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BACKGROUND. The aim of this meta‐analysis was to compare patient‐reported outcomes (PROs) between programmed death receptor‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) inhibitors and standard‐of‐care therapy in patients with advanced cancer. METHODS. We searched randomized controlled trials (RCTs) comparing single‐agent PD‐1/PD‐L1 inhibitors (nivolumab, pembrolizumab, atezolizumab, avelumab, or durvalumab) with standard‐of‐care therapy in patients with advanced cancer reporting PROs with generic measures: the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (QLQ‐C30) and the EuroQol Five Dimensions Questionnaire. The summary outcomes were changes in PROs from baseline to follow‐up within and between treatment groups and time to deterioration (TTD) in PROs based on clinically meaningful change. RESULTS. A total of 6,334 patients from 13 RCTs were included: six nivolumab, five pembrolizumab, and two atezolizumab trials. For the QLQ‐C30 global health status/quality of life, the pooled difference in mean change between treatment groups was 5.1 (95% confidence interval [CI], 3.3–6.9; p < .001) favoring PD‐1/PD‐L1 inhibitors. The pooled mean change from baseline in PD‐1/PD‐L1 inhibitors and controls was 0.1 (95% CI, −2.2, 2.5) and − 6.1 (95% CI, −8.4, −3.8), respectively. The TTD was significantly longer with PD‐1/PD‐L1 inhibitors, with a hazard ratio of 0.72 (95% CI, 0.55–0.93; p = .011). Similarly, significantly better outcomes were noted with PD‐1/PD‐L1 inhibitors on most of the other PRO measures. CONCLUSION. PD1/PD‐L1 inhibitors maintained health‐related quality of life to a greater degree and had less worsening in symptoms than standard‐of‐care therapy even though patients on these immune modulators were on treatment longer. The better PRO profile further supports the clinical benefit of this treatment strategy for advanced cancer. IMPLICATIONS FOR PRACTICE. We conducted a systematic review and meta‐analysis to compare patient‐reported outcomes (PROs) of programmed death receptor‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) inhibitors and standard‐of‐care therapy in patients with advanced cancer. PD‐1/PD‐L1 inhibitors were associated with consistently smaller PRO score deterioration from baseline to follow‐up for different health‐related quality‐of‐life and symptoms scales. In addition, the time to deterioration in multiple PRO domains was significantly longer with PD‐1/PD‐L1 inhibitors. Taken together, these findings indicate that the patients treated with PD‐1/PD‐L1 inhibitors maintained health‐related quality of life to a greater degree and had less symptom burden compared with those treated with standard‐of‐care therapy.

Bloodstream infection (BSI) is a frequent complication observed in patients with febrile neutropenia (FN). BSI risk factors and incidence vary depending on chemotherapy types and prophylactic antimicrobial agents. We clarified these issues by post-hoc analysis of a prospective clinical trial cohort for severe FN in hematological malignancy.We performed an intention-to-treat analysis of 413 high-risk patients and 1272 blood culture sets.Overall, 356 patients (86.2%) developed FN, and 20.8% had BSI complications. Prophylactic antimicrobials did not prevent complications of FN and BSI, but the incidence of BSIs of Gram-negative (GN) bacteria was lower than in the non-prophylaxis group (23.8% vs. 56.7%). Multinational Association of Supportive Care in Cancer (MASCC) scores 20 were significantly correlated with the incidence of BSI, whereas MASCC scores 21 were not (41.7% vs. 17.2%). The only significant risk factors were hypotension and dehydration. axillary temperatures were higher in GN-caused BSIs than in Gram-positive-caused BSIs and in patients with negative blood culture results (38.7 °C vs. 38.2 °C vs. 38.0 °C). The higher the fever, the higher the incidence of BSI and GN bacteremia.MASCC score and axillary temperature are strong predictors of BSI. Non-administration of prophylactic antimicrobials and GN-caused BSI are correlated.UMIN00010411.

Lynch syndrome is a hereditary disease characterized by an increased risk of colorectal and other cancers. Germline variants in the mismatch repair (MMR) genes are responsible for this disease. Previously, we screened the MMR genes in colorectal cancer patients who fulfilled modified Amsterdam II criteria, and multiplex ligation-dependent probe amplification (MPLA) identified 11 structural variants (SVs) of MLH1 and MSH2 in 17 patients. In this study, we have tested the efficacy of long read-sequencing coupled with target enrichment for the determination of SVs and their breakpoints. DNA was captured by array probes designed to hybridize with target regions including four MMR genes and then sequenced using MinION, a nanopore sequencing platform. Approximately, 1000-fold coverage was obtained in the target regions compared with other regions. Application of this system to four test cases among the 17 patients correctly mapped the breakpoints. In addition, we newly found a deletion across an 84 kb region of MSH2 in a case without the pathogenic single nucleotide variants. These data suggest that long read-sequencing combined with hybridization-based enrichment is an efficient method to identify both SVs and their breakpoints. This strategy might replace MLPA for the screening of SVs in hereditary diseases.

Hereditary colorectal cancer (HCRC) accounts for

[Purpose] Few prospective studies have assessed anthracycline-associated cardiotoxicity in patients with sarcoma. We evaluated cardiotoxicity in patients with soft-tissue sarcomas administered doxorubicin in the phase III ANNOUNCE trial (NCT02451943)., [Patients and Methods] Patients were anthracycline-naïve adults with locally advanced or metastatic disease and left ventricular ejection fraction (LVEF) ≥50%. Patients could receive eight cycles of doxorubicin at 75 mg/m2. The cardioprotectant, dexrazoxane, was allowed at investigator discretion. Symptomatic cardiac adverse events (AEs) were recorded using Medical Dictionary for Regulatory Activities and graded using Common Terminology Criteria for Adverse Events 4.0. LVEF deterioration was measured by echocardiogram or multigated acquisition scan, defined as a decrease to 10%., [Results] A total of 504 patients received ≥1 cycles of doxorubicin [median cumulative dose, 450.3 mg/m2 (range, 72.3–634.0)]. Median follow-up of cardiac AEs was 28 weeks. Dexrazoxane was coadministered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving, [Conclusions] Although follow-up was short, these results suggest doxorubicin can be administered at high cumulative doses (>450 mg/m2), with a low rate of cardiotoxicities, in the context of dexrazoxane coadministration., This study was funded by Eli Lilly and Company. W.D. Tap was funded, in part, through NIH/NCI Cancer Center Support grant P30 CA008748. Medical writing was provided by Dr. Jonathan Pitt (Evidera) and funded by Eli Lilly and Company. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

In the course of our screening program for novel chemotherapeutic candidates from plants against adult T-cell leukemia/lymphoma, the extracts of Asclepias curassavica L. showed potent activity against MT-1 and MT-2 cells. Therefore, we attempted to isolate their active components. We identified a new cardenolide, 19-dihydrocalactinic acid methyl ester (1), along with 16 known cardenolides (2-17). Their structures were determined on the basis of spectroscopic data. Almost all of the isolated cardenolides inhibited the growth of both tumor cell lines. All the doubly linked cardenolides (11-17) except for 14 showed more potent activity than the other cardenolides. A comparison of the activities of 11, 14 and 16 revealed that the presence of hydroxy or acetoxy functional groups at C-16 led to a decrease in the activity. The 50% effective concentration (EC50) value of calotropin (11) against MT-2 cells was comparable to the potency of the clinical antineoplastic drug doxorubicin. The cytotoxic effect of 11 toward normal mononuclear cells obtained from the peripheral blood (PB-MNCs) was observed at a concentration 6 to 12 times higher than that used to induce growth inhibition against MT-1 and MT-2 cells. The proportions of annexin V-positive cells after 72 h of treatment with 11 were increased, indicating that it significantly induced apoptosis in MT-1 and MT-2 cells in a concentration-dependent manner. Cell cycle experiments demonstrated that 11 arrested MT-1 and MT-2 cells at the G2/M phase. Therefore, compound 11 may be a promising candidate for the treatment of adult T-cell leukemia/lymphoma.

Patients with cancer should appropriately receive antiemetic therapies against chemotherapy-induced nausea and vomiting (CINV). Antiemetic guidelines play an important role in managing CINV. Accordingly, the first Japanese antiemetic guideline published in 2010 by the Japan Society of Clinical Oncology (JSCO) has considerably aided Japanese medical staff in providing antiemetic therapies across chemotherapy clinics. With the yearly advancements in antiemetic therapies, the Japanese antiemetic guidelines require revisions according to published evidence regarding antiemetic management worldwide. A revised version of the first antiemetic guideline that considered several upcoming evidences had been published online in 2014 (version 1.2), in which several updated descriptions were included. The 2015 JSCO clinical practice guideline for antiemesis (version 2.0) (in Japanese) has addressed clinical antiemetic concerns and includes four major revisions regarding (1) changes in emetogenic risk categorization for anti-cancer agents, (2) olanzapine usage as an antiemetic drug, (3) the steroid-sparing method, and (4) adverse drug reactions of antiemetic agents. We herein present an English update summary for the 2015 JSCO clinical practice guideline for antiemesis (version 2.0).

A previous randomized phase 2 study of hepatocellular carcinoma revealed that the c‐Met inhibitor tivantinib as second‐line treatment significantly prolonged progression‐free survival in a subpopulation whose tumor samples highly expressed c‐Met (MET‐high). Accordingly, this phase 3 study was conducted to evaluate the efficacy of tivantinib as a second‐line treatment for Japanese patients with MET‐high hepatocellular carcinoma. This randomized, double‐blind, placebo‐controlled study was conducted at 60 centers in Japan. Hepatocellular carcinoma patients with one prior sorafenib treatment and those with MET‐high tumor samples were eligible for inclusion. Registered patients were randomly assigned to either the tivantinib or placebo group at a 2:1 ratio and were treated with twice‐a‐day oral tivantinib (120 mg bid) or placebo until the discontinuation criteria were met. The primary endpoint was progression‐free survival while the secondary endpoints included overall survival and safety. Between January 2014 and June 2016, 386 patients provided consent, and 195 patients were randomized to the tivantinib (n = 134) or placebo (n = 61) group. Median progression‐free survival was 2.8 (95% confidence interval: 2.7‐2.9) and 2.3 (1.5‐2.8) mo in the tivantinib and placebo groups, respectively (hazard ratio = 0.74, 95% confidence interval: 0.52‐1.04, P = .082). Median overall survival was 10.3 (95% confidence interval: 8.1‐11.6) and 8.5 (6.2‐11.4) mo in the tivantinib and placebo group, respectively (hazard ratio = 0.82, 95% confidence interval: 0.58‐1.15). The most common tivantinib‐related grade ≥3 adverse events were neutropenia (31.6%), leukocytopenia (24.8%), and anemia (12.0%). This study did not confirm the significant efficacy of tivantinib as a second‐line treatment for Japanese patients with MET‐high hepatocellular carcinoma. (NCT02029157)., Results of JET‐HCC.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Objective We conducted a questionnaire survey of oncology specialists to investigate the frequency of administration of different drugs for the management of chemotherapy-induced peripheral neuropathy in Japan in 2015. Our group published Clinical Guidelines for the Management of Chemotherapy-Induced Peripheral Neuropathy in 2017 (CIPN-GL2017). In these guidelines, we recommended duloxetine only. To verify the effect of the publication of the CIPN-GL2017, we conducted a questionnaire survey in 2019. Methods In 2015 and again in 2019, we investigated the use of vitamin B12, antiepileptic agents, duloxetine, antidepressants other than duloxetine, non-steroidal anti-inflammatory drugs, opioids and the Kampo compound (goshajinkigan) in a questionnaire employing a three-point scale wherein A implies routine or prophylactic administration, B implies occasional administration and C implies infrequent administration. Results We sent the questionnaires via email to 971 diplomates of the Subspecialty Board of Japanese Society of Medical Oncology in 2015 and 1239 diplomates in 2019. The administration ratio (A + B) of duloxetine for numbness and pain was 46.8 and 31.7%, respectively, in 2015 and 68.9% (P Conclusions It is possible that the publication of CIPN-GL2017 influenced administration preferences of oncology specialists.

Data on long-term outcomes of familial adenomatous polyposis (FAP) are unclear in Japan because a nationwide registry system is lacking. We assessed overall survival, incidence of neoplasms, fecal incontinence, and postoperative follow-up status of patients with FAP treated surgically in our hospital. In total, 154 patients with FAP who underwent radical surgery from 1981 to 2017 in our department were available for the questionnaire. Sixty-five patients, 36 of whom were followed at our hospital, were assessed using clinical records and the questionnaire. The median follow-up time was 187 months (interquartile range, 93.5–296 months). The median age at surgery was 36 years (range, 12–69 years). The 5-, 10-, 15-, and 20-year overall survival rate was 100%, 98%, 95%, and 89%, respectively. All five deaths were caused by diseases other than colorectal cancer. FAP-related neoplasms comprised 23 colorectal cancers, five duodenal cancers, three gastric cancers, five thyroid cancers, two ileal pouch cancers, and nine desmoid tumors. The incidence of desmoid tumors was significantly associated with the operation date. The duration from radical surgery to neoplasm onset significantly differed by neoplasm type. Forty-five of 54 patients (excluding those who died or underwent ileostomy) developed fecal incontinence (median Wexner score of 8). Surgical procedures involving hand-sewn sutures with rectal mucosal stripping were significantly associated with fecal incontinence and the Wexner score. Fifty-eight of the 60 surviving patients underwent follow-up examinations. Overall survival was favorable. Fecal incontinence depended on the surgical procedures. Most patients continued to receive follow-up examinations. No. 3112 by Institutional Review Board of Hyogo College of Medicine

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 of one of four different protein (MLH1, MSH2, MSH6, and PMS2), which are the products of mismatch repair genes. An abnormal EPCAM gene at the position adjacent to the MSH2 gene also inhibits MSH2 expression and causes Lynch syndrome.

In modern society, the population, wealth and social functions are increasingly concentrated in a few large cities. Such concentration brings about efficiency while at the same time it increases the vulnerability of the society. To address this issue, the Science Council of Japan (SCJ) published a proposal entitled “Shape Cities and Societies Safer against Severe Earthquakes”. It makes a variety of suggestions for enhancing the seismic resilience of large cities, including: (1) comprehensive thinking based on the latest scientific knowledge and rich imagination; (2) selection of sites suitable for residence and social activities; (3) introducing the urban seismic coefficient; (4) promoting the enhancement of the seismic performance of buildings and civil structures; (5) easing the concentration of population and functions; (6) building communities that enable shelter and escape; (7) resilient technology of information and communication system and its effective utilization; (8) preparation and implementation of emergency response after earthquakes; (9) development and application of new structural seismic technology; (10) learning from domestic and foreign earthquake disasters and launching of international cooperation and knowledge sharing and (11) taking actions from a multidisciplinary perspective. The proposal is introduced in this paper.

In the mid‐18th century, Great Britain gave birth to the Industrial Revolution. The modern era started in Europe where there were no severe natural disasters caused by earthquakes. By the 19th century, the industrial movement had swept into Asia. In 1868, Japan began importing science and technology from Europe and USA. Subsequently, Japan's civilization, culture, and politics also changed. Over time, cities like Tokyo, Osaka, and Nagoya became epicenters for modern Japanese life. Although Japan has always been concerned about earthquakes, its people focused more on economic growth during the modernization process than on protecting mega‐cities from possible natural disasters. Other Asian countries also have a similar pattern of development. The Science Council of Japan, which was established after World War II, strives to help build safe and secure societies where people can live in peace and contentment. The council has frequently published important proposals on past large‐scale domestic earthquake disasters. In this paper, we propose the idea of “Moving toward cities where earthquakes will not cause a grievous disaster,” which was announced by the Science Council of Japan on August 23, 2017. The proposal focuses on large cities where people, information, wealth, and assets are highly concentrated, and aims to build communities no longer devastated by major earthquakes.

Purpose Adequate cancer pain management (CPM) is challenging in resource-limited settings, where current international guideline recommendations are difficult to implement owing to constraints such as inadequate availability and accessibility of opioids, limited awareness of appropriate opioid use among patients and clinicians, and lack of guidance on how to translate the best evidence into clinical practice. The multinational and multidisciplinary CAncer Pain managEment in Resource-limited settings (CAPER) Working Group proposes a two-step initiative to bridge clinical practice gaps in CPM in resource-limited settings. Methods A thorough review of the literature, a steering committee meeting in February 2017, and post-meeting teleconference discussions contributed to the development of this initiative. As a first step, we developed practical evidence-based CPM algorithms to support healthcare providers (HCPs) in tailoring treatment according to availability of and access to resources. The second part of the initiative proposes a framework to support an effective implementation of the CPM algorithms that includes an educational program, a pilot implementation, and an advocacy plan. Results We developed CPM algorithms for first-line use, breakthrough cancer pain, opioid rotation, and refractory cancer pain based on the National Comprehensive Cancer Network guidelines and expert consensus. Our proposed educational program emphasizes the practical elements and illustrates how HCPs can provide optimal CPM according to evidence-based guidelines despite varied resource limitations. Pilot studies are proposed to demonstrate the effectiveness of the algorithms and the educational program, as well as for providing evidence to support a draft advocacy document, to lobby policymakers to improve availability and accessibility of analgesics in resource-limited settings. Conclusions These practical evidence-informed algorithms and the implementation framework represent the first multinational step towards achieving optimal CPM in resource-limited settings. Electronic supplementary material The online version of this article (10.1007/s00520-018-4471-z) contains supplementary material, which is available to authorized users.

Background: Patients (pts) with hormone receptor-positive (HR+) and non-life threatening advanced or metastatic breast cancer (BC) are usually treated with sequential endocrine therapies. Endocrine therapies are continued until tumor cells acquire resistance to them, following which pts are switched to cytotoxic chemotherapy. Entinostat (ENT) is an oral inhibitor of class I histone deacetylases (HDACs) and is expected to be used for endocrine therapy-resistant pts. The efficacy of ENT in combination with an aromatase inhibitor (AI) for HR+ BC was demonstrated in a previous randomized phase 2 study. Because of the lack of data on safety and pharmacokinetics (PK) in Japanese HR+ BC pts, we performed this dose escalation phase 1 study to investigate the safety of ENT monotherapy and combination therapy with exemestane (EXE) in postmenopausal women with advanced or recurrent HR+ BC. Secondary objectives were to assess PK and efficacy. Methods: This study was based on a 3+3 dose escalation design. Postmenopausal women with advanced or recurrent HR+ HER2- BC previously treated with nonsteroidal AIs and with ECOG PS 0-1 were enrolled. The dose limiting toxicities (DLT) of ENT monotherapy (3 mg/qw, 5 mg/qw, or 10 mg/q2w) in Cohort 1-3 and those of ENT (5 mg/qw or 3 mg/qw) in combination with EXE 25 mg/qd in Cohort 4-5 were assessed for 7 and 28 days, respectively. Pts continued ENT (3 mg or 5 mg) in combination with EXE even after the DLT observation period until disease progression or discontinuation for other reasons. Adverse events (AEs) were graded per NCI-CTCAE version 4.03. Tumor response was evaluated by RECIST version 1.1 every 8 weeks. ENT concentration was measured intensively. Samples of peripheral blood mononuclear cells (PBMC) were collected to measure protein lysine hyperacetylation and for immune subset analysis. Optional tumor biopsies for biomarker assessment were collected before and during treatment. Results: Twelve pts were enrolled and three each were assigned to Cohort 1-4 between Nov 2015 and Sept 2016. Neither DLT nor grade 3-5 AE occurred. As no DLT occurred in Cohort 4, Cohort 5 was omitted as originally planned. The drug-related AEs observed in ≥2 pts during the DLT observation period were grade 1-2 hypophosphatemia (1 pt each in Cohort 2, 3, and 4), grade 1 nausea (1 pt in Cohort 3 and 2 pts in Cohort 4), and grade 1-2 platelet count decreased (2 pts in Cohort 4). AUC0-168 increased in a dose proportional manner. As of May 2017, 4 pts continue to receive study treatment, including one treated for more than 18 months. Biomarker data including protein lysine hyperacetylation and immune subset in PBMC and results of paired biopsy samples will be reported. Conclusions: This study showed the tolerability of the combination therapy of ENT 5 mg with EXE 25 mg in Japanese pts. There were no new safety concerns as compared to those reported previously. Following this result, a randomized phase 2 study for Japanese pts is planned. Clinical trial information : NCT02623751. Citation Format: Shimomura A, Masuda N, Tamura K, Yasojima H, Sawaki M, Nishimura Y, Saji S, Iwata H. A phase 1 study of KHK2375 (entinostat) as monotherapy and in combination with exemestane in Japanese patients with hormone receptor-positive, HER2-negative, advanced or recurrent breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-11-06.

This abstract was withdrawn by the authors.

Background Evidence of eribulin therapy for metastatic breast cancer (MBC) in clinical practice is not well documented. Methods We retrospectively analyzed the safety and efficacy of eribulin in 29 MBC patients from 2011 to 2016 at Fukuoka University Hospital. Results The median patient age, number of courses, total dose, and relative dose intensity were as follows: 65 years, five courses, 8.6 mg/m2, and 75%, respectively. One patient achieved a complete response, (CR) six a partial response (PR), eight stable disease (SD) and 14 patients exhibited progressive disease. The objective response rate (ORR: CR + PR) was 24.1%, and the clinical benefit rate (CBR: CR + PR + SD) was 51.7%. The median progression-free survival was 90 days (95% confidence interval [CI] 67–126) and median overall survival was 264 days (95% CI 198–357). In patients who previously received 2–4 regimens, the ORR was 28.5% and the CBR was 57.1%. In patients who received 5–12 regimens, the ORR was 20% and the CBR was 45%. Chemotherapy was administered to 20 patients (69%) after eribulin administration, and the median overall survival rate of cases that achieved greater than a PR was 1088 days. The most frequent treatment-related grade 3/4 adverse events were neutropenia (55.2%), and febrile neutropenia (20.1%). Grade 3 peripheral neuropathy occurred in 13.8% of patients, but was not exacerbated even if present before treatment. Conclusion Eribulin is effective for MBC patients who have received multiple chemotherapies. Neutropenia and febrile neutropenia may develop after heavy prior therapy.

Adult T-cell leukemia-lymphoma (ATL) has been divided into 4 clinical subtypes: acute, lymphoma, chronic, and smoldering. The aim of this study is to develop a novel prognostic index (PI) for chronic and smoldering ATL. We conducted a nationwide retrospective survey on ATL patients, and 248 fully eligible individuals were used in this analysis. In the univariate analysis, sex, performance status, log10 (soluble interleukin-2 receptor [sIL-2R]), neutrophils count, and lymphadenopathy showed values of P < .05 in training samples. A multivariate analysis was performed on these factors, and only log10 (sIL-2R) was identified as an independent prognostic factor in training samples. Using a regression coefficient of this variable, a prognostic model was formulated to identify different levels of risk: indolent ATL-PI (iATL-PI) = 1.51 × log10 (sIL-2R [U/mL]). The values calculated by iATL-PI were divided into 3 groups using a quartile point. In the validation sample, median survival times (MSTs) were 1.6 years, 5.5 years, and not reached for patients in the high-, intermediate-, and low-risk groups, respectively (P < .0001). To make the scoring system clinically practicable, we simplified iATL-PI according to trichotomizing sIL-2R at 1000 and 6000 U/mL, using a quartile point. Patients with more than 6000 U/mL sIL-2R were categorized into the high-risk group, less than and equal to 1000 U/mL into the low-risk group, and the others into the intermediate-risk group, and MSTs were 1.6 years, not reached, and 5.5 years, respectively (P < .0001). iATL-PI has potential as a novel tool for a risk-adapted therapeutic approach.

Central nervous system (CNS) involvement is a serious complication in patients with diffuse large B-cell lymphoma (DLBCL) and evaluating CNS risk is an important issue. Using the standard international prognostic index (IPI) and CNS-IPI, a recently proposed model including IPI risk factors and adrenal/kidney involvement, we assessed CNS risk in 1220 untreated DLBCL patients who received R-CHOP without prophylaxis. According to the standard IPI, the cumulative incidences of CNS involvement at 2 years were 1.3, 4.6, 8.8, and 12.7% in the low-, low-intermediate-, high-intermediate-, and high-risk groups, respectively (p .001). This result is comparable with that of the CNS-IPI. Patients with breast involvement tended to have lower risk according to the standard IPI but showed frequent CNS involvement, similar to patients with testis involvement. The standard IPI is also a useful predictor of CNS involvement. Patients with breast/testis involvement would be candidates for prophylaxis regardless of the standard IPI risk.

Background Cancer chemotherapy is associated with a variety of side effects/adverse events. It is very important that patients adhere to the planned chemotherapy regimen, which necessitates a minimum of side effects and that these side effects be kept under control. We have investigated patients’ concerns and symptoms during chemotherapy with the aim to seek solutions that will improve patients’ quality of life during chemotherapy. Methods Forty-nine patients with malignant diseases on parenteral antineoplastic agents were sequentially enrolled in this study. These patients completed a questionnaire consisting of 42 items related to non-physical concerns and 52 items of physical symptoms related to chemotherapy. Each patient was also asked to select the three items among these 94 items which affected him/her the most. Results The median age of the cancer patients was 62 years and the male-to-female ratio was 18:31. Among the non-physical concerns, the most frequently chosen concern was ‘affects my family or partner,’ followed by anxiety related to treatment. Regarding the physical symptoms, the most frequent complaints were fatigue, alopecia and constipation, while the most troublesome symptoms were nausea, poor taste and paresthesia. Overall, the most frequently expressed concerns were ‘affects my family or partner’ and anxiety related to treatment. Male patients suffered most from fever, fatigue and nausea, and female patients complained more of poor taste and gastrointestinal problems. Conclusion Patient perceptions of adverse events associated with cancer chemotherapy apparently have changed from physical symptoms to non-physical concerns. In our patient cohort ‘affects my family or partner’ was the most important concern. One important point to note is that female patients often complained of poor taste because this meant they were unable to cook well. Electronic supplementary material The online version of this article (doi:10.1007/s10147-017-1117-y) contains supplementary material, which is available to authorized users.

Background: In patients with HER2-positive metastatic breast cancer (MBC) who progressed on trastuzumab (H)-based therapy, both continuing H beyond progression and switching to lapatinib (L) in combination with chemotherapy are valid options. However, it is unclear which strategy is more effective and how we can select a proper strategy in each patient. Methods: We conducted an open label, multicenter, randomized phase II trial to comparatively evaluate efficacy and safety of H + capecitabine (X) (HX) or L + X (LX) in women with HER2-positive MBC who were previously treated with taxanes and progressed on H-containing regimens. Patients treated with more than two chemotherapy regimens for MBC were excluded. Those treated with pertuzumab and/or T-DM1 were allowed to enroll in this study. Patients with brain metastases were also included if they are asymptomatic. Patients received H (4mg/kg loading then 2mg/kg weekly or 8mg/kg loading then 6mg/kg every 3 weeks) and X (2500 mg/m2/day on days 1-14 every 3weeks) in HX arm and L (1250 mg/day) and X (2000 mg/m2/day on days 1-14 every 3weeks) in LX arm until progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate (ORR), proportion of subjects progressing with brain metastases as site of first progression, and safety.We also assessed biomarkers in tumor tissues and circulating cell-free DNA. Results: Between May 2011 and December 2014, 86 patients (43 in HX arm and 43 in LX arm) were enrolled in this study. Median age was 58 years (range 34-81), ECOG performance status was 0 (63%), 1 (35%), or 2 (2%), 63% had hormone receptor-positive disease, 15% had brain metastases, 56% had relapsed after primary surgery, and 23% had received adjuvant or neo-adjuvant trastuzumab. Median follow-up time was 44.6 months. Median PFS was 6.1 months in HX arm and 7.1 months in LX arm (hazard ratio 0.81 90% CI 0.55-1.21; p=0.39), median OS was 31.0 months in HX arm and not reached in LX arm (hazard ratio 0.58 95% CI 0.26-1.31; p=0.18), ORR was 40% in HX arm and 41% in LX arm (p=1.00), disease control rate was 73% in HX arm and 92% in LX arm (p=0.038), and proportion of subjects progressing with brain metastases as site of first progression was 5% in HX arm and 5% in LX arm. Grade 3-4 toxicities included hand-foot syndrome (21% in HX arm and 21% in LX arm) and diarrhea (9% in HX arm and 16% in LX arm). In subgroup analyses, PFS benefit in LX arm compared to HX arm was significantly larger among patients who had received previous systemic treatment for metastatic disease for less than 1 year (interaction p=0.007). Subgroup analyses by biomarkers will be presented at the meeting. Conclusions: In women with HER2-positive MBC previously treated with trastuzumab and taxanes, lapatinib + capecitabine tended to yield better PFS and OS than trastuzumab beyond progression + capecitabine, although they were not statistically significant.Background: In patients with HER2-positive metastatic breast cancer (MBC) who progressed on trastuzumab (H)-based therapy, both continuing H beyond progression and switching to lapatinib (L) in combination with chemotherapy are valid options. However, it is unclear which strategy is more effective and how we can select a proper strategy in each patient. Methods: We conducted an open label, multicenter, randomized phase II trial to comparatively evaluate efficacy and safety of H + capecitabine (X) (HX) or L + X (LX) in women with HER2-positive MBC who were previously treated with taxanes and progressed on H-containing regimens. Patients treated with more than two chemotherapy regimens for MBC were excluded. Those treated with pertuzumab and/or T-DM1 were allowed to enroll in this study. Patients with brain metastases were also included if they are asymptomatic. Patients received H (4mg/kg loading then 2mg/kg weekly or 8mg/kg loading then 6mg/kg every 3 weeks) and X (2500 mg/m2/day on days 1-14 every 3weeks) in HX arm and L (1250 mg/day) and X (2000 mg/m2/day on days 1-14 every 3weeks) in LX arm until progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate (ORR), proportion of subjects progressing with brain metastases as site of first progression, and safety.We also assessed biomarkers in tumor tissues and circulating cell-free DNA. Results: Between May 2011 and December 2014, 86 patients (43 in HX arm and 43 in LX arm) were enrolled in this study. Median age was 58 years (range 34-81), ECOG performance status was 0 (63%), 1 (35%), or 2 (2%), 63% had hormone receptor-positive disease, 15% had brain metastases, 56% had relapsed after primary surgery, and 23% had received adjuvant or neo-adjuvant trastuzumab. Median follow-up time was 44.6 months. Median PFS was 6.1 months in HX arm and 7.1 months in LX arm (hazard ratio 0.81 90% CI 0.55-1.21; p=0.39), median OS was 31.0 months in HX arm and not reached in LX arm (hazard ratio 0.58 95% CI 0.26-1.31; p=0.18), ORR was 40% in HX arm and 41% in LX arm (p=1.00), disease control rate was 73% in HX arm and 92% in LX arm (p=0.038), and proportion of subjects progressing with brain metastases as site of first progression was 5% in HX arm and 5% in LX arm. Grade 3-4 toxicities included hand-foot syndrome (21% in HX arm and 21% in LX arm) and diarrhea (9% in HX arm and 16% in LX arm). In subgroup analyses, PFS benefit in LX arm compared to HX arm was significantly larger among patients who had received previous systemic treatment for metastatic disease for less than 1 year (interaction p=0.007). Subgroup analyses by biomarkers will be presented at the meeting. Conclusions: In women with HER2-positive MBC previously treated with trastuzumab and taxanes, lapatinib + capecitabine tended to yield better PFS and OS than trastuzumab beyond progression + capecitabine, although they were not statistically significant. Citation Format: Takano T, Tsurutani J, Takahashi M, Yamanaka T, Sakai K, Ito Y, Fukuoka J, Kimura H, Kawabata H, Tamura K, Matsumoto K, Aogi K, Sato K, Nishio K, Nakagawa K, Saeki T. A randomized phase II trial of trastuzumab + capecitabine versus lapatinib + capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes: WJOG6110B/ELTOP [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-14.

Background: Anti-HER2 treatment using trastuzumab (Tmab) has contributed to improving the clinical outcome of HER2-positive breast cancerpatients. However, some patients do not respond to Tmab therapy and the combination of Lapatinib and capecitabine (LC) is an effective treatment option after progression on Tmab. Hormone receptor status is also an important factor for deciding if the patient should be treated with endocrine therapy as well. The aim of this study was to investigate the clinical significance of hormone receptor status in biomarker expression and to evaluate the efficacy of lapatinib therapy. Materials and Methods: Eighty patients with HER2 positive breast cancer refractory to Tmab were enrolled in this prospective trial (KBC-SG 1107) between December 2011 and March 2014. The following treatment began after enrollment; lapatinib 1250-mg tablets were administered orally once daily and capecitabine (2000 mg/m2 per day) on days 1 to 14 every 21 days until disease progression or until severe adverse events. Total HER2 (H2T), p95HER2 (p95), and total HER3 (H3T) expression levels were quantified in formalin-fixed paraffin embedded samples using VeraTag assays. ER and progesterone receptor (PgR), PTEN and p95 expressions were evaluated using immunohistochemistry (IHC) and PIK3CA mutation using direct sequencing. Statistical analyses were performed using SPSS (ver. 21). A two-sided P Results: The ER- and PgR-positive rates were 55.0% and 33.8%, respectively. The response rate to LC was 30% (CR: 1 case; PR: 23 cases), the clinical benefit rate was 51.3% and the median progression-free survival (PFS) was 174.5 days. Both ER and PgR negativity significantly correlated with higher H2T (cutoff: 13.8), p95HER2 (cutoff: 2.8) and PTEN expression levels (cutoff: H score of 100). Lower H2T expression levels and PIK3CA mutation rates were often observed in the non-responders (both: p=0.087). The ER and PgR status did not correlate with response. A high p95 and PTEN expression significantly correlated with longer PFS in ER and/or PgR positive cases (p=0.02 and 0.03), respectively. The overall survival (OS) after LC significantly correlated with the number of recurrence organs (p=0.0002) but not with the p95 and PTEN expression levels. Conclusion: LC therapy was effective in Tmab-refractory HER2 positive breast cancer. Moreover, the biomarker expression differed depending on the ER/PgR status and a high p95 and PTEN expression correlated with longer PFS in ER and/or PgR positive cases. Further study is necessary to validate these findings. Citation Format: Arima N, Nishimura R, Toh U, Tanaka M, Saimura M, Okumura Y, Saito T, Tanaka T, Teraoka M, Shimada K, Koga T, Kurashita K, Todoroki H, Ueo H, Ohi Y, Toyoshima S, Mitsuyama S, Tamura K. The importance of hormone receptor status on biomarker expression and the efficacy of lapatinib plus capecitabine therapy after progression on trastuzumab in HER2 positive recurrent and advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-25.

We conducted a nationwide survey on chemotherapy-induced nausea and vomiting (CINV) in Japan and demonstrated good compliance with Japanese CINV guidelines, resulting in good control of vomiting. However, almost half the patients experienced breakthrough CINV. We analyzed the survey results in relationship to the management of patients with breakthrough CINV. This multicenter, prospective, observational study analyzed data for 1910 patients in Japan scheduled for moderately or highly emetogenic chemotherapy (MEC and HEC, respectively). Patients who developed CINV despite prophylactic use of antiemetics were administered rescue drugs. Patients who received cisplatin-based HEC (C-HEC), non-cisplatin-based HEC (N-HEC), or MEC were evaluated separately. A total of 989 patients experienced CINV, of whom 412 (44%) received rescue antiemetics during the study period. The rate at which patients with breakthrough CINV were started on rescue drugs ranged from 13% to 24%. Rescue drugs were given more frequently on days 2–4 for C-HEC and MEC and on days 1–2 for N-HEC. Eighty-six percent of patients received metoclopramide or domperidone. 5-HT3 receptor antagonists, antipsychotics, and anti-anxiety drugs were used for 11–5% of patients. The mean duration of antiemetic use was 2.6 days. Fewer than half of the patients with breakthrough CINV were treated with rescue antiemetics, suggesting that CINV was mild in the remaining patients. However, CINV was sufficiently severe to prevent eating in other patients, indicating the need for new drugs with different mechanisms to control CINV.

Lynch syndrome (LS) is an autosomal dominantly inherited disease predisposed to not only colorectal cancer but also other LS-related tumors. Although the clinical and genetic characteristics of LS in Western countries have been well characterized, the information of Japanese LS is limited. As a collaborative study of Japanese Society for Cancer of the Colon and Rectum (JSCCR), we registered colorectal cancer (CRC) patients who fulfilled the modified Amsterdam II criteria including gastric cancer as an LS-related tumor. Among 4030 CRC patients initially registered in this project, 85 patients (2.1%) fulfilled the modified criteria. An additional 26 patients who met the same criteria were enrolled in the analysis. We analyzed three major responsible genes, MLH1, MSH2, and MSH6 by direct sequencing, and further performed multiplex ligation-dependent probe amplification for MLH1 and MSH2. Consequently, we identified pathogenic variants in 64 of the 111 patients comprising of 34 patients in MLH1, 28 in MSH2, and 2 in MSH6. It is of note that large structural alterations were found in 17 patients. Among the 64 patients, 11 patients would not have been enrolled in the analysis if gastric cancer were not included in the modified criteria. In addition, 10 of the 64 variant carriers (15.6%) had medical history of gastric cancer. Furthermore, the standardized incidence ratio of gastric cancer in the LS patients to the Japanese population is estimated to be as high as 20.2. These data underscore the importance of gastric cancer in the diagnosis and healthcare of Japanese LS patients.

Objective The aim of this survey was to describe how geriatric oncology is integrated in undergraduate teaching and graduate training as well as in daily clinical oncology practice in Japan. Methods All schools of medicine in Japan are allied with graduate schools of medicine. We conducted a survey of all Japanese medical and graduate schools (n = 81), and designated cancer hospitals (n = 437) from July 2018 to August 2018. The survey of the schools asked about existence of geriatrics division and geriatric oncology service and if an education curriculum in geriatrics and geriatric oncology was used. The survey of designated cancer hospitals requested general hospital information and the current practice patterns of general geriatric and cancer patients. Results Forty-eight medical schools (59%) participated in this survey, and teaching in geriatrics and geriatric oncology was implemented in 23 schools and 1 school, respectively. Forty-two graduate schools of medicine (52%) responded; five had an education curriculum in geriatrics, but none provided geriatric oncology training. Among 151 participating hospitals (35%), 5 had a geriatrics division and 20 hospitals employed geriatricians. There was no geriatric oncology service or geriatric oncology specialists in any of the 151 hospitals. Seventy percent of the hospitals reported performing a geriatric assessment for at least some older adults with cancer. Conclusions This survey provides information on the current state of Japanese education and clinical practice in geriatric oncology. In Japan, a nation with among the largest population of older citizens in the world, education and training greatly need to be promoted to disseminate a core set of geriatrics knowledge and skills to students, trainees and healthcare professionals.

Background Cancer cachexia is characterized by weight loss and is associated with increased morbidity and mortality in patients with cancer. Anamorelin (ONO‐7643; ANAM) is a novel and selective ghrelin receptor agonist that improves appetite, lean body mass (LBM), body weight, and anorexia. Methods This multicenter, open‐label, single‐arm study investigated the efficacy and safety of 100 mg anamorelin in 50 Japanese patients with advanced and unresectable gastrointestinal (colorectal, gastric, or pancreatic) cancer. ANAM was administered once daily over 12 weeks. The primary endpoint was the proportion of patients that maintained or gained LBM over the course of the study. Secondary endpoints included changes in LBM, body weight, quality of life (QoL), and nutritional status biomarkers. Results The proportion of patients who responded to treatment was 63.3% (95% CI, 48.3%‐76.6%), with a least square mean ± SE change in LBM and body weight from baseline of 1.89 ± 0.36 kg and 1.41 ± 0.61 kg, respectively. Appetite‐related questions on the QoL questionnaire showed that ANAM improved appetite. Adverse events occurred in 79.6% of patients, and the most common treatment‐related adverse events were increased γ‐glutamyl transpeptidase (8.2%), diabetes mellitus (6.1%), hyperglycemia (6.1%), and prolonged QRS complex (6.1%). Conclusions ANAM improved anorexia and patients' nutritional status, resulting in rapid increases in LBM and body weight in patients with advanced gastrointestinal cancer who had cancer cachexia. ANAM treatment was well tolerated over 12 weeks. ANAM is a potential clinically beneficial pharmacotherapeutic option for patients with advanced gastrointestinal cancer who have cancer cachexia., The receipt of 100 mg anamorelin increases lean body mass and improves symptoms of anorexia and nutritional status in patients with advanced gastrointestinal cancer who have cancer cachexia. Anamorelin is well tolerated in these patients.

e13005 Background: In Japan, eribulin has been approved for inoperative or recurrent breast cancer, following treatment with an anthracyclines and a taxanes. We reported the efficacy and safety of eribulin as a first-line to third-line treatment in patients with advanced/metastatic breast cancer (MBC) previously treated with anthracylinsanthracyclines and taxanes (Breast 2017). Briefly, the main inclusion criteria were as follows: no history of eribulin administration; an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2,; human epidermal growth factor receptor 2 (HER2)-negative,; 20–75 years; ≥4 weeks from the last dose of chemotherapy, or ≥2 weeks from the last dosing of endocrine or radiation therapy; measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1; sufficient organ function; life expectancy of ≥3 months; and no significant abnormalities on electrocardiogram. Patients in this clinical trial were enrolled between December 1, 2011, and November 30, 2013. Eribulin was administered intravenously at a dose of 1.4 mg/m2 during a 2-5 min infusion on days 1 and 8 every 3 weeks. In contrast, baseline neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) were reported to predict progression-free survival (PFS) or overall survival (OS). However, these reports were mainly retrospective analysis. Therefore, retrospective evaluation of NLR/ALC in a prospective clinical trial is important to understand the association between NLR/ALC and OS/PFS. Methods: Of 47 prospectively enrolled patients in a previous trial, 45 patients were retrospectively evaluated for baseline NLR/ACL and at the time of 3 cycles of eribulin. The association between NLR/ALC and OS/PFS was also were analyzed for association with OS/PFS. The Kaplan-Meier method was used to estimate the OS/PFS distribution. The cut-off values for baseline NLR and ALC were set at 3 and 1500 /ul, respectively. Results: The median OS of patients with a baseline NLR < 3 was significantly longer than that of patients with a baseline NLR ≥ ≧3 (769 days vs. 409 days; log-rank test p = 0.0333). The median OS of patients with a baseline ALC ≥ ≧1500 was also significantly longer than that of patients with a baseline ALC < 1500 (964 days vs.vs 427 days; log-rank test p = 0.0425). Association between baseline NLR/ALC and PFS were not seen, and also association between at the time of 3 cycles of NLR/ALC and OS/PFS were not seen neither. Conclusions: Baseline NLR and ALC in the patients with HER2- negative breast cancer who plan to treat eribulin may predict overall survival. Clinical trial information: UMIN000007121.

During the course of our studies towards the identification of promising chemotherapeutic candidates from plants against two human T-cell lymphotropic virus type I-infected T-cell lines (MT-1 and MT-2), we screened 17 extracts from 9 rutaceous plants against MT-1 and MT-2 cells. The extracts from the aerial parts and roots of Boenninghausenia japonica, as well as the leaves and roots of Ruta graveolens showed potent antiproliferative effects. After activity-guided fractionation, we isolated 44 compounds from two rutaceous plants, including three new compounds (1-3), which were classified into 26 coumarin analogs (13 coumarins, 8 furanocoumarins, 4 dihydrofuranocoumarins and one dihydropyranocoumarin), 15 alkaloid analogs (7 quinolone alkaloids, 4 acridone alkaloids, 3 furanoquinoline alkaloids and one tetrahydroacridone alkaloid) and 3 flavonoid glycosides. Structure-activity relationship studies were also evaluated. The coumarin compounds (2, 3 and 7-9) bearing a 3-dimethylallyl moiety showed potent activity. Similarly, of all the furanocoumarins evaluated in the current study, compound 17 bearing a 3-dimethylallyl group also showed potent activity. A dihydrofuranocoumarin (27) bearing a 3-dimethylallyl moiety showed the most potent activity. Following 27, compound 28 showed potent activity. These results therefore suggested that the presence of a 3-dimethylallyl moiety was important to the antiproliferative activity of these coumarin analogs.

Summary Pegfilgrastim is a pegylated form of the granulocyte‐colony stimulating factor, filgrastim. Herein, we report the results of a multicentre, randomized, double‐blind phase III trial comparing the efficacy and safety of pegfilgrastim with filgrastim in patients with malignant lymphoma. Patients were randomized to receive either a single subcutaneous dose of pegfilgrastim or daily subcutaneous doses of filgrastim on day 4 after the completion of cyclophosphamide, cytarabine, etoposide and dexamethasone ± rituximab (CHASE(R); day 1–3) chemotherapy. The primary endpoint was the duration of severe neutropenia (DSN), defined as the number of days with neutrophil count

Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan.An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period.Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups.Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy.http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.

Background: Taselisib (GDC-0032) is an orally bioavailable, potent and selective phosphoinositide 3-kinase (PI3K) inhibitor. Preclinical data showed that taselisib had increased antitumor activity against PIK3CA (gene encoding the PI3Kα isoform) mutant tumors. This study aimed to investigate the safety, tolerability and pharmacokinetics (PK) of taselisib as monotherapy and in combination with fulvestrant in Japanese patients (pts). Materials and methods: A 3+3 design was used. In Phase Ia, pts with advanced solid tumors received taselisib tablet monotherapy (2, 4 or 6 mg once daily [QD]), and safety and PK were evaluated. In Phase Ib, pts with hormone receptor-positive locally advanced or metastatic breast cancer received taselisib (2 or 4 mg QD) in combination with fulvestrant (500 mg at a time), and safety and PK were evaluated. Maximal administered doses of 6 mg QD as a single agent and 4 mg QD in combination with fulvestrant were based upon prior clinical trial experience with taselisib (Juric D. et al. AACR 2013, Abstract LB-64; Juric D. et al. SABCS 2013, Abstract PD1-3). Results: As of 15 Mar 2015, 9 pts (PIK3CA mutant: 2 pts) were enrolled in Phase Ia and 3 pts in Phase Ib. Phase Ia dose-escalation study has been completed and Phase Ib is ongoing. In Phase Ia, no dose-limiting toxicity (DLT) was observed at any dose level tested (maximum administered dose of 6 mg QD). Common (≥3 pts) adverse reactions (ARs) were stomatitis (4 pts), rash (3 pts) and diarrhea (3 pts); the only Grade ≥3 AR was neutropenia (1 pt). Partial response was observed in 1 pt who received taselisib 4 mg and had a PIK3CA mutant breast tumor. Stable disease was observed in 4 pts. Cmax and AUC indicated a dose-proportional PK profile of taselisib within the dose range tested. Moreover, taselisib PK in Japanese pts was consistent with the PK reported from North American and European pts (Juric D. et al. AACR 2013, Abstract LB-64). In Phase Ib, 3 pts received taselisib 2 mg in combination with fulvestrant and no DLT was observed. Preliminary ARs were similar to those with monotherapy and no Grade ≥3 AR was reported. Confirmation of tolerability of taselisib 4 mg in combination with fulvestrant is under evaluation. Conclusion: Taselisib monotherapy was well tolerated in Japanese pts up to a dose of 6 mg, which is the recommended dose in non-Japanese pts. Promising preliminary activity of monotherapy was observed in advanced solid tumors, especially in a pt with PIK3CA mutant tumor. The combination of taselisib 2 mg with fulvestrant is well tolerated. Investigation of tolerability of taselisib 4 mg in combination with fulvestrant is ongoing. Final results of this study will be presented here at the Symposium this year. Citation Format: Kobayashi T, Nakano K, Tomomatsu J, Nara E, Ito Y, Kobayashi K, Fukada I, Araki K, Shimomura A, Shimoi T, Kodaira M, Yunokawa M, Yonemori K, Shimizu C, Nakamura K, Kotani N, Inatani M, Tamura K, Takahashi S. Phase Ia/Ib study of taselisib (GDC-0032), a potent and selective phosphoinositide 3-kinase inhibitor, in Japanese patients with advanced solid tumors or hormone receptor-positive locally advanced or metastatic breast cancer (JO29196 study). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-10.

Background/aim The incidence of delayed chemotherapy-induced nausea and vomiting (CINV), especially nausea, in gynecologic cancer patients who receive paclitaxel and carboplatin (TC) chemotherapy is unclear. We assessed risk factors for delayed CINV in these patients, and examined whether it was controlled with combination antiemetic therapy. Materials and methods Data were pooled from two prospective studies, and compared between the two antiemetic prophylaxis groups using inverse probability of treatment weighted (IPTW) analysis. Results Among the 182 evaluable patients (mean age: 56.2 years), three antiemetics gave better overall control than two for delayed nausea (42.9% vs. 57.4%,) and vomiting (13.8% vs. 34.5%). Risk factor for delayed nausea was age [odds ratio (OR)=0.953; p=0.0898[and use of two antiemetics (vs. three antiemetics) for delayed vomiting (OR=0.304; p=0.0732). Conclusion A combination of three antiemetics controls delayed CINV among patients who undergo TC chemotherapy. Identification of risk factors can facilitate personalized treatments.

We herein report a case of systemic phaeohyphomycosis by Exophiala dermatitidis (E. dermatitidis) with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). The patient had been taking oral corticosteroids for years to control the GVHD. Yeast-like fungi were identified in a blood culture, so treatment with micafungin (150 mg/day) was begun, with no improvement. The patient passed away on hospital Day 12. A sequence analysis of rRNA revealed the isolate to be E. dermatitidis. This report brings attention to an emerging mycosis of community-acquired Exophiala species infection in the very-late phase after allogenic HSCT in patients with chronic GVHD.

Peripheral T cell lymphomas are an aggressive group of non-Hodgkin lymphomas with poor outcomes for most subtypes and no accepted standard of care for relapsed patients. This study evaluated the efficacy and safety of forodesine, a novel purine nucleoside phosphorylase inhibitor, in patients with relapsed peripheral T cell lymphomas. Patients with histologically confirmed disease, progression after ≥ 1 prior treatment, and an objective response to last treatment received oral forodesine 300 mg twice-daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Forty-eight patients (median age, 69.5 years; median of 2 prior treatments) received forodesine. In phase 1 (n = 3 evaluable), no dose-limiting toxicity was observed during the first 28 days of forodesine treatment. In phase 2 (n = 41 evaluable), the ORR for the primary and final analyses was 22% (90% CI 12–35%) and 25% (90% CI 14–38%), respectively, including four complete responses (10%). Median PFS and OS were 1.9 and 15.6 months, respectively. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Dose reduction and discontinuation due to adverse events were uncommon. Secondary B cell lymphoma developed in five patients, of whom four were positive for Epstein-Barr virus. In conclusion, forodesine has single-agent activity within the range of approved therapies in relapsed peripheral T cell lymphomas, with a manageable safety profile, and may represent a viable treatment option for this difficult-to-treat population.

Lynch syndrome is a genetic disorder related to cancer predisposition, including colorectal cancer, endometrial cancer, and ovarian cancer. Germline mutations in mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2, are responsible for this condition. Cancer tissue specimens resected from small bowel adenocarcinoma in a Japanese patient showed decreased expression of MLH1 and PMS2 by immunohistochemistry testing. Finally, a novel MLH1 mutation, c.1833dup, was identified in this patient.

The authors have developed a digital beam forming dynamic imaging radar system, ”VirA.” It is a cutting-edge non-contact measurement technology for space-continuous vibration monitoring of buildings. In this research, the authors have presented the vibration monitoring method by conducting vibration measurements of an actual tall building. Experiments were performed to compare the performances of two time-synchronized radars and a conventional vibrometer. Frequency analysis was performed and the dominant frequencies were compared with those determined from the conventional vibrometer.

We conducted this study to establish whether drinking alcohol alters the risk of early-onset colorectal cancer (CRC) in Japanese patients with Lynch syndrome (LS). The subjects were 66 LS patients with pathogenic mutation of mismatch repair genes (MLH1, MSH2, and MSH6) from the nationwide Japanese retrospective multicenter study. Cox proportional hazards modeling was used to investigate the factors correlating with early-onset CRC diagnosis, using clinical data such as gender, tobacco use, alcohol consumption, body mass index, gene mutation (MLH1, MSH2 vs MSH6), and family cancer history. Alcohol was significantly correlated with an increased risk of early-onset CRC [HR 2.44, 95% CI 1.13-5.16 (p = 0.02)], but tobacco use was not [HR 0.8, 95%CI 0.38-1.62 (p = 0.53)]. These findings suggest that alcohol consumption is correlated with an earlier onset of CRC in Japanese patients with LS.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of peripheral T-lymphocytes with a poor prognosis. This multicenter, two-stage, single-arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression-free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17-31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression-free survival (PFS) was 38 (95% CI; 18–106) days. All patients developed ≥1 adverse events (AEs), and 80% of patients had ≥1 grade 3/4 AEs; however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.

Tazobactam/piperacillin (4.5 g for adults and 90 mg/kg body weight for children, every 6 h) was administered to Japanese patients with febrile neutropenia to evaluate its defervescence and clinical efficacy and safety. The pharmacokinetics in children were also examined. Defervescence efficacy at day 4 of the treatment was achieved in 50.0% of 94 adult and 62.5% of 8 pediatric patients, respectively. The defervescence efficacy rate in relation to the neutrophil count in adults was 37.5% for the patients with a neutrophil count of less than 100/μL and 62.5% for that between 100 and 500/μL. The clinical efficacy rate at day 7 and at the end or discontinuation of the treatment was 79.6% and 59.1% in adult patients, respectively, and 57.1% and 75.0% in pediatric patients, respectively. Fifteen strains of causative bacteria were isolated in 13 adult patients at baseline. All strains were eradicated within 4 days of the treatment. The side effects that occurred in adult and pediatric patients during the treatment were all known and not specific to febrile neutropenia patients. The pharmacokinetics profiles of tazobactam/piperacillin in children with febrile neutropenia are unlikely to be different from those in children with a common bacterial infection and without any immunosuppressive conditions. The study results in Japanese patients with febrile neutropenia demonstrate that tazobactam/piperacillin treatment is efficacious and safe in adults. As for pediatric patients, given the limited number of cases studied, further investigation is needed (Clinical trial number: Japic CTI-121728).

The purpose of this article is to disseminate the standard of antiemetic therapy for Japanese clinical oncologists. On the basis of the Appraisal of Guidelines for Research and Evaluation II instrument, which reflects evidence-based clinical practice guidelines, a working group of the Japanese Society of Clinical Oncology (JSCO) reviewed clinical practice guidelines for antiemesis and performed a systematic review of evidence-based domestic practice guidelines for antiemetic therapy in Japan. In addition, because health-insurance systems in Japan are different from those in other countries, a consensus was reached regarding standard treatments for chemotherapy that induce nausea and vomiting. Current evidence was collected by use of MEDLINE, from materials from meetings of the American Society of Clinical Oncology National Comprehensive Cancer Network, and from European Society of Medical Oncology/Multinational Association of Supportive Care in Cancer guidelines for antiemesis. Initially, 21 clinical questions (CQ) were selected on the basis of CQs from other guidelines. Patients treated with highly emetic agents should receive a serotonin (5-hydroxytryptamine; 5HT3) receptor antagonist, dexamethasone, and a neurokinin 1 receptor antagonist. For patients with moderate emetic risk, 5HT3 receptor antagonists and dexamethasone were recommended, whereas for those receiving chemotherapy with low emetic risk dexamethasone only is recommended. Patients receiving high-emetic-risk radiation therapy should also receive a 5HT3 receptor antagonist. In this paper the 2010 JSCO clinical practice guidelines for antiemesis are presented in English; they reveal high concordance of Japanese medical circumstances with other antiemetic guidelines that are similarly based on evidence.