Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity.

The epidermis is the outermost layer of the skin and the body's primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.

Beneficial Effects of Dietary Nitrite on a Model of Nonalcoholic Steatohepatitis Induced by High-Fat/High-Cholesterol Diets in SHRSP5/Dmcr Rats: A Preliminary Study.

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. Endothelial dysfunction caused by hepatic lipotoxicity is an underlying NASH pathology observed in the liver and the cardiovascular system. Here, we evaluated the effect of dietary nitrite on a rat NASH model. Stroke-prone, spontaneously hypertensive 5/Dmcr rats were fed a high-fat/high-cholesterol diet to develop the NASH model, with nitrite or captopril (100 mg/L, each) supplementation in drinking water for 8 weeks. The effects of nitrite and captopril were evaluated using immunohistochemical analyses of the liver and heart tissues. Dietary nitrite suppressed liver fibrosis in the rats by reducing oxidative stress, as measured using the protein levels of nicotinamide adenine dinucleotide phosphate oxidase components and inflammatory cell accumulation in the liver. Nitrite lowered the blood pressure in hypertensive NASH rats and suppressed left ventricular chamber enlargement. Similar therapeutic effects were observed in a captopril-treated rat NASH model, suggesting the possibility of a common signaling pathway through which nitrite and captopril improve NASH pathology. In conclusion, dietary nitrite attenuates the development of NASH with cardiovascular involvement in rats and provides an alternative NASH therapeutic strategy.

[A Case of Rapidly Growing Sarcomatoid Urothelial Carcinoma of the Renal Pelvis and Ureter].

75 year-old man followed up regularly for the treatment of lung cancer came to our hospital with a chief complaint of general malaise. Blood test results showed deterioration in the renal function, and computed tomography (CT) confirmed left hydronephrosis. He was admitted to the hospital with the diagnosis of obstructive pyelonephritis. Despite antibiotic therapy after the left ureteral stent placement, CT on day 19 of hospitalization showed an enlarged soft tissue shadow along the renal pelvis and ureter, which was suspected to be peripelvic urinary extravasation caused by stent occlusion. We decided that conservative treatment would not improve his condition and conducted surgical therapy considering the possibility of malignancy. Intraoperatively, viscous and fragile tumor affected the renal pelvis and ureter. The operation resulted in left nephrectomy because radical resection was impossible. The pathological diagnosis was sarcomatoid urothelial carcinoma of the renal pelvis with ureter origin. He died due to multipleorgan failureon day 20 after theope ration. Were port a caseof sarcomatoid urothelial carcinoma in the upper urinary tract that was difficult to diagnose preoperatively based on imaging studies.

Fucoxanthin inhibits hepatic oxidative stress, inflammation, and fibrosis in diet-induced nonalcoholic steatohepatitis model mice.

Nonalcoholic steatohepatitis (NASH) is associated with hepatocyte injury, excessive oxidative stress, and chronic inflammation in fatty liver, and can progress to more severe liver diseases, such as cirrhosis and hepatocellular carcinoma. However, currently there are no effective therapies for NASH. Marine carotenoid, fucoxanthin (Fx), abundant in brown seaweeds, has variable biological properties, such as anti-cancer, anti-inflammatory, anti-oxidative and anti-obesity. However, the effect of Fx on the development of NASH has not been explored. We investigated the protective effects of Fx in diet-induced NASH model mice fed choline-deficient L-amino acid-defined high fat diet (CDAHFD). Fx administration significantly attenuated liver weight gain and hepatic fat accumulation, resulting in the alleviation of hepatic injury. Furthermore, the Fx-fed mice, not only exhibited reduced hepatic lipid oxidation, but also decreased mRNA expression levels of inflammation and infiltration-related genes compared to that of the CDAHFD-fed mice. Moreover, fucoxanthinol and amarouciaxanthin A, two Fx metabolites exerted anti-inflammatory effects in the liver via inhibiting the chemokine production in hepatocytes. In case of fibrosis, one of the features of advanced NASH, the expression of fibrogenic factors including activated-hepatic stellate cell marker was significantly decreased in the liver of Fx-fed mice. Thus, the present study elucidated that dietary Fx not only inhibited hepatic oxidative stress and inflammation but also prevented early phase of fibrosis in the diet-induced NASH model mice.

[The Safety of Laparoscopic Radical Cystectomy during Initial Phases in a Japanese Multicenter Cohort].

We evaluated the safety of laparoscopic radical cystectomy (LRC) during initial phases and its learning curve in a Japanese multicenter cohort by studying 436 patients who underwent LRC with no robot assistance at 10 institutions in Japan. We divided the patients into three groups according to cumulative surgical volume at each institution (first 10 cases, 11-30 cases, after 31 cases in each institution), and compared perioperative and pathologic variables among the three groups. The first, second, and third groups included 100, 166, 170 patients, respectively. The preoperative variables were similar in the three groups except for the rate of neoadjuvant chemotherapy. The methods of LRC procedure, such as urinary diversion, the extent of lymph node dissection, and concomitant urethrectomy or nephroureterectomy, were similar in the three groups. Mean operative time was 629, 562 and 531 minutes, respectively, and mean blood loss was 755, 650 and 435 ml, respectively. Both values decreased over time with the institution's experience. There was no significant difference among the three groups in the rate of positive surgical margin, the number of retrieved lymph nodes, and the rate of intra- and postoperative complications. LRC was safely performed during initial phases with an acceptable complication rate and without compromising oncological results, although operative time was longer and blood loss increased.

[A Surgically Resected Case of Lung Metastases and Sister Mary Joseph's Nodule 24 Months after Operation for Pancreatic Cancer].

Metastatic umbilical tumors from internal malignancy, known as Sister Mary Joseph's Nodule(SMJN), are a relatively rare prognostic sign. An 86-year-old woman with pancreatic body carcinoma underwent distal pancreatectomy for D2 lymph node removal in 20XX. No peritoneal dissemination was found at that time. Postoperative chemotherapy was not administered due to her age. Eighteen months postoperatively, tumor marker values increased and chest computed tomography(CT) revealed a single mass in the left lung. We resected the suspected lung metastasis. Positron emission tomography-CT performed 23 months postoperatively for increased tumor marker values after resection showed a 18F-fluorodeoxyglucose accumulation ofapproximately 4 cm in the umbilicus. The diagnosis by biopsy was umbilical metastasis ofthe pancreatic cancer. No recurrence or other metastases were found, so we performed an umbilical tumor resection and abdominoplasty 24 months postoperatively. No peritoneal dissemination was found in her abdomen and the ascites cytology was negative. The tumor was in the subcutaneous tissue; thus, the possibility of infiltration from the primary site or peritoneal dissemination was low. The tumor marker values decreased after the resection. She was followed-up without postoperative anticancer chemotherapy. However, the tumor marker values increased again, so chemotherapy was initiated. We report a case ofresection of pancreatic cancer and operation for lung and umbilical metastases of pancreatic cancer.

[Percutaneous Fibrin Glue Injection for Persistent Urinary Leakage after Partial Nephrectomy : A Case Report].

A 69-year-old man with left atrophic kidney was referred to our hospital because of a 5.7 cm solid mass in the lower pole of right kidney revealed by computed tomography for evaluation of aortic aneurysm. An open transperitoneal partial nephrectomy was performed, and final pathological diagnosis was clear cell carcinoma, grade 2, pT1b, pNx. One month postoperatively, a computed tomography revealed 16 cm retroperitoneal fluid collection which was diagnosed as urinoma due to urinary leakage from partial nephrectomy scar of the right lower calyx. Following percutaneous drainage of a 6 Fr Pigtail catheter, 6 Fr double-J ureteral stent and urethral catheter were placed, but the discharge through the percutaneous drain continued to be 700 to 1,000 ml/day. Forty-one days after drainage, two open-end catheters (5 Fr) were directed into the urinary fistula lumen through the percutaneous tract and 6 ml of fibrin glue was injected under fluoroscopic guidance. Four days later, another 2 ml of fibrin glue was injected because of a small amount of residual urinary leakage and percutaneous drainage catheter was removed. Thereafter, urinary leakage was completely cured and ureteral stent and urethral catheter were removed.

[Risk Factors for Mortalityin Patients with Urosepsis].

Urosepsis is not uncommon and sometimes causes a critical condition including death. We retrospectivelyanaly zed the risk factors for mortalityin urosepsis. We treated 80 patients as urosepsis from 2010 to 2014 in our hospital. Five patients (6%) died within 30 days of hospitalization. The median age of the patients who died of urosepsis was 92 years (range, 83-95 years). The main causes of urosepsis were complicated pyelonephritis in 4 patients and emphysematous pyelonephritis in one. In the subgroup analysis of elderly patients over 75 years old, bad performance status and lower serum albumin were significantlyrelated to mortality(p ＝0.033, 0.046). The elderlypatients, especiallywith bad performance status and lower serum albumin, are more likelyto die.

Subclassification of high-risk clinically organ-confined prostate cancer for early cancer-specific mortality after radical prostatectomy.

OBJECTIVE: High-risk clinically localized prostate cancer is seen in a highly heterogeneous population with a wide variation of clinical aggressiveness and a novel subclassification for the better prediction of clinical outcomes is needed. The aim of this study is to validate a modified D'Amico risk criteria for substratification of high-risk prostate cancer with regard to the prediction of biochemical recurrence, clinical progression-free survival or prostate cancer-specific mortality after radical prostatectomy. METHODS: We conducted a retrospective multicenter cohort study including 461 clinically organ-confined (cT1-2), D'Amico high-risk prostate cancer patients who underwent radical prostatectomy with pelvic lymph node dissection. The modified criteria subclassified D'Amico high-risk patients into high-risk (n = 189, single high-risk parameter and two low-risk parameters) and very high-risk (n = 272, at least one more intermediate or high-risk parameter in addition to the qualifying high-risk parameter) groups. Biochemical recurrence-free survival, clinical progression-free survival, prostate cancer-specific mortality and overall survival were analyzed. RESULTS: The very high-risk group, compared with high-risk group, had significantly poorer biochemical recurrence (5- and 10-year biochemical recurrence-free rates: 52.8 vs 73.9% and 42.1 vs 61.7%, respectively, P < 0.0001), clinical progression-free survival (5- and 10-year survivals: 91.8 vs 98.2% and 80.5 vs 98.2%, respectively, P = 0.0013) and prostate cancer-specific mortality (5- and 10-year mortalities: 2.5 vs 0.0% and 6.7 vs 0.0%, respectively, P = 0.0124). CONCLUSION: D'Amico high-risk patients can achieve very favorable outcomes unless they are classified as very high risk. Our novel subclassification method is very simple and useful for better patient counseling and decision-making in the pretreatment setting.

[Advanced Adenocarcinoma of the Bladder after Augmentation Gastrocystoplasty].

A 29-year-old woman had undergone gastrocystoplasty with Mitrofanoff appendicovesicostomy for urethral trauma at 9 years of age. Since then, she was being followed up for performing clean intermittent self-catheterization at regular intervals. Twenty years after the surgery, she presented with gross hematuria. Ultrasonographic findings revealed bilateral hydronephrosis. Cystoscopy and computed tomography (CT) revealed invasive bladder cancer with pelvic lymph node metastases. A biopsy confirmed the diagnosis of adenocarcinoma with signet ring cell carcinoma. Subsequently, neo-adjuvant combination chemotherapy with TS-1 and cisplatin (CDDP) was initiated, which was followed by open radical cystectomy with extended pelvic lymphadenectomy. The tumor was found to infiltrate from the anastomotic site into the entire native bladder and histopathological diagnosis was muscle invasive adenocarcinoma with neuroendocrine differentiation and lymph node metastasis (ypT3bN2). TS-1 was continued as adjuvant chemotherapy and the patient did not have any evidence of recurrence for 12 months postoperatively.

CLINICAL OUTCOMES OF EXTERNAL-BEAM RADIOTHERAPY COMBINED WITH NEOADJUVANT ANDROGEN DEPRIVATION THERAPY FOR HIGH-RISK PROSTATE CANCER.

(Purpose) We investigated the outcome of external-beam radiotherapy (EBRT) with neoadjuvant androgen deprivation therapy (NeoADT) for high-risk prostate cancer defined by National Comprehensive Cancer Network (NCCN) guideline. (Patients and method) From 2002 to 2013, 70 patients with high-risk prostate cancer (PSA ≥20 ng/ml or clinical T stage ≥T3a, Gleason score ≥8) were treated with NeoADT and EBRT. EBRT consisted of three-dimensional conformal or intensity modulated radiotherapy with or without whole-pelvic radiation. Biochemical failure was defined according to the Phoenix definition. Biochemical progression-free survival (bPFS) and overall survival (OS) were calculated by Kaplan-Meier method, and prognostic factors for bPFS were analyzed by using the Cox proportional hazard model. (Result) The median age and initial prostate-specific antigen (PSA) level were 72 years old and 25.2 ng/ml, respectively. 43 patients had PSA level ≥20 ng/ml, 51 patients had clinical stage ≥T3a, 27 patients had Gleason score ≥8. The number of risk factors patients possessed was 1 (RiskN-1) in 31 patients, 2 (RiskN-2) in 27 patients and 3 (RiskN-3) in 12 patients. Median EBRT dose and duration of Neo ADT were 74 Gy and13.0 months, respectively. Whole-pelvic radiation was administered in 7 patients. After median follow-up of 4.8 years, biochemical and clinical failure occurred in 23 and 2 patients, respectively. No patients died of cancer. Five-year/8-year bPFS and OS were 63%/54% and 100%/91%, respectively. In multivariate analysis, three high-risk factor of NCCN guideline (PSA, clinical stage, Gleason score) did not predict outcome after EBRT independently, but RiskN (-1 vs -2, 3, HR 35.35, 95%CI 2.51-498.05, p<0.01) and pre-EBRT PSA (continuous, hazard ratio 1.31, 95%CI 1.01-1.71, p<0.05) were the significant predictors of bPFS. Five-year/8-year bPFS in RiskN-1 group and RiskN-2 or -3 group were 89%/79% and 47%/39%, respectively. Grade 3/4 adverse events (CTCAE ver4.0-JCOG) occurred in 2 patients. (Conclusion) Median dose of 74 Gy EBRT with intermediate-term NeoADT was safe and beneficial for high-risk prostate cancer. The number of risk factors and pre-EBRT PSA level were the independent prognostic factors for biochemical progression-free survival.

[THE IMPACT OF LOWER URINARY TRACT SYMPTOMS ON GENERIC HEALTH-RELATED QUALITY OF LIFE IN MALE PATIENTS WITHOUT CO-MORBIDITY].

PURPOSE: We investigated the impact of lower urinary tract symptoms (LUTS) on generic health-related quality of life (HRQOL) in male patients without co-morbidity. PATIENTS AND METHOD: From 2003 to 2011, a total 567 men who presented out urological department completed the questionnaires including International Prostate Symptom Score (IPSS), incontinence-frequency score (IFS) from the UCLA prostate cancer index, MOS 36-Item Short-Form Health Survey (SF-36). Among 230 patients with no coexisting morbidity, the relations between each LUTS score of IPSS indices and IFS and 8 domain scores of SF-36 were analyzed by Pearson's product-moment correlation and stepwise multiple regression analysis. RESULT: Univariate analysis showed that the IFS had a significant correlation with all of 8 domain scores of SF-36, and also the IPSS item scores of urgency, nocturia and straining correlated significantly with multiple domain scores of SF-36. In multiple regression analysis, the proportionate contributions of LUTS to each SF-36 domain scores were low (R2 was 10% or less). Incontinence was considered as the most influential factor that had a negative impact on HRQOL in 7 SF-36 domains of physical functioning, role-physical, bodily pain, general health perception, vitality, social functioning and mental health. Additionally, nocturia, straining and urgency were significantly associated with deficit of HRQOL in 4 SF-36 domains (role-physical, general health perception, role-emotional, mental health), 2 domains (bodily pain, social functioning) and 1 domain (role-emotional) of SF-36, respectively. CONCLUSION; Among LUTS, incontinence, nocturia and straining were the most important symptoms in association with the negative impact on generic HRQOL measured by SF-36.

[Rechallenge of everolimus for metastatic renal cell carcinoma after recovery from grade 3 interstitial lung disease: a case report].

We report a case of the rechallenge of everolimus for metastatic renal cell carcinoma (RCC) after successful recovery from grade 3 interstitial lung disease (ILD). A 76-year-old man with metastatic RCC developed grade 3 ILD one month after the initiation of everolimus therapy (10 mg/day). ILD subsided in 4 months after the withdrawal of everolimus and treatment with corticosteroids. Half dose (5 mg/day) of everolimus was rechallenged for 9 months until another grade 3 ILD developed. Everolimus kept the disease under control for 13 months including the discontinuation period.

[Observational study on urinary status following HoLEP].

We assessed the safety, and postoperative urinary status of holmium laser enucleation of the prostate (HoLEP) for the treatment of benign prostatic hyperplasia (BPH). Of the initial 117 patients who underwent HoLEP from November 2004 to March 2011, 49 were followed up for two yearsor longer. These 49 patients were evaluated once preoperatively, and at the 3rd, 6th, 12th, 24th, 48th, and 60th month postoperatively using International Prostate Symptom Scores (I-PSS) total and sub-score, quality of life score (QOL), maximum flow rate (Qmax), and post-voiding residual urine volume (PVR). The median estimated transition zone and enucleated volume were 45. 1 and 47. 9 g, respectively. Evaluation scores showed significant improvementsthroughout the follow-up. I-PSS total scoresimproved from 21 points(before surgery) to 6 points(12 monthsafter surgery), QOL scoresimproved from 5 pointsto 2 points, Qmax improved from 6.8 ml/s to 17.4 ml/s, and PVR improved from 101 ml to 26 ml, respectively. Transient urinary incontinence was noted in 14 patients (28.5%). One case showed a Clavien grade 3 complication of postoperative bleeding. No blood transfusion or re-surgery for BPH was required. In conclusion, HoLEP proved to be a safe and effective therapy, with potential to become a new gold standard for treating BPH.

[Risk factors for recurrence in pT3aN0M0 renal cell carcinoma according to 2009 TNM classification].

The TNM classification of renal cell carcinoma was updated in 2009. In this new classification system, T3a consists of tumors with renal vein involvement and tumors with fat invasion. To assess risk factors for recurrence, we retrospectively reviewed 89 patients with pT3aN0M0 renal cell carcinoma who underwent radical or partial nephrectomy between 1992 and 2011. Analyzed risk factors for recurrence were age, gender, tumor size, grade, v factor, infiltrative growth (INF), adjuvant interferon, surgical technic (radical or partial), clinical T classification, renal vein thrombus, and pathological fat invasion. The median follow-up was 52.2 months. Five-year recurrence-free survival rate was 69.0%. Within the pT3a subcategory, the five-year recurrence-free survival was 76.7% in patients with fat invasion only, 42.9% in patients with renal vein thrombus only, and 28.6% in patients with the two concomitant features. On univariate analysis, tumor size, grade, INF, clinical T classification, and renal vein thrombus were significantly associated with recurrence. On multivariate analysis, INF (p = 0.023, HR 3.927) was an independent risk factor for recurrence. In pT3aN0M0 renal cell carcinoma, INF significantly affects recurrence, and patients with both fat invasion and renal vein thrombus have worst prognosis.

[The safety and efficacy of sunitinib using a modified regimen (2 weeks on/1 week off) for treatment of metastatic renal cell carcinoma].

We prospectively investigated the safety and efficacy of sunitinib using a modified regimen (2 weeks on/1 week off) in 24 patients (22 males, 2 females ; age range 39-86 years, median 64 years) with metastatic renal cell carcinoma (RCC). During the observation period (3-62 weeks, median 21 weeks), thrombocytopenia was seen in 13 (54.2%), leukopenia in 11 (45.8%), hand-foot syndrome in 5 (20.8%), hypertension in 4 (16.7%), and hypothyroidism in 3 (12.5%) patients, while grade 3 or higher adverse events were found in 4 (16.7%), 1 (4.2%), 1 (4.2%), 2 (8.3%), and 0 patients, respectively. Of the 21 patients evaluable for response, 5 (23. 8%) showed partial response, 8 (38.1%) stable disease, and 8 (38.1%) progressive disease. This new modified regimen may lead to a reduction in adverse events for treatment of patients with metastatic RCC as a substitute for the standard dosing regimen of sunitinib.

Cytotoxic T Lymphocytes Regenerated from iPS Cells Have Therapeutic Efficacy in a Patient-Derived Xenograft Solid Tumor Model.

Current adoptive T cell therapies conducted in an autologous setting are costly, time consuming, and depend on the quality of the patient's T cells. To address these issues, we developed a strategy in which cytotoxic T lymphocytes (CTLs) are regenerated from iPSCs that were originally derived from T cells and succeeded in regenerating CTLs specific for the WT1 antigen, which exhibited therapeutic efficacy in a xenograft model of leukemia. In this study, we extended our strategy to solid tumors. The regenerated WT1-specific CTLs had a strong therapeutic effect in orthotopic xenograft model using a renal cell carcinoma (RCC) cell line. To make our method more generally applicable, we developed an allogeneic approach by transducing HLA-haplotype homozygous iPSCs with WT1-specific TCR α/ß genes that had been tested clinically. The regenerated CTLs antigen-specifically suppressed tumor growth in a patient-derived xenograft model of RCC, demonstrating the feasibility of our strategy against solid tumors.

Circadian rhythms of micturition during jet lag.

Micturition behavior follows regular day/night fluctuations, and unwanted increase in micturition could occur during night in jet lag condition. To clarify the effect of jet lag on micturition behavior, we simultaneously detected circadian micturition patterns and locomotor activity rhythms of mice under experimental jet lag conditions, by applying the improved automated Voided Stain on Paper (aVSOP) method. When wild-type (WT) mice were phase-advanced for 8 hours, day-night variation of micturition was disrupted suddenly, and this irregular daily micturition continued until 8 days, although their activity rhythms entrained gradually day by day until 8 days. We also examined how jet lag induced changes of micturition in Per-null mice lacking Per1, Per2 and Per3 genes, whose endogenous clock is completely disrupted. We found both micturition and locomotor activity of Per-null mice promptly entrained to the new LD cycle. These findings suggest that the irregular micturition during jet lag is caused along with the gradual shift of the endogenous clock, and paradoxically, jet lag-associated abnormality was absent when endogenous circadian oscillations were genetically disrupted.