Impact of postoperative complications on long-term survival in bladder cancer patients.

OBJECTIVE: To determine the impact of postoperative complications on long-term survival outcomes in patients with bladder cancer undergoing radical cystectomy. METHODS: This retrospective multi-institutional study included 766 bladder cancer patients who underwent radical cystectomy between 2011 and 2017. Patient characteristics, perioperative outcomes, all complications within 90 days after surgery and survival outcomes were collected. Each complication was graded based on the Clavien-Dindo system, and grouped using a standardized grouping method. The Comprehensive Complication Index, which incorporates all complications into a single formula weighted by their severity, was utilized. Overall survival and recurrence-free survival (local, distant or urothelial recurrences) were stratified by Comprehensive Complication Index (high: ≥26.2; low: <26.2). A multivariate model was utilized to identify independent prognostic factors. RESULTS: The incidence of any and major complications (≥Clavien-Dindo grade III) was 70 and 24%, respectively. In terms of Comprehensive Complication Index, 34% (261/766) of the patients had ≥26.2. Patients with Comprehensive Complication Index ≥ 26.2 had shorter overall survival (4-year, 59.5 vs. 69.8%, respectively, log-rank test, P = 0.0037) and recurrence free survival (51.9 vs. 60.1%, respectively, P = 0.0234), than those with Comprehensive Complication Index < 26.2. The Cox multivariate model identified the age, performance status, pT-stage, pN-stage and higher CCI (overall survival: HR = 1.35, P = 0.0174, recurrence-free survival: HR = 1.26, P = 0.0443) as independent predictors of both overall survivial and recurrence-free survival. CONCLUSIONS: Postoperative complications assessed by Comprehensive Complication Index had adverse effects on long-term survival outcomes. Physicians should be aware that major postoperative complications can adversely affect long-term disease control.

Interleukin 6/gp130 axis promotes neural invasion in pancreatic cancer.

BACKGROUND: Nerve invasion (N-inv) is an important prognostic factor in pancreatic ductal adenocarcinoma (PDAC). Elucidation of circulating N-inv stimulators could provide deeper insights and novel perspectives for PDAC therapy. The interleukin (IL)-6/gp130 axis was evaluated in this study as a candidate N-inv stimulator. METHODS: A human pancreatic cancer (PC) cell, Capan-1, was confirmed to have the stimulant activity of IL-6/gp130 axis through the evaluation of mRNA, cell surface protein and intracellular protein levels and chemotaxis and wound healing assay. The upregulation of IL-6/gp130 axis was evaluated using tumor-derived IL-6 level and intratumoral pSTAT3 expression in N-inv of murine sciatic nerves by intraneural injection of Capan-1 cell (N-inv model) and using resected pancreatic cancer tissue and clinical data from 46 PDAC patients. RESULTS: mRNA and protein expressions of IL-6 and IL-6 receptor were found in whole cell lysate and condition medium from PC cell. Cell surface protein expression of gp130 were clearly detected on PC cell. IL-6 promoted migration and chemotaxis of PC cell. Serum IL-6 and tumoral IL-6 mRNA levels in N-inv model mice were significantly higher than those in subcutaneous tumor mice (p = 0.004 and p = 0.002, respectively). Silencing of IL-6 and gp130 on PC cell and administration of an anti-IL-6 receptor antibody, tocilizumab, suppressed N-inv, compared to each control (p = 0.070, p = 0.118 and p = 0.122, respectively). In PDAC patients, the high-N-inv group showed poor prognosis (p =0.059) and elevated serum levels of IL-6 and C-reactive protein, synthesis of which is promoted by IL-6, compared to those in the low-N-inv group (p = 0.006 and p = 0.075, respectively). Tumoral gp130 expression at N-inv was higher than that in the primary pancreatic tumor (p = 0.026). CONCLUSION: Biological activity of IL-6/gp130 axis promoted N-inv in murine model and was upregulated in PDAC patients with severe N-inv. This study is the first evidence that the IL-6/gp130 axis offers a potential therapeutic target in PDAC with N-inv.

Comparative study of postoperative complications after radical cystectomy during the past two decades in Japan: Radical cystectomy remains associated with significant postoperative morbidities.

OBJECTIVES: During the past 2 decades, in order to improve perioperative and oncological outcomes, a minimally invasive approach, neoadjuvant chemotherapy (NAC), and an enhanced postoperative recovery program after surgery have been introduced into routine clinical practice of radical cystectomy (RC). Our aim was to examine the differences in clinical practice and postoperative complications after RC by comparing our previous and current cohorts. MATERIALS AND METHODS: A retrospective multi-institutional study. We collected all complications within 90 days after surgery between 2011 and 2017 (current cohort), and categorized them according to a standardized methodology. Then, we compared the outcomes with those in our previous study (previous cohort, 1997-2010). A multivariate logistic regression model was utilized to determine predictors of complications in the current cohort. RESULTS: A total of 838 patients were newly collected (current cohort), and 919 from the previous cohort were included in the subsequent analyses. In the current cohort, the rate of performing NAC was significantly higher (13% vs. 4%, respectively, P < 0.0001), and 26% (222/838) underwent laparoscopic RC (LRC, without robotic assistance: n = 210, with robotic assistance: n = 12). There was no significant difference in the overall complication [69% (580/838) vs. 68% (629/919), respectively, P = 0.7284] or major complication (Grades 3-5) [25% (211/838) vs. 22% (201/919), respectively, P = 0.1022] rates between the 2 cohorts. In both cohorts, the most frequent categories were infectious, gastrointestinal, wound-related, and genitourinary. In the current cohort, the performance status (odds ratio, OR = 2.11, P = 0.0013) and operative time (OR = 1.003, P = 0.0016) remained significant predictors of major complications. NAC was not associated with any or major complications. CONCLUSIONS: Surgical complications related to RC still remain significant problems, despite the recent improvements in surgical techniques and perioperative care. NAC did not increase the complications.

Clinical and Tumor Characteristics of Patients with High Serum Levels of Growth Differentiation Factor 15 in Advanced Pancreatic Cancer.

We aimed to evaluate the association of circulating growth differentiation factor 15 (GDF-15) with cachexia symptoms and the biological activity of advanced pancreatic cancer (APC). Treatment-naïve patients with liver metastasis of APC or with benign pancreatic disease were retrospectively analyzed. Clinical data, blood samples, and biopsy specimens of liver metastasis were collected prior to anti-cancer treatment. Serum GDF-15 levels and multiple protein expressions in lysates extracted from liver metastasis were measured by enzyme-linked immuno-sorbent assay and reverse-phase protein array, respectively. The cut-off for serum GDF-15 was determined as 3356.6 pg/mL, the mean plus two standard deviations for benign pancreatic disease. The high-GDF-15 group was characterized as showing low Karnofsky performance status (KPS) (p = 0.037), poor Eastern Cooperative Oncology Group performance status (ECOG-PS) (p = 0.049), severe appetite loss (p = 0.011), and high serum levels of carbohydrate antigen 19-9 (p = 0.019) and C-reactive protein (p = 0.009). Tumors of the high-GDF-15 group expressed high levels of phosphorylated (p)JNK (p = 0.007) and pAkt (p = 0.040). APC patients with high serum GDF-15 showed signatures of cachexia and activation of the signaling pathways involving Akt and JNK in the tumor. This study indicated circulating GDF-15 could be associated with cachectic symptoms in APC.

A Guide for Businesses and Employers Responding to Novel Coronavirus disease (COVID-19): 4th edition.

The Japanese Society of Travel and Health (JSTH) and the Japanese Society for Occupational Health (JSOH) have compiled "Novel Coronavirus Information" together as a joint document, which has been shared with the public on their respective websites since February 2020. In May 11, 2020, this document was to be published as "A Guide for Businesses and Employers Responding to Novel Coronavirus Disease (COVID-19)" (hereinafter referred to as "this Guide"). This Guide was prepared for persons in charge of COVID-19 control measures in their workplace. It should be used at the discretion of each business operator according to their workplace environment. The examples of infection control measures shown in this Guide are not guaranteed to work for all situations, and they do not limit or bind actual measures being put in place. When selecting actual measures, it is necessary to obtain new information and thoroughly understand individual cases and situations. This Guide was prepared based on findings and reports about the virus and response measures taken by the relevant ministries (Ministry of Health, Labour and Welfare, Ministry of Foreign Affairs, etc.) that could be confirmed as of December 15, 2020. Therefore, the contents of this Guide may need to be modified in the future, depending on changes in the situations mentioned above. In the preparation of this Guide, every effort has been made to ensure the accuracy of currently obtainable information. However, neither JSTH or JSOH shall be held liable for any unfavorable circumstance, such as loss and damage (including lost profits and various expenses), harmful rumors, etc. experienced by a business operator, his/her employees, and any other persons concerned as a result of various measures considered/implemented using this Guide by persons responsible for infection control in the workplace.

The Japanese Medical Science Federation COVID-19 Expert Opinion English Version.

In 2020, the COVID-19 pandemic has had unprecedented impacts on various aspects of the world. Each academic society has published a guide and/or guidelines on how to cope with COVID-19 separately. As the one and only nationwide association of academic societies that represent medical science in Japan, JMSF has decided to publish the expert opinion to help patients and care providers find specifically what they want. This expert opinion is a summary of recommendations by many academic societies and will be updated when necessary. Patients that each academic society targets differ even though they suffer from the same COVID-19, and recommendations can be different in a context-dependent manner. Readers are supposed to be flexible and adjustable when they use this expert opinion.

Effect of Sucrose on Cisplatin-induced Fatigue-like Behavior in Mice: Comparison With Fructose and Glucose.

Background/Aim: Fatigue is the most common symptom in patients with cancer undergoing radiation therapy or cancer chemotherapy. However, cancer-related fatigue remains undertreated and poorly understood. Materials and Methods: Mice were administered a single dose of cisplatin (10 mg/kg, intraperitoneally) or saline (as a control) and then treated with sucrose, fructose, glucose (each at 500 or 5,000 mg/kg, orally), or saline (control) daily for 4 days. cisplatin-induced fatigue-like behavior was investigated by assessment of running activity on a treadmill. The influence of glucose intake on tumor growth was also examined in Lewis lung carcinoma (LLC)-bearing mice. Results: Administration of sucrose and glucose improved cisplatin-induced fatigue-like behavior in mice, whereas administration of fructose showed only slight antifatigue effects. Although glucose-fed mice showed increased tumor growth, this was balanced out by the powerful cytotoxicity of cisplatin. Conclusion: Sucrose, and especially glucose, may improve patient quality of life during treatment with anticancer agents by preventing fatigue without interfering with the antitumor effects of cisplatin.

Effects of hypertonic saline versus mannitol in patients with traumatic brain injury in prehospital, emergency department, and intensive care unit settings: a systematic review and meta-analysis.

BACKGROUND: Intracranial pressure control has long been recognized as an important requirement for patients with severe traumatic brain injury. Hypertonic saline has drawn attention as an alternative to mannitol in this setting. The aim of this study was to assess the effects of hypertonic saline versus mannitol on clinical outcomes in patients with traumatic brain injury in prehospital, emergency department, and intensive care unit settings by systematically reviewing the literature and synthesizing the evidence from randomized controlled trials. METHODS: We searched the MEDLINE database, the Cochrane Central Register of Controlled Trials, and the Igaku Chuo Zasshi (ICHUSHI) Web database with no date restrictions. We selected randomized controlled trials in which the clinical outcomes of adult patients with traumatic brain injury were compared between hypertonic saline and mannitol strategies. Two investigators independently screened the search results and conducted the data extraction. The primary outcome was all-cause mortality. The secondary outcomes were 90-day and 180-day mortality, good neurological outcomes, reduction in intracranial pressure, and serum sodium level. Random effects estimators with weights calculated by the inverse variance method were used to determine the pooled risk ratios. RESULTS: A total of 125 patients from four randomized trials were included, and all the studies were conducted in the intensive care unit. Among 105 patients from three trials that evaluated the primary outcome, 50 patients were assigned to the hypertonic saline group and 55 patients were assigned to the mannitol group. During the observation period, death was observed for 16 patients in the hypertonic saline group (32.0%) and 21 patients in the mannitol group (38.2%). The risks were not significant between the two infusion strategies (pooled risk ratio, 0.82; 95% confidence interval, 0.49-1.37). There were also no significant differences between the two groups in the other secondary outcomes. However, the certainty of the evidence was rated very low for all outcomes. CONCLUSIONS: Our findings revealed no significant difference in the all-cause mortality rates between patients receiving hypertonic saline or mannitol to control intracranial pressure. Further investigation is warranted because we only included a limited number of studies.

The Putative Glyoxalase 1 Inhibitor Piceatannol Exhibits Both Anxiolytic-like and Antitumor Effects in Mice.

BACKGROUND/AIM: This study aimed to determine the anxiolytic effect of a putative glyoxalase 1 inhibitor, piceatannol, as well as its antitumor activities on the stress-induced tumor growth of Lewis lung carcinoma. MATERIALS AND METHODS: The anxiolytic activities of piceatannol (1-30 mg/kg) were assessed using the elevated plus maze (EPM) test. We also evaluated the pharmacological modulation of stress-induced tumor growth; the mice were treated with piceatannol (3 and 30 mg/kg) from the 10th day till the 19th day after administration of the LLC cells. RESULTS: At the low dose (3 mg/kg), piceatannol significantly increased the time spent in the open arms of the EPM test when compared with the vehicle. At higher doses (30 mg/kg), it significantly suppressed the stress-induced enhancement of tumor growth. CONCLUSION: A low dose of piceatannol exerts an anxiolytic effect, and high doses have an antitumor effect.

The "histological replacement growth pattern" represents aggressive invasive behavior in liver metastasis from pancreatic cancer.

BACKGROUND: In the case of liver metastasis (LM), tumors showing the replacement growth pattern (RGP), in which metastatic cells infiltrate and replace hepatocytes with minimal desmoplastic reaction and inflammatory cell infiltration, associate with a poor prognosis. The heterogeneity, frequency, and prognostic value of the RGP in LM from pancreatic cancer (PCa) are not well known. METHODS: In the circumference of treatment-naïve resected LMs from patients with PCa, the heterogeneity of the GP was assessed. Next, the clinicopathological features of LMs showing the RGP in needle biopsy specimens were investigated in patients with treatment-naïve advanced PCa. RESULTS: Thirteen of the 14 (93%) in all resected LMs and 7 of the 9 (78%) in RGP component GP in resected LMs showed homogeneous GP. A RGP was found in 50% of the needle biopsy specimens of LMs obtained from 107 patients. The median overall survival times in the RGP group and non-RGP group were 3.6 and 10.4 months. Multivariate analysis identified RGP as an independent poor prognostic factor. Median value of CD8 positive percentage in RGP was lower than that in non-RGP (0.75 vs 1.46, P = .04). Median overall survival times in low CD8 groups tend to be shorter than those in high CD8 group (8.2 vs 4.2 months). CONCLUSION: Most LMs from PCa show a homogeneous GP. The RGP was observed in about a half of the LMs from PCa patients, and was identified as a poor prognostic factor.

Impact of pharmacy collaborating services in an outpatient clinic on improving adverse drug reactions in outpatient cancer chemotherapy.

BACKGROUND: Collaboration between pharmacists, doctors, and nurses in outpatient treatment is beneficial; however, such services are limited in Japan due to the lack of a healthcare reimbursement fee for outpatient pharmacy services at outpatient clinic. OBJECTIVE: We evaluated the impact of a service in which clinical pharmacists collaborated with an oncologist at an outpatient clinic in the treatment of adverse drug reactions in outpatient cancer chemotherapy. METHODS: We performed a retrospective cohort study using patients' medical records and treatment diaries. Subjects were patients who received outpatient chemotherapy via a clinical pharmacist collaboration service provided by six outpatient pharmacists and an oncologist at an outpatient clinic between June and August 2016. RESULTS: During the study period, the total number of outpatient services was 2508, with 2055 (81%) related to chemotherapy. The six outpatient pharmacists provided interventions to 498 of the 2055 cases (24%). Of the 498 interventions, 103 (20%), in addition to oncologist's prescription, were suggested treatments for adverse drug reactions due to cancer chemotherapy. Oncologists approved a total of 82 prescription suggestions from pharmacists (79%) to 63 patients. Fifty-seven percent (n = 47) of the adverse drug reactions were improved following the pharmacists' suggested prescriptions. CONCLUSIONS: This is the first study to clarify the benefits of outpatient pharmacy services in which pharmacists collaborate with oncologists at an outpatient clinic for the management of adverse drug reactions in cancer patients in Japan.

Bladder cancer detection by urinary extracellular vesicle mRNA analysis.

OBJECTIVE: Urinary extracellular vesicles (EV) could be promising biomarkers for urological diseases. In this retrospective feasibility study, we conducted biomarker screening for early stage bladder cancer using EV mRNA analysis. METHODS: Biomarker candidates were identified through RNA-seq analysis of urinary EV from patients with non-muscle invasive bladder cancer (N=3), advanced urothelial cancer (N=3), no residual tumor after TURBT (N=2), and healthy and disease controls (N=4). Diagnostic performance was evaluated by RT-qPCR in a larger patient group including bladder cancer (N=173), renal pelvis and ureter cancer (N=33), no residual tumor and non-cancer disease control (N=36). RESULTS: Urinary EV SLC2A1, GPRC5A and KRT17 were overexpressed in pT1 and higher stage bladder cancer by 20.6-fold, 18.2-fold and 29.5-fold, respectively. These genes allowed detection of non-muscle invasive bladder cancer (AUC: 0.56 to 0.64 for pTa, 0.62 to 0.80 for pTis, and 0.82 to 0.86 for pT1) as well as pT2 and higher muscle invasive bladder cancer (AUC: 0.72 to 0.90). Subgroup analysis indicated that these markers could be useful for the detection of cytology-negative/-suspicious and recurrent bladder cancers. CONCLUSION: Three urinary EV mRNA were discovered to be elevated in bladder cancer. Urinary EV mRNA are promising biomarkers of urothelial cancer and worth further investigation.

Characterization of low active ghrelin ratio in patients with advanced pancreatic cancer.

PURPOSE: Acyl ghrelin is an orexigenic peptide. Active ghrelin ratio, the ratio of acyl ghrelin to total ghrelin, has an important role in physiological functions and gastrointestinal symptoms. However, low active ghrelin ratio-related characteristics, gastrointestinal symptoms, and chemotherapy-induced gastrointestinal toxicity in patients with advanced pancreatic cancer have not been previously evaluated. The goal of this study was to identify low active ghrelin ratio-related factors in treatment-naïve advanced pancreatic cancer patients. METHODS: Patients with treatment-naïve advanced pancreatic cancer were eligible for inclusion in this study. Active ghrelin ratio and clinical parameters of patients were prospectively recorded. Factors correlated with low active ghrelin ratio and survival were analyzed. RESULTS: In total, 92 patients were analyzed. Low active ghrelin ratio-related factors were advanced age (P < 0.01), severe appetite loss (P < 0.01), and decreased cholinesterase (P < 0.01). The adverse events of grade 2 or higher anorexia tended to increase in patients with low active ghrelin ratio. However, no differences were found in survival and body composition between low and high active ghrelin ratio groups. CONCLUSIONS: Low active ghrelin ratio was related to lack of appetite and low cholinesterase and tended to be related to anorexia grade 2 or higher in patients with treatment-naïve advanced pancreatic cancer.

The C-terminal domain is sufficient for host-binding activity of the Mu phage tail-spike protein.

The Mu phage virion contains tail-spike proteins beneath the baseplate, which it uses to adsorb to the outer membrane of Escherichia coli during the infection process. The tail spikes are composed of gene product 45 (gp45), which contains 197 amino acid residues. In this study, we purified and characterized both the full-length and the C-terminal domains of recombinant gp45 to identify the functional and structural domains. Limited proteolysis resulted in a Ser64-Gln197 sequence, which was composed of a stable C-terminal domain. Analytical ultracentrifugation of the recombinant C-terminal domain (gp45-C) indicated that the molecular weight of gp45-C was about 58 kDa and formed a trimeric protomer in solution. Coprecipitation experiments and a quartz crystal microbalance (QCM) demonstrated that gp45-C irreversibly binds to the E. coli membrane. These results indicate that gp45 shows behaviors similar to tail-spike proteins of other phages; however, gp45 did not show significant sequence homology with the other phage tail-spike structures that have been identified.

Construction of neourethra using flipped anterior bladder wall tube in a prepubertal girl with complete disruption of urethra.

A rare case of urethral construction using flipped anterior bladder wall tube in an 8-year-old girl with complete disruption of the urethra and vagina accompanying pelvic fracture was reported. Following a split of the pubic symphysis, the vagina was reconstructed with end-to-end anastomosis. The neourethra was constructed tubularizing and flipping anterior bladder wall flap caudally to proximal site of the original urethra after fascial sling procedure. After catheter removal, this girl has been continent and voided normally. In conclusion, flipped anterior bladder wall tube technique for urethral construction is suitable in prepubertal girls with complete disruption of the urethra.

Passive smoking is associated with lower serum HDL-C levels in school children.

BACKGROUND: In recent years, a number of studies have reported that exposure to environmental tobacco smoke (ETS) reduces high-density lipoprotein cholesterol (HDL-C) levels in children, as well as in adults. Further, a number of countries have indicated that passive smoking increases the risk of early arteriosclerosis onset. Here, to evaluate the effects of ETS exposure, we conducted a cross-sectional epidemiological study on primary school children in Japan using answers from a questionnaire survey, as well as urine cotinine and lipid metabolism-related variable measurements. METHODS: A total of 121 sixth-grade primary school children participated in this study by completing a questionnaire about their food intake, lifestyle and family smoking habits. Early in the morning, we also measured height, weight, blood pressure, serum levels of total cholesterol, triglyceride, HDL-C, and blood sugar, as well as urine levels of cotinine and creatinine under unfed conditions. RESULTS: From the questionnaire, 40 and 81 children reported being exposed and not exposed to ETS, respectively. Serum HDL-C levels, which were adjusted for the degree of corpulence and exercise habits, were significantly lower in the passive smoker group than the non-passive-smoker group (65.3 and 72.1 mg/dL, respectively; P= 0.012). In addition, proportional differences in serum HDL-C levels were also observed based on the amount of cigarettes smoked at home by family members of the child. CONCLUSIONS: Results suggest that ETS exposure at home is associated in a dose-related manner with lower serum HDL-C levels in primary school children. In addition, our results suggest that smoking in the presence of children who are not usually exposed to ETS increases the risk of arteriosclerosis. Given these findings, we strongly recommend the establishment of anti-passive-smoking measures.

Evaluation of the control banding method--comparison with measurement-based comprehensive risk assessment.

The control banding method, or "control banding", is a simplified risk assessment system for chemical handling tasks. This system is supposed to provide assessment results of reasonable quality without expert involvement. The objective of this study was to evaluate the appropriateness of control banding judgment on the basis of workplace safety. A common approach for assessing workplace risk, which is called "comprehensive risk assessment" in this study, is to measure workers' exposure and compare it with relevant occupational exposure limits. Risk assessment was performed with control banding (COSHH Essentials, UK) at 12 workplaces of a petroleum company in Japan, where health risks had already been assessed separately through comprehensive risk assessment by experts and control technologies implemented accordingly. The obtained control banding judgments were then examined with regard to their adequacy by comparing them with existing control technologies. There was majority of cases (seven) where judgments by control banding were identified as "over-controlled"; there was no judgments identified as "under-controlled". Control banding also requested the seeking of expert advice in the majority of cases (eight). Thus, it was demonstrated that control banding tends to provide safe-sided judgment. A possible interpretation of this is that control banding is inherently designed to secure workplace safety by compensating for its insufficient exposure information with safe-sided judgment criteria and by requiring experts' intervention in high-risk cases. Control banding could be widely and effectively utilized in Japan, especially by employers in small enterprises, provided that the above characteristics are pre-acknowledged and health experts are made available. To this aim, it is essential to develop new local health experts and establish institutional mechanisms for facilitating employers' access to expert advice. It should however be noted that the number of workplaces evaluated in this study was small.

A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death.

We describe the synthesis and properties of a small molecule mimic of Smac, a pro-apoptotic protein that functions by relieving inhibitor-of-apoptosis protein (IAP)-mediated suppression of caspase activity. The compound binds to X chromosome- encoded IAP (XIAP), cellular IAP 1 (cIAP-1), and cellular IAP 2 (cIAP-2) and synergizes with both tumor necrosis factor alpha (TNFalpha) and TNF-related apoptosis-inducing ligand (TRAIL) to potently induce caspase activation and apoptosis in human cancer cells. The molecule has allowed a temporal, unbiased evaluation of the roles that IAP proteins play during signaling from TRAIL and TNF receptors. The compound is also a lead structure for the development of IAP antagonists potentially useful as therapy for cancer and inflammatory diseases.