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Patients with advanced cancer undergo comprehensive genomic profiling in Japan only after treatment options have been exhausted. Patients with a very poor prognosis were not able to undergo profiling tests, resulting in a selection bias called length bias, which makes accurate survival analysis impossible. The actual impact of length bias on the overall survival of patients who have undergone profiling tests is unclear, yet appropriate methods for adjusting for length bias have not been developed. To assess the length bias in overall survival, we established a simulation-based model for length bias adjustment. This study utilized clinicogenomic data of 8813 patients with advanced cancer who underwent profiling tests at hospitals throughout Japan between June 2019 and April 2022. Length bias was estimated by the conditional Kendall τ statistics and was significantly positive for 13 of the 15 cancer subtypes, suggesting a worse prognosis for patients who underwent profiling tests in early timing. The median overall survival time in colorectal, breast, and pancreatic cancer from the initial survival-prolonging chemotherapy with adjustment for length bias was 937 (886-991), 1225 (1152-1368), and 585 (553-617) days, respectively (median; 95% credible interval). Adjusting for length bias made it possible to analyze the prognostic relevance of oncogenic mutations and treatments. In total, 12 tumor-specific oncogenic mutations correlating with poor survival were detected after adjustment. There was no difference in survival between FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) or gemcitabine with nab-paclitaxel-treated groups as first-line chemotherapy for pancreatic cancer. Adjusting for length bias is an essential part of utilizing real-world clinicogenomic data., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: To clarify the efficacy and safety profile of immune checkpoint inhibitors (ICIs) for elderly patients with metastatic renal cell carcinoma (mRCC)., Methods: We retrospectively evaluated 149 mRCC patients treated with nivolumab monotherapy as subsequent therapy (n = 89) and nivolumab plus ipilimumab as first-line therapy (n = 60) at 5 affiliated institutions. The patients were divided according to age: > 70 (elderly) vs. ≤ 70 years (young). Efficacy was analyzed by comparing progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) between elderly and young patients. Safety was assessed by comparing the incidence rates of immune-related adverse events (irAEs)., Results: In the nivolumab monotherapy group, 34/89 patients (38%) were classified as elderly. There was no significant difference in PFS (p = 0.607), OS (p = 0.383), ORR (p = 0.0699), or DCR (p = 0.881) between elderly and young patients. In the nivolumab plus ipilimumab group, 20/60 patients (33%) were classified as elderly. There was no significant difference in PFS (p = 0.995), OS (p = 0.714), ORR (p = 0.763), or DCR (p = 1.000) between the two groups. The incidence rate of irAEs was not significantly different in the nivolumab (any grade: p = 0.121; grade ≥ 3: p = 0.542) or in the nivolumab plus ipilimumab (any grade: p = 0.666; grade ≥ 3: p = 0.576) group; a higher rate of gastrointestinal irAEs was observed in elderly than in young patients (any grade 15% vs. 3%)., Conclusions: The efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab were comparable between elderly and young patients. Thus, chronological age alone should not be a contraindication in the use of ICIs for mRCC., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer., Materials and Methods: Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m 2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m 2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety., Results: Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks., Conclusion: Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer., Competing Interests: Junzo HamanishiResearch Funding: MSD, Ono Pharmaceutical, Sumitomo Dainippon Pharma Noriyuki KatsumataConsulting or Advisory Role: Nippon Zoki Pharmaceutical Co, Ltd Kimio UshijimaHonoraria: AstraZeneca, Chugai Pharmaceutical, Takeda, Nippon Kayaku, MSD, Kaken Pharmaceutical, Kyowa Kirin InternationalResearch Funding: AstraZeneca, Chugai Pharmaceutical, Takeda, Kaken Pharmaceutical, Nippon Kayaku, Mochida Pharmaceutical Co, Ltd, Taiho Pharmaceutical, Eisai, Ono Pharmaceutical, AbbVie, MSD Tadashi KimuraHonoraria: Nobelpharma Co, Ltd, GE Healthcare Japan, Mochida Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co, Ltd, Bayer Pharmaceuticals, Aska PharmaceuticalConsulting or Advisory Role: Fermata Pharma, Rohto PharmaceuticalResearch Funding: Fuji Pharma, Nippon Shinyaku, Takeda Yakuhin, Taihou Yakuhin, Mochida Pharmaceutical Co, Ltd, Nihon Seiyaku, Zeria Pharmaceutical Koji MatsumotoHonoraria: Chugai Pharmaceutical, AstraZeneca, Kyowa Hakko Kirin, Eisai, MSD K.K., Eli Lilly Japan K.K., Taiho Oncology, AbbVie, PfizerResearch Funding: Ono Pharmaceutical, MSD, AstraZeneca, Novartis, Chugai Pharmaceutical, Eisai Kimihiko ItoHonoraria: AstraZenecaConsulting or Advisory Role: AstraZeneca, AbbVie, Nippon Shinyaku, TerumoUncompensated Relationships: Kansai Clinical Oncology Group Hidemichi WatariHonoraria: MSD K.K., Tsumura & Co, AstraZeneca, Aska Pharmaceutical Co, Ltd, Terumo, Bayer Yakuhin, Kaken Pharmaceutical, Mochida Pharmaceutical Co, Ltd, Daiichi Sankyo/UCB Japan, Chugai Pharmaceutical, TakedaConsulting or Advisory Role: Decision Resources Group Japan, Kaken Pharmaceutical, Chugai PharmaceuticalResearch Funding: Hokkaido Welfare Federation of Agricultural Cooperatives, Kaken Pharmaceutical, Mochida Pharmaceutical Co, Ltd, Taiho Pharmaceutical, Chugai Pharmaceutical, Hokkaido Cancer Society, TakedaOther Relationship: T-PEC Nobutaka TakahashiHonoraria: Olympus, Ethicon/Johnson & Johnson, Intuitive Surgical, Kaken Pharmaceutical Kosei HasegawaHonoraria: MSD K.K., Daiichi Sankyo, Bayer Yakuhin, Bristol-Myers Squibb K.K., Chugai Pharmaceutical, AstraZeneca, EisaiConsulting or Advisory Role: MSD K.K., Kaken PharmaceuticalResearch Funding: Ono Pharmaceutical, Daiichi Sankyo, Takeda Kan YonemoriHonoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho PharmaceuticalConsulting or Advisory Role: Chugai Pharmaceutical, Ono Pharmaceutical, Novartis, EisaiResearch Funding: Ono Pharmaceutical Kazuhiro TakeharaHonoraria: Takeda Pharmaceutical Company, AstraZeneca, Eisai, Chugai Pharmaceutical, MSD, Mochida Pharmaceutical Co, LtdResearch Funding: Chugai Pharmaceutical Hitoshi NiikuraHonoraria: Takeda Sari NakaoUncompensated Relationships: Japanese Gynecologic Oncology Group Toshiaki SaitoHonoraria: Nippon Kayaku, Kyowa Hakko Kirin, Eisai, Kaken Pharmaceutical CompanyResearch Funding: Chugai Pharmaceutical, Taiho Pharmaceutical Takayuki EnomotoHonoraria: AstraZeneca, MSD, Chugai Pharmaceutical Satoru NagaseHonoraria: Chugai Pharmaceutical, AstraZeneca Aikou OkamotoHonoraria: AstraZeneca K.K., MSD, Chugai Pharmaceutical, TakedaConsulting or Advisory Role: AstraZeneca K.K., Chugai PharmaceuticalSpeakers' Bureau: AstraZeneca K.K.Research Funding: Kissei Pharmaceutical, Meiji Holdings, Pfizer, Fuji Pharma, Taiho Pharmaceutical, Kaken Pharmaceutical, Chugai Pharmaceutical, Tsumura & Co, Daiichi Sankyo Company, Ltd, Shinnihonseiyaku, Mochida Pharmaceutical Co, Ltd, Aska Pharmaceutical Co, Ltd, Takeda, Terumo Yoshito TeraiResearch Funding: Ethicon/Johnson & Johnson, MSD, Covidien, Terumo, Daiichi Sankyo/UCB Japan, Chugai Pharmaceutical, Taiho Pharmaceutical Akira TakazawaEmployment: Ono Pharmaceutical Yusuke TakahashiEmployment: Ono PharmaceuticalStock and Other Ownership Interests: Ono Pharmaceutical Yoshinobu NambaEmployment: Ono PharmaceuticalHonoraria: Boehringer Ingelheim Daisuke AokiHonoraria: AstraZeneca K.K., MSD K.K., Takeda, Chugai Pharmaceutical, Myriad GeneticsConsulting or Advisory Role: Takeda, MSD K.K., AstraZeneca K.K.Speakers' Bureau: AstraZeneca K.K., Takeda Keiichi FujiwaraHonoraria: Kyowa Hakko Kirin, Zeria Pharmaceutical, Nippon Kayaku, Chugai Pharmaceutical, Eisai, Taiho Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, TakedaConsulting or Advisory Role: AstraZeneca, MSD, Taiho Pharmaceutical, Eisai, Takeda, Genmab, AbbVie, Pfizer, NanoCarrierResearch Funding: Eisai, Kaken Pharmaceutical, Chugai Pharmaceutical, Shionogi, ImmunoGen, ONCOtherapeutics, AstraZeneca, Eli Lilly, Zeria Pharmaceutical, Ono Pharmaceutical, MSD, Genmab, Regeneron, Merck KGaA, Ono PharmaceuticalTravel, Accommodations, Expenses: Pfizer, AbbVie, MSDNo other potential conflicts of interest were reported.

Background: The recent improvements in anti-cancer therapy following first-line treatment can potentially impact post-progression survival. We evaluated the factors that influence post-progression survival in advanced recurrent ovarian cancer., Methods: Eighty-nine patients who underwent first-line treatment between June 2005 and December 2017 were included. The post-progression survival was defined as the difference between overall survival and initial progression-free survival. The effects of age, histology, stage, optimal surgery, secondary debulking surgery, bevacizumab administration, platinum sensitivity, and olaparib maintenance in recurrence were compared and independent risk factors were determined., Results: The median follow-up duration was 60.0 months (range: 2-181). Platinum-sensitive recurrence had longer post-progression survival than platinum-resistant (P < 0.001). Inclusion of bevacizumab in first-line treatment did not produce a significant difference in post-progression survival (P = 0.462). Secondary debulking surgery (P = 0.013), bevacizumab administration (P < 0.001), and olaparib maintenance (P = 0.001) during recurrence increased post-progression survival. In multivariate analysis, histologies other than serous or endometrioid (hazard ratio = 2.389; 95% confidence interval = 1.200-4.754; P = 0.013) and non-bevacizumab usage in recurrence (hazard ratio = 4.484; 95% confidence interval = 1.939-10.370; P < 0.001) were independently correlated with poorer prognosis. Bevacizumab administration beyond progressive disease elicited improved post-progression survival (P < 0.001). In patients receiving bevacizumab in first-line treatment, exclusion of bevacizumab in the recurrent therapy (hazard ratio = 5.507; 95% confidence interval = 2.301-12.124; P < 0.001) was independently correlated with poorer prognosis., Conclusions: The continuous use of bevacizumab beyond progressive disease improves post-progression survival suggesting its important role in first-line and recurrence treatment for ovarian cancer., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess the efficacy and safety of dose-dense weekly paclitaxel plus carboplatin (ddTC) with or without bevacizumab compared to conventional, tri-weekly paclitaxel plus carboplatin (cTC) with or without bevacizumab, in metastatic or recurrent cervical carcinoma not amenable to curative local therapy., Methods: Patients were randomly assigned to either the cTC or ddTC arm. The cTC regimen was paclitaxel 175 mg/m 2 and carboplatin at an area under the curve (AUC) of 5 on day 1. The ddTC regimen was paclitaxel 80 mg/m 2 on day 1, 8, 15 and carboplatin at AUC of 5 on day 1. Both cTC and ddTC treatments were repeated every 3 weeks for up to 9 cycles. After bevacizumab was approved in Japan, patients in both arms received bevacizumab 15 mg/kg if not contraindicated. The primary endpoint of phase II part was response rate (RR). If the RR of ddTC+bevacizumab was found to be at least 5% better than to cTC + bevacizumab, the study would proceed to phase III part, which had overall survival as its primary endpoint., Clinical Trial Information: jRCTs031180007., Results: In total, 122 patients were randomly assigned to either the cTC arm (cTC + bevacizumab: 32; cTC:29) or the ddTC arm (ddTC+bevacizumab: 30; ddTC:31). The RR for patients on cTC + bevacizumab was 67.9%, and for patients on ddTC+bevacizumab 60.7%, cTC: 55.2%, and ddTC: 50.0%., Conclusions: The study did not meet the primary endpoint of phase II portion. Dose-dense, weekly paclitaxel plus carboplatin is not promising for metastatic or recurrent cervical carcinoma., Competing Interests: Declaration of Competing Interest None of the authors reports that they have any conflict of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: It remains unclear how early treatment interruption of nivolumab plus ipilimumab due to immune-related adverse events affects the outcome of previously untreated metastatic renal cell carcinoma (mRCC)., Objective: To investigate the prognostic impact of the early interruption of nivolumab plus ipilimumab, used as first-line therapy for mRCC., Patients and Methods: We retrospectively evaluated 59 intermediate- or poor-risk mRCC patients who received nivolumab plus ipilimumab as first-line therapy. Based on whether early treatment interruption was implemented within the initial four treatment cycles (i.e., 3 months) or not, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were compared. The prognostic association was further compared with that of 186 patients treated with tyrosine kinase inhibitors (TKIs) as first-line therapy., Results: Twenty-three of the 59 patients (39%) experienced interruption of nivolumab plus ipilimumab therapy. The patients with interruption had longer PFS (p = 0.0055), similar OS (p = 0.366), and likely higher ORR (p = 0.0660) than those without interruption. Of the patients treated with TKIs, 60 of 186 (32%) experienced interruption, with shorter PFS (p = 0.0121), similar OS (p = 0.378), and similar ORR (p = 0.738) than those without interruption. In the 23 patients with nivolumab plus ipilimumab interruption, high-dose corticosteroids were administered in seven patients (30%). PFS (p = 0.638), OS (p = 0.968), or ORR (p = 0.760) did not differ based on corticosteroid administration., Conclusions: Early treatment interruption, which exerted a negative effect for TKIs, was a preferable event for nivolumab plus ipilimumab when considering PFS. Furthermore, early administration of high-dose corticosteroids did not diminish the anti-tumor effect of nivolumab plus ipilimumab.

Aim: The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy., Methods: Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (<4.0 ng/mL) during first-line androgen deprivation therapy were enrolled and administered abiraterone acetate (1000 mg) plus prednisolone (10 mg). A minimum of 48 patients were required according to Simon's minimax design. The primary endpoint was prostate-specific antigen response rate (≥50% prostate-specific antigen decline by 12 weeks), secondary endpoints included prostate-specific antigen progression-free survival and overall survival. Safety parameters were also assessed., Results: For efficacy, 49/50 patients were evaluable. Median age was 73 (range: 55-86) years. The median duration of initial androgen deprivation therapy was 32.4 (range: 13.4-84.1) weeks and 48 patients experienced prostate-specific antigen progression within 1-year after initiation of androgen deprivation therapy. prostate-specific antigen response rate was 55.1% (95% confidence interval: 40.2%-69.3%), median prostate-specific antigen-progression-free survival was 24.1 weeks, and median overall survival was 102.9 weeks (95% confidence interval: 64.86 not estimable [NE]). Most common adverse event was nasopharyngitis (15/50 patients, 30.0%). The most common ≥grade 3 adverse event was alanine aminotransferase increased (6/50 patients, 12.0%)., Conclusions: Abiraterone acetate plus prednisolone demonstrated a high prostate-specific antigen response rate of 55.1%, suggesting tumor growth still depends on androgen synthesis in patients with early metastatic castration-resistant prostate cancer. However, prostate-specific antigen-progression-free survival was shorter than that reported in previous studies. Considering the benefit-risk profile, abiraterone acetate plus prednisolone would be a beneficial treatment option for patients with chemotherapy-naive metastatic prostate cancer who show early castration resistance., (© The Author(s) 2020. Published by Oxford University Press.)

Background: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited., Methods: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group., Results: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001)., Conclusion: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown., Competing Interests: Conflict of interest statement K.I. reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, Merck Sharp & Dohme (MSD), Ono Pharmaceutical and Taiho Pharmaceutical. T.Y. reported receiving grants from Takeda Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, Bayer, Astellas and Eli Lilly and receiving personal fees from Takeda Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi Sankyo, Bayer, Merck Serono, Pfizer, Huya Bioscience, Gilead Sciences and EP-CRSU. H.H. reported receiving grants from MSD, A2 Healthcare Corp., inVentiv Health Japan, Astellas, Daiichi Sankyo, Novartis, AbbVie, Quintiles/IQVIA Services, ICON Japan, Chugai Pharmaceutical, Takeda Pharmaceutical, EP-CRSU CO., GRITSTONE ONCOLOGY, Linical Co., Eli Lilly, Eisai Co., Bristol Myers Squibb company, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, PAREXEL International Corp., SymBio Pharmaceuticals Limited, Ono Pharmaceutical, Merck Serono Co./Merck Biopharma, AstraZeneca, CMIC Shift Zero, Kissei Pharmaceutical, Kyowa Hakko Kirin, EPS Corporation, Bayer Yakuhin, Syneos Health, EPS International, Pfizer R&D Japan G.K and Otsuka Pharmaceutical and receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyorin Pharmaceutical, MSD, Ono Pharmaceutical, Novartis, Pfizer, Shanghai Haihe Biopharm and Taiho Pharmaceutical. Y.H. reported receiving grants from Janssen Pharmaceutical, MSD and Ono Pharmaceutical and receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono Pharmaceutical and Taiho Pharmaceutical. K.N. reported receiving grants from Boehringer Ingelheim and receiving personal fees from Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Pfizer, Ono Pharmaceutical and Roche Diagnostics. H.K. reported receiving personal fees from Eli Lilly and Taiho Pharmaceutical. Y.O. reported no relevant conflicts of interests. T.Y. reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, Chugai Pharmaceutical, Novartis, Pfizer and MSD. T.S. reported receiving grants from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda Pharmaceutical, AbbVie, Bayer Yakuhin, Kissei Pharmaceutical, LOXO Oncology and Merck Serono and receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda Pharmaceutical, Astellas, Bristol Myers Squibb, Kyowa Hakko Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, Thermo Fisher Scientific and Precision Medicine Asia Co. Ltd. K.A. reported receiving personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb and Ono Pharmaceutical. T.F. reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, Novartis, Ono Pharmaceutical, Pfizer and Taiho Pharmaceutical. T.K. reported receiving grants from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Meyers Squibb and Merck Biopharma and receiving personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Meyers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim, Nippon Kayaku and Novartis. A.N. reported receiving personal fees from MSD, Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Boehringer Ingelheim and Kyowa Kirin. K.T. reported receiving grants from Boehringer Ingelheim, Chugai Pharmaceutical and Ono Pharmaceutical and receiving personal fees from Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical, AbbVie, Pfizer, SRL, MSD, Novartis and Kyowa Kirin. K.H. reported receiving personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Ono Pharmaceutical, Chugai Pharmaceutical, Pfizer and Taiho Pharmaceutical. T.Y. reported receiving grants from Ono Pharmaceutical and receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, MSD and Boehringer Ingelheim. H.D. reported receiving grants from Chugai Pharmaceutical, Pfizer and Eli Lilly and receiving personal fees from Chugai Pharmaceutical and Boehringer Ingelheim. S.S. reported no relevant conflicts of interests. D.F. reported receiving grants from AstraZeneca and Chugai Pharmaceutical and receiving personal fees from AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, Eli Lilly and Novartis. M.M. reported receiving personal fees from AstraZeneca, MSD, Ono Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, Shionogi, Taiho Pharmaceutical and Novartis. K.M. reported receiving grants from Boehringer Ingelheim and Eli Lilly and receiving personal fees from Chugai Pharmaceutical and Novartis. T.A. reported no relevant conflicts of interests. A.T. reported no relevant conflicts of interests. S.M. reported receiving personal fees from Chugai Pharmaceutical, Boehringer Ingelheim, MSD, Eli Lilly, AstraZeneca, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis, Bristol Myers Squibb and Kyowa Hakko Kirin. S.W. reported receiving grants from Boehringer Ingelheim and receiving personal fees from Eli Lilly, Pfizer, Novartis Pharma, AstraZeneca, Chugai Pharma, Bristol Meyers Squibb, Boehringer Ingelheim, MSD, Ono Pharmaceutical, Daiichi Sankyo and Taiho Pharmaceutical. H.A. reported receiving grants from Chugai Pharmaceutical and receiving personal fees from Chugai Pharmaceutical, Pfizer and Novartis. O.H. reported receiving grants from GlaxoSmithKline, AstraZeneca, Novartis, Kyorin, Bayer Yakuhin, Boehringer Ingelheim and Daiichi Sankyo and receiving personal fees from GlaxoSmithKline, AstraZeneca, Novartis, Bayer Yakuhin and Boehringer Ingelheim. K.S. reported no relevant conflict of interests. S.H. reported no relevant conflict of interests. K.A. reported no relevant conflict of interests. A.B. reported receiving personal fees from Chugai Pharmaceutical, Pfizer and Novartis. A.K. reported receiving grants from the Japan Society for the Promotion of Science, Boehringer Ingelheim, Chugai Pharmaceutical, Lilly and Ono Pharmaceutical and receiving personal fees from Boehringer Ingelheim, Chugai Pharmaceutical, Lilly, Ono Pharmaceutical, Novartis, Taiho Pharmaceutical and Pfizer. M.O. reported no relevant conflict of interests. K.N. reported receiving grants from MSD, A2 Healthcare Corp., inVentiv Health Japan, Astellas, Daiichi Sankyo, Novartis, AbbVie, Quintiles/IQVIA Services, ICON Japan, Chugai Pharmaceutical, Takeda Pharmaceutical, EP-CRSU CO., GRITSTONE ONCOLOGY, Linical Co., Eli Lilly, Eisai Co., Bristol Myers Squibb company, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, PAREXEL International Corp., SymBio Pharmaceuticals Limited, Ono Pharmaceutical, Merck Serono Co./Merck Biopharma, AstraZeneca, CMIC Shift Zero, Kissei Pharmaceutical, Kyowa Hakko Kirin, EPS Corporation, Bayer Yakuhin, Syneos Health, EPS International, Pfizer R&D Japan G.K and Otsuka Pharmaceutical; receiving personal fees from AstraZeneca, Nichi-Iko Pharmaceutical, Astellas, Takeda Pharmaceutical, MSD, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb company, Boehringer Ingelheim, Eli Lilly, Novartis, SymBio Pharmaceuticals Limited, Pfizer, Chugai Pharmaceutical, Clinical Trials Co., NANZANDO Co., MEDICUS SHUPPAN, Publishers Co., YODOSHA CO., Care Net, Nikkei Business Publications, Reno. Medical, Daiichi Sankyo, KYORIN Pharmaceutical, Thermo Fisher Scientific, Medical Review Co., YOMIURI TELECASTING CORPORATION, Roche Diagnostics, Nippon Kayaku Co., Bayer Yakuhin, Merck Biopharma Co., Medical Mobile Communications Co., AbbVie and 3H Clinical Trial Inc. and receiving consulting and advisor fees from Takeda Pharmaceutical, KYORIN Pharmaceutical, Ono Pharmaceutical, Pfizer and Eli Lilly. N.Y. reported receiving grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Daiichi Sankyo, Ono Pharmaceutical, Astellas, MSD, Pfizer, Takeda, AstraZeneca, Terumo and Toppan and receiving personal fees from Chugai Pharmaceutical, Eli Lilly, MSD, AstraZeneca, Ono Pharmaceutical, Novartis, Pfizer and Boehringer Ingelheim., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Cisplatin(CDDP)is a key drug for head and neck cancer therapy, but frequently induces severe adverse events including renal dysfunction. Nedaplatin(CDGP)was developed and is used in Japan; it has certain benefits over CDDP. Unlike CDDP, CDGP treatment does not require hydration. However, CDGP is not used globally and thus safety information is lacking. Therefore, we surveyed safety profiles for CDGP-based chemotherapy., Methods: A survey was conducted at Showa University Hospital. Thirty-eight patients treated for head and neck cancer combined with radiotherapy(RTx)and tegafur- gimeracil-oteracil(S-1)between April 2012 and March 2015 were included. Laboratory-based adverse events(WBC, Hb, platelet[Plt], SCr, Alb)and oral mucositis were assessed according to CTCAE v5.0. Time-onset profiles for adverse events were evaluated after starting chemoradiotherapy., Results: In 38 patients, Plt nadir was observed following 40(30-70)Gy and sustained for 14(7-35)days. WBC patterns followed similar profiles, but for Hb, nadir was observed following 60(40- 70)Gy and was less frequently sustained throughout the RTx. Alb and SCr levels were not correlated with therapy. Oral mucositis was observed following 50(10-70)Gy., Conclusion: In conclusion, at approximately 40 Gy, we observed decreases in WBC and Plt, with an increase in oral mucositis. Based on these results, medical staffs must closely monitor patients, especially at doses within range of 40 Gy.

The efficiency of upfront consolidation with high-dose chemotherapy/autologous stem-cell transplantation (HDCT/ASCT) for newly diagnosed high-risk diffuse large B-cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high-risk DLBCL patients having an age-adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R-CHOP-14 (arm A) or 3 cycles of R-CHOP-14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2-y progression-free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow-up of 40.3 mo, 2-y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%-81.2%) and 66.7% (95% CI: 48.8%-79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%-85.7%) and 83.3% (95% CI: 66.6%-92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non-hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R-CHOP-14 showed higher 2-y PFS and less toxicity compared with R-CHOP-14/CHASER in patients with high-risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN-CTR, UMIN000003823)., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: To evaluate treatment efficacy of cisplatin, etoposide, and irinotecan combined therapy (PEI), platinum-rechallenge chemotherapy (Pt-Re) and amrubicin monotherapy (AMR) for patients with sensitive relapsed small cell lung cancer (SCLC)., Patients and Methods: We defined sensitive relapse as treatment-free interval (TFI) ≥90 days. We retrospectively collected patients' data from medical records between September 2002 and December 2016. Patients with sensitive relapsed SCLC who received second-line chemotherapy were separated into those treated with PEI, with Pt-Re, or with AMR., Results: Seventy-one patients (16 PEI group, 27 Pt-Re group, and 28 AMR group) were assessable for efficacy. No significant differences in patient characteristics were found among the three groups. The median overall survival (MST) was 29.3 months in the PEI group, 24.6 months in the Pt-Re group, and 20.6 months in the AMR group (p=0.042)., Conclusion: A significant difference was observed in the overall survival of patients treated with PEI, Pt-Re and AMR and the MST of PEI was the longest., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Patients in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate-risk group have heterogeneous prognoses and thus may benefit from improved risk stratification., Objective: The aim of this study was to analyze inflammatory parameters such as C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) as prognostic markers for IMDC intermediate-risk patients., Methods: Patients with metastatic clear cell renal cell carcinoma (n = 71) with IMDC intermediate risk who received tyrosine kinase inhibitors as first-line therapy were included in this retrospective study. Multivariate Cox regression analyses were performed to identify prognostic factors for overall survival (OS)., Results: As first-line systemic therapy, 46 (65%), 19 (27%), and 6 (8%) patients received sunitinib, sorafenib, and pazopanib, respectively. An IMDC prognostic score of 1 and 2 were observed in 34 (48%) and 37 (52%) patients, respectively. Mean CRP level was 1.06 mg/dL, and mean NLR was 3.0. Multivariate Cox regression revealed several factors significantly associated with poor OS, including NLR ≥ 3 (vs NLR < 3; hazard ratio [HR] 2.57; p = 0.0228), CRP level ≥ 1 mg/dL (vs CRP < 1 mg/dL; HR 2.89; p = 0.0279), and two or more metastatic organs (vs one organ; HR 3.77; p = 0.0008). Using these risk factors, patients were stratified into the following three risk categories: F0 (no prognostic factors; n = 20), in which the median OS (mOS) was not achieved; F1 (1 prognostic factor; n = 31), in which the mOS was 31 months; and F2-3 (2 or 3 prognostic factors; n = 20) in which the mOS was 13 months (log-rank p < 0.0001)., Conclusion: CRP, NLR, and the number of metastatic organs were independent prognostic factors in IMDC intermediate-risk patients.

This study aimed to explore the tolerability and safety of platinum combination chemotherapy in malnourished patients with advanced non-small cell lung cancer (NSCLC) and poor performance status (PS). We retrospectively reviewed NSCLC patients with a PS of 2 who received first-line platinum combination chemotherapy at the Shizuoka Cancer Center between December 2009 and December 2014. Nutritional status was classified using the Glasgow Prognostic Score (GPS), which is an indicator of systemic inflammation and malnutrition. The malnourished group included patients with a GPS of 2, and the well-nourished group included patients with a GPS of 0-1. Among the 31 consecutive eligible patients, the malnourished group completed fewer chemotherapy cycles than the well-nourished group (median: 2 cycles vs. 4 cycles, p = 0.0091). Hematological and non-hematological toxicities were similar in both groups. The malnourished group also experienced poorer outcomes than the well-nourished group (response rate: 0% vs. 25%; median progression-free survival: 1.7 months vs. 4.9 months, p = 0.018; and median overall survival: 5.7 months vs. 8.3 months, p = 0.028). Malnutrition might decrease the tolerability and efficacy of platinum combination chemotherapy for patients with advanced NSCLC and poor PS.

A randomized controlled trial has been initiated to compare chemotherapy containing dose-dense paclitaxel plus carboplatin with or without bevacizumab to a conventional regimen containing tri-weekly paclitaxel plus carboplatin with or without bevacizumab. Eligible patients are those with stage IVB, recurrent or persistent cervical carcinoma not amenable to curative treatment with local therapy. Patients are randomly assigned to either the conventional or dose-dense regimen. However, patients who are at increased risk of adverse events following bevacizumab administration will not receive this drug. The primary endpoint of phase II part is response rate. If the response rate of the dose-dense regimen is better than that of conventional regimen, this study will proceed to phase III, where the primary endpoint is overall survival. Secondary endpoints in phase III part are progression-free survival, response rates, adverse events, serious adverse events and the proportion of non-hospitalization periods compared with planned treatment periods.

Background: Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial., Methods: In the phase 2-3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1-3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m 2 ], given on day 1, plus cyclophosphamide [750 mg/m 2 ], doxorubicin [50 mg/m 2 ], vincristine [1·4 mg/m 2 , capped at 2·0 mg] given intravenously on day 3, and oral prednisone [100 mg once daily on days 3-7]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121., Findings: Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25-41; R-CHOP-14 39%, 31-47; hazard ratio 0·89, 95% CI 0·67-1·17). In 248 patients with grade 1-3a follicular lymphoma, progression-free survival was 39% (33-45) at 8 years and 36% (30-42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5-6·0) at 5 years, 8·5% (5·4-12·4) at 8 years, and 9·3% (6·1-13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1-12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3-5·5)., Interpretation: R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up-both of which could lead to death., Funding: National Cancer Center and Ministry of Health, Labour and Welfare of Japan., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although induction immunochemotherapy including high-dose cytarabine and rituximab followed by high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) is recommended for younger patients (≤65 years old) with untreated mantle cell lymphoma (MCL), no standard induction and HDC regimen has been established. We conducted a phase II study of induction immunochemotherapy of R-High-CHOP/CHASER followed by HDC of LEED with ASCT in younger patients with untreated advanced MCL. Eligibility criteria included untreated MCL, stage II bulky to IV, and age 20-65 years. Patients received 1 cycle of R-High-CHOP followed by 3 cycles of CHASER every 3 weeks. Peripheral blood stem cells (PBSC) were harvested during CHASER. LEED with ASCT was delivered to patients who responded to R-High-CHOP/CHASER. Primary endpoint was 2-year progression-free survival (PFS). From June 2008 to June 2012, 45 patients (median age 59 years; range 38-65 years) were enrolled. PBSC were successfully harvested from 36 of 43 patients. Thirty-five patients completed ASCT. Two-year PFS was 77% (80% CI 68-84), which met the primary endpoint. Five-year PFS and overall survival were 52% (95% CI 34-68%) and 71% (95% CI 51-84%), respectively. Overall response and complete response rates after induction immunochemotherapy were 96% and 82%, respectively. The most common grade 4 toxicities were hematological. In younger patients with untreated MCL, R-High-CHOP/CHASER/LEED with ASCT showed high efficacy and acceptable toxicity, and it can now be considered a standard treatment option., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A 34-year-old man, diagnosed with paraganglioma of the urinary bladder, was referred to our hospital. Computed tomography showed a bladder tumor measuring 64 mm along with right obturator lymphadenopathy. Abnormal uptake was observed on 123 I-MIBG scintigraphy. The tumor was, therefore, diagnosed as malignant paraganglioma. We performed cystectomy, pelvic lymph node dissection, and neobladder reconstruction. Pathological examination revealed a malignant paraganglioma of the urinary bladder with right obturator lymph node metastasis. Postoperatively, both the uptake on 123 I-MIBG scintigraphy and catecholamine levels in blood and urine normalized. However, 22 months later, positoron emission tomography-computed tomography showed the presence of 2 recurrent tumors in the pelvis. The patient underwent 9 courses of cyclophosphamide, vincristine, and dacarbazine chemotherapy and MIBG radiotherapy twice, following which the tumor size decreased by 35% and catecholamine levels normalized once again. At about 2 years of follow-up, the patient was found to be free of recurrence.

Purpose: This study was to determine the incidence and risk factors of febrile neutropenia in chemotherapy-naïve Japanese patients treated systemically with etoposide plus platinum for lung cancer., Methods: The study was a retrospective analysis of 244 patients who were monitored for febrile neutropenia through multiple cycles of the combination of etoposide with platinum, and the associations between incidence of febrile neutropenia and patient characteristics were evaluated., Results: Eighty-eight patients were treated with etoposide plus cisplatin and 156 were treated with etoposide plus carboplatin. Of the 244 patients treated, 198 (81.1%) completed 4 cycles for chemotherapy. Febrile neutropenia was observed in 48 of 244 patients (19.7%), including 18 of 88 (20.5%) patients who received etoposide plus cisplatin and 30 of 156 (19.2%) patients who received etoposide plus carboplatin. Grade 3 or 4 of neutropenia was experienced by a total of 208 patients (85.2%); 79 of 88 (89.8%) receiving etoposide plus cisplatin and 129 of 156 (82.7%) receiving etoposide plus carboplatin. Male gender and previous radiotherapy were identified by multivariate analysis as independent risk factors for febrile neutropenia., Conclusions: These results contrast with findings in Western patients and suggest that ethnic differences exist in the incidence of febrile neutropenia in patients receiving etoposide plus platinum chemotherapy. In addition, our results suggest that primary prophylaxis with granulocyte colony-stimulating factor should be considered for patients with these risk factors for febrile neutropenia prior to treatment with etoposide plus platinum.

Introduction: Alectinib and crizotinib have been approved for the therapy of NSCLC caused by anaplastic lymphoma kinase gene (ALK) rearrangement. The effect of alectinib or crizotinib on overall survival (OS) in patients with ALK-rearranged NSCLC remains unknown., Methods: A multicenter retrospective study was conducted to compare OS between patients receiving alectinib and crizotinib and between patients treated with alectinib and those treated sequentially with crizotinib and then alectinib after crizotinib failure. The time to treatment failure (TTF), progression-free survival (PFS), and OS were compared., Results: Sixty-one patients with ALK-rearranged NSCLC were enrolled. Forty-six patients were treated with anaplastic lymphoma kinase (ALK) inhibitors (31 with crizotinib, 28 with alectinib, and 13 with both ALK inhibitors). The response rate was 66.7% for the crizotinib-treated group and 80.8% for the alectinib-treated group. Among all patients, TTF and PFS were significantly prolonged in the alectinib-treated group compared with in the crizotinib-treated group. Subgroup analyses revealed significantly prolonged TTF for alectinib compared with crizotinib therapy in the ALK inhibitor-naive population. OS was significantly longer in the alectinib-treated group than in the crizotinib-treated group. The TTF and OS of patients treated sequentially with crizotinib and then with alectinib after crizotinib failure tended to be longer than those of patients treated with alectinib alone., Conclusions: Therapy with alectinib alone was significantly superior to therapy with crizotinib alone in terms of TTF, PFS, and OS, and sequential therapy with crizotinib and alectinib after crizotinib failure tended to provide a better OS benefit than did therapy with alectinib alone in patients with ALK-positive NSCLC. However, large-scale prospective studies are needed to confirm these observations., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

A 61-year-old, HIV-negative, immunocompetent woman was admitted to our hospital for significant weight loss, painful swelling of her right cheek, and rapid growth of a tumor in the right hard palate. A CT scan revealed a neoplastic lesion in the right maxillary sinus, extending to the surrounding soft bone tissue and oral cavity, as well as multiple osteolytic lesions in the skull. A pathologic examination revealed that the neoplastic cells in the oral cavity were plasmablasts tending to appear as differentiated plasma cells. The tumor cells strongly expressed CD138, Vs38c, EBER, and MYC, and were negative for CD20 and CD19. The MIB-1 index was 90%, and MYC/IgH fusion gene was detected by fluorescence in situ hybridization analysis. Based on these clinical and pathological findings, we confirmed the diagnosis of plasmablastic lymphoma. This disease has characteristics of aggressive lymphoma originating from differentiated plasma cells. Treatment was initiated with dose-adjusted EPOCH added to a concurrent bortezomib regimen. After completion of four cycles, the patient achieved and sustained complete remission.

A 62-year-old man with CHOP refractory adult T-cell leukemia/lymphoma (ATLL) received anti-CC chemokine receptor 4 antibody (mogamulizumab) combined with CHOP and achieved complete remission. At 71 days after the final administration of mogamulizumab, he received umbilical cord blood transplantation (CBT) using reduced intensity conditioning. Umbilical cord blood engraftment was confirmed on day16. Grade II acute graft-versus-host disease (GVHD) was diagnosed on day60 and was controlled by administration of methylprednisolone. There was no evidence of relapse at 9 months after CBT. Ratios of regulatory T cells in CD4 positive T cells were remarkably low during all of these periods. Since mogamulizumab reduces regulatory T cells, the frequency and severity of acute GVHD were reported to be increased in patients administered mogamulizumab before allogenic stem cell transplantation. Further experiences are needed for selecting optimal donor sources, the portability period and GVHD prophylaxis for patients using mogamulizumab before allogeneic stem cell transplantation.

Background: We conducted a phase III, non-inferiority trial comparing upfront primary debulking surgery (PDS) and interval debulking surgery (IDS) following neoadjuvant chemotherapy (NAC) for stage III/IV ovarian, tubal, and peritoneal cancers (JCOG0602). Two earlier studies, EORTC55971 and CHORUS, demonstrated non-inferior survival of patients treated with NAC. However, they could not evaluate true treatment invasiveness because of adding diagnostic laparotomy or laparoscopy before treatment in over 30% of both arms of EORTC55971 and in 16% of NAC arm of CHORUS., Methods: Patients were randomised into the standard arm (PDS followed by eight cycles of paclitaxel and carboplatin [TC]) and NAC arm (four cycles of TC, IDS, and four cycles of TC). In the standard arm, IDS was optional for patients who had undergone suboptimal or incomplete PDS. Treatment invasiveness was compared between arms (UMIN000000523)., Results: Between November 2006 and October 2011, 301 patients were randomised. In the standard arm, 147/149 underwent PDS and 49 underwent IDS. In the NAC arm, 130/152 underwent IDS. The NAC arm required fewer surgeries (mean 0.86 versus 1.32, p < 0.001) and shorter total operation time (median 273 min versus 341 min, p < 0.001) than the standard arm and required a lower frequency of abdominal organ resection (23.7% versus 37.6%, p = 0.012) or distant metastases resection (3.9% versus 10.7%, p = 0.027). In the NAC arm IDS, blood/ascites loss was smaller (median 787 ml versus 3235 ml, p < 0.001) and albumin transfusion and G3/4 adverse events after surgery in total were less frequent (26.2% versus 58.5%, p < 0.001; 4.6% versus 15.0%, p = 0.005, respectively)., Conclusion: Our findings demonstrated that NAC treatment is less invasive than standard treatment. NAC treatment may become the new standard treatment for advanced ovarian cancer when non-inferior survival is confirmed in the planned primary analysis in 2017., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Primary intracranial rhabdomyosarcoma is quite rare, and its prognosis is poor compared with that for rhabdomyosarcoma in other organs. The authors present a case of pineal rhabdomyosarcoma successfully managed with multimodal therapy including surgery, chemotherapy, radiation, and high-dose chemotherapy (HDC) followed by autologous peripheral blood stem cell transplantation (HDC/APBSCT). An 8-year-old girl presenting with headache and nausea was referred to the authors' institution. Computed tomography and MRI revealed a pineal tumor associated with obstructive hydrocephalus. Subsequently, an emergent endoscopic tumor biopsy and third ventriculostomy were performed. The patient's symptoms immediately improved. The most likely pathological diagnosis was embryonal rhabdomyosarcoma. Chemotherapy with etoposide, cyclophosphamide, cisplatin, pirarubicin, ifosfamide, actinomycin D, and vincristine was followed by a second-look operation and whole-brain and craniospinal radiation. Because the intraoperative findings and pathological examination of the second operation suggested a definitive diagnosis of rhabdomyosarcoma and the presence of viable residual tumor cells, HDC with etoposide and melphalan was followed by APBSCT. The patient was discharged from the hospital without residual tumor or any neurological deficit. No recurrence was observed at 30 months. This is the first case of primary pineal rhabdomyosarcoma treated with HDC/APBSCT. Although the efficacy of HDC/APBSCT for rhabdomyosarcoma has not been established, the prognosis of primary intracranial rhabdomyosarcoma treated with conventional treatment is quite poor. High-dose chemotherapy followed by APBSCT may contribute to a better prognosis for primary intracranial rhabdomyosarcoma.

Background: Substance P contributes to the hypersensitivity reaction (HSR) to paclitaxel in a rat model. Aprepitant acts as an inhibitor of the binding of substance P to the neurokinin-1 receptor and, consequently, may reduce the frequency of paclitaxel-induced HSR. While aprepitant has a prophylactic effect against vomiting caused by high-dose cisplatin, the benefits of aprepitant have not been clearly demonstrated in patients receiving paclitaxel and carboplatin (TC) combination chemotherapy., Methods: We conducted a multicenter, placebo-controlled, double-blind, randomized study in Japanese patients with gynecologic cancer who received TC combination chemotherapy. Patients received aprepitant or placebo together with both a 5-HT3 receptor antagonist and dexamethasone prior to chemotherapy. The primary endpoint was the proportion of patients with HSR, and the secondary endpoints were the proportion of patients with "no vomiting", "no significant nausea", and complete response, respectively., Results: Of the 324 randomized patients, 297 (151 in the aprepitant group; 146 in the placebo group) were evaluated. The percentage of patients with HSR (9.2 vs. 7.5 %, respectively; P = 0.339) was not significantly different between the groups. The percentage of "no vomiting" patients (78.2 vs. 54.8 %; P < 0.0001), "no significant nausea" patients (85.4 vs. 74.7 %; P = 0.014), and patients showing complete response (61.6 vs. 47.3 %, P = 0.0073) was significantly higher in the aprepitant group than in the placebo group., Conclusion: The administration of aprepitant did not have a prophylactic effect on the HSR but was effective in reducing nausea and vomiting in gynecologic cancer patients receiving TC combination chemotherapy.

This study investigated the relationship between quality of life (QOL) and efficacy or occurrence of adverse events in patients who were administered lenalidomide and dexamethasone (Len+Dex) therapy for relapsed or refractory multiple myeloma (MM) in the hematology department at Obihiro Kosei Hospital from September 2010 to September 2012. QOL was evaluated using a quality of life questionnaire for cancer patients treated with anticancer drugs (QOL-ACD). The average QOL score of 7 patients receiving 4 cycles of Len+Dex treatment decreased 5 points from baseline Len+Dex treatment. The change in QOL score was significantly correlated with changes in serum M-protein (correlation coefficient: R=0.777). However, there was no significant correlation between adverse events and the change in QOL score. Our results indicate that QOL may be improved by the effects of Len+Dex treatment.

The patient was a 39-year-old woman who was referred to our hospital with suspicion of locally-advanced breast cancer. After several tests, she received a diagnosis of cT4bN1M1 (liver), Stage Ⅳbreast cancer. The liver metastasis was located in S4, and was 1 cm in size. Core needle biopsy was performed on the breast tumor; the pathological diagnosis was invasive ductal carcinoma (scirrhous carcinoma), nuclear Grade (NG) 3, and HER2-positive. She received epirubicin plus cyclophosphamide (EC) followed by docetaxel (DOC) plus pertuzumab (PER) plus trastuzumab (HER). After chemotherapy, the liver metastasis and axillary lymph node metastases had disappeared on imaging findings, showing a complete response (CR), but the primary breast tumor remained, showing a partial response (PR). She underwent mastectomy and axillary lymph node dissection for local control. After surgery, no metastases including liver metastases were seen on CT. The patient is currently receiving tamoxifen and anti-HER2 therapy.

A 60-year-old man who had bloody stools after sigmoid colonoscopy was admitted to our hospital. A digital examination and sigmoid colonoscopy showed a type 2 circular tumor at location Rb with incomplete mobility and tumor hemorrhage, and the result of a biopsy was moderately differentiated adenocarcinoma (tub2). Computed tomography and magnetic resonance imaging suggested a possibility of invasion of the primary rectal tumor to the sacrum. The clinical stage was cT4bN0M0H0P0, cStage Ⅱ, which is generally not treatable by surgery. Sigmoid colostomy was performed, and a central venous port was implanted. After a preoperative treatment consisting of 3 courses of mFOLFOX6 and radiation therapy, the clinical stage changed to ycT2N0M0H0P0, ycStageⅠ. Super-low anterior resection and covering ileostomy were performed 46 days after the preoperative treatment. A pathological examination revealed no residual cancer cells in the primary lesion and lymph node (Grade 3, pCR). The patient has been disease-free for 4 years and 9 months after the operation.

Aim: The aim of this study was to investigate prognostic factors, including postoperative chemotherapy regimen, for the treatment of ovarian yolk sac tumour (YST), and resulting fertility outcome., Methods: A multi-institutional retrospective investigation was undertaken to identify patients with ovarian pure or mixed YST who were treated between 1980 and 2007. Postoperative chemotherapy regimen and other variables were assessed in univariate and multivariate analyses. Additionally, the reproductive safety of the BEP (bleomycin, etoposide and cisplatin) regimen was evaluated., Results: There were 211 patients enrolled from 43 institutions. The BEP regimen and a non-BEP regimen were administered to 112 and 99 patients as postoperative chemotherapy, respectively. In univariate and multivariate analyses, age⩾22, alpha-fetoprotein⩾33,000 ng/ml, residual tumours after surgery and non-BEP regimen were independently and significantly associated with poor overall survival (OS). BEP was significantly superior to non-BEP in 5-year OS (93.6% versus 74.6%, P=0.0004). Reduced-dose BEP (<75% standard-dose bleomycin and<50% etoposide dose) was significantly associated with poorer 5-year OS compared with standard-dose BEP (89.4% versus 100%, P=0.02 and 62.5% versus 96.9%, P=0.0002). All patients who underwent fertility-sparing surgery recovered their menstrual cycles. Sixteen of 23 patients receiving BEP (70.0%) and 13 of 17 patients receiving non-BEP (76.5%) who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 21 and 19 healthy children, respectively., Conclusions: The results of the present study suggest that standard-dose BEP should be administered for ovarian YST. BEP is as safe as non-BEP for preserving reproductive function., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of non-Hodgkin lymphoma and displays an aggressive clinical course with poor outcome. To identify prognostic factors for AITL, we retrospectively analyzed 36 patients with AITL. The median age was 74 years with 83% of the patients having advanced stage. Eighty-three percent received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like chemotherapies, resulting in an overall response rate of 63%. With a median follow-up of 9 years, the estimated overall survival at 5 years was 33.3%. Median serum level of soluble interleukin-2 receptor (sIL-2R) was 5615 U/mL at diagnosis, and over 10 000 U/mL of sIL-2R was identified as a significant poor prognostic factor, independent of the International Prognostic Index, Prognostic Index for peripheral T-cell lymphoma and Prognostic index for AITL (hazard ratio [HR], 4.42; 95% confidence interval [CI], 1.49-13.11; log-rank, p < 0.01). Our study shows that an ultra-high level of serum sIL-2R at diagnosis is a significant poor prognostic biomarker for AITL.

We reviewed the clinical records of 3 patients with anal squamous cell carcinoma treated with chemoradiotherapy (CRT). Case 1: The patient was diagnosed with StageI (T1N0M0) and treated with cisplatin (CDDP)+5-FU+radiation. Chemotherapy was discontinued after the second course because of adverse effects. She achieved partial response(PR), and underwent a salvage surgery. Seven months after the surgery, she died from other comorbidities. Case 2: The patient was diagnosed with Stage I (T1N0M0) and treated with CDDP+5-FU+radiation. Chemotherapy was discontinued after the second course because of adverse effects. He achieved PR, and underwent a salvage surgery. Three years and 7 months after the surgery, he died from other comorbidities. Case 3: The patient was diagnosed with Stage IIIB (T4N1M0) and treated with MMC+S-1+radiation. Chemotherapy was discontinued after the first course because of adverse effects. She achieved complete response (CR) and is still surviving without cancer recurrence. We conclude that CRT is an effective treatment for anal squamous cell carcinoma.

Background: We conducted a multicenter phase II trial to assess the suitability of three types of chemotherapy (docetaxel plus S-1, irinotecan plus S-1, or S-1 alone) for patients with advanced gastric cancer by means of the collagen gel droplet embedded culture-drug sensitivity test (CD-DST). To our knowledge, this is the first multicenter clinical trial that has employed CD-DST to choose anticancer agents for the treatment of advanced gastric cancer., Methods: Subjects (n = 64) were patients with advanced or recurrent gastric cancer. Patients were allocated to one of the treatment regimens on the basis of CD-DST results. Outcome of the patients was compared between the groups deemed chemosensitive or chemoresistant by the CD-DST., Results: Thirty-three patients showed high sensitivity (T/C ratio <60 %) to at least one type of anticancer agent (sensitive group), and 31 showed low sensitivity (T/C ratio ≥60 %) to all agents (resistant group). Specifically, the 1-year survival rate was significantly higher in the sensitive group (78.5 %; 95 % CI, 67.2-94.7 %) than in the resistant group (54.7 %; 95 % CI, 38.7-74.3 %; P = 0.019), whereas time to progression (TTP) was significantly longer in the sensitive group (59.8 %; 95 % CI, 48.2-81.7 %) than in the resistant group (30.0 %; 95 % CI 13.6-46.4 %; P = 0.023). Median survival time was also significantly longer in the sensitive group (15.5 months; 95 % CI, 12.8-18.2) than in the resistant group (12.5 months; 95 % CI, 10.2-14.9; P = 0.038)., Conclusions: CD-DST predicts the outcome of patients undergoing chemotherapy for advanced gastric cancer, presumably through evaluating chemosensitivity.

Therapy-related myelodysplastic syndrome and acute myelogenous leukemia are increasingly being recognized as treatment complications in patients receiving chemotherapy or radiotherapy for previous neoplasms. However, therapy-related chronic myelogenous leukemia is relatively rare. A 61-year-old woman with a history of radiation therapy for breast cancer had previously, in 2007, received 4 courses of chemotherapy (RFM: rituximab, fludarabine, and mitoxantrone) for follicular lymphoma. In 2010, she was diagnosed with chronic-phase chronic myelogenous leukemia (CML) with Philadelphia chromosome but no other cytogenetic anomalies. Although a complete cytogenetic response (CCyR) was achieved with imatinib therapy, she developed leukocytosis with lymphoblasts and lymphoid crisis was diagnosed in January 2013. G-banded karyotyping showed 45, XX, -7, t, (9;22)(q33;q11.2). Unrelated bone marrow stem cell transplantation was performed after she had achieved a CCyR with dasatinib therapy. Polymerase chain reaction detected no major bcr/abl transcript in her bone marrow 42 days after transplantation. The majority of secondary leukemias resulting from the use of cytotoxic drugs can be divided into two well-defined groups depending on whether the patient has received alkylating agents or topoisomerase II inhibitors. However, concerns regarding the leukemogenic potential of fludarabine-based chemotherapy are growing. The potential risk of therapy-related leukemias including CML needs to be considered following fludarabine-based chemotherapy.

Background: CD8+ cytotoxic T cells and forkhead box P3 (FOXP3)+ regulatory T cells are major players in tumor immunity. Increased CD8+ tumor-infiltrating lymphocytes (TILs) and high CD8/FOXP3 TIL ratios are associated with improved survival. Neoadjuvant chemoradiotherapy (CRT) can result in tumor regression; however, immunomodulation during CRT for rectal cancer has not been thoroughly assessed. We investigated whether neoadjuvant CRT altered the in situ immune cell population and clinical implications of TIL accumulation before and after CRT., Methods: We recruited 93 rectal cancer patients who underwent neoadjuvant CRT and radical resection. Pretreatment biopsy and post-CRT resected specimens were immunostained for CD8 and FOXP3, and the densities of stromal (STL) and intraepithelial (IEL) immunopositive TILs were determined separately. In addition, 54 patients with resections but without neoadjuvant CRT were enrolled for comparison., Results: CD8+ STL density doubled after CRT (average counts: 92 vs. 230 per microscopic field using a 20 × objective lens; P < 0.0001), whereas FOXP3+ STL counts remained stable (109 vs. 109). Compared with non-CRT cases, CRT increased CD8+ STL density. Multivariate analyses demonstrated that high post-CRT CD8 + STL density was associated with better prognosis (5-year recurrence-free survival: 87.5 vs. 57.8 %; P = 0.0058) and that a high pretreatment CD8/FOXP3 IEL ratio was a predictor of favorable tumor regression (P = 0.0029)., Conclusions: Favorable anticancer immunity occurred after CRT for rectal cancer by altering TIL subsets. A high CD8/FOXP3 IEL ratio before CRT and a high CD8+ STL density after CRT were associated with a favorable clinical outcome.

We report a 58-year-old Japanese man with acute lymphoblastic leukemia. On the seventh day of his second course of consolidation therapy, he developed herpes zoster, and on the 17th day, he developed a high fever, dyspnea, and lapsed into a coma. Streptococcus constellatus was isolated from blood culture. Despite intensive therapy, multiple organ failure progressed rapidly, and he died on the 19th day. Pathological examination of autopsy specimens revealed bone marrow necrosis and fat embolism in multiple organs. In this patient, sepsis led to bone marrow necrosis and, subsequently, to fat embolism.

Objective: We previously reported on the role of cytoreduction in 248 patients with surgical stage IVb endometrial cancer (EMCA). This study aimed to evaluate the clinical characteristics, prognosis according to initial treatment, and impact of preoperative chemotherapy in the overall population of patients with clinical and surgical stage IVb EMCA., Methods: A multi-institutional retrospective analysis was performed in 426 patients diagnosed with clinical and surgical stage IVb EMCA from 1996 to 2005. Factors associated with overall survival (OS) were identified using univariate and multivariate analyses., Results: The median OS for all 426 patients was 14 months. Patients were divided into three groups according to their initial treatment: primary surgery group (n=279), primary chemotherapy group (n=125), and palliative care group (n=22). The median OS times for these groups were 21, 12, and 1 month, respectively (p<0.0001). Patients in the primary surgery group had better performance status (PS) and lower numbers of extra-abdominal metastases than those in the primary chemotherapy group. Multivariate analysis identified good PS, endometrioid histology, absence of clinical intra-abdominal stage IVb metastasis, hysterectomy, and chemotherapy as independent predictors of OS. In the primary chemotherapy group, 59 patients subsequently underwent surgery, and these patients had similar OS to those in the primary surgery group., Conclusions: Hysterectomy and chemotherapy may prolong OS in selected patients with stage IVb EMCA. Our data suggest that primary chemotherapy followed by surgery may be a useful treatment choice in patients not suitable for primary surgery., (© 2013.)

Neuroendocrine carcinoma (NEC) of the anal canal is a comparatively rare tumor with a poor prognosis. We report herein a case of NEC of the anal canal with multiple bone metastases that was successfully treated with combined therapy. A 63-year-old man was referred to our hospital with the chief complaint of anal and back pain. A tumor was found in the anal canal, and pathologic examination revealed it to be NEC( Ki-67 expression>50%); fluorodeoxyglucose( FDG) positron emission tomography (PET)-computed tomography (CT) showed multiple bone metastases. Initially, a l-leucovorin/5- fluorouraci(l 5-FU)/oxaliplatin( L-OHP)(: mFOLFOX6)/bevacizumab( Bmab) regimen and octreotide were administered to treat the unresectable and advanced NEC. Strontium-89 and zoledronate were used to treat pain related to the bone metastases. After 3 months, the tumor and bone metastases became difficult to identify. The patient experienced grade 2 neurotoxicity after 5 months, and thus, we stopped L-OHP administration. After 10 months, we reintroduced L-OHP because of additional progression of the bone metastases.

A 62-year-old woman was diagnosed as having rectal cancer and underwent low anterior resection. The final pathological diagnosis was RS, type 3, circ, mod>muc>por>,pSE, ly1, v1, pN2, sH0, sP0, cM0, fStage IIIb, with KRAS mutation. Adjuvant chemotherapy with tegafur-uracil( UFT) plus Leucovorin( LV) was administered for 6 months. Ten months after surgery, right internal iliac and common iliac lymph node metastasis and peritoneal dissemination were diagnosed. In October 2009, capecitabine plus oxaliplatin (CapeOX) plus bevacizumab (Bmab) therapy was initiated. In May 2010, diagnostic imaging revealed a complete response after 42 months. In the present report, we describe the case of a patient with rectal cancer who experienced postoperative recurrence and achieved long-term complete response with CapeOX plus Bmab therapy. We also include a brief review of the literature.

A 58-year-old woman had a very large advanced rectal cancer( with wild-type K-RAS expression). Abdominal computed tomography( CT) revealed a space-occupying lesion in the pelvis and an enlarged lymph node. We established a diagnosis of unresectable rectal cancer and subsequently performed transverse colostomy. The patient received 6 courses of Leucovorin, fluorouracil, and oxaliplatin( mFOLFOX6) plus panitumumab( Pmab), 2 courses of simplified Leucovorin plus 5-fluorouraci(l sLV5-FU) plus Pmab, and 1 course of Pmab. The size of the primary tumor decreased remarkably after chemotherapy. Low anterior resection was performed. The pathological stage was T4a, N0, M1, Stage IVa. The results from this case suggest that mFOLFOX6 plus Pmab preoperative chemotherapy is a useful regimen for the treatment of locally advanced K-RAS wild-type rectal cancer.

A 62-year-old man presented to a hospital with left buttock pain, and sacral neoplasia was suspected. He was referred to our hospital. Colonoscopy( CS) and bone biopsy showed rectal cancer with metastasis to the sacrum. There was no bleeding or ileus associated with the primary lesion, and the sacral metastasis was unresectable; therefore, we decided to provide palliative care for pain relief. Radiation therapy( 40 Gy) was performed on the sacral metastasis and included the primary lesion, and zoledronate was administered concomitantly. Both CS and computed tomography (CT) showed tumor regression of both the primary and metastatic lesions, and the patient's carcinomatous pain was alleviated. Irinotecan, 5- fluorouracil, and Leucovorin (FOLFIRI)+cetuximab was administered to reduce the progression of the primary lesion. After 3 months, CT showed significant tumor regression of both the primary and metastatic lesions. The sacral metastasis was no longer evident on the CT images, and positron emission tomography( PET)-CT did not show fluorodeoxyglucose (FDG) accumulation. The primary lesion had shrunk and become flat, but biopsy indicated residual lesion. Although clinically the frequency of bone metastasis of colon cancer has been reported to be 8.6 to 10.7%, single metastasis is not often seen. In this report, we present a case of advanced rectal cancer with bone metastasis, which was successfully treated with chemo-radiation therapy.

A case of recurrent pancreatic cancer effectively responded to S-1 and irinotecan combined with third-line chemotherapy (IRIS) with PSK. The patient was a 75-year-old female. In October 2007, a pancreatoduodenectomy was performed, followed with 6 courses of systemic adjuvant chemotherapy of gemcitabine (GEM). Three months after finishing the adjuvant chemotherapy, a recurrence of para-aortic lymph node metastasis was confirmed. We resumed the second-line chemotherapy of S-1/GEM (GS) with PSK. GS therapy was continued for about 3 years, until the recurrent lesion was found to have increased after 30 courses. Nevertheless, we continued up to 39 courses. In November 2011, we started third-line chemotherapy using S-1/irinotecan (IRIS) with PSK. The regimen was S-1 of 80 mg/body/day, continuously administered for day 1-14th, followed by a discontinuation for 2 weeks. CPT-11 100 mg/body/day was administered on day 1 and 15th; and PSK of 3 g/ body/day was continued, until it resulted in increased recurrent lesions. After the end of 4 courses, recurrent lesions started to respond partially. Currently, the patient is being treated as an outpatient. This case indicates that IRIS (S-1/CPT-11) is an effective therapy when pancreatic cancer fails to respond to GS therapy.

Interferons (IFNs) have been tested for the therapeutic effects in various types of malignancy, but mechanisms of the anti-tumors effects and the differential biological activities among IFN members are dependent on respective cell types. In this study, we examined growth inhibitory activities of type I and III IFNs on 5 kinds of human mesothelioma cells bearing wild-type p53 gene, and showed that type I IFNs but not type III IFNs decreased the cell viabilities. Moreover, growth inhibitory activities and up-regulated expression levels of the major histocompatibility complexes class I antigens were greater with IFN-β than with IFN-α treatments. Cell cycle analyses demonstrated that type I IFNs increased S- and G2/M-phase populations, and subsequently sub-G1-phase fractions. The cell cycle changes were also greater with IFN-β than IFN-α treatments, and these data collectively showed that IFN-β had stronger biological activities than IFN-α in mesothelioma. Type I IFNs-treated cells increased p53 expression and the phosphorylation levels, and activated apoptotic pathways. A combinatory use of IFN-β and cisplatin or pemetrexed, both of which are the current first-line chemotherapeutic agents for mesothelioma, produced synergistic anti-tumor effects, which were also evidenced by increased sub-G1-phase fractions. These data demonstrated firstly to our knowledge that IFN-β produced synergistic anti-tumor effects with cisplatin or pemetrexed on mesothelioma through up-regulated p53 expression.

Purpose: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA)., Methods: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108., Results: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone (n = 55) or ACNU + PCZ (n = 56) in the intention-to-treat population were 27.4 and 22.4 months (p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone (n = 40) or ACNU + PCZ (n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events., Conclusions: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM.

Background: Good local control of high-grade non-small round cell soft tissue sarcomas (NSRCSTSs) has been achieved with significant advances in surgical techniques and radiotherapy. However, the role of chemotherapy remains controversial. Our aim was to investigate the efficacy, feasibility and adverse effects of neoadjuvant and adjuvant chemotherapy with modified mesna, adriamycin, ifosfamide and dacarbazine (MAID) regimen for NSRCSTSs., Methods: We conducted a retrospective review of 40 consecutive patients (29 men, 11 women; median age 47 years) with high-grade NSRCSTSs treated in two referral centers between 2004 and 2009 (median follow-up 38.5 months). Patients with distant or nodal metastases at diagnosis were excluded. The regimen consisted of ifosfamide 2,500 mg/m(2)/6 h (days 1-3), mesna 2,500 mg/m(2)/6 h (days 1-3), tetrahydropyranyl adriamycin 20 mg/m(2)/0.5 h (days 1-3), and dacarbazine 300 mg/m(2)/1 h (days 1-3)., Results: Among the 26 evaluable patients, there were 8 with a partial response, 15 with stable disease, and 3 with progressive disease. Two- and 5-year overall survival rates were 92 and 86%, respectively, and corresponding disease-free survival rates were 80 and 77%. All relapses were metastases without local recurrence. Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 38, 18, and 21 patients, respectively. No serious infectious complications occurred due to the administration of granulocyte colony-stimulating factor and prophylactic antibiotics. No other life-threatening serious adverse events were observed., Conclusion: The modified MAID regimen achieved a better outcome with less serious adverse events than previously reported and is a potential option in the management of NSRCSTSs. Further evaluation with long-term follow-up is required.

We report a case of sigmoid colon cancer, successfully treated by a multidisciplinary strategy for local recurrence and distant metastases. This 60-year-old male patient underwent sigmoidectomy for sigmoid colon cancer. Three years after the operation, local recurrence with invasion to the left ureter was found, and we performed colectomy and left nephroureterectomy. One year after the resection, a second relapse lesion was discovered, which was considered unresectable, and was treated instead with radiation therapy(total 50 Gy). One year after the radiation therapy, five pulmonary metastases each of 12 mm in diameter were found in both lungs. He had renal dysfunction due to nephrectomy. Several regimens of chemotherapy [irinotecan (CPT-11), capecitabine+oxaliplatin (CapeOx) and CPT-11+panitumumab] were performed. He is still alive 7.5 years after the initial surgery and 4.5 years after the first recurrence.

A 67-year-old woman presented with a right inguinal mass in May 2006. CT scan showed lymph node involvement from the right inguinal to the common iliac and (18)F-FDG-PET revealed uptake in those areas. Biopsy results indicated Langerhans cell sarcoma (LCS). Interestingly, tumor cells expressed a high MIB1 index of 30%. We administered doxorubicin, ifosfamide, and mesna (AIM) chemotherapy, which were reported to effectively treat soft tissue sarcoma. After 5 courses of AIM therapy and involved-field radiation for residual diseases and a relapsed lesion on her right cervical node, she has remained in complete remission for more than 4 years. LCS is an intractable malignant disease and the optimal therapeutic strategy remains unclear. The AIM regimen combined with radiation therapy may be an effective treatment option for this disease.

A 52-year-old man underwent ileocecal resection for cecal cancer, followed by left hepatectomy and S6 partial resection for liver metastasis. A month later, abdominal computed tomography revealed metastases in the mediastinal lymph nodes, para-aortic lymph nodes, and left adrenal gland. After 4 courses of the capecitabine plus oxaliplatin(CapeOX) regimen and 4 courses of CapeOX plus bevacizumab, a complete response was observed regarding the lymph nodes metastasis. Then, left adrenalectomy was performed for the residual left adrenal metastasis. CapeOX plus bevacizumab was administered as a postoperative chemotherapy for 8 courses, Capecitabine was started due to adverse reactions, such as peripheral neuropathy (grade 2) and a gastric ulcer. After the gastric ulcer healed, capecitabine plus bevacizumab was administered for 5 courses. The patient has had no recurrence for almost 2 years since the resection of the adrenal metastasis.

A 48-year-old man with respiratory discomfort was diagnosed with rectal cancer with carcinomatous lymphangiosis, together with lung and sternum metastasis. As the patient's performance status(PS) was 2, mFOLFOX6+bevacizumab (Bmab)therapy with a 20% reduction in the dose was started. Three courses of this treatment resulted in improved respiratory function, and his PS dropped to 1. A chest computed tomography(CT) scan taken after four courses of this treatment indicated that pleural effusion had almost disappeared, and that the shadow on the lung had also reduced. However, after 20 courses of this treatment the disease had progressed. The regimen was changed to irinotecan (CPT-11)+Bmab administration. All of these chemotherapeutic treatments were administered on an outpatient basis. Sixteen months after the diagnosis of rectal cancer, the patient died. In recent years, combination chemotherapy for unresectable colorectal cancer has become recognized as a standard regimen, though adverse effects frequently occur. Thus, intensive chemotherapy is not always recommended for patients with poor PS. In this report, we presented a case of pulmonary metastases from rectal cancer, carcinomatous lymphangiosis, and sternum metastasis that was successfully treated with mFOLFOX6+Bmab.

Objective: To evaluate the incidence and clinical significance of retropharyngeal lymph node metastasis in hypopharyngeal cancer., Methods: Pretreatment computed tomography and/or magnetic resonance images of 152 patients treated between 1998 and 2009 were retrospectively reviewed. The prognostic significance of retropharyngeal lymph node metastasis for 116 patients who received definitive treatment was also analyzed., Results: Twelve patients (8%) were radiologically positive for retropharyngeal lymph node metastasis. Tumors originating from the posterior wall showed significantly higher incidence of retropharyngeal lymph node than those originating from other sites (23.8 vs. 5.3%, P = 0.01). The majority of patients with retropharyngeal lymph node involvement experienced distant metastasis. The overall survival rate of patients with retropharyngeal lymph node metastasis was worse than in those lacking retropharyngeal lymph node involvement (0 vs. 68.8% at 2 years, P < 0.01), and so was the cause-specific survival rate (0 vs. 74% at 2 years, P < 0.01)., Conclusions: Patients with hypopharyngeal cancer, especially those with posterior wall tumors, are at high risk for retropharyngeal lymph node involvement. Patients with retropharyngeal lymph node metastasis developed distant metastasis frequently, and showed dismal outcomes.