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Background: Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved to treat locally advanced/metastatic urothelial carcinoma (mUC) in patients with susceptible FGFR3/2 alterations (FGFRalt) who progressed after platinum-containing chemotherapy. FGFR-altered tumours are enriched in luminal 1 subtype and may have limited clinical benefit from anti-programmed death-(ligand) 1 [PD-(L)1] treatment. This cohort in the randomized, open-label phase III THOR study assessed erdafitinib versus pembrolizumab in anti-PD-(L)1-naive patients with mUC., Patients and Methods: Patients ≥18 years with unresectable advanced/mUC, with select FGFRalt, disease progression on one prior treatment, and who were anti-PD-(L)1-naive were randomized 1 : 1 to receive erdafitinib 8 mg once daily with pharmacodynamically guided uptitration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety., Results: The intent-to-treat population (median follow-up 33 months) comprised 175 and 176 patients in the erdafitinib and pembrolizumab arms, respectively. There was no statistically significant difference in OS between erdafitinib and pembrolizumab [median 10.9 versus 11.1 months, respectively; hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.92-1.51; P = 0.18]. Median PFS for erdafitinib and pembrolizumab was 4.4 and 2.7 months, respectively (HR 0.88; 95% CI 0.70-1.10). ORR was 40.0% and 21.6% (relative risk 1.85; 95% CI 1.32-2.59) and median duration of response was 4.3 and 14.4 months for erdafitinib and pembrolizumab, respectively. 64.7% and 50.9% of patients in the erdafitinib and pembrolizumab arms had ≥1 grade 3-4 adverse events (AEs); 5 (2.9%) and 12 (6.9%) patients, respectively, had AEs that led to death., Conclusions: Erdafitinib and pembrolizumab had similar median OS in this anti-PD-(L)1-naive, FGFR-altered mUC population. Outcomes with pembrolizumab were better than assumed and aligned with previous reports in non- FGFR-altered populations. Safety results were consistent with the known profiles for erdafitinib and pembrolizumab in this patient population., Competing Interests: Disclosure AOS has received honoraria from Astellas, AstraZeneca, Bavarina Nordic, Basilea, Bicycle Therapeutics, Bristol Myers Squibb, G1 Therapeutics, Genentech, Gilead, Ideeya Biosciences, Immunomedics, Janssen, Loxo, Merck, Mirati, Nektar, Seattle Genetics, and Taiho and research funding (institutional) from Basilea Pharmaceutica, Bristol Myers Squibb, Janssen, Loxo, Merck, Millennium, and Nektar. NM has received honoraria (personal) from Sanofi; research funding (institutional) from Amgen, Astellas Pharma, AstraZeneca, Bayer, Chugai Pharm, Eisai, Janssen, Lilly, Merck Sharp & Dohme, Pfizer, PRA Health Science, Roche, Seagen, Taiho, and Takeda; and has been reimbursed for travel, accommodations, or expenses (personal) from Pfizer. SHP has received honoraria from Merck, Ono Pharma Korea, and Pfizer; served as a consultant for Janssen Oncology; and received institutional research support from Merck Sharp & Dohme. RAH has received personal fees from Aspen Parkside Hospital, Merck, and Pfizer; consulting fees from Bristol Myers Squibb, Roche, Merck Sharp & Dohme, Janssen Oncology, Nektar, and Bayer; honoraria from Janssen Oncology; has been reimbursed for travel, accommodations, or expenses from Janssen Oncology, Roche/Genentech, MSD Oncology, and Nektar; has other financial or non-financial interests with Merck Sharp & Dohme, Roche, Bristol Myers Squibb, and Janssen; and has a leadership or fiduciary role at Cancer Clinic London Liability Partnership, outside of the submitted work. EFB has received honoraria from Exelixis, Janssen, Merck, Novartis, and Pfizer; research funding (personal) from Astellas and Pfizer; and research funding (institutional) from Astellas, Bristol Myers Squibb, Janssen, Merck, Pfizer, Roche/Genentech, and Seagen. NH has received consulting fees from Astellas, AstraZeneca, Bristol Myers Squibb, Gilead, Janssen, Merck, and Pfizer. MO has served as a consultant for Sanofi, Astellas, and Bayer; has participated in a speaker’s bureau for Regeneron; and has been reimbursed for travel, accommodation, and expenses by Sanofi and Regeneron. BPV has served as a consultant for Astellas Pharma, Astra Zeneca, Bayer, Bristol Myers Squibb, and Novartis; has received honoraria from Astellas, Bristol Myers Squibb, Eusa Pharma, Ipsen, Merck Sharp & Dohme, Pierre Fabre, Pfizer, and Roche; and has been reimbursed for travel, accommodations, or expenses by Bristol Myers Squibb, Janssen-Cilag, Merck, Novartis, and Pfizer. BL has received honoraria from Janssen and has been reimbursed for travel, accommodations, or expenses by Astellas, Jassen, and Pfizer. UB has participated in a speaker’s bureau for and/or received travel and accommodation grants from Astellas, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, and Merck Sharp & Dohme and has received research funding (institutional) from Ipsen. YK serves as a functional service provider for Janssen. ST, SA, KD, and SM are employed by Janssen Research & Development and have stock or stock options with Johnson & Johnson. YL has received consulting fees from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Immunomedics, Janssen (and institutional), MSD Oncology (and institutional), Loxo/Lilly, Pfizer/EMD Serono, Roche, and Taiho Pharmaceutical; has been reimbursed for travel, accommodations, or expenses from Astellas, AstraZeneca, Janssen Oncology, MSD Oncology, and Roche; and has received research funding (institutional) from Astellas Pharma, AstraZeneca, Basilea, Bristol Myers Squibb, Exelixis, Gilead Sciences, Incyte, Janssen Oncology, Merck KGaA, MSD Oncology, Nektar, Pfizer, Roche, Sanofi, and Taiho Pharmaceutical., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction: This exploratory analysis evaluated efficacy and safety data for enfortumab vedotin versus chemotherapy over a median follow-up of ∼2 years from EV-301., Materials and Methods: Patients with locally advanced/metastatic urothelial carcinoma with prior platinum-containing chemotherapy and disease progression during/after programmed cell death protein 1/ligand 1 inhibitor treatment were randomized to enfortumab vedotin or chemotherapy (docetaxel, paclitaxel, vinflunine). Endpoints were overall survival (primary), progression-free survival (PFS), objective response, and safety., Results: In total, 608 patients were included (enfortumab vedotin, n = 301; chemotherapy, n = 307). With a median follow-up of 23.75 months, 444 deaths had occurred (enfortumab vedotin, n = 207; chemotherapy, n = 237). Risk of death was reduced by 30% with enfortumab vedotin versus chemotherapy [hazard ratio (HR) 0.70 (95% confidence interval [CI] 0.58-0.85); one-sided, log-rank P = 0.00015]; PFS improved with enfortumab vedotin [HR 0.63 (95% CI 0.53-0.76); one-sided, log-rank P < 0.00001]. Treatment-related adverse event rates were 93.9% for enfortumab vedotin and 91.8% for chemotherapy; grade ≥ 3 event rates were 52.4% and 50.5%, respectively. Grade ≥ 3 treatment-related decreased neutrophil count (14.1% versus 6.1%), decreased white blood cell count (7.2% versus 1.4%), and anemia (7.9% versus 2.7%) were more common with chemotherapy versus enfortumab vedotin; maculopapular rash (7.4% versus 0%), fatigue (6.8% versus 4.5%), and peripheral sensory neuropathy (5.1% versus 2.1%) were more common with enfortumab vedotin. Of special interest adverse events, treatment-related skin reactions occurred in 47.3% of patients receiving enfortumab vedotin and 15.8% of patients receiving chemotherapy; peripheral neuropathy occurred in 48.0% versus 31.6%, respectively, and hyperglycemia in 6.8% versus 0.3%., Conclusions: After a median follow-up of ∼2 years, enfortumab vedotin maintained clinically meaningful overall survival benefit versus chemotherapy, consistent with findings from the EV-301 primary analysis; PFS and overall response benefit remained consistent. Adverse events were manageable; no new safety signals were observed., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing., Findings: Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9-30·2) for the talazoparib group and 24·6 months (14·4-30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months-not reached) for talazoparib plus enzalutamide and 21·9 months (16·6-25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51-0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3-4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group., Interpretation: Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations., Funding: Pfizer., Competing Interests: Declaration of interests NA has received an honorarium for consultancy since May, 2020, from the following: Astellas Pharma, AstraZeneca, AVEO, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead Sciences, Immunomedics, Janssen, Lilly, and MEI Pharma, and research funding (institution) from Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Clovis Oncology, CRISPR Therapeutics, Eisai, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Immunomedics, Janssen, Lava, Lilly, Merck, Nektar, Neoleukin, Novartis, ORIC Pharmaceuticals, Pfizer, Rexahn, Roche, Sanofi, Seagen, Takeda, and TRACON. AAA reports honoraria from Aculeus Therapeutics, Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix Pharmaceuticals, and Tolmar; consulting fees from Aculeus Therapeutics, Astellas Pharma, Janssen, and Novartis; participation on advisory boards for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; participation on a data safety monitoring board for OncoSec; research funding (institution unless stated otherwise) from Aptevo Therapeutics, Astellas Pharma (investigator), AstraZeneca (investigator), Bionomics, Bristol Myers Squibb, Exelixis, Gilead Sciences, GlaxoSmithKline, Hinova Pharmaceuticals, Ipsen, Janssen, Lilly, MedImmune, Merck Serono (investigator), MSD, Novartis, Pfizer, Sanofi, and Synthorx; and travel, accommodations, and/or expenses from Amgen, Astellas Pharma, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar; and receiving medical writing services from Astellas Pharma, Exelixis, and Pfizer; he is Chair of the Urologic Oncology Group for the Clinical Oncology Society of Australia, and Chair of the Translational Research Subcommittee and on the Scientific Advisory Committee for the ANZUP Cancer Trials Group. JC reports a consulting or advisory role for Advanced Accelerator Applications/Novartis, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Johnson & Johnson, MSD Oncology, Pfizer, Roche, and Sanofi; participation in speakers' bureau for Astellas Pharma, Bayer, and Johnson & Johnson; research funding (institution) from AB Science, Aragon Pharmaceuticals, AROG Pharmaceuticals, Astellas Pharma, AstraZeneca, AVEO Pharmaceuticals, Bayer, Blueprint Medicines, BN ImmunoTherapeutics, Boehringer Ingelheim España, Bristol Myers Squibb International Corporation, Clovis Oncology, Cougar Biotechnology, Deciphera, Exelixis, Genentech, GlaxoSmithKline, Incyte, Janssen-Cilag International, Karyopharm Therapeutics, Laboratoires Leurquin Mediolanum, Lilly, MedImmune, Millennium Pharmaceuticals, Nanobiotix, Novartis Farmacéutica, Pfizer, Puma Biotechnology, Roche, Sanofi Aventis, SFJ Pharmaceuticals Group, and Teva; and travel, accommodations, and/or expenses from AstraZeneca, BMS, Ipsen, and Roche. APF reports honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; a consulting or advisory role for Bayer, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; stock or stock options in Brazilian Information Oncology; and research funding from AstraZeneca, Bristol Myers Squibb, CAPES – CNPq, Foundation Medicine, Ipsen, MSD, and Roche; and travel, accommodations and/or expenses from Astellas Pharma, AstraZeneca, BMS, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche. NM reports honoraria (personal) from Sanofi; research funding (institution) from Amgen, Astellas Pharma, AstraZeneca, Bayer, Chugai Pharma, Eisai, Janssen, Lilly, MSD, Pfizer, PRA Health Science, Roche, Seagen, Taiho, and Takeda; and travel, accommodations, and/or expenses (personal) from Pfizer. DH reports honoraria (personal) from Advanced Accelerator Applications/Novartis, Astellas Pharma, Bayer, Bristol Myers Squibb, EUSA Pharma, Ferring, Ipsen, Janssen, MSD, and Novartis; participation on a data safety monitoring board or advisory board for Astellas Pharma, AstraZeneca, Bayer, Eisai, Ipsen, Janssen, Novartis, Organon, Pfizer, and Roche; and research funding (institution) from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, MSD, Pfizer, and Roche. UDG reports a consulting or advisory role for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Dompé Farmaceutici, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, and PharmaMar; research funding (institution) from AstraZeneca, Roche, and Sanofi; and travel, accommodations, and/or expenses from Ipsen and Pfizer. PCCF reports a consulting or advisory role for MSD and travel, accommodations, and/or expenses from Pfizer. RJJ reports honoraria from Astellas Pharma, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, MSD, Pfizer, and Roche; a consulting or advisory role for Astellas Pharma, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, MSD, Novartis, Pfizer, and Roche; research funding from Astellas Pharma, Bayer, Clovis Oncology, Exelixis, and Roche; and travel, accommodations, and/or expenses from Bayer and Janssen. NDS reports a consulting or advisory role for AbbVie, Alessa Therapeutics, Akido, Amgen, Arquer, Asieris, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, CG Oncology, Clarity Pharmaceuticals, Clovis Oncology, Dendreon, Exact Imaging, Exact Sciences, FerGene, FIZE Medical, Foundation Medicine, GenesisCare, Genentech, Guardant Ferring, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, Mdxhealth, Merck, Minomic, Myovant Sciences, Myriad Genetics, Nymox, Pacific Edge Biotechnology, Pfizer, Photocure, PlatformQ, Profound, Promaxo, Propella Therapeutics, Protara, Sanofi, Sesen Bio, Speciality Networks, Telix Pharmaceuticals, Tolmar, UroGen Pharma, Vaxiion, and Vessi; providing expert testimony for Ferring; and leadership or other fiduciary role in other board, society, committee, or advocacy group with Photocure. CD reports participation on advisory boards for Astellas Pharma, Bayer, Janssen, and Pfizer; and research funding from AstraZeneca, Bayer, Dendreon, Hengrui Pharmaceuticals, Janssen, Laekna Therapeutics, Myovant Sciences, and Pfizer. SZ reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen (personal and institution), Bayer, (personal and institution), Bristol Myers Squibb (institution), Eisai (personal), Janssen (personal), MSD (institution), Novartis (personal), and Pfizer (institution); participation on a data safety monitoring board or advisory board for Amgen (personal and institution), Bayer (personal and institution), Bristol Myers Squibb (institution), Eisai (personal), Janssen (personal), MSD (institution), Novartis (personal), and Pfizer (institution); research funding (institution) from Eisai; and travel, accommodations, and/or expenses from Amgen, Astellas Pharma, AstraZeneca, Ipsen, Janssen, Merck, MSD, and Pfizer. JO reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas Pharma, AstraZeneca, Bayer, BMS Norway, Eisai, Ipsen, Janssen-Cilag, Merck, and Roche; participation on a data safety monitoring board or advisory board for Astellas Pharma, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen-Cilag, Merck, and Roche; and travel, accommodations, and/or expenses from Astellas Pharma. XL, CGH, NDiS, and FZ are employees of Pfizer and may hold Pfizer stock/stock options. KF reports honoraria (institution) for participation in advisory boards and talks from Advanced Accelerator Applications/Novartis, Amgen, Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Daiichi Sankyo, Janssen, MSD, Novartis, Pfizer, and Sanofi; and honoraria (personal) for participation in advisory boards from Arvinas, CureVac, MacroGenics, and Orion. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Adding ipatasertib to abiraterone and prednisone/prednisolone significantly improved radiographic progression-free survival for patients with metastatic castration-resistant prostate cancer (mCRPC) with PTEN-loss tumours by immunohistochemistry in the IPATential150 trial (NCT03072238). Here we characterise the safety of these agents in subpopulations and assess manageability of key adverse events (AEs)., Materials and Methods: In this randomised, double-blind, phase 3 trial, patients with previously untreated asymptomatic or mildly symptomatic mCRPC were randomised 1:1 to receive ipatasertib-abiraterone or placebo-abiraterone (all with prednisone/prednisolone). AEs were analysed, focusing on key AEs of diarrhoea, hyperglycaemia, rash and transaminase increased., Results: 1097 patients received study medication and were assessed for safety (47% with PTEN-loss tumours by immunohistochemistry and 20% were Asian). Ipatasertib was associated with increased Grade 3/4 AEs and AEs leading to treatment discontinuation vs placebo. The rate of discontinuation of ipatasertib was 18% in patients with PTEN-loss and 21% overall. The frequencies of all-grade, Grade 3/4 and serious AEs were similar between the PTEN-loss and overall populations. Diarrhoea, hyperglycaemia, rash and transaminase elevation were more frequent in ipatasertib-treated patients, appearing rapidly after treatment initiation (median onset: 8-43 days for ipatasertib arm and 56-104 days for placebo). The ipatasertib discontinuation rate was 32% and 18% in Asian and non-Asian patients, respectively, despite similar baseline characteristics and Grade 3/4 AE frequencies between groups., Conclusions: Ipatasertib plus abiraterone had an overall tolerable safety profile consistent with known toxicities. More AEs leading to drug discontinuation were observed with ipatasertib than placebo, but incidence would likely be lessened with prophylactic measures., (Copyright © 2023. Published by Elsevier Inc.)

Background: The previous second-line treatment for HER2-positive metastatic breast cancer were ado-trastuzumab emtansine (T-DM1); however, its activity is decreased in tumors with heterogenous, reduced, or loss of HER2 expression. Trastuzumab deruxtecan (T-DXd) has recently been developed as a novel antibody-drug conjugate to overcome resistance to T-DM1. However, clinical evidence on its ability to overcome this resistance is limited., Materials and Methods: We retrospectively analyzed data for patients with HER2-positive metastatic breast cancer who received T-DXd at our institution from April 2020 to March 2021. We evaluated the associations between clinicopathological and molecular biomarkers and the efficacy of T-DXd., Results: Twenty-two patients were enrolled in this study. The median progression-free survival (PFS) was 9.7 months (95% confidence interval [CI], 7.0-not reached [NR]), and the objective response rate (ORR) was 61.9%. The ORR and PFS were comparable between patients with HER2 immunohistochemistry scores of 3+ and 2+/1+ at initial diagnosis (ORR: 50.0% vs. 72.7%, p = 0.39; median PFS, 9.7 months [95%CI, 2.6-NR] vs. 8.3 months [95%CI, 7.1-NR]; hazard ratio, 1.86 [95%CI, 0.53-6.57], p = 0.34). Two patients with heterogenous HER2 expression had a partial response or long stable disease (≥6 months). Three of four patients with re-biopsy samples after anti-HER2 targeted therapy and with latest HER2 immunohistochemistry scores of 1+ experienced partial responses (75.0%) to T-DXd, but none had responded to prior T-DM1., Conclusions: T-DXd demonstrated favorable activity in clinical practice. Moreover, T-DXd showed meaningful benefit in patients with heterogeneity, reduction, or loss of HER2 expression., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: TAS-115 is an oral multikinase inhibitor targeting the MET proto-oncogene, vascular endothelial growth factor receptor, and colony-stimulating factor 1 receptor. We evaluated the efficacy and safety of TAS-115 in castration-resistant prostate cancer (CRPC) patients with bone metastases., Patients and Methods: This phase II study, conducted in Japan, comprised 2 cohorts of CRPC patients. Cohort A included patients with bone metastasis and no history of docetaxel; TAS-115 200 to 400 mg/d was administered with abiraterone and prednisone. Cohort B included patients with symptomatic multiple bone metastases, post- or unfit for docetaxel, randomized 1:1 to receive TAS-115 400 or 600 mg/d orally, once daily, in a repeated weekly schedule of 5 days on/2 days off. The primary endpoint was bone scan index (BSI) response rate at Week 12 in each dose group., Results: Cohorts A and B included 24 and 26 patients, respectively. The 12-week BSI response rates for 200, 300, and 400 mg were 0%, 33.3%, and 16.7% in Cohort A, and for 400 and 600 mg were 7.1% and 25.0% in Cohort B. The best BSI response rates for 200, 300, and 400 mg were 0%, 66.7%, and 16.7% in Cohort A, and for 400 and 600 mg were 7.1% and 33.3% in Cohort B. A ≥ 30% reduction in BPI-SF score was shown in 57.7% of patients in Cohort B. The most frequent Grade ≥ 3 adverse drug reactions were hypophosphatemia (20.8%) in Cohort A and anemia (23.1%) in Cohort B., Conclusion: TAS-115 appears to demonstrate anti-tumor activity and acceptable tolerability in CRPC patients with bone metastases., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Visceral crisis in metastatic breast cancer (MBC) is defined as severe organ dysfunction requiring rapidly efficacious therapy. Although weekly paclitaxel plus bevacizumab (wPTX + BV) achieves a high response rate in human epidermal growth factor receptor 2 (HER2)-negative MBC, the efficacy and safety of wPTX + BV for visceral crisis is unclear., Methods: We retrospectively investigated patients with MBC with visceral crisis who received wPTX + BV. Visceral crisis was defined as follows: liver dysfunction (aspartate or alanine aminotransferase >200 U/L or total bilirubin >1.5 mg/dl), respiratory dysfunction (carcinomatous lymphangiomatosis, SpO 2 <93% in ambient air or required thoracentesis), superior vena cava (SVC) syndrome, or bone marrow carcinomatosis. The primary outcome was the proportion of patients on-treatment with wPTX + BV after 12 weeks. We also investigated time to treatment failure (TTF), overall survival (OS), objective response rate (ORR), and adverse events., Results: A total of 44 patients with respiratory dysfunction (n = 29), liver dysfunction (n = 10), bone marrow carcinomatosis (n = 7), and SVC syndrome (n = 2) were eligible for this investigation. The proportion of patients on-treatment with wPTX + BV after 12 weeks was 63% (30/44), and the other patients discontinued wPTX + BV because of adverse events (n = 5) and disease progression (n = 9). Median TTF and OS, and the ORR were 131 days and 323 days, and 41%, respectively. No treatment-related death occurred., Conclusion: wPTX + BV achieved favorable efficacy and safety for treating patients with visceral crisis and may therefore be considered an option for the treatment of this acutely severe clinical condition., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The PI3K/AKT and androgen-receptor pathways are dysregulated in metastatic castration-resistant prostate cancers (mCRPCs); tumours with functional PTEN-loss status have hyperactivated AKT signalling. Dual pathway inhibition with AKT inhibitor ipatasertib plus abiraterone might have greater benefit than abiraterone alone. We aimed to compare ipatasertib plus abiraterone with placebo plus abiraterone in patients with previously untreated mCRPC with or without tumour PTEN loss., Methods: We did a randomised, double-blind, phase 3 trial at 200 sites across 26 countries or regions. Patients aged 18 years or older with previously untreated asymptomatic or mildly symptomatic mCRPC who had progressive disease and Eastern Collaborative Oncology Group performance status of 0 or 1 were randomly assigned (1:1; permuted block method) to receive ipatasertib (400 mg once daily orally) plus abiraterone (1000 mg once daily orally) and prednisolone (5 mg twice a day orally) or placebo plus abiraterone and prednisolone (with the same dosing schedule). Patients received study treatment until disease progression, intolerable toxicity, withdrawal from the study, or study completion. Stratification factors were previous taxane-based therapy for hormone-sensitive prostate cancer, type of progression, presence of visceral metastasis, and tumour PTEN-loss status by immunohistochemistry. Patients, investigators, and the study sponsor were masked to the treatment allocation. The coprimary endpoints were investigator-assessed radiographical progression-free survival in the PTEN-loss-by-immunohistochemistry population and in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03072238., Findings: Between June 30, 2017, and Jan 17, 2019, 1611 patients were screened for eligibility and 1101 (68%) were enrolled; 554 (50%) were assigned to the placebo-abiraterone group and 547 (50%) to the ipatasertib-abiraterone group. At data cutoff (March 16, 2020), median follow-up duration was 19 months (range 0-33). In the 521 (47%) patients who had tumours with PTEN loss by immunohistochemistry (261 in the placebo-abiraterone group and 260 in the ipatasertib-abiraterone group), median radiographical progression-free survival was 16·5 months (95% CI 13·9-17·0) in the placebo-abiraterone group and 18·5 months (16·3-22·1) in the ipatasertib-abiraterone group (hazard ratio [HR] 0·77 [95% CI 0·61-0·98]; p=0·034; significant at α=0·04). In the intention-to-treat population, median progression-free survival was 16·6 months (95% CI 15·6-19·1) in the placebo-abiraterone group and 19·2 months (16·5-22·3) in the ipatasertib-abiraterone group (HR 0·84 [95% CI 0·71-0·99]; p=0·043; not significant at α=0·01). Grade 3 or higher adverse events occurred in 213 (39%) of 546 patients in the placebo-abiraterone group and in 386 (70%) of 551 patients in the ipatasertib-abiraterone group; adverse events leading to discontinuation of placebo or ipatasertib occurred in 28 (5%) in the placebo-abiraterone group and 116 (21%) in the ipatasertib-abiraterone group. Deaths due to adverse events deemed related to treatment occurred in two patients (<1%; acute myocardial infarction [n=1] and lower respiratory tract infection [n=1]) in the placebo-abiraterone group and in two patients (<1%; hyperglycaemia [n=1] and chemical pneumonitis [n=1]) in the ipastasertb-abiraterone group., Interpretation: Ipatasertib plus abiraterone significantly improved radiographical progression-free survival compared with placebo plus abiraterone among patients with mCRPC with PTEN-loss tumours, but there was no significant difference between the groups in the intention-to-treat population. Adverse events were consistent with the known safety profiles of each agent. These data suggest that combined AKT and androgen-receptor signalling pathway inhibition with ipatasertib and abiraterone is a potential treatment for men with PTEN-loss mCRPC, a population with a poor prognosis., Funding: F Hoffmann-La Roche and Genentech., Competing Interests: Declaration of interests All authors report editorial assistance from F Hoffmann-La Roche. CS reports grants or personal fees, or both from Janssen, F Hoffmann-La Roche and Genentech, Sanofi, Astellas, Pfizer, Bayer, and Lilly, during the conduct of the study; and has a patent abiraterone plus cabozantinib issued to Exelixis, a patent parthenolide as treatment for cancer licensed to Indiana University, and a patent dimethylaminoparthenolide as treatment for cancer licensed to Leuchemix, outside of the submitted work. SB reports serving as advisory board member for Astellas, Janssen, Pfizer, BMS, F Hoffmann-La Roche, Ipsen, MSD, Merck, AAA, and AstraZeneca, outside of the submitted work. CNS reports grants and non-financial support from F Hoffmann-La Roche during the conduct of the study; and personal fees from Pfizer, MSD, Merck, AstraZeneca, Astellas, Sanofi and Genzyme, F Hoffmann-La Roche and Genentech, Incyte, and Clovis, outside of the submitted work. KNC reports grants from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees, or both from Astellas, AstraZeneca, Constellation Pharma, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Point Biopharma, F Hoffmann-La Roche, and Sanofi, outside of the submitted work. DO reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants, personal fees, or non-financial support from Astellas Pharma, Bayer, Janssen, AstraZeneca, Clovis Oncology, Astellas Medivation, F Hoffmann-La Roche and Genentech, Pfizer, Tokai Pharmaceuticals, Ipsen, MSD, and Daiichi Sankyo, outside of the submitted work. SS reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees, or both from Amgen, MSD, Merck Serono, F Hoffmann-La Roche and Genentech, AstraZeneca, and Novartis, outside of the submitted work. CM reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and personal fees from Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, BMS, Celgene, Debiopharm Group, F Hoffmann-La Roche and Genentech, Innate Pharma, Ipsen, Janssen, Lilly, MSD, Novartis, Orion, Pfizer, PharmaMar, Sanofi, and Taiho, outside of the submitted work. NM reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees, or both from Janssen, MSD, Chugai, Astellas, Eli Lilly, Taiho, Pfizer, and Sanofi, outside of the submitted work. BA reports grants from F Hoffmann-La Roche, during the conduct of the study; and grants, personal fees, or non-financial support from Astellas, AstraZeneca, Bayer, BMS, Eisai, Ferring, Ipsen, Janssen, MSD, Pfizer, F Hoffmann-La Roche, and Sanofi, outside of the submitted work. RG reports grants from F Hoffmann-La Roche, during the conduct of the study; and grants, personal fees, or non-financial support from Astellas, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen, MSD, Pfizer, F Hoffmann-La Roche, Sanofi, and Pierre Fabre, outside of the submitted work. LC reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study. GVA reports grants from MSD, BMS, Merck-Serono, F Hoffmann-La Roche, Pfizer, AstraZeneca, Beigene, Ipsen, and Janssen, outside of the submitted work. EB reports personal fees from Sanofi Aventis, Astellas Pharmaceuticals, Roche Hellas, Bayer, Janssen Pharmaceuticals, GlaxoSmithKline, Pierre Fabre, and Merck, outside of the submitted work. JP reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees from Astellas Pharma, AstraZeneca, Bayer, BMS, Eisai, EUSA Pharma, Ipsen, Janssen-Cilag, MSD Oncology, Pierre Fabre, F Hoffmann-La Roche, Sanofi, Clovis Oncology, and MSD, and grants, personal fees, and non-financial support from Pfizer, outside of the submitted work. M-LH-Y, JGal, and JGar are employees of F Hoffmann-La Roche. GC, JH, and MJW are employees of Genentech. JSdB reports personal fees and grants from F Hoffmann-La Roche and Genentech, during the conduct of the study; grants, personal fees, or travel expenses from AstraZeneca, GlaxoSmithKline, Pfizer, Taiho, Daiichi, Bayer, Orion Pharma, F Hoffmann-La Roche and Genentech, Merck Serono, Sierra Oncology, MSD, Astellas, Cellcentric, Sanofi Aventis, and Vertex Pharmaceuticals, and personal fees or travel expenses from Terumo, Menarini and Silicon Biosystems, Bioexcel Therapeutics, Eisai, and Qiagen, outside of the submitted work; and has a patent for DNA damage repair inhibitors for treatment of cancer (patent number WO 2005 053662 licensed to AstraZeneca) and a patent for 17-substituted steroids useful in cancer treatment (patent number US 5604213 licensed to Janssen). All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

An association between the development of overall or specific immune-related adverse events (irAEs) and outcomes of immune checkpoint inhibitors has recently been suggested. To address this emerging association in patients with urothelial cancer receiving pembrolizumab, we conducted a multicenter retrospective analysis, which is the first and largest in an Asian cohort as well as a systematic literature review. We retrospectively evaluated 97 patients with advanced urothelial cancer treated with pembrolizumab as second- or later-line treatment between January 2018 and March 2019. irAEs were categorized by the involved organs and graded using Common Terminology Criteria for Adverse Events version 5.0. Associations between irAEs and pembrolizumab efficacy, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. In our review of the literature, 28 studies, including 9 studies involving patients with urothelial cancer and 19 studies reporting the association between outcomes and spectrum of irAEs, were analyzed. Patients with irAEs had significantly higher ORR (52% vs. 16%, P < .01), longer PFS (11.0 months vs. 3.6 months, P < .01) and OS (median not reached vs. 13.1 months, P = .12) than in patients without irAEs. Endocrine (P = .02), pneumological (P = .06), and other (gastrointestinal, hematological, hepatic) (P = .04) irAEs were associated with increased ORR, whereas skin irAEs were not. Endocrine irAEs (P = .04) was associated with improved OS, whereas pneumological and skin irAEs were not. The association between the occurrence of irAEs and clinical efficacy of immune checkpoint inhibitors was consistently supported by the multiple studies we reviewed. The association between clinical outcomes and the spectrum of organs/systems affected by irAEs seems to be inconsistent and could be dependent on tumor type. irAEs were associated with a higher ORR and better survival of patients with advanced urothelial cancer treated with pembrolizumab., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Data on the safety and efficacy of cabazitaxel in patients aged ≥80 years with castration-resistant prostate cancer (CRPC) are limited. We report the safety (adverse drug reactions [ADRs]) and efficacy (overall survival [OS], time to treatment failure [TTF], and prostate-specific antigen [PSA] response rates) in patients aged <80 or ≥80 years treated with cabazitaxel for CRPC in clinical practice., Materials and Methods: We performed post-hoc subgroup analyses of a Japanese post-marketing surveillance study involving 662 patients with CRPC treated with cabazitaxel between September 2014 and June 2016., Results: In patients aged <80 (n = 610) and ≥80 years (n = 49), median PSA at baseline was 168.7 and 109.0 ng/mL, and 86.7% and 83.7% of patients were previously treated with enzalutamide and/or abiraterone. ADRs (all grade) occurred in 77.2% and 79.6% of patients aged <80 and ≥80 years, with grade three/worse ADRs in 61.8% and 63.3% of patients. Hematologic toxicities were the most common grade three/worse ADRs, including neutropenia, febrile neutropenia, and anemia in both subgroups. No specific ADRs were observed in patients aged ≥80 years. The PSA response and median OS and TTF were 28.3%, 292 days, and 116 days in patients aged ≥80 years, and 29.7%, 319 days, and 125 days in patients aged <80 years., Conclusion: Cabazitaxel could be a treatment option for CRPC in patients aged ≥80 years based on its safety and efficacy profiles. This is the first report to investigate the safety and efficacy of cabazitaxel in patients aged ≥80 years with CRPC., Competing Interests: Declaration of Competing Interest Nobuaki Matsubara has received personal fees from Janssen, MSD, AstraZeneca, and Sanofi, and research grants from Janssen, MSD, Roche, Lilly, Taiho, BMS, and AstraZeneca. Hideyasu Matsuyama has served on an advisory board for Sanofi. Kazuhiro Suzuki has received personal fees from Sanofi, Takeda, Astellas, AstraZeneca, Janssen, Daiichi-Sankyo, Chugai, Kyowa-Kirin, and Bayer, and research grants from Takeda, Astellas, AstraZeneca, Daiichi-Sankyo, Chugai, Kyowa-Kirin, and Bayer. Hirotaka Kazama, Shoko Tsukube, and Takeshi Seto are employees of Sanofi., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: There has been no established clinical evidence for using sequential treatment in castration-resistant prostate cancer (CRPC). Despite evident cross-resistance, androgen receptor axis-targeted agents (ARTAs), namely abiraterone (ABI) and enzalutamide (ENZ), are often used sequentially owing to less toxicity compared with chemotherapy., Patients and Methods: A multicenter retrospective review of chemotherapy-naive patients with CRPC who had received ABI followed by ENZ (ABI-to-ENZ) or ENZ followed by ABI (ENZ-to-ABI) was conducted. Combined progression-free survival (PFS), overall survival (OS), and prostate-specific antigen (PSA) response (≥ 50% PSA decline) to each drug were compared between the 2 groups at the median follow-up of 36.0 months., Results: There were no significant differences in combined PFS (12.4 vs. 10.9 months; hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.72-1.23; P = .6594) or OS (28.3 vs 29.3 months; HR, 0.96; 95% CI, 0.66-1.38; P = .8314) between the ABI-to-ENZ and ENZ-to-ABI groups. PSA response rate was not significantly different in first-line ARTAs (48.9% vs. 58.4%; P = .153) but significantly higher in ENZ as a second-line ARTA (40.4% vs. 13.7%; P < .0001). Although multivariate analysis revealed that the ABI-to-ENZ sequence was associated with favorable PFS on second-line ARTA (HR, 0.65; 95% CI, 0.49-0.85; P = .0019), it was not associated with an increased combined PFS or OS., Conclusion: With relatively longer follow-up, ARTA sequence did not affect clinical outcomes of CRPC treatment except for PSA response and PFS on a second-line ARTA. These findings will be useful information in clinical decision-making, particularly in chemotherapy-unfit patients with CRPC., (Copyright © 2019. Published by Elsevier Inc.)

Background: Previous studies have revealed that higher exposure of axitinib leads to better prognosis in metastatic renal-cell carcinoma. We thus assessed individualized dosing of axitinib on the basis of the first-dose area under the concentration-time curve from 0 to 12 hours (AUC 0-12 ) for sunitinib-pretreated metastatic renal-cell carcinoma patients., Patients and Methods: In this prospective single-arm trial, the starting dose of axitinib was 5 mg twice daily. A series of blood samples were taken at predetermined times after the first dose to calculate AUC 0-12 . On day 15 of axitinib administration, the dose was adjusted to ensure ≥ 150 ng·h/mL AUC 0-12 at steady state according to first-dose AUC 0-12 . The primary end point was the 6-month progression-free survival rate., Results: Twenty-six Japanese patients were enrolled. The median recommended dose based on the first-dose AUC 0-12 was 2.5 mg (range, 1-16 mg) twice daily. The 6-month progression-free survival rate for all enrolled patients and per-protocol set, from which 3 patients were excluded for not adjusting to the recommended dose on day 15, was 84.6% (95% confidence interval, 65.5-94.1) and 82.6% (95% confidence interval, 61.8-93.3), respectively. The most common nonhematologic adverse events were hypertension, hand-foot syndrome, fatigue, and decreased appetite. Eighteen patients (75%) developed grade 3 hypertension; however, actual blood pressure could be controlled using antihypertensive agents. Other adverse events were manageable during the protocol treatment., Conclusion: Individualized dosing of axitinib based on the first-dose AUC 0-12 might have promising efficacy and manageable toxicity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Abiraterone (AA) and enzalutamide (ENZA) are increasingly being used in chemotherapy-naive patients with metastatic castration-resistant prostate cancer owing to efficacy and favorable toxicity. However, the order in which they should be administered has not been determined., Patients and Methods: We retrospectively reviewed the records of chemotherapy-naive patients with metastatic castration-resistant prostate cancer who had received sequential treatment with either AA followed by ENZA (AA-ENZA) or the converse (ENZA-AA). Prostate-specific antigen (PSA) response rates (defined as ≥ 50% PSA decline from baseline), first-line progression-free survival (PFS), second-line PFS, combined PFS (defined as first-line PFS plus second-line PFS), and overall survival are compared between the 2 sequence groups., Results: A total of 97 patients received sequential treatment with AA and ENZA; 50 patients were in the AA-ENZA group, and 47 patients were in the ENZA-AA group. The PSA response rate to first-line treatment was not significantly different between AA (48%) and ENZA (51%) (P = .840). However, a significant difference was observed in the PSA response rate to second-line treatment (AA, 6.4% vs. ENZA, 30%; P = .004). The median combined PFS was not significantly different between sequence groups (hazard ratio, 0.71; 95% confidence interval, 0.46-1.08; log-rank P = .105). The order of addition also had no significant effect on median overall survival (hazard ratio, 0.98; 95% confidence interval, 0.64-1.52; log-rank P = .834)., Conclusion: With the exception of the second-line PSA response, there was no significant difference in clinical outcomes between the AA-ENZA and ENZA-AA groups. Our results might be useful reference in daily practice, especially for patients who do not have a suitable general condition for chemotherapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: An important clinical question of great interest to clinicians is how to best sequence androgen receptor targeted agents (ARTAs) and chemotherapy for metastatic castration-resistant prostate cancer (mCRPC), but the answer is still unclear., Materials and Methods: To evaluate and compare the clinical outcomes of ARTA and docetaxel (DTX) as second-line treatment in the post first-line ARTA, we conducted a retrospective analysis of chemotherapy-naive mCRPC patients who had received sequential treatment with ARTA followed by another ARTA (ARTA-ARTA) or ARTA followed by DTX (ARTA-DTX)., Results: A total of 97 patients were treated with the ARTA-ARTA sequence and 42 with the ARTA-DTX sequence. A prostate-specific antigen (PSA) response to the second-line treatment was observed in 18.6% in the ARTA-ARTA and in 33.3% in the ARTA-DTX sequence, but the difference in PSA response was not statistically significant (P = .057). The median progression-free survival (PFS) was significantly different between ARTA and DTX in the second-line treatment (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.24-0.59; P < .001). The favorable outcome in the ARTA-DTX sequence compared with the ARTA-ARTA sequence remained (HR, 0.51, 95% CI, 0.33-0.80; P = .004) in the combined PFS (first-line PFS + second-line PFS). However, no statistically significant difference in overall survival (OS) between the 2 groups was observed (HR, 0.60; 95% CI, 0.34-1.09; P = .095). In multivariate analysis, the ARTA-DTX sequence was identified as an independent prognostic factor for combined PFS, but not OS., Conclusion: ARTA-DTX might improve clinical outcomes in terms of second-line PFS and combined PFS, compared with the ARTA-ARTA sequence. However, this significance was not observed for OS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population., Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m 2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125., Findings: Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96-4·47] vs 2·76 months [2·60-2·96]; hazard ratio [HR] 0·757, 95% CI 0·607-0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8-30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4-18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1-2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab., Interpretation: To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma., Funding: Eli Lilly and Company., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: In endovascular embolization for intracranial aneurysms, it is important to properly control the coil insertion force. However, the force can only be subjectively detected by the subtle feedback experienced by neurointerventionists at their fingertips. The authors envisioned a system that would objectively sense and quantify that force. In this article, coil insertion force was measured in cases of intracranial aneurysm using this sensor, and its actual clinical application was investigated., Methods: The sensor consists of a hemostatic valve (Y-connector). A little flexure was intentionally added in the device, and it creates a bend in the delivery wire. The sensor measures the change in the position of the bent wire depending on the insertion force and translates it into a force value. Using this, embolization was performed for 10 unruptured intracranial aneurysms., Results: The sensor adequately recorded the force, and it reflected the operators' usual clinical experience. The presence of the sensor did not affect the procedures. The sensor enabled the operators to objectively note and evaluate the insertion force and better cooperative handling was possible. Additionally, other members of the intervention team shared the information. Force records demonstrated the characteristic patterns according to every stage of coiling (framing, filling, and finishing)., Conclusions: The force sensor system adequately measured coil insertion force in intracranial aneurysm coil embolization procedures. The safety of this sensor was demonstrated in clinical application for the limited number of patients. This system is useful adjunct for assisting during coil embolization for an intracranial aneurysm., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Prostate-specific antigen (PSA) flare is a well-known phenomenon in patients with prostate cancer treated with luteinizing hormone-releasing hormone agonist and chemotherapy. However, its incidence and the significance for the clinical outcomes of patients treated with abiraterone acetate (AA) are uncertain., Patients and Methods: A multicenter retrospective analysis of chemotherapy-naive patients treated with AA for metastatic castration-resistant prostate cancer (mCRPC) was conducted. The baseline characteristics, treatment history of mCRPC, and serum PSA kinetics during AA treatment were collected. The log-rank test was applied to compare progression-free survival (PFS) between patient groups with a PSA flare according to the different definitions and immediate PSA declines., Results: The data from 83 patients were analyzed. An immediate PSA decline of any amount was observed in 59 patients (71.1%). According to the various definitions of PSA flare, its incidence ranged from 6.0% to 10.8%. Although the median interval to the peak PSA level was 0.95 month, regardless of the PSA flare definition, the interval to the PSA nadir showed a wide range of 2.8 to 7.6 months. In PSA flare subgroup, the median PFS in patients with any PSA decline to less than the baseline and > 30% decline from the baseline was 12.4 months. The PFS duration of PSA flare patients did not significantly differ from that of patients with an immediate PSA decline of any amount and immediate > 30% decline without PSA flare., Conclusion: The PSA flare phenomenon is not rare event during AA treatment. A PSA decline during AA treatment, with or without a PSA flare, was associated with favorable clinical outcomes. Thus, AA should not be withdrawn early in patients with mCRPC in whom an initial, isolated PSA increase has been observed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Understanding of self-protection activity of the bacteria and interaction with drug substances has significant importance for designing of effective drug delivery system for treatment of biofilm infections. Recently silver nanoparticle has attracted attention as antibacterial substance for drug delivery system because of its high antibacterial activity. Here, efflux of silver nanoparticles obtained from within the prepared silver-decorated poly (DL-lactide-co-glycolide) (Ag PLGA) nanoparticles derived from Staphylococcus epidermidis bacterial cell was successfully visualized using scanning transmission electron microscopy (STEM). We also revealed the interaction between prepared Ag PLGA nanoparticles and the bacterial cells at the nanoscale level using field emission scanning electron microscopy and STEM, after a pretreatment process by an ionic liquid. This finding is significant to understand a fundamental function of S. epidermidis bacterial cells, which is not explored previously. The results suggest that Ag PLGA nanoparticles could demonstrate high efficacy against biofilm infections., (Copyright © 2016. Published by Elsevier B.V.)

Background: We aimed to evaluate the efficacy and safety of irinotecan monotherapy as a third- or fourth-line treatment for advanced non-small cell lung cancer (NSCLC) patients., Methods: Patients with advanced NSCLC refractory to 2 or more previous regimens were treated with 80 mg/m2 irinotecan on days 1, 8, and 15, every 4 weeks. The primary endpoint was the overall response rate (ORR), whereas secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity profiles., Results: From December 2007 to April 2009, 32 patients (median age, 60 years) were enrolled. Most of the patients (75.0%) were male, and 18.8% had a performance status of 2. Six partial responses to irinotecan monotherapy were observed (ORR, 18.8%: 95% confidence interval, 5.3%-32.3%). The disease control rate (DCR) was 78.1%, median PFS was 4.0 months, and median survival time (MST) was 10.4 months. Grade 3-4 neutropenia was observed in 22% of patients, but other toxic effects were moderate. No cases of grade 3-4 diarrhea or treatment-related death were noted. Of the 15 patients for whom progressive disease represented the best response to previous treatment regimens, 2 exhibited a partial response and 9 showed stable disease after irinotecan monotherapy, with a DCR of 73.3%, median PFS of 4.4 months, and MST of 8.2 months., Conclusions: Irinotecan monotherapy is effective for advanced NSCLC patients who have previously failed 2 or more treatment regimens., (Copyright © 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

For the purpose of nationwide surveillance of the antimicrobial susceptibility of bacterial respiratory pathogens collected from patients in Japan, the Japanese Society of Chemotherapy conducted a third year of nationwide surveillance during the period from January to April 2008. A total of 1,097 strains were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections. Susceptibility testing was evaluable with 987 strains (189 Staphylococcus aureus, 211 Streptococcus pneumoniae, 6 Streptococcus pyogenes, 187 Haemophilus influenzae, 106 Moraxella catarrhalis, 126 Klebsiella pneumoniae, and 162 Pseudomonas aeruginosa). A total of 44 antibacterial agents, including 26 β-lactams (four penicillins, three penicillins in combination with β-lactamase inhibitors, four oral cephems, eight parenteral cephems, one monobactam, five carbapenems, and one penem), three aminoglycosides, four macrolides (including a ketolide), one lincosamide, one tetracycline, two glycopeptides, six fluoroquinolones, and one oxazolidinone were used for the study. Analysis was conducted at the central reference laboratory according to the method recommended by the Clinical and Laboratory Standard Institute (CLSI). The incidence of methicillin-resistant S. aureus (MRSA) was as high as 59.8%, and those of penicillin-intermediate and penicillin-resistant S. pneumoniae (PISP and PRSP) were 35.5 and 11.8%, respectively. Among H. influenzae, 13.9% of them were found to be β-lactamase-non-producing ampicillin (ABPC)-intermediately resistant (BLNAI), 26.7% to be β-lactamase-non-producing ABPC-resistant (BLNAR), and 5.3% to be β-lactamase-producing ABPC-resistant (BLPAR) strains. A high frequency (76.5%) of β-lactamase-producing strains was suspected in Moraxella catarrhalis isolates. Four (3.2%) extended-spectrum β-lactamase-producing K. pneumoniae were found among 126 strains. Four isolates (2.5%) of P. aeruginosa were found to be metallo β-lactamase-producing strains, including three (1.9%) suspected multidrug-resistant strains showing resistance to imipenem, amikacin, and ciprofloxacin. Continual national surveillance of the antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis.

Object: The Wada test is had been the most reliable for determining speech dominance. Drugs injected into the internal carotid artery, however, may be heterogeneously distributed as the result of asymmetry of the anterior cerebral arteries and the presence of a fetal-type posterior cerebral artery. Variations in drug distribution could occasionally alter consciousness and complicate the evaluation of the test results. We examined selective propofol injection into the M1 segment of the middle cerebral artery (MCA Wada test)., Methods: For the MCA Wada test (17 patients), 7 or 8 mg of propofol was injected via a microcatheter navigated into the M1 segment, and language function was evaluated by patient performing several tasks. The conventional Wada test (internal carotid artery [ICA] Wada test) was performed in four patients (both the ICA and MCA Wada tests were performed in one patient). The efficacy and adverse effects of both procedures were evaluated; all tests were performed by well-trained interventional neuroradiologists., Results: Immediately after propofol injection during the MCA Wada test, patients developed transient contralateral hemiplegia and transient aphasia (in the case of injection on the dominant side). Confusion and other severe adverse effects did not occur during the MCA Wada test, but two of four patients who underwent the ICA Wada test showed altered consciousness that affected the performance of the test., Conclusions: The MCA Wada test is a feasible and reliable preoperative evaluation, if performed by a trained team of interventional neuroradiologists., (Published by Elsevier Inc.)

We aimed to evaluate the risk factors, including the hospital epidemiology of methicillin-resistant Staphylococcus aureus (MRSA), for central venous line-associated and laboratory-confirmed bloodstream infections (CLA-BSI and LC-BSI, respectively). The risk factors examined included the age and sex of patients, whether or not they were in the surgery service, the number of days of central line (CL) placement, the monthly number of inpatients and those positive for MRSA, and whether the standard or maximal barrier precautions were observed at CL insertion. As the outcome factors, we selected CLA-BSI and LC-BSI, while precluding repeated isolation within 28 days. Of a total of 22,723 device days in 927 patients with CL placement, we observed 81 CLA-BSIs and 40 LC-BSIs, rates of 3.56 and 1.76 (/1000 device-days), respectively. Logistic regression analysis revealed a single significant factor, CL placement of more than 30 days, with odds ratios of 3.038 [95% confidence interval (CI) 1.733-5.326; P < 0.001] for CLA-BSI and 3.227 (95% CI 1.427-7.299; P = 0.005) for LC-BSI. Both BSIs included MRSA in seven events without temporal clusters. We conclude that the factor of long CL placement outweighs other risk factors, including the hospital epidemiology of MRSA.

For the purpose of a nationwide surveillance of the antimicrobial susceptibility of bacterial respiratory pathogens in patients in Japan, the Japanese Society of Chemotherapy conducted their second year survey, during the period from January to August, 2007. A total of 1178 strains were collected from clinical specimens obtained from adult patients with well-diagnosed respiratory tract infections. Susceptibility testing was evaluable for 1108 strains (226 Staphylococcus aureus, 257 Streptococcus pneumoniae, 6 Streptococcus pyogenes, 206 Haemophilus influenzae, 120 Moraxella catarrhalis, 122 Klebsiella pneumoniae, and 171 Pseudomonas aeruginosa). A total of 44 antibacterial agents, including 26 beta-lactams (four penicillins, three penicillins in combination with beta-lactamase inhibitors, four oral cephems, eight parenteral cephems, one monobactam, five carbapenems, and one penem), three aminoglycosides, four macrolides (including ketolide), one lincosamide, one tetracycline, two glycopeptides, six fluoroquinolones, and one oxazolidinone were used for the study. Analysis was conducted at the central reference laboratory according to the method recommended by the Clinical and Laboratory Standards Institute (CLSI). The incidence of methicillinresistant Staphylococcus aureus (MRSA) was high, at 59.7%, and the incidences of penicillin-intermediateresistant and -resistant Streptococcus pneumoniae (PISP and PRSP) were 30.4% and 5.1%, respectively. Among Haemophilus influenzae strains, 19.9% of them were found to be beta-lactamase-non-producing ampicillin (ABPC)-intermediately-resistant (BLNAI), 29.1% to be beta-lactamasenon-producing ABPC-resistant (BLNAR), and 6.7% to be beta-lactamase-producing ABPC-resistant (BLPAR) strains. Extended-spectrum beta-lactamase-producing Klebsiella pneumoniae was not isolated. Two isolates (1.2%) of Pseudomonas aeruginosa were found to be metallo-beta-lactamase-producing strains, including one (0.6%) suspected multidrug-resistant strain showing resistance to imipenem, amikacin, and ciprofloxacin. These data will be a useful reference for future periodic surveillance studies and for investigations to control resistant infections as well. Continued surveillance is required to prevent the further spread of these antimicrobial resistances.

We intended to evaluate the risk factors for catheter-related bloodstream infection (CR-BSI) with central venous (CV) catheters. For the hub of the CV line, we used three-way stopcocks in the first year of the study and closed needleless connectors (NCs) in the second year. Background factors included the age and sex of patients; the ward; the specialty service; the CV catheter and its days of placement; and the staff compounding the intravenous infusion, i.e., either nurses, who disinfect hands-free, or pharmacists using clean benches. Outcome factors included positive culture from the blood-related samples and the body temperature estimate. Of a total of 29 221 device-days in 1073 patients, positive cultures showed an overall incidence of 2.26 per 1000 device-days. Multivariate analysis showed a higher odds ratio of positive cultures for the ICU (odds ratio [OR], 4.415; 95% confidence interval [CI], 2.054-9.490]) and for CV catheter placement for more than 30 days (OR, 7.529; 95% CI, 4.279-13.247), but no significance for male sex (OR, 1.752; 95% CI, 0.984-3.119) or for pharmacists' compounding (OR, 2.150; 95% CI, 0.974-4.749). Univariate analysis showed no significance for the following factors: age more than 70 years (OR, 0.968; 95% CI 0.561-1.641), the surgery service (OR, 1.029; 95% CI, 0.582-1.818), double-lumen CV catheters (OR, 0.841; 95% CI, 0.465-1.521), or the NC (1.107; 95% CI, 0.673-1.821). We conclude that the theoretical benefit of the NC, the abolished dead space in the hub, contributed little to the outcomes of blood-related culture. The hands-free disinfection may have resulted in comparable odds ratios for the nurses and the pharmacists compounding the infusions.

The Japanese Society of Chemotherapy (JSC) conducted the first nationwide surveillance of bacterial respiratory pathogens during the period from January to August 2006. With the cooperation of 32 medical institutions throughout Japan, a total of 924 strains belonging to seven clinically relevant bacterial species were collected from adult patients with well-diagnosed respiratory tract infections (RTIs). Antimicrobial susceptibility testing of the 887 evaluable strains (205 Staphylococcus aureus, 200 Streptococcus pneumoniae, 9 Streptococcus pyogenes, 165 Haemophilus influenzae, 91 Moraxella catarrhalis, 74 Klebsiella pneumoniae, and 143 Pseudomonas aeruginosa) to 42 antibacterial agents was conducted at the Central Laboratory of the Research Center for Anti-infective Drugs of the Kitasato Institute, according to recommendations issued by the Clinical and Laboratory Standards Institute (CLSI). The antibacterial agents employed were 25 beta-lactams, three aminoglycosides, four macrolides (including one azalide and one ketolide), one lincosamide, one tetracycline, two glycopeptides, five fluoroquinolones, and one oxazolidinone. The incidence of methicillin-resistant S. aureus (MRSA) was 63.4%, and the incidences of penicillin-intermediately resistant S. pneumoniae (PISP) and penicillin-resistant S. pneumoniae (PRSP) were 35.0% and 4.0%, respectively. Among H. influenzae, 21.2% of the strains were found to be beta-lactamase-nonproducing ampicillin (ABPC)-intermediately resistant (BLNAI), 29.1% to be beta-lactamase-nonproducing ABPC-resistant (BLNAR), and 4.8% to be beta-lactamaseproducing ABPC-resistant (BLPAR) strains. The incidence of extended-spectrum beta-lactamase-producing K. pneumoniae was 2.7% (2 of 74 strains). Three (2.1%) of the 143 P. aeruginosa strains were found to be metallo-beta-lactamaseproducing, including 1 (0.7%) multidrug-resistant strain. Through the nationwide surveillance, we obtained fundamental antimicrobial susceptibility data of clinically relevant bacterial pathogens in adult RTI to various antibacterial agents. These data will be a useful reference for future periodic surveillance studies, as well as for investigations to control antimicrobial-resistant pathogens.

The use of antimicrobials in broilers is considered to be a cause of the appearance of vancomycin-resistant enterococci (VRE). Once VRE penetration occurs, whatever its origin, it is difficult to expel the enterococci from the intestine because of their multiple resistance, whether natural or acquired. In this study, we evaluated the prevention of VRE colonization by the dietary supplementation of a cell-wall preparation of Enterococcus faecalis strain EC-12 (EC-12) in newly hatched broilers that were challenged by experimental infection with VRE. The chicks were fed a basal diet supplemented with 0.05% (wt/wt) EC-12 powder for 15 d. The control group and that administered Lactobacillus sp. were fed the basal diet. The VRE challenge was administered orally when the chicks were 2 d old (d 0). Dietary EC-12 reduced VRE colonization in the intestine from d 3 to 14. Total IgA in the cecal digesta and total IgG in the serum were higher on d 14 in the EC-12 treatment group. However, VRE-specific and EC-12-specific antibodies were not affected in serum. Hence, it appeared that dietary EC-12 stimulated the gut immune system and reinforced the immune reaction against the VRE challenge to accelerate its defecation from the chick intestine.

The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) modulates the effectiveness of alkylating agents. However, the relationship between MGMT and the sensitivities to other agents has not been explored. In the present study, the association between MGMT expression and the cellular sensitivity to the platinum agent, CDDP was examined in four human oral cancer cell lines. CDDP depleted MGMT protein and mRNA levels in all four cell lines. Two cell lines with low MGMT expression were sensitive to an alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine and CDDP, whereas two other cell lines with high MGMT expression were resistant to both agents. Furthermore, the addition of the MGMT inhibitor, O6-benzylguanine (O6-BG), invariably enhanced CDDP sensitivity. CDDP depleted MGMT expression, and CDDP sensitivity was enhanced by O6-BG. These results provide valuable information about the relationship between MGMT expression and CDDP sensitivity in oral cancer chemotherapy.

Maspin, which belongs to the serine protease inhibitor (serpin) superfamily, has been proposed as a potent tumor suppressor that inhibits cell motility, invasion, angiogenesis, and metastasis. In the present study, we examined the effects of 5-aza-2(')-deoxycytidine (5-aza-dC), a demethylating agent, and FR901228, a histone deacetylase (HDAC) inhibitor, on maspin expression in oral cancer cell lines. The expression levels of maspin mRNA were divided into two groups, which was the maspin low-expressed and high-expressed cell lines in the 12 oral cancer cell lines. The maspin promoter contained only a few methylated CpG sites in the maspin low-expressed cell lines. Moreover, the methylation status was not altered after 5-aza-dC treatment. However, the transcription of the maspin gene was clearly increased following 5-aza-dC treatment in a number of oral cancer cell lines. These results imply that an action of 5-aza-dC is separate from induction of promoter demethylation. Treatment with FR901228 resulted in a time-dependent stimulation of the re-expression of maspin mRNA as early as 4 h after treatment in the maspin downregulated cells. The re-expression of the maspin gene may contribute to the recuperation of biological functions linked to FR901228 such as an inhibitory effect on tumor angiogenesis and cell invasion. These results indicate that maspin and its target genes may be excellent leads for future studies on the potential benefits of FR901228, a HDAC inhibitor, in cancer therapy.

Closely related peptides such as neurotensin and angiotensin analogues were separated by capillary zone electrophoresis using a nonionic surfactant, sucrose monododecanoate, as a micelle forming reagent. These peptides were detected by an on-line coupled mass spectrometer using an electrospray ionization interface. However, the presence of the micelles in the separation solution drastically reduced the sensitivity of the mass spectrometer. Therefore, a partial filling technique was employed to prevent the micelles from entering the mass spectrometric interface. A part of the capillary from the injection end was filled with the micellar solution in this technique. Analytes passed through the micellar zone during the electrophoresis and when the separated analytes reached the detection end of the capillary, the micellar zone was still behind the analyte zones, because the nonionic surfactant moved very slowly in acidic conditions. Thus the technique was very useful for mass spectrometric detection for CE when the micellar solution was employed for separation. The optimization of separation and detection conditions was investigated.

Although a number of growth factors and their receptors are involved in the proliferation and differentiation of primordial germ cells (PGCs), the only factor that has been shown to be active in vivo is Steel factor, a ligand for c-Kit. To identify new growth factor receptors that may be required for PGCs function in vivo, we used an reverse transcription-polymerase chain reaction-based strategy to screen for protein kinase genes expressed in PGC-derived embryonic germ cells. We report here that one such gene encoding the receptor tyrosine kinase, Sky, is expressed in both PGCs and their supporting cells in male genital ridges after 11.5 dpc. Interestingly, Sky expression was not detected in female genital ridges, although transcripts were detected in supporting cells in the developing ovary at later stages. Gas 6, a ligand for Sky, was also expressed in interstitial cells which surround Sky positive cells in genital ridges, and, in addition, it supported PGC growth or survival in culture. After birth, Sky expression in testis was restricted to Sertoli cells, and Gas 6 was detected around peritubular cells and Leydig cells. These results suggest that Gas 6-Sky signaling plays a role in PGC growth, sexual differentiation, and Sertoli cell functions in vivo. Sky expression in Sertoli cells diminished by 3 weeks of age, when haploid germ cells first appear. On the other hand, the expression in Sertoli cells was markedly upregulated in the testis of germ cell-deficient W/Wv and jsd/jsd mice. The results suggest that signals from differentiated germ cells suppress Sky gene expression in Sertoli cells. High-resolution chromosomal mapping of Sky is also reported.

Genetic instability at microsatellites in some colorectal cancer (CRC) have been linked to the defects of human mismatch repair genes, but the targets of these defective genes have been largely unknown. We screened CRC specimens for alteration of E2F-4 gene by analyzing both cDNA and genomic sequences along with replication error (RER+) phenotype. Two out of 20 sporadic CRC patients showed RER+ phenotype. We found tumor-specific copy number alteration in 13 consecutive trinucleotide (CAG) repeats within the coding exon of E2F-4 exclusively in these 2 specimens. Thus, E2F-4 may be a clue of the target gene of defective repair genes in CRC with genetic instability in addition to the TGF-beta type II receptor gene.

Seven patients with hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA) are presented. This is the first comprehensive evaluation of what is a unique disorder, half way between the cerebellar atrophies and the hereditary motor and sensory neuropathies. In addition to cerebellar ataxia and peripheral neuropathy, the most frequent features in HMSNCA were nystagmus, dysarthria, mental impairment and tremor. Pyramidal signs or autonomic nerve dysfunction was never revealed. Scoliosis or kyphoscoliosis was not noted. Progression of the disorder was very slow, most of the patients being ambulatory more than 10 years after the onset. Most of the patients had hypoalbuminemia. Half-life periods of serum albumin were normal and decreased synthesis of albumin in the liver was suspected. An autosomal recessive inheritance was strongly suggested, because of healthy consanguineous parents and affected siblings in these families. The segregation ratio was 0.32 +/- 0.10 and was close to the expected ratio of 0.25 in an autosomal recessive inheritance.

The separation of 24 dansylamino acids was investigated by capillary electrophoresis with an additive of micelles of a non-ionic surfactant, Tween 20. Although two pairs of peaks, norvaline and methionine derivatives, and didansyltyrosine and solvent (methanol), did not show good resolution, other dansylamino acids were well separated within 70 min using 100 mM Tween 20 and pH 2.40. The theoretical plate numbers calculated for dansylamino acids were 28,000-111,000 with a 19-cm capillary column.

Diffuse intestinal arteriovenous malformation (AVM) is very rare. We describe a case of diffuse AVM involving the jejunum and the total colon in an adult. In addition, mesenteric varices without portal hypertension is demonstrated on angiography of the superior mesenteric artery. The high flow through the AVMs may be a major component in the etiology of the mesenteric varices in our case.

A case of abdominal wall desmoid which enlarged toward the liver and mimicked an intra-abdominal tumor is presented. T*2-weighted MR images clearly demonstrated the tumor's continuity with the rectus abdominis muscle. The case presented suggests MRI may provide more valuable information concerning the origin of a right-upper-quadrant mass than CT does. However, the nature of the signals and attachment which this case showed were so unusual for desmoids that this case has not been diagnosed accurately.

A rare adult case of retroperitoneal ganglioneuroma in which magnetic resonance imaging (MRI) clearly demonstrated unusual extension of the tumor across the midline is reported. Dynamic MR imaging was very useful to distinguish benign ganglioneuroma from other retroperitoneal tumors, especially neuroblastoma and pheochromocytoma.

In some patients with paraneoplastic cerebellar degeneration (PCD), autoantibodies against neural components have been identified. Here, we demonstrate a major 58 kd protein antigen in an immunoblot of human cerebellum by serum from a patient with PCD. Immunohistochemically, the serum recognized neural cells especially Purkinje cells in a human brain. To identify the details of the target antigens for the antibody, we isolated a cDNA clone from a human cerebellar library. Homology searches revealed a similarity with the zinc finger proteins. PCD related proteins reported here may be important to maintain neural cells especially those in the cerebellum, and further studies on this molecule may help us elucidate the causes of degenerative or autoimmune diseases in the cerebellum.

To estimate regional left ventricular (LV) diastolic filling patterns in hypertrophic cardiomyopathy (HCM), a computer-assisted method by applying "sector analysis" to ECG forward and reverse gated radionuclide ventriculography was developed. Fourteen patients with HCM (four with localized septal hypertrophy, seven with apical hypertrophy and three with septal and apical hypertrophy according to echocardiography) were observed at rest. After establishing serial 20 msec imaged frames, the LV region of interest was subdivided into eight sectors radiating from the geometric center. A time-activity curve was generated for each sector and was fitted by third-order harmonics of the Fourier series. From each fitted curve, the regional peak filling rate (rPFR) and the time of rPFR (rTPFR) in the forward gating method and regional atrial contribution to filling (rAC/FV) in the reverse gating method were calculated. The coefficient of variance of rTPFR was used as an index of LV diastolic asynchrony. In HCM, a prominent delay of rTPFR was observed in the hypertrophied regions. The coefficient of variance of rTPFR correlated inversely with global LVPFR (r = -0.62, p less than 0.05), indicating that diastolic asynchrony is one of the determinants of the LV early filling rate. Regional AC/FV was augmented in the hypertrophied regions, indicating the important role of atrial systolic LV filling for slowed early filling. Thus, this new method provides valuable information concerning regional diastolic LV wall mechanics in HCM.