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Introduction: The impact of migraine on patients' lives, including challenges they face before getting access to appropriate medical management, is not well understood. The ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE [OVERCOME (Japan)] 2nd study was conducted to provide information regarding burden and experience with migraine throughout the life course., Methods: This cross-sectional, population-based, nationwide online survey was conducted in adults with or without migraine. The migraine group reported their headache features and experiences in medical management since headache onset. Migraine's burden and impact were assessed with various PRO instruments. Migraine and non-migraine groups reported their experiences in life events and answered questions on self-esteem. Subgroup analyses by the number of monthly headache days (MHD) were performed., Results: The migraine group (n = 19,590) was numerically younger [mean (SD) age 40.5 (13.1) years vs. 53.1 (17.8) years] and included more females (68.8% vs. 52.1%) than the non-migraine group (n = 2219). The migraine group had mean (SD) 3.5 (5.2) MHDs; 24.2-56.7% had moderate-to-very severe disease burden per various PRO instruments. Headaches started when respondents with migraine were 17.8 years old; 86.7% started over-the-counter medications at 19.4 years of age. Only 46.4% self-reported migraine diagnosis by a physician and 25.1% received an oral preventive drug, almost a decade after headache onset. Up to 16.8% reported poor support/lack of understanding from either teachers or parents during school life. The migraine group had numerically more frequent job changes and divorce, and lower self-esteem, than the non-migraine group. Across assessments, increased MHDs tended to worsen outcomes., Conclusion: Migraine affected many individuals from an early stage, but timely support and medical intervention were insufficient. This may negatively impact important life events, cause long-term impairment, and decrease self-esteem. Hence, improving the social understanding and medical environment for migraine to provide timely support is essential., Competing Interests: Declarations. Conflict of Interest: Daisuke Danno serves on the advisory boards of and received speaker honoraria from Amgen K.K., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K. and Otsuka Pharmaceutical Co. Ltd. Shiho Suzuki received speaker honoraria from Amgen K.K., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., and Otsuka Pharmaceutical Co. Ltd. Tsubasa Takizawa is a consultant/advisor and/or serves on an advisory board for Eli Lilly Japan K.K., Otsuka Pharmaceutical Co. Ltd., Amgen K.K., Pfizer Japan Inc., and Teijin Pharma Ltd. He received speaker honoraria from Eli Lilly Japan K.K., Daiichi Sankyo Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Amgen K.K., Kowa Company, Ltd., Kyowa Kirin Co. Ltd., Eisai Co. Ltd., UCB Japan Co. Ltd., Takeda Pharmaceutical Company Ltd., and Santen Pharmaceutical, a grant from Pfizer Japan Inc., and research funding from Eli Lilly Japan K.K. and Tsumura & Co. outside the submitted work. Ryotaro Ishii received consulting fees from Amgen K.K., Eli Lilly Japan K.K., Daiichi Sankyo Co. Ltd., and Otsuka Pharmaceutical Co. Ltd; speaker honoraria from Amgen K.K., Daiichi Sankyo Co. Ltd., and Otsuka Pharmaceutical Co. Ltd. Masayuki Hamakawa is an employee of Social Survey Research Information Co., Ltd. Data collection and statistical analyses in this study were performed by Social Survey Research Information Co., Ltd. and sponsored by Eli Lilly Japan K.K. Yoshinori Tanizawa, Satoshi Osaga, and Mika Komori are employees of Eli Lilly Japan K.K. and may own stock/stock options of Eli Lilly and Company. Ethical Approval: The Medical Corporation TOUKEIKAI Kitamachi Clinic ethics committee approved this study (number BGQ09531) on April 19, 2023. This study was conducted in accordance with ethical principles originating from the Declaration of Helsinki and that were consistent with Good Pharmacoepidemiology Practices. All survey respondents provided electronic informed consent, and all data were anonymized before analysis., (© 2024. The Author(s).)

Introduction: There is no information on the incidence of severe hypoglycemia in real-world patients with diabetes receiving ultra-rapid lispro (URLi). This post-marketing, observational, safety study assessed the incidence proportion and incidence rate of the first severe hypoglycemia event requiring a hospital visit in URLi-treated patients. It also compared the risk of severe hypoglycemia between patients treated with URLi or other rapid-acting insulin analogs (RAIAs)., Methods: Claims data were obtained from a nationwide hospital-based administrative database in Japan (Medical Data Vision). Adults with diabetes who initiated URLi or other RAIA on/after June 01, 2020, were followed up through May 31, 2023. Severe hypoglycemia was identified using a validated algorithm. Incidence proportion and incidence rate of the first severe hypoglycemia event requiring a hospital visit was described in URLi-treated patients (descriptive analysis). These outcomes were also compared against propensity score (PS)-matched other RAIA-treated patients (comparator; comparative analysis). Hazard ratio (HR) and 95% confidence interval (CI) was estimated with a Cox proportional hazards model., Results: The descriptive analysis' URLi-treated cohort included 17,838 patients [mean (standard deviation, SD) age 65.9 (15.7) years; 58.3% male]. The majority had type 2 diabetes (75.7%). The incidence proportion of the first severe hypoglycemia event requiring a hospital visit was 0.6% (95% CI 0.5, 0.8) and the incidence rate was 1.7 per 100 person-years (95% CI 0.7, 4.3). The comparative analysis included 10,592 URLi-treated and 52,917 comparator-treated patients. The incidence rate of severe hypoglycemia did not significantly differ between these cohorts (HR 0.8; 95% CI 0.5, 1.1; p = 0.132;., Conclusion: This study did not show a statistically significant increase in the incidence and risk of the first severe hypoglycemia event requiring a hospital visit in real-world URLi-treated patients in Japan, compared with a PS-matched cohort of other RAIA-treated patients., Competing Interests: Declarations. Conflict of Interest: All authors (Seiko Mizuno, Machiko Minatoya, Satoshi Osaga, Rina Chin, Makoto Imori) are employees of Eli Lilly Japan K.K. and are minor stockholders of Eli Lilly and Company. Ethical Approval: This study was conducted in accordance with ethical principles originating from the Declaration of Helsinki of 1964 and its later amendments and that were consistent with Good Pharmacoepidemiology Practices. This study used retrospective de-identified data so ethical review and informed consent were not required, consistent with the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects. Data were purchased from MDV after obtaining the necessary permissions., (© 2024. The Author(s).)

Background: Chronic lymphocytic leukemia (CLL) is a rare form of lymphoma in Japan. This study aimed to explore hematologists' motivations and considerations in making treatment decisions for CLL., Methods: Responses from hematologists treating CLL, obtained through an online survey, were descriptively analyzed. Subgroup analyses by preferred first-line (1L) treatment, years of clinical experience, and level of interest in CLL were conducted., Results: Out of 107 hematologists surveyed, 82.2% identified Bruton tyrosine kinase inhibitors (BTKi) as their primary choice for 1L treatment; the reasons included established clinical evidence (61.4%) and oral administration convenience (56.8%). Key factors influencing 1L treatment selection among those favoring BTKi included the presence of 17p deletion, TP53 mutation, and patient's fitness status. BTKi was favored by 92.6% of hematologists with < 10 years of clinical experience and by 78.8% with more experience. The main reasons for choosing BTKi included safety (50.0%) and tolerance (46.7%) among hematologists who stated they had a specific interest in CLL and the oral administration route (62.1%) among hematologists with lower interest. When BTKi was used as 1L therapy, venetoclax-based regimens were preferred for second-line treatment. The most common concern about BTKi was substantial out-of-pocket costs., Conclusion: Although many Japanese hematologists select their treatment based on clinical evidence, variations exist in treatment strategies, possibly associated with hematologists' experience and interest in CLL. These findings underscore the importance of further promoting evidence-based treatments to ensure that all physicians can make informed decisions. Future research should explore additional factors that influence CLL treatment decisions., Competing Interests: Declarations. Conflict of interest: Junichiro Yuda received research funds from AbbVie GK, Daiichi Sankyo Co. Ltd., Chugai Pharmaceutical Co., Ltd., Genmab K.K., Novartis Pharma K.K., Amgen K.K., Takeda Pharmaceutical Co. Ltd., Bristol-Myers Squibb K.K., Incyte Biosciences Japan G.K., Janssen Pharmaceutical K.K., Sumitomo Pharma Co., Ltd., MSD K.K., and Mitsubishi Tanabe Pharma Corporation. Chaochen Wang, Tomoko Terasawa, Masaomi Tajimi, Satoshi Osaga, and Yoshinori Tanizawa are employed full-time by Eli Lilly Japan K.K. and are minor stockholders of Eli Lilly and Company. Moemi Miura and Shori Takaoka are full-time employees of Social Survey Research Information Co., Ltd., (© 2024. The Author(s).)

Objective: To describe the actual communication of patients with breast cancer on oral abemaciclib treatment and the motivating factors to continue treatment., Methods: An online survey was conducted in July and August 2023 across Japan among patients aged ≥18 years who were undergoing or had prior experience with abemaciclib treatment and physicians who had prescribed abemaciclib during the past year., Results: Responses from 80 patients and 78 physicians were obtained. The main explanations patients received from their physicians before/after starting treatment were related to side effects (90%)and effectiveness(88%). Regarding management of side effects, both patients(66%)and physicians(54%) responded that"easy-to-understand explanations on how to deal with side effects"is necessary. The proportion of patients who received an explanation from their physician on how to deal with side effects was relatively low. A notable challenge experienced by patients when they had side effects was "I don't know how severe my symptoms should be before contacting or visiting the hospital"., Conclusions: The results of this survey suggest that specific, easy-to-understand information from healthcare professionals on adverse events and how to deal with them could help patients more appropriately self-manage abemaciclib treatment.

Migraine is a disease that is difficult to be recognized by those around the patients, even though it causes significant hindrances. In this study, we conducted an exploratory comparison of the perceptions on migraine among patients, family members living with them, and physicians treating migraine patients. Patients and family members shared a common understanding on the pain of migraine, and hoped to spend more/better time together as a family. However, although family members felt compassion for the patients, lack of understanding by and patients' concern for the surroundings led to feelings of resignation and endurance on the side of patients. Regarding physicians' medical care, our results suggested the importance to understand the wishes and obstacles of each patient and to propose treatment accordingly. In order to reduce the burden of migraine, it is necessary to create an environment and raise awareness that allows people around the patients to understand and support the pain and hopes that each patient feels.

Introduction: The impacts of migraine on daily life, including daily activities and fundamental health indicators (sleep and mental health), have not been described in detail for people with migraine in Japan., Methods: The cross-sectional ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) study was conducted between July and September 2020. Impacts of migraine on housework, family/social/leisure activities, driving, and sleep were assessed using questions from the Migraine Disability Assessment (MIDAS), Migraine-Specific Quality-of-Life Questionnaire, and Impact of Migraine on Partners and Adolescent Children scales and questions developed for OVERCOME (Japan). The Migraine Interictal Burden Scale (MIBS-4) evaluated burden on days without headaches. Depression and anxiety were assessed with the Patient Health Questionnaire (PHQ-8) and Generalized Anxiety Disorder (GAD-7) scales, respectively. Impacts on daily life were also described across MIDAS/MIBS-4 categories., Results: Among 17,071 respondents with migraine, 24.8% required assistance with housework at least sometimes. Migraine interfered with relationships, leisure, and social activities at least sometimes for 31.8%, 41.6%, and 18.0% of respondents, respectively. Between headache days, 26.8% of respondents worried about planning social/leisure activities at least sometimes. Among respondents living with family (N = 13,548), migraine also had impacts on participation in and enjoyment of family activities. Among respondents who drove (N = 10,921), 43.9% reported that symptoms interfered with driving at least sometimes. Migraine interfered with sleep and mood at least sometimes for 52.7% and 70.7% of respondents, respectively. PHQ-8 and GAD-7 thresholds for clinical depression and anxiety were met by 28.6% and 22.0% of respondents, respectively. Impact of migraine on daily life increased with increasing severity of MIDAS/MIBS-4 categories., Conclusion: The burden of migraine on daily activities, sleep, and mental health is substantial for people with migraine in Japan. In clinical practice, it is important to evaluate the impact of migraine on daily life in addition to migraine symptoms., (© 2024. The Author(s).)

Using the Japanese version of the Impact of Migraine on Partners and Adolescent Children (IMPAC) and Family Question prepared based on IMPAC, we investigated the impact of migraine on family members from the perspectives of both patients and their family members. Our results showed that migraine had an impact on the family members living with the patients in Japan as well, and the perception of migraine differed partially between patients and their family members. We also found that the Japanese version of the IMPAC showed a correlation with existing instruments to evaluate impact of migraine, indicating its validity. The application of this study's findings in clinical practice could help alleviate the disease burden of migraine on patients and their family members.

Background and Objective: Real-world evidence on persistence of interleukin-17 inhibitors (IL-17i) as a drug class among Japanese patients with psoriasis is lacking. Hence, we aimed to describe persistence rates of IL-17is among patients with psoriasis including psoriasis vulgaris (PsO), psoriatic arthritis (PsA), and generalized pustular psoriasis (GPP) or erythrodermic psoriasis (EP) in Japan., Methods: We analyzed claims data from the Medical Data Vision database. Patients ≥15 years old with a psoriasis diagnosis and an IL-17i prescription between November 2016 and August 2020 were included and followed through August 2021. Persistence rates of the IL-17i class among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP), and persistence rates of ixekizumab, secukinumab, or brodalumab among patients with PsO or PsA were analyzed using Kaplan-Meier method. Analyses were conducted in the bio-naïve and bio-experienced subgroups., Results: The IL-17i class had >50% persistence rates up to 36 months among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP). 36-Month persistence rates for ixekizumab, secukinumab, and brodalumab were 46.2% to 57.7% in patients with PsO and 43.0% to 48.4% in patients with PsA. Across analyses, bio-naïve patients demonstrated similar or greater persistence rates than bio-experienced patients., Conclusion: IL-17is' persistence rates over 36 months were >50% among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP) in Japan.

Objective: The purpose of this study was to evaluate the performance of algorithms for identifying cases of severe hypoglycemia in Japanese hospital administrative data., Methods: This was a multicenter, retrospective, observational study conducted at 3 acute-care hospitals in Japan. The study population included patients aged ≥18 years with diabetes who had an outpatient visit or hospital admission for possible hypoglycemia. Possible cases of severe hypoglycemia were identified using health insurance claims data and Diagnosis Procedure Combination data. Sixty-one algorithms using combinations of diagnostic codes and prescription of high concentration (≥20% mass/volume) injectable glucose were used to define severe hypoglycemia. Independent manual chart reviews by 2 physicians at each hospital were used as the reference standard. Algorithm validity was evaluated using standard performance metrics., Results: In total, 336 possible cases of severe hypoglycemia were identified, and 260 were consecutively sampled for validation. The best performing algorithms included 6 algorithms that had sensitivity ≥0.75, and 6 algorithms that had positive predictive values ≥0.75 with sensitivity ≥0.30. The best-performing algorithm with sensitivity ≥0.75 included any diagnoses for possible hypoglycemia or prescription of high-concentration glucose but excluded suspected diagnoses (sensitivity: 0.986 [95% confidence interval 0.959-1.013]; positive predictive value: 0.345 [0.280-0.410]). Restricting the algorithm definition to those with both a diagnosis of possible hypoglycemia and a prescription of high-concentration glucose improved the performance of the algorithm to correctly classify cases as severe hypoglycemia but lowered sensitivity (sensitivity: 0.375 [0.263-0.487]; positive predictive value: 0.771 [0.632-0.911])., Conclusion: The case-identifying algorithms in this study showed moderate positive predictive value and sensitivity for identification of severe hypoglycemia in Japanese healthcare data and can be employed by future pharmacoepidemiological studies using Japanese hospital administrative databases., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Satoshi Osaga, Rina Chin, Makoto Imori, and Machiko Minatoya are employees of Eli Lilly Japan K.K. and minor shareholders in Eli Lilly and Company. Takeshi Kimura and Yasuyuki Okumura are employees of Real World Data Co, Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Osaga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lethal giant larvae homolog 2 (LLGL2) and solute carrier family 7 member 5 (SLC7A5) have been reported to be involved in resistance to endocrine therapy. This study aimed to assess the effects of LLGL2/SLC7A5 co-expression in predicting prognosis and response to tamoxifen therapy in ERα-positive breast cancer patients according to LLGL2/SLC7A5 mRNA and protein expression in long-term follow-up invasive breast cancer tissues. We identified that low LLGL2/SLC7A5 mRNA co-expression (LLGL2 low /SLC7A5 low ) was associated with disease-free survival (DFS) compared with other combination groups in all breast cancer patients. In ERα-positive breast cancer patients, LLGL2 low /SLC7A5 low showed longer DFS and overall survival (OS) compared with LLGL2 high /SLC7A5 high and a positive trend of longer survival compared with the other combination groups. We also observed that LLGL2 low /SLC7A5 low showed longer survival compared with LLGL2 high /SLC7A5 high in ERα-positive breast cancer patients receiving adjuvant tamoxifen therapy. Multivariate analysis demonstrated that LLGL2 low /SLC7A5 low was an independent favorable prognostic factor of both DFS and OS, not only in all breast cancer patients, but also in ERα-positive breast cancer patients. High co-expression of LLGL2 and SLC7A5 protein showed a positive trend of shorter survival. Our study showed that co-expression of LLGL2 and SLC7A5 mRNA is a promising candidate biomarker in early breast cancer patients., (© 2022. The Author(s).)

The purpose of this study was to investigate adherence to adjuvant endocrine therapy (ET) and the factors affecting demotivation and motivation to continue adjuvant ET. In patients with hormone receptor-positive breast cancer in Japan, an online survey was conducted from June to July 2021 to investigate the treatment effects, side effects, concerns about side effects(for demotivation only), convenience of hospital visits, treatment duration, concerns about recurrence/progression, treatment cost, support from healthcare professionals, and support from family, the patient association, and peers(for motivation only). According to the responses from 263 patients, the most common factor affecting demotivation to continue adjuvant ET was the burden of side effects, and the most common factor affecting motivation to continue adjuvant ET was concerns about recurrence/progression. Continuous relief of the burden of side effects from the early stage of treatment, and mental support for concerns about recurrence/progression, as well as explaining and promoting the risks and benefits of continuing treatment, are considered to lead to motivation to continue adjuvant ET(Fig. 1: Summary of this survey).

Objectives: To evaluate neonatal outcomes after the use of a cervical pessary in Japanese women with short cervical length (CL) less than 25 mm., Methods: This multicenter study involved women with singleton pregnancies between 20 and 29+6 gestational weeks and a CL of less than 25 mm. The primary outcome was preterm birth (PTB) before 34 weeks of gestation. This study was registered in the Japan Registry of Clinical Trials (JRCT: jRCTs042180102)., Results: Two hundred pregnant women were enrolled; 114 in the pessary group and 86 in the expectant management group as controls. In the pessary group, all 114 neonates were investigated for perinatal outcomes, and 112 pregnant women were investigated for primary, and secondary outcomes. In the control group, 86 pregnant women were investigated for primary and secondary outcomes and 86 neonates were investigated for neonatal outcomes. There were no significant differences in PTB in ≤34, ≤37, and ≤28 weeks of gestation or in preterm rupture of membranes (PROM) ≤34 weeks between the groups. The gestational weeks at birth and birth weight were significantly higher in the pessary group. Regression analysis demonstrated that the CL decreased without a pessary, whereas the shortening rate was suppressed during the intervention. No significant differences were observed in adverse neonatal outcomes, chorioamnionitis, or preterm PROM., Conclusions: The cervical pessary effectively reduced CL shortening during pregnancy resulting in an average increased gestational age, however, did not reduced the rates of preterm birth., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

HECT domain E3 ubiquitin ligase 1 (HECTD1) has been reported to be a negative regulator of epithelial-mesenchymal transition and to decrease breast cancer invasion and metastasis. However, the clinical significance and detailed role of HECTD1 in breast cancer remain elusive. We investigated the role of HECTD1 in two large breast cancer cohorts at our institution and The Cancer Genome Atlas using mRNA expression and bioinformatics analysis. We also examined the prognostic significance of HECTD1 mRNA expression by multivariate analysis and HECTD1 protein expression by immunohistochemistry using our cohort. HECTD1 mRNA expression was significantly lower in breast cancer tissues compared with those in adjacent normal tissues (P<0.001). HECTD1 mRNA expression levels also differed among breast cancer subtypes. Decreased HECTD1 mRNA expression was significantly associated with aggressive tumor characteristics, including large tumor size and high histological grade. HECTD1 mRNA expression was inversely associated with mitochondrial cellular respiratory function (oxidative phosphorylation (P<0.001, FDR q -value <0.001) the respiratory chain complex (P<0.001, FDR q -value <0.001) and reactive oxygen species (P<0.001, FDR q -value <0.001), but not with epithelial-mesenchymal transition, in breast cancer tissues. Low expression of HECTD1 mRNA was associated with shorter disease-free survival (log-rank: P=0.013) and overall survival (log-rank: P=0.038) in breast cancer patients. Multivariate analysis also identified low HECTD1 mRNA expression level as an independent risk factor for disease-free (hazard ratio: 1.54, 95% confidence interval: 1.11-2.13, P=0.009) and overall (hazard ratio: 1.50, 95% confidence interval: 1.01-2.24, P=0.046) survival among breast cancer patients. There was no association of HECTD1 protein expression with HECTD1 mRNA expression and prognosis. In conclusion, we identified low expression of HECTD1 mRNA as an independent poor prognostic factor in breast cancer and showed that HECTD1 mRNA expression was inversely correlated with genes involved in mitochondrial cellular respiratory function in breast cancer., Competing Interests: None., (AJCR Copyright © 2022.)

Background/aims: Although risk factors of reflux esophagitis (RE) have been investigated in numerous cross-sectional studies, little is known about predictive factors associated with future onset of RE. We investigated time courses of clinical parameters before RE onset by a longitudinal case-control study using health checkup records., Methods: We used health checkup records between April 2004 and March 2014 at 9 institutions in Japan. A multivariate logistic regression analysis was performed to evaluate associations of baseline clinical parameters with RE. The time courses of the clinical parameters of RE subjects were compared with those of non-RE subjects by the mixed-effects models for repeated measures analysis or longitudinal multivariate logistic analysis., Results: Initial data were obtained from 230 056 individuals, and 2066 RE subjects and 4132 non-RE subjects were finally included in the analysis. Body mass index, alanine aminotransferase, smoking, acid reflux symptoms, hiatal hernia, and absence of atrophic gastritis at baseline were independently associated with RE. The time courses of body mass index, fasting blood sugar, triglyceride, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, percentages of acid reflux symptoms, feeling of fullness, and hiatal hernia in the RE group were significantly worse than in the non-RE group., Conclusions: The RE group displayed a greater worsening of the clinical parameters associated with lifestyle diseases, including obesity, diabetes, hyperlipidemia, and fatty liver for 5 years before RE onset compared with the non-RE group. These results suggest that RE is a lifestyle disease and thus lifestyle guidance to at-risk person may help to prevent RE onset.

Bortezomib (Btz) shows robust efficacy in patients with multiple myeloma (MM); however, some patients experience suboptimal responses and show specific toxicities. Therefore, we attempted to identify specific HLA alleles associated with Btz-related toxicities and response to treatment. Eighty-two transplant-ineligible patients with newly diagnosed MM enrolled in a phase II study (JCOG1105) comparing two less intensive melphalan, prednisolone, plus Btz (MPB) regimens were subjected to HLA typing. The frequency of each allele was compared between the groups, categorized based on toxicity grades and responses to MPB therapy. Among 82 patients, the numbers of patients with severe peripheral neuropathy (PN; grade 2 or higher), skin disorders (SD; grade 2 or higher), and pneumonitis were 16 (19.5%), 15 (18.3%), and 6 (7.3%), respectively. Complete response was achieved in 10 (12.2%) patients. Although no significant HLA allele was identified by multiple comparisons, several candidates were identified. HLA-B*40:06 was more prevalent in patients with severe PN than in those with less severe PN (odds ratio [OR] = 6.76). HLA-B*40:06 and HLA-DRB1*12:01 were more prevalent in patients with SD than in those with less severe SD (OR = 7.47 and OR = 5.55, respectively). HLA-DRB1*08:02 clustered in the group of patients with pneumonitis (OR = 11.34). Complete response was achieved in patients carrying HLA-DQB1*03:02, HLA-DQB1*05:01, and HLA-DRB1*01:01 class II alleles. HLA genotyping could help predict Btz-induced toxicity and treatment efficacy in patients with MM, although this needs further validation., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Although chronic postsurgical pain (CPSP) after breast cancer surgery is a common and prevalent postsurgical adverse event, the need for CPSP treatment has not been investigated. This study examined the proportion of patients who needed treatment for CPSP and associated predictors., Methods: We conducted a cross-sectional study with female patients who underwent breast cancer surgery at our institution. Participants were aged ≤ 65 years at the time of this study and were at least 1 year post surgery. The questionnaire examined the presence of and need for treatment for CPSP and included the Japanese version of the Concerns about Recurrence Scale (CARS-J). Multivariate analyses were used to identify independent predictors of needing treatment for CPSP., Results: In total, 305 patients completed the questionnaire. The mean time since surgery was 67.1 months; 156 (51%) patients developed CPSP after breast cancer surgery and 61 (39%) needed treatment for CPSP. Among patients that developed CPSP, the fear of breast cancer recurrence as assessed by the CARS-J (odds ratio [OR] 2.59, 95% confidence interval [CI] 1.14-6.28, P = 0.028) and ≥ 2 postsurgical pain regions (OR 2.52, 95% CI 1.16-5.57, P = 0.020) were independent predictors of needing treatment for CPSP., Conclusions: This study is the first to identify the proportion and predictors of patients who need treatment for CPSP. Fear of breast cancer recurrence and ≥ 2 postsurgical pain regions may predict the need for CPSP treatment among patients following breast cancer surgery., (© 2021. The Japanese Breast Cancer Society.)

A subset of essential thrombocythemia (ET) cases are negative for disease-defining mutations on JAK2, MPL, and CALR and defined as triple negative (TN). The lack of recurrent mutations in TN-ET patients makes its pathogenesis ambiguous. Here, we screened 483 patients with suspected ET in a single institution, centrally reviewed bone marrow specimens, and identified 23 TN-ET patients. Analysis of clinical records revealed that TN-ET patients were mostly young female, without a history of thrombosis or progression to secondary myelofibrosis and leukemia. Sequencing analysis and human androgen receptor assays revealed that the majority of TN-ET patients exhibited polyclonal hematopoiesis, suggesting a possibility of reactive thrombocytosis in TN-ET. However, the serum levels of thrombopoietin (TPO) and interleukin-6 in TN-ET patients were not significantly different from those in ET patients with canonical mutations and healthy individuals. Rather, CD34-positive cells from TN-ET patients showed a capacity to form megakaryocytic colonies, even in the absence of TPO. No signs of thrombocytosis were observed before TN-ET development, denying the possibility of hereditary thrombocytosis in TN-ET. Overall, these findings indicate that TN-ET is a distinctive disease entity associated with polyclonal hematopoiesis and is paradoxically caused by hematopoietic stem cells harboring a capacity for cell-autonomous megakaryopoiesis., (© 2021. The Author(s).)

In end-of-life care, rehabilitation for terminally ill cancer patients is inconsistently provided and rarely discussed. We sought to clarify the prevalence of unmet rehabilitation need for patients admitted to inpatient hospice/palliative care units as perceived by bereaved family members. We conducted a nationwide questionnaire survey of 1001 family members of cancer patients who died at inpatient hospices/palliative care units. For cancer patients who did not receive rehabilitation, we asked if family members perceived that the patient would have wanted rehabilitation intervention. Data were obtained from 416 respondents. Of these, 281 (67.5%) cases received no rehabilitation. The need for physical modalities was the most frequently reported (27.8%; 95% CI: 22.6-33.4), followed by relief of dyspnea (25.6%; 95% CI: 20.6-31.1) and treatment of edema (23.8%; 95% CI: 19.0-29.3). A non-negligible proportion of bereaved families reported unmet need for rehabilitation related to symptom management in inpatient hospices/palliative care units., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Reflux esophagitis is known to be more prevalent in males, and previous studies have suggested sex differences in its risk factors. However, little is known about sex differences in the time-course of risk factors before reflux esophagitis onset. Thus, we conducted a retrospective longitudinal study using health checkup records. From the records of 230,056 individuals obtained from nine institutes in Japan, we selected 1,558 male reflux esophagitis cases, 3,116 male controls, 508 female reflux esophagitis cases, and 1,016 female controls were selected. We compared time-courses of risk factors between the case and control groups and identified abdominal circumference (AC), diastolic blood pressure, alanine transaminase (ALT), and current smoking in males and body mass index (BMI) in females as sex-specific risk factors. We also found that AC and ALT in males and BMI in females were significantly different between the reflux esophagitis case and control groups during the five years before reflux esophagitis onset. Our results suggest that visceral fat-type obesity and fatty liver in males and higher BMI in females are more frequently observed in reflux esophagitis cases several years before reflux esophagitis onset, and that proactive intervention to lifestyle can help prevent reflux esophagitis in both males and females., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2021 JCBN.)

Background: Intestinal perfusion at the anastomotic site is thought to be one of the most influential risk factors for postoperative anastomotic leakage (AL). We evaluated the efficacy of indocyanine green (ICG) fluorescence imaging at the stump of the proximal colon in left-sided colectomy or rectal resection in terms of decreasing the incidence of AL., Methods: Prospectively collected data were retrospectively evaluated. Patients who underwent left-sided colectomy or rectal resection were enrolled (ICG group; n = 197), and patients who had undergone a similar procedure before the ICG group were enrolled from the charts as historical controls (HC group; n = 187). After ICG evaluation, anastomosis was performed where fluorescence was sufficient. The incidence of AL was compared between the ICG and HC groups. Propensity score (PS)-matched data were analyzed to clarify the risk of AL., Results: AL occurred in 6 patients (3.3%) in the ICG group and 17 (10.7%) in the HC group. ICG evaluation revealed 179 patients with good fluorescence and 18 with poor/none perfusion (9.1%). The transection line was changed in all patients with poor/none fluorescence. Three of these 18 patients developed AL (16.7%), though transection line was changed at which is thought to be good. We hope AL in poor/none fluorescence can be prevented at the same rate of cases with good fluorescence. Actually, the rate of that was significantly higher compared with good fluorescence patients (P = 0.038). 93 patients in each group were compared by PS-matched data analysis, which showed the AL rate in the ICG group was significantly lower than that in the HC group (3.2% vs 10.8%, respectively; P = 0.046)., Conclusions: Even though this study has limitations of comparison of data prospectively collected and retrospectively analyzed, intraoperative ICG fluorescence imaging evaluation could significantly decrease the incidence of AL.

Purpose: Retinoic acid-induced 2 (RAI2) has been shown to be a putative suppressor of the early hematogenous dissemination of tumor cells to the bone marrow in breast cancer. Here, we investigated the associations of RAI2 mRNA and protein expression with clinicopathological factors and prognosis in breast cancer patients with long-term follow-up., Methods: Invasive breast cancer tissues (n = 604) were analyzed for RAI2 mRNA expression. We examined the associations of clinicopathological factors with the expression levels of RAI2 mRNA in these samples. We also analyzed RAI2 protein expression by immunohistochemistry in invasive breast cancer tissues (n = 422)., Results: We identified significant positive associations between low expression of RAI2 mRNA and shorter disease-free survival (DFS), breast-cancer-specific survival (BCSS), and overall survival (OS) in breast cancer patients. We also identified significant positive associations between negative for RAI2 protein expression and shorter DFS, BCSS, and OS in breast cancer patients. Low RAI2 mRNA and negative for RAI2 protein expression were positively associated with larger tumor size, higher tumor grade, and ERα-negativity. Multivariate analyses indicated that not only RAI2 mRNA but also RAI2 protein expression were independent risk factors for both DFS and BCSS in breast cancer patients. The median follow-up periods were 10.3 and 9.3 years for the RAI2 mRNA and protein expression analyses, respectively., Conclusions: Our findings suggest that RAI2 has a role in the metastasis of breast cancer, and that RAI2 expression could be a promising candidate biomarker of prognosis in breast cancer patients.

Patients with primary myelofibrosis (PMF) have a poorer prognosis than those with other subtypes of myeloproliferative neoplasms (MPNs). To investigate the relationship between gene mutations and the prognosis of Japanese PMF patients, we analyzed mutations in 72 regions located in 14 MPN-relevant genes (CSF3R, MPL, JAK2, CALR, DNMT3A, TET2, EZH2, ASXL1, IDH1/2, SRSF2, SF3B1, U2AF1, and TP53) utilizing a target resequencing platform. In our cohort, ASXL1 mutations were more frequently detected in both overt and prefibrotic PMF patients than other mutations. The frequency of ASXL1 mutations was slightly higher among overt PMF patients than among prefibrotic PMF patients (44.6% vs 25.0%, FDR = 0.472). Decision tree classification algorithms revealed that ASXL1, EZH2, and SRSF2 mutations were associated with a poor prognosis for overt PMF. Overall survival was significantly shorter in patients harboring ASXL1, EZH2, or SRSF2 mutations than in those without these mutations (p = 0.03). These results suggest that, as reported in Western countries, MIPSS70 is applicable to Japanese PMF patients and ASXL1, EZH2, and SRSF2 mutations may be utilized as surrogate markers of a poor prognosis.

Purpose: Improving the safety of general wards is a key to reducing serious adverse events in the postoperative period. We investigated the characteristics, treatment, and outcomes of postoperative patients managed by a rapid response system (RRS) in Japan to improve postoperative management., Methods: This retrospective study analyzed cases requiring RRS intervention that were included in the In-Hospital Emergency Registry in Japan. We analyzed data reported by 34 Japanese hospitals between January 2014 and March 2018, mainly focusing on postoperative patients for whom the RRS was activated within 7 days of surgery. Non-postoperative patients, for whom the RRS was activated in all other settings, were used for comparison as necessary., Results: There were 609 (12.7%) postoperative patients among the total patients in the registry. The major criteria were staff concerns (30.2%) and low oxygen saturation (29.7%). Hypotension, tachycardia, and inability to contact physicians were observed as triggers significantly more frequently in postoperative patients when compared with non-postoperative patients. Among RRS activations within 7 days of surgery, 68.9% of activations occurred within postoperative day 3. The ordering of tests (46.8%) and fluid bolus (34.6%) were major interventions that were performed significantly more frequently in postoperative patients when compared with non-postoperative patients. The rate of RRS activations resulting in ICU care was 32.8%. The mortality rate at 1 month was 16.2%., Conclusion: Approximately, 70% of the RRS activations occurred within postoperative day 3. Circulatory problems were a more frequent cause of RRS activation in the postoperative group than in the non-postoperative group.

Background: Antegrade percutaneous ureterolithotripsy (URSL) could be a treatment option for large and/or impacted proximal ureteral stones, which are difficult to treat. To review the current approach and treatment outcomes and to compare the efficacy of retrograde and antegrade URSL for large proximal ureteral stones, we evaluated the unique perspectives of both surgical modalities., Methods: This systematic literature review and meta-analysis was performed in July 2020. Articles on human studies and treatment of ureteral stones with URSL were extracted from the PubMed, MEDLINE, Embase, Cochrane Library, Scopus, and the Japan Medical Abstracts Society databases without any language restrictions. The risks of bias for randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs) were assessed using the Cochrane risk of tool and the Risk of Bias in Non-randomized Studies- of Interventions tool, respectively., Results: A total of 10 studies, including seven RCTs and three non-RCTs, were selected for the analysis; 433 and 420 cases underwent retrograde and antegrade URSL, respectively. The stone-free rate (SFR) was significantly higher in antegrade URSL than in retrograde URSL (SFR ratio: 1.17, 95% CI: 1.12-1.22; P<0.001), while the hospital stay was significantly longer in antegrade URSL than in retrograde URSL (standardized mean difference: 2.56, 95% CI: 0.67-4.46; P=0.008). There were no significant differences in the operation time and the overall complication rate between the two approaches., Conclusions: Despite the heterogeneity of data and bias limitations, this latest evidence reflects real practice data, which may be useful for decision making., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau-20-1296). The authors have no conflicts of interest to declare., (2021 Translational Andrology and Urology. All rights reserved.)

The purpose of this study was to examine differences in texture features between olfactory neuroblastoma (ONB) and sinonasal squamous cell carcinoma (SCC) on contrast-enhanced CT (CECT) images, and to evaluate the predictive accuracy of texture analysis compared to radiologists' interpretations. Forty-three patients with pathologically-diagnosed primary nasal and paranasal tumor (17 ONB and 26 SCC) were included. We extracted 42 texture features from tumor regions on CECT images obtained before treatment. In univariate analysis, each texture features were compared, with adjustment for multiple comparisons. In multivariate analysis, the elastic net was used to select useful texture features and to construct a texture-based prediction model with leave-one-out cross-validation. The prediction accuracy was compared with two radiologists' visual interpretations. In univariate analysis, significant differences were observed for 28 of 42 texture features between ONB and SCC, with areas under the receiver operating characteristic curve between 0.68 and 0.91 (median: 0.80). In multivariate analysis, the elastic net model selected 18 texture features that contributed to differentiation. It tended to show slightly higher predictive accuracy than radiologists' interpretations (86% and 74%, respectively; P = 0.096). In conclusion, several texture features contributed to differentiation of ONB from SCC, and the texture-based prediction model was considered useful.

Background/aims: Functional gastrointestinal disorders (FGIDs) are diagnosed and classified using the latest Rome IV criteria, released in 2016. Epidemiology of FGID diagnosed by the Rome IV criteria and current clinical application of gastrointestinal motility testing in Asian countries are not well known. The aims of this survey are to elucidate the present situation of epidemiology and diagnostic tests of FGID in clinical practice in some East and Southeast Asian countries., Methods: The questionnaire focusing on current situation of FGID diagnosis and gastrointestinal motility testing was distributed to members of the International Gastroenterology Consensus Symposium study group and collected to be analyzed., Results: The prevalence rates of subtypes of both functional dyspepsia (FD) and irritable bowel syndrome (IBS) are relatively similar in all Asian countries. In these countries, most patients underwent both upper endoscopy and Helicobacter pylori test to diagnose FD. Colonoscopy was also frequently performed to diagnose IBS and chronic constipation. The frequency of gastrointestinal motility testing to examine gastric emptying and colonic transit time varied among Asian countries., Conclusions: This survey revealed epidemiology of FGIDs and current status of gastrointestinal motility testing in some East and Southeast Asian countries., (© 2020 S. Karger AG, Basel.)

Context: In end-of-life care, rehabilitation for patients with cancer is considered to be an important means for improving patients' quality of death and dying., Objectives: To determine whether the provision of rehabilitation for patients with cancer in palliative care units is associated with the achievement of a good death., Methods: This study involved a cross-sectional, anonymous, and self-report questionnaire survey of families of patients with cancer who died in palliative care units in Japan. We evaluated the short version of Good Death Inventory (GDI) on a seven-point scale. A logistic regression model was used to calculate the propensity score. Covariates included in this model were survey year, patients' characteristics, and families' characteristics. The associations between rehabilitation and GDI were tested using trend tests after propensity score matching adjustment., Results: Of the 1965 family caregivers who received the questionnaires, available data were obtained from 1008 respondents (51.2%). Among them, 285 (28.2%) cases received rehabilitation in palliative care units. There was no difference in total GDI score between the groups with and without rehabilitation. In exploratory analyses, patients receiving rehabilitation were significantly more likely to feel maintaining hope and pleasure (mean 4.50 [SE 0.10] vs. 4.05 [0.11], respectively; effect size [ES] 0.31; P = 0.003), good relationships with medical staff (mean 5.67 [SE 0.07] vs. 5.43 [0.09], respectively; ES 0.22; P = 0.035), and being respected as an individual (mean 6.08 [SE 0.06] vs. 5.90 [0.07], respectively; ES 0.19; P = 0.049) compared with patients not receiving rehabilitation., Conclusion: Rehabilitation in palliative care units may contribute to several domains of quality of death and dying, particularly maintaining hope and pleasure. Further research is needed to investigate whether palliative rehabilitation contributes to the achievement of a good death., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) with mid-range left ventricular ejection fraction (LVEF) (HFmrEF) is considered a new category of HF and LVEF < 50%, which is the upper threshold of LVEF for HFmrEF, is thought to represent a mild decrease in LV contractile performance. We aimed to consider an LVEF threshold value to be taken as a surrogate for impairment of LV contractile performance, resulting in new-onset HF. We enrolled 398 patients with LVEF ≥ 40% that underwent cardiac catheterization. Using the LV pressure recording with a catheter-tipped micromanometer, we calculated the inertia force of late systolic aortic flow (IFLSAF), which was sensitive to the slight impairment in LV contractile performance. We evaluated the utility of the IFLSAF for predicting future cardiovascular death or hospitalization for HF. We performed a receiver operating characteristic (ROC) curve analysis to determine the best LVEF threshold value for distinguishing whether the LV maintained the IFLSAF. A multivariate Cox proportional-hazards model revealed that the loss of IFLSAF was significantly associated with the future adverse events (HR: 7.798, 95%CI 2.174-27.969, p = 0.002). According to the ROC curve analysis, an LVEF ≥ 58% indicated that the LV could maintain the IFLSAF. We concluded that the loss of IFLSAF, which could reflect even slight impairment in LV contractile performance, was a reliable indicator for new-onset HF in patients with LVEF ≥ 40%. LVEF ≥ 58% could be taken as a surrogate for the IFLSAF maintenance; this threshold could be useful for risk stratification of new-onset HF in patients with preserved LVEF.

Background: Postoperative hoarseness after general anesthesia is associated with patient discomfort and dissatisfaction. A recent large retrospective study showed that single-lumen endotracheal tube intubation by a trainee did not alter the incidence of postoperative pharyngeal symptoms compared with intubation by a senior anesthesiologist. However, there is limited information about the relationship between the anesthesiologist's experience and hoarseness after double-lumen endotracheal tube intubation. We tested the hypothesis that double-lumen endotracheal tube intubation performed by a trainee increases the incidence of postoperative hoarseness compared to intubation by a senior anesthesiologist., Methods: This retrospective observational study included patients who underwent lung resection between April 2015 and March 2018 at a university hospital. Double-lumen endotracheal tube intubation was carried out with a Macintosh laryngoscope. We divided the patients into 2 groups - one group comprised of patients who were intubated by a trainee anesthesiologist with < 2 years of experience, and the other group comprised of those who underwent intubation by a senior anesthesiologist with ≥2 years of experience. The primary outcome was the incidence of postoperative hoarseness 24 h after surgery and we collected data on postoperative hoarseness using a checklist of postanesthetic adverse events. One-to-one propensity score matching was conducted and P values < 0.05 were considered statistically significant., Results: There was a total of 256 eligible patients, of which 153 underwent intubation by trainee anesthesiologists, and the remaining 103 patients were intubated by a senior anesthesiologist. The one-to-one propensity score matching resulted in 96 pairs of patients for the groups. The incidence of postoperative hoarseness 24 h after surgery was significantly higher in patients who were intubated by a trainee anesthesiologist than in patients who were intubated by a senior anesthesiologist (9.4% vs. 2.1%, respectively; P = 0.03)., Conclusions: Double-lumen endotracheal tube intubation by trainee anesthesiologists with < 2 years of experience increased the incidence of postoperative hoarseness 24 h after surgery compared to intubation by senior anesthesiologists with ≥2 years of experience.

We investigated the incidence of cardiotoxicity, its risk factors, and the clinical course of cardiac function in patients with malignant lymphoma (ML) who received a cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen. Among all ML patients who received a CHOP regimen with or without rituximab from January 2008 to December 2017 in Nagoya City University hospital, 229 patients who underwent both baseline and follow-up echocardiography and had baseline left ventricular ejection fraction (LVEF) ≥50% were analyzed, retrospectively. Cardiotoxicity was defined as a ≥10% decline in LVEF and LVEF < 50%; recovery from cardiotoxicity was defined as a ≥5% increase in LVEF and LVEF ≥50%. Re-cardiotoxicity was defined as meeting the criteria of cardiotoxicity again. With a median follow-up of 1132 days, cardiotoxicity, symptomatic heart failure, and cardiovascular death were observed in 48 (21%), 30 (13%), and 5 (2%) patients, respectively. Multivariate analysis demonstrated that history of ischemic heart disease (hazard ratio (HR), 3.15; 95% CI, 1.17-8.47, P  = .023) and decreased baseline LVEF (HR per 10% increase, 2.55; 95% CI, 1.49-4.06; P  < .001) were independent risk factors for cardiotoxicity. Recovery from cardiotoxicity and re-cardiotoxicity were observed in 21 of 48, and six of 21, respectively. Cardiac condition before chemotherapy seemed to be most relevant for developing cardiotoxicity. Furthermore, Continuous management must be required in patients with cardiotoxicity, even after LVEF recovery., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

A ketogenic diet is expected to be an effective support therapy for patients with cancer, but the degree and duration of carbohydrate restriction are unclear. We performed a case series study of a new ketogenic diet regimen in patients with different types of stage IV cancer. Carbohydrates were restricted to 10 g/day during week one, 20 g/day from week two for three months, and 30 g/day thereafter. A total of 55 patients participated in the study, and data from 37 patients administered the ketogenic diet for three months were analyzed. No severe adverse events associated with the diet were observed. Total ketone bodies increased significantly, and both fasting blood sugar and insulin levels were suppressed significantly for three months after completion of the study. Five patients showed a partial response on Positron emission tomography-computed tomography (PET-CT) at three months. Three and seven patients showed complete and partial responses, respectively at one year. Median survival was 32.2 (maximum: 80.1) months, and the three-year survival rate was 44.5%. After three months on the ketogenic diet, the serum Alb, BS, and CRP (ABC) score could be used to stratify the patients into groups with significantly different survival rates ( p < 0.001, log-rank test). Our ketogenic diet regimen is considered to be a promising support therapy for patients with different types of advanced cancer., Competing Interests: This study was partly performed under a joint research between the University of Osaka, Meiji Co., Ltd., and Nissin Oillio. Hagihara holds the position of Joint Research Chair in collaboration with Meiji Co., Ltd. who produced the ketogenic formula, and Nisshin Oillio produced the MCT oil. Kajimoto is a member of the Joint Research group. Other authors have no competing interests.

Background: During chemotherapy, hyponatremia is one of the most frequently encountered adverse effects. This study aimed to investigate the prognostic impact of hyponatremia induced by systemic chemotherapy (HIC) using a propensity matching method in cumulative pooled data., Methods: Between January 2011 and July 2017, 2129 patients were administered systemic chemotherapy for malignancy in various organs at Nagoya City University Hospital. Patients were divided into two groups: a grade 0-1 group (control group) and a grade 3-4 group (severe group) according to the severity of HIC appearing within 30 days after starting treatment. Kaplan-Meier curves were used for survival and recurrence analyses using a propensity case-matched analysis., Result: The number of severe HIC patients was 93 (4.4%). In platinum-containing regimens, HIC appeared at higher frequencies. In the 21.2 months median follow-up period, the median OS (mOS) in the severe group was 49.1 months, which was significantly worse than the mOS in the control group; the OS in the control group did not reach the median. Univariate and multivariate analyses of associated factors in patients with grade 3-4 HIC revealed that renal dysfunction, cisplatin-containing regimen, and infusion of more than 5000 mL fluid was associated with HIC., Conclusion: This study suggests that severe HIC in the first treatment cycle affects survival time. Chemotherapy patients receiving extensive hydration should be required to undergo frequent monitoring of serum sodium levels, especially patients receiving platinum-containing regimens.

Purpose: Recently, several investigators reported that costal cartilage does not overgrow in pectus excavatum (PE). We wished to clarify whether costochondral length is longer in PE than the normal thorax and we tried to clarify the change of the shape of precordial concavity according to the growth in PE., Methods: We evaluated 243 CT axial images of patients with PE and 246 CT axial images of patients without thoracic deformity. We divided the fifth costal cartilage into several lengths. We considered each part to be a straight line and calculated the length of the lines. We compared the approximate costochondral length between PE and normal thorax. We analyzed the distance between both anterior tips of fifth rib, and the ratio of the width and the depth of concavity to thoracic diameter in PE., Conclusions: The costochondral length in patients with PE is highly likely to be longer than that of the normal thorax. The length of costal cartilage may be longer in asymmetric PE than symmetric PE. It may start in infantile period in PE that the thoracic shape turns into asymmetry from symmetry. The precordial concavity of PE may be shaped by overgrowth of both costal cartilages and ribs.

Background: It is difficult to objectively evaluate chemotherapy-related adverse events early in elderly patients with urothelial carcinoma. A delayed response causes a reduction in quality of life (QoL). Wearable activity systems that objectively record life logs have recently been used., Objectives: This study was undertaken to verify the reliability and effectiveness of a wearable activity system (Fitbit) to monitor subjective symptoms in an objective manner during chemotherapy for elderly patients with urothelial cancer (UC)., Materials and Methods: This was a cohort prospective study. Elderly patients with UC were enrolled who received short hydration gemcitabine and cisplatin (shGC) combination therapy at Nagoya City University Hospital from January 2018 to March 2020. A Fitbit was used to monitor heart rate, distance moved, and cardio zone time. Heart rate was also monitored by an oscillometric method. The relationship between Fitbit recordings and perceived adverse events, such as fatigue, constipation and nausea, observed during chemotherapy was investigated using a general linear mixed effects model., Results: Twenty-one of 28 inpatients were enrolled and observed for a total of 824 days. A significant, moderately strong correlation was found between two measurements of heart rate (Pearson's r = 0.65, p < 0.05). The measurement of fatigue using Fitbit was effective (p = 0.03)., Conclusion: Fitbit monitoring can measure the QoL of a patient and was useful for monitoring elderly patients with UC undergoing shGC therapy in an outpatient setting. Fitbit may be useful for monitoring outpatients and their QoL during chemotherapy., (Copyright © 2020. Published by Elsevier Ltd.)

T-helper (Th)17.1 cells exhibit high pathogenicity in inflammatory diseases. This study aimed to identify the changes in the proportions of Th subsets, including Th17.1, which are associated with abatacept treatment response in Japanese patients with rheumatoid arthritis. On the basis of the results, we assessed whether Th17.1 is a potential cellular biomarker. Multicolor flow cytometry was used to determine the circulating Th subsets among CD4+ T lymphocytes in 40 patients with rheumatoid arthritis before abatacept treatment. All the patients received abatacept treatment for 24 weeks; changes in disease activity score, including 28-joint count C-reactive protein, and responsiveness indicated by other indices to abatacept treatment were evaluated according the European League Against Rheumatism criteria (good and moderate responders and nonresponders). The correlation between the abatacept responses and the proportions of Th subsets (baseline) was analyzed. Logistic regression analysis with inverse probability weighting method was performed to calculate the odds ratio adjusted for patient characteristics. The proportion of baseline Th17.1 cells was significantly lower in patients categorized as good responders than in those categorized as non-good responders (moderate responders and nonresponders; p = 0.0064). The decrease in 28-joint count C-reactive protein after 24 weeks of abatacept therapy showed a significant negative correlation with the proportion of Th17.1 cells. The adjusted odds ratio for achieving good response in patients with baseline Th17.1 levels below the median value was 14.6 (95% confidence interval, 2.9-72.3; p = 0.0021) relative to that in the remaining patients. The proportion of Th17.1 cells at baseline is a good candidate for predicting abatacept treatment response in Japanese patients. These novel findings may represent a significant step in the pursuit of precision medicine., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SM and ST have received speaking fees from Ono Pharmaceutical Co., Ltd. TN and AN have received grants and speaking fees from Ono Pharmaceutical Co., Ltd. All other authors declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: The aim of the present study was to determine if the HLA phenotype is related to severe sacroiliitis in Japanese patients with psoriatic arthritis. Methods: This study was a single-center, retrospective, cross-sectional, observational study. We reviewed the clinical information and radiologic examinations of patients with psoriatic arthritis (PsA) who visited our hospital from January 2011 to December 2016. Radiographic changes in the sacroiliac joints were assessed by four independent investigators according to the recommendations of the Assessment of Spondyloarthritis International Society. Results: Of 113 PsA patients, 63 (55.8%) had sacroiliitis. The HLA phenotype was investigated in 39 patients. Ordered logistic regression analysis revealed that the presence of HLA-B46 was an independent risk factor for severe sacroiliitis in Japanese PsA patients (odds ratio 3.2; 95% confidence interval 1.16-9.81). Therefore, the clinical features were divided into two groups according to the presence of HLA-B46. Both the Nail Psoriasis Severity Index and grade of sacroiliitis were significantly higher in the HLA-B46-positive group (Mann-Whitney U test; p  = .0003 and p  = .028, respectively). Conclusion: HLA-B46 is considered a risk factor for severe sacroiliitis in Japanese patients with PsA.

Femoral anteversion has been assessed with ultrasound using femoral neck tilting angle (FN-TA); however, femoral torsion angle (FTA), which is defined using FN-TA and condylar axis tilting angle, has not been assessed with ultrasound. This study aimed to establish the ultrasonographic assessment of FTA (US-FTA) by comparing data obtained through US-FTA and computed tomography (CT). Twenty-one patients (age range, 38-82 y) with 21 intact hips were included. In the US-FTA, the femoral head and anterior tubercle of the greater trochanter were used as bony landmarks. The intra-rater and inter-rater reliabilities and standard error of measurement (SEM) of US-FTA were 0.994 (SEM 0.93) and 0.994 (SEM 0.94), respectively. A strong agreement was found between FTA variables obtained with ultrasound and CT (R = 0.939, p < 0.001). Ultrasound is useful and can be a valid alternative to CT for the evaluation of the femoral torsion angle without radiation exposure., (Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of the study is to investigate depressive symptoms before and after the initiation of chemotherapy and their impact on overall survival (OS) among patients with hematological malignancies., Methods: We performed a prospective analysis of consecutive patients with newly diagnosed malignant lymphoma or multiple myeloma enrolled between September 2010 and March 2016. We evaluated depression symptoms at two time points: before starting chemotherapy (T1) and 1 month later (T2), using PHQ-9 and known prognostic factors. We allocated participants with depressive symptoms at T1 and/or T2 to a depression group that was subdivided as follows: new depressive symptoms at T2, ("new-onset"), remission of depressive symptoms at T2 ("remission"), and persistent depressive symptoms from T1 to T2 ("persistent"). The main outcome, OS, was evaluated using Kaplan-Meier methods and multivariate Cox proportional hazards modeling., Results: Of the 294 eligible participants, we analyzed 255 patients, including 83 with depression. There were 19 participants in the new-onset, 38 in the remission, and 26 in the persistent depression group. The OS of participants with depression was significantly shorter than that of those without depression (adjusted hazard ratio [AjHR] 2.43; 95% confidence interval [CI] 1.43-4.12; P < .001). Using the never-depressive symptoms group as a reference group, AjHRs were as follows: new-onset, 1.91 (95% CI, 0.77-4.75; 0.166); remission, 2.98 (95% CI, 1.55-5.74; 0.001), and persistent, 2.17 (95%CI, 1.01-4.68; 0.047)., Conclusions: Among patients with mature lymphoid malignancy, the group with depression at baseline had a poorer survival, both in the group that remained depressive and the group that recovered from depressive symptoms., (© 2019 John Wiley & Sons, Ltd.)

Chronic low-grade inflammation can cause several metabolic syndromes. Patients with psoriasis, a chronic immunological skin inflammation, often develop diabetes. However, it is not clear to date how psoriasis leads to, or is correlated with, glucose intolerance. Here, we investigate whether psoriasis itself is correlated with hyperglycemia in humans and mice. In patients, the severity of psoriasis was correlated with high blood glucose levels, and treatment of psoriasis by phototherapy improved insulin secretion. Imiquimod-induced systemic and cutaneous inflammation in mice, with features of human psoriasis, also resulted in hyperglycemia. Although it should be determined if psoriasis-like cutaneous inflammation alone can induce hyperglycemia, imiquimod-treated mice showed impairment of insulin secretion without significant islet inflammation. Administration of anti-IL-17A monoclonal antibody improved hyperglycemia in patients with psoriasis and imiquimod-treated mice with psoriasiform features. These results suggest that hyperglycemia is highly associated with psoriasis, mainly through IL-17., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Video-assisted thoracoscopic surgery (VATS) lobectomy is performed widely for patients with clinical stage I non-small cell lung cancer (NSCLC) because of its superior short-term outcomes to those of thoracotomy lobectomy. However, the long-term outcomes of VATS lobectomy vs. thoracotomy lobectomy remain controversial., Methods: We reviewed the clinical data of 202 consecutive patients who underwent lobectomy for clinical stage IA NSCLC at our institution between January, 2008 and December, 2013. Stage IA NSCLC was confirmed pathologically in 162 of these patients, 60 of whom underwent VATS lobectomy and 102 of whom underwent thoracotomy lobectomy. We compared the perioperative clinical factors and outcomes of these two groups, using a propensity score-matched analysis., Results: In an analysis of 58 matched cases, the VATS group showed less blood loss, a shorter duration of chest tube placement, a shorter postoperative hospital stay, and a lower peak C-reactive protein value, despite a longer operative time. The VATS group also had significantly longer survival than the thoracotomy group [5-year overall survival, 100% vs. 87%, respectively (p = 0.01); 5-year disease-free survival, 100% vs. 86% (p = 0.03)]., Conclusions: These findings suggest that VATS may have better long-term as well as short-term outcomes than thoracotomy for patients with early-stage NSCLC.

Therapeutic hypothermia following neonatal encephalopathy is neuroprotective. However, approximately one in two cooled infants still die or develop permanent neurological impairments. Further understanding of variables associated with the effectiveness of cooling is important to improve the therapeutic regimen. To identify clinical factors associated with short-term outcomes of cooled infants, clinical data of 509 cooled infants registered to the Baby Cooling Registry of Japan between 2012 and 2014 were evaluated. Independent variables of death during the initial hospitalization and survival discharge from the cooling hospital at ≤28 days of life were assessed. Death was associated with higher Thompson scores at admission (p < 0.001); higher heart rates after 3-72 hours of cooling (p < 0.001); and higher body temperature after 24 hours of cooling (p = 0.002). Survival discharge was associated with higher 10 minutes Apgar scores (p < 0.001); higher blood pH and base excess (both p < 0.001); lower Thompson scores (at admission and after 24 hours of cooling; both p < 0.001); lower heart rates at initiating cooling (p = 0.003) and after 24 hours of cooling (p < 0.001) and lower average values after 3-72 hours of cooling (p < 0.001); higher body temperature at admission (p < 0.001); and lower body temperature after 24 hours and lower mean values after 3-72 hours of cooling (both p < 0.001). Survival discharge was best explained by higher blood pH (p < 0.05), higher body temperature at admission (p < 0.01), and lower body temperature and heart rate after 24 hours of cooling (p < 0.01 and <0.001, respectively). Lower heart rate, higher body temperature at admission, and lower body temperature during cooling were associated with favorable short-term outcomes.

Studies have previously shown that mutant calreticulin (CALR), found in a subset of patients with myeloproliferative neoplasms (MPNs), interacts with and subsequently promotes the activation of the thrombopoietin receptor (MPL). However, the molecular mechanism behind the activity of mutant CALR remains unknown. Here we show that mutant, but not wild-type, CALR interacts to form a homomultimeric complex. This intermolecular interaction among mutant CALR proteins depends on their carboxyl-terminal domain, which is generated by a unique frameshift mutation found in patients with MPN. With a competition assay, we demonstrated that the formation of mutant CALR homomultimers is required for the binding and activation of MPL. Since association with MPL is required for the oncogenicity of mutant CALR, we propose a model in which the constitutive activation of the MPL downstream pathway by mutant CALR multimers induces the development of MPN. This study provides a potential novel therapeutic strategy against mutant CALR-dependent tumorigenesis via targeting the intermolecular interaction among mutant CALR proteins.

Background: The family members of terminally ill patients are often requested to make difficult surrogate decisions during palliative care. This study sought to clarify the appropriate communication style for physicians as perceived by family members confronting difficult surrogate decision-making., Methods: This experimental psychological study used scripted videos. In the videos, the physician described treatment options including continuous deep sedation to the family members of patients with cancer and terminal delirium using an autonomous or paternalistic style. Medical professionals with clinical experience in oncology were randomly assigned to either group viewing the videos. The primary outcomes were physician compassion, decisional conflict and emotion scores. We also evaluated the communication style preference., Results: In total, 251 participants completed this study. Although participants in both groups reported high physician compassion, participants in the autonomous style group reported lower compassion scores (reflecting higher physician compassion) (mean 15.0 vs. 17.3, P = 0.050), lower decisional conflicts scores (51.1 vs. 56.8, P = 0.002) and comparable emotions compared with those in the paternalistic style group. Seventy-six percent of participants preferred the autonomous style., Conclusions: Regarding difficult surrogate decision-making, the autonomous style might be more appropriate than the paternalistic style. However, various factors, such as family members' communication style preferences, family members' values, physician-family relationships and ethnic cultures, should be considered.

Background: Preclinical studies show that opioids promote angiogenesis, tumor progression, and metastasis, resulting in shorter survival., Objective: To explore whether opioids are associated with the overall survival (OS) of patients with incurable nonsmall cell lung cancer (NSCLC)., Design: Prospective cohort study of patients with NSCLC., Setting: We investigated patients newly diagnosed with advanced or post-operative recurrent NSCLC between April 2013 and December 2015 at a single institute., Measurements: We evaluated OS, opioid requirements, opioid doses, pain levels, and prognostic factors of advanced NSCLC. The effects of variables on survival were analyzed using univariable and multivariable models. Patients were stratified according to oral morphine equivalents (OMEs)/day (<60 or ≥60 mg) to assess the association between opioid dose and OS., Results: We analyzed 150 patients, including 64 who received opioid treatment during follow-up. The median OS was 242 days in the opioid group and 627 days in the no-opioid group (log-rank p < 0.001). Multivariable models revealed that the opioid requirement was an independent predictor of shorter OS, after adjustment for prognostic variables, including sex, histology, stage, history of systemic chemotherapy, and performance status (hazard ratio 1.73, 95% confidence interval 1.137-2.631). There was no significant difference in OS between patients who received ≥60 mg OME/day for 250 days versus <60 OME/day for 242 days., Conclusions: The opioid dose does not shorten the survival of patients with advanced NSCLC. The opioid requirement is associated with shorter survival when opioids are administered any time during the clinical course, independent of the influence of other key factors.