provision. In addition, Information about the medical tests with high DCS values clarity [adjusted odds ratio (aOR), 0.54; 95% confidence interval (CI) 0.30-0.97] and support (aOR, 0.53; 95% CI 0.33-0.85) showed negative significance. For inadequate information perception about treatments and other services, all 5 DCS scales (uncertainty, informed, values clarity, support, and effective decision) were negatively related. Global score of inadequate information provision also showed negative association with high DCS effective decision (aOR, 0.43; 95% CI 0.26-0.71) and DCS uncertainty (aOR, 0.46; 95% CI 0.27-0.77)., Conclusion: This study found that inadequate levels of perceived information correlated with several demographic and clinical characteristics. In addition, sufficient perceived information levels may be related to low levels of DC., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Laninamivir is a long-acting antiviral requiring only a single dose for the treatment of influenza infection, making it an attractive alternative to existing neuraminidase inhibitors that require multiple doses over many days. Like zanamivir, laninamivir is administered to patients by inhalation of dry powder. To date, studies investigating the effectiveness of laninamivir or zanamivir in a ferret model of influenza infection have administered the drug in a solubilised form. To better mimic the delivery action of laninamivir in humans, we assessed the applicability of a Dry Powder Insufflator™ (DPI) as a delivery method for laninamivir octanoate (LO) in ferrets to determine the effectiveness of this drug in reducing influenza A and B virus infections. In vitro characterisation of the DPI showed that both the small particle sized LO (0.7-6.0μm diameter) and the large particle sized lactose carrier (20-100μm diameter) were effectively discharged. However, LO delivered to ferrets via the DPI prior to infection with either A(H1N1)pdm09 or B viruses had a limited effect on nasal inflammation, clinical symptoms and viral shedding compared to placebo. Our preliminary findings indicate the feasibility of administering powder drugs into ferrets, but a better understanding of the pharmacokinetics and pharmacodynamics of LO in ferrets following delivery by the DPI is warranted prior to further studies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Context: High body mass index (BMI) is linked to an increased risk of developing pancreatic cancer (PC). However, in patients with advanced PC (APC), especially those receiving palliative chemotherapy, the impact of BMI on survival has not been investigated fully., Objectives: To assess changes in BMI during the course of APC and their impact on patient survival, specifically for those receiving palliative chemotherapy., Methods: Consecutive patients with APC, all of whom were treated with palliative chemotherapy, were enrolled during 2003-2010. Clinical characteristics and prognoses were analyzed., Results: A total of 425 patients participated (median age, 60.1 years). At diagnosis of APC, patients' BMI distribution of patients was as follow: <18.5 (45, 10.6%); 18.5-19.9 (67, 15.8%); 20.0-22.4 (156, 36.7%); 22.5-24.9 (107, 25.2%); 25.0-29.9 (49, 11.5%); and ≥ 30.0 (1, 0.2%). Median overall survival (OS) was 8.1 months (95% confidence interval 7.2, 9.1). Precancer BMI and baseline BMI (at diagnosis) had no impact on OS. Weight loss at diagnosis (precancer weight minus weight at diagnosis) and weight loss during first-line chemotherapy (both stipulated as BMI change ≥ 1) were associated with shortened OS (hazard ratio, 1.300; P = 0.012 and hazard ratio, 1.367; P = 0.010, respectively)., Conclusion: In patients with APC undergoing palliative chemotherapy, decreases in BMI at APC diagnosis and during chemotherapy are more hazardous for OS than precancer BMI or baseline BMI (at diagnosis) as absolute values. Further studies are needed to validate this finding and investigate strategies to maintain BMI during chemotherapy in this setting., (Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Axillary osmidrosis is a distressing problem. Since the secretion from apocrine glands is believed to be responsible for malodour, many treatment modalities have been developed to remove the glands. Local surgery with the excision of the apocrine glands has been proved to be most effective. We introduce the treatment of axillary osmidrosis, using Versajet (Versajet hydrosurgery system, Smith & Nephew, Memphis, TN, USA). From October 2010 to February 2012, 31 patients (21 females and 10 males) whose age ranged from 12 to 63 years were treated. All patients were followed up for 13.1 months on average. Thirty patients were very satisfied and recommended this procedure and one patient was satisfied with the result. We experienced one haematoma and one wound dehiscence. Excision of glands, using Versajet, makes the operation a simple and efficient procedure. Moreover, precise and even debridement reduces complications by preserving the skin flap and subdermal plexus., (Copyright © 2013. Published by Elsevier Ltd.)

Background: We analyzed the significance of class III beta-tubulin (TUBB3) expression in curatively resected non-small cell lung cancer as a prognostic marker along with previously reported excision repair cross complementation group 1 (ERCC1)., Methods: One hundred and thirty-six consecutive patients were included in this retrospective study. Patients who received adjuvant chemotherapy were excluded. We used immunohistochemistry to evaluate TUBB3 and ERCC1 expression on tissue microarray in duplicate. Semiquantitative H score was used for the scoring of tumor staining., Results: Sixty percent of patients had stage I disease, 17% stage II, 18% stage IIIA, and 5% stage IIIB. TUBB3 H score showed bimodal distribution with the minimum at the value of 4, which was used as a cutoff value for determination of TUBB3 positivity. TUBB3 was expressed in 60 patients (44%). Patients with a positive TUBB3 expression survived shorter than did the patients with a negative expression (5-year overall survival [OS] rate was 40% versus 61%; p = 0.005/5-year disease-free survival rate was 34% versus 55%; p = 0.024). ERCC1 expression showed tendency for prolonged OS without reaching statistical significance. A multivariate analysis that incorporated covariates including TUBB3 expression, age, stage, EGFR mutation status, histology, and ERCC1 expression showed that TUBB3 was an independent unfavorable prognostic factor for OS (hazard ratio 2.083; p = 0.008) and relapse free survival (hazard ratio 1.978; p = 0.020)., Conclusions: TUBB3 expression is an independent unfavorable prognostic marker in patients with curatively resected non-small cell lung cancer who did not receive adjuvant chemotherapy.

Background: We evaluated the efficacy and toxicity of combination chemotherapy with capecitabine and cisplatin (XP) in patients with metastatic hepatocellular carcinoma (HCC)., Patients and Methods: From September 2003 to July 2007, we enrolled patients with HCC who had more than one measurable extrahepatic metastatic lesion. Patients received oral capecitabine (2000 mg/m(2)/day) with a schedule of 2 weeks on and 1 week off and cisplatin (60 mg/m(2)) on the first day of the 3-week cycle., Results: The study cohort consisted of 32 patients with a median age of 53 years. Overall response rate was 6.3% and disease control rate was 34.4%. The median time to progression (TTP) was 2.0 months [95% confidence interval (CI) 1.5-2.4] and the median overall survival (OS) time was 12.2 months (95% CI 6.5-17.8). The grade 3/4 hematologic toxic effects included thrombocytopenia (7.6%), neutropenia (4.3%) and anemia (2.1%). The grade 3/4 non-hematologic toxic effects included elevated hepatic aminotransferase (12.9%), jaundice (3.2%), mucositis (3.2%) and nausea (3.2%). There was no treatment-related mortality., Conclusions: Based on the observed response rate and TTP, XP combination chemotherapy showed modest antitumor efficacy in patients with metastatic HCC as systemic first-line treatment. However, XP combination chemotherapy showed tolerable toxicity and demonstrated favorable OS time.

Background: Although recent studies suggest high accuracy of breast magnetic resonance imaging (MRI) in predicting residual tumor extent after neo-adjuvant systemic treatment (NST), its use is still controversial. In this study, we aimed to identify predictive factors of MRI accuracy after NST to determine a subgroup of patients in whom the use of MRI provides best additional benefit., Materials and Methods: Clinicopathologic and molecular profiles of breast cancer patients were investigated and their relationships with MRI accuracy were analyzed., Results: From January 2006 to February 2008, 195 patients received NST and preoperative MRI. In overall, MRI predicted residual tumor extent with higher accuracy than ultrasonography. Triple-negative (TN) tumors showed highest correlation between MRI-measured and pathologic tumor size (r = 0.781) when compared with other subtypes. Multivariate analysis showed age and HER2 expression status as independent factors predicting MRI accuracy. When patients were classified based on their age and HER2 status, relatively older patients (>45) with HER2-negative tumors showed highest MRI accuracy. This finding was further validated using an independent cohort of 63 consecutive patients., Conclusion: Age and HER2 status independently affected MRI accuracy after NST. This observation may guide more tailored approach in using MRI in breast cancer patients undergoing NST.

A-kinase anchoring protein 12 (AKAP12) gene is frequently inactivated in human gastric cancer and in several other cancers due to promoter hypermethylation. However, the biological function of AKAP12 in tumorigenesis remains to be identified. Aneuploidy, a hallmark of cancer cells, is often caused by abnormal cell division. In the present study, AKAP12 was found to localize to the cell periphery during interphase and to the actomyosin contractile ring during cytokinesis. Furthermore, AKAP12 depletion using small interfering RNA increased the number of multinucleated cells, and disrupted the completion of cytokinesis. Interestingly, the inhibition of myosin light chain kinase (MLCK), a key regulator of actomyosin contractility, removed AKAP12 from the cell periphery during interphase and from the contractile ring during cytokinesis, suggesting that AKAP12 might be a downstream effector of MLCK. Our findings implicate AKAP12 in the regulation of cytokinesis progression, and suggest a novel role for AKAP12 tumor suppressor.

Recent studies have shown that liposuction aspirates from rat, rabbit, mouse, and human sources contain pluripotent adipose tissue-derived stromal cells (ASCs) that can differentiate into various mesodermal cell types, including osteoblasts, myoblasts, chondroblasts, and preadipocytes. To develop a research model for autologous bone tissue engineering, we isolated ASCs from human liposuction aspirates (hASCs) and induced their osteogenic differentiation in three-dimensional poly(dl-lactic-co-glycolic acid) (PLGA) scaffolds. Human liposuction aspirates were proteolytically digested and centrifuged to obtain hASCs. After primary culture in control media and expansion to three passages, the cells were seeded in two-dimensional plates or three-dimensional PLGA scaffolds and cultured in osteogenic media for 4 weeks. In two-dimensional culture, osteogenesis was assessed by RT-PCR analysis of the osteogenic-specific bone sialoprotein mRNA, by alkaline phosphatase staining, and by von Kossa staining. In three-dimensional culture, osteogenesis was assessed by von Kossa and alizarine red S staining at 1, 2, and 4 weeks following osteogenic induction. hASCs incubated in two-dimensional osteogenic media stained positively for alkaline phosphatase and with von Kossa stain after 2 weeks of differentiation. Expression of the osteogenesis-specific bone sialoprotein gene was detected by RT-PCR after 2 weeks of differentiation. PLGA scaffolds seeded with hASCs showed multiple calcified extracellular matrix nodules by von Kossa and alizarine red S staining after 2 weeks of differentiation. In conclusion, the authors identified an osteogenic potential of hASCs and demonstrated osteogenic differentiation of hASCs into an osteogenic lineage in three-dimensional PLGA scaffolds.

Vascular endothelial growth factor receptors (VEGFRs) perform pivotal roles in both tumor growth and angiogenesis. In this study, we report that histone deacetylase inhibitors (HDIs) induce a reduction in VEGFR1 and VEGFR2 protein expression via the inhibition of class II histone deacetylases (HDACs) in human cancer cell lines. After HDI treatment, VEGFR1 and VEGFR2 were shown to be downregulated in a proteasome-dependent manner. HDI treatment induced a reduction in the binding of heat shock protein (Hsp) 90 to VEGFR1 or VEGFR2, followed by an increase of the binding of Hsp70 to VEGFR1 or VEGFR2. However, we noted no remarkable changes in the binding of Hsp90/Hsp70 to VEGFR3. HDI treatment effectively inhibited the activities of HDAC6 and HDAC10. Furthermore, the knock-down of HDAC6 or HDAC10, which was accomplished via the siRNA transfection, induced depletion of VEGFR1 or VEGFR2 proteins. Overall, these results indicate that HDAC6 and HDAC10 play important roles in Hsp-mediated VEGFR regulation.

Background: Optimal chemotherapy for advanced biliary tract cancer (BTC) is yet to be defined. We carried out this study to evaluate the efficacy and toxicity of combination chemotherapy with S-1 and cisplatin in metastatic or relapsed BTC., Patients and Methods: Patients with pathologically proven BTC were eligible. The chemotherapy regimen consisted of S-1 (40 mg/m(2) p.o. b.i.d. from D1-14) and cisplatin (60 mg/m(2) on D1), repeated every 3 weeks., Results: Fifty-one BTC patients (metastatic:relapsed = 37:14, Gall-bladder:intrahepatic bile ducts:extrahepatic bile ducts = 16:25:10) were enrolled from January 2005 to December 2006. Median age was 57 years (range, 31-71) and most patients had a good performance status. The overall response rate was 30% [95% confidence interval (CI), 17.3-42.7] and complete response was observed in two patients (4%), partial response in 13 (26%), stable disease in 21 (42%), and progressive disease in 9 (18%). With a median follow-up of 12.4 months, the median time to progression was 4.8 months (95% CI, 3.3-6.3) and median overall survival was 8.7 months (95% CI, 6.0-11.4). Major toxic effects were grade 3/4 neutropenia (8.9% of all cycles) and febrile neutropenia was observed in six cycles (2.7% of all cycles)., Conclusion: Combination chemotherapy with S-1 and cisplatin was a moderately effective outpatient-based regimen in BTC patients. Toxic effects were moderate but manageable.

A-kinase anchoring protein 12 (AKAP12) is known to function as a scaffold protein and as a putative tumor suppressor. However, little is known about the biological role of AKAP12 in hepatic cells. In this study, we performed micro-array analysis to identify the downstream pathway of AKAP12A, and found that AKAP12A overexpression up-regulates the expressions of several cholesterol-associated genes including HMG-CoA reductase and LDL receptor, which have been reported to be controlled by sterol regulatory element binding protein-2 (SREBP-2). It was found that AKAP12A activates SREBP-2 in hepatic cells, as demonstrated by the presence of its cleavage product, whereas the activation of sterol regulatory element binding protein-1 was not remarkably changed. Moreover, AKAP12A-induced SREBP-2 activation was found to depend on SREBP cleavage-activating protein (SCAP), as inhibition of SCAP by RNAi or sterols blocked SREBP-2 activation in response to AKAP12A overexpression. Interestingly, the hydrophobic amine U18666A caused dramatic movement of AKAP12A from the plasma membrane to cytosol and lysosomal membranes. Moreover, cholesterol depletion from the plasma membrane (using methyl-beta-cyclodextrin) caused a shift of AKAP12A from the plasma membrane to the cytoplasm. Cholesterol binding assay revealed that the N-terminal region of AKAP12A binds directly to cholesterol in vitro. Furthermore, AKAP12A overexpression enhanced [3H]-cholesterol efflux to extracellular acceptors, suggesting that AKAP12A may activate SREBP-2 by increasing cholesterol efflux. In conclusion, the present study suggests that AKAP12A is a novel regulator of cellular cholesterol metabolism.

DNA methyltransferase 3B has been demonstrated to mediate gene silencing. The mechanisms how DNA methyltransferase 3B is targeted to specific regions and represses gene transcription, however, are not well understood. Here we show that by using yeast two-hybrid screening, DNA methyltransferase 3B interacts with the human polycomb protein, hPc2. This interaction was verified via co-immunoprecipitation and GST pull-down assay. Sequential deletion analysis showed that the region of DNA methyltransferase 3B responsible for interaction is mapped to the N-terminal regulatory domain. By performing a cDNA microarray analysis in HCT 116 cells, we identified that the expression of fibroblast growth factor receptor 3 is significantly increased upon the small interference RNA-mediated knockdown of hPc2, suggesting fibroblast growth factor receptor 3 as a potential target of hPc2. We further found that DNA methyltransferase 3B enhances hPc2-mediated transcriptional repression of fibroblast growth factor receptor 3, which does not require its de novo methyltransferase activity. Taken together, these results suggest that DNA methyltransferase 3B functions as a co-repressor of polycomb protein in inducing transcriptional repression independent of DNA methylation.

Background/aims: HCV-infection leads to development of liver fibrosis, causing morbidity and mortality. Multiple factors influence the progression of fibrosis, including genetic factors. Since HCV is an RNA virus, a role for TLR7 in the immune response against HCV is likely. No systematic analysis of TLR7 single nucleotide polymorphisms (SNPs) has been published., Methods: We sequenced TLR7 in 52 women and investigated SNPs with an allele frequency >5% in 807 patients with chronic HCV-infection by melting curve analysis. We analyzed the effect of TLR7 SNPs on grade of inflammation and stage of fibrosis as determined by liver biopsy., Results: We detected five TLR7 SNPs, three of which showed a frequency >5%. One variant, c.1-120T>G, was more common in patients with no or little inflammation than in patients with grades 2-4 (10.7% vs. 6.1%; P=0.034). The variant was also enriched in patients with no or little fibrosis compared to those with higher stages (12.6% vs. 6.6%; P=0.005). The difference was fully attributable to male patients., Conclusions: This is the first analysis of TLR7 SNPs in patients with chronic HCV-infection. Our data suggest that the c.1-120G TLR7 allele offers protection from the development of inflammation and fibrosis in male patients with chronic HCV-infection.

DNA methyltransferases (DNMT) 3B is a de novo DNMT that represses transcription independent of DNMT activity. In order to gain a better insight into DNMT3B-mediated transcriptional repression, we performed a yeast two-hybrid analysis using DNMT3B as a bait. Of the various binding candidates, ZHX1, a member of zinc-finger and homeobox protein, was found to interact with DNMT3B in vivo and in vitro. N-terminal PWWP domain of DNMT3B was required for its interaction with homeobox motifs of ZHX1. ZHX1 contains nuclear localization signal at C-terminal homeobox motif, and both ZHX1 and DNMT3B were co-localized in nucleus. Furthermore, we found that ZHX1 enhanced the transcriptional repression mediated by DNMT3B when DNMT3B is directly targeted to DNA. These results showed for the first the direct linkage between DNMT and zinc-fingers homeoboxes protein, leading to enhanced gene silencing by DNMT3B.

Employing neural stem cells from the brain cortex of E12 rat embryos, we investigated the possible role of phospholipase D (PLD) in the synaptogenesis and neurite formation of neural cells during differentiation. Expression level of PLD1 increased during neuronal differentiation of the neural stem cells, resulting in increased PLD activity. Expression level of synapsin I, a marker of synaptogenesis, also increased as the differentiation of neural stem cells progressed. To figure out the effect of PLD on synapsin I expression, we treated the neural stem cells with phorbol myristate acetate (PMA) to stimulate PLD activity. Increased PLD activity induced by PMA treatment resulted in elevated synapsin I expression and neurite outgrowth during neuronal differentiation. To further confirm the role of PLD in neurite outgrowth, we transfected the dominant-negative form of rat PLD1 cDNA (DN-rPLD1) into neural stem cells to downregulate PLD activity. Overexpression of DN-rPLD1 showed the complete inhibition of neurite outgrowth of neural stem cells under differentiation condition. While transfection of DN-rPLD1 did not affect the synapsin I expression, overexpression of rPLD1 resulted in increased synapsin I expression of the neural cells. These results suggest that PLD1 plays a critical role in neurite outgrowth during differentiation of the neural stem cells. In conclusion, this is the first evidence to show that PLD1 acts as an important regulator of neurite outgrowth in neural stem cell by promoting neuronal differentiation via increase of synapsin I expression.

A bovine dopamine transporter (bDAT) cDNA was transfected into CV-1 cells, a cell line that lacks vesicular storage and release mechanisms. Using this cell line, the effects of neuroleptic drugs on DAT-mediated uptake and release of dopamine (DA) were examined. All of the neuroleptic drugs tested, inhibited DA uptakes in DAT expressing cells, and most of them were shown to promote spontaneous release of DA at the same time. These results imply that neuroleptic drugs would cause an overflow of DA in the synaptic cleft of extrapyramidal dopaminergic neurons, which could be one of the possible mechanisms of drug-induced tardive dyskinesia.