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  • Magnitude of advantage in tumor response contributes to a better correlation between treatment effects on overall survival and progression-free survival: a literature-based meta-analysis of clinical trials in patients with metastatic colorectal cancer
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-16
    Yosuke Yoshida, Masayuki Kaneko, Mamoru Narukawa

    Although it is suggested that the endpoints originated from the concept of tumor shrinkage dynamics, such as early tumor shrinkage and depth of response, are strongly associated with overall survival (OS) in patients with metastatic colorectal cancer (mCRC), they are yet to be validated as a single surrogate endpoint of OS by themselves. This study aimed to investigate the impact of advantage in tumor response on the correlation between treatment effects on progression-free survival (PFS) and OS in mCRC patients.

  • Clinical characteristics and surgical outcomes of retroperitoneal tumors: a comprehensive data collection from multiple departments
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-16
    Naoto Sassa, Yukihiro Yokoyama, Yoshihiro Nishida, Suguru Yamada, Hiroo Uchida, Hiroaki Kajiyama, Masato Nagino, Yasuhiro Kodera, Momokazu Gotoh

    There are only a limited number of comprehensive reports for retroperitoneal tumors (RPTs). The aim of this study was to perform an interdepartmental data collection for RPTs and to comprehensively clarify the clinical characteristics of this rare disease.

  • Multicenter prospective phase II trial of nivolumab in patients with unresectable or metastatic mucosal melanoma
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-14
    Motoo Nomura, Isao Oze, Toshiki Masuishi, Tomoya Yokota, Hironaga Satake, Shunichiro Iwasawa, Ken Kato, Masashi Andoh

    Abstract Background Mucosal melanoma is a rare and aggressive malignancy with poorer response compared with cutaneous melanoma. Prospective trials of immune checkpoint inhibitors in unresectable or metastatic mucosal melanoma have not been reported. Purpose This phase II trial assessed the efficacy and safety of nivolumab monotherapy for unresectable or metastatic mucosal melanoma. Patients and methods Eligibility criteria were as follows: histological diagnosis of unresectable or metastatic mucosal melanoma; age ≥ 20 years; ECOG performance status 0 or 1; and with measurable lesions. Patients received nivolumab 2 mg/kg every 3 weeks. The primary endpoint was the response rate (RR) according to Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were overall survival, progression-free survival, disease control rate, and toxicity. Results Twenty patients were enrolled between December 2014 and July 2017. Two patients without measurable lesions and one patient with uveal melanoma were excluded from analysis of efficacy. The best overall RR was 23.5%. One patient achieved a complete response, three partial response, and five stable disease as their best response. The median progression-free survival was 1.4 months (95% CI 1.2–2.8). The median overall survival was 12.0 months (95% CI 3.5 to not reached). The 1-year overall survival was 50.0% (95% CI 25.9–70.0%). Treatment-related adverse events of grades 3 or 4 occurred in 15% (3/20) of the patients. Grade 3 adverse events were resolved by corticosteroid treatment. Conclusion Although this trial met the primary endpoint, the RR was still unsatisfactory. Therefore, further treatment development is required.

  • Clinical outcomes and prognostic factors in patients with newly diagnosed metastatic prostate cancer initially treated with androgen deprivation therapy: a retrospective multicenter study in Japan
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-09
    Shintaro Narita, Shingo Hatakeyama, Masahiro Takahashi, Toshihiko Sakurai, Sadafumi Kawamura, Senji Hoshi, Masanori Ishida, Toshiaki Kawaguchi, Shigeto Ishidoya, Jiro Shimoda, Hiromi Sato, Atsushi Koizumi, Koji Mitsuzuka, Tatsuo Tochigi, Norihiko Tsuchiya, Chikara Ohyama, Yoichi Arai, Kyoko Nomura, Tomonori Habuchi

    Abstract Purpose Clinical outcomes of patients with newly diagnosed metastatic hormone-naïve prostate cancer (mHNPC) and initially treated with androgen deprivation therapy (ADT) were evaluated. Methods The medical records of 605 consecutive mHNPC patients with initial ADT or combined androgen blockade (CAB) at nine study centers between 2008 and 2016 were retrospectively reviewed. Castration-resistant prostate cancer (CRPC)-free and overall survival (OS) were estimated by the Kaplan–Meier method. The association of pretreatment risk factors with CRPC-free survival and OS was evaluated by Cox proportional hazard models and differences in survival were classified by the number of risk factors. Results Median follow-up was 2.95 years, median CRPC-free survival was 21.9 months and median OS was 5.37 years. Multivariable analysis found that four risk factors, a Gleason score ≥ 9, lymph node metastasis, an extent of disease score ≥ 2, and serum LDH of > 220 IU were independently associated with both CRPC-free survival and OS. Median CRPC-free survival of low-risk patients with no or one factor was 86.5 months, 17.9 months in intermediate-risk patients with two or three factors, and 11.0 months in high-risk patients with four factors. Median OS was 4.72 years in intermediate- and 2.44 years in high-risk patients. It was not reached in low-risk patients. Conclusion In this series, CRPC-free and OS of a subset of mHNPC patients in Japan who were treated with ADT or CAB had better CRPC-free and overall survivals in Japan. Risk-adapted treatment based on the presence of novel prognostic factors may be beneficial for selected mHNPC patients.

  • Lung cancer incidence and mortality in relationship to hormone replacement therapy use among women participating in the PLCO trial: a post hoc analysis
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-09
    Omar Abdel-Rahman

    To evaluate the impact of hormone replacement therapy (HRT) on the incidence and mortality of lung cancer among female participants in the prostate, lung, colorectal, and ovary (PLCO) trial.

  • Immune-resistant mechanisms in cancer immunotherapy
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-09
    Yutaka Kawakami, Shigeki Ohta, Mohammad A. Sayem, Nobuo Tsukamoto, Tomonori Yaguchi

    Immune checkpoint inhibitors (ICI) such as PD-1/PD-L1 antibodies (Abs) and CTLA4 Abs and T cell-based adoptive cell therapies are effective for patients with various cancers. However, response rates of ICI monotherapies are still limited due to lack of immunogenic antigens and various immune-resistant mechanisms. The latter includes adaptive immune resistance that is caused by anti-tumor T cells (e.g. PD-L1 induced by IFN-γ from T cells) and primary immune resistance that is caused by cancer cells (e.g. immunosuppressive cytokines produced by cancer cells). Further understanding of the immune-resistant mechanisms, which may be possible through comparative analyses of responders and non-responders to the immunotherapies, will lead to the identification of new diagnostic biomarkers and therapeutic targets for development of effective cancer immuno therapies.

  • High-grade complication is associated with poor overall survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-08
    Joey Wee-Shan Tan, Grace Hwei Ching Tan, Wai Yee Ng, Chin-Ann Johnny Ong, Claramae Shulyn Chia, Khee Chee Soo, Melissa Ching Ching Teo

    Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly used in peritoneal carcinomatosis (PC) management. This modality is criticized for its high morbidity and mortality. We evaluate the morbidity and mortality of patients undergoing this procedure in our institution.

  • Correction to: Impact of oral voriconazole during chemotherapy for acute myeloid leukemia and myelodysplastic syndrome: a Japanese nationwide retrospective cohort study
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-06
    Ikuyo Tsutsumi, Susumu Kunisawa, Chikashi Yoshida, Masanori Seki, Takuya Komeno, Kiyohide Fushimi, Satoshi Morita, Yuichi Imanaka

    In the original publication, in Figure 1 the month range of DPC Database has been given incorrectly.

  • Current issues and perspectives in PD-1 blockade cancer immunotherapy
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-03
    Kenji Chamoto, Ryusuke Hatae, Tasuku Honjo

    Abstract Programmed cell death 1 (PD-1) signal receptor blockade has revolutionized the field of cancer therapy. Despite their considerable potential for treating certain cancers, drugs targeting PD-1 still present two main drawbacks: the substantial number of unresponsive patients and/or patients showing recurrences, and side effects associated with the autoimmune response. These drawbacks highlight the need for further investigation of the mechanisms underlying the therapeutic effects, as well as the need to develop novel biomarkers to predict the lack of treatment response and to monitor potential adverse events. Combination therapy is a promising approach to improve the efficacy of PD-1 blockade therapy. Considering the increasing number of patients with cancer worldwide, solving the above issues is central to the field of cancer immunotherapy. In this review, we discuss these issues and clinical perspectives associated with PD-1 blockade cancer immunotherapy.

  • Treatment intensity and control rates in combining external-beam radiotherapy and radioactive iodine therapy for metastatic or recurrent differentiated thyroid cancer
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-02
    Kenji Makita, Yasushi Hamamoto, Shintaro Tsuruoka, Noriko Takata, Yusuke Urashima, Masao Miyagawa, Teruhito Mochizuki

    Abstract Background To evaluate the treatment outcomes of external-beam radiotherapy (EBRT) with or without radioactive iodine therapy (RAIT) for metastatic or recurrent lesions of differentiated thyroid cancer (DTC). Methods Between August 1997 and March 2018, 73 lesions (distant metastases, 50; regional lymph-node metastases, 17; postoperative tumor-bed recurrences, 6) in 36 patients that had received EBRT with or without RAIT were reviewed. Doses of EBRT were 8–70 Gy (median 40 Gy). Seventeen patients received RAIT after EBRT. Results Median follow-up time of imaging studies was 14 months (range 1–110 months). Two-year overall survival rates and control rates of EBRT sites were 71% and 62%, respectively. Two-year control rates for EBRT of < 30 Gy (n = 7), 30 Gy (n = 13), 31–49 Gy (n = 25), 50 Gy (n = 20), and > 50 Gy (n = 8) were 0%, 56%, 53%, 79%, and 100%, respectively. There were statistically significant differences in control rates between < 30 Gy and 30 Gy (p = 0.003), and between 50 Gy and > 50 Gy (p = 0.037). Control rates of > 50 Gy were significantly better compared to ≤ 50 Gy (p = 0.021). Two-year control rates with (n = 28) and without (n = 45) post-EBRT RAIT were 89% and 45%, respectively (p = 0.009). In multivariate analysis, EBRT of > 50 Gy and post-EBRT RAIT were significant independent factors for favorable control of EBRT sites (hazard ratio [HR], 5.72; 95% confidence interval [CI], 1.21–27.1; p = 0.028 and HR, 2.98; 95% CI, 1.28–6.98; p = 0.012, respectively). Conclusion EBRT of > 50 Gy and post-EBRT RAIT appeared to be useful for long-term control of EBRT sites for metastatic or recurrent lesions of DTC.

  • Barriers for sperm cryopreservation in advanced germ cell tumor patients: a 20-year experience
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-01
    Katsuhiro Ito, Kentaro Ichioka, Sachiko Dahal, Yoshiyuki Matsui, Takahiro Nakayama, Hiroshi Hatayama, Osamu Ogawa, Hiromitsu Negoro

    Abstract Background This study aimed to investigate barriers to sperm cryopreservation for patients with advanced germ cell tumors. Methods We reviewed data collected from patients who underwent chemotherapy for advanced germ cell tumors in our institutions from 1996 to 2016. We divided sperm cryopreservation procedures into three steps: offering information about sperm cryopreservation, patients’ decision making and sperm collection, and investigating the barriers in each step. Results Of the 91 patients, 43 (47%) successfully completed sperm cryopreservation. Thirty (33%) patients were not offered information about sperm cryopreservation from the doctors. Nine patients (9.9%) were offered but declined preservation. Nine patients (9.9%) were not able to provide sperm because of azoospermia (5) and anejaculation (4). Among 43 patients who successfully provided sperm, 10 (23%) had their cryopreserved sperm used for 21 cycles of in vitro fertilization. Ten pregnancies and 7 fatherhoods were achieved. Thirteen patients (30%) had their cryopreserved sperm discarded without use, whereas 20 (47%) continued preserving their sperm for a median 12.5 years. Conclusions Not only offering proper information about sperm cryopreservation, but also shared decision making prior to chemotherapy, and considering fertility preservation before orchiectomy are imperative. The rate of use of preserved sperm was relatively high, but decision making for sperm disposal should also be supported.

  • LINC00163 inhibits the invasion and metastasis of gastric cancer cells as a ceRNA by sponging miR-183 to regulate the expression of AKAP12
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2020-01-01
    Jun Zhang, Hai-yan Piao, Shuai Guo, Yue Wang, Tao Zhang, Zhi-chao Zheng, Yan Zhao

    Gastric cancer (GC) is the most common and aggressive cancer of the digestive system and poses a serious threat to human health. Since genes do not work alone, our aim was to elucidate the potential network of mRNAs and noncoding RNAs (ncRNAs) in this study.

  • Association of the primary tumor’s SUVmax with survival after surgery for clinical stage IA esophageal cancer: a single-center retrospective study
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-23
    Yutaka Miyawaki, Hiroshi Sato, Naoto Fujiwara, Shuichiro Oya, Hirofumi Sugita, Yasumitsu Hirano, Tomohiko Yamane, Shinichi Sakuramoto, Kojun Okamoto, Shigeki Yamaguchi, Isamu Koyama

    Abstract Background Compared to other esophageal cancers, clinical stage IA esophageal cancer generally has a good prognosis, although a subgroup of patients has a poor prognosis. Unfortunately, clinical diagnoses of invasion depth or lymph node metastasis are not always accurate, which make it difficult to identify patients with a high risk of postoperative recurrence using the tumor-node-metastasis staging system. Fluorodeoxyglucose-positron emission tomography may help guide the identification of malignant tumors and the evaluation of their malignant grade based on glucose metabolism. We aimed to evaluate the association between pre-operative fluorodeoxyglucose-positron emission tomography findings and the postoperative prognosis of patients with clinical stage IA esophageal cancer. Methods This single-center retrospective study evaluated pre-esophagectomy fluorodeoxyglucose-positron emission tomography findings from 38 patients with clinical stage IA esophageal cancer. Receiver operating characteristic curve analysis was performed to evaluate the prognostic significance of the primary tumor having low and high SUVmax values (cut-off: 3.56). Results Overall survival (log-rank p = 0.034) and progression-free survival (log-rank p = 0.008) were significantly different between the groups with low SUVmax values (n = 18) and high SUVmax values (n = 20). Furthermore, the primary tumor’s SUVmax value was related to pathological vascular invasion (p = 0.045) and distant metastasis (p = 0.042). Conclusion The SUVmax of the primary tumor is a predictor of postoperative survival for clinical stage IA esophageal cancer. Thus, using fluorodeoxyglucose-positron emission tomography to evaluate the primary tumor’s glucose metabolism may reflect the tumor’s grade and potentially compensate for inaccuracies in tumor-node-metastasis staging.

  • Postoperative D-dimer elevation affects tumor recurrence and the long-term survival in gastric cancer patients who undergo gastrectomy
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-21
    Kentaro Hara, Toru Aoyama, Tsutomu Hayashi, Masato Nakazono, Shinsuke Nagasawa, Yota Shimoda, Yuta Kumazu, Masakatsu Numata, Takanobu Yamada, Hiroshi Tamagawa, Manabu Shiozawa, Soichiro Morinaga, Norio Yukawa, Yasushi Rino, Munetaka Masuda, Takashi Ogata, Takashi Oshima

    Abstract Introduction We retrospectively evaluated the blood coagulation activity using the D-dimer level in the early period after gastrectomy and investigated whether postoperative hypercoagulation affects tumor recurrence and long-term survival in gastric cancer patients. Methods The study involved 650 patients who underwent curative resection for gastric cancer at Kanagawa Cancer Center between July 2009 and July 2013. They were divided into a low-D-dimer group (LD group) and high-D-dimer group (HD group) according to the median D-dimer level on postoperative day (POD) 7. The risk factors for overall survival (OS) and relapse-free survival (RFS) were identified. Results Of the 448 enrolled patients, 218 were classified into the LD group and 230 into the HD group. The 5-year OS rates after surgery were 90.8% and 81.3% in the LD and HD groups, respectively (p < 0.001). The 5-year RFS rates after surgery were 89.9% and 76.1% in the LD and HD groups, respectively (p < 0.001). A high D-dimer level on POD 7 (≥ 4.9 μg/ml) was identified as an independent predictive factor for both the OS (hazard ratio [HR] 1.955, 95% confidence interval [CI] 1.158–3.303, p = 0.012) and RFS (HR 2.182, 95% CI 1.327–3.589, p = 0.002). Furthermore, hematological recurrence was significantly more frequent in the HD group than in the LD group (p = 0.014). Conclusion A high D-dimer level on POD 7 may predict tumor recurrence and the long-term survival in patients who undergo gastrectomy for locally advanced gastric cancer. Patients with an elevated postoperative D-dimer level need careful observation and diagnostic imaging to timely detect tumor recurrence.

  • Comparable efficacy and safety between second-line and later-line nivolumab therapy for metastatic renal cell carcinoma
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-19
    Hiroki Ishihara, Toshio Takagi, Tsunenori Kondo, Hironori Fukuda, Hidekazu Tachibana, Kazuhiko Yoshida, Junpei Iizuka, Hirohito Kobayashi, Masayoshi Okumi, Hideki Ishida, Kazunari Tanabe

    The aim of this study was to compare the efficacy and safety of nivolumab as second-line and later-line (third-line or thereafter) therapy in metastatic renal cell carcinoma (mRCC).

  • Impact of peripheral neuropathy induced by platinum in first-line chemotherapy on second-line chemotherapy with paclitaxel for advanced gastric cancer
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-18
    Ryo Otsuka, Satoru Iwasa, Takako Yanai, Hidekazu Hirano, Hirokazu Shoji, Yoshitaka Honma, Natsuko Okita, Atsuo Takashima, Ken Kato, Hironobu Hashimoto, Masatoshi Sekiguchi, Yoshinori Makino, Narikazu Boku, Masakazu Yamaguchi

    Abstract Background Fluoropyrimidine plus platinum, followed by paclitaxel (PTX) plus ramucirumab is a recommended treatment strategy for advanced gastric cancer (AGC). We investigated how peripheral neuropathy (PN), induced by platinum in first-line chemotherapy, affected the tolerability of second-line chemotherapy with PTX (2nd-PTX). Methods The subjects were AGC patients who received second-line chemotherapy with PTX (2nd-PTX) after the failure of platinum-based chemotherapy between March 2015 and June 2018. We retrospectively reviewed PN severity, and dose reduction and/or discontinuation due to PN during 2nd-PTX, and compared the cumulative incidence of grade 2 PN between the two groups according to first-line chemotherapy containing oxaliplatin (L-OHP) or cisplatin (CDDP). Results The L-OHP and CDDP groups consisted of 50 patients each. PN severity before 2nd-PTX was grade 1/2 in 46/12% of patients in the L-OHP group, and 100/0% in the CDDP group. The worst grades of chemotherapy-induced PN during 2nd-PTX were grades 1/2/3 in 40/34/14% of patients in the L-OHP group, and 36/18/0% in the CDDP group. Median time to grade 2 PN after starting second-PTX was 2.5 months in the L-OHP group and 8.6 months in the CDDP group (hazard ratio 3.34, p = 0.002). The frequencies of a PN-related dose reduction and/or discontinuation of PTX were 18% in the L-OHP group and 8% in the CDDP group (p = 0.234). Conclusions The severity of PN and tolerability of 2nd-PTX may be affected by first-line chemotherapy with L-OHP or CDDP for AGC.

  • Prognostic scores for evaluating the survival benefit of regorafenib or trifluridine/tipiracil in patients with metastatic colorectal cancer: an exploratory analysis of the REGOTAS study
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-14
    Toshikazu Moriwaki, Shota Fukuoka, Toshiki Masuishi, Atsuo Takashima, Yosuke Kumekawa, Takeshi Kajiwara, Kentaro Yamazaki, Taito Esaki, Akitaka Makiyama, Tadamichi Denda, Yukimasa Hatachi, Takeshi Suto, Naotoshi Sugimoto, Masanobu Enomoto, Toshiaki Ishikawa, Tomomi Kashiwada, Eiji Oki, Yoshito Komatsu, Akihito Tsuji, Kenji Tsuchihashi, Daisuke Sakai, Hideki Ueno, Takao Tamura, Kimihiro Yamashita, Yasuhiro Shimada

    Although regorafenib or trifluridine/tipiracil (FTD/TPI) has been recognized as a later-line standard treatment in patients with metastatic colorectal cancer (mCRC), not all patients have beneficial outcomes. This study aimed to develop a prognostic scoring system for evaluating the overall survival (OS) benefit.

  • Prognostic significance of serum p53 antibody according to KRAS status in metastatic colorectal cancer patients
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-13
    Nobuya Daitoku, Yuji Miyamoto, Yuki Sakamoto, Ryuma Tokunaga, Yukiharu Hiyoshi, Yohei Nagai, Masaaki Iwatsuki, Shiro Iwagami, Naoya Yoshida, Hideo Baba

    Serum anti-p53 antibody is used clinically as a tumor marker of colorectal cancer. However, its prognostic significance in patients with metastatic colorectal cancer (mCRC) remains unclear. KRAS status may influence the host immune response against tumor progression. In the present study, we investigated the prognostic significance of serum anti-p53 in mCRC patients with wild-type KRAS and mutant KRAS treated with systemic chemotherapy.

  • Lack of association between interleukin-22 gene polymorphisms and cancer risk: a case–control study and a meta-analysis
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-12
    Huan Wang, Chao Huang, Yuxiao Liu, Puyu Yang, Yuxiao Liao, Xiuli Gu, Xianhong Feng, Bifeng Chen

    Abstract Background Interleukin-22 (IL22) has been implicated in inflammation and tumorigenesis. The association between IL22 gene polymorphisms and cancer risk has been widely explored. However, the limited sample sizes of previous studies may produce inadequate statistical power and conflicting results, which calls for further investigations. In this study, we recruited a total of 1490 cancer patients (480 liver cancer patients, 550 lung cancer patients, and 460 gastric cancer patients) and 800 normal controls to explore the associations between IL22 gene polymorphisms (rs1179251, rs2227485, rs2227511, and rs2227473) and cancer risk. Method The genotyping was performed with polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and Sanger sequencing. Results Our results showed that none of the four IL22 gene polymorphisms was associated with the risk of liver, lung or gastric cancer in Hubei Han Chinese population. To improve the statistical strength, a meta-analysis was further conducted. The results further confirmed our present findings and showed that rs1179251, rs2227485, and rs2227473 were not associated with cancer risk in total or stratified analysis. Conclusion Consequently, the rs1179251, rs2227485, rs2227511, and rs2227473 polymorphisms may not be associated with cancer risk. However, further investigations using larger samples in different ethnic populations are required.

  • Associations between expression levels of nine core nucleotide excision repair genes in lymphocytes and risk of head and neck squamous cell carcinomas in a Chinese population
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-12
    Pengyu Ren, Xiaorong Niu, Chang Liu, Junsong Liu, Honghui Li, Qian Zhao, Juanli Xing, Yanxia Bai, Yiqian Liang, Peng Han

    Head and neck squamous cell carcinomas (HNSCCs) are one of the most common cancers in the world, and nucleotide excision repair (NER) is involved in HNSCCs susceptibility. We investigated whether mRNA expression levels of nine core NER genes were associated with risk of HNSCCs in a Chinese population.

  • Long-term outcomes of multimodal therapy combining definitive chemoradiotherapy and salvage surgery for T4 esophageal squamous cell carcinoma
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-11
    Kotaro Sugawara, Koichi Yagi, Yasuhiro Okumura, Masato Nishida, Susumu Aikou, Hiroharu Yamashita, Hideomi Yamashita, Yasuyuki Seto

    Abstract Background Survival outcomes of patients with cT4 esophageal squamous cell carcinoma (ESCC) remain extremely poor. We aimed to investigate long-term outcomes and identify prognostic factors in patients treated by definitive chemoradiotherapy (dCRT) alone or with dCRT plus salvage surgery (SALV) for cT4 ESCC. Patients and methods In total, 73 patients completing dCRT were analyzed. Patients achieving clinical complete response (CR) received follow-up evaluations thereafter. For patients diagnosed with clinical partial response (PR), potentially curative SALV was generally performed. Possible prognostic factors included demographic data, tumor staging, blood chemistry profiles, and esophageal stenosis. Results The 1- and 3-year overall survival (OS) rates of the 73 patients were 67.1% and 40.8%, respectively. Twenty-one patients (29%) achieved clinical CR with dCRT alone. Among 35 patients (48%) with clinical PR, 31 underwent SALV and 4 opted for non-surgical treatments. In the dCRT-alone group (n = 42), patients with clinical CR-PR (n = 25) showed significantly better 3-year OS than those who responded poorly to dCRT (stable or progressive) (n = 17) (67.5% vs. 0%, P < 0.001). In the SALV group (n = 31), curative SALV (n = 22, 73%) provided significantly better 3-year OS than non-curative SALV (58.7% vs. 0%, P < 0.001). Multivariable analysis revealed stenosis before dCRT (P = 0.02) and pretreatment elevated CRP (P = 0.02) to be independently associated with poor outcomes. Conclusions The multimodal treatment strategy combining dCRT and SALV is rational for treating cT4 ESCC patients. When curative resection is feasible, SALV can provide good long-term survival outcome for patients who responded to dCRT but did not achieve clinical CR with dCRT alone.

  • A randomized, double-blind, comparison of radium-223 and placebo, in combination with abiraterone acetate and prednisolone, in castration-resistant metastatic prostate cancer: subgroup analysis of Japanese patients in the ERA 223 study
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-10
    Nobuaki Matsubara, Go Kimura, Hiroji Uemura, Hirotsugu Uemura, Motonobu Nakamura, Satoshi Nagamori, Atsushi Mizokami, Hiroaki Kikukawa, Makoto Hosono, Seigo Kinuya, Heiko Krissel, Jonathan Siegel, Yoshiyuki Kakehi

    ERA 223 compared concurrent abiraterone acetate/prednisolone (AAP) plus radium-223 with AAP plus placebo in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. We report data from a subgroup of Japanese patients in ERA 223.

  • Efficacy of modified FOLFOX6 chemotherapy for patients with unresectable pseudomyxoma peritonei
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-10
    Sakura Hiraide, Keigo Komine, Yuko Sato, Kota Ouchi, Hiroo Imai, Ken Saijo, Masahiro Takahashi, Shin Takahashi, Hidekazu Shirota, Masanobu Takahashi, Chikashi Ishioka

    Pseudomyxoma peritonei (PMP) is a rare malignancy, and there is insufficient evidence about systemic chemotherapy for this disease.

  • Low incidence of late recurrence in patients with intermediate-risk prostate cancer treated by intensity-modulated radiation therapy plus short-term androgen deprivation therapy
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-09
    Rihito Aizawa, Kenji Takayama, Kiyonao Nakamura, Takahiro Inoue, Toshinari Yamasaki, Takashi Kobayashi, Shusuke Akamatsu, Osamu Ogawa, Takashi Mizowaki

    This study evaluated the long-term outcomes of intensity-modulated radiation therapy (IMRT) combined with short-term neoadjuvant androgen deprivation therapy (ADT) in patients with intermediate-risk (IR) prostate cancer (PCa).

  • Changing pattern of tumor markers in recurrent colorectal cancer patients before surgery to recurrence: serum p53 antibodies, CA19-9 and CEA
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-09
    Mitsunori Ushigome, Hideaki Shimada, Yasuyuki Miura, Kimihiko Yoshida, Tomonori Kaneko, Takamaru Koda, Yasuo Nagashima, Takayuki Suzuki, Satoru Kagami, Kimihiko Funahashi

    The clinical impact of monitoring serum p53 antibodies, carbohydrate antigen19-9, and carcinoembryonic antigen in patients with colorectal cancer has not been fully evaluated.

  • The utility of ground-glass attenuation score for anticancer treatment-related acute exacerbation of interstitial lung disease among lung cancer patients with interstitial lung disease
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-09
    Naoki Nishiyama, Takayuki Honda, Manabu Sema, Tatsuo Kawahara, Yasuto Jin, Ichiro Natsume, Tomoshige Chiaki, Takaaki Yamashita, Yoshikazu Tsukada, Reiko Taki, Yoshihiro Miyashita, Kazuhito Saito, Tomoya Tateishi, Hiroyuki Sakashita, Yasunari Miyazaki

    Acute exacerbation (AE) of interstitial lung disease (ILD) is a fatal adverse event in the treatment of lung cancer patients with ILD. The value of pre-treatment radiological findings obtained by high-resolution computed tomography for the detection of anticancer treatment-related AE of ILD has not been established.

  • Prognostic significance of hyponatremia induced by systemic chemotherapy in a hospital-based propensity score-matched analysis
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-06
    Yosuke Sugiyama, Taku Naiki, Yoshihiko Tasaki, Yuki Kondo, Tomoya Kataoka, Toshiki Etani, Keitaro Iida, Satoshi Nozaki, Ryosuke Ando, Satoshi Osaga, Takahiro Yasui, Kazunori Kimura

    During chemotherapy, hyponatremia is one of the most frequently encountered adverse effects. This study aimed to investigate the prognostic impact of hyponatremia induced by systemic chemotherapy (HIC) using a propensity matching method in cumulative pooled data.

  • Therapeutic drug monitoring of regorafenib and its metabolite M5 can predict treatment efficacy and the occurrence of skin toxicities
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-12-05
    Daiki Taguchi, Masahiro Inoue, Koji Fukuda, Taichi Yoshida, Kazuhiro Shimazu, Kazuma Fujita, Hiroyuki Okuyama, Nobuhisa Matsuhashi, Akihito Tsuji, Kazuhiro Yoshida, Masatomo Miura, Hiroyuki Shibata

    Regorafenib is a multiple tyrosine kinase inhibitor, and the use of this drug is approved for the treatment of cancers that are resistant to chemotherapy, which include advanced colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma. However, the drug causes adverse events, including skin toxicities that require dose modification in approximately 75% of cases. At present, the blood concentration of regorafenib is not assessed in clinical settings; thus, we recently developed a method that can assess the blood concentration of the drug using high-performance liquid chromatography.

  • Detectability of prostate cancer in different parts of the gland with 3-Tesla multiparametric magnetic resonance imaging: correlation with whole-mount histopathology.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : null
    Katsuhiro Ito,Akihiro Furuta,Akira Kido,Yuki Teramoto,Shusuke Akamatsu,Naoki Terada,Toshinari Yamasaki,Takahiro Inoue,Osamu Ogawa,Takashi Kobayashi

    BACKGROUND We investigated whether the detectability of prostate cancer with 3-Tesla (3T) multiparametric magnetic resonance imaging (mpMRI) differs by tumor location. METHODS We identified 136 patients with prostate cancer who underwent 3-T mpMRI before prostatectomy at a single academic center. Two uroradiologists scored all MRIs with Prostate Imaging-Reporting and Data System version 2 (PI-RADS v2). A genitourinary pathologist mapped tumor foci from serial whole-mount radical prostatectomy sections. We assessed concordance of images with cancer sites. Tumor foci with Gleason score ≥  3 + 4 or volume ≥ 0.5 mL were considered significant. RESULTS A total of 122 foci in 106 cases were identified with mpMRI. Twenty-four were PI-RADS 3, 52 were 4, and 46 were 5. A total of 274 tumor foci were identified with whole-mount pathology. The sensitivity stratified by location to detect significant cancer with a PI-RADS cutoff value of 3 was 56.0% overall, 50.0% in the peripheral zone (PZ), 71.2% in the transitional zone (TZ), 62.4% anterior, 49.5% posterior, 42.0% apical, 63.6% in the midgland, and 43.8% in the gland base. In multivariate analysis, tumor location was not a significant predictor of identification by mpMRI. Tumor volume, Gleason score, and index tumor status were significantly associated with identification by mpMRI. CONCLUSIONS mpMRI detected the majority of high-grade and large cancers, but had low sensitivity in the PZ, posterior, and apex and base of the gland. The high prevalence of low-volume, low-Gleason score index tumors, as well as satellite tumors in those areas, accounted for the difference.

  • Predictive value of 18F-FDG PET/CT for acute exacerbation of interstitial lung disease in patients with lung cancer and interstitial lung disease treated with chemotherapy.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : null
    Kimitaka Akaike,Koichi Saruwatari,Seitaro Oda,Shinya Shiraishi,Hiroshi Takahashi,Shohei Hamada,Shinji Iyama,Yuko Horio,Yusuke Tomita,Sho Saeki,Shinichiro Okamoto,Hidenori Ichiyasu,Kazuhiko Fujii,Takuro Sakagami

    BACKGROUND We examined whether fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) performed before chemotherapy could predict the onset of acute exacerbation of interstitial lung disease (AE-ILD) in patients with lung cancer and ILD treated with chemotherapy. METHODS Thirty-three patients with lung cancer and ILD who underwent 18F-FDG PET/CT and were treated with chemotherapy at Kumamoto University Hospital between April 2006 and March 2018 were retrospectively analyzed. The maximum standardized uptake value (SUVmax) of interstitial lesions was measured to quantify the background ILD activity. A prediction model of AE-ILD was developed using logistic regression analyses for the SUVmax, and receiver operating characteristic (ROC) curve analyses were conducted. RESULTS Among the 33 patients, 7 experienced AE-ILD. The SUVmax of contralateral interstitial lesions was significantly higher in patients with vs. without AE-ILD (median SUVmax: 2.220 vs. 1.795, P = 0.025). Univariable logistic regression analyses showed that the SUVmax of contralateral interstitial lesions trended towards being significantly associated with the onset of AE-ILD [odds ratio: 8.683, 95% confidence interval (CI) 0.88-85.83, P = 0.064]. The area under the ROC curve of the SUVmax for predicting AE-ILD was 0.780 (95% CI 0.579-0.982, P = 0.025). The optimal cut-off value for SUVmax was 2.005, with sensitivity and specificity values of 0.857 and 0.769, respectively. CONCLUSIONS The SUVmax of contralateral interstitial lesions in 18F-FDG PET/CT images might be useful for predicting the onset of AE-ILD in patients with lung cancer and ILD treated with chemotherapy.

  • Preoperative lymphocyte-to-monocyte ratio predicts postoperative infectious complications after laparoscopic colorectal cancer surgery.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : null
    Tunyaporn Kamonvarapitak,Akihisa Matsuda,Satoshi Matsumoto,Supaschin Jamjittrong,Nobuyuki Sakurazawa,Youichi Kawano,Takeshi Yamada,Hideyuki Suzuki,Masao Miyashita,Hiroshi Yoshida

    BACKGROUND AND AIM Postoperative infectious complications (POI), which can increase length of hospital stay, medical cost, and worsen overall survival, are a concern in minimally invasive colorectal cancer (CRC) surgeries. Recent reports showed that relatively new inflammation-based score, lymphocyte-to-monocyte ratio (LMR) is an independent predictor of long-term outcomes after CRC surgeries. In this study, LMR was evaluated as a predictor of short-term postoperative outcomes. PATIENTS AND METHODS This was a single-institutional retrospective study of 211 consecutive patients who had undergone laparoscopic CRC surgery with primary tumor resection from January 2014 to August 2015 at Nippon Medical School Chiba Hokusoh Hospital. The patients were divided into two groups (no POI; n = 176 and POI; n = 35). The associations between inflammation-based scores, namely neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and LMR, and the occurrence of POI were investigated. Receiving operator characteristic curve analysis was used to determine the cutoff point of preoperative LMR. RESULTS Low LMR (cut-off 3.46), long operative time, and smoking were found to be independent predictors of POI in a multivariate analysis (LMR: Odds ratio 5.61, 95% confidence interval 1.98-15.9, P = 0.001). Patients with low LMR also appeared to have more advanced and aggressive tumours. CONCLUSION This is the first study to report that the lower LMR is a predictive factor of POI after laparoscopic CRC surgery, and it may provide additional information for treatment decisions to prevent POI.

  • The efficacy and safety of the addition of olanzapine to ondansetron and dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : null
    Veerisa Vimolchalao,Siwat Sakdejayont,Ploytuangporn Wongchanapai,Shama Sukprakun,Pattama Angspatt,Wilai Thawinwisan,Piyachut Chenaksara,Virote Sriuranpong,Chanida Vinayanuwatikun,Napa Parinyanitikun,Nattaya Poovorawan,Suebpong Tanasanvimon

    OBJECTIVE To evaluate the efficacy and safety of the addition of olanzapine to ondansetron and dexamethasone for chemotherapy-induced nausea vomiting (CINV) prevention in patients receiving highly emetogenic chemotherapy (HEC). METHODS In this randomized, double-blind, placebo-controlled, crossover study, we randomly assigned chemotherapy-naïve patients receiving HEC to receive olanzapine or placebo in addition to ondansetron and dexamethasone. All subjects were crossed over to another treatment arm on second-cycle chemotherapy. The primary endpoint was complete response (CR) rate defined as no vomiting and no use of rescue drugs. RESULTS At the first cycle, there were significantly more patients with CR in the olanzapine group than in the placebo group in overall phase (68.7% vs. 25.0%, p < 0.001), acute phase (0-24 h) (75.0% vs. 31.2%, p < 0.001) and delayed phase (24-120 h) (68.7% vs. 43.7%, p = 0.038). After crossover, there were significantly more patients with CR in the olanzapine group than in the placebo group in overall phase (67.2% vs. 25.0%, p < 0.001), acute phase (71.9% vs. 32.8%, p < 0.001) and delayed phase (67.2% vs. 37.5%, p < 0.001). In crossover analysis, the olanzapine group had significantly lower mean nausea (1.28 vs. 3.05, p < 0.001) and fatigue (3.5 vs. 4.58, p < 0.001) scores but higher mean appetite (2.5 vs. 1.55, p = 0.003) and sleepiness (3.26 vs. 2.2, p < 0.001) scores. There were no grade 3 and 4 anti-emetic-drug-related toxicities. Mean QT interval changes did not different between two groups (-4.30 vs. -1.86, p = 0.69). CONCLUSION The addition of olanzapine to ondansetron and dexamethasone significantly improved CINV prevention and was safe in patients receiving HEC.

  • Significance of RAS mutations in pulmonary metastases of patients with colorectal cancer.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : null
    Takamichi Igarashi,Kimihiro Shimizu,Kengo Usui,Takehiko Yokobori,Yoichi Ohtaki,Seshiru Nakazawa,Kai Obayashi,Toshiki Yajima,Sumihito Nobusawa,Takahiro Ohkawa,Ryuji Katoh,Yoko Motegi,Hiroomi Ogawa,Norifumi Harimoto,Tatsuo Ichihara,Yasumasa Mitani,Hideaki Yokoo,Akira Mogi,Ken Shirabe

    BACKGROUND RAS/BRAF mutations of colorectal cancer (CRC) play a crucial role in carcinogenesis and cancer progression and need to be considered for the therapeutic strategy choice. We used next-generation-sequencing (NGS) technology to assess RAS/BRAF mutation differences between primary CRC and corresponding pulmonary metastases (PMs). METHODS We examined the mutation statuses of the KRAS 12/13/61/146, NRAS 12/13/61/146, and BRAF 600 codons in genomic DNA from fresh-frozen or formalin-fixed paraffin-embedded tissues derived from 34 primary lesions and 52 corresponding PMs from 36 patients with CRC. RESULTS We found RAS mutations in 76% (26/34) of primary CRC lesions and in 86% (31/36) of PMs. While 27% (7/26) of the primary CRC RAS mutations were heterogeneous, all the RAS mutations in PMs were homogeneous. Of the mutations in PMs, 71% (22/31) were KRAS G>A transitions, of which 82% (18/22) were KRAS G12D or G13D. The RAS mutation discordance between primary tumors and PMs was 12.1% (4/33). RAS mutations with the same genotyping were detected in all synchronous and metachronous PMs from 9 patients. We found no BRAF mutations in either primary or pulmonary tissues. CONCLUSION Our NGS analysis suggests that RAS mutations of PM of patients with CRC are more common than initially thought. The presence of KRAS mutations in CRC specimens, especially G12D or G13D mutations, seems to promote PM formation.

  • Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-07-06
    Kazuo Tamura,Motohide Kaneda,Mashu Futagawa,Miho Takeshita,Sanghyuk Kim,Mina Nakama,Norihito Kawashita,Junko Tatsumi-Miyajima

    Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal-dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family, it results from a loss-of-function mutation in one of four different genes (MLH1, MSH2, MSH6, and PMS2) encoding mismatch repair proteins. Being located immediately upstream of the MSH2 gene, EPCAM abnormalities can affect MSH2 and cause Lynch syndrome. Mismatch repair proteins are involved in repairing of incorrect pairing (point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites) that can arise during DNA replication. MSH2 forms heterodimers with MSH6 or MSH3 (MutSα, MutSβ, respectively) and is involved in mismatch-pair recognition and initiation of repair. MLH1 forms a complex with PMS2, and functions as an endonuclease. If the mismatch repair system is thoroughly working, genome integrity is maintained completely. Lynch syndrome is a state of mismatch repair deficiency due to a monoallelic abnormality of any mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently shown as a microsatellite instability in tumors. Children with germline biallelic mismatch repair gene abnormalities were reported to develop conditions such as gastrointestinal polyposis, colorectal cancer, brain cancer, leukemia, etc., and so on, demonstrating the need to respond with new concepts in genetic counseling. In promoting cancer genome medicine in a new era, such as by utilizing immune checkpoints, it is important to understand the genetic and genomic molecular background, including the status of mismatch repair deficiency.

  • Nivolumab in patients with unresectable locally advanced or metastatic urothelial carcinoma: CheckMate 275 2-year global and Japanese patient population analyses.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-06-21
    Chikara Ohyama,Takahiro Kojima,Tsunenori Kondo,Yoshio Naya,Takamitsu Inoue,Yoshihiko Tomita,Masatoshi Eto,Shinichi Hisasue,Hirotsugu Uemura,Wataru Obara,Eiji Kikuchi,Padmanee Sharma,Matthew D Galsky,Arlene Siefker-Radtke,Gary Grossfeld,Sandra Collette,Kyna Gooden,Go Kimura

    BACKGROUND Nivolumab has demonstrated antitumor activity and manageable safety in the single-arm, phase II CheckMate 275 study in patients with unresectable locally advanced or metastatic platinum-resistant urothelial carcinoma. We report updated results of the global population and a subanalysis of Japanese patients from this study. METHODS Patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) confirmed by blinded independent review committee (BIRC) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS) by BIRC and overall survival (OS). Safety was also reported. The minimum follow-up was 21 months. RESULTS Overall, 270 patients were treated with nivolumab globally; 23 patients were Japanese. In the global and Japanese populations, respectively, ORR per BIRC was 20.4% and 21.7%; median PFS was 1.9 (95% confidence interval [CI] 1.9-2.3) and 3.8 months (95% CI 1.9-7.2); and median OS was 8.6 (95% CI 6.1-11.3) and 21.0 months (95% CI 7.2-not reached). The most common any grade treatment-related adverse events were fatigue (18.1%) and diarrhea (12.2%) in the global population; the most common in the Japanese population were diarrhea (26.1%) and pyrexia (13.0%). Grade 3 or 4 treatment-related adverse events occurred in 61 (22.6%) and seven (30.4%) of the global and Japanese patients, respectively. CONCLUSIONS Nivolumab continues to show antitumor activity and survival in the global population of CheckMate 275. Meaningful clinical benefit was also observed in Japanese patients. No new safety signals were identified.

  • Elevated serum soluble interleukin-2 receptor levels increase malignancy-related risk in patients on chronic hemodialysis.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-06-12
    Chen XiaoHong,Shen Bo,Xiang FangFang,Guo Man,Zou JianZhou,Liu ZhongHua,Lv WenLv,Cao XueSen,Ding XiaoQiang,Zhang Boheng

    BACKGROUND Patients on chronic hemodialysis (HD) have an increased incidence of malignancy due to decreased immunity. Soluble interleukin-2 receptor (sIL-2R), as an immunomodulator, seemed to have an effect in the process of malignancy. In this study, we aimed to evaluate the clinical significance of increased sIL-2R in the course of malignancy among HD patients. METHODS Patients who undergoing chronic hemodialysis were followed for 24 months. Risk factors for malignancy events and malignancy-related mortality during the 2-year follow-up period were investigated among various clinicopathological variables. RESULTS Of the 363 patients included in this research, 47 patients (12.95%) had a prior history of treated malignancy. During the 2-year follow-up period, malignancy events were detected in 15 (4.12%) patients. Sixty-seven patients died during the study period, of which nine patients (13.43%) were died of malignancy. Malignancy events reduced 2-year mortality significantly (log-rank = 23.02, P < 0.0001). Both high sIL-2R levels ( ≥ 2-fold upper limit of the normal value) (OR 6.6, P = 0.006) and a prior history of treated malignancy (OR 4.12, P = 0.018)were identified by multivariate logistic analysis as independent determinants for malignancy events. However, only the levels of sIL-2R (used as a continuous variable) had the significantly predictive effect on malignancy events and malignancy-related mortality in the following 2 years. CONCLUSIONS Elevated sIL-2R levels was commonly seen in serum of HD patients. And this elevated level increased the risk of malignancy. Aside from its role as a biomarker, sIL-2R may also exert biological effects in the course of malignancy.

  • Tumor growth patterns on magnetic resonance imaging and treatment outcomes in patients with locally advanced cervical cancer treated with definitive radiotherapy.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-05-13
    Shintaro Tsuruoka,Masaaki Kataoka,Yasushi Hamamoto,Akifumi Tokumasu,Kotaro Uwatsu,Hiromitsu Kanzaki,Noriko Takata,Hirofumi Ishikawa,Ayaka Ouchi,Teruhito Mochizuki

    BACKGROUND To evaluate the prognostic value of tumor growth patterns on magnetic resonance (MR) images in patients with locally advanced cervical cancer (LACC) treated with definitive radiotherapy or concurrent chemoradiotherapy (RT/CCRT). METHODS We retrospectively reviewed 102 patients with LACC who received definitive RT/CCRT and who underwent MR imaging before RT/CCRT. Growth patterns on pretreatment T2-weighted MR images were classified into expansive or infiltrative type according to tumor morphologic patterns in the myometrium and/or parametrial space. RESULTS The median age was 60 years (range 26-90 years). The median follow-up time was 47.7 months (range 5.7-123 months). The numbers of patients with stages IB, II, III, and IVA were 17, 39, 43, and 3, respectively. The 3-year overall survival (OS) rates for stages IB, II, III, and IV were 87%, 76%, 74%, and 67%, respectively. Regarding growth patterns on MR images, 31 were of expansive type and 71 were of infiltrative type. The infiltrative type was significantly associated with lower OS and locoregional recurrence-free survival (LRRFS) than the expansive type (3-year OS, 70% vs. 93%, p = 0.003; 3-year LRRFS, 64% vs. 94%, p = 0.001). On multivariate analysis, infiltrative tumor growth patterns were a significant independent factor for low OS (hazard ratio [HR], 3.81; 95% confidence interval [CI] 1.26-16.7; p = 0.015) and low LRRFS (HR, 4.27; 95% CI 1.43-18.5; p = 0.007). CONCLUSION Tumor growth patterns on MR images could be an indicator of survival and locoregional control in patients with LACC treated with definitive RT/CCRT.

  • Does the extension of the type of hysterectomy contribute to the local control of endometrial cancer?
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-05-10
    Tetsuya Hasegawa,Megumi Furugori,Kazumi Kubota,Mikiko Asai-Sato,Aiko Yashiro-Kawano,Hisamori Kato,Yuka Oi,Hiroyuki Shigeta,Keiko Segawa,Masakazu Kitagawa,Yuko Mine,Haruya Saji,Reiko Numazaki,Yasuyo Maruyama,Emi Ohnuma,Hanako Taniguchi,Ken Sugiura,Etsuko Miyagi,Tatsuya Matsunaga,

    OBJECTIVE To examine the necessity and sufficiency of different types of hysterectomy for the surgical treatment of endometrial cancer. METHODS This was a multicenter collaborative study conducted by 11 institutions. Among patients with stage I-III endometrial cancer who underwent surgery as the initial treatment (only chemotherapy was provided if adjuvant therapy was needed) from 2001 to 2012, we retrospectively examined the type of hysterectomy, clinicopathological factors, recurrence rate over a maximum period of 5 years, and the site of recurrence. The local recurrence rate was examined by univariate and multivariate analyses. RESULTS Among 1335 patients, 982 (73.6%) underwent simple hysterectomy (SH) and 353 (26.4%) underwent modified radical hysterectomy (mRH) and were observed for a mean duration of 51.8 months. No significant difference was observed in the rate of local recurrence between the SH and mRH groups (p = 0.928). In multivariate analysis, clinicopathological factors independently associated with localized recurrence included postmenopausal status [hazard ratio (HR) 5.036, 95% confidence interval (CI) 1.506-16.841, p = 0.009], with stages II (HR 3.337, 95% CI 1.701-6.547, p < 0.001) and III (HR 2.445, 95% CI 1.280-4.668, p = 0.007), vs stage I and histological type 2 (HR 1.610, 95% CI 0.938-2.762, p = 0.001). CONCLUSIONS For endometrial cancer patients requiring surgery, the selection of a more extensive type of hysterectomy did not reduce the rate of local recurrence. Therefore, there is little significance in performing mRH in such cases.

  • Prognostic value of serum C-reactive protein level prior to second-line treatment in intermediate risk metastatic renal cell carcinoma patients.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-05-09
    Kimiharu Takamatsu,Ryuichi Mizuno,Nobuyuki Tanaka,Toshikazu Takeda,Shinya Morita,Kazuhiro Matsumoto,Takeo Kosaka,Toshiaki Shinojima,Eiji Kikuchi,Hiroshi Asanuma,Masafumi Oyama,Shuji Mikami,Mototsugu Oya

    BACKGROUND The later-line treatment of metastatic renal cell carcinoma (mRCC) has been drastically changing by the development of immune-oncology drugs and molecular targeted treatment in recent years. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is useful for second-line setting, this model has the problem that over 50% patients are classified as intermediate risk group. The aim of this study is to evaluate whether the serum C-reactive protein (CRP) levels prior to second-line treatment could divide intermediate risk group patients. METHODS We retrospectively reviewed 82 consequent intermediate-risk mRCC patients who received second-line molecular targeted therapy. We classified patients who had serum CRP higher than 0.5 mg/dl in elevated CRP group because the median baseline serum CRP level before second-line treatment was 0.51 mg/dl. We assessed the prognostic impact of serum CRP levels prior to second-line treatment initiation to predict overall survival (OS). RESULTS Thirty-three out of 82 (40%) patients demonstrated elevated baseline CRP levels. The median OS of elevated and non-elevated CRP group was 11.5 (95% CI 5.4-17.5) and 29.4 (95% CI 25.5-33.5) months, respectively (p = 0.001). The serum CRP elevation could predict prognosis in intermediate risk patients treated with second-line treatment (HR 2.5, 95% CI 1.4-4.2, p = 0.001). CONCLUSIONS The serum CRP levels after first-line treatment termination could divide intermediate risk group mRCC patients into two prognostic subgroups in second-line targeted treatment setting.

  • Mutation landscape and tumor mutation burden analysis of Chinese patients with pulmonary sarcomatoid carcinomas.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-05-09
    Xiaohong Liang,Qing Li,Bin Xu,Song Hu,Qianyun Wang,Yan Li,Yun Zong,Sujuan Zhang,Chong Li

    INTRODUCTION Pulmonary sarcomatoid carcinoma (PSC) is a group of rare tumors with the presence of both cancerous and sarcoma components in tumor. In this study, we explore their cancer genomic background and the relationship with clinical prognosis. MATERIALS AND METHODS A cohort of 32 PSC patients were retrospectively collected from the First People's Hospital of Changzhou between 2005 and 2016. Targeted next-generation sequencing (NGS) of 416 cancer-relevant genes was performed on 32 PSC tumors. RESULTS EGFR (28%), KRAS (22%), and MET (16%) are the most commonly mutated oncogenes, while the top mutated tumor suppressor genes are TP53 (69%) and RB1 (25%). The majority of EGFR mutations are rare mutations, some of which have not been reported before. Moreover, 4 out of 6 MET alterations are exon 14 skipping, far more frequent than in NSCLC. Interestingly, ARID1A was found to be co-mutated with TP53 at all times. The tumor mutation burden (TMB) is ranging from 3.3 to 52.2 per megabase (MB) with a median of 11.7 per MB and 13 patients have more than 20 mutations per MB. Patients mutated in BRCA2, KMT2B, SMARCA4 or TSC2 have significantly higher TMB compared to patients with wide-type genes. CONCLUSION Our study characterizes the genetic background of Chinese PSC patients and demonstrates the importance of involving EGFR rare mutations and MET exon 14 skipping targeted therapies into clinical trials for treating PSC patients. High TMB are seen in about 40.6% Chinese patients with PSC, which could benefit from immune checkpoint inhibitors.

  • Clinical background and outcomes of risk-reducing salpingo-oophorectomy for hereditary breast and ovarian cancers in Japan.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-05-06
    Hidetaka Nomura,Masayuki Sekine,Shiro Yokoyama,Masami Arai,Takayuki Enomoto,Nobuhiro Takeshima,Seigo Nakamura

    BACKGROUND This study aimed to identify the clinical background and treatment outcomes of risk-reducing salpingo-oophorectomy (RRSO) in Japan for women with hereditary breast and ovarian cancer (HBOC). METHODS In the present retrospective observational study, we examined the Japanese HBOC Consortium's (JHC) database. This database contains 11,711 probands who received BRCA genetic testing, or their relatives, with any cancer in 2433 pedigrees. This study was supported by the registration committee of the JHC. RESULTS We analyzed 488 individuals diagnosed with HBOC, of which 153 (31.4%) underwent RRSO. Of the latter patients, 88 carried BRCA1 mutation (B1); 62 carried BRCA2 mutation (B2); and 3 carried both mutations. During a mean follow-up period of 2.6 years (range 0-12.6), one patient developed a primary peritoneal cancer (PPC). Clinical background comparison for individuals who underwent RRSO vs. those > 45 years of age who did not undergo RRSO revealed that significant factors were represented by B1 (p < 0.0001); child bearing (p < 0.00001); and breast cancer history (p < 0.01). However, family history of ovarian cancer and menopause status were not significantly different. CONCLUSION Over 30% HBOC's in Japan underwent RRSO. In Japan, individuals with breast cancer history and B1 generally underwent RRSO, whereas those who did not bear a child mostly avoided RRSO.

  • Establishment and validation of a novel survival prediction scoring algorithm for patients with non-small-cell lung cancer spinal metastasis.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-04-28
    Shizhao Zang,Qin He,Qiyuan Bao,Yuhui Shen,Weibin Zhang

    BACKGROUND This study was to develop an algorithm capable of predicting the survival of patients with NSCLC spinal metastasis for individualized therapy. METHODS We identified 176 consecutive patients with NSCLC spinal metastasis between 2006 and 2017. Twenty-four features, including age, gender, smoking, KPS, paralysis, histological subtype, tumor stage, surgery, EGFR status, CEA, CA125, CA19-9, NSE, SCC, CYFRA21-1, calcium, AKP, albumin, the number of spinal, extra-spinal bone and visceral metastasis, time to metastasis, pathological fracture, and primary or secondary metastasis, were retrospectively analyzed. Features associated with survival in the multivariate analyses were included in a scoring model, which was prospectively validated in another 63 patients (NCT03363685). RESULTS The median follow-up period was 12.00 months (interquartile range 6.00-23.40 months). One hundred forty-seven patients died during follow-up, with a median survival of 13.6 months being observed. Multivariate analysis revealed that the following features were associated with survival: age, smoking, CA125, SCC, KPS, and EGFR status. A scoring system based on these features was created to stratify patients into low-risk (0-3), intermediate-risk (4-6) and high-risk (7-10) groups, whose estimated median survival times 29.10, 10.40 and 3.90 months, respectively. The Harrell's c-index was 0.72. Model validation supported this model's validity and reproducibility. CONCLUSIONS In patients with NSCLC spinal metastasis, survival was associated with age, smoking, CA125, SCC, KPS, and EGFR status. A validated scoring system based on these features was devised that can predict the survival times of those patients. This scoring system provides a basis for applying the NOMS framework and for facilitating individual treatment.

  • Trends in incidence and long-term survival of Japanese women with vulvar cancer: a population-based analysis.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-04-27
    Yusuke Tanaka,Yutaka Ueda,Mamoru Kakuda,Asami Yagi,Akiko Okazawa,Tomomi Egawa-Takata,Shinya Matsuzaki,Eiji Kobayashi,Kiyoshi Yoshino,Keisuke Fukui,Yuri Ito,Tomio Nakayama,Tadashi Kimura

    OBJECTIVE The incidence and long-term survival analysis for vulvar cancer, due to its rarity, has not been fully described in Asian population. The objective of the study is to determine the trends in incidence and long-term survival for vulvar cancer in a Japanese population, using a population-based cancer registry data in Osaka, Japan. METHODS The age-standardized incidence rate of 389 cases of vulvar squamous cell carcinoma (SCC) diagnosed between 1976 and 2010 was calculated, using the 1985 model population of Japan. The annual percentage change (APC) of the age-standardized incidence was estimated by the joinpoint regression models. The 5- and 10-year relative survival of 290 cases with vulvar SCC diagnosed between 1976 and 2008 were analyzed, using a cohort or period approach. Using the 10-year relative survival, the conditional 5-year survival for patients who lived for some years after diagnosis was also calculated. RESULTS We have found that the age-standardized incidence rate for vulvar cancer trended downward during the period of 1979-1992 (APC - 6.3%; 95% confidence interval (CI) [- 11.3% to - 1.0%]), whereas it trended upward from 1993 to 2010 (APC 1.9%; 95% CI [- 0.7% to 4.6%]). There was no statistically significant difference for the 5- and 10-year relative survival between the two periods of 1976-2000 and 2001-2008. A statistically significant increase in the conditional 5-year survival at 2 years after diagnosis was observed (48.4%; 95% CI [41.1-55.3] versus 75.6%; 95% CI [64.0-83.9]). CONCLUSION Despite an increasing trend in vulvar cancer incidence among Japanese population, the relative survival rate for vulvar cancer did not change over the 35 years of this study. We found that the conditional 5-year survival for vulvar cancer, as patients survived additional years, approached within reach of 100%. These data can provide valuable information for both patients and clinicians.

  • Association of SNPs in the OBFC1 gene and laryngeal carcinoma in Chinese Han male population.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-04-25
    Peng Han,Zhongping Dang,Zhen Shen,Hao Dai,Yanxia Bai,Baiya Li,Yuan Shao

    BACKGROUND Laryngeal carcinoma (LC) is one of common diagnosed head and neck malignancies. Telomere length has been reported involved in malignant transformation and tumorigenesis. We speculate that single nucleotide polymorphisms (SNPs) in telomere length-related gene oligonucleotide/oligosaccharide-binding folds containing 1 (OBFC1) may have an association with LC in Chinese Han male population. METHODS To prove this hypothesis, we performed a case-control study to analyze the OBFC1 polymorphisms in 172 LC patients and 180 healthy controls. A total of five SNPs (i.e., rs9325507, rs3814220, rs12765878, rs11191865, rs9420707) were selected for further genotyping. RESULTS There was a significant difference in rs9325507 T allele frequency (OR = 0.88, 95% CI 0.64-1.21, P = 0.036) and rs11191865 A allele frequency (OR = 0.86, 95% CI 0.62-1.18, P = 0.009) between patient and control groups. In addition, the rs9325507 T/C genotype, rs3814220 G/A genotype, rs12765878 C/T genotype and rs11191865 A/G genotype had a lower risk of LC based on the results of logistic regression model analysis. CONCLUSIONS The results indicate a potential association between OBFC1 and LC risk in Chinese Han male population. Further work is required to confirm these results and explore the mechanisms of these effects.

  • Current status of site-specific cancer registry system for the clinical researches: aiming for future contribution by the assessment of present medical care.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-04-24
    Koichi Hirata,Masafumi Imamura,Toshiyoshi Fujiwara,Tsuguya Fukui,Toshiharu Furukawa,Mitsukazu Gotoh,Kenichi Hakamada,Megumi Ishiguro,Yoshihiro Kakeji,Hiroyuki Konno,Hiroaki Miyata,Masaki Mori,Kenji Okita,Masami Sato,Akiko Shibata,Ichiro Takemasa,Michiaki Unno,Kohei Yokoi,Toshihiko Nishidate,Masahiko Nishiyama

    BACKGROUND The current status of site-specific cancer registry has not been elucidated, but sufficient system is found in some societies. The purpose of this study was to clear the present condition of site-specific cancer registries in Japan and to suggest for the improvement. METHODS The questionnaire was conducted by the study group of the Ministry of Health, Labor, and Welfare. It consisted of 38 questions, conflicts of interest, clinical research method, informed consent and funding for registry. We distributed this questionnaire to 28 academic societies, which had published the clinical practice guideline(s) assessed under Medical Information Network Distribution Service (MINDS). RESULTS The concept of the importance in assessment for medical quality by the data of the site-specific cancer registry was in good consensus. But the number of the society with the mature registry was limited. The whole-year registry with the scientific researches in the National Clinical Database (NCD) and in the Translational Research Informatics Center (TRI) might seem to be in success, because assured enhancement may be estimated. Now, academic societies have the structural factors, i.e., the financial limitation in the registry maintenance and the data analysis, and in the difficulty of employment of the researchers with skill and talent. CONCLUSIONS To manage the site-specific cancer registry effectively, the scientific registry system will be essentially important. Each academic society had much experienced highly qualified clinical researches in past. Accordingly, the scientific suggestion and co-operation should be of great importance for the improvement.

  • Cell-type-specific sensitivity of bortezomib in the methotrexate-resistant primary central nervous system lymphoma cells.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-04-18
    Azusa Hayano,Yasuo Takashima,Ryuya Yamanaka

    BACKGROUND Methotrexate (MTX) is used in first-line treatment of primary central nervous system lymphoma (PCNSL), but most cases result in relapse-acquired resistance to MTX. However, only few studies have reported on internal changes and chemotherapies in PCNSL. METHODS In this study, we generated two MTX-resistant PCNSL cell lines, designated MTX-HKBML and MTX-TK, in addition to a MTX-resistant Burkitt lymphoma cell line, designated MTX-RAJI. We examined gene expression changes and drug sensitivity to a proteasome inhibitor, bortezomib, in these cells. RESULTS Cytotoxic tests revealed that the 50% inhibitory concentration for MTX in MTX-HKBML is markedly higher than that in the other two cell lines. Expression of the genes in MTX and folate metabolisms, including gamma-glutamyl hydrolase and dihydrofolate reductase, are upregulated in both MTX-HKBML and MTX-TK, whereas the gene expression of folylpolyglutamate synthetase, thymidylate synthase, and methylenetetrahydrofolate dehydrogenase 1 were upregulated and downregulated in MTX-HKBML and MTX-TK, respectively, on the other hand, bortezomib sensitivity was observed in MTX-TK, as compared with control TK, but not in MTX-HKBML. CONCLUSION These results indicate the cell-type-specific changes downstream of metabolic pathways for MTX and folate, bortezomib sensitivity, and purine and pyrimidine syntheses, in each PCNSL cell line. The MTX-resistant lymphoma cell lines established may be useful for in vitro relapse models for MTX and development of salvage chemotherapy and drug discovery.

  • Feasibility of initial treatment in elderly patients with ovarian cancer in Japan: a retrospective study.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-04-18
    Seiko Bun,Mayu Yunokawa,Takahiro Ebata,Mayumi Kobayashi Kato,Tatsunori Shimoi,Tomoyasu Kato,Kenji Tamura

    PURPOSE The purpose of this study was to evaluate the real world situation and clarify the problem in initial treatment for elderly patients with ovarian cancer in Japan. METHODS We used the ovarian cancer database, containing all patients diagnosed and treated with International Federation of Gynecology and Obstetrics Stage I-IV ovarian cancer at the National Cancer Center Hospital in Japan from June 2008 to April 2013. Patients were stratified into two groups based on age: an elderly group, aged 70 years or older, and a younger group, aged below 70 years. We retrospectively assessed the rate of receiving standard therapy, and the feasibility and safety of chemotherapy compared with younger patients. RESULTS In total, 244 patients (elderly group, 36 patients; younger group, 208 patients) were analyzed. A significantly lower proportion of elderly patients than younger patients received standard therapy (15.7% vs. 32.5%, p = 0.026). Even for the elderly group, 95% patients underwent surgery in our institution. Conversely the rate of patients receiving nonstandard chemotherapy in the elderly group was significantly higher than in the younger group (30.5% vs. 9.6%, p = 0.01). CONCLUSIONS This study clarified the type of treatment being performed in the field, and the proportion of elderly ovarian cancer patients receiving standard therapy compared with younger patients in Japan. In addition, the actual situation of elderly patients in Japan might be different from that in Western countries. We need to evaluate the appropriate treatment for elderly patients in Japan.

  • High diagnostic efficacy of 5-aminolevulinic acid-induced fluorescent urine cytology for urothelial carcinoma.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-04-13
    Gaku Yamamichi,Wataru Nakata,Masaru Tani,Go Tsujimura,Yuichi Tsujimoto,Mikio Nin,Akihiro Mimura,Hideaki Miwa,Masao Tsujihata

    BACKGROUND In general, urine cytology is often problematic because of its low sensitivity, especially for low-grade urothelial carcinoma (UC) in clinical practice. To improve the sensitivity, we focused on 5-aminolevulinic acid (5-ALA), because recent studies suggested that 5-ALA-induced urine cytology can be used for photodynamic diagnosis. In this study, we evaluated the diagnostic efficacy of 5-ALA-induced fluorescent urine cytology for UC. METHODS We included in this study 318 patients comprising 158 non-cancer patients, 84 bladder tumor patients, and 76 upper urinary tract urothelial carcinoma (UUT-UC) patients treated in our institution from March 2013 to September 2018. Using the same voided urine sample, we compared sensitivity and specificity between conventional urine cytology and 5-ALA-induced fluorescent urine cytology. RESULTS Overall, the sensitivity of 5-ALA-induced fluorescent urine cytology was significantly higher than that of conventional urine cytology (86.9% vs. 69.4%; p = 0.0002), and the specificity was equivalently high (96.2% vs. 95.6%; p = 1.0). In subgroup analysis, the high sensitivity of 5-ALA-induced fluorescent urine cytology was also detected regardless of age, sex, and tumor type. However, in terms of stage and grade, differences were only detected in patients with less than pTa stage (89.2% vs. 52.1%; p = 0.0001) and low-grade tumor (91.5% vs. 51.1%; p < 0.0001). CONCLUSIONS 5-ALA-induced fluorescent urine cytology was significantly more effective for UC diagnosis when compared with the conventional cytology, especially in patients with low-stage and low-grade tumors. These findings indicate that 5-ALA-induced fluorescent urine cytology may potentially be a very useful tool for clinical use.

  • Predictive factors for short-term biochemical recurrence-free survival after robot-assisted laparoscopic radical prostatectomy in high-risk prostate cancer patients.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-04-12
    Mitsugu Kanehira,Ryo Takata,Shuhei Ishii,Akito Ito,Daiki Ikarashi,Tomohiko Matsuura,Yoichiro Kato,Wataru Obara

    BACKGROUND We aimed to assess the short-term oncological outcomes of robot-assisted laparoscopic radical prostatectomy to determine the predictive factors associated with biochemical recurrence in high-risk prostate cancer patients. METHODS A total of 331 patients with localized prostate cancer underwent robot-assisted laparoscopic radical prostatectomy. Of them, 113 patients were diagnosed with high-risk prostate cancer according to the D'Amico risk group classification. We evaluated the association between pre- or postoperative predictive factors and biochemical recurrence using Cox regression analysis. RESULTS The 2-year biochemical recurrence-free survival rate was 65.0% in the high-risk group. On univariate analyses, PSA level > 20 ng/mL, Gleason pattern 5 component on biopsy, pathological stage T3 or higher, perineural invasion, and positive surgical margin were predictive factors for biochemical recurrence. On multivariate analysis, PSA level > 20 ng/mL, Gleason pattern 5 component on biopsy, perineural invasion, and positive surgical margin were identified as independent predictive factors. The 2-year biochemical recurrence-free survival rate was 36.5% for patients with PSA level > 20 ng/mL and/or Gleason pattern 5 component on biopsy. CONCLUSIONS PSA level > 20 ng/mL and/or presence of the Gleason pattern 5 component on biopsy are predictive factors for early biochemical recurrence after robot-assisted laparoscopic radical prostatectomy in high-risk prostate cancer patients. We considered that these patients require a combined modality therapy to improve their prognosis.

  • Laparoscopic radical cystectomy in octogenarians: analysis of a Japanese multicenter cohort.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-04-12
    Katsuhiro Ito,Toru Kanno,Atsuro Sawada,Ryoichi Saito,Takashi Kobayashi,Hitoshi Yamada,Takahiro Inoue,Osamu Ogawa

    BACKGROUNDS This study aimed to describe the morbidity and mortality in older patients undergoing laparoscopic radical cystectomy (LRC) and compare the outcomes of LRC between octogenarians and younger patients (< 80 years) in a Japanese multicenter cohort. METHODS We identified 433 patients (80 octogenarians) who underwent LRC in a retrospective multicenter database from 10 institutions. The perioperative outcomes and the 90-day and late (> 90-day) complications according to the Clavien-Dindo classification were compared between the octogenarians and younger patients. Recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) were measured by the Kaplan-Meier method. RESULTS Compared with the younger group, the octogenarian group included a significantly higher proportion of women, patients with a lower body mass index, patients with a lower preoperative albumin level, and patients with a history of abdominal surgery. The 90-day rates of all complications and major complications (grades III-V) were 50.0% and 20.0% among octogenarians and 54.7% and 16.4% among younger patients. The 90-day mortality rate among octogenarians was 3.8%. The 2-year RFS, CSS, and OS rates for octogenarians stratified by pathological stage was 95.2, 100, and 100% for ≤ pT1; 50.7, 76.6, and 56.1% for pT2; 33.6, 82.5, and 72.6% for ≥ pT3; and 23.1, 42.2, and 37.5% for pN + or distant metastasis, respectively. There was significant difference between octogenarians and younger patients only in 2-year OS for pT2 (56.1% vs 87.7%, p = 0.03). CONCLUSIONS This study revealed that LRC can be performed for selected octogenarians with a complication rate similar to that of younger patients. Appropriate risk evaluation and modification of surgical procedures are necessary for octogenarians.

  • Carbon-ion radiotherapy for lymph node oligo-recurrence: a multi-institutional study by the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS).
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-04-11
    Noriyuki Okonogi,Takuya Kaminuma,Tomoaki Okimoto,Makoto Shinoto,Naoyoshi Yamamoto,Shigeru Yamada,Kazutoshi Murata,Tatsuya Ohno,Yoshiyuki Shioyama,Hiroshi Tsuji,Takashi Nakano,Tadashi Kamada

    BACKGROUND The efficacy of carbon-ion radiotherapy (C-ion RT) for lymph node (LN) oligo-recurrence has only been evaluated in limited single-center studies. We aimed to investigate the benefit of C-ion RT for LN oligo-recurrence in a large multi-center study. METHODS Patients who received C-ion RT between December 1996 and December 2015 at 4 participating facilities and who met the following eligibility criteria were included: (i) histological or clinical diagnosis of LN recurrence; (ii) controlled primary lesion; (iii) no recurrence other than LN; (iv) LN recurrence involved in a single lymphatic site; and (v) age ≥ 20 years. RESULTS A total of 323 patients were enrolled. Median follow-up period was 34 months for surviving patients. The most common dose fractionation of C-ion RT was 48.0 Gy (relative biological effectiveness) in 12 fractions. Forty-seven patients had a history of RT at the recurrent site. The 2-year local control (LC) and overall survival (OS) rates after C-ion RT were 85% and 63%, respectively. Only 1 patient developed grade-3 toxicity. Factors such as LN diameter, histology, and history of previous RT did not correlate with LC. Smaller diameters (< 30 mm) and numbers (≤ 3) of LN metastases as well as longer disease-free intervals post-primary therapy (≥ 16 months) were associated with significantly better OS. CONCLUSIONS C-ion RT for LN oligo-recurrence appeared to be effective and safe. C-ion RT may provide a survival benefit to patients with LN oligo-recurrence, particularly to those with few LN metastases, smaller LN diameters, and longer disease-free intervals.

  • Identification of SERPINE1, PLAU and ACTA1 as biomarkers of head and neck squamous cell carcinoma based on integrated bioinformatics analysis.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-04-03
    Ke Yang,Shizhou Zhang,Dongsheng Zhang,Qian Tao,Tianqi Zhang,Guijun Liu,Xingguang Liu,Tengda Zhao

    BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is the six leading cancer by incidence worldwide. The 5-year survival rate of HNSCC patients remains less than 65% due to lack of symptoms in the early stage. Hence, biomarkers which can improve detection of HNSCC should improve clinical outcome. METHODS Gene expression profiles (GSE6631, GSE58911) and the Cancer Genome Atlas (TCGA) HNSCC data were used for integrated bioinformatics analysis; the differentially expressed genes (DEGs) were then subjected to functional and pathway enrichment analysis, protein-protein interaction (PPI) network construction. Subsequently, module analysis of the PPI network was performed and overall survival (OS) analysis of hub genes in subnetwork was studied. Finally, immunohistochemistry was used to verify the selected markers. RESULTS A total of 52 up-regulated and 80 down-regulated DEGs were identified, which were mainly associated with ECM-receptor interaction and focal adhesion signaling pathways. Importantly, a set of prognostic signatures including SERPINE1, PLAU and ACTA1 were screened from DEGs, which could predict OS in HNSCC patients from TCGA cohort. Experiment of clinical samples further successfully validated that these three signature genes were aberrantly expressed in the oral epithelial dysplasia and HNSCC, and correlated with aggressiveness of HNSCC patients. CONCLUSIONS SERPINE1, PLAU and ACTA1 played important roles in regulating the initiation and progression of HNSCC, and could be identified as key biomarkers for precise diagnosis and prognosis of HNSCC, which will provide potential targets for clinical therapies.

  • Current clinical topics of Lynch syndrome.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2018-05-11
    Kohji Tanakaya

    Lynch syndrome (LS) is one of the most common genetic cancer syndromes, occurring at a rate of 1 per 250-1000 in the general population. This autosomal dominant disease is caused by a germline variant in one of the four mismatch repair genes, MSH2, MLH1, MSH6, PMS2, or the EPCAM gene. LS develops at early ages in colorectal cancer (CRC), endometrial cancer, and various other associated tumors. Accurate diagnosis of LS and utilization of various risk-reduction strategies such as surveillance, prophylactic surgery, and chemoprevention could improve clinical outcomes. The efficacy of surveillance has only been proven for CRC; however, specialists have proposed surveillance for other LS associated tumors. Universal screening for tumor tissue using microsatellite instability testing or the mismatch repair protein immunochemistry in all CRC or endometrial cancers is recommended not only as a diagnostic tool for LS, but also as a predictive, prognostic, and therapeutic marker. Next-generation sequencing methods have revealed several conditions with phenotypes similar to LS, such as Lynch-like syndrome, constitutional mismatch repair deficiency syndrome, and polymerase proofreading-associated polyposis. Distinguishing LS from these similar conditions is clinically important, since clinical management for patients differs according to the conditions. Recently, immune checkpoint inhibitors have been shown to be a promising treatment against mismatch repair-deficient (dMMR) solid tumors. The efficacy of immune-checkpoint inhibitors in LS-associated tumors has been shown to be similar to that in sporadic dMMR tumors. This review discusses current clinical topics related to LS screening, diagnosis, surveillance, and therapy.

  • Prognostic value of alkaline phosphatase in hormone-sensitive prostate cancer: a systematic review and meta-analysis.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : null
    Keiichiro Mori,Florian Janisch,Mehdi Kardoust Parizi,Hadi Mostafaei,Ivan Lysenko,Dmitry V Enikeev,Shoji Kimura,Shin Egawa,Shahrokh F Shariat

    PURPOSE To assess the prognostic value of alkaline phosphatase in patients with hormone-sensitive prostate cancer. METHODS A systematic review and meta-analysis was performed using the PUBMED, Web of Science, Cochrane Library, and Scopus in April 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared hormone-sensitive prostate cancer patients with high vs. low alkaline phosphatase to determine its predictive value for overall survival, cancer-specific survival, and progression-free survival. We performed a formal meta-analysis of these outcomes. RESULTS 42 articles with 7938 patients were included in the systematic review and 28 studies with 5849 patients for the qualitative assessment. High alkaline phosphatase was associated with worse overall survival (pooled HR 1.72; 95% CI 1.37-2.14) and progression-free survival (pooled HR 1.30; 95% CI 1.10-1.54). In subgroup analyses of patients with "high-volume" and "low-volume", alkaline phosphatase was associated with the overall survival (pooled HR 1.41; 95% CI 1.21-1.64 and pooled HR 1.64; 95% CI, 1.06-2.52, respectively). CONCLUSIONS In this meta-analysis, elevated serum levels of alkaline phosphatase were associated with an increased risk of overall mortality and disease progression in patients with hormone-sensitive prostate cancer. In contrast, those were not associated with an increased risk of cancer-specific mortality. Alkaline phosphatase was independently associated with overall survival in both patients with "high-volume" and "low-volume" hormone-sensitive prostate cancer. Alkaline phosphatase may be useful for being integrated into prognostic tools that help guide treatment strategy, thereby facilitating the shared decision making process.

  • Considering bone health in the treatment of prostate cancer bone metastasis based on the results of the ERA-223 trial.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-09-05
    Atsushi Mizokami,Go Kimura,Yasuhisa Fujii,Shiro Hinotsu,Kouji Izumi

  • The prognostic value of routine second transurethral resection in patients with newly diagnosed stage pT1 non-muscle-invasive bladder cancer: results from randomized 10-year extension trial.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-11-25
    Askin Eroglu,Rahmi Gokhan Ekin,Gokhan Koc,Rauf Taner Divrik

    PURPOSE To evaluate the impact of routine second TUR on the long-term outcome of patients with newly diagnosed stage pT1 non-muscle-invasive bladder cancer (NMIBC) MATERIAL AND METHODS: A total of 210 patients (mean age 62.1 years, 89.5% were males) with stage pT1 NMIBC who underwent first TUR were prospectively randomized into two groups including second TUR (n = 105) and no second TUR (n = 105) groups. Data on recurrence, disease progression, 7-year and 10-year recurrence-free survival (RFS), progression-free survival (PFS) and overall survival (OS) were recorded. RESULTS The median follow-up time was 119 months (IQR 65-168). Per-protocol (PP) analysis revealed that compared to patients without second TUR, patients with second TUR had significantly higher 5-year, 7-year and 10-year rates for RFS (59.4%, 57.9% and 54.8% vs. 36.3%, 31.7% and 26.8%, respectively, p < 0.001) and PFS (93.3%, 91.9% and 90.4% vs. 74.0%, 71.4% and 68.5%, respectively, p < 0.001). According to PP and intention-to-treat (ITT) analyses, the 10-year OS rate was significantly higher in patients with second TUR (59.1 vs. 40.8%, p = 0.004). Multivariate analysis revealed that undergoing second TUR (OR 1.661, 95% CI 1.156-2.385, p = 0.006) was an independent determinant of prolonged OS. CONCLUSIONS In conclusion, these findings indicate the prognostic value of second TUR in stage pT1 NMIBC patients, not only for RFS and PFS advantages but also for the long-term OS advantage. Therefore, second TUR should be routinely performed in all stage pT1 NMIBC patients with life expectancy of at least 10 years, given the positive contribution to all oncological outcomes.

  • The impact of postoperative inflammation on recurrence in patients with colorectal cancer.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : null
    Daiki Matsubara,Tomohiro Arita,Masayoshi Nakanishi,Yoshiaki Kuriu,Yasutoshi Murayama,Michihiro Kudou,Hirotaka Konishi,Shuhei Komatsu,Atsushi Shiozaki,Eigo Otsuji

    BACKGROUND Systemic inflammatory response is strongly linked to among cancer development, progression and poor prognosis. The aim of this study was to clarify the impact of postoperative serum C-reactive protein (CRP) levels on the prognoses of patients with colorectal cancer (CRC). METHODS A total of 467 patients with stage I-III CRC who underwent curative surgery were retrospectively analyzed. To precisely evaluate the effect of postoperative inflammatory status on prognosis in CRC patients, we excluded patients with postoperative complication or elevated preoperative CRP level (CRP > 1.0 mg/dL). Patients were divided into two groups based on their highest post-resection CRP levels (max CRP): the low CRP group (LCG; < 9.0 mg/dL, n = 385) and high CRP group (HCG; ≥ 9.0 mg/dL, n = 82). Furthermore, the effect of inflammation on malignant potential of CRC cells was evaluated using in vitro peritoneal dissemination model. RESULTS HCG patients showed significantly worse recurrence-free survival (RFS) than LCG patients (p = 0.012). Multivariate analysis revealed that a higher max CRP was an independent prognostic factor for RFS (HR: 2.07, 95% CI 1.04-3.96, p = 0.038). Concerning the risk factors for high max CRP level, multivariate analysis revealed that older age (p < 0.001), male sex (p < 0.001), higher BMI (p = 0.005), right-sided colorectal cancer (p = 0.008), and longer operative time (p = 0.007) were independent risk factors. A higher max CRP was also significantly associated with peritoneal recurrence (p < 0.001). Additionally, recombinant cytokines enhanced the adhesive ability of CRC cells to mesothelial cell in vitro (p < 0.05). CONCLUSIONS Postoperative inflammation may be a possible mechanism portending the poor prognosis of CRC patients.

  • Validation of prognostic impact of number of extrathoracic metastases according to the eighth TNM classification: a single-institution retrospective study in Japan.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-08-28
    Kosuke Sakai,Joji Kuramoto,Akitoshi Kojima,Hiroaki Nishimura,Yoshiki Kuwabara,Maiko Toda,Yumiko Kobayashi,Satoshi Kikuchi,Yusuke Hirata,Yuriko Mikami-Saito,Shintaro Mikami,Hiroyuki Kyoyama,Gaku Moriyama,Akihiko Gemma,Kazutsugu Uematsu

    BACKGROUND In the eighth edition of the TNM classification of lung cancer, the M1b and M1c descriptors are newly defined by the number of extrathoracic metastases. To verify the prognostic value of these descriptors in Japan, we reclassified our cases and re-evaluated prognosis in M1b and M1c patients. METHODS All non-small cell lung cancer (NSCLC) patients with extrathoracic metastases who visited Saitama Medical Center from 2010 to 2016 were evaluated, divided according to the eighth edition of the TNM classification criteria into two groups (M1b, patients with single extrathoracic metastasis, and M1c, patients with multiple extrathoracic metastases), and followed up until December 31, 2017. Survival time analysis was performed using the Kaplan-Meier method, and between-group differences in overall survival time (OS) were evaluated by the log-rank test. RESULTS A total of 231 NSCLC patients were divided into 57 patients with M1b and 174 with M1c. Median OS was 15.2 months (95% confidence interval [CI]: 9.3-19.9) and 7.3 months (95% CI 5.7-10.7) for M1b and M1c, respectively, with no significant between-group difference (P = 0.239). However, after excluding patients with epidermal growth factor receptor (EGFR) mutation or echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene, median OS was 12.9 months (95% CI 7.2-19.9) for M1b and 5.4 months (95% CI 3.8-6.3) for M1c, respectively, showing a significant difference (P = 0.029). CONCLUSIONS The effect of therapy directed toward EGFR mutation or EML4-ALK fusion gene might obscure the significant prognostic difference between M1b and M1c.

  • Prognostic relevance of ATM protein in uveal melanoma and its association with clinicopathological factors.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-08-05
    Jayanti Jha,Mithalesh Kumar Singh,Lata Singh,Neelam Pushker,Mandeep Singh Bajaj,Seema Sen,Seema Kashyap

    PURPOSE Uveal melanoma (UM) is an intraocular malignancy commonly arising from choroid which can cause visual loss or metastasis. Ataxia-telangiectasia mutated (ATM) protein is an activator of DNA damage response and its role in uveal melanoma (UM) is still unexplored. Therefore, the study aims to detect the expression and localization of ATM protein and its association with clinicopathological parameters METHODS: Expression of nuclear ATM (nATM) was investigated on 69 formalin fixed paraffin embedded choroidal melanoma samples by immunohistochemistry and validated by western blotting. Results were then correlated with clinical and histopathological parameters. Prognostic significance was determined by the Kaplan-Meier analysis and the multivariate analysis by Cox's hazard proportional method. RESULTS Loss of nATM was observed in 65% of cases, which was statistically significant with the reduced disease-free survival (p = 0.042). This loss was more frequently found in cases with high-risk histopathological factors like epithelioid cell type, tumor infiltrating lymphocytes and high pigmentation which might help in the progression of melanoma. On multivariate analysis, extraocular spread and loss of nATM were found to be independent prognostic factors (p < 0.05). CONCLUSION Our data suggest that loss of nATM protein might serve as a poor prognostic marker in the pathogenesis of uveal melanoma which may lead to increased risk of metastasis.

  • Tandem high-dose chemotherapy with topotecan-thiotepa-carboplatin and melphalan-etoposide-carboplatin regimens for pediatric high-risk brain tumors.
    Int. J. Clin. Oncol. (IF 2.503) Pub Date : 2019-07-29
    Jung Yoon Choi,Hyoung Jin Kang,Kyung Taek Hong,Che Ry Hong,Yun Jeong Lee,June Dong Park,Ji Hoon Phi,Seung-Ki Kim,Kyu-Chang Wang,Il Han Kim,Sung-Hye Park,Young Hun Choi,Jung-Eun Cheon,Kyung Duk Park,Hee Young Shin

    BACKGROUND High-dose chemotherapy (HDC) and autologous stem-cell transplantation (auto-SCT) are used to improve the survival of children with high-risk brain tumors who have a poor outcome with the standard treatment. This study aims to evaluate the outcome of HDC/auto-SCT with topotecan-thiotepa-carboplatin and melphalan-etoposide-carboplatin (TTC/MEC) regimens in pediatric brain tumors. METHODS We retrospectively analyzed the data of 33 children (median age 6 years) who underwent HDC/auto-SCT (18 tandem and 15 single) with uniform conditioning regimens. RESULTS Eleven patients aged < 3 years at diagnosis were eligible for HDC/auto-SCT to avoid or defer radiotherapy. In addition, nine patients with high-risk medulloblastoma (presence of metastasis and/or postoperative residual tumor ≥ 1.5 cm2), eight with other high-risk brain tumor (six CNS primitive neuroectodermal tumor, one CNS atypical teratoid/rhabdoid tumor, and one pineoblastoma), and five with relapsed brain tumors were enrolled. There were three toxic deaths, and two of which were due to pulmonary complications. The main reason for not performing tandem auto-SCT was due to toxicities and patient refusal. The event-free survival (EFS) and overall survival (OS) rates of all patients were 59.4% and 80.0% at a median follow-up with 49.1 months from the first HDC/auto-SCT, respectively. The EFS/OS rates of patients aged < 3 years at diagnosis, high-risk medulloblastoma, other high-risk brain tumor, and relapsed tumors were 50.0/81.8%, 87.5/85.7%, 66.7/88.9%, and 20.0/60.0%, respectively. CONCLUSIONS Although tandem HDC/auto-SCT with TTC/MEC regimens showed promising survival rates, treatment modifications are warranted to reduce toxicities. The survival rates with relapsed brain tumors were unsatisfactory despite HDC/auto-SCT, and further study is needed.

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上海纽约大学William Glover