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Polymorphisms in the 5-flanking region of the tumor necrosis factor (TNF)-α gene were examined to study the genetic background of type 1 diabetes in Japanese. Five different biallelic polymorphisms were examined in 136 type 1 diabetic patients and 300 control subjects. The frequencies of individuals carrying TNF-α-857T allele (designated as TNFP-D allele) or -863A/-1,031C allele (designated as TNFP-B allele) were significantly increased in the patients as compared with the controls. Since these TNF-α alleles are in linkage disequilibria with certain DRB1 and HLA-B alleles, two-locus analyses were carried out. The TNFP-D allele did not increase the risk in either the presence or absence of the DRB1∗0405 or HLA-B54 allele, while the DRB1∗0405 and HLA-B54 alleles per se could confer susceptibility in both the TNFP-D allele-positive and -negative populations. Moreover, an odds ratio was remarkably elevated in the population carrying both DRB1∗0405 and HLA-B54. Similarly, the TNFP-B allele did not show significant association with the disease in either the HLA-B61-positive or -negative population, while the HLA-B61 allele could significantly increase the risk in the TNFP-B allele-positive population. These data suggest that the associations of TNFP-D and -B alleles may be secondary to their linkage disequilibria with the susceptible HLA class I and class II alleles. Because HLA-B and DRB1 genes were independently associated, both of these genes may be contributed primarily to the pathogenesis of type 1 diabetes in Japanese. [ABSTRACT FROM AUTHOR]

Aging has pronounced effects on mammalian tissues and cells, but the impacts of aging on salivary gland function are relatively unknown. This study aims to evaluate the effects of aging on submandibular gland (SMG) and parotid gland (PG) functions in the male senescence-accelerated mouse. In vivo analysis at the systemic level revealed that salivary secretion induced by pilocarpine, a muscarinic agonist, from the SMG was significantly decreased in aged mice, whereas salivary secretion from the PG was not affected. To evaluate organ-level function, the SMG was perfused with the muscarinic agonists carbachol and calcium ionophore A23187 ex vivo to induce salivary secretion, and decreased saliva production was also observed in the aged SMG. Histological analysis revealed the presence of CD4-positive lymphocytes infiltrating the aged SMG. Furthermore, real-time PCR revealed that the aged SMG exhibited accelerated cell aging, increased levels of the inflammatory cytokine interleukin-6, and decreased mRNA levels of the water channel protein aquaporin-5 (AQP5). In summary, these results demonstrate that SMG function in aged mice was diminished, and that cell senescence, chronic inflammation, and the decreased gene expression of AQP5 are the likely causes of hyposalivation in the SMG of aged mice.

Corticosteroids are used in the treatment of many diseases; however, they also induce various side effects. Dexamethasone is one of the most potent corticosteroids, and it has been reported to induce the side effect of impaired salivary gland function. This study aimed to evaluate the effects of dexamethasone on mouse submandibular gland function to gain insight into the mechanism of dexamethasone-induced salivary hypofunction. The muscarinic agonist carbachol (CCh) induced salivary secretion and was not affected by short-term dexamethasone treatment but was decreased following long-term dexamethasone administration. The expression levels of the membrane proteins Na + -K + -2Cl - cotransporter, transmembrane member 16A, and aquaporin 5 were comparable between the control and long-term dexamethasone treatment groups. The CCh-induced increase in calcium concentration was significantly lower in the presence of extracellular Ca 2+ in the long-term dexamethasone treatment group compared to that in the control group. Furthermore, CCh-induced salivation in the absence of extracellular Ca 2+ and Ca 2+ ionophore A23187-induced salivation was comparable between the control and long-term dexamethasone treatment groups. Moreover, salivation induced by the Ca 2+ -ATPase inhibitor thapsigargin was diminished in the long-term dexamethasone treatment group. In summary, these results demonstrate that short-term dexamethasone treatment did not impair salivary gland function, whereas long-term dexamethasone treatment diminished store-operated Ca 2+ entry, resulting in hyposalivation in mouse submandibular glands.

Background: CT-guided marking technique is rarely used in abdominal or urologic surgery. We developed and performed a marking technique for a small tumor, undetectable by ultrasound, using CT guidance before laparoscopic resection of the tumor. Case Presentation: A 73-year-old woman with a history of breast cancer underwent right colectomy with D3 lymph node dissection for ascending colon cancer. Five years after the operation, a solitary tumor was found in the right pararenal region of the retroperitoneal space on enhanced abdominal CT. The tumor was 20 mm in diameter and undetectable by ultrasound, so we performed a marking technique using CT guidance before the operation. Placing the patient in a prone position on the CT table, a 22-gauge needle was inserted into the Gerota's fascia percutaneously and a mixed fluid containing India ink and Iopamidol was injected para to the tumor by the radiologist. During the surgery, the marker was clearly identified and the cutting line was determined to ensure a sufficient surgical margin. The tumor was laparoscopically resected as planned. The histopathologic diagnosis was adenocarcinoma, compatible with metastasis of colon cancer. The postoperative course was uneventful and the patient remained free of disease at 10 months after surgery. Conclusion: When resecting small tumors or tumors with an irregular margin, a marking technique is conducted before the surgery. But, preoperative CT-guided marking has not been applied generally for resection of intraabdominal lesion yet. CT-guided marking can be effective when performing minimally invasive and curable surgery on small tumors. This is the first report of an effective CT-guided marking before retroperitoneal laparoscopic tumorectomy. We believe that this technique provides an important therapeutic option for small tumors that may be undetectable by ultrasound., Competing Interests: No competing financial interests exist.

We examined whether exposure to mild hyperbaric oxygen inhibits the decrease of dopaminergic neurons in the substantia nigra of a neurotoxic animal model with Parkinson's disease. Mice injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and probenecid twice a week were divided into two groups: mice with mild hyperbaric oxygen and those without. The mice with mild hyperbaric oxygen were exposed to 1317hPa with 45% oxygen for 3h, three times a week. The decrease in dopaminergic neurons of mice with Parkinson's disease was inhibited by 11 weeks of exposure to mild hyperbaric oxygen. We conclude that exposure to mild hyperbaric oxygen is effective in preventing the progression of Parkinson's disease., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Hypofunction of different organs in the body is associated with diabetes, including in the oral cavity. Diabetes is often associated with xerostomia, but the underlying mechanism is not well characterized. Thus, the mechanisms underlying diabetes-induced xerostomia were investigated in this study in KK-A y mice as an experimental model of type 2 diabetes., Methods: The mechanisms involved in diabetes-induced xerostomia were investigated using the ex vivo glandular perfusion technique, histological analysis, and immunohistochemical and intracellular signaling analyses., Results: Ex vivo submandibular gland secretions from KK-A y mice decreased by 30% following stimulation with 0.3 μmol/L carbachol (CCh), a cholinergic agonist. Acinar cell weight was comparable between KK-A y and control mice, whereas duct cell weight was significantly greater in KK-A y mice. Concentrations of Na + and Cl - in the secreted saliva decreased significantly in KK-A y mice, supporting the finding of increased ductal tissue in KK-A y mice. Immunohistochemistry revealed no significant differences between KK-A y and control mice in terms of the expression of Cl - and water channels, Na + -K + -2Cl - cotransporters, and membrane proteins critical for fluid secretion. Cellular signaling analysis revealed that the increase in [Ca 2+ ] i in response to 0.3 μmol/L CCh was reduced by 30% in KK-A y mice, although there was no significant difference in the thapsigargin (1.0 μmol/L)-induced increase in store-depleted calcium between KK-A y and control mice., Conclusions: These results demonstrate that submandibular fluid secretion is diminished in KK-A y mice because of a diminished increase in [Ca 2+ ] i . Duct cell weight increased in KK-A y mice, possibly leading to increased ion reabsorption and thus decreased Na + and Cl - concentrations in the secreted saliva., (© 2017 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.)

Herein, we report two cases of urethral clear cell carcinoma in two patients who had previously undergone radical hysterectomyfor utetine cancer. Case 1 presented with bloodyvaginal discharge and case 2 presented with acute urinaryretention. Magnetic resonance imaging revealed a periurethral tumor in both cases. Both cases were suspected to be recurrence at first. However, pathological findings of the transurethral resection-biopsyshowed clear cell adenocarcinoma in both cases. Subsequentlyradical cystourethrectomy and pelvic lymphadenectomy were performed in both cases. Surgical findings showed tumor invasion of the vaginal muscularis in case 1 and invasion of the anterior wall of the vagina and bladder neck in case 2. Although adjuvant postoperative therapywas not performed, there has been no evidence of recurrence to date.

Objective The current study investigated whether or not patients taking multiple daily oral medications for lifestyle-related chronic diseases would have positive perspectives on changing one of their medications to a once-weekly one. Methods A total of 1,071 Japanese outpatients participated in the current study. We performed a questionnaire-based survey and compared the current satisfaction with the ongoing daily oral treatment (current daily-only treatment) and an expected satisfaction with an imaginary oral treatment changing one of their daily oral medications to a once-weekly oral medication (imaginary daily-and-weekly treatment). Results Medications were taken for diabetes mellitus in 72% of the patients, for dyslipidemia in 54%, and for circulatory diseases, including hypertension, in 73%. Compared to their satisfaction with the current daily-only treatment, an expected satisfaction with the imaginary daily-and-weekly treatment was on average significantly attenuated (p<0.001, effect size d=0.49). The prevalence of a higher satisfaction score for the imaginary daily-and-weekly treatment versus the current daily-only treatment was 30% in the overall population. The prevalence was 59%, 40%, 29%, 14%, and 8% in the 1st, 2nd, 3rd, 4th, and 5th quintile of the satisfaction score with the current daily-only treatment (p<0.001 for trend). Conclusion Treatment satisfaction would be on average attenuated if one of the multiple daily oral medications was changed to a once-weekly one. Improvement in the satisfaction was less expected in the subgroup that was more satisfied with the current daily-only treatment.

This report presents a new case of mucormycosis encountered in penguin characterized by morphological variation of hyphae and presence of sporangia with numerous sporangiospores. A 4.5-year-old Magellanic penguin (Spheniscus magellanicus) died after exhibiting anorexia, poor nutritional condition and dyspnea. Multiple nodular lesions were observed in the thoracic and abdominal regions. Histopathologically, hyphae of various sizes were seen in the lungs, air sac and nodular lesions. Myriad sporangiospores and several sporangia were observed in/around the bronchi or parabronchi. The very narrow and short hyphae in the nodules were not consistent with the characteristics of Mucorales. However, for most hyphae, including those in the nodules, sporangiospores and sporangia, immunohistochemistry revealed Mucorales-positive reactions. In addition, these fungi were identified as Rhizomucor pusillus by gene analysis.

Background: We aimed to evaluate the prognostic significance of hyponatremia in patients with metastatic clear cell renal cell carcinoma (RCC) treated with a tyrosine kinase inhibitor (TKI)., Methods: This study included a total of 209 consecutive Japanese patients undergoing radical nephrectomy who were subsequently treated with either sunitinib or sorafenib as a first-line therapy for metastatic clear cell RCC. In this series, normal natremia and hyponatremia prior to the introduction of TKI was defined as a serum sodium level >136 and ≤136 mEq/L, respectively., Results: Patients were classified into 165 (78.9 %) with normal natremia and 44 (21.1 %) with hyponatremia. Progression-free survival (PFS) in the hyponatremia group (median 10.0 months) was significantly poorer than that in the normal natremia group (median 28.4 months). Overall survival (OS) in the hyponatremia group (median 20.9 months) was significantly poorer than that in the normal natremia group (median 38.5 months). Multivariate analyses identified hyponatremia, in addition to the existence of sarcomatoid components in radical nephrectomy specimens, high serum C-reactive protein levels, and low serum albumin levels, as poor prognostic factors for both PFS and OS. There were significant differences in both PFS and OS according to the number of these 4 independent risk factors that were positive (negative for any risk factors vs positive for 1 or 2 risk factors vs positive for 3 or 4 risk factors)., Conclusions: Hyponatremia appears to be one of the most powerful prognostic predictors in Japanese patients treated with a TKI as a first-line agent against metastatic clear cell RCC.

We investigated whether 10 mg per day of azilsartan, one-half of the normal dosage, would be non-inferior to 8 mg per day of candesartan cilexetil for controlling blood pressure in Japanese patients with hypertension. In this open-label, randomized, crossover trial, 309 hypertensive Japanese adults treated with 8-mg candesartan cilexetil were randomized into two arms and received either 10-mg azilsartan or 8-mg candesartan cilexetil in a crossover manner. The primary efficacy outcome was systolic blood pressure, and the margin of non-inferiority was set to be 2.5 mm Hg. The participants were 67±11 years old, and 180 (58%) were male. The baseline systolic and diastolic blood pressure levels were 127.1±13.2 and 69.7±11.2 mm Hg, respectively. During the study period, the difference in systolic blood pressure between the treatments with 10-mg azilsartan and 8-mg candesartan cilexetil was -1.7 mm Hg, with the two-sided 95% confidence interval (CI) ranged from -3.2 to -0.2 mm Hg. The upper boundary of the 95% CI was below the margin of 2.5 mm Hg, confirming the non-inferiority of 10-mg azilsartan to 8-mg candesartan cilexetil. The difference also reached significance (P=0.037). The corresponding difference in diastolic blood pressure was -1.4 (95% CI: -2.4 to -0.4) mm Hg (P=0.006). Treatment with 10-mg azilsartan was similar to 8-mg candesartan cilexetil in its association with rare adverse events. In conclusion, 10-mg azilsartan was non-inferior to 8-mg candesartan cilexetil for controlling systolic blood pressure in Japanese hypertensive patients already being treated with 8-mg candesartan cilexetil.

Background: We retrospectively investigated the efficacy and safety of temsirolimus, an inhibitor of the mammalian target of rapamycin, in patients with metastatic renal cell carcinoma (mRCC) on hemodialysis (HD)., Methods: This study included ten HD patients who were diagnosed with mRCC following radical nephrectomy and subsequently treated with temsirolimus between December 2010 and June 2012. Medical records of these patients were reviewed to evaluate the response to temsirolimus and treatment-related toxicities., Results: Baseline characteristics of the patients are as follows: median age was 61 years, five patients had a Karnofsky performance status of ≤80, and two, six, and two patients were classified into favorable, intermediate, and poor risk group, respectively, according to the Memorial Sloan-Kettering Cancer Center risk model. Initially, all patients received 25 mg intravenous temsirolimus weekly; however, dose modification was necessary in four patients, resulting in a relative dose intensity of 89.5 % throughout this study. All patients, except for one with progressive disease, were judged to have stable disease following treatment with temsirolimus. Six patients are still under treatment with temsirolimus, whereas four have stopped receiving temsirolimus because of the occurrence of progressive disease in three and that of adverse events (AEs) in one. Although all patients experienced AEs related to temsirolimus, severe AEs corresponding to ≥ grade 3 occurred in only four, including thrombocytopenia in two, anemia in one, and asthenia in one., Conclusions: Treatment with temsirolimus is well tolerated and could provide comparatively favorable cancer control in Japanese mRCC patients undergoing HD.

Objectives: To retrospectively assess the significance of gender as a predictor of intravesical recurrence following nephroureterectomy for urothelial carcinoma of the upper urinary tract (UC-UUT)., Materials and Methods: This study included 502 consecutive patients (360 male and 142 female) who were diagnosed as having clinically localized UC-UUT and underwent nephroureterectomy. Clinicopathologic outcomes of these patients were analyzed focusing on the impact of gender., Results: The incidence of intravesical recurrence in male patients (41.9%) was significantly greater than that in female patients (27.5%). Despite the lack of significant differences in cancer-specific and overall survivals with respect to gender, the intravesical recurrence-free survival in male patients was significantly worse than that in female patients. Of several parameters examined, univariate analysis identified gender, tumor site, and tumor focality as significant predictors of intravesical recurrence following nephroureterectomy. Of these, only gender and tumor site appeared to be independently associated with intravesical recurrence-free survival on multivariate analysis. Furthermore, there was a significant difference in intravesical recurrence-free survival according to positive numbers of these two independent factors; that is, intravesical recurrence occurred in 12 of 55 patients who were negative for both risk factors (21.8%), 96 of 280 positive for a single risk factor (34.3%), and 82 of 167 positive for both risk factors (49.1%)., Conclusions: The incidence of intravesical recurrence following nephroureterectomy for UC-UUT is comparatively high. Therefore, it would be potentially important to perform careful follow-up targeting intravesical recurrence for such patients, particularly for male patients and/or patients with tumor located at the ureter., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the expression levels of heat shock protein 70 (HSP70) in human urothelial cancer of the bladder and to assess the therapeutic effects of treatment with small interfering RNA (siRNA) targeting HSP70 on human bladder cancer KoTCC-1 cells., Materials and Methods: HSP70 expression in bladder cancer specimens obtained from 235 patients were evaluated by immunohistochemical staining. We then analyzed changes in the growth and chemosensitivity of KoTCC-1 cells following treatment with HSP70 siRNA., Results: Expression levels of HSP70 protein in bladder cancer specimens were significantly related to major prognostic indicators, including pathologic stage and tumor grade. Treatment of KoTCC-1 with HSP70 siRNA resulted in a dose-dependent inhibition of HSP70 expression. HSP70 siRNA significantly inhibited the growth of KoTCC-1 compared with that after treatment with scrambled control siRNA. Among several chemotherapeutic agents, the most powerful synergistic cytotoxic effect was observed when KoTCC-1 was treated with gemcitabine plus HSP70 siRNA, which induced more than 50% reduction in the IC50 of gemcitabine. Furthermore, a significant increase in the subG0-G1 fraction of KoTCC-1 and the DNA fragmentation was observed only after combined treatment with HSP70 siRNA and sublethal doses of gemcitabine, but not after treatment with either agent alone. Similarly, caspase-3 and caspase-9, but not caspase-8, in KoTCC-1 were synergistically activated by combined treatment with gemcitabine and HSP70 siRNA., Conclusions: Silencing of HSP70 expression using siRNA could be an attractive therapeutic strategy for bladder cancer by inducing inhibition of tumor growth as well as enhancing chemosensitivity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A 70-year-old male presented with intermittent macroscopic hematuria. There was no history of previous trauma or pelvic operation. At first, we were unable to clarify the origin of the hematuria, but 3D computed tomography revealed an arteriovenous malformation (AVM) consisting of multiple feeding vessels arising from the bilateral, especially right, internal iliac artery. Treatment with transcatheter arterial embolization (TAE) with a combination of lipiodol and N-butyl-2-cyanoacrylate twice was effective. He needs to be followed up carefully for recurrence of AVM.

Objectives: To compare the accuracy to diagnose micrometastases to pelvic lymph nodes (LNs) in patients undergoing radical prostatectomy (RP) by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) targeting several genes specifically expressed in the prostate., Materials and Methods: Expression of prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), human kallikrein 2 (hK2), prostate stem cell antigen (PSCA), and differential display code 3 (DD3) in 2215 LNs isolated from 120 patients with localized prostate cancer were assessed by fully quantitative real-time RT-PCR., Results: In addition to pathologically diagnosed LN metastases in 11 patients, real-time RT-PCR targeting PSA, PSMA, hK2, PSCA, and DD3 further identified micrometastases in 23, 29, 31, 15, and 11, respectively. In this series, biochemical recurrence (BR) occurred in 32 patients, of whom 25, 22, 28, 10, and 9 were diagnosed as having micrometastases by real-time RT-PCR targeting PSA, PSMA, hK2, PSCA, and DD3, respectively. Univariate analysis identified pathologic stage, pathologic LN metastases, Gleason score, surgical margin status, and micrometastases detected by real-time RT-PCR targeting PSA, PSMA, hK2, and their combinations as significant predictors for BR-free survival (BRFS), of which only surgical margin status and micrometastases detected by real-time RT-PCR targeting PSA and hK2 appeared to be independently associated with BRFS on multivariate analysis., Conclusions: Of PSA, PSMA, hK2, PSCA, DD3, and their combinations, combined analysis of PSA and/or hK2 expression in pelvic LNs by real-time RT-PCR could provide findings most precisely predicting BRFS following RP., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To investigate the expression levels of multiple molecular markers in radical nephrectomy specimens from patients with metastatic renal cell carcinoma (RCC) treated with sunitinib in order to identify factors predicting susceptibility to this agent., Materials and Methods: This study included a total of 40 consecutive patients undergoing radical nephrectomy, who were diagnosed as having metastatic RCC and subsequently treated with sunitinib. Expression levels of 10 molecular markers, including Bcl-2, Bcl-xL, Bax, phosphorylated Akt, p44/42 mitogen-activated protein kinase, and signal transducers and activation of transcription 3, vascular endothelial growth factor receptor (VEGFR)-1 and -2, and platelet-derived growth factor receptor-α and -β, in primary RCC specimens were assessed by immunohistochemical staining., Results: Of several factors examined, tumor grade and the expression level of VEGFR-2 were shown to have significant impacts on response to sunitinib in these 40 patients. Progression-free survival (PFS) was significantly associated with the expression levels of VEGFR-2 in addition to tumor grade, performance status, Memorial Sloan-Kettering Cancer Center risk classification and pretreatment c-reactive protein level on univariate analysis. Of these significant factors, only VEGFR-2 expression appeared to be independently related to PFS on multivariate analysis. In fact, PFS in patients with strong expression of VEGFR-2 was significantly favorable compared with that in those with weak expression of VEGFR-2., Conclusions: Collectively, these findings suggest that it would be useful to consider expression levels of potential molecular markers, particularly VEGFR-2, as well as conventional clinical parameters to select metastatic RCC patients likely to benefit from treatment with sunitinib., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: To analyze the impact of sunitinib treatment on health-related quality of life (HRQOL) in Japanese patients with metastatic renal cell carcinoma (mRCC)., Methods: This study prospectively included 90 consecutive patients with mRCC treated with sunitinib for at least 3 months. HRQOL in these patients was assessed using the Medical Outcomes Study 36-Item Short Form (SF-36) consisting of 8 multi-item scales measuring health status., Results: There were no significant differences in any of the 8 scores in these 90 patients between surveys conducted before and 3 months after sunitinib treatment. Three months after treatment, all 8 scores in patients who had some degree of tumor shrinkage were more favorable than those in the remaining patients, and there were significant differences in 2 of the 8 scale scores (role limitations because of emotional problems, mental health) between these two groups. However, there were no significant differences in any scale scores except one (social function) between patients with and without severe adverse events (AEs). Furthermore, a significant time-dependent improvement was observed in one score (body pain), while there were no significant differences in the remaining 7 scores 3, 6 and 12 months after sunitinib treatment in 29 patients who could be followed for at least 12 months., Conclusions: Although this was a non-randomized study including a comparatively small number of patients, these findings suggest that efficacy rather than AE is likely to be associated with HRQOL in Japanese mRCC patients treated with sunitinib.

Background: The aim of this study was to evaluate the use of sunitinib as third-line therapy for metastatic renal cell carcinoma (mRCC)., Methods: This study included a total of 35 consecutive Japanese patients with mRCC who were treated with third-line sunitinib after sequential use of cytokine therapy (interferon-α and/or interleukin-2) and sorafenib between September 2008 and December 2010. The clinical outcomes of third-line sunitinib in these patients were retrospectively reviewed., Results: Of the 35 patients, 3 (8.6%), 28 (80.0%) and 4 (11.4%) were judged to have a partial response, stable disease and progressive disease, respectively, as the best response to sunitinib. The median progression-free survival (PFS) and overall survival (OS) of these patients following the introduction of sunitinib were 10.9 and 14.2 months, respectively. Of several factors examined, response to sorafenib and performance status appeared to be independently associated with PFS and OS, respectively, on multivariate analyses. The common grade 3-4 adverse events related to third-line sunitinib were thrombocytopenia (51.4%), neutropenia (42.9%) and hypertension (14.3%)., Conclusion: Despite the low response rate, third-line sunitinib is well tolerated and could provide comparatively favorable prognostic outcomes in Japanese patients with mRCC after first-line cytokine therapy and second-line sorafenib; therefore, treatment with sunitinib could be one on the therapeutic options for patients with mRCC even after the failure of sequentially performed systemic therapies, such as cytokine therapy and sorafenib.

Objectives: To investigate the expression levels of multiple molecular markers in radical nephrectomy specimens from patients with metastatic renal cell carcinoma (RCC) treated with sorafenib in order to identify factors predicting susceptibility to this agent., Materials and Methods: This study included 45 consecutive patients undergoing radical nephrectomy for clear cell RCC who were diagnosed as having metastatic diseases refractory to cytokine therapy and subsequently treated with sorafenib. Expression levels of 19 molecular markers involved in the regulation of apoptosis, cell cycle, signal transduction, and angiogenesis in primary RCC specimens were measured by immunohistochemical staining., Results: There was no molecular marker having significant impact on the prediction of response to sorafenib. However, progression-free survival (PFS) was significantly associated with the expression levels of Bcl-xL and platelet-derived growth factor receptor (PDGFR)-α in addition to the presence of bone metastasis and C-reactive protein level on univariate analysis. Of these significant factors, PDGFR-α expression and the presence of bone metastasis appeared to be independently related to PFS by multivariate analysis. Furthermore, there were significant differences in PFS according to positive numbers of these 2 independent risk factors; that is, disease progression occurred in 2 of 7 patients who were negative for risk factor, 19 of 34 positive for a single risk factor, and 6 of 6 positive for both risk factors., Conclusions: Collectively, these findings suggest that it would be useful to consider expression levels of potential molecular markers, particularly PDGFR-α, as well as clinical parameters to select metastatic RCC patients likely to benefit from treatment with sorafenib., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Unlabelled: What's known on the subject? and What does the study add? There have been few studies evaluating the prognostic value of epithelial-mesenchymal transition markers in renal cell carcinoma (RCC); therefore, the significance of these markers in the prognosis of patients with RCC, particularly that in those with localized disease, remains largely unknown. Consideration of the expression levels of potential epithelial-mesenchymal transition markers, particularly clusterin and Twist in addition to conventional prognostic parameters, would contribute to the prediction of disease recurrence after radical nephrectomy for localized renal cell carcinoma., Objective: • To evaluate the expression of multiple molecular markers involved in the process of epithelial-mesenchymal transition (EMT) in renal cell carcinoma (RCC) with the aim of clarifying the prognostic significance of these markers in patients undergoing radical nephrectomy., Patients and Methods: • The expression levels of 11 EMT markers, including E-cadherin, N-cadherin, β-catenin, γ-catenin, clusterin, Slug, Snail, Twist, vimentin, ZEB1 and ZEB2, in radical nephrectomy specimens from 122 patients with clinically localized RCC were measured by immunohistochemical staining., Results: • In this series, disease recurrence occurred in 39 (32.0%) patients, with a 5-year recurrence-free survival rate of 64.4%. • Univariate analysis identified expression levels of E-cadherin, clusterin, Twist and vimentin, in addition to C-reactive protein (CRP) level, pathological stage and microvascular invasion, as significant predictors for disease recurrence. • Of these, expression levels of clusterin and Twist, CRP levels and microvascular invasion appeared to be independently related to disease recurrence on multivariate analysis. • There were significant differences in recurrence-free survival according to positive numbers of these four independent factors: disease recurrence occurred in two of 26 patients negative for any risk factor (7.7%), 23 of 73 patients positive for one or two risk factors (31.5%) and 14 of 23 patients positive for three or four risk factors (60.9%)., Conclusion: • Consideration of the expression levels of potential EMT markers, particularly clusterin and Twist, in RCC specimens, in addition to conventional prognostic parameters, contributes to the accurate prediction of disease recurrence after radical nephrectomy for localized RCC., (© 2012 BJU INTERNATIONAL.)

Objective: • To retrospectively review oncological outcomes following surgical resection in Japanese patients with pT1 renal cell carcinoma (RCC)., Patients and Methods: • The present study included a total of 832 consecutive Japanese patients who underwent either radical or partial nephrectomy and were subsequently diagnosed as having localized pT1 RCC. • The significance of several clinicopathological factors in their postoperative outcomes was analysed., Results: • The median (range) age of the 832 patients was 66 (31-90) years. Radical and partial nephrectomies were performed for 710 patients (85.3%) and 122 patients (14.7%), respectively. Distribution of pathological stage was pT1a in 582 patients (70.0%) and pT1b in 250 patients (30.0%). • During the observation period (median 44 months, range 3-114 months), postoperative disease recurrence developed in 38 patients (4.6%) and death occurred in 34 (4.1%). The 5-year recurrence-free and overall survival rates were 93.6% and 94.1%, respectively. • Of several factors examined, only age at diagnosis was identified as an independent predictor of both postoperative disease recurrence and overall survival in these patients. Furthermore, there were significant differences in the recurrence-free and overall survivals among patient groups stratified by age at diagnosis., Conclusion: • These findings suggest that age at diagnosis is a significant predictor of disease recurrence as well as overall survival in patients with pT1 RCC following surgical resection; therefore, intensive follow-up of older patients is necessary even for those with pT1 RCC., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

The present study reports our experience with five renal cell carcinoma (RCC) patients with brain metastases treated with sunitinib and radiotherapy. All patients had undergone radical nephrectomy. Before treatment with sunitinib, radiotherapy for brain metastases, either by gamma-knife surgery or whole brain radiation, was carried out. After treatment with sunitinib, shrinkage of brain metastases was achieved in all patients with complete response, partial response and stable disease in two, one and two patients, respectively. Although progression of brain metastases occurred in four of the five patients, additional gamma-knife surgery was effective in three patients. Over a 12.5-month follow up, four patients, including three who maintained their best response, remained alive. The remaining one patient died of disease progression. Despite the observation of several adverse events after treatment with sunitinib, there was no intracerebral hemorrhage in any patient. These findings suggest that sunitinib combined with radiation therapy can be safely carried out in RCC patients with brain metastases and provides a favorable prognosis in these cases. However, considering their frequent progression, it would be important to carry out careful follow up for these patients by focusing on the control of brain metastases.

Objectives: To review clinical outcomes and to identify clinicopathological variables as predictors of disease recurrence in a cohort of Japanese patients undergoing radical nephrectomy for renal cell carcinoma (RCC)., Methods: The present study included a total of 710 consecutive Japanese patients who underwent radical nephrectomy and were diagnosed as having localized pT1 RCC. The significance of several clinicopathological factors in predicting postoperative disease recurrence was assessed by univariable and multivariable analyses., Results: Median age was 66 years (range 32-90 years). Open and laparoscopic radical nephrectomies were carried out for 436 (61.4%) and 274 (38.6%) patients, respectively. Tumor size was 4 cm or less in 461 (64.9%) patients and greater than 4 cm and 249 (35.1%) patients. During the observation period (median 36 months; range 3-111 months), postoperative disease recurrence developed in 37 patients (5.2%), of whom 10 (1.4%) died of disease progression. The 1-, 3- and 5-year recurrence-free survival rates were 98.3%, 95.0% and 92.7%, respectively. Age at diagnosis and tumor size were found to be significantly associated with recurrence-free survival at both univariable and multivariable analysis. Furthermore, there were significant differences in the recurrence-free survival with respect to both independent predictors., Conclusions: Age at diagnosis in addition to tumor size appears to be independently related to disease recurrence in Japanese patients with pT1 RCC. Thus, an intensive follow up for older patients seems to be advisable., (© 2010 The Japanese Urological Association.)