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Cardiac treatment-emergent adverse events in the two trial groups

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 2, 88.5% receiving 450–2, and 90% receiving ≥600 mg/m2) and did not affect treatment efficacy. LVEF deterioration was seen in 62 of 153 (40.5%) patients who received a cumulative dose 2, 82 of 159 patients (51.6%) who received 450–2, and 50 of 89 patients (56.2%) who received ≥600 mg/m2. Grade ≥3 cardiac dysfunction occurred in 2% of patients at 2, 3% at 450–2, and 1.1% at ≥600 mg/m2. Incidence of treatment-related cardiac AEs was low across all dose ranges.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.See related commentary by Benjamin and Minotti, p. 3809

Cancer cachexia is a syndrome characterized by anorexia and decreased body weight. This study evaluated the efficacy and safety of anamorelin, an orally active, selective ghrelin receptor agonist, in patients with cancer cachexia and a low body mass index (BMI).This multicenter, open-label, single-arm study enrolled Japanese patients with non-small cell lung cancer or gastrointestinal cancer with cancer cachexia (BMI 20 kg/mOne hundred two patients were eligible and enrolled. The means and standard deviations for age and BMI were 71.0 ± 8.2 years and 17.47 ± 1.48 kg/mAnamorelin improved body weight and anorexia-related symptoms in patients with cancer cachexia and a low BMI with durable efficacy and favorable safety and tolerability.Anamorelin is a drug that stimulates appetite and promotes weight gain. This clinical trial was aimed at determining its efficacy and safety in Japanese cancer patients with a low body mass index and cachexia, a syndrome associated with anorexia and weight loss. Anamorelin was found to improve body weight and anorexia-related symptoms in these patients, and these effects were durable for up to 24 weeks. Moreover, anamorelin was generally well tolerated. These findings suggest that anamorelin is a valuable treatment option for patients with cancer cachexia and a low body mass index.

Background A questionnaire survey was conducted to assess the implementation status of geriatric assessment in cancer treatment and the potential for collaboration between medical care and the long-term care insurance system. Methods Questionnaires were sent to 795 facilities in Japan. The questions were instructed to be answered via an online survey (SurveyMonkey®), which began in September 2020 and closed on 31 October 2020. The questionnaire consisted of 8 questions on the status of geriatric assessment implementation and 15 questions on the long-term care insurance system. Results In total, 631 departments in 340 (42.8%) of 795 hospitals and clinics provided responses. Approximately 81.5% of the departments did not perform geriatric assessment. The common reasons were lack of knowledge about geriatric assessment (54.0%) and lack of personnel (35.5%). Even if geriatric assessment was conducted, 63.6% of departments did not utilize geriatric assessment results in clinical practice. Approximately 61.7% of respondents were familiar with the long-term care insurance system and 62.9% with the certification process. Moreover, 28% of respondents used certification examination results in treatment planning. Conclusions Geriatric assessment is less recognized than the long-term care insurance system, and its results are rarely used in clinical practice. However, 28% of certification examination results are utilized in treatment decision-making. Notably, this survey first showed the incorporation of the long-term care insurance system into the medical care of vulnerable elderly patients with cancer.

Elderly cancer patients requiring surgical treatment are increasing, and the deterioration of quality of life and shortening of healthy life expectancy due to postoperative complications represent major problems. This study investigated the current status of medical treatment, including perioperative evaluations, for elderly cancer patients requiring surgical treatment at cancer treatment facilities nationwide. A total of 436 cancer care facilities around Japan were invited to participate in this web-based survey regarding management of cancer patients ≥ 65 years old who had undergone surgical treatment in 2018. A total of 919 department heads from 245 facilities agreed to participate. Although most respondents answered that performance status, preoperative examinations, and comorbidities were important when deciding on a treatment plan, age, Geriatric Assessment (GA), and guidelines were "not important" for > 10% of all respondents. GA was familiar to 195 department heads (21%), and awareness of GA was significantly lower among respondents from medical education institutions than the other types of hospitals (18.5% vs 26.3%; P = 0.006). This large survey revealed that the use of GA is not widespread, and its awareness in medical education institutions remains low. We believe that accumulating evidence of geriatric oncology surgery is an urgent issue in Japan.

Purpose The Japanese Society of Medical Oncology published a guideline (GL) on febrile neutropenia (FN) in 2017. The study’s purpose is to reveal how widely GL penetrated among physicians and surgeons providing chemotherapy. Methods A questionnaire survey was conducted with SurveyMonkey™ for members of the Japanese Association of Supportive Care in Cancer and relevant academic organizations. Each question had four options (always do, do in more than half of patients, do in less than half, do not at all) and a free description form. Responses were analyzed with statistical text-analytics. Result A total of 800 responses were retrieved. Major respondents were experts with more than 10-year experience, physicians 54%, and surgeons 46%. Eighty-seven percent of respondents knew and used GL. Forty-eight percent assessed FN with Multinational Association of Supportive Care in Cancer (MASCC) score “always” or “more than half.” Eighty-one percent chose beta-lactam monotherapy as primary treatment in high-risk patients. Seventy-seven percent did oral antibacterial therapy in low-risk patients ambulatorily. Seventy-eight percent administered primary prophylactic G-CSF (ppG-CSF) in FN frequency ≥ 20% regimen. Fifty-nine percent did ppG-CSF for high-risk patients in FN frequency 10–20% regimen. Ninety-seven percent did not use ppG-CSF in FN frequency Conclusion GL is estimated to be widely utilized, but some recommendations were not followed, presumably due to a mismatch with actual clinical practices in Japan.

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.

Li‐Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome, and the majority of patients with LFS have been identified with germline variants in the p53 tumor suppressor (TP53) gene. In the past three decades, considerable case reports of TP53 germline variants have been published in Japan. To the best of our knowledge, there have been no large‐scale studies of Japanese patients with LFS. In this study, we aimed to identify Japanese patients with TP53 germline variants and to reveal the characteristics of LFS in Japan. We collected reported cases by reviewing the medical literature and cases diagnosed at the institutions of the authors. We identified 68 individuals from 48 families with TP53 germline pathogenic or likely pathogenic variants. Of the 48 families, 35 (72.9%) had missense variants, most of which were located within the DNA‐binding loop. A total of 128 tumors were identified in the 68 affected individuals. The 128 tumor sites were as follows: breast, 25; bones, 16; brain, 12; hematological, 11; soft tissues, 10; stomach, 10; lung, 10; colorectum, 10; adrenal gland, 9; liver, 4; and others, 11. Unique phenotype patterns of LFS were shown in Japan in comparison with those in a large national LFS cohort study in France. Above all, a higher frequency of patients with stomach cancer was observed in Japanese TP53 germline variant carriers. These results may provide useful information for the clinical management of LFS in Japan., Comparing this study in Japan with a large national Li‐Fraumeni syndrome cohort study in France, the unique phenotype patterns of Li‐Fraumeni syndrome was shown in Japan. Especially, the higher frequency of patients with stomach cancer in Japanese TP53 germline variants carriers was shown.

Background High blood pressure (HBP) has become a public health issue worldwide. The relationship between high BP and changes in the body mass index (BMI) category in Japanese pubertal children has not yet been examined. To resolve this issue, we examined existing data with a focus on the primordial prevention of high BP signs, including elevated BP, among pubertal children aged 12 and 15 years. Methods Height, body weight, and BP data were examined from health checkups of 18,247 children conducted between 1993 and 2000 in the Karatsu Study, which was a cohort of pediatric lifestyle-related disease prevention medical health checkups in Japan. BP and BMI were assessed using the updated American Academy of Pediatrics (AAP) guidelines and Endocrine Society's clinical practice guidelines definitions, respectively. Results Follow-up data were obtained from 7,090 subjects (50.5% boys). Stage 2 hypertension (HTN) was detected in 3% and 2.7% of boys and girls aged 12 years, respectively, and in 2.7% and 1% of boys and girls aged 15 years, respectively. Among children aged 15 years, 1.4% were newly classified with stage 2 hypertension, and 15.6% exhibited improvements to a normal BP. A binomial logistic regression analysis of high BP and BMI category changes revealed odds ratios (OR) in the group with a deteriorated BMI category of 1.51 (95% confidence interval (CI), 1.17-1.94), 2.30 (95%CI, 1.66-3.17), and 6.83 (95%CI, 4.14-11.29) for elevated BP, stage 1 hypertension, and stage 2 hypertension, respectively. Conclusion High BP in puberty positively correlated with BMI category changes. Considering the presence of the tracking phenomenon in hypertension, BP monitoring is an essential part of the early strategy for the prevention of lifestyle-related diseases in childhood, and improvements in BP control are crucial in early life.

Immunohistochemistry of mismatch repair proteins is a universal strategy for Lynch syndrome screening. In this case, Lynch syndrome was suspected, because MLH1 and PMS2 expression was negative by IHC. However, mismatch repair genetic analysis revealed a variant of unknown significance of c.454-13A > G in MLH1. Therefore, we performed reverse transcription-PCR using mRNA extracted from the patient’s lymphocytes and detected a heterozygous gene allele indicating splicing abnormalities that complex splicing, with exon 5 followed by only the first codon (ACG) of exon 6 and leading to exon 7 of the MLH1. Two years later, this mutation was corrected to “likely pathogenic”. For Lynch syndrome in which mismatch repair protein expression is undetectable by immunohistochemistry, reverse transcription-PCR may be useful to identify an intronic variant of unknown significance as the likely pathogenic variant.

Introduction Invasive fungal diseases are crucial causes of morbidity and mortality among patients with febrile neutropenia (FN). Though liposomal amphotericin B (L-AMB) is one of the agents recommended for first-line empirical antifungal therapy in patients with FN, large-scale clinical studies have not been performed in Japan. Methods An open-label prospective multi-center study was carried out to evaluate the safety and efficacy of L-AMB in Japanese patients with FN suspected of having fungal infection. Results Of the 426 patients registered, safety and efficacy evaluations were conducted for 424 and 399, respectively. By clinical response criteria using 5 composite endpoints, the response rate was 46.6% (186/399). The response rate by age were 54.5% (child: 30/55), 47.5% (adult: 97/204), 42.1% (elderly: 59/140) respectively. Regarding the composite endpoints, resolution of fever was observed in 61.2% (244/399), no breakthrough fungal infection in 99.0% (395/399), survival for 7 days or longer after the completion of treatment in 83.7% (334/399), no discontinuation of treatment due to toxicity or lack of efficacy in 60.9% (243/399), and successful treatment of any baseline fungal infection in 10/18. Adverse drug reactions (ADRs) developed in 61.1% (259/424), and frequent ADRs were hypokalemia, kidney dysfunction, and liver dysfunction, as previously reported. Conclusions The safety and efficacy profile of L-AMB in Japanese patients with FN suspected of having fungal infection were elucidated for the first time, through the analysis of a large number of cases including pediatric patients under real-world clinical settings collected in this nationwide study.

Objectives The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings. Methods From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy. Results The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2–79.4) and 79.6% (71.0–86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2–80.9%) and 78.0% (65.3–87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups. Conclusions The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT.

Background/aim Irinotecan is rarely used on the metastatic breast cancer (MBC) setting. S-1 is an oral mixture of tegafur, gimeracil and oteracil. We conducted this pilot study to assess efficacy and safty of chemotherapy with combined irinotecan and S-1 (IRIS). Patients and methods Irinotecan was given intravenously at 80 mg/m2 on days 1 and 8 and S-1 was given orally at 80-120 mg/day depending on body surface area for 2 weeks, repeating the cycle every 3 weeks. Results Twenty-two patients were enrolled in the study. Median age was 50.5 years (range=26-72). Nineteen patients were evaluable for response. Median overall survival and progression-free survival were 672 days (95% CI=420-967) and 166 days (95% CI=76-814), respectively. Conclusion The IRIS regimen has an acceptable safety profile and modest efficacy against MBC in patients previously heavily treated with chemotherapy. This regimen has potential to treat MBC.

PURPOSE Empiric antifungal therapy (EAT) is recommended for persistent febrile neutropenia (FN), but in most patients, it is associated with overtreatment. The D-index, calculated as the area surrounded by the neutrophil curve and the horizontal line at a neutrophil count of 500/μL, reflects both the duration and depth of neutropenia and enables real-time monitoring of the risk of invasive fungal infection in individual patients at no cost. We investigated a novel approach for patients with persistent FN called D-index–guided early antifungal therapy (DET), in which antifungal treatment is postponed until a D-index reaches 5,500 or the detection of positive serum or imaging tests, and compared it with EAT in this multicenter open-label noninferiority randomized controlled trial. PATIENTS AND METHODS We randomly assigned 423 patients who underwent chemotherapy or hematopoietic stem-cell transplantation for hematologic malignancies to the EAT or DET group. The prophylactic use of antifungal agents other than polyenes, echinocandins, or voriconazole was allowed. Micafungin at 150 mg per day was administered as EAT or DET. RESULTS In an intent-to-treat analysis of 413 patients, the incidence of probable/proven invasive fungal infection was 2.5% in the EAT group and 0.5% in the DET group, which fulfilled the predetermined criterion of noninferiority of the DET group (−2.0%; 90% CI, −4.0% to 0.1%). The survival rate was 98.0% versus 98.6% at day 42 and 96.4% versus 96.2% at day 84. The use of micafungin was significantly reduced in the DET group (60.2% v 32.5%; P < .001). CONCLUSION A novel strategy, DET, decreased the use and cost of antifungal agents without increasing invasive fungal infections and can be a reasonable alternative to empiric or preemptive antifungal therapy.

Background We previously reported the results of a prospective study of chemotherapy‐induced nausea and vomiting (CINV) in a cohort of patients who received carboplatin‐based chemotherapy and were selected from a nationwide registry of those scheduled for moderately (MEC) or highly emetogenic chemotherapy (HEC) by the CINV Study Group of Japan. Of 1,910 previously registered patients (HEC: 1,195; MEC: 715), 400 patients received carboplatin‐based chemotherapy. The frequency of CINV was determined, and the risk factors for CINV were assessed. Materials and Methods CINV data were collected from 7‐day diaries. Risk factors for CINV were identified using logistic regression models. Results Of 400 patients scheduled for carboplatin‐based chemotherapy, 267 patients received two antiemetics (5‐hydroxytryptamine‐3 receptor antagonist [5‐HT3 RA] and dexamethasone [DEX]), 118 patients received three antiemetics (5‐HT3 RA, DEX, and neurokinin‐1 receptor antagonist [NK1 RA]), and 15 were nonadherent to the treatment. In these patients, the CINV overall, acute, and delayed phase rates of complete response (CR), defined as no vomiting with no rescue medication, were 67.0%, 98.2%, and 67.5%, respectively. The rates of no nausea were 55.6%, 94.0%, and 56.1%, respectively, and those of no vomiting were 81.3%, 99.0%, and 81.8%, respectively. Older age was associated with a decreased non‐CR, whereas female sex, history of pregnancy‐related emesis, and dual antiemetic therapy were associated with an increased non‐CR during the overall period. Conclusion In a clinical practice setting, in patients who received carboplatin‐based chemotherapy, adherence is quite high and appropriate antiemetic prophylaxis requires a triple antiemetic regimen including NK1 RA. Implications for Practice For patients receiving carboplatin‐based chemotherapy, triple antiemetic therapy with 5‐hydroxytryptamine‐3 receptor antagonist, dexamethasone, and neurokinin‐1 receptor antagonist should be given prophylactically regardless of risk factor status., Chemotherapy‐induced nausea and vomiting reduces quality of life and treatment adherence. This article reports on the incidence of this adverse event and identifies risk factors using a nationwide registry of patients who underwent carboplatin‐based chemotherapy.

Purpose The Japanese Society of Medical Oncology (JSMO) published a guideline (GL) on febrile neutropenia (FN) in 2017. This study aims to identify promoting factors and disincentives for complying with GL recommendations according to attributes of doctors providing chemotherapy. Methods A questionnaire survey was conducted with SurveyMonkey™ for physician members of the Japanese Association of Supportive Care in Cancer and relevant academic organizations. Each question had four options (always do, do in more than half of patients, do in less than half, do not at all) and a free description form. Responses were analyzed according to the respondents’ attributes. Result Seven hundred eighty-eight out of retrieved 801 responses were available for analysis. Multivariable analysis demonstrated that the percentage of GL users was higher among women and Japanese Society of Clinical Oncology members. The overall compliance rate was higher among women, JSMO members, and board-certified medical oncologists. Internists emphasized the significance of collecting blood cultures at FN onset, and surgeons stressed the importance of G-CSF prophylaxis. Hematologists were less likely to adhere to recommendations on risk assessment of FN by the Multinational Association of Supportive Care in Cancer score and administration of gammaglobulin products. However, those are acceptable due to the characteristics of their practice. Eight recommendations had no difference in compliance rates between users and non-users, some of whose statements were ambiguous and discretionary. Conclusion Women were more likely to use and adhere to GL. The recommendations should be developed considering the characteristics of specialty and subspecialty and avoiding ambiguity and discretionary statements.

Summary Objectives By using data from the CEDMIC trial (n = 413), we conducted a post-hoc analysis of the diagnostic value of biomarker monitoring and chest computed tomography (CT) scans for the early detection of invasive fungal disease (IFD) in neutropenic hematological patients. Methods IFDs were defined in accordance with the EORTC/MSG definition with some modifications. Biomarkers such as Aspergillus galactomannan (GM) and (1→3)-β-D-glucan (βDG) were measured weekly. Results The positive predictive value (PPV) of GM and βDG in cases of high-risk treatment were 0.70 and 0.69, while those in low-risk treatment were 0.08 and 0, respectively. All of the positive biomarkers that were measured before the development of fever in low-risk treatment were false positives. The proportion of patients who had abnormal chest CT findings was 19% in persistent fever at 4–6 days, 57% at 7 days or later and 36% in recurrent fever. Sixty-nine percent of the patients who had abnormal findings at 7 days or later did not have abnormalities at 4–6 days. Conclusions Afebrile screening of biomarkers in low-risk treatment is not useful. Chest CT should be reevaluated in persistent fever lasting for 7 days or longer even in patients who did not have abnormalities within 6 days.

Elderly cancer patients requiring surgical treatment are increasing, and the deterioration of quality of life and shortening of healthy life expectancy due to postoperative complications represent major problems. This study investigated the current status of medical treatment, including perioperative evaluations, for elderly cancer patients requiring surgical treatment at cancer treatment facilities nationwide. A total of 436 cancer care facilities around Japan were invited to participate in this web-based survey regarding management of cancer patients ≥65 years old who had undergone surgical treatment in 2018. A total of 919 department heads from 245 facilities agreed to participate. Although most respondents answered that performance status, preoperative examinations, and comorbidities were important when deciding on a treatment plan, age, Geriatric Assessment (GA), and guidelines were "not important" for >10% of all respondents. GA was familiar to 195 department heads (21%), and awareness of GA was significantly lower among respondents from medical education institutions than the other types of hospitals (18.5% vs 26.3%; P = 0.006). This large survey revealed that the use of GA is not widespread, and its awareness in medical education institutions remains low. We believe that accumulating evidence of geriatric oncology surgery is an urgent issue in Japan.

Background: During chemotherapy for hematological malignancies, febrile neutropenia (FN) is a frequent and serious complication. The causative organisms of FN vary from era to era and depending on bacterial resistance in each country. Therefore, epidemiological data are required for each era and country from prospective large clinical trials. We previously reported a prospective clinical trial indicating the importance of the D-index, a measure of neutropenia severity (CEDMIC trial, J Clin Oncol. 2020 10; 38: 815). We hypothesized that analyzing these data would provide accurate contemporary epidemiological data for hematological malignancies. Furthermore, as encountered in practice, we suspected that gram-negative (GN) bloodstream infections (BSIs) are more common at high body temperatures (BTs) than at low BTs and examined the relationship between causative bacteria and BT. Patients and Methods: Between June 2013 and April 2017, we enrolled patients with hematological malignancies aged 16-79 years post-chemotherapy or -stem cell transplantation (SCT) with expected neutropenia durations >7 days. Neutrophil counts Results: In total, 423 patients were enrolled, and 413 (median age: 56 years) were included in the intention-to-treat analyses (Table 1). The treatments included induction chemotherapy (n=67), Allo-SCT (n=106), Auto-SCT (n=158), and others (n=82). Prophylactic Abx were administered in 281 (68.5%) patients (only quinolone, n=222; with β-lactam, n=59). Prophylaxis rates were significantly higher in the Allo-SCT (n=94, 88.7%, p38.5°C/ Conclusion: In FN patients with high-risk hematological malignancies in Japan, the frequency of GP BSIs is high. Prophylactic Abx use reduces the GN BSI risk but not the FN or BSI risk. Fever severity and BC positivity at FN onset are strongly associated. The BTs of patients with GN BSIs are high. Disclosures Kanda: Astellas Pharma: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Merck Sharp & Dohme: Honoraria; Pfizer: Honoraria, Research Funding; Shionogi: Research Funding; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Otsuka: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Janssen: Honoraria; Mundipharma: Honoraria. Kimura:Takeda Pharmaceuticals: Honoraria; Astellas Pharma: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Merck Sharp & Dohme: Honoraria; Nippon Kayaku: Honoraria; Kyowa Hakko Kirin: Honoraria; Ono Pharmaceutical: Honoraria; Celgene: Honoraria; Asahi Kasei: Honoraria. Oyake:Astellas Pharma: Honoraria; Bayer: Research Funding; Chugai Pharma: Honoraria, Research Funding; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Bristol-Myers Squibb Japan: Honoraria; Pfizer: Honoraria; Sionogi: Research Funding. Tamura:Asahi Kasei: Honoraria; Ono Pharmaceutical: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria.

This study evaluated the association of physical prefrailty with the prevalence of inadequate nutrients among community-dwelling Japanese elderly women.This cross-sectional study included 120 older women (age range, 65-79 years) at an elders college. Frailty was evaluated using the Japanese version of the Cardiovascular Health Study (J-CHS). Participants were classified as either prefrailty (1-2 deficits) or nonfrailty (0 deficits) based on set criteria. Both groups were compared in terms of physical function, exercise time, nutrient intake, and food group intake estimated by Food Frequency Questionnaire Based on Food Groups (FFQg), and estimated prevalence of inadequate nutrient intake, which was evaluated using each dietary reference value, set as the estimated average requirement (EAR) and dietary goal (DG), based on the Dietary Reference Intakes (DRIs) for Japanese, 2020.Of the participants, 45.0% exhibited physical prefrailty. Binary logistic regression analysis identified that vitamin C intake below EAR (OR, 7.12; 95% CI, 1.47-34.41, p=0.014) was the only factor associated with physical prefrailty.In addition to measuring physical function, dietary surveys and evaluation of nutritional adequacy by DRIs are expected to be useful for the early prevention of physical prefrailty by linking to nutrition education among community-dwelling Japanese elderly adults.

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 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.

Background This prospective, post-marketing observational study in Japanese patients aimed to evaluate the safety and effectiveness of daily afatinib use in general practice. Methods This non-interventional study (NCT02131259) enrolled treatment-naïve and pre-treated patients with inoperable/recurrent EGFR mutation-positive NSCLC, eligible for afatinib treatment as per the afatinib label in Japan. Patients received afatinib at the approved dose (20, 30, 40, or 50 mg/day; physician decision), and were observed following treatment initiation for 52 weeks or until premature discontinuation. Primary endpoint was the incidence of adverse drug reactions (ADRs). Secondary endpoints included ADRs of special interest, and objective response rate (ORR). Post hoc Cox multivariate analyses were used to assess prognostic factors associated with the incidence of ADRs. Results 1602 patients, at 374 sites (April 2014–March 2015), were included in the analysis; 307 (19%) were aged ≥ 75 years. The most frequently reported ADRs (all/grade 3–4) were diarrhea (78%/15%), rash/acne (59%/6%), stomatitis (31%/4%), and nail effects (38%/4%). Serious ADRs resulting in death occurred in 18 patients (1%). 762 patients (48%) had ≥ 1 afatinib dose reduction and 366 (23%) discontinued due to ADRs; the most common reason for both was diarrhea (8.2% and 6.7%, respectively). ORR was 40.1%. Conclusions Real-world treatment of 1602 Japanese patients with afatinib was associated with a predictable ADR profile. Afatinib showed effectiveness in inoperable/recurrent EGFR mutation-positive NSCLC, especially as first-line treatment. As with other EGFR TKIs, prompt management of adverse events is needed in the Japanese population, to reduce serious events and outcomes, including interstitial lung disease. Electronic supplementary material The online version of this article (10.1007/s10147-019-01439-5) contains supplementary material, which is available to authorized users.

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.

[Background] JBCRG-16 (NeoLath) study is a five-arm study to evaluate the efficacy and safety of lapatinib and trastuzumab (6 weeks) followed by lapatinib and trastuzumab plus weekly paclitaxel (12 weeks) with/without prolongation of anti-HER2 therapy prior to chemotherapy (18 vs. 6 weeks), and with/without endocrine therapy in patients with HER2+ and/or estrogen receptor (ER)+ disease. The primary endpoint was pathological complete response (pCR) rate and pCR rate was 47.9% (Masuda N, et al. Breast Cancer, 2018). It is recently reported that microRNAs (miRNAs) are stably present in serum and potentially useful in the diagnosis and evaluation of treatment of cancer. We performed exploratory analysis of detecting pCR by comprehensive analysis of serum miRNAs. [Materials and Methods] Serum samples were obtained from study participants who received neoadjuvant systemic therapy with trastuzumab, lapatinib and paclitaxel. Before profiling of miRNAs, the overall serum samples were randomly devided in two sets, namely the training set and the testing set with pCR or non-pCR. Pathological complete response (pCR) was defined as the absence of residual invasive cancer of the resected breast specimen and all sampled regional lymph nodes. Total RNA was extracted from a 300 ul serum sample using 3D-Gene® RNA extraction reagent from a liquid sample kit. A comprehensive quantitative expression analysis of miRNA was performed using the by DNA chip 3D-Gene®, which was designed to detect 2565 miRNA sequences registered in miRBase release 21 (http://www.mirbase.org/). The expression level of miRNAs were normalized by internal control (miR-2861, miR-149-3p and miR-4463). Clinicopathological data was retrieved from trial data. [Results] A total of 112 samples were obtained. Seventy were used in the training set and others were used in the testing set. Median age was 54 years (range 26-70). Sixty-five (58%) patients were pre-menopausal. ER was positive in 59 patients (52.7%). Fourteen (12.5%) were T1c, 78 (69.6%) were T2 and 20 (17.9%) were T3. Fifty-seven (50.9%) patients were node-positive. Fifty-nine (52.7%) patients achieved pCR. The formula with the combination of three miRNAs (miR-A, miR-B, miR-C) was found to be able to predict pCR. This set had a sensitivity of 62.5%, specificity of 86.7% and accuracy of 71.8% in the testing cohort. Area under curve of receiver operationg characteristic curve was 0.753. [Conclusion] The combination of three miRNAs has potential to predict pCR in patients who received neoadjuvant combination therapy of trastuzumab, lapatinib and paclitaxel in HER2-positive primary breast cancer. The further analysis of changing expression of miRNAs during neoadjuvant therapy is underway and further results will be presented in the symposium. Citation Format: Shimomura A, Masuda N, Kawauchi J, Takizawa S, Ichikawa M, Matasuzaki J, Kuroi K, Hara H, Yamamoto N, Inoue K, Suganuma N, Aogi K, Ohno S, Tamura K, Ochiya T, Toi M. Predicting pathological complete response by the combination of microRNAs in patients with HER2-positive primary breast cancer who received neoadjuvant combination therapy of trastuzumab, lapatinib and paclitaxel: Results from JBCRG-16 (NeoLath) study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-16.

Background DS-8201a is a HER2-targeting antibody-drug conjugate with a high drug-to-antibody ratio of 7 to 8. A novel cleavable peptide-based linker joins the humanized HER2 antibody to a topoisomerase I inhibitor payload. In an ongoing phase 1 study (J101), DS-8201a was tested at doses of 0.8 to 8.0 mg/kg and tolerated with no predefined dose-limiting toxicities; 5.4 and 6.4 mg/kg doses were recommended for expansion. Subjects with HER2-positive breast cancer (BC) treated at these 2 doses had an overall response rate (ORR) of 54.5% (54/99). The phase 2 DESTINY-BREAST01 trial began enrollment in August 2017 with a dose-finding stage, including 5.4, 6.4, and 7.4 mg/kg. To determine the recommended dose for continued development in HER2-positive BC, a comprehensive analysis of observed data and exposure-response (ER) from both trials was performed. Methods A population-PK (PPK) model was developed using data from all subjects with available concentration data. Individual exposure parameters (Cmin, Cmax, AUC) were estimated from the PPK model and used in the ER analyses. ER analyses were conducted using logistic regression or Cox proportional hazard modeling for efficacy (ORR, duration of response, and PFS) and safety (nausea, diarrhea, left ventricular ejection fraction, neutropenia, anemia, thrombocytopenia, dose reductions due to TEAE, discontinuations due to TEAE, and interstitial lung disease [ILD]). Results As of 18 Apr 2018, in J101, there are 111 HER2-positive BC subjects treated at 5.4- or 6.4-mg/kg doses. As of 25 Apr 2018, DESTINY-BREAST01 enrolled 65 HER2-positive BC subjects across 3 doses (5.4, 6.4, and 7.4 mg/kg). Confirmed ORRs in J101 for HER2-positive BC subjects at 5.4 and 6.4 mg/kg were 52.6% (20/38) and 55.7% (34/61), respectively. In J101, AEs Grade ≥3 were reported in 35.6% (16/45) at 5.4 mg/kg and 50% (33/66) at 6.4 mg/kg. The relationship between DS-8201a intact Cmin and ORR was statistically significant (P=0.035). There was a trend of improved PFS with higher intact exposures (P=0.238). Statistically significant relationships were observed between exposures and the following safety endpoints based on logistic regression: neutropenia (any grade, P=0.003; Grade ≥3, P=0.037), anemia (any grade, P=0.002; Grade ≥3, P Conclusions In J101, DS-8201a demonstrated an acceptable safety profile and high response rates in HER2-positive BC at both doses. The ER analyses showed a statistically significant relationship between exposures and ORR (with a trend for higher PFS at higher doses), as well as exposures and risk of key adverse events. Considering the predicted benefit/risk profile, 5.4 mg/kg is the recommended dose for continued development of DS-8201a in the DESTINY-BREAST01 trial and in phase 3 clinical trials in HER2-positive BC. Citation Format: Tamura K, Modi S, Tsurutani J, Takahashi S, Krop IE, Iwata H, Wada R, Yin O, Garimella T, Sugihara M, Zhang L, Lee C, Yver A, Baselga J. Dose justification for DS-8201a, a HER2-targeted antibody-drug conjugate, for HER2-positive breast cancer: Observed clinical data and exposure-response analyses [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-10.

Background: HER2-targeted therapies have improved survival for advanced HER2-positive breast cancers (BC), but none have been approved for tumors with low levels of HER2 expression (ie, HER2 IHC 1+ or 2+/ISH-negative). Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a potent topoisomerase I inhibitor payload by a cleavable peptide-based linker, which is designed to have broad antitumor activity in HER2-expressing tumors. It has a drug-to-antibody ratio of 7 to 8, a novel linker that is stable in plasma and that is selectively cleaved by lysosomal cathepsins which are upregulated in cancer cells, and its payload has a short systemic half-life. In 2015, a phase 1 study (NCT02564900) was initiated to evaluate the safety and efficacy of DS-8201a in subjects with advanced HER2-expressing or HER2-mutated solid tumors, including HER2-low expressing BC. In this study, the overall confirmed response rate (ORR) in the evaluable subjects was 49.3% (103/209) (April 2018 data cutoff; Iwata H, et al. ASCO 2018). Expanded results from the HER2-low expressing BC subjects are presented here. Methods: This ongoing phase 1 trial included 2 parts. The dose escalation part served to determine the dose-limiting toxicities, the maximum tolerated dose, and to select the recommended dose for expansion (RDE). The dose expansion part further evaluated the safety, tolerability, and efficacy of the DS-8201a at the RDE (5.4 and 6.4 mg/kg; q3wks) in various advanced HER2-expressing or HER2-mutated solid tumors, including heavily pretreated HER2-low BC (IHC 1+ or 2+, ISH-negative). Enrollment of HER2-low subjects is ongoing. Results: At the cutoff date of 18 April 2018, data from 34 HER2-low BC subjects were collected. The median age was 55.8 (range; 33, 75) years, the median number of prior endocrine therapies was 2, and the median number of prior chemotherapies was 3. In this HER2-low BC population, most patients had hormone receptor (HR)-positive disease (85.3%; 29/34); of which 17.2% (5/29) received prior treatment with a CDK4/6 inhibitor. The confirmed ORR was 50.0% (17/34), the disease control rate was 85.3% (29/34), the median time to response was 2.8 (range; 1.2, 13.8) months, the median duration of response (DOR) was 11.0 months, and the median progression-free survival (PFS) was 12.9 months. In the subgroup with HR-positive disease, the ORR was 55.2% (16/29), the median DOR was 11.0 months, and the median PFS was 13.6 months. After exclusion of 8 HER2-low subjects who received prior HER2-targeted therapy, the ORR was 46.2% (12/26). In the overall study, among the 145 BC subjects who received ≥1 dose of DS-8201a (5.4 or 6.4 mg/kg), the most frequent grade ≥3 adverse events included anemia (14.5%), and decreased counts of neutrophils (13.8%) and white blood cells (10.3%). There were 4 fatal cases of interstitial lung disease/pneumonitis in BC subjects, including 2 fatal cases in HER2-low BC subjects. Conclusions: In this study, DS-8201a showed substantial antitumor activity and acceptable safety in heavily pretreated HER2-low BC. Citation Format: Modi S, Tsurutani J, Tamura K, Park H, Sagara Y, Murthy R, Iwata H, Krop IE, Doi T, Redfern C, Moreno-Aspitia A, Redman R, Lee C, Sugihara M, Fujisaki Y, Takahashi S. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-low expressing breast cancer: Updated results of a large phase 1 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-02.

Combined oral cyclophosphamide and capecitabine (XC) chemotherapy is used for metastatic breast cancer (MBC) patients. We report herein two MBC patients who developed severe hemorrhagic cystitis after XC therapy. Case 1: A 67-year-old woman with MBC had received XC therapy for 2.5 years. After a sudden onset of lower abdominal pain and gross hematuria, cystoscopy revealed a urinary bladder mucosa showing diffuse dilation of the capillaries and a large blood clot. A total dose of 60.8 g cyclophosphamide had been given and the XC regimen was discontinued immediately. The patient experienced frequent episodes of bladder tamponade over 18 months and underwent continuous bladder irrigation and cystoscopic fulguration. Hyperbaric oxygen therapy (HBOT) provided only temporary relief and the patient subsequently developed hemorrhagic shock. A bilateral ureterostomy was eventually performed. Case 2: A 65-year-old woman with MBC was given XC for 3 years, but this was discontinued after she developed new lung lesions. The patient was given a total dose of 78.4 g of cyclophosphamide. A month later, the patient complained of intermittent gross hematuria, which progressed to persistent macroscopic hematuria for 1 week. She underwent continuous bladder irrigation with saline, without an improvement in her bladder tamponade. Subsequently, the bleeding ceased completely after HBOT. Some MBC cases can be controlled for a long time with XC therapy. For those cases, we need to realize that severe hemorrhagic cystitis may occur. Even at a low dose, requires testing periodically for occult blood in the urine to detect the early stages of cystitis.

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.

Background/aim Although neurokinin-1 receptor antagonists are approved chemotherapy drugs in Japan, no nationwide surveys have been performed to validate chemotherapy-induced nausea and vomiting (CINV) guidelines in clinical practice. This study evaluated CINV in patients with haematological malignancies starting first-time chemotherapy. Patients and methods A nationwide CINV survey on patients with haematological malignancies was conducted at 118 institutions. Patients undergoing moderately emetic chemotherapy (n=17) and highly emetic chemotherapy (HEC; n=180) were compared. Results Forty-one patients undergoing HEC received triple antiemetics. Female gender and young age were risk factors for early-phase nausea, while female gender remained a risk factor for late-phase nausea and vomiting. Among 125 patients receiving CHOP (doxorubicin, cyclophosphamide, vincristine, prednisone)-like regimens, complete response and complete control were increased in patients receiving triple antiemetics, compared to those with double antiemetics. Conclusion Guideline compliance was very low. Although not statistically significant, there was a trend for reduced CINV and improved disease control for triple versus double antiemetics, suggesting that triple antiemetics should be considered for HEC, especially in young female patients with non-Hodgkin lymphoma receiving CHOP-like regimens.

Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known FANC genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FANC genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. FANCA and FANCG pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one FANCA and two FANCG hot spot mutations, which are found at low percentages (0.04-0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). FANCB was the third most common complementation group and only one FANCC case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing FANC gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.