A Case of Type 1 Diabetes Mellitus With Endogenous Insulin Secretory Depletion Confirmed in Two Weeks.

Type 1 diabetes mellitus (T1DM) is manifested as a decrease in endogenous insulin secretion. With this report, we present a case of T1DM where a rapid decline in insulin secretion was observed in a short span of time. A 56-year-old female patient presented with cold-like symptoms with subsequent dry mouth and malaise to the hospital. Three weeks later, she was diagnosed with diabetic ketoacidosis based on the presence of hyperglycemia, metabolic acidosis, and positive ketone bodies. Her serum connecting peptide (CPR) levels substantially decreased (1.31 to 0.19 ng/mL after two weeks) and she was eventually diagnosed with T1DM. We hypothesized that a subtype T1DM with a longer beta cell loss rate than conventional fulminant type 1 diabetes was involved. This subtype showed characteristics of immune checkpoint inhibitor-associated fulminant type 1 diabetes and is suggested to exist among those diagnosed with conventional acute-onset type 1 diabetes. Finally, we recommend that diabetic ketoacidosis of unknown etiology should be investigated for the concurrent presence of T1DM.

Multicomponent Intervention for Overactive Bladder in Women: A Randomized Clinical Trial.

Importance: Although the cognitive components of behavioral therapy for overactive bladder (OAB) are widely recognized, there is a lack of studies evaluating the effectiveness of multicomponent interventions that include cognitive components as a treatment for OAB. Objective: To examine the efficacy of a multicomponent intervention in improving health-related quality of life (HRQOL) for women with moderate to severe OAB. Design, Setting, and Participants: This multicenter, open-label, randomized clinical trial was conducted in Japan among women aged 20 to 80 years who had moderate to severe OAB. Participants were recruited from 4 institutions between January 16, 2020, and December 31, 2022, through self-referral via advertisement or referral from the participating institutions. Interventions: Participants were randomized 1:1 by minimization algorithm using an internet-based central cloud system to four 30-minute weekly sessions of a multicomponent intervention or waiting list. Both groups continued to receive baseline treatment throughout the study period. Main Outcomes and Measures: The primary outcome was the least-squares mean changes from baseline through week 13 in HRQOL total scores of the OAB questionnaire between 2 groups. Secondary outcomes included OAB symptom score and frequency volume chart. Results: A total of 79 women were randomized to either the intervention group (39 participants; mean [SD] age, 63.5 [14.6] years) or the waiting list control group (40 participants; mean [SD] age, 63.5 [12.9] years). One participant from each group dropped out from the allocated intervention, while 5 participants in the intervention group and 2 in the control group dropped out from the primary outcome assessment at week 13. Thirty-six participants (92.3%) in the intervention group and 35 (87.5%) in the control group had moderate OAB. The change in HRQOL total score from baseline to week 13 was 23.9 points (95% CI, 18.4-29.5 points) in the intervention group and 11.3 points (95% CI, 6.2-16.4 points) in the waiting list group, a significant difference of 12.6 points (95% CI, 6.6-18.6 points; P < .001). Similar superiority of the intervention was confirmed for frequency of micturition and urgency but not for OAB symptom score. Conclusions and Relevance: These findings demonstrate that a multicomponent intervention improves HRQOL for women with moderate to severe OAB and suggest that the cognitive component may be an effective treatment option for women with OAB. Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000038513.

Effects of thienopyridine class antiplatelets on bleeding outcomes following robot-assisted radical prostatectomy.

This study aimed to assess the effects of thienopyridine-class antiplatelet agents (including ticlopidine, clopidogrel, and prasugrel) on bleeding complications in patients who underwent robot-assisted radical prostatectomy. This cohort study used a database for robot-assisted radical prostatectomy at 23 tertiary centers nationwide between 2011 and 2022. Patients who received thienopyridines (thienopyridine group) were compared with those who received aspirin monotherapy (aspirin group). The primary outcome was the incidence of bleeding complications. High-grade complications were defined as Clavien-Dindo grade III or higher. The risks of these outcomes were evaluated using inverse probability of treatment weighted regression models. The study results demonstrated that thienopyridine therapy was associated with a higher risk of overall bleeding complications (OR: 3.62, 95%CI 1.54-8.49). The increased risks of the thienopyridine group were detected for low-grade bleeding complications (OR: 3.20, 95%CI 1.23-8.30) but not for high-grade bleeding complications (OR: 5.23, 95%CI 0.78-34.9). The increased risk of bleeding complications was not observed when thienopyridine was discontinued (OR: 2.52, 95%CI 0.83-7.70); however, it became apparent when it was continued perioperatively (OR: 4.35, 95%CI 1.14-16.61). In conclusion, thienopyridine increased the incidence of bleeding complications, particularly low-grade bleeding complications, following robot-assisted radical prostatectomy. These bleeding effects emerged when thienopyridine was continued perioperatively.

Tertiary Lymphoid Tissues Are Microenvironments with Intensive Interactions between Immune Cells and Proinflammatory Parenchymal Cells in Aged Kidneys.

SIGNIFICANCE STATEMENT: Ectopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms underlying TLT expansion and their effect on renal regeneration remain unclear. The authors report that single-nucleus RNA sequencing and validation experiments demonstrate that TLTs potentially amplify inflammation in aged injured kidneys. Lymphocytes within TLTs promote proinflammatory phenotypes of the surrounding proximal tubules and fibroblasts within the TLTs via proinflammatory cytokine production. These proinflammatory parenchymal cells then interact with immune cells by chemokine or cytokine production. Such cell-cell interactions potentially increase inflammation, expand TLTs, and exacerbate kidney injury. These findings help illuminate renal TLT pathology and suggest potential therapeutic targets. BACKGROUND: Ectopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms that expand TLTs and underlie exacerbation of kidney injury remain unclear. METHODS: We performed single-nucleus RNA sequencing (snRNA-seq) on aged mouse kidneys with TLTs after ischemia-reperfusion injury. The results were validated using immunostaining, in situ hybridization of murine and human kidneys, and in vitro experiments. RESULTS: Using snRNA-seq, we identified proinflammatory and profibrotic Vcam1+ injured proximal tubules (PTs) with NF κ B and IFN-inducible transcription factor activation. VCAM1 + PTs were preferentially localized around TLTs and drove inflammation and fibrosis via the production of multiple chemokines or cytokines. Lymphocytes within TLTs expressed Tnf and Ifng at high levels, which synergistically upregulated VCAM1 and chemokine expression in cultured PT cells. In addition, snRNA-seq also identified proinflammatory and profibrotic fibroblasts, which resided within and outside TLTs, respectively. Proinflammatory fibroblasts exhibited STAT1 activation and various chemokine or cytokine production, including CXCL9/CXCL10 and B cell-activating factor, contributing to lymphocyte recruitment and survival. IFN γ upregulated the expression of these molecules in cultured fibroblasts in a STAT1-dependent manner, indicating potential bidirectional interactions between IFN γ -producing CXCR3 + T cells and proinflammatory fibroblasts within TLTs. The cellular and molecular components described in this study were confirmed in human kidneys with TLTs. CONCLUSIONS: These findings suggest that TLTs potentially amplify inflammation by providing a microenvironment that allows intense interactions between renal parenchymal and immune cells. These interactions may serve as novel therapeutic targets in kidney diseases involving TLT formation.

Sexual function using the EORTC QLQ-TC26 in testicular cancer survivors: A multi-institutional, cross-sectional study.

OBJECTIVE: To evaluate sexual function after treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 (EORTC QLQ-TC26) questionnaire in Japanese testicular cancer (TC) survivors in a multi-institutional, cross-sectional study. METHODS: This study enrolled TC survivors who visited any of eight high-volume institutions in Japan from 2018 to 2019. After obtaining informed consent, participants completed the EORTC QLQ-TC26 questionnaires. We evaluated sexual function after treatment for TC using the EORTC QLQ-TC26 and analyzed the impact of treatment on sexual function in TC survivors. RESULTS: A total of 567 TC survivors responded to the EORTC QLQ-TC26. Median age at the time of response was 43 years (interquartile range [IQR] 35-51 years), and median follow-up period after treatment was 5.2 years (IQR 2.2-10.0 years). Sexual function, particularly ejaculatory function, was significantly lower after post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) than after Surveillance or Chemotherapy groups (p < 0.05). In the PC-RPLND group, nerve-sparing procedure preserved postoperative ejaculatory function after RPLND compared with the non-nerve-sparing and offered improved ejaculatory function with time. On multivariate analysis, RPLND was a significant predictor of post-treatment ejaculatory dysfunction, particularly without nerve-sparing (odds ratio 3.0, 95% CI 1.2-7.7, p < 0.05). In addition, TC survivors with nerve-sparing RPLND had higher sexual activity than those without. CONCLUSION: This survey of the EORTC QLQ-TC26 showed that sexual function and activity in TC survivors after RPLND was reduced in the absence of nerve-sparing techniques.

Tumor immune microenvironment and clinical outcomes in stage IV urothelial cancer: YODO study.

BACKGROUND: Bladder cancer is the 10th most common cancer globally, with a growing incidence in Japan. Evaluation of molecular, genetic, and cellular biomarkers that predict treatment response and prognosis in patients with metastatic urothelial carcinoma (mUC) may help optimize sequential treatment strategies with chemotherapy and immune checkpoint inhibitors (ICIs). METHODS: This multicenter, retrospective cohort study, evaluated programmed death-ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and cancer-immune phenotype as predictive prognostic biomarkers following first-/second-line treatment in Japanese adult patients with mUC. The primary endpoint was prevalence of PD-L1 expression. Secondary endpoints were TMB, overall survival (OS), and progression-free survival (PFS) from initiation of first-line treatment, and exploratory endpoints were cancer-immune phenotype, OS, PFS, and treatment response according to potential biomarker status. RESULTS: Of the 143 patients included (mean age 71.7 years), PD-L1 expression was high in 29.4% of patients. Non-synonymous TMB was high in 33.6% and low in 66.4%. Cancer-immune phenotype was immune-desert in 62.9%, immune-excluded in 30.8%, and inflamed in 6.3%. Median OS and PFS following first-line treatment were 18.2 and 7.4 months, respectively. Overall response to second-line treatment was slightly better with high versus low/negative PD-L1 expression. PD-L1 expression and TMB were non-significant predictors of OS or PFS, whereas immune-excluded phenotype was associated with better OS in comparison with immune-desert phenotype. CONCLUSION: PD-L1 expression and TMB were non-significant predictors of prognosis after first-line treatment in Japanese patients with mUC, but cancer-immune phenotype may be an important prognostic factor in chemotherapy-ICI sequential treatment strategies. Clinical trial registration number UMIN000037727.

Impact of Long-term Adjuvant Hormonal Therapy in High-dose IMRT for Unfavorable Locally Advanced Prostate Cancer.

BACKGROUND/AIM: The aim of this study was to evaluate the benefit of adding long-term adjuvant hormonal therapy to high-dose intensity-modulated radiation therapy for locally advanced prostate cancer patients with multiple unfavorable risks. PATIENTS AND METHODS: All cT3-4N0M0 prostate cancer patients with Gleason score 8-10 and prostate-specific antigen ≥30 ng/ml who received intensity-modulated radiation therapy to the prostate and seminal vesicle alone (78 Gy in 39 fractions) between September 2000 and June 2017 at our institution were analyzed retrospectively. All patients received short-term neoadjuvant hormonal therapy. Before May 2011, salvage hormonal therapy was initiated when prostate-specific antigen levels exceeded 4.0 ng/ml (early salvage hormonal therapy cohort). In June 2011, 2-year adjuvant hormonal therapy was added (adjuvant hormonal therapy cohort). Clinical outcomes were retrospectively compared using the log-rank test. RESULTS: In total, 88 patients (44 in both cohorts) were analyzed. Median follow-up periods were 10.9 and 6.1 years in early salvage hormonal therapy and adjuvant hormonal therapy cohorts, respectively. No significant difference in overall survival rates was observed (p=0.58). Disease controls were significantly better in the adjuvant hormonal therapy cohort: 95.5 versus 73.6% for castration-resistant prostate cancer-free rate (p=0.04), and 73.6 versus 34.1% for biochemical failure-free rate (p<0.001), both at 8 years, respectively. CONCLUSION: Among locally advanced prostate cancer patients with multiple unfavorable risks, adding long-term adjuvant hormonal therapy to high-dose intensity-modulated radiation therapy resulted in significantly better disease control than short-term hormonal therapy, even when salvaged early after biochemical failure.

Risk analyses of nocturia on incident poor sleep and vice versa: the Nagahama study.

Cross-sectional relationships between nocturia and sleep problems have been well evaluated but the risk association for each incidence is scarcely reported. This analysis included 8076 participants of the Nagahama study in Japan (median age 57, 31.0% male) and associations between nocturia and self-reported, sleep-related problems (poor sleep) were evaluated cross-sectionally. Causal effects on each new-onset case were analyzed longitudinally after 5 years. Three models were applied: univariable analysis, adjustment for basic variables (i.e., demographic and lifestyle variables) and full adjustment for basic and clinical variables. The overall prevalences of poor sleep and nocturia were 18.6% and 15.5%, while poor sleep was positively associated with nocturia (OR = 1.85, p < 0.001) and vice versa (OR = 1.90, p < 0.001). Among 6579 good sleep participants, 18.5% developed poor sleep. Baseline nocturia was positively associated with this incident poor sleep (OR = 1.49, p < 0.001, full adjustment). Among 6824 non-nocturia participants, the nocturia incidence was 11.3%. Baseline poor sleep was positively associated with this incident nocturia (OR = 1.26, p = 0.026); such associations were significant only in women (OR = 1.44, p = 0.004) and under-50-year-old groups (OR = 2.82, p < 0.001), after full adjustment. Nocturia and poor sleep associate with each other. Baseline nocturia can induce new-onset poor sleep while baseline poor sleep may induce new-onset nocturia only in women.

Efficacy and Tolerability of Second-line Pembrolizumab With Radiation Therapy in Advanced Urothelial Carcinoma.

BACKGROUND/AIM: Considering the limited data available on immune checkpoint inhibitors and radiation combination therapy in advanced urothelial carcinoma, this study evaluated the survival benefit and associated toxicity of adding radiation therapy to second-line pembrolizumab. PATIENTS AND METHODS: We retrospectively examined 24 consecutive patients with advanced bladder or upper urinary tract urothelial carcinoma and for whom second-line pembrolizumab was initiated between August 2018 and October 2021 in combination with radiation therapy (with curative intent in 12 patients, and palliative intent in 12 patients). Their survival outcomes and toxicities were compared with those of propensity-score-matched cohorts from a Japanese multicenter study with similar characteristics who received pembrolizumab monotherapy. RESULTS: The median follow-up periods after pembrolizumab initiation were 15 months for the curative cohort and 4 months for the palliative cohort. The median overall survival was 27.7 months for the curative cohort and 4.8 months for the palliative cohort. Compared with the matched pembrolizumab monotherapy cohort, overall survival was better among the curative cohort although not statistically significant (p=0.13), but similar between the palliative and matched pembrolizumab monotherapy cohorts (p=0.44). There was no difference in the incidence of grade ≥2 adverse events between the combination and monotherapy cohorts, irrespective of the intent of radiation therapy. CONCLUSION: The combination of radiation therapy and pembrolizumab can be performed with a clinically acceptable safety profile, and the addition of radiation therapy to immune checkpoint inhibitors may improve survival outcome after pembrolizumab treatment in cases where the intent of radiation therapy is curative.

Extracellular vesicles secreted from bone metastatic renal cell carcinoma promote angiogenesis and endothelial gap formation in bone marrow in a time-dependent manner in a preclinical mouse model.

Introduction: Bone is a major metastatic site of renal cell carcinoma (RCC). Recently, it is well recognized that bone metastatic tumor cells remodel bone marrow vasculature. However, the precise mechanism underlying cell-cell communication between bone metastatic RCC and the cells in bone marrow remains unknown. Extracellular vesicles (EVs) reportedly play crucial roles in intercellular communication between metastatic tumor cells and bone marrow. Therefore, we conducted the current study to clarify the histological alteration in vascular endothelium in bone marrow induced by EVs secreted from bone metastatic RCC cells as well as association between angiogenesis in bone marrow and bone metastasis formation. Materials and methods: We established a bone metastatic RCC cell line (786-O BM) by in vivo selection and observed phenotypic changes in tissues when EVs were intravenously injected into immunodeficient mice. Proteomic analysis was performed to identify the protein cargo of EVs that could contribute to histological changes in bone. Tissue exudative EVs (Te-EVs) from cancer tissues of patients with bone metastatic RCC (BM-EV) and those with locally advanced disease (LA-EV) were compared for in vitro function and protein cargo. Results: Treatment of mice with EVs from 786-O BM promoted angiogenesis in the bone marrow in a time-dependent manner and increased the gaps of capillary endothelium. 786-O BM EVs also promoted tube formation in vitro. Proteomic analysis of EVs identified aminopeptidase N (APN) as a candidate protein that enhances angiogenesis. APN knockdown in 786-O BM resulted in reduced angiogenesis in vitro and in vivo. When parental 786-O cells were intracardially injected 12 weeks after treatment with786-O BM EVs, more bone metastasis developed compared to those treated with EVs from parental 786-O cells. In patient samples, BM-EVs contained higher APN compared to LA-EV. In addition, BM-EVs promoted tube formation in vitro compared to LA-EVs. Conclusion: EVs from bone metastatic RCC promote angiogenesis and gap formation in capillary endothelium in bone marrow in a time-dependent manner.

Evaluation of sexual function after dutasteride treatment in patients with once-negative prostate biopsy and benign prostate hyperplasia.

INTRODUCTION: Patients with benign prostatic hyperplasia are usually treated with 5α-reduced inhibitors (5ARIs) such as finasteride and dutasteride. However, studies on the influence of 5ARIs on sexual function have been controversial. In this study, we evaluated the impact of dutasteride treatment for erectile function in patients with once-negative prostate biopsy and benign prostate hyperplasia. PATIENTS AND METHODS: 81 patients with benign prostate hyperplasia were enrolled in a one-armed prospective study. They were administrated 0.5 mg/day of dutasteride for 12 months. Patient characteristics and changes of International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF)-15 scores at baseline and 12 months after dutasteride administration were examined. RESULTS: The mean ± standard deviation (SD) age of the patients was 69.4 ± 4.9 years and the prostate volume was 56.6 ± 21.3 mL, respectively. The mean ± SD prostate volume and PSA levels were decreased 25.0 and 50.9%, respectively, after 12 months of dutasteride administration. IPSS total, voiding subscore, storage subscore, and quality of life score significantly improved after 12 months of dutasteride administration. No statistically significant change in IIEF-total score from 16.3 ± 13.5 to 18.8 ± 16.0 (p = 0.14), IIEF-EF score from 5.1 ± 6.9 to 6.4 ± 8.3 (p = 0.13) were observed. There was no decrease in erectile function severity. CONCLUSION: Twelve months administration of dutasteride for patients with BPH improved urinary function and did not increase the risk of sexual dysfunction.

Association of SNPs in the PAI1 Gene with Disease Recurrence and Clinical Outcome in Bladder Cancer.

PURPOSE: Bladder cancer (BCa) is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. In previous studies, we and others have described the functional influence of plasminogen activator inhibitor-1 (PAI1) in bladder cancer development. While polymorphisms in PAI1 have been associated with increased risk and worsened prognosis in some cancers, the mutational status of PAI1 in human bladder tumors has not been well defined. METHODS: In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects. RESULTS: Sequencing analyses identified two clinically relevant 3' untranslated region (UTR) single nucleotide polymorphisms (SNPs) in PAI1 (rs7242; rs1050813). Somatic SNP rs7242 was present in human BCa cohorts (overall incidence of 72%; 62% in Caucasians and 72% in Asians). In contrast, the overall incidence of germline SNP rs1050813 was 18% (39% in Caucasians and 6% in Asians). Furthermore, Caucasian patients with at least one of the described SNPs had worse recurrence-free survival and overall survival (p = 0.03 and p = 0.03, respectively). In vitro functional studies demonstrated that SNP rs7242 increased the anti-apoptotic effect of PAI1, and SNP rs1050813 was related to a loss of contact inhibition associated with cellular proliferation when compared to wild type. CONCLUSION: Further investigation of the prevalence and potential downstream influence of these SNPs in bladder cancer is warranted.

Identification of the α2 chain of interleukin-13 receptor as a potential biomarker for predicting castration resistance of prostate cancer using patient-derived xenograft models.

BACKGROUND: Several treatment strategies use upfront chemotherapy or androgen receptor axis-targeting therapies for metastatic prostate cancer. However, there are no useful biomarkers for selecting appropriate patients who urgently require these treatments. METHODS: Novel patient-derived xenograft (PDX) castration-sensitive and -resistant models were established and gene expression patterns were comprehensively compared. The function of a gene highly expressed in the castration-resistant models was evaluated by its overexpression in LNCaP prostate cancer cells. Protein expression in the tumors and serum of patients was examined by immunohistochemistry and ELISA, and correlations with castration resistance were analyzed. RESULTS: Expression of the α2 chain of interleukin-13 receptor (IL13Rα2) was higher in castration-resistant PDX tumors. LNCaP cells overexpressing IL13Rα2 acquired castration resistance in vitro and in vivo. In tissue samples, IL13Rα2 expression levels were significantly associated with castration-resistant progression (p < 0.05). In serum samples, IL13Rα2 levels could be measured in 5 of 28 (18%) castration-resistant prostate cancer patients. CONCLUSION: IL13Rα2 was highly expressed in castration-resistant prostate cancer PDX models and was associated with the castration resistance of prostate cancer cells. It might be a potential tissue and serum biomarker for predicting castration resistance in prostate cancer patients.

Up-regulation of secretory leukocyte protease inhibitor in human samples might have a potential role of predicting prostate cancer recurrence and progression after surgery and hormonal therapy.

Using new castration-resistant prostate cancer (CRPC) cell lines developed from LNCaP cells as a model for CRPC, we searched for novel biomarkers by analyzing the proteins secreted in culture supernatants. The results showed that the levels of secretory leukocyte protease inhibitor (SLPI) in these cell lines were 4.7-6.7 times higher than those secreted in parental LNCaP. Patients with localized prostate cancer (PC) and who expressed SLPI had a significantly lower prostate-specific antigen (PSA) progression-free survival rate than those who did not. Multivariate analysis revealed that SLPI expression was an independent risk factor for PSA recurrence. By contrast, when immunostaining of SLPI was performed on consecutive prostate tissue samples obtained from 11 patients, both in hormone naive (HN) and castration resistant (CR) conditions, only one patient expressed SLPI in the HNPC state; however, four of the 11 patients expressed SLPI in the CRPC state. In addition, two of these four patients were resistant to enzalutamide, and there was a discrepancy between their serum PSA levels and radiographic progression of the disease. These results suggest that SLPI can be a predictor of prognosis in patients with localized PC and disease progression in CRPC patients.

Ten-year outcomes of whole-pelvic intensity-modulated radiation therapy for prostate cancer with regional lymph node metastasis.

BACKGROUND: Management of pelvic node-positive prostate cancer has been challenging and controversial. We conducted a study to evaluate the outcomes of whole-pelvic (WP) simultaneous integrated boost (SIB) intensity-modulated radiation therapy (IMRT) combined with androgen deprivation therapy (ADT). METHODS: A total of 67 consecutive patients with cT1c-4N1M0 prostate cancer were definitively treated by WP SIB-IMRT. Neoadjuvant ADT (median: 8.3 months) was administered in all cases. WP SIB-IMRT was designed to simultaneously deliver 78, 66.3, and 58.5 Gy in 39 fractions to the prostate plus seminal vesicles, metastatic lymph nodes (LNs), and the pelvic LN region, respectively. Adjuvant ADT (median: 24.7 months) was administered in 66 patients. RESULTS: The median follow-up period was 81.6 months (range: 30.5-160.7). Biochemical relapse-free, overall, and prostate cancer-specific survival rates at 10 years were 59.8%, 79.6%, and 86.3%, respectively. Loco-regional recurrence was not observed. Being in International Society of Urological Pathology grade group 5 and having a posttreatment detectable nadir prostate-specific antigen (PSA) level (≥0.010 ng/ml) were significantly associated with worse prostate cancer-specific survival and progression of castration resistance. The 10-year cumulative incidence rates of grade 2 and 3 late toxicities were, respectively, 1.5% and 0% for genitourinary, 0% and 1.5% for gastrointestinal events. No grade 4 acute or late toxicities were observed. CONCLUSIONS: WP SIB-IMRT can be safely administered to patients with pelvic node-positive prostate cancer. Since grade group 5 and detectable nadir PSA levels are risks for castration resistance, we may need to increase the intensity of treatment for such cases.

qShot MALDI analysis: A rapid, simple, convenient, and reliable quantitative phospholipidomics approach using MALDI-TOF/MS.

Matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS) has potential applications in the qualitative analysis of phospholipids (PLs). However, its capability for quantitative analysis is limited by the unavailability and/or high cost of isotope-labeled internal standards (interSTDs, e.g., 1-oleoyl (d7)-2-hydroxy-sn-glycero-3-phosphocholine, 1-pentadecanoyl-2-oleoyl (d7)-sn-glycero-3-phosphocholine). This study investigated and validated whether only two PL interSTDs could be used to normalize the entire PL species in a complex bio-lipid background (i.e., urinary lipid extracts). The normalized intensities of PL ionization standards (ionSTDs) were found to have better linear regressions (R2 > 0.984 for all PL subcategories) than those of traditional methods, such as total ion current and matrix-peak normalization methods. Furthermore, the intra-day precision of all the analyte concentrations after normalizing using our ionSTD method was superior to those of traditional methods. The inter-day precision of all the negatively charged analytes also differed statistically between our ionSTD and the two traditional methods. Meanwhile, a comparison of the three normalization methods revealed that the precision of all the positive analytes using the ionSTD method was comparable. Consequently, a cost-effective, fast, simple, convenient, and reliable quantitative method, defined as "qShot MALDI analysis," was developed to analyze PLs that could potentially be applied in clinical biomarker screening, especially in a negative mode.

The Effect of a Pre-consultation Tablet-Based Questionnaire on Changes in Consultation Time for First-Visit Patients With Diabetes: A Single-Case Design Preliminary Study.

Background and objective It has been reported that physicians spend about 50% of their time in the outpatient department doing non-face-to-face patient work, such as charting and desk activities. Work outside of patient consultations is often considered a burden. In this study, we aimed to examine whether the use of pre-consultation tablet-based questionnaires for first-visit diabetic patients had any impact on the time spent for consultation. Methods The sole participant was a diabetologist with more than 20 years of experience. The time spent in the clinic was compared via a single-case experimental design (ABAB) using paper- and tablet-based questionnaires for a total of 20 first-visit diabetic patients. Results The median pre-clinical time without patients was significantly shorter in the tablet group than in the paper group (two minutes and 45 seconds vs. five minutes and 39 seconds; p=0.003). The median clinical time with patients in the tablet group was significantly longer than that in the paper group (19 minutes and 37 seconds vs. 11 minutes and 25 seconds; p=0.026). The total clinical time was not significantly different between the two groups (p=0.25). Conclusions Our results suggest that tablet-based pre-consultation questionnaires may have an impact on the allocation of time for medical examinations and improve the quality of diabetes care.

Detection of Euglycemic Diabetic Ketoacidosis During Thoracic Surgery 75 Hours After Empagliflozin Discontinuation.

Euglycemic diabetic ketoacidosis (eDKA) has been increasingly reported as an adverse event of sodium-glucose cotransporter 2 inhibitors (SGLT2i), and the accompanying information on the drug recommends discontinuation three days prior to scheduled surgery. We present a case of a 50-year-old woman who developed eDKA during surgery for a metastatic lung tumor 75 hours after discontinuing SGLT2i. In this case, the onset of eDKA was detected using intraoperative blood gas analysis and urinary ketone measurements. Hence, perioperative eDKA can occur even after three or more days of SGLT2i withdrawal.

Drowning case complicated with a cardiopulmonary arrest and severe ARDS saved with a good neurological outcome by ECMO: A case report.

Cardiopulmonary arrest (CPA) due to drowning has an extremely high mortality rate, and very few cases have good neurological outcomes. Severe respiratory failure can occur even after resuscitation. A 66 year old woman with a history of refractory epilepsy had a CPA due to drowning. Approximately 20 min after drowning, she was resuscitated and transported to the hospital, and extracorporeal membrane oxygenation (ECMO) was introduced on day two due to continued severe respiratory failure caused by acute respiratory distress syndrome (ARDS). After the introduction of ECMO, her respiratory status gradually improved and ECMO was discontinued on day 12. Approximately 6 months after drowning, she visited our hospital for a follow-up with a cerebral performance category of 1. Since cases of CPA due to drowning with a short drowning time or hypothermia are expected to have good neurological outcomes, the introduction of ECMO should be considered as a treatment for ARDS after resuscitation.

Bmal1 Regulates Prostate Growth via Cell-Cycle Modulation.

The circadian clock system exists in most organs and regulates diverse physiological processes, including growth. Here, we used a prostate-specific Bmal1-knockout mouse model (pBmal1 KO: PbsnCre+; Bmal1fx/fx) and immortalized human prostate cells (RWPE-1 and WPMY-1) to elucidate the role of the peripheral prostate clock on prostate growth. Bmal1 KO resulted in significantly decreased ventral and dorsolateral lobes with less Ki-67-positive epithelial cells than the controls. Next, the cap analysis of gene expression revealed that genes associated with cell cycles were differentially expressed in the pBmal1 KO prostate. Cdkn1a (coding p21) was diurnally expressed in the control mouse prostate, a rhythm which was disturbed in pBmal1 KO. Meanwhile, the knockdown of BMAL1 in epithelial RWPE-1 and stromal WPMY-1 cell lines decreased proliferation. Furthermore, RWPE-1 BMAL1 knockdown increased G0/G1-phase cell numbers but reduced S-phase numbers. These findings indicate that core clock gene Bmal1 is involved in prostate growth via the modulation of the cell cycle and provide a rationale for further research to link the pathogenesis of benign prostatic hyperplasia or cancer with the circadian clock.