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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., Four factors, HLA‐B4006, female (sex), Arm A (treatment course), and bone pain, were chosen as explanatory variables using the stepwise method. The carriers of HLA‐B4006 showed the highest odds ratio for the risk of bortezomib‐induced peripheral neuropathy.

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).

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. 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). 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. 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.

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.

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. 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. 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). 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.

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

To investigate whether surgery and stereotactic body radiotherapy (SBRT) yield comparable outcomes for clinical stage (c-stage) I non-small-cell lung cancer (NSCLC), propensity score-matching (PSM) analysis was conducted. This single-institutional retrospective study included patients who underwent surgery (n = 574) or SBRT (n = 182) between 2004 and 2014. PSM was performed based on tumor diameter, age, sex, performance status, forced expiratory volume, Charlson comorbidity index, and ground glass nodules (GGN) defined as cTis or cT1mi according to the 8th TNM classification. The median follow-up durations for the surgery and SBRT groups were 66 and 69 months, respectively. The multivariate analysis revealed that non-GGN was a significant factor for poorer overall survival (OS) and disease-free survival (DFS): hazard ratio (HR) 19.95% confidence interval (CI) 4.7–79, P

Heart failure (HF) with mid-range left ventricular ejection fraction (LVEF) (HFmrEF) is considered a new category of HF and LVEF 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.

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. 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. 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. 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.

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.

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 endocrine therapy in ERα-positive breast cancer patients by using LLGL2/SLC7A5 mRNA and protein expression in long-term follow-up invasive breast cancer tissues. We identified that low LLGL2/SLC7A5 mRNA co-expression (LLGL2low/SLC7A5low) was associated with disease-free survival (DFS) compared with other combination groups in all breast cancer patients. In ERα-positive breast cancer patients, LLGL2low/SLC7A5low showed longer DFS and overall survival (OS) compared with LLGL2high/SLC7A5high and a positive trend of longer survival compared with other combination groups. We also observed that LLGL2low/SLC7A5low showed longer survival compared with LLGL2high/SLC7A5high in ERα-positive breast cancer patients receiving adjuvant tamoxifen therapy. Multivariate analysis demonstrated that LLGL2low/SLC7A5low 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.

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

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.

Background Lethal giant larvae homolog 2 (LLGL2) functions as a promoter of tumor growth and localizes at cell junctions and membranes with solute carrier family 7 member 5 (SLC7A5) in estrogen receptor α (ERα)-positive breast cancer. LLGL2 and 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 endocrine therapy in ERα-positive breast cancer patients. Methods The associations of clinicopathological factors with LLGL2 and SLC7A5 expression or LLGL2/SLC7A5 co-expression at the mRNA and protein level were assessed in invasive breast cancer patients with long-term follow-up. The median follow-up period was approximately10 years. Survival curves were analyzed using the Kaplan–Meier method and verified by the log-rank test. A Cox proportional hazards regression analysis was used for univariate and multivariate analyses of prognostic values using stepwise linear regression. Results We identified a positive association between low mRNA expression of LLGL2 or SLC7A5 alone and longer disease-free survival (DFS) and overall survival (OS) in ERα-positive breast cancer patients, but not in ERα-negative patients. We also identified that low LLGL2/SLC7A5 mRNA co-expression (LLGL2low/SLC7A5low) was associated with longer survival compared with other combination groups in all breast cancer patients. In ERα-positive breast cancer patients, LLGL2low/SLC7A5low showed longer survival compared with LLGL2high/SLC7A5high and a positive trend of longer survival compared with other combination groups. We also observed that LLGL2low/SLC7A5low showed longer survival compared with LLGL2high/SLC7A5high in ERα-positive breast cancer patients receiving adjuvant tamoxifen therapy. Multivariate analysis demonstrated that LLGL2low/SLC7A5low was an independent favorable prognostic factor of both DFS and OS in ERα-positive breast cancer patients. High co-expression of LLGL2 and SLC7A5 protein showed a positive trend of shorter survival. Conclusions Our study showed that co-expression of LLGL2 and SLC7A5 mRNA is a promising candidate biomarker and suggested that the LLGL2–SLC7A5 axis may be a therapeutic target in early breast cancer patients, especially in those receiving adjuvant tamoxifen therapy.

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

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. 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. 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)]. These findings suggest that VATS may have better long-term as well as short-term outcomes than thoracotomy for patients with early-stage NSCLC.

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.

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 using mRNA and protein expression, and bioinformatics. We examined the prognostic significance of HECTD1 by multivariate analysis. HECTD1 mRNA expression (HECTD1 expression) was lower in breast cancer compared with adjacent normal tissues. HECTD1 expression levels also differed among breast cancer subtypes. Decreased HECTD1 expression was significantly associated with aggressive tumour characteristics, including large tumour size and high histological grade. HECTD1 expression was inversely associated with mitochondrial cellular respiratory function and reactive oxygen species in breast cancer tissues. Multivariate analysis identified low HECTD1 mRNA expression level as an independent risk factor for disease-free (P = 0.009) and overall (P = 0.046) survival among breast cancer patients. There was no association of HECTD1 protein expression with mRNA expression and prognosis. HECTD1 mRNA expression is a candidate prognostic biomarker in breast cancer. The poor prognosis of patients with low HECTD1 mRNA expression may be associated with increased mitochondrial respiratory function.

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

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.

Purpose: 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; 151 (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] 2.22, 95% confidence interval [CI]: 1.30–3.81, P=0.004) 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.

令和2年度

Background Anthracycline-induced cardiotoxicity is a serious complication in patients with malignant lymphoma (ML) who received chemotherapy, which threatens life prognosis and quality of life of patients. However, incidence and risk factors of cardiotoxicity in patients with ML who undergo intensive chemotherapy which aims complete remission is not clarified. Furthermore, prognosis after cardiotoxicity and that after recovery from cardiotoxicity have not been elucidated. Method We screened 443 ML patients who received either rituximab (R)-CHOP or CHOP regimen between January 2008 and December 2017 at Nagoya City University Hospital. Two handled forty-four patients who underwent echocardiography before and after chemotherapy were enrolled and data were analyzed retrospectively. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) of 10% or greater and an LVEF was below 50%. Partial recovery was defined as a 5% or more of increase in LVEF and an LVEF was ≥50% after cardiotoxicity. Complete recovery was defined as an increase in LVEF became more than 95% of the baseline value. Patient's basic characteristics, chemotherapeutic regimen, laboratory data, echocardiographic data, and prognosis were collected from the medical records by two cardiologists and two hematologists. Result At baseline, the median age was 71 years, the median cumulative dose of doxorubicin was 302 mg/m2 and the median LVEF was 69%. During the follow-up period, cardiotoxicity was observed in 52 out of 244 patients (21%), 30 patients (12%) had a symptomatic heart failure, and 5 patients died from cardiovascular cause. Thirty-five patients developed cardiotoxicity during the first year of chemotherapy. Multivariate analysis identified that only the baseline LVEF (HR 0.949, 95% CI 0.919–0.981, p=0.002) was an independent risk factor for cardiotoxicity. In our study, patients who received more than 200 mg/m2 of doxorubicin developed cardiotoxicity frequently. Among 52 patients who experienced cardiotoxicity, partial recovery and full recovery were observed in 18 (35%) and 4 (8%) patients, respectively. Four patients without recovery died due to heart failure and 1 patient with partial recovery died suddenly. Six out of 18 patients with partial recovery developed re-cardiotoxicity. Conclusion ML patients who undergo more than 200 mg/m2 of doxorubicin need a watchful follow-up. Only a baseline LVEF was an independent risk factor for cardiotoxicity. one third of patients with partial recovery developed re-cardiotoxicity. Funding Acknowledgement Type of funding source: None

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.

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.

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 that by a senior anesthesiologist. However, little is known about the relationship between anesthesiologist experience and hoarseness after double-lumen endotracheal tube intubation. We tested the hypothesis that double-lumen endotracheal tube intubation by a trainee increases the incidence of postoperative hoarseness compared with that by a senior anesthesiologist.Methods: This retrospective observational study included patients who underwent lung resection from April 2015 to March 2018 in a university hospital. Patients underwent double-lumen endotracheal tube intubation with a Macintosh laryngoscope. We divided the patients into two groups: one group comprising patients whose tracheas were intubated by a trainee anesthesiologist and the other comprising those whose tracheas were intubated by a senior anesthesiologist. The primary outcome was the incidence of postoperative hoarseness 24 h after surgery. We collected data on postoperative hoarseness using a checklist of postanesthetic adverse events. One-to-one propensity score matching was performed. P values of Results: There were 256 eligible patients; 153 patients underwent intubation by trainee anesthesiologists, and the remaining 103 patients underwent intubation by senior anesthesiologists. The one-to-one propensity score matching generated 96 pairs of patients for the groups. The incidence of postoperative hoarseness 24 h after the surgery was significantly higher in patients whose tracheas were intubated by a trainee anesthesiologist than in those whose tracheas were intubated by a senior anesthesiologist (9.4% vs. 2.1%, respectively; P = 0.03).Conclusions: Double-lumen endotracheal tube intubation by trainee anesthesiologists increased the incidence of postoperative hoarseness 24 h after the surgery compared with intubation by senior anesthesiologists.

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&ndash, 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 &lt, 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.

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.

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. 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. 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.

Preclinical studies show that opioids promote angiogenesis, tumor progression, and metastasis, resulting in shorter survival.To explore whether opioids are associated with the overall survival (OS) of patients with incurable nonsmall cell lung cancer (NSCLC).Prospective cohort study of patients with NSCLC.We investigated patients newly diagnosed with advanced or post-operative recurrent NSCLC between April 2013 and December 2015 at a single institute.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.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 versus60 OME/day for 242 days.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.

In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of the postnatal brain migrate tangentially in chain-like cell aggregates toward the olfactory bulb (OB) through the rostral migratory stream (RMS). After reaching the OB, the chains are dissociated and the neuroblasts migrate individually and radially toward their final destination. The cellular and molecular mechanisms controlling cell–cell adhesion during this detachment remain unclear. Here we report that Fyn, a nonreceptor tyrosine kinase, regulates the detachment of neuroblasts from chains in the male and female mouse OB. By performing chemical screening andin vivoloss-of-function and gain-of-function experiments, we found that Fyn promotes somal disengagement from the chains and is involved in neuronal migration from the RMS into the granule cell layer of the OB. Fyn knockdown or Dab1 (disabled-1) deficiency caused p120-catenin to accumulate and adherens junction-like structures to be sustained at the contact sites between neuroblasts. Moreover, a Fyn and N-cadherin double-knockdown experiment indicated that Fyn regulates the N-cadherin-mediated cell adhesion between neuroblasts. These results suggest that the Fyn-mediated control of cell–cell adhesion is critical for the detachment of chain-forming neuroblasts in the postnatal OB.SIGNIFICANCE STATEMENTIn the postnatal brain, newly born neurons (neuroblasts) migrate in chain-like cell aggregates toward their destination, where they are dissociated into individual cells and mature. The cellular and molecular mechanisms controlling the detachment of neuroblasts from chains are not understood. Here we show that Fyn, a nonreceptor tyrosine kinase, promotes the somal detachment of neuroblasts from chains, and that this regulation is critical for the efficient migration of neuroblasts to their destination. We further show that Fyn and Dab1 (disabled-1) decrease the cell–cell adhesion between chain-forming neuroblasts, which involves adherens junction-like structures. Our results suggest that Fyn-mediated regulation of the cell–cell adhesion of neuroblasts is critical for their detachment from chains in the postnatal brain.

Somatic mutations in JAK2, MPL, and CALR are found in approximately 80% of patients with essential thrombocythemia (ET), whereas the remaining patients are negative for disease-defining mutations and are defined as triple-negative (TN). Studies have shown that some patients with TN-ET harbor non-canonical mutations in JAK2 and MPL; however, the failure to identify recurrent mutations in most patients has made the pathogenesis of TN-ET ambiguous (Milosevic Feenstra et al. Blood 2016, Cabagnols et al. Blood 2016). In this study, we screened 483 patients suspected as having ET in a single center, performed mutation analysis for JAK2 V617F, CALR exon 9, and MPL exon 10, and centrally reviewed bone marrow specimens. We identified 23 patients with TN-ET based on the WHO 2016 criteria. Sequencing analysis of these patients revealed non-canonical mutations in JAK2 and MPL in 4 cases. Whole exome-sequencing analysis of genomic DNA from peripheral blood and CD3-positive cells from 9 patients revealed that 2 patients harbored somatic mutations in other genes; 7 patients showed no detectable somatic mutation. A STAT5 reporter assay revealed that unlike JAK2 V617F and MPL W515L, all non-canonical mutants of JAK2 or MPL activated STAT5 similar to wild-type proteins, suggesting that these mutations did not drive the disease. Statistical analysis of clinical records revealed that patients with TN-ET were mostly young (median age of 36.0 years), female (18/23, 78.3%), and had neither a history of thrombosis nor progression to secondary myelofibrosis and leukemia, demonstrating the unique characteristics of TN-ET. The presence of clonal hematopoiesis, analyzed using genomic DNA purified from granulocytes of peripheral blood from female patients in a human androgen receptor assay, revealed that only 1 out of 15 patients was clonal. Hypothesizing that TN-ET was reactive thrombocytosis, the concentrations of cytokines promoting platelet production such as thrombopoietin (TPO) and interleukin-6 (IL-6) in the serum were analyzed. However, no significant differences in concentrations were observed among ET with driver mutations, TN-ET, and healthy individuals. We next examined the capacity of hematopoietic stem cells from patients with TN-ET to form megakaryocytic colonies. CD34-positive cells purified from cryopreserved bone marrow cells were cultured in the absence or presence of TPO. CD34-positive cells derived from patients with TN-ET exhibited an equivalent capacity to form megakaryocytic colonies compared to those from patients with ET harboring a driver mutation, even in the absence of TPO (Figure 1). Thus, in TN-ET, megakaryopoiesis may have been induced in a cell-autonomous manner. In 10 patients with TN-ET with available blood count data, no sign of thrombocytosis was observed before ET development, indicating that thrombocytosis was not hereditary but rather occurred via an alternate mechanism, such as aberrations in epigenomic regulation that induced cellular transformation (Ohnishi et al, Cell 2015). Taken together, TN-ET is a distinctive disease entity associated with polyclonal hematopoiesis and paradoxically caused by hematopoietic stem cells harboring a capacity for cell-autonomous megakaryopoiesis. Figure 1 Disclosures Komatsu: Takeda Pharmaceutical Co., Ltd, Novartis Pharma KK, Shire Japan KK: Speakers Bureau; PPMX: Consultancy, Research Funding; Meiji Seika Pharma Co., Ltd.: Patents & Royalties: PCT/JP2020/008434, Research Funding; AbbVie: Other: member of safety assessment committee in M13-834 clinical trial.; Otsuka Pharmaceutical Co., Ltd., Shire Japan KK, Novartis Pharma KK, PharmaEssentia Japan KK, Fuso Pharmaceutical Industries, Ltd., Fujifilm Wako Pure Chemical Corporation, Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Takeda Pharmaceutica: Research Funding; Otsuka Pharmaceutical Co., Ltd., PharmaEssentia Japan KK, AbbVie GK, Celgene KK, Novartis Pharma KK, Shire Japan KK, Japan Tobacco Inc: Consultancy.

T helper 17.1 cells (Th17.1) are highly pathogenic T cells in inflammatory diseases. This study aimed to identify Th cell biomarkers, including the analysis of Th17.1, that predict therapeutic response to abatacept in patients with rheumatoid arthritis. The circulating Th subsets among CD4+ T lymphocytes in 40 patients with rheumatoid arthritis before abatacept treatment were determined using multicolor flow cytometry. All patients received abatacept treatment for 24 weeks, and the change in disease activity score, including 28-joint count C-reactive protein, and the responsiveness of other indices to abatacept treatment were evaluated according the European League Against Rheumatism criteria [good responders, moderate responders, and non-responders]. The correlation between the abatacept responses and the Th subsets (baseline) was analyzed. Logistic regression analysis with inverse probability weighting method was conducted to calculate 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 non-responders; p = 0.0064). The decrease in 28-joint count C-reactive protein after 24 weeks of abatacept therapy also 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 level 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 the prediction of response to abatacept treatment. These novel findings may represent an important step in the pursuit of precision medicine.