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Purpose: The prognosis of patients with pT3 upper tract urothelial carcinoma (UTUC) varies. The current study aimed to further classify patients with pT3 UTUC into different survival outcome groups based on tumor location and site of invasion. Methods: This retrospective study included 323 patients with pT3 UTUC who underwent nephroureterectomy at 11 hospitals in Japan. Histological and clinical data were obtained via a chart review. Univariate and multivariate Cox proportional hazards analyses showed the effect of different variables on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: The median age of the patients was 72 years. Patients with pT3 UTUCs were divided into two groups: those with renal parenchymal invasion only (pT3a, n = 95) and those with peripelvic or periureteral fat invasion (pT3b, n = 228). pT3b UTUC was significantly associated with hydronephrosis, low preoperative estimated glomerular filtration rate (eGFR), histological nodal metastasis, nuclear grade 3, lymphovascular invasion (LVI), carcinoma in situ, and positive surgical margin. Based on the univariate analyses, patients with pT3b UTUC had a significantly lower 5-year RFS (42.4% vs. 70.1%, p < 0.0001), 5-year CSS (54.3% vs. 80.0%, p = 0.0002), and 5-year OS (47.8% vs. 76.8%, p < 0.0001) than those with pT3a UTUC. According to the multivariate analyses, nodal metastasis, LVI, adjuvant chemotherapy, preoperative eGFR, nuclear grade (RFS only), surgical margin (RFS only), and Charlson comorbidity index (OS only), but not pT3b stage, were associated with survival. Conclusion: Compared with pT3a UTUC, pT3b UTUC was significantly associated with worse histological features, consequently resulting in unsatisfactory survival outcomes. [ABSTRACT FROM AUTHOR]

We aimed to assess the association between heated tobacco product (HTP) use and high-density lipoprotein cholesterol (HDL-C) concentration. Our study included 12,268 workers from five companies (Study I) and 36,503 workers from another large company (Study II). Participants were categorized into five groups: never smokers, past smokers, exclusive HTP users, dual users of cigarettes and HTPs, and exclusive cigarette smokers. We analyzed the data of Studies I and II separately and then pooled these estimates using a fixed-effect model. Of the 48,771 participants, 9.3% were exclusive HTP users, and 6.0% were dual users. Exclusive HTP users had modestly but significantly lower concentrations of HDL-C than never smokers, with the pooled mean difference being − 1.1 (95% CI − 1.5 to − 0.6) mg/dL. Dual users showed a further reduction (mean difference − 3.7 (− 4.2 to − 3.2) mg/dL), which was comparable to that of exclusive cigarette smokers versus never smokers (mean difference − 4.3 (− 4.7 to − 3.9) mg/dL). The pooled odds ratios (95% CIs) of having low HDL-C (< 40 mg/dL for men and 50 mg/dL for women) were 1, 0.99 (0.90–1.11), 1.25 (1.09–1.43), 2.02 (1.76–2.32), and 2.09 (1.88–2.32) for never smokers, past smokers, exclusive HTP users, dual users, and exclusive cigarette smokers, respectively. In conclusion, exclusive HTP users had lower HDL-C concentrations than never smokers, although higher than exclusive cigarette smokers. Moreover, dual users had HDL-C concentrations similar to those in exclusive cigarette smokers. [ABSTRACT FROM AUTHOR]

Lymph node dissection is an indispensable component of radical cystectomy for bladder cancer. Information obtained with lymph node dissection is highly predictive of patient survival, affecting decision‐making for adjuvant therapy (diagnostic role). Also, lymph node dissection provides survival benefits in certain patients by removing metastasized nodes (therapeutic role). However, an optimal extent of lymph node dissection has not been established yet. Data from surgical mapping studies showed that approximately 10% of the primary lymphatic landing sites were common iliac nodes, suggesting that lymph node dissection below the common iliac bifurcation is suboptimal. Several retrospective studies have shown a possible survival advantage with more extended lymph node dissection. However, the results of the first prospective randomized controlled trial failed to prove the survival advantage of extended lymph node dissection up to the level of the inferior mesenteric artery, compared with lymph node dissection below the bifurcation of the common iliac artery. Currently, lymph node dissection templates recommended by major guidelines are not consistent with each other. Furthermore, the evidence is limited in the settings of neoadjuvant chemotherapy, robot‐assisted surgery and high‐risk non‐muscle‐invasive disease. Physicians need to decide the extent of lymph node dissection for each patient, taking into account the potential survival benefit and possible harms of extended lymph node dissection. Another randomized controlled trial is currently underway and will provide further evidence shortly. [ABSTRACT FROM AUTHOR]

Aims/Introduction: We examined a prospective association between serum creatinine levels and diabetes. Materials and Methods: The present study included 31,343 male workers without diabetes, and aged between 20 and 64 years at baseline. We calculated the cumulative average of their serum creatinine over the study period. We defined diabetes as either glycated hemoglobin levels ≥6.5%, random glucose levels ≥200 mg/dL, fasting glucose levels ≥126 mg/dL or receiving antidiabetic treatment. Cox proportional hazards regression analysis was carried out to estimate the hazard ratio (HR) and 95% confidence interval (CI). Results: With a median observation of 7.7 years, 2,509 participants developed diabetes. After adjusting for age, smoking, body mass index, hypertension and dyslipidemia, lower cumulative average serum creatinine levels were related to a greater diabetes risk: HRs were 1.56 (95% CI 1.35–1.82), 1.22 (1.09–1.35) and 1.06 (0.96–1.17) for the participants with serum creatinine <0.70, 0.70–0.79 and 0.80–0.89 mg/dL, respectively, compared with those with 0.90–1.20 mg/dL (P for trend <0.001). The serum creatinine‐diabetes association was more pronounced among older adults (serum creatinine <0.70 vs 0.90–1.20 mg/dL, HR 1.66, 95% CI 1.37–2.00) than younger adults (HR 1.32, 95% CI 1.02–1.71; P for interaction by age group = 0.001). Conclusions: Low serum creatinine is associated with an increased risk of diabetes. Screening serum creatinine levels can be used to identify those who are at high risk of diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Aims/Introduction: We previously developed a 3‐year diabetes risk score in the working population. The objective of the present study was to develop and validate flexible risk models that can predict the risk of diabetes for any arbitrary time‐point during 7 years. Materials and Methods: The participants were 46,198 Japanese employees aged 30–59 years, without diabetes at baseline and with a maximum follow‐up period of 8 years. Incident diabetes was defined according to the American Diabetes Association criteria. With routine health checkup data (age, sex, abdominal obesity, body mass index, smoking status, hypertension status, dyslipidemia, glycated hemoglobin and fasting plasma glucose), we developed non‐invasive and invasive risk models based on the Cox proportional hazards regression model among a random two‐thirds of the participants, and used another one‐third for validation. Results: The range of the area under the receiver operating characteristic curve increased from 0.73 (95% confidence interval 0.72–0.74) for the non‐invasive prediction model to 0.89 (95% confidence interval 0.89–0.90) for the invasive prediction model containing dyslipidemia, glycated hemoglobin and fasting plasma glucose. The invasive models showed improved integrated discrimination and reclassification performance, as compared with the non‐invasive model. Calibration appeared good between the predicted and observed risks. These models performed well in the validation cohort. Conclusions: The present non‐invasive and invasive models for the prediction of diabetes risk up to 7 years showed fair and excellent performance, respectively. The invasive models can be used to identify high‐risk individuals, who would benefit greatly from lifestyle modification for the prevention or delay of diabetes. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the impact of preoperative chronic kidney disease (CKD) on oncological outcomes after radical cystectomy (RC) for bladder cancer.Methods: We reviewed the medical records of patients with urothelial bladder carcinoma who underwent RC with curative intent at seven hospitals between 1990 and 2013. After excluding patients with a history of upper urinary tract urothelial cancer or neoadjuvant chemotherapy, we analyzed 594 cases for the study. Preoperative estimated glomerular filtration rate (eGFR) was calculated using the three-variable Japanese equation for GFR estimation from serum creatinine level and age. Patients were divided into four groups of different CKD stages based on eGFR values (mL/min/1.73 m2), i.e., ≥ 60 (CKD stages G1–2), 45–60 (G3a), 30–45 (G3b), and < 30 (G4–5). Survival was estimated using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards regression analyses addressed survivals after RC.Results: Median age of patients was 67 years. Patients were classified into CKD stages: G1–2 (n = 388; 65.3%), G3a (n = 122; 20.5%), G3b (n = 51; 8.6%), and G4–5 (n = 33; 5.6%). During a median follow-up of 4.0 years, 200 and 164 patients showed cancer progression and died of bladder cancer, with the 5-year progression-free survival (PFS) and cancer-specific survival (CSS) of 64.9 and 70.2%, respectively. On multivariate analyses, CKD stages of G3b or greater, advanced pT stage, lymph node metastasis, and positive lymphovascular invasion were independent poor prognostic factors for PFS and CSS.Conclusions: We demonstrated that the advanced preoperative CKD stage was significantly associated with poor oncological outcomes of the bladder cancer after RC. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of adjuvant systemic chemotherapy for locally advanced (pT3-4pN0/xM0) upper tract urothelial carcinoma (UTUC). Materials and methods: We retrospectively reviewed the medical records of 109 patients with pT3-4pN0/xM0 UTUC who had undergone radical nephroureterectomy between 1996 and 2013 at our four institutions. The patients were divided into two groups: those who received adjuvant chemotherapy (AC group) and those who did not (surgery-alone: SA group). All chemotherapy regimens were cisplatin-based. Cox proportional hazards regression models addressed the associations between clinicopathological factors and recurrence-free survival (RFS) and cancer-specific survival (CSS). Results: Forty-three (39.5%) out of the 109 patients underwent one to four cycles of adjuvant chemotherapy after nephroureterectomy. Median follow-up was 46.5 months. There were no significant differences in the background characteristics of the two groups, except for age. Recurrence developed in 11 (25.6%) and 29 (43.9%) patients in the AC and SA groups, respectively. Ultimately, six (14.0%) and 18 (27.3%) patients in the AC and SA groups, respectively, died of disease progression. On univariate analysis, hydronephrosis, nuclear grade, lymphovascular invasion, and adjuvant chemotherapy were significantly associated with both RFS and CSS. Charlson comorbidity index was associated only with CSS. On multivariate analysis, adjuvant chemotherapy was the only independent factor associated with improved RFS ( p = 0.0178, HR = 0.41). Moreover, adjuvant chemotherapy ( p = 0.0375, HR = 0.33), lower nuclear grade ( p = 0.0070), and the absence of hydronephrosis ( p = 0.0493) were independently associated with better CSS. Conclusion: Locally advanced (pT3-4pN0/xM0) UTUC patients who underwent cisplatin-based adjuvant chemotherapy demonstrated better RFS and CSS than those without adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to elucidate the details of bone metastasis (BM) and the resulting skeletal-related events (SREs), and survival and prognostic factors, in urothelial cancer (UC) patients with BM. Methods: A total of 48 UC patients with BM who were treated at our institution between 1994 and 2013 were enrolled. Details of BM and SREs were investigated. The Kaplan-Meier method was used to estimate survival duration. Relationships between several clinical features and survival were analyzed using the log-rank test and the Cox hazard model. Results: Of the 48 patients, 39 (81.3%) were male, with a median age at diagnosis of BM of 68 years [interquartile range (IQR), 61-75 years]. Frequent metastatic sites included the pelvis (31 patients, 64.6%) and spine (28, 58.3%). SREs occurred in 31 patients (64.6%) at a median duration of 0.9 months (IQR, 0.3-5.4 months) after diagnosis of BM, including radiation therapy ( n = 23; 74.2%), spinal cord compression ( n = 4; 12.9%), pathological fracture ( n = 3; 9.7%) and hypercalcemia ( n = 1; 3.2%). Median overall survival periods after diagnosis of BM and SREs were 6.2 and 5.6 months, respectively. On multivariate analysis, factors significantly associated with survival after BM were performance status [hazard ratio (HR) for ≥2 vs. 0-1, 4.94; P = 0.0003], liver metastasis (HR, 4.08; P = 0.0018), chemotherapy after BM (HR, 0.31; P = 0.0018), and use of bone-modifying agents (HR, 0.36; P = 0.0147). Conclusions: We revealed clinicopathological factors that are predictive of prognosis of UC patients with BM. Although the prognosis is poor, chemotherapy and bone-modifying agents may confer survival benefits. [ABSTRACT FROM AUTHOR]

Background: We evaluated short- and long-term renal function in patients after radical cystectomy with urinary diversion and identified risk factors for the deterioration of renal function. Methods: This retrospective study comprised 91 patients who underwent radical cystectomy and urinary diversion for bladder cancer and survived ≥3 years after surgery. The estimated glomerular filtration rate (eGFR) was calculated, and longitudinal changes of eGFR were assessed. Deterioration in renal function in early and late postoperative years was defined as a ≥25 % decrease in the eGFR from preoperative to postoperative year one, and a reduction in the eGFR of >1 mL/min/1.73 m annually in subsequent years, respectively. Univariate and multivariate logistic regression analyses were used to evaluate its association with clinicopathologic features. Results: The median follow-up period after surgery was 7 years (range 3-26). The mean eGFR decreased from preoperative 65.1 to 58.9 mL/min/1.73 m 1 year after the surgery, followed by a continuous decline of ~1.0 mL/min/1.73 m per year thereafter. Multivariate analyses identified ureteroenteric stricture as the sole risk factor associated with early renal function deterioration [odds ratio (OR) 4.22, p = 0.037]. Diabetes mellitus (OR 8.24, p = 0.015) and episodes of pyelonephritis (OR 4.89, p = 0.038) were independently associated with the gradual decline in the late postoperative period. Conclusion: In cystectomy patients with urinary diversion, the rapid deterioration of renal function observed during the first year after surgery and the gradual but continuous decline in function thereafter were found to be associated with different risk factors. [ABSTRACT FROM AUTHOR]

Background: Several prognostic models predicting survival of patients with metastatic urothelial carcinoma (UC) have been developed; however, of them, the first model by Bajorin in 1999 is still the most representative and widely used, and validations of newer models are lacking. This study aimed to validate three major prognostic models for metastatic UC constructed based on clinical trials. Methods: We reviewed 200 patients with metastatic UC who received first-line chemotherapy at our five affiliate institutions between 2003 and 2011. Using this multi-institutional cohort, we validated the following models: the 'Bajorin model,' a model consisting of visceral metastasis and performance status; the 'Apolo model,' a nomogram including visceral metastasis, performance status, albumin and hemoglobin; and the 'Galsky model,' a nomogram including leukocyte count, number of sites of visceral metastases, site of primary tumor, performance status and lymph node metastasis. Harrell's c-index was calculated for each model. Cox proportional hazards regression model was used for multivariate analysis. Results: Among 200 patients, 171 (85.5 %) died during the follow-up, with a median survival of 12.0 months. Multivariate analysis demonstrated ECOG performance status, visceral metastasis and leukocyte count to be independent predictors of overall survival. C-index results (95 % confidence interval) were Bajorin: 0.86 (0.74-0.95); Apolo: 0.89 (0.78-0.98); and Galsky: 0.82 (0.69-0.93). Conclusions: All models were demonstrated to have high external validities in real-world patients, and of them, the 'Apolo model' achieved the highest c-index in the present population. Further studies with larger populations are needed for establishment of the next standard model. [ABSTRACT FROM AUTHOR]

Objective: Risk models and scores have been developed to predict incidence of type 2 diabetes in Western populations, but their performance may differ when applied to non-Western populations. We developed and validated a risk score for predicting 3-year incidence of type 2 diabetes in a Japanese population. Methods: Participants were 37,416 men and women, aged 30 or older, who received periodic health checkup in 2008–2009 in eight companies. Diabetes was defined as fasting plasma glucose (FPG) ≥126 mg/dl, random plasma glucose ≥200 mg/dl, glycated hemoglobin (HbA1c) ≥6.5%, or receiving medical treatment for diabetes. Risk scores on non-invasive and invasive models including FPG and HbA1c were developed using logistic regression in a derivation cohort and validated in the remaining cohort. Results: The area under the curve (AUC) for the non-invasive model including age, sex, body mass index, waist circumference, hypertension, and smoking status was 0.717 (95% CI, 0.703–0.731). In the invasive model in which both FPG and HbA1c were added to the non-invasive model, AUC was increased to 0.893 (95% CI, 0.883–0.902). When the risk scores were applied to the validation cohort, AUCs (95% CI) for the non-invasive and invasive model were 0.734 (0.715–0.753) and 0.882 (0.868–0.895), respectively. Participants with a non-invasive score of ≥15 and invasive score of ≥19 were projected to have >20% and >50% risk, respectively, of developing type 2 diabetes within 3 years. Conclusions: The simple risk score of the non-invasive model might be useful for predicting incident type 2 diabetes, and its predictive performance may be markedly improved by incorporating FPG and HbA1c. [ABSTRACT FROM AUTHOR]

Background Evidence from observational studies is limited regarding longitudinal patterns of lifestyles and diabetes onset. In occupational settings, physical activity at work is an important factor to consider when implementing health promotion. Methods This is a cohort study among 25,646 workers without diabetes in Japan. We calculated lifestyle scores using 5 low-risk lifestyle factors: no-smoking, avoiding heavy alcohol use, engaging exercise, avoiding sleep deprivation, and keeping healthy weight, yielding the total score of 0 to 5 each year. We identified lifestyle patterns over 3 years by group-based trajectory modelling. Diabetes was defined by blood glucose, HbA1c, or self-report. Hazard ratios (95% confidence intervals) for incident diabetes were calculated using Cox regression. Results We detected five lifestyle patterns from a whole sample. During a mean follow-up of 6.6 years, 2,223 developed diabetes. Overall, healthier lifestyles were associated with a lower diabetes risk. Among sedentary workers, the multivariable-adjusted hazard ratios (95% confidence intervals) were 1.00 (reference) for persistently unhealthy pattern, 0.70 (0.60, 0.80) for persistently moderately healthy pattern, 0.45 (0.38, 0.53) for persistently mostly healthy pattern, 0.38 (0.28, 0.52) for improved to completely healthy pattern, and 0.24 (0.17, 0.32) for persistently completely healthy pattern. Similar results were obtained among not-sedentary workers. Conclusions Healthier lifestyles were associated with a lower risk of developing diabetes among participants who were sedentary at work and those who were not sedentary at work, respectively. Key messages Adherence to healthy lifestyles is important to prevent diabetes for working adults regardless of occupational physical activity level. [ABSTRACT FROM AUTHOR]

A recent study analyzed the use of pembrolizumab, an immune checkpoint inhibitor, beyond disease progression in patients with advanced solid tumors. The study found that pembrolizumab had meaningful efficacy in a subset of patients treated beyond progressive disease. In the case of urothelial carcinoma (UC), pembrolizumab has significantly improved survival rates and changed the treatment strategy. However, the efficacy of continuing immune checkpoint inhibitors beyond disease progression in advanced UC remains controversial, and further research is needed to optimize later-line treatments. Other treatments, such as enfortumab vedotin, erdafitinib, and sacituzumab govitecan, are also being explored for advanced UC. [Extracted from the article]

Abstract: Recent US clinical trial demonstrated that CT screening prevents lung cancer death among high risk individuals. However, it remains unclear whether wide implementation of low-dose CT screening for lung cancer can decrease mortality in the community. Among residents in Hitachi City (Japan), where nearly 40% of inhabitants aged 50–69 years were estimated to have participated in the screening at least once from 1998 through 2009, the trend of lung cancer mortality was described in relation to the timing of implementation of the CT screening. Cancer mortality data were obtained from regional cancer registry and standardized mortality ratio (SMR) of lung cancer was calculated for each 5-year period during 1995–2009. In both men and women aged 60 years or older, age-specific lung cancer mortality rates were generally lower during 2005–2009 as compared with those during 1995–2004. For combined men and women aged 50–79 years, SMR was nearly unity prior to or during introductory phase of CT screening and during early period of implementation; however, it was significantly decreased during 2005–2009, well after the implementation of CT screening, with SMR (95% confidence interval) being 0.76 (0.67–0.86). Results suggest that wide implementation of low-dose chest CT screening may decrease lung cancer mortality in the community 4–8 years after introduction of the screening. [Copyright &y& Elsevier]

Objectives: Although the treatment strategy for advanced urothelial carcinoma (aUC) has drastically changed since pembrolizumab was introduced in 2017, studies revealing current survival rates in aUC are lacking. This study aimed to assess (1) the improvement in survival among real‐world patients with aUC after the introduction of pembrolizumab and (2) the direct survival‐prolonging effect of pembrolizumab. Methods: This multicenter retrospective study included 531 patients with aUC undergoing salvage chemotherapy, including 200 patients treated in the pre‐pembrolizumab era (2003–2011; earlier era) and 331 patients treated in a recent 5‐year period (2016–2020; recent era). Using propensity score matching (PSM), cancer‐specific survival (CSS) and overall survival (OS) were compared between the earlier and recent eras, in addition to between the recent era, both with and without pembrolizumab use, and the earlier era. Results: After PSM, the recent era cohort had significantly longer CSS (21 months) and OS (19 months) than the earlier era cohort (CSS and OS: 12 months). In secondary analyses using PSM, patients treated with pembrolizumab had significantly longer CSS (25 months) and OS (24 months) than those in the earlier era cohort (CSS and OS: 11 months), whereas patients who did not receive pembrolizumab in the recent era had similar outcomes (CSS and OS: 14 months) as the earlier era cohort (CSS and OS: 12 months). Conclusions: Patients with aUC treated in the recent era exhibited significantly longer survival than those treated before the introduction of pembrolizumab. The improved survival was primarily attributable to the use of pembrolizumab. [ABSTRACT FROM AUTHOR]

Arai E, Nakagawa T, Wakai-Ushijima S, Fujimoto H & Kanai Y (2012) Histopathology 60, E12-E18 DNA methyltransferase 3B expression is associated with poor outcome of stage I testicular seminoma Aims: To examine in testicular seminomas the expression of DNA methyltransferase 3B (DNMT3B), which is known to be associated with early embryonic development and carcinogenesis, and to obtain a predictive marker for relapse of stage I seminomas. Methods and results: Immunohistochemical examination of DNMT3B was performed in 88 cases of seminoma, 35 (39.8%) of which showed widely scattered nuclear immunoreactivity for DNMT3B, and 53 (60.2%) of which were completely negative. The incidence of focal DNMT3B expression was higher in stage III seminomas (5/5, 100%) than in stage I (25/70, 35.7%) or stage II (5/13, 38.5%) seminomas ( P = 0.011). In stage I seminomas there were no significant correlations between DNMT3B expression and tumour size, invasion of the rete testis, or lymphatic or vascular involvement. Six of 25 cases (24%) showing DNMT3B expression relapsed, whereas only 3/45 cases (6.7%) lacking such expression did so ( P = 0.037). Patients with seminomas showing DNMT3B expression had a significantly lower relapse-free survival rate than patients whose tumours lacked this feature ( P = 0.0464). Conclusions: Patients with seminomas showing focal DNMT3B expression are at increased risk of relapse, and should be followed up carefully. [ABSTRACT FROM AUTHOR]

Abstract: The effectiveness of lung cancer screening using low-dose chest computed tomography (CT) remains elusive. The present study examined the prognosis of patients with lung cancer detected on CT screening in Japanese men and women. Subjects were 210 patients with primary lung cancer identified on CT screening at two medical facilities in Hitachi, Japan, where a total of 61,914 CT screenings were performed among 25,385 screenees between 1998 and 2006. Prognostic status of these patients was sought by examining medical records at local hospitals, supplemented by vital status information from local government. The 5-year survival rate was estimated according to the characteristics of patients and lung nodule. A total of 203 (97%) patients underwent surgery. During a 5.7-year mean follow-up period, 19 patients died from lung cancer and 6 died from other causes. The estimated 5-year survival rate for all patients and for those on stage IA was 90% and 97%, respectively. Besides cancer stage, smoking and nodule appearance were independent predictors of a poor survival; multivariable-adjusted hazard ratio (95% confidence interval) was 4.7 (1.3, 16.5) for current and past smokers versus nonsmokers and 4.6 (1.6, 13.9) for solid nodule versus others. Even patients with solid shadow had a 5-year survival of 82% if the lesion was 20mm or less in size. Results suggest that lung cancers detected on CT screening are mostly curative. The impact of CT screening on mortality at community level needs to be clarified by monitoring lung cancer deaths. [Copyright &y& Elsevier]

Background: Many men develop a rising PSA after initial therapy for prostate cancer. While some of these men will develop a local or metastatic recurrence that warrants further therapy, others will have no evidence of disease progression. We hypothesized that an expression biomarker panel can predict which men with a rising PSA would benefit from further therapy. Methodology/Principal Findings: A case-control design was used to test the association of gene expression with outcome. Systemic (SYS) progression cases were men post-prostatectomy who developed systemic progression within 5 years after PSA recurrence. PSA progression controls were matched men post-prostatectomy with PSA recurrence but no evidence of clinical progression within 5 years. Using expression arrays optimized for paraffin-embedded tissue RNA, 1021 cancerrelated genes were evaluated-including 570 genes implicated in prostate cancer progression. Genes from 8 previously reported marker panels were included. A systemic progression model containing 17 genes was developed. This model generated an AUC of 0.88 (95% CI: 0.84-0.92). Similar AUCs were generated using 3 previously reported panels. In secondary analyses, the model predicted the endpoints of prostate cancer death (in SYS cases) and systemic progression beyond 5 years (in PSA controls) with hazard ratios 2.5 and 4.7, respectively (log-rank p-values of 0.0007 and 0.0005). Genes mapped to 8q24 were significantly enriched in the model. Conclusions/Significance: Specific gene expression patterns are significantly associated with systemic progression after PSA recurrence. The measurement of gene expression pattern may be useful for determining which men may benefit from additional therapy after PSA recurrence. [ABSTRACT FROM AUTHOR]

We report a case of primary adenocarcinoma of the rete testis in a 55-year-old man with pulmonary metastases that were detected 11 months prior to the diagnosis of the primary lesion. Primary adenocarcinoma of the rete testis is an extremely rare malignant tumor with a poor outcome. The most common primary symptom is a scrotal mass, often accompanied by hydrocele and chronic epididymitis. The diagnosis is often delayed because of non-specific clinical presentation and symptoms. We cannot forget that rete testis is a possible primary site for a primary, unknown metastatic adenocarcinoma. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the safety and efficacy of allogeneic hematopoietic stem cell transplantation with a reduced-intensity conditioning regimen (RIST) for interferon-α–refractory metastatic renal cell carcinoma (RCC).Patients and methods: Of 26 patients referred to the National Cancer Center Hospital for possible RIST between June 2000 and April 2002, an HLA-identical relative was identified for 12 patients. Nine patients underwent RIST. The conditioning regimen consisted of fludarabine 180 mg/m2 or cladribine 0.66 mg/kg, plus busulfan 8 mg/kg and rabbit antithymocyte globulin 5 mg/kg. Graft-vs-host disease (GVHD) prophylaxis was cyclosporine alone.Results: All patients achieved engraftment without grade III to IV nonhematologic regimen-related toxicity. All patients achieved complete donor-type chimerism without donor lymphocyte infusion by day 60. Four patients developed acute GVHD, and four developed chronic GVHD. One patient (11%) achieved partial response. As of July 2003, six patients were alive at median follow-up of 681 days. The actuarial overall survival rate was 89% at 1 year and 74% at 2 years. The overall survival rate tended to be higher in the 12 patients with a matched donor than in the other 14 patients without a matched donor (p = 0.088).Conclusion: Our RIST procedure is feasible without severe toxicity. The efficacy of RIST for RCC should be confirmed in phase II/III clinical trials. [Copyright &y& Elsevier]

Water-repellent thin films were fabricated on silicon or germanium wafers by spin-coating sol mixtures of fluoroalkyalkoxysilane (FAS) and bis-(trialkoxysilyl)alkanes with various carbon-chain lengths (Cn: (C2H5O)3Si(CH2)nSi(OC2H5)3, and Cf: (CH3O)3SiC2H4(CF2)6C2H4Si(OCH3)3; n=1, 2, and 8. C0 is defined as Si(OC2H5)4). Before heat treatment, the contact angle of hexadecane on the films increased in the order Cf, C1, C0, C2 and C8 when the FAS concentration in the sol mixture was above 5 mmol/l. With heat treatment higher than 70 °C, the contact angles on the films decreased and the longer the carbon-chain lengths of Cn and Cf the greater the decrease. We show that during spin-coating of the Cn films, FAS accumulates on the outer surface of the film. In Cn films, with n=0, separation of FAS is governed by the repulsion between the non-polar and polar chemical groups while with n ≧ 1, separation is governed by repulsion between the fluoroalkyl-chains and the alkyl-chains. It is speculated that heat treatment causes FAS evaporation, which increases as the carbon-chain length of Cn or Cf increases, owing to the differences in their readiness to undergo hydration. [Copyright &y& Elsevier]

Study objective: To evaluate the feasibility of lung cancer screening using low-dose spiral CT as a part of annual health examinations. Design: Nonrandomized, screening practice. Methods: From April 1998 to August 2000, CT screening was performed as a part of annual health examinations on a total of 7,956 individuals who belonged to the Hitachi Employee's Health Insurance Group. Of those participants, 5,568 were rescreened 1 year later. When a noncalcified solitary pulmonary nodule (SPN) ≥ 8 mm was detected on CT screening, a detailed CT scan was carried out approximately 1 month later. Results: During the baseline screening, a total of 2,865 noncalcified SPNs were detected among the 7,956 participants. Primary lung cancer was histologically confirmed in 40 patients (41 lesions). The prevalence was 0.44% of all participants from the baseline, and 0.07% from the repeated screening. Thirty-five of 41 tumors were stage I. Current or former smokers represented only 17 of 40 cases. The detection rate was rather high in female participants. Conclusion: Low-dose spiral CT seems to be a promising method for screening early lung cancer as a part of annual health examinations. Female and nonsmoking subjects should be included in the baseline screening. However, for yearly repeat screening, the participants may be selected on the basis of gender, smoking history, and results at the baseline screening. [ABSTRACT FROM AUTHOR]

Antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using the national surveillance data, comprising 793 bacterial strains from eight clinically relevant species. Data were collected for the fourth national surveillance project from July 2020 to December 2021 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was supervised with the cooperation of 43 medical institutions throughout Japan. Fluoroquinolone required a minimum inhibitory concentration (MIC) of 2–64 mg/L to inhibit the 330 tested Escherichia coli strains. The proportion of levofloxacin-resistant E. coli strains increased from 28.6% in 2008 to 29.6% in 2011, 38.5% in 2015, and 44.5% in 2021. The proportion of levofloxacin-resistant strains of Pseudomonas aeruginosa also increased from previous survey results, showing a continuing downward trend. Conversely, the proportion of levofloxacin-resistant strains of Enterococcus faecalis decreased relative to previous reports. Neither multidrug-resistant P. aeruginosa nor carbapenem-resistant Enterobacteriaceae were detected. For methicillin-resistant Staphylococcus aureus (MRSA), the proportion of vancomycin-susceptible strains (MIC of 2 μg/mL) decreased from 14.7% to 7.7%. Bacterial strains that produced extended-spectrum β-lactamase included E. coli (82/330 strains, 24.8%), Klebsiella pneumoniae (11/68 strains, 16.2%), and Proteus mirabilis (4/26 strains, 15.4%). As compared to previous surveillance reports, these strains showed an increase in proportion over the years. [ABSTRACT FROM AUTHOR]

Dimension reduction has been used to visualise the distribution of multidimensional microbiome data, but the composite variables calculated by the dimension reduction methods have not been widely used to investigate the relationship of the human gut microbiome with lifestyle and disease. In the present study, we applied several dimension reduction methods, including principal component analysis, principal coordinate analysis (PCoA), non-metric multidimensional scaling (NMDS), and non-negative matrix factorization, to a microbiome dataset from 186 subjects with symptoms of allergic rhinitis (AR) and 106 controls. All the dimension reduction methods supported that the distribution of microbial data points appeared to be continuous rather than discrete. Comparison of the composite variables calculated from the different dimension reduction methods showed that the characteristics of the composite variables differed depending on the distance matrices and the dimension reduction methods. The first composite variables calculated from PCoA and NMDS with the UniFrac distance were strongly associated with AR (FDR adjusted P = 2.4 × 10–4 for PCoA and P = 2.8 × 10–4 for NMDS), and also with the relative abundance of Bifidobacterium and Prevotella. The abundance of Bifidobacterium was also linked to intake of several nutrients, including carbohydrate, saturated fat, and alcohol via composite variables. Notably, the association between the composite variables and AR was much stronger than the association between the relative abundance of individual genera and AR. Our results highlight the usefulness of the dimension reduction methods for investigating the association of microbial composition with lifestyle and disease in clinical research. [ABSTRACT FROM AUTHOR]

A total of 739 patients underwent RARP as initial treatment for PCa from November 2011 to October 2018. Data on BCR status, clinical and pathological parameters were collected from the clinical records. After excluding cases with neoadjuvant and/or adjuvant therapies, presence of lymph node or distant metastasis, and positive SM, a total of 537 cases were eligible for the final analysis. The median follow-up of experimental cohort was 28.0 (interquartile: 18.0–43.0) months. We identified the presence of International Society of Urological Pathology grade group (ISUP-GG) ≥ 4 (Hazard ratio (HR) 3.20, 95% Confidence Interval (95% CI) 1.70–6.03, P < 0.001), lymphovascular invasion (HR 2.03, 95% CI 1.00–4.12, P = 0.049), perineural invasion (HR 10.7, 95% CI 1.45–79.9, P = 0.020), and maximum tumor diameter (MTD) > 20 mm (HR 1.9, 95% CI 1.01–3.70, P = 0.047) as significant factors of BCR in the multivariate analysis. We further developed a risk model according to these factors. Based on this model, 1-year, 3-year, and 5-year BCR-free survival were 100%, 98.9%, 98.9% in the low-risk group; 99.1%, 94.1%, 86.5% in the intermediate-risk group; 93.9%, 84.6%, 58.1% in the high-risk group. Internal validation using the bootstrap method showed a c-index of 0.742 and an optimism-corrected c-index level of 0.731. External validation was also carried out using an integrated database derived from 3 other independent institutions including a total of 387 patients for the final analysis. External validation showed a c-index of 0.655. In conclusion, we identified risk factors of biochemical failure in patients showing negative surgical margin after RARP and further developed a risk model using these risk factors. [ABSTRACT FROM AUTHOR]

Although the albumin-to-globulin ratio (AGR) is a promising biomarker, no study has investigated its prognostic significance for advanced urothelial carcinoma (UC). This study conformed to the REporting recommendations for tumor MARKer prognostic studies (REMARK) criteria. We retrospectively reviewed 176 patients with advanced UC treated with pembrolizumab between 2018 and 2020. We evaluated the associations between pretreatment clinicopathological variables, including the AGR and performance status (PS), with progression-free survival, cancer-specific survival, and overall survival. The Cox proportional hazards model was used for univariate and multivariable analyses. The AGR was dichotomized as < 0.95 and ≥ 0.95 based on receiver operating characteristic curve analysis. After excluding 26 cases with missing data from the total of 176 cases, 109 (73%) patients experienced disease progression, 75 (50%) died from UC, and 6 (4%) died of other causes (median survival = 12 months). Multivariate analyses identified PS ≥ 2 and pretreatment AGR < 0.95 as independent poor prognostic factors for all endpoints. Furthermore, a prognostic risk model incorporating these two variables achieved a relatively high concordance index for all endpoints. This is the first report to evaluate the significance of AGR in advanced UC. Pretreatment AGR < 0.95 may serve as a prognostic marker for advanced UC treated with pembrolizumab. [ABSTRACT FROM AUTHOR]

Objectives: Protein Z (PZ) is a γ‐carboxyglutamic acid protein present in plasma that is involved in blood coagulation. Detailed analysis of urinary stones from patients with urolithiasis has revealed that PZ is often found in urinary stones composed of calcium oxalate monohydrate. In this study, we compared blood and urinary PZ concentrations between healthy individuals and patients with urolithiasis. Methods: Plasma and urine were collected from healthy individuals and patients with urolithiasis who provided informed consent. PZ was detected as a urinary stone matrix protein in some of the patients. PZ was quantified by ELISA, creatinine was measured by the enzymatic method, and the total protein concentration was measured by the Bradford method. Results: The plasma PZ level was 2.54 ± 1.02 μg/mL in healthy individuals and that in urolithiasis patients classified by stone history were from 1.16 ± 0.77 to 3.73 ± 1.09 μg/mL, which was not significantly different. The urinary excretion of PZ (PZ/creatinine) was also not different in patients with urolithiasis and in healthy individuals (from 54.1 ± 40.9 to 95.4 ± 69.4 ng/mg vs. 73.3 ± 36.0 ng/mg). A positive correlation was found between the plasma PZ level and creatinine‐corrected urinary PZ concentration (r = 0.46). Conclusions: Both the plasma level and urinary excretion of PZ in urolithiasis patients were not significantly different with normal individuals. PZ detected in urinary stones as a matrix protein is thought to be incorporated into urinary stones regardless of blood and urine levels of PZ. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to identify prognostic clinicopathological factors and to create a nomogram able to predict overall survival (OS) in recurrent urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC).Materials and Methods: Among 1,087 patients with UCB who had undergone RC at our 11 institutions between 1990 and 2010, 306 patients who subsequently developed distant metastasis or local recurrence or both were identified. Clinical data were collected with medical record review. Univariate and multivariate Cox regression models addressed OS after recurrence. A nomogram predicting postrecurrence OS was constructed based on Cox proportional hazards model, without using postrecurrence factors (systemic chemotherapy and resection of metastasis). The performance of the nomogram was internally validated by assessing concordance index and calibration plots.Results: Of the 306 patients, 268 died during follow-up with a median survival of 7 months (95% CI: 5.8-8.5). Postrecurrence chemotherapy was administered in 119 patients (38.9%). Multivariable analysis identified 9 independent predictors for OS; period of time from RC to recurrence (time-to-recurrence), symptomatic recurrence, liver metastasis, hemoglobin level, serum alkaline phosphatase level, serum lactate dehydrogenase level, serum C-reactive protein level, postrecurrence chemotherapy, and resection of metastasis. A nomogram was formed with the following 5 variables to predict OS: time-to-recurrence, symptomatic recurrence, liver metastasis, albumin level, and alkaline phosphatase level. Concordance index rate was 0.75 (95% CI: 0.72-0.78) by internal validation using Bootstraps with 1,000 resamples. Calibration plots showed that the nomogram fitted well.Conclusions: We identified 9 clinicopathological factors as independent OS predictors in postcystectomy recurrence of UCB. We also created a validated nomogram with 5 variables that efficiently stratified those patients regardless of eligibility for chemotherapy. The nomogram would be useful for acquiring relevant prognostic information and for stratifying patients for clinical trials. [ABSTRACT FROM AUTHOR]

Background: Prognostic value of immune cells is not clear in testicular germ cell tumors (TGCTs). We aimed to investigate the prognostic value of tumor-infiltrating neutrophils in TGCTs.Methods: A total of 102 patients who underwent orchiectomy for TGCT were investigated for CD66b positive tumor-infiltrating neutrophils (CD66b + TINs). Immmunostaining for CD66b was performed in 102 sections as described. Clinicopathological parameters as well as cancer specific survival and overall survival were assessed for correlation with CD66b + TIN density.Results: High density group was significantly correlated with tumor diameter ≥ 10 cm, presence of nodal/distant metastasis, S stage, diagnosis of nonseminomatous germ cell tumor (NGCT), and presence of venous invasion (p = 0.0198, p < 0.0001, p = 0.0275, p = 0.0004, and p = 0.0287, respectively). It was also significantly associated with cancer-specific and overall survival (logrank p = 0.0036, and p = 0.0002, respectively). Multivariate analysis showed that increased CD66b + TIN was an independent prognostic factor for overall survival (p = 0.0095).Conclusions: Increased CD66b + TIN was significantly associated with presence of metastasis, S stage, and nonseminomatous germ cell tumor diagnosis. It was also an independent prognostic factor of overall survival in patients with TGCT. [ABSTRACT FROM AUTHOR]

Molecular targeted therapy using poly (ADP-ribose) polymerase inhibitors has improved survival in patients with castration-resistant prostate cancer (CRPC). However, this approach is only effective in patients with specific genetic mutations, and additional drug discovery targeting epigenetic modulators is required. Here, we evaluated the involvement of the transcriptional coregulator ESS2 in prostate cancer. ESS2-knockdown PC3 cells dramatically inhibited proliferation in tumor xenografts in nude mice. Microarray analysis revealed that ESS2 regulated mRNA levels of chromodomain helicase DNA binding protein 1 (CHD1)-related genes and other cancer-related genes, such as PPAR-γ, WNT5A, and TGF-β, in prostate cancer. ESS2 knockdown reduced nuclear factor (NF)-κB/CHD1 recruitment and histone H3K36me3 levels on the promoters of target genes (TNF and CCL2). In addition, we found that the transcriptional activities of NF-κB, NFAT and SMAD2/3 were enhanced by ESS2. Tamoxifen-inducible Ess2-knockout mice showed delayed prostate development with hypoplasia and disruption of luminal cells in the ventral prostate. Overall, these findings identified ESS2 acts as a transcriptional coregulator in prostate cancer and ESS2 can be novel epigenetic therapeutic target for CRPC. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is associated with cancer risk; however, little is known regarding its relationship with the risk of cancer-related premature death and long-term sick leave (LTSL), which can lead to a substantial loss in working years. The present study aimed to quantify the all-site and site-specific associations between MetS and the risk of severe cancer events (a composite outcome of LTSL and mortality due to cancer) in a large working population in Japan. Methods: We recruited 70,875 workers (59,950 men and 10,925 women), aged 20–59 years, who attended health check-ups in 2011 (10 companies) and 2014 (2 companies). All workers underwent follow up for severe cancer events until March 31, 2020. MetS was defined in accordance with the Joint Interim Statement. Cox regression models were used to quantify the association between baseline MetS and severe cancer events. Results: During 427,379 person-years of follow-up, 523 participants experienced the outcome consisting of 493 LTSLs of which 124 eventually resulted in death, and 30 deaths without taking LTSL. The adjusted hazard ratios (HR) (95% confidence intervals [CI]) for composite severe events due to all-site, obesity-related, and non-obesity-related cancer among those with vs. without MetS were 1.26 (1.03, 1.55), 1.37 (1.04, 1.82), and 1.15 (0.84, 1.56), respectively. In cancer site-specific analyses, MetS was associated with an increased risk of severe events due to pancreatic cancer (HR, 2.06; 95% CI, 0.99–4.26). When mortality was treated solely as the endpoint, the association was significant for all-site (HR, 1.58; 95% CI, 1.10–2.26), and obesity-related (HR, 1.59; 95% CI, 1.00–2.54) cancer. Additionally, a greater number of MetS components was associated with a greater risk of both severe cancer events and cancer-related mortality (P trend < 0.05). Conclusion: Among Japanese workers, MetS was associated with an increased risk of severe cancer events, especially those due to obesity-linked cancer. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the prognostic significance of the pretreatment neutrophil-to-lymphocyte ratio in patients with metastatic urothelial carcinoma who underwent salvage chemotherapy. Methods We reviewed 200 metastatic urothelial carcinoma patients who received salvage chemotherapy at our five affiliate institutions between 2003 and 2011. The associations of pretreatment clinicopathological factors, including neutrophil-to-lymphocyte ratio, with cancer-specific survival and overall survival from the start of chemotherapy were assessed. Cox proportional hazards model was used for multivariate analysis. Results A total of 15 cases with missing data were excluded. Among the remaining 185 patients, 157 died during follow up, with a median survival of 13.0 months. Multivariate analysis showed that the pretreatment neutrophil-to-lymphocyte ratio ≥3, Eastern Cooperative Oncology Group performance status ≥2 and liver metastasis were independent poor prognostic factors, both for cancer-specific survival and overall survival. A prognostic model predicting overall survival was constructed based on the number of these three variables (0, 1 and ≥ 2). The classified patients showed significantly different overall survival (each P < 0.0001, log-rank test), with Harrell's concordance index as high as 0.81. Conclusions Pretreatment neutrophil-to-lymphocyte ratio elevation was an independent poor prognostic factor for metastatic urothelial carcinoma undergoing salvage chemotherapy. Our newly constructed prognostic model including the pretreatment neutrophil-to-lymphocyte ratio proved to be an excellent discriminator of overall survival. [ABSTRACT FROM AUTHOR]

The clinical significance of random bladder biopsies in primary non-muscle-invasive bladder cancer is unclear. The present study investigated the significance of positive random bladder biopsies in primary T1 NMIBC. The present study retrospectively reviewed the records of 71 patients with primary pT1N0M0 bladder cancer who underwent transurethral resection of the bladder tumor (TURBT) and concomitant random bladder biopsy. A total of 12 patients who received cystectomy immediately following the TURBT were excluded, and the remaining 59 patients were included in the analysis. Random bladder biopsy was defined as a cold-cup biopsy of pre-specified normal-looking areas in the bladder. The association of clinicopathological factors, including random biopsy results, with intravesical recurrence were assessed by univariate and multivariate Cox proportional hazards analyses. Of the 59 patients, 15 (25%) demonstrated carcinoma in situ (CIS) lesions on random bladder biopsy: Five (33%) in biopsy specimens alone and the remaining 10 (67%) in biopsy and TUR specimens. Positive random biopsy was associated with preoperative positive urine cytology (P=0.011) and small size of the main tumor (P=0.008). Multivariate analysis demonstrated positive random biopsy as the sole independent poor prognostic factor for intravesical recurrence (hazard ratio: 4.69, P=0.014). The five patients who had CIS detected in biopsy specimens alone had worse, although non-significantly worse, recurrence-free survival compared with those with CIS detected in biopsy and TUR specimens (P=0.100). In conclusion, positive bladder random biopsy, equivalent to the presence of CIS, was an independent predictor of recurrence in primary T1 bladder cancer. Given that one-third of CIS lesions could not have been detected without biopsy, random bladder biopsy should be considered for patients with T1 tumors [ABSTRACT FROM AUTHOR]

This study compared the time profile of FEV1 after COPD diagnosis among rapid decliners, slow decliners, and sustainers in the year of COPD diagnosis. COPD subjects were identified from the annual medical checkup records of Hitachi, Ltd., employees in Japan (April 1998-March 2019). Subjects were categorized into 3 groups (rapid decliner [decrease of FEV1 ≥ 63 mL/year], slow decliner [< 63 and ≥ 31 mL/year], and sustainer [< 31 mL/year]) for 5 years. The time profile of FEV1 was compared using mixed-effects model for 5 years after diagnosis; risk factors of rapid decliner were detected using logistic model/gradient boosting decision tree. Of 1294 eligible subjects, 18.6%, 25.7%, and 55.7% were classified as rapid decliners, slow decliners, and sustainers, respectively. The annual rates of FEV1 decline were similar 3 years before and until COPD diagnosis. The mean FEV1 in rapid decliners was 2.82 ± 0.04 L in year 0 and 2.41 ± 0.05 L in year 5, and in sustainers, it was 2.67 ± 0.02 L and 2.72 ± 0.02 L (year 0, p = 0.0004). In conclusion, FEV1 declined yearly before diagnosis and the time profiles of FEV1 were different in the 3 groups after COPD diagnosis. Therefore, appropriate treatment of the 3 groups with regular lung function tests is necessary to follow FEV1 decline after COPD onset. [ABSTRACT FROM AUTHOR]

Aims: We aimed to assess the cross-sectional association of heated tobacco product (HTP) use with prediabetes and diabetes. Methods: The present analysis included 8950 workers from 5 companies (Study I) and 31,341 workers from another large company (Study II), who participated in the Japan Epidemiology Collaboration on Occupational Health Study. The participants were divided into five groups: never smokers, past smokers, exclusive HTP users, dual users of cigarettes and HTPs, and exclusive cigarette smokers. Diabetes and prediabetes were defined according to the fasting blood glucose and HbA1c levels and self-reported diabetes treatment, using the American Diabetes Association criteria. We analyzed the data of Study I and II separately, and then pooled these estimates using the fixed-effect models, with adjustment for a wide range of covariates. Results: In this study that included 40,291 participants (mean age, 46.6 years; men, 84.3%), about half of the current tobacco-related product users reported using HTPs. Exclusive HTP users had higher odds of prediabetes (pooled odds ratio 1.36; 95% CI 1.25–1.47) and diabetes (1.68; 95% CI 1.45–1.94) than never smokers. Similarly, dual users also had increased odds of prediabetes (pooled odds ratio, 1.26; 95% CI 1.13–1.39) and diabetes (1.93; 95% CI 1.63–2.29). The strength of these associations was comparable to that of cigarette smokers. We observed significantly higher HbA1c and fasting blood glucose levels among both exclusive HTP users and dual users compared to never smokers. Conclusion: HTP use was associated with an increased likelihood of prediabetes and diabetes. Prospective studies are warranted to confirm the cross-sectional association. [ABSTRACT FROM AUTHOR]

Purpose: Small cell carcinoma of the urinary bladder (SCCB) is known for its aggressive clinical features and poor prognosis. No prognostic factor has been established so far. The aim of this study was to assess the significance of possible prognostic factors, including serum neuron-specific enolase (NSE), an established biomarker for small cell lung carcinoma. Methods: We retrospectively reviewed 31 patients with primary SCCB treated at our eight affiliate institutions between 2001 and 2014. The association of various clinicopathological factors at diagnosis, including the serum NSE value, with cancer-specific survival (CSS) was assessed. The log-rank test and Cox proportional hazards model were used for univariate and multivariate analyses, respectively. Results: Nineteen (61.3 %) died of SCCB during the follow-up, with a median survival time of 12.7 months. Prognostic factors were analyzed for the 25 patients after excluding six with missing data. Univariate analysis demonstrated that stage (extensive disease) and serum NSE ≥25 ng/ml were significantly associated with worse CSS. Multivariate analysis identified increased serum NSE value as a sole independent predictor of CSS (hazard ratio 18.52, p = 0.0022). Conclusions: Serum NSE value at diagnosis was an independent prognostic factor for primary SCCB and may serve as a useful biomarker in the management of SCCB. [ABSTRACT FROM AUTHOR]

Both small cell carcinoma and sarcomatoid carcinoma of the urinary bladder are highly aggressive tumors, and a concurrence of these tumors is extremely rare. We report a case of urinary bladder cancer with small cell carcinoma as a predominant component, accompanied by sarcomatoid carcinoma and conventional urothelial carcinoma (UC). Although the small cell carcinoma component had resolved on receiving chemoradiotherapy, rapid growth of the residual tumor led to a fatal outcome. A 47-year-old man presented with occasional bladder irritation and had a 2-year history of asymptomatic hematuria. Cystoscopy revealed a huge mass in the urinary bladder, and transurethral resection was performed. Microscopically, small cell carcinoma was detected as the major tumor component. Spindle-shaped sarcomatoid cells were also observed that were intermingled with small cell carcinoma and conventional UC. In addition, a sheet-like growth of the lipoblast-like neoplastic cells was observed focally. Initially, by providing chemoradiotherapy, we achieved a marked tumor regression; however, the tumor rapidly regrew after the completion of chemoradiotherapy, and the patient underwent radical cystectomy. Only conventional UC and sarcomatoid carcinoma were identified in the cystectomy specimen. The patient died of the disease 4 months after cystectomy. Urinary bladder cancer may include a combination of multiple aggressive histologies as in the present case. Because the variation in the tumor components may affect the efficacy of therapy, a correct diagnosis of every tumor component is necessary. [ABSTRACT FROM AUTHOR]

Aims/Introduction Muscle strength training has been suggested to improve glucose metabolism; however, epidemiological evidence regarding strength training's effects on diabetes risk is scarce. We prospectively examined the association between strength training and the risk of type 2 diabetes in Japanese men and women. Materials and Methods The sample included health checkups on 26,630 Japanese male and female workers aged 30-64 years without diabetes at baseline. Weekly time spent on strength training was elicited using a self-reported questionnaire. Type 2 diabetes was diagnosed based on hemoglobin A1c, fasting glucose, random plasma glucose and self-report in an annual health checkup. Hazard ratio ( HR) and its 95% confidence interval ( CI) for incident diabetes was estimated using a Cox proportional hazards model. Results During a mean follow up of 5.2 years with 139,748 person-years, 1,770 individuals developed diabetes. Age- and sex-adjusted HR for diabetes was 0.58 (95% CI 0.42-0.79) in those who engaged in strength training compared with those who engaged in no strength training. After further adjusting for potential confounders, the corresponding HR was 0.66 (95% CI 0.48-0.90). Additional adjustment for body mass index did not materially change the result; the HR was 0.70 (95% CI 0.51-0.96). The association was more pronounced in individuals aged 50 years or older than those aged <50 years, although the difference in the association by age was not significant. Conclusions These results suggest that engagement in strength training could help to reduce the risk of type 2 diabetes in a Japanese working population. [ABSTRACT FROM AUTHOR]

The aim of this study was to clarify DNA methylation profiles determining the clinicopathological diversity of urothelial carcinomas. Genome-wide DNA methylation analysis was performed using the Infinium HumanMethylation450 BeadChip in 46 paired samples of non-cancerous urothelium (N) and corresponding cancerous tissue (T), and 26 samples of normal control urothelium obtained from patients without urothelial carcinomas (C). For genes of interest, correlation between DNA methylation and mRNA expression was examined using the Cancer Genome Atlas database. In addition, the role of a selected target for cancer-relevant endpoints was further examined in urothelial carcinoma cell lines. The genes showing significant differences in DNA methylation levels between papillary carcinomas and more aggressive non-papillary (nodular) carcinomas were accumulated in signaling pathways participating in cell adhesion and cytoskeletal remodeling. Five hundred ninety-six methylation sites showed differences in DNA methylation levels between papillary and nodular carcinomas. Of those sites, that were located in CpG-islands around transcription start site, 5′-untranslated region or 1st exon, 16 genes exhibited inverse correlations between DNA methylation and mRNA expression levels. Among the latter, only the KLF11 gene showed papillary T sample-specific DNA hypermethylation in comparison to C and N samples. The DNA methylation levels of KLF11 were not significantly different between T samples and N samples or T samples and C samples for patients with papillo-nodular or nodular carcinomas. Knockdown experiments using the urothelial carcinoma cell lines HT1376 and 5637, which are considered models for papillary carcinoma, revealed that KLF11 participates in altering the adhesiveness of cells to laminin-coated dishes, although cell growth was not affected. These data indicate that DNA hypermethylation of KLF11 may participate in the generation of papillary urothelial carcinomas through induction of aberrant cancer cell adhesion to the basement membrane. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: To investigate the association of diabetes and prediabetes with long-term sickness absence (LTSA) due to mental disorders or specific mental disorders.Methods: A prospective cohort study was conducted using data from the Japan Epidemiology Collaboration on Occupational Health Study. A total of 62,065 workers who received health check-ups in 2011 (nine companies) or 2014 (two companies) and were followed up to March 31, 2020 were included in this study. Diabetes status was defined based on the American Diabetes Association criteria, and diabetes was differentiated into diabetes with/without anti-diabetic treatment for additional analysis. A Cox proportional hazards regression model was used to investigate these associations.Results: During maximum 8-year follow-up period, 1024 participants underwent LTSA due to mental disorders. The adjusted hazard ratio (aHR) and corresponding 95% confidence interval (CI) of LTSA due to all mental disorders were 1.10 (0.88-1.38) and 1.45 (1.07-1.98) for prediabetes and diabetes, respectively. Diabetic individuals with/without treatment were both at a high risk of LTSA due to mental disorders. For specific mental disorders, diabetes was associated with a higher risk of LTSA due to reaction to severe stress and adjustment disorders (aHR = 3.02, 95% CI = 2.01-4.52) while it was marginally associated with LTSA due to depressive episode (aHR = 1.25, 95% CI = 0.98-1.60). Prediabetes was also associated with LTSA due to reaction to severe stress and adjustment disorders (aHR = 1.41, 95% CI = 1.08-1.84).Conclusions: The present study suggests the importance of screening diabetes status and providing psychological support for decreasing the risk of LTSA due to mental disorders within working populations. [ABSTRACT FROM AUTHOR]

Aims: It is well known that healthy lifestyles measured at one time‐point are inversely associated with diabetes risk. The impact of transitions in combined lifestyles in real settings remains unknown. Materials and Methods: The trajectory patterns of combined lifestyles over three years were identified using group‐based trajectory modeling in 26,647 adults in Japan. Two types of indices (not having the unhealthy lifestyle [easy goal] and having healthiest lifestyles [challenging goal]) were developed using five lifestyle factors: smoking, alcohol consumption, exercise, sleep duration, and body weight control. This index was calculated using the yearly total score (0–5; higher score indicated healthier lifestyles). Diabetes was defined by high plasma glucose level, high hemoglobin A1c level, and self‐report. Results: Five trajectory patterns were identified for each index and it was shown that healthier patterns are associated with a lower risk of type 2 diabetes during 6.6 years of average follow‐up. For example, with a challenging‐goal, compared with a persistently very unhealthy pattern, the adjusted hazard ratios (95% confidence intervals) were 0.65 (0.59, 0.73), 0.50 (0.39, 0.64), 0.43 (0.38, 0.48), and 0.33 (0.27, 0.41) for 'persistently unhealthy', 'improved from unhealthy to moderately healthy', 'persistently moderately healthy', and 'persistently mostly healthy' patterns, respectively. Conclusions: Our data reinforce the importance of improving and maintaining health‐related lifestyles to prevent diabetes. [ABSTRACT FROM AUTHOR]

Several studies suggest the involvement of dietary habits and gut microbiome in allergic diseases. However, little is known about the nutritional and gut microbial factors associated with the risk of allergic rhinitis (AR). We recruited 186 participants with symptoms of AR and 106 control subjects without symptoms of AR at the Hitachi Health Care Center, Japan. The habitual consumption of 42 selected nutrients were examined using the brief-type self-administered diet history questionnaire. Faecal samples were collected and subjected to amplicon sequencing of the 16S ribosomal RNA gene hypervariable regions. Association analysis revealed that four nutrients (retinol, vitamin A, cryptoxanthin, and copper) were negatively associated with AR. Among 40 genera examined, relative abundance of Prevotella and Escherichia were associated with AR. Furthermore, significant statistical interactions were observed between retinol and Prevotella. The age- and sex-adjusted odds of AR were 25-fold lower in subjects with high retinol intake and high Prevotella abundance compared to subjects with low retinol intake and low Prevotella abundance. Our data provide insights into complex interplay between dietary nutrients, gut microbiome, and the development of AR. [ABSTRACT FROM AUTHOR]

Objective Recent studies have shown an improvement in prostate cancer diagnosis with the use of 3.0- Tesla magnetic resonance imaging. We retrospectively assessed the ability of this imaging technique to predict side-specific extracapsular extension of prostate cancer. Methods From October 2007 to August 2011, prostatectomy was carried out in 396 patients after preoperative 3.0- Tesla magnetic resonance imaging. Among these, 132 (primary sample) and 134 patients (validation sample) underwent 12-core prostate biopsy at the National Cancer Center Hospital of Tokyo, Japan, and at other institutions, respectively. In the primary dataset, univariate and multivariate analyses were carried out to predict side-specific extracapsular extension using variables determined preoperatively, including 3.0- Tesla magnetic resonance imaging findings ( T2-weighted and diffusion-weighted imaging). A prediction model was then constructed and applied to the validation study sample. Results Multivariate analysis identified four significant independent predictors ( P < 0.05), including a biopsy Gleason score of ≥8, positive 3.0- Tesla diffusion-weighted magnetic resonance imaging findings, ≥2 positive biopsy cores on each side and a maximum percentage of positive cores ≥31% on each side. The negative predictive value was 93.9% in the combination model with these four predictors, meanwhile the positive predictive value was 33.8%. Good reproducibility of these four significant predictors and the combination model was observed in the validation study sample. Conclusions The side-specific extracapsular extension prediction by the biopsy Gleason score and factors associated with tumor location, including a positive 3.0- Tesla diffusion-weighted magnetic resonance imaging finding, have a high negative predictive value, but a low positive predictive value. [ABSTRACT FROM AUTHOR]

Aims: Data are limited regarding how shift work is linked to the development of type 2 diabetes, especially among workers at high risk of diabetes. We examined the risk of diabetes according to shift-work conditions over several years among Japanese adults. Methods: This prospective study enrolled 17,515 workers (age 40–78 years). Shift work was self-reported at annual health examinations over time from 2004 to 2017 and categorized as shift workers or non-shift workers. Diabetes was defined as fasting plasma glucose, random glucose, HbA1c, and self-reported use of antidiabetic medications. The association of shift work and diabetes was quantified using Cox regression. Results: During a follow-up of 8.1 years in median, 2071 incident cases of diabetes were documented. Compared with non-shift work, shift work showed a significantly elevated hazard ratios of developing diabetes. Shift work showed a 19% (95% confidence intervals: 3–37%) higher hazard ratios for diabetes, after adjustment for demographic-, cardiometabolic-, and work-related factors. Further adjustment for lifestyle factors and body mass index did not materially change this association (a 16% increase; 95% confidence intervals, 1–34%). This relationship was replicated among workers with prediabetes. Conclusions: Engaging in shift work may increase the risk of developing diabetes independently of lifestyle factors and body mass index, even among prediabetic workers. [ABSTRACT FROM AUTHOR]

Introduction: Management of patients with atypical urinary cytology (class III) of the upper urinary tract is often complicated because some patients develop upper urinary tract urothelial carcinoma (UTUC). Here, we aimed to help define the optimal management of these patients. Methods: We investigated 31 patients who underwent retrograde ureteropyelography (RP) and were diagnosed with atypical findings of upper urinary tract cytology. Results: UTUC was revealed in 17 of 31 patients during the follow-up period of 1 year or longer. Tumor-like lesions and wall thickening in the upper urinary tract on initial computed tomography (CT) were significant predictors of UTUC (p = 0.0002 and p = 0.012, respectively). All 11 patients with tumor-like lesions and 3 of 8 patients with wall thickening on initial CT underwent nephroureterectomy, and UTUC was confirmed histologically. Moreover, 3 of 12 patients with hydronephrosis only or with normal findings later went on to develop UTUC. Repeated RP performed within 6 months from the initial RP was able to distinguish patients with UTUC from those without, even in individuals with normal CT findings. Discussion/Conclusion: Repeated RP based on initial CT findings is recommended in patients with atypical urinary cytology of the upper urinary tract. Nephroureterectomy without repeated RP may be warranted in patients with tumor-like lesions on initial CT findings. [ABSTRACT FROM AUTHOR]

Physical activity has been linked to a lower risk of chronic kidney disease (CKD); however, evidence on the relationship between domain-specific physical activity and CKD is scarce. This study aimed to examine the risk of CKD in relation to leisure-time, occupational, and commuting physical activities in a large occupational cohort in Japan. Participants were 17,331 workers (20–65 years old) without CKD and were followed-up for a maximum period of 13 years. Incident CKD was defined as an estimated glomerular filtration rate of < 60 mL/min/1.73 m2 and/or proteinuria determined using the dipstick test. The Cox proportional hazards models were used to examine the associations. During 147,752 person-years of follow-up, 4013 participants developed CKD. Workers who were standing or walking at work and those who were fairly active at work had adjusted hazard ratios of 0.88 (95% confidence interval 0.86–0.96) and 0.89 (95% confidence interval 0.78–1.02), respectively, for developing CKD than sedentary workers. Leisure-time physical activity and walking for commute were not associated with CKD risk. Our findings suggest that occupational, but not leisure-time and commuting physical activities, is associated with a lower CKD risk. [ABSTRACT FROM AUTHOR]

Objective: Prediabetes has been suggested to increase risk for death; however, the definitions of prediabetes that can predict death remain elusive. We prospectively investigated the association of multiple definitions of prediabetes with the risk of death from all causes, cardiovascular disease (CVD), and cancer in Japanese workers.Research Design and Methods: The study included 62,785 workers who underwent a health checkup in 2010 or 2011 and were followed up for death from 2012 to March 2019. Prediabetes was defined according to fasting plasma glucose (FPG) or glycated hemoglobin (HbA1c) values or a combination of both using the American Diabetes Association (ADA) or World Health Organization (WHO)/International Expert Committee (IEC) criteria. The Cox proportional hazards regression model was used to investigate the associations.Results: Over a 7-year follow-up, 229 deaths were documented. Compared with normoglycemia, prediabetes defined according to ADA criteria was associated with a higher risk of all-cause mortality (hazard ratio [HR] 1.53; 95% CI 1.12-2.09) and death due to cancer (HR 2.37; 95% CI 1.45-3.89) but not with death due to CVD. The results were materially unchanged when prediabetes was defined according to ADA FPG, ADA HbA1c, WHO FPG, or combined WHO/IEC criteria. Diabetes was associated with the risk of all-cause, CVD, and cancer deaths.Conclusions: In a cohort of Japanese workers, FPG- and HbA1c-defined prediabetes, according to ADA or WHO/IEC, were associated with a significantly increased risk of death from all causes and cancer but not CVD. [ABSTRACT FROM AUTHOR]

Background: Few studies have investigated the association between tobacco smoking and sick leave (SL) in Japan.Methods: We followed 70 896 workers aged 20-59 years (60 133 males, 10 763 females) between April 2012 and March 2017. A Cox proportional hazards model was used to investigate the associations between smoking (smoking status and intensity) and long-term SL (ie, SL lasting ≥30 consecutive days). Cause-specific analyses were also conducted.Results: A total of 1777 people took long-term SL during a follow-up of 307 749 person years. Compared with never-smokers, current smokers were at a higher risk of long-term SL (hazard ratio [HR] = 1.32; 95% confidence interval [CI] = 1.19 to 1.48). Cause-specific analyses revealed that current smoking was associated with a higher risk of SL due to all physical disorders (HR = 1.44, 95% CI = 1.22 to 1.69), cancer (HR = 1.49, 95% CI = 1.10 to 2.01), cardiovascular disease (CVD; HR = 2.16, 95% CI = 1.31 to 3.55), and injuries/external causes (HR = 1.83, 95% CI = 1.31 to 2.58). Former smokers were at a higher risk of SL due to cancer at a borderline significance level (HR = 1.38, 95% CI = 0.99 to 1.92). Low-intensity smoking (ie, 1-10 cigarettes smoked per day) was associated with all-cause SL, SL due to CVD, and SL due to injuries/external causes compared with never-smokers.Conclusion: In a large cohort of working-age Japanese, smoking was associated with a greater risk of long-term SL. Greater effort is needed to mitigate disease burden associated with smoking at workplace in Japan.Implications: Our study contributes to the literature on the association between smoking and SL in several ways. First, the study was conducted among a Japanese working population. While the association has been extensively studied in Western setting, few attempts have been made elsewhere. Second, cause-specific analyses were undertaken in our study. Third, we paid attention to the effect of low-intensity smoking on SL given that there is growing evidence of an elevated health risk associated with low-intensity smoking. [ABSTRACT FROM AUTHOR]