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Introduction: Neoadjuvant chemotherapy (NAC) is increasingly used prior to radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Systemic recurrence (SR) carries a dismal prognosis. We sought to determine risk factors associated with SR in this setting., Methods: We evaluated a multi-center database of patients with UTUC who received cisplatin-based NAC before RNU. Final pathology at RNU was dichotomized into ypT<2 vs ypT≥2. Univariable and multivariable analyses were performed to identify risk factors associated with SR. Three groups were defined based on the number of significant risk factors (groups 1, 2, 3 for 0-1, 2, 3 risk factors, respectively) and evaluated for recurrence-free survival (RFS) using the Kaplan-Meier method., Results: 106 patients were identified between 2004 and 2018. Median age was 67.0 years [IQR = 61-73.3]; 57 (54%) and 49 (46 %) patients received MVAC and GC, respectively. Final pathological stage was ypT<2 in 57 (54%); 23% (24/106) had SR. On univariable analysis, pathological variables on final specimen including ypT≥2, lymphovascular invasion (ypLVI), and nodal involvement were associated with SR. On multivariable analysis, ypLVI OR = 4.1 (95% CI 1.2-13.6; P = 0.024) and pathological nodal involvement OR = 4.5 (95% CI 1.3-15.7; P = 0.017) were predictive of recurrence. Stratifying by the number of risk factors, the 2-year RFS was 95%, 55%, and 18% for groups 1, 2, and 3 respectively (log-rank <0.001)., Conclusion: This model evaluates the risk of SR following NAC and RNU to guide counseling and decision-making after surgery. Adverse pathological variable including ypLVI and nodal involvement, in combination with ypT-stage, are strongly associated with SR., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Overproduction of free radicals is controlled by antioxidant defense mechanisms. These defense mechanisms are achieved by antioxidant enzymes such as catalase (CAT). The current study aimed to assess the changes in steroid hormones, oxidant/antioxidants biomarkers, lipid profiles/liver functions indices, renal function biomarkers and minerals metabolism in non-pregnant, lactating or pregnant one-humped she-camels ( Camelus dromedarius ) pre-synchronized with controlled internal drug releasing. The study also focused on the correlational relationships between steroid hormones and the oxidant/antioxidant biomarkers, lipid profiles and liver functions indices, renal functions and mineral metabolism in these she-camels. The study was conducted on apparently healthy dromedary she-camels ( n = 60) during breeding season. A sexually active camel-bull was introduced to she-camels pre-synchronized with CIDR. Fifty to sixty days after natural mating, she-camels were examined for pregnancy. She-camels were divided into three main groups according to both pregnancy and lactation as following: pregnant (PREG, n = 38) which was kept as control one, non-pregnant and lactating (LACT, n = 8), and non-pregnant and non-lactating she-camels (NPREG, n = 14). Steroid hormones, i.e., progesterone (P 4 ), estradiol (E 2 ) and cortisol, oxidant indictors, i.e., malondialdehyde (MDA), antioxidant biomarkers, i.e., superoxide dismutase (SOD), total antioxidant capacity (TAC), CAT and reduced glutathione (GSH), lipid profiles indices, renal functions and related minerals were assessed. The present study confirmed the efficacy of using CIDR for synchronization in she-camels. Significant elevations in serum steroids hormones in PREG compare with LACT and NPREG. The highest concentrations of MDA as lipid peroxidation and oxidative stress indictors and lowest levels of antioxidant biomarkers except for SOD, i.e., TAC, CAT and GSH, were reported in PREG compared with LACT and NPREG. PREG showed the highest liver enzymes activities and lowest total protein values. Remarkable increases in serum concentrations of renal function parameters and phosphorous (P) were observed in PREG when compared with the other two groups. The investigated she-camels revealed significant correlation between steroid hormones and the oxidant biomarkers, antioxidant biomarkers, liver functions, renal functions and minerals metabolism parameters. P 4 showed positive correlations with antioxidant biomarkers, i.e., TAC, CAT and GSH, and serum aspartate aminotransferase (AST) activities, whereas negative correlations were reported between P 4 and renal functions biomarkers, i.e., blood urea nitrogen (BUN), creatinine (Cr) and creatinine kinase (CK), and minerals metabolism parameters, i.e., P and magnesium (Mg), in CIDR pre-synchronized she-camels. In contrast, E 2 and cortisol showed negative correlations with antioxidant biomarkers, i.e., TAC, CAT and GSH, lipid profiles/liver functions indices, i.e., AST, alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT), CK and Mg, however, positive correlations were demonstrated between E 2 and cortisol, and MDA, Cr and P in investigated she-camels. In conclusion, the present study confirmed the efficacy of using CIDR for synchronization in she-camels. The highest MDA levels as indictors for oxidative stress and the lowest antioxidant levels, i.e., TAC, CAT and GSH, except for SOD in pregnant she-camels, were attributable to physiological oxidative stress as excellent compensatory responses observed in the PREG group to face such a physiologic stage. Moreover, lower P levels in non-pregnant she-camels would be contributed to failure of conception or early embryonic death. The investigated she-camels revealed significant correlations between steroid hormones and the oxidant indicators, antioxidant biomarkers, lipid profile indices and renal functions biomarkers that provided better understanding for physiological stress during pregnancy in camels.

Background: Parasitic infection is one of the main problems in equidae, particularly donkeys., Aim: This study evaluated the oxidative stress in donkeys infected with Strongylus spp by determining the correlation between antioxidants levels; malondialdehyde (MDA), total antioxidant capacity (TAC), and the severity of parasitic infection. It also compared the therapeutic efficacy of piperazine citrate as an oral anthelmintic drug and Doramectin as an injectable one., Methods: The study was conducted on 40 donkeys naturally infected with Strongylus spp. These donkeys were divided into two groups (20 donkeys each) according to treatment; One group was treated with piperazine citrate (P ip TG) and the other with doramectin (D ora TG). Thorough clinical examination, hematological, biochemical, and parasitological assays were performed before (Day 0) and after treatment (Days 7, 14, 21, and 28). All data were statistically analyzed by independent-sample t -test or paired t -test., Results: In both groups, mean values of MDA were significantly reduced, while those of TAC were significantly elevated after treatment on days 7, 14, 21, and 28. These significant changes were reported after treatment between P ip TG and D ora TG in favor of D ora TG. Serum concentrations of MDA were significantly reduced, while those of TAC were significantly elevated for D ora TG treatment group when their values were compared with those of P ip TG either on days 7, 14, 21, or 28. Significant correlations were reported in P ip TG and D ora TG. Negative significant correlations were reported between fecal egg count (FEC) and each of whole blood picture indices (RBCS, Hb, and PCV), serum TAC and faecal egg count reduction percentage FECR%. A positive correlation was seen between FEC and MDA. MDA exhibited a negative correlation with both blood picture and TAC; hence, TAC was positively correlated with these blood picture indices in both P ip TG and D ora TG. In P ip TG, anthelmintic resistance ( R ) was present on days 7 and 14, while it was suspected ( S ) at day 21 then it was absent ( N ) at day 28. In D ora TG, anthelmintic resistance was suspected ( S ) on day 7, then it became absent ( N ) on days 14, 21, and 28 post therapy., Conclusion: The immunological status of the infected donkeys had greatly improved after treatment. The therapeutic efficacy of injectable doramectin was more efficient than that of oral piperazine citrate in Strongylus spp. infected donkeys., Competing Interests: The authors declare that they have no conflicts of interest.

Methotrexate (MTX) has been used for treatment of autoimmune diseases, inflammatory disorders as rheumatic arthritis, and different types of cancers. However, it has shown adverse effects on vital organs. The current study was conducted to investigate the toxic effect of MTX on the hippocampus, cerebellum, liver and kidneys of adult male albino rats. MTX was injected weekly at 5 mg/kg body weight via I/P injection for 6 weeks. At the end of the experiment, histopathological, immunohistochemical and biochemical evaluation were performed on the hippocampus, cerebellum, liver, and kidney tissues of the sacrificed rats. We observed that methotrexate induced neural tissue damage in the hippocampus and cerebellum, degeneration of hepatocytes, congestion of the central vein and blood sinusoids of the liver, distortion in the renal corpuscles and necrosis of the renal tubule. Immunohistochemical findings revealed strong positive expression of Caspase-3, PCNA and GFAP. Biochemical studies revealed significant elevation in the serum levels of AST and ALT, in addition to high serum concentrations of creatinine and urea. Also, MTX injection increased MDA, while it decreased GSH, SOD and AChE levels. We conclude the ability of MTX to induce oxidative stress that results into apoptosis and tissue injury, leading to neurotoxicity, hepatotoxicity, and nephrotoxicity., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Objective: Whether pathologic stage at radical nephroureterectomy (RNU) can serve as an appropriate surrogate for oncologic outcomes in patients with high-grade (HG) upper tract urothelial carcinoma (UTUC) treated with neoadjuvant chemotherapy (NAC) is not defined. We sought to determine whether patients who achieve pathologically non-muscle-invasive (ypT0, ypTa, ypT1, ypTis) HG UTUC after receipt of NAC exhibit oncologic outcomes comparable to those who are inherently low stage without chemotherapy., Methods: We identified 647 UTUC patients who underwent RNU among 3 institutions from 1993to2016. Patients with low or unknown grade, pathologic muscle invasion, or receipt of adjuvant chemotherapy were excluded. We compared clinicopathologic data and oncologic outcomes between pT0-1 and ypT0-1 patients. Kaplan-Meier analysis was used to assess overall (OS), cancer-specific (CSS), and systemic recurrence-free (RFS) survival. Predictors of these endpoints were identified using Cox regression., Results: 234 (43 ypT0-1, 191 pT0-1) patients with HG UTUC were included. Two patients exhibited pathologic complete response after NAC. OS (P = 0.055), CSS (P = 0.152), and RFS (P = 0.098) were similar between ypT0-1 and pT0-1 patients. Predictors of worse outcomes included African-American race (RFS, CSS, and OS), Charlson score (OS), and systemic recurrence (OS and CSS)., Conclusions: Patients with HG UTUC who achieve ypT0-1 stage after NAC exhibit favorable oncologic outcomes comparable to those inherently non-muscle-invasive who do not receive chemotherapy. Improvements in clinical staging will play an important role in better defining candidacy for NAC in treating HG UTUC while minimizing overtreatment. Furthermore, pathologic stage may serve as an appropriate early surrogate for oncologic endpoints in designing clinical trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Greater understanding of the efficiency of nanoparticles will assist future research related to male reproductive performance. The current study was performed to assess the potency of selenium nanoparticles (SeNPs) in alleviating deltamethrin (DLM)-induced detrimental effects on sperm characteristics, oxidative status, sexual behavior, and the histological structure of the testes and epididymis in male rats. Thirty-two male Wister rats were divided into four groups according to treatment received orally by gavage 3 times/week for 60 days; control, DLM (0.6 mg/kg bwt), SeNPs (0.5 mg/kg bwt), and DLM-SeNPs groups. DLM caused a significant reduction in sperm count, motility, and viability percent, as well as in body weight and serum testosterone level, blood total antioxidant capacity (TAC), and glutathione peroxidase (GPx) activity. The DLM-treated group showed a significant increase in blood malondialdehyde (MDA) concentration and sperm abnormalities (%), as well as a significant reduction in sexual activity, manifested as an increase in mount, intromission, or ejaculation latency and a reduction in mount or intromission frequency. These toxic effects were confirmed by histological alterations, represented by a significant reduction in the diameter of the seminiferous tubules and spermatogenesis. Conversely, treatment with SeNPs improved DLM-induced negative effects on sperm characteristics, testosterone, and antioxidant biomarkers, as well as behavioral and histopathological alterations. The SeNPs treated group showed improved semen parameters, antioxidant status, and sexual performance. In conclusion, SeNPs may represent an effective treatment for reducing the detrimental effects of DLM on male fertility, and lead to enhanced male reproductive performance., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The objective of this study was to determine whether standardized treatment of germ cell tumors (GCTs) could overcome sociodemographic factors limiting patient care., Methods: The records of all patients undergoing primary treatment for GCTs at both a public safety net hospital and an academic tertiary care center in the same metropolitan area were analyzed. Both institutions were managed by the same group of physicians in the context of multidisciplinary cancer care. Patients were grouped by care center; clinicopathologic features and outcomes were analyzed., Results: Between 2006 and 2018, 106 and 95 patients underwent initial treatment for GCTs at the safety net hospital and the tertiary care center, respectively. Safety net patients were younger (29 vs 33 years; P = .005) and were more likely to be Hispanic (79% vs 11%), to be uninsured (80% vs 12%; P < .001), to present via the emergency department (76% vs 8%; P < .001), and to have metastatic (stage II/III) disease (42% vs 26%; P = .025). In a multivariable analysis, an absence of lymphovascular invasion (odds ratio [OR], 0.30; P = .008) and an embryonal carcinoma component (OR, 0.36; P = .02) were associated with decreased use of adjuvant treatment for stage I patients; hospital setting was not (OR, 0.67; P = .55). For patients with stage II/III nonseminomatous GCTs, there was no difference in the performance of postchemotherapy retroperitoneal lymph node dissection between the safety net hospital and the tertiary care center (52% vs 64%; P = .53). No difference in recurrence rates was observed between the cohorts (5% vs 6%; P = .76)., Conclusions: Sociodemographic factors are often associated with adverse clinical outcomes in the treatment of GCTs; they may be overcome with integrated, standardized management of testicular cancer., (© 2020 American Cancer Society.)

Introduction: There is controversy regarding the benefit of a grossly complete transurethral resection of bladder tumor (TURBT) for muscle-invasive bladder cancer (MIBC) in patients prior to neoadjuvant chemotherapy (NAC). Advocates for this approach suggest a higher response rate to NAC, while others suggest this can increase the surgical risk for no clear benefit., Methods: We retrospectively reviewed our institutional radical cystectomy (RC) database from 2011 to 2018 for patients who received an adequate course of cisplatin-based NAC for nonmetastatic MIBC. Univariable and multivariable logistic regression analyses were performed to identify factors associated with complete response [ypT0] or no residual muscle invasive bladder cancer [ypT < 2] following NAC based on clinicopathologic characteristics and grossly complete or incomplete TURBT., Results: A total of 167 patients received NAC followed by RC for MIBC during the study period and 100 patients were included in the analysis due to known status of the completeness of TURBT-of these 49 patients underwent complete resection while 51 patients underwent incomplete resection prior to NAC. There were no significant differences in baseline clinicopathologic characteristics between patients who had complete vs. incomplete TURBT. At the time of RC, the overall ypT0 rate was 24% (n = 24), while the overall rate of ypT < 2 was 45%. On logistic regression, there was no association between completeness of TURBT and ypT0 or ypT < 2. Age, histology, and organ-confined disease were not significantly associated with response to NAC. Only smoking status (current or prior history) was negatively associated with ypT0 on univariable and multivariable analysis (odds ratio = 0.36, 95% confidence interval: [0.14-0.91], P = 0.031)., Conclusion: We found no association between response to cisplatin-based NAC and completeness of TURBT in a cohort of MIBC patients. The study is limited by its retrospective nature and lack of ability to predict response to NAC based on TURBT tissue evaluation., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: Despite immune checkpoint inhibitor (ICI) approval for metastatic renal cell carcinoma (mRCC) in 2015, cytoreductive nephrectomy (CN) is guided by extrapolation from earlier classes of therapy. We evaluated survival outcomes, timing, and safety of combining CN with modern immunotherapy (IO) for mRCC., Methods: From 96,329 renal cancer cases reported to the NCDB between 2015 and 2016, we analyzed 391 surgical candidates diagnosed with clear cell mRCC treated with IO ± CN and no other systemic therapies. Primary outcome was overall survival (OS) stratified by the performance of CN (CN + IO vs. IO alone). Secondary outcomes included OS stratified by the timing of CN, pathologic findings, and perioperative outcomes., Results: Of 391 patients, 221 (56.5%) received CN + IO and 170 (43.5%) received IO only. Across a median follow-up of 14.7 months, patients who underwent CN + IO had superior OS (median NR vs. 11.6 months; hazard ratio 0.23, P < 0.001), which was upheld on multivariable analyses. IO before CN resulted in lower pT stage, grade, tumor size, and lymphovascular invasion rates compared to upfront CN. Two of 20 patients (10%) undergoing CN post-IO achieved complete pathologic response in the primary tumor (pT0). There were no positive surgical margins, 30-day readmissions, or prolonged length of stay in patients undergoing delayed CN., Conclusion: Using a large, national, registry-based cohort, we provide the first report of survival outcomes in mRCC patients treated with CN combined with modern IO. Our findings support an oncologic role for CN in the ICI era and provide preliminary evidence regarding the timing and safety of CN relative to IO administration., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for metastatic renal cell carcinoma. The appropriate duration for ICI treatment is not clear, however. Analyses of landmark trials reveal that some patients exhibit sustained durable responses to ICIs even after treatment discontinuation, resulting in prolonged treatment-free intervals that can mitigate potential toxicities and the considerable financial burden associated with treatment. Adaptive approaches with PD1 monotherapy and combination immunotherapy tailored to tumor response are ongoing. More efforts will be needed to clarify the ideal ICI dosing regimen to maximize oncological benefit while minimizing treatment-related adverse effects and costs. PATIENT SUMMARY: We reviewed considerations surrounding treatment strategies when using immunotherapy to treat patients with kidney cancer. It is clear that some patients can experience prolonged cancer control when discontinuing immunotherapy. However, individualized approaches will be necessary to strike a balance between optimizing patient outcomes and reducing unnecessary side effects and cost., (Copyright © 2019. Published by Elsevier B.V.)

Background and Aim: One of the most common cutaneous infections seen in veterinary canine practice is canine demodicosis. Demodicosis is a parasitic skin infection with a possible impact on acute-phase proteins (APPs) and oxidant-antioxidant balance. This study aimed to estimate the possible alterations in hematological, biochemical, oxidant-antioxidant, and APP (C-reactive protein [CRP] and albumin) profiles in naturally infected dogs with demodicosis., Materials and Methods: This study enrolled 21 dogs that were divided into two groups: The control group including 7 apparently healthy dogs and the diseased group including 14 dogs with generalized demodicosis. Demodicosis was confirmed through microscopic detection. Blood samples were collected for the estimation of CBC, total protein, albumin, alanine transaminase, aspartate aminotransferase, blood urea nitrogen, creatinine, superoxide dismutase (SOD), glutathione peroxidase (GPx), total antioxidant capacity (TAC), catalase (CAT), malondialdehyde (MDA), and CRP levels., Results: Significant reduction in red blood cells along with significant elevation in white blood cells was recorded in the diseased group compared with the control group. There was also significant elevation in MDA, TAC, SOD, and CRP levels along with significant reduction in GSH-Px and CAT levels in the diseased group., Conclusion: Based on these findings, a relationship between canine generalized demodicosis and oxidant-antioxidant disequilibrium could be suggested. Evidence of this relation manifested in the elevation in MDA and SOD levels and reduction in GPx and CAT levels as a consequence to the release of ROS resulting from Demodex infection. CRP elevation is expected in canine demodicosis., (Copyright: © Salem, et al.)

Objective: To evaluate the pathologic response, safety, and feasibility of nephrectomy following receipt of immune checkpoint inhibition (ICI) for renal cell carcinoma (RCC)., Methods: Patients who underwent nephrectomy for RCC after exposure to nivolumab monotherapy or combination ipilimumab/nivolumab were reviewed. Primary surgical outcomes included operative time (OT), estimated blood loss (EBL), length of stay (LOS), readmission rates, and complication rates. Pathologic response in the primary and metastatic sites constituted secondary outcomes., Results: Eleven nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 180 days. Six patients received 1 to 4 cycles of ipilimumab/nivolumab, while 5 received 2 to 12 infusions of nivolumab preoperatively. Five surgeries were performed laparoscopically, and 4 patients underwent concomitant thrombectomy. One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no detectable malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 ml, and 4 days, respectively. Four patients experienced a complication, including 3 that were addressed with interventional radiology procedures. One patient died of progressive disease >3 months after surgery, and 1 patient succumbed to pulmonary embolism complicated by sepsis. No complications or readmissions were noted in 6 patients., Conclusion: Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. Timing of the nephrectomy relative to checkpoint dosing did not seem to impact outcome. Biopsies of lesions responding radiographically to ICI may warrant attention prior to surgical excision., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Using a large, nationally representative, population-based cancer registry, this study systematically evaluated the impact of the location and burden of extranodal testicular germ cell tumor (TGCT) metastases on survival., Methods: Men with stage III TGCTs captured by the Surveillance, Epidemiology, and End Results registry from 2010 to 2015 with distant extranodal metastases were identified. Clinicopathologic information was collected, and patients were subdivided according to the specific organ site or sites of metastatic involvement (lung, liver, bone, and/or brain). Kaplan-Meier analysis and multivariable Cox regression were used to evaluate cancer-specific survival (CSS), and model performance was assessed with Harrell's C statistic., Results: Nine hundred sixty-nine patients with stage III TGCTs were included with predominantly nonseminomatous histology (84%). Most patients (91%) had pulmonary metastases, whereas 20%, 10%, and 10% had liver, bone, and brain metastases, respectively. Over a median follow-up of 21 months, 19% of these men died of TGCTs. When they were grouped by the primary site of metastasis, patients with more than 1 extrapulmonary metastasis exhibited the worst CSS (hazard ratio [HR] vs isolated pulmonary involvement, 4.27; 95% confidence interval [CI], 2.60-7.00; P < .01). Among patients with isolated extrapulmonary involvement, those with brain metastases had the poorest survival (HR, 3.24; 95% CI, 1.98-5.28; P < .01), and they were followed by patients with liver (HR, 2.29; 95% CI, 1.56-3.35; P < .01) and bone metastases (HR, 1.97; 95% CI, 1.11-3.50; P = .02). Harrell's C statistic (multivariable) was 0.71., Conclusions: The site of metastatic involvement affects survival outcomes for patients with TGCTs, and this may reflect both the aggressive biology and the challenging treatment of these tumors. Further incorporation of organotropism into current prognostic models for metastatic TGCTs warrants attention., (© 2019 American Cancer Society.)

Purpose of Review: The recent approval of immune checkpoint inhibitors (ICI) revolutionized the treatment paradigm for metastatic renal cell carcinoma (mRCC). However, the role of cytoreductive nephrectomy is not well defined in this setting. Here, we review the contemporary role and timing of cytoreductive nephrectomy for advanced RCC in the era of immunotherapy., Recent Findings: Evidence concerning combination systemic therapy and cytoreductive nephrectomy in the multimodal management of mRCC is primarily limited to studies conducted in the targeted therapy era. The oncologic role of cytoreductive nephrectomy in the setting of ICI remains largely undefined and is supported primarily by case reports. Nonetheless, patient selection for cytoreductive nephrectomy is paramount, and appropriate candidacy in the ICI era will likely be refined as increasing evidence emerges. Until then, a cautious balance between perceived oncologic benefit and risks of intervention must be exercised. Several trials are ongoing to help shed light on patient selection, technical feasibility, and optimal timing of cytoreductive nephrectomy in the immunotherapy era., Summary: Although the role and timing for cytoreductive nephrectomy remain to be further elucidated in the immunotherapy era, patient selection remains critical for treatment planning. Further studies are urgently needed to better define the role of cytoreductive nephrectomy in this setting.

There are several treatment approaches for stage II germ cell tumors (GCTs), and a thorough understanding of the staging classification and histologic differences in tumor biology and therapeutic responsiveness is critical to determine an effective, multimodal management strategy that involves urologists, medical oncologists, and radiation oncologists. This article discusses contemporary management strategies for stage II GCTs, including chemotherapy, radiotherapy, retroperitoneal lymph node dissection (RPLND), and surveillance. Patient selection, histology, and extent of lymphadenopathy drive management, and, as both treatment and detection strategies continue to emerge and be refined, the management of patients with stage II GCT continues to evolve., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose of Review: Understanding the molecular basis underlying testicular germ cell tumors (TGCTs) may help improve patient outcomes, particularly for patients with poorer risk or chemoresistant disease. Here, we review the major contemporary advances in elucidating TGCT genetics by discussing patterns of TGCT inheritance, recent genomic and transcriptomic discoveries in TGCT, and the role of genetics in predicting therapeutic resistance and in guiding treatment., Recent Findings: In the absence of a major high-penetrance TGCT susceptibility gene, inheritance is likely driven by a complex polygenic model with considerable variation. The most common genomic alterations found in TGCTs include gains in chromosome 12p and mutations in KIT, KRAS, and NRAS, particularly in seminomas. Sensitivity to cisplatin-based chemotherapy likely relies on intact TP53, reciprocal loss of heterozygosity, and high mitochondrial priming. Targetable mutations are uncommon in TGCTs, however, posing a challenge for the development of effective personalized therapies. Consistent with the characteristically low tumor mutational burden, immune checkpoint inhibitors do not appear to be effective for most TGCTs., Summary: Refinements in next-generation sequencing techniques over the last few years have enabled considerable advances in elucidating the genomic, transcriptomic, and epigenetic landscape of TGCTs. Future efforts focused on developing novel treatment modalities are needed.

Introduction: The systemic options for managing metastatic renal cell carcinoma (mRCC) have expanded considerably over the past decade. Initially limited to cytokines, clinicians may now choose from several classes of targeted therapies and, most recently, immune checkpoint inhibitors. Areas covered: In this review, we discuss the role and timing of cytoreductive nephrectomy (CN) and its evolution starting with cytokines, and then alongside the emergence of targeted therapy and novel immunotherapy with immune checkpoint inhibitors. Patient selection remains the most critical determinant in offering CN, and the anticipated survival benefits of CN must be weighed against the surgical morbidity and potential delay to receipt of systemic therapies. Expert opinion: Proper patient selection is key for decision-making in mRCC. Prospective data is urgently needed to define the role of CN in the contemporary immunotherapy era, with greater personalization of prognostic models.

Purpose of Review: To evaluate contemporary sex-specific differences in upper tract urothelial carcinoma (UTUC) by reviewing diagnostic considerations, clinicopathologic features, oncologic outcomes, environmental exposures, and regional variation in UTUC by sex., Recent Findings: Although some contemporary studies implicate sex-based differences in UTUC, the literature concerning the effect of sex on clinicopathologic features and oncologic outcomes in UTUC reveals mixed findings. Factors accounting for the time to diagnosis in UTUC seem to differ between men and women. The epidemiology and outcomes of UTUC are largely influenced by geographic variation in the disease, which may be due to differences in exposure to environmental risk factors. Sex-based variations and potential differences in disease biology remain to be elucidated., Summary: A global consensus on the effect of sex on clinicopathologic characteristics and oncologic outcomes in UTUC has not been established definitively. Review of this topic does, however, shed light on important considerations given differences in the time to diagnosis, risk factors, and regional variation by sex. Further studies evaluating genetic, anatomic, physiologic, and socioeconomic differences between men and women with UTUC may provide further insight into understanding the effect of sex in UTUC.

Introduction: The treatment and management of prostate cancer continues to evolve; newer classes of agents and combination therapies are being developed and some are being investigated in early phase clinical trials., Areas Covered: We discuss investigational hormonal agents for the treatment of prostate cancer and focus primarily on luteinizing hormone releasing hormone (LHRH) agonists in early stage trials. We look at agents that target the hormonal axis, including anti-androgens, gonadotropins, estrogenic agents and progestogenic agents and other non-hormonal agents often used in combination with LHRH agonists. We review these candidates in the specific clinical niche in which they might find utility., Expert Opinion: Of all candidate compounds being evaluated in clinical trials, very few will receive FDA approval. Few, if any of the investigational agents discussed here will be used routinely in clinical practice for treating prostate cancer. Recognizing the reasons for the failure of agents to advance to later stage trials is important. Furthermore, a thorough understanding of the mechanisms underlying prostate cancer pathogenesis, including various points in the HGPA and parallel pathways, will help identify potentially actionable targets.

Oxylipins are metabolized from dietary ω3 and ω6 polyunsaturated fatty acids and are involved in an inflammatory response. Adipose tissue inflammatory background is a key factor of metabolic disorders and it is accepted that dietary fatty acids, in terms of quality and quantity, modulate oxylipin synthesis in this tissue. Moreover, it has been reported that diet supplementation in ω3 polyunsaturated fatty acids resolves some inflammatory situations. Thus, it is crucial to assess the influence of dietary polyunsaturated fatty acids on oxylipin synthesis and their impact on adipose tissue inflammation. To this end, mice fed an ω6- or ω3-enriched standard diet ( ω6/ω3 ratio of 30 and 3.75, respectively) were analyzed for inflammatory phenotype and adipose tissue oxylipin content. Diet enrichment with an ω3 polyunsaturated fatty acid induced an increase in the oxylipins derived from ω6 linoleic acid, ω3 eicosapentaenoic, and ω3 docosahexaenoic acids in brown and white adipose tissues. Among these, the level of pro-resolving mediator intermediates, as well as anti-inflammatory metabolites, were augmented. Concomitantly, expressions of M2 macrophage markers were increased without affecting inflammatory cytokine contents. In vitro, these metabolites did not activate macrophages but participated in macrophage polarization by inflammatory stimuli. In conclusion, we demonstrated that an ω3-enriched diet, in non-obesogenic non-inflammatory conditions, induced synthesis of oxylipins which were involved in an anti-inflammatory response as well as enhancement of the M2 macrophage molecular signature, without affecting inflammatory cytokine secretion.

Despite the potential antimicrobial and water purification benefits of chitosan-based nanocomposites, there are growing concerns regarding the hazards of leached nanoparticles (NPs) to the in-contact circumference. The antibacterial performance of the nanocomposites of chitosan with silver and copper NPs and carbon nanotubes was assessed with an emphasis on their impact on fish health. The minimal inhibitory concentrations of each preparation and the growth curves of Aeromonas hydrophila exposed to different nanocomposites were measured. Five groups of Oreochromis niloticus were exposed to chitosan nanocomposites for three weeks. A combination of a low concentration of the NPs in the chitosan matrix improved their antimicrobial properties. However, aqueous exposure to these materials still had hazardous effects on fish health. Experimental groups of O. niloticus exposed to these nanocomposites exhibited oxidative stress, tissue DNA fragmentation and higher expression of pro-inflammatory and immune-related genes such as TNF-α and IL1β. Various pathological tissue alterations were observed in gills, liver, spleen and intestine. Exposure to some of the prepared nanocomposites led to significant DNA damage in hepatic cells with a marked increase in the apoptotic index., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as β3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFβ signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFβ signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by β3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The recent characterization of functional brown adipose tissue in adult humans has opened new perspectives for regulation of energy expenditure with respect to obesity and diabetes. Furthermore, dietary recommendations have taken into account the insufficient dietary intake of ω3 PUFAs and the concomitant excessive intake of ω6 PUFA associated with the occurrence of overweight/obesity. We aimed to study whether ω3 PUFAs could play a role in the recruitment and function of energy-dissipating brown/brite adipocytes. We show that ω3 PUFA supplementation has a beneficial effect on the thermogenic function of adipocytes. In vivo, a low dietary ω6:ω3 ratio improved the thermogenic response of brown and white adipose tissues to β3-adrenergic stimulation. This effect was recapitulated in vitro by PUFA treatment of hMADS adipocytes. We pinpointed the ω6-derived eicosanoid prostaglandin (PG)F2α as the molecular origin because the effects were mimicked with a specific PGF2α receptor agonist. PGF2α level in hMADS adipocytes was reduced in response to ω3 PUFA supplementation. The recruitment of thermogenic adipocytes is influenced by the local quantity of individual oxylipins, which is controlled by the ω6:ω3 ratio of available lipids. In human nutrition, energy homeostasis may thus benefit from the implementation of a more balanced dietary ω6:ω3 ratio., (Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.)

Objective: Thermogenic adipocytes (i.e. brown or brite/beige adipocytes) are able to burn large amounts of lipids and carbohydrates as a result of highly active mitochondria and enhanced uncoupled respiration, due to UCP1 activity. Although mitochondria are the key organelles for this thermogenic function, limited human data are available., Methods/results: We characterized changes in the mitochondrial function of human brite adipocytes, using hMADS cells as a model of white- to brite-adipocyte conversion. We found that profound molecular modifications were associated with morphological changes in mitochondria. The fission process was partly driven by the DRP1 protein, which also promoted mitochondrial uncoupling., Conclusion: Our data demonstrate that white-to-brite conversion of human adipocytes relies on molecular, morphological and functional changes in mitochondria, which enable brite/beige cells to carry out thermogenesis., (Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Oxylipins are bioactive metabolites derived from the oxygenation of ω3 and ω6 polyunsaturated fatty acids, triggered essentially by cyclooxygenase and lipoxygenase activities. Oxylipins are involved in the development and function of adipose tissue and their productions are strictly related to diet quality and quantity. Oxylipins signal via cell surface membrane (G Protein-coupled receptors) and nuclear receptors (peroxisome proliferator-activated receptors), two pathways playing a pivotal role in adipocyte biology. In this review, we made an attempt to cover the available knowledge about synthesis and molecular function of oxylipins known to modulate adipogenesis, adipocyte function and phenotype conversion, with a focus on their interaction with peroxisome proliferator-activated nuclear receptor family., (Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Purpose: We compared renal function outcomes among patients in the surveillance and intervention arms of the DISSRM registry., Materials and Methods: Patients were grouped into chronic kidney disease stages by estimated glomerular filtration rate range. Cases were considered up staged if a more advanced chronic kidney disease stage was entered during followup. Chronic kidney disease up staging-free survival was compared among groups using Kaplan-Meier analysis and paired comparisons log rank tests. Multivariate Cox regression identified independent predictors of chronic kidney disease up staging-free survival., Results: A total of 162 patients met the study inclusion criteria, with 68 in the surveillance arm, 65 undergoing partial nephrectomy, 15 undergoing radical nephrectomy, and 14 undergoing cryoablation. Median tumor size was 2.2cm. Mean estimated glomerular filtration rate change was significantly larger for radical nephrectomy vs. surveillance (-9.2 vs. -0.5ml/min/1.73m 2 ) and for radical vs. partial nephrectomy (-9.2 vs. -1.9ml/min/1.73m 2 ) (P = 0.001). No other groups differed significantly. On Kaplan-Meier analysis, patients undergoing radical nephrectomy had significantly worse chronic kidney disease up staging-free survival vs. those treated with partial nephrectomy (P = 0.029), surveillance (P = 0.007), and cryoablation (P = 0.019). No other groups differed significantly. On multivariate analysis, radical nephrectomy independently predicted poor chronic kidney disease up staging-free survival (odds ratio vs. surveillance 30.6, P = 0.001). Neither partial nephrectomy (P = 0.985) nor cryoablation (P = 0.976) predicted poor chronic kidney disease up staging-free survival relative to surveillance., Conclusions: Patients in the surveillance arm had superior estimated glomerular filtration rate preservation compared to those in the radical nephrectomy but not the partial nephrectomy arm. In certain patients with small renal masses, surveillance and partial nephrectomy may offer comparable renal functional outcomes. This could be partly attributable to a modest estimated glomerular filtration rate decrease associated with surveillance itself. A thorough understanding of the renal functional impacts of treatment modalities is critical in the management of small renal masses., (Copyright © 2017. Published by Elsevier Inc.)

In response to cold or β3-adrenoreceptor stimulation brown adipose tissue (BAT) promotes non-shivering thermogenesis, leading to energy dissipation. BAT has long been thought to be absent or scarce in adult humans. The recent discovery of thermogenic brite/beige adipocytes has opened the way to development of novel innovative strategies to combat overweight/obesity and associated diseases. Thus it is of great interest to identify regulatory factors that govern the brite adipogenic program. Here, we carried out global microRNA (miRNA) expression profiling on human adipocytes to identify miRNAs that are regulated upon the conversion from white to brite adipocytes. Among the miRNAs that were differentially expressed, we found that Let-7i-5p was down regulated in brite adipocytes. A detailed analysis of the Let-7i-5p levels showed an inverse expression of UCP1 in murine and human brite adipocytes both in vivo and in vitro. Functional studies with Let-7i-5p mimic in human brite adipocytes in vitro revealed a decrease in the expression of UCP1 and in the oxygen consumption rate. Moreover, the Let-7i-5p mimic when injected into murine sub-cutaneous white adipose tissue inhibited partially β3-adrenergic activation of the browning process. These results suggest that the miRNAs Let-7i-5p participates in the recruitment and the function of brite adipocytes.

Objective: In rodents and humans, besides brown adipose tissue (BAT), islands of thermogenic adipocytes, termed "brite" (brown-in-white) or beige adipocytes, emerge within white adipose tissue (WAT) after cold exposure or β3-adrenoceptor stimulation, which may protect from obesity and associated diseases. microRNAs are novel modulators of adipose tissue development and function. The purpose of this work was to characterize the role of microRNAs in the control of brite adipocyte formation., Methods/results: Using human multipotent adipose derived stem cells, we identified miR-125b-5p as downregulated upon brite adipocyte formation. In humans and rodents, miR-125b-5p expression was lower in BAT than in WAT. In vitro, overexpression and knockdown of miR-125b-5p decreased and increased mitochondrial biogenesis, respectively. In vivo, miR-125b-5p levels were downregulated in subcutaneous WAT and interscapular BAT upon β3-adrenergic receptor stimulation. Injections of an miR-125b-5p mimic and LNA inhibitor directly into WAT inhibited and increased β3-adrenoceptor-mediated induction of UCP1, respectively, and mitochondrial brite adipocyte marker expression and mitochondriogenesis., Conclusion: Collectively, our results demonstrate that miR-125b-5p plays an important role in the repression of brite adipocyte function by modulating oxygen consumption and mitochondrial gene expression.

Brite adipocytes recently discovered in humans are of considerable importance in energy expenditure by converting energy excess into heat. This property could be useful in the treatment of obesity, and nutritional aspects are relevant to this important issue. Using hMADS cells as a human cell model which undergoes a white to a brite adipocyte conversion, we had shown previously that arachidonic acid, the major metabolite of the essential nutrient Ω6-linoleic acid, plays a major role in this process. Its metabolites PGE2 and PGF2 alpha inhibit this process via a calcium-dependent pathway, whereas in contrast carbaprostacyclin (cPGI2), a stable analog of prostacyclin, activates white to brite adipocyte conversion. Herein, we show that cPGI2 generates via its cognate cell-surface receptor IP-R, a cyclic AMP-signaling pathway involving PKA activity which in turn induces the expression of UCP1. In addition, cPGI2 activates the pathway of nuclear receptors of the PPAR family, i.e. PPARα and PPARγ, which act separately from IP-R to up-regulate the expression of key genes involved in the function of brite adipocytes. Thus dual pathways are playing in concert for the occurrence of a browning process of human white adipocytes. These results make prostacyclin analogs as a new class of interesting molecules to treat obesity and associated diseases., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Brown adipose tissue (BAT) is essential for adaptive thermogenesis and dissipation of caloric excess through the activity of uncoupling protein (UCP)-1. BAT in humans is of great interest for the treatment of obesity and related diseases. In this study, the expression of Twik-related acid-sensitive K(+) channel (TASK)-1 [a pH-sensitive potassium channel encoded by the potassium channel, 2-pore domain, subfamily K, member 3 (Kcnk3) gene] correlated highly with Ucp1 expression in obese and cold-exposed mice. In addition, Task1-null mice, compared with their controls, became overweight, mainly because of an increase in white adipose tissue mass and BAT whitening. Task1(-/-)-mouse-derived brown adipocytes, compared with wild-type mouse-derived brown adipocytes, displayed an impaired β3-adrenergic receptor response that was characterized by a decrease in oxygen consumption, Ucp1 expression, and lipolysis. This phenotype was thought to be caused by an exacerbation of mineralocorticoid receptor (MR) signaling, given that it was mimicked by corticoids and reversed by an MR inhibitor. We concluded that the K(+) channel TASK1 controls the thermogenic activity in brown adipocytes through modulation of β-adrenergic receptor signaling., (© FASEB.)

Introduction: Partial cystectomy use has historically been limited by stringent selection criteria. We compared outcomes following partial cystectomy at our institution with those in other contemporary series. Also, we specifically characterized outcomes in patients with tumors in bladder locations traditionally considered unamenable to partial cystectomy., Methods: Patients who underwent partial cystectomy for primary bladder cancer from 1990 to 2012 were identified from our database. Clinical and pathological data were reviewed. Survival analyses were performed using Kaplan-Meier methods. Cox regression was done to identify factors associated with survival and recurrence., Results: A total of 55 patients were included in analysis. Five-year overall, disease specific and recurrence-free survival was 70.3%, 77.0% and 39.4%, respectively. When controlling for clinical and pathological covariates, lymphovascular invasion predicted decreased recurrence-free survival (HR 10.6, p = 0.025). Perioperative morbidity and mortality rates were 4% and 5%, respectively. In 8 patients (15%) trigone tumors required ureteral reimplantation. Two of the 8 patients (25%) experienced complications, including hydronephrosis and bladder neck contracture, which were treated conservatively. Cancer recurred in 2 of the 8 patients (25%) and both were treated successfully. None of the 8 patients died of bladder cancer., Conclusions: Patients treated with partial cystectomy for primary bladder cancer had satisfactory cancer control and favorable perioperative morbidity consistent with other contemporary reports. Patients with tumors in the bladder trigone, historically considered poor candidates for partial cystectomy, also had good oncologic outcomes without significant complications related to reimplantation. Our data further support partial cystectomy in select patients with bladder cancer.

Human brown adipocytes are able to burn fat and glucose and are now considered as a potential strategy to treat obesity, type 2 diabetes and metabolic disorders. Besides their thermogenic function, brown adipocytes are able to secrete adipokines. One of these is visfatin, a nicotinamide phosphoribosyltransferase involved in nicotinamide dinucleotide synthesis, which is known to participate in the synthesis of insulin by pancreatic β cells. In a therapeutic context, it is of interest to establish whether a potential correlation exists between brown adipocyte activation and/or brite adipocyte recruitment, and adipokine expression. We analyzed visfatin expression, as a pre-requisite to its secretion, in rodent and human biopsies and cell models of brown/brite adipocytes. We found that visfatin was preferentially expressed in mature adipocytes and that this expression was higher in brown adipose tissue of rodents compared to other fat depots. However, using various rodent models we were unable to find any correlation between visfatin expression and brown or brite adipocyte activation or recruitment. Interestingly, the situation is different in humans where visfatin expression was found to be equivalent between white and brown or brite adipocytes in vivo and in vitro. In conclusion, visfatin can be considered only as a rodent brown adipocyte biomarker, independently of tissue activation.

Purpose: We compared renal function outcomes among patients in the surveillance and intervention arms of the DISSRM registry., Materials and Methods: Patients were grouped into chronic kidney disease stages by estimated glomerular filtration rate range. Cases were considered up staged if a more advanced chronic kidney disease stage was entered during followup. Chronic kidney disease up staging-free survival was compared among groups using Kaplan-Meier analysis and paired comparisons log rank tests. Multivariate Cox regression identified independent predictors of chronic kidney disease up staging-free survival., Results: A total of 162 patients met the study inclusion criteria, with 68 in the surveillance arm, 65 undergoing partial nephrectomy, 15 undergoing radical nephrectomy and 14 undergoing cryoablation. Median tumor size was 2.2 cm. Mean estimated glomerular filtration rate change was significantly larger for radical nephrectomy vs surveillance (-9.2 vs -0.5 ml/minute/1.73 m(2)) and for radical vs partial nephrectomy (-9.2 vs -1.9 ml/minute/1.73 m(2)) (p=0.001). No other groups differed significantly. On Kaplan-Meier analysis patients undergoing radical nephrectomy had significantly worse chronic kidney disease up staging-free survival vs those treated with partial nephrectomy (p=0.029), surveillance (p=0.007) and cryoablation (p=0.019). No other groups differed significantly. On multivariate analysis radical nephrectomy independently predicted poor chronic kidney disease up staging-free survival (odds ratio vs surveillance 30.6, p=0.001). Neither partial nephrectomy (p=0.985) nor cryoablation (p=0.976) predicted poor chronic kidney disease up staging-free survival relative to surveillance., Conclusions: Patients in the surveillance arm had superior estimated glomerular filtration rate preservation compared to those in the radical nephrectomy but not the partial nephrectomy arm. In certain patients with small renal masses surveillance and partial nephrectomy may offer comparable renal functional outcomes. This could be partly attributable to a modest estimated glomerular filtration rate decrease associated with surveillance itself. A thorough understanding of the renal functional impacts of treatment modalities is critical in the management of small renal masses., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Renal cell carcinoma is the most common cancer of the kidneys that is primarily treated with surgery, including removal of part or all the involved kidney depending on size and tumor, complexity, and patient characteristics. Partial nephrectomy historically was restricted to cases of solitary kidney or bilateral tumors. It was then started for masses smaller than 4 cm and currently is even studied and justified in tumors smaller than 7 cm if surgically feasible. Although partial nephrectomy preserves kidney tissue and, therefore, delays or prevents the new onset of CKD and ESRD, radical nephrectomy is still overused even for the small tumors. Studies have shown that although this practice is driven by an easier complete removal of the kidney especially in the era of minimally invasive surgery, partial nephrectomy is successful in curing cancer and achieving excellent cancer-specific survival in addition to its benefits on cardiovascular health. Nowadays interest in preserving healthy kidney tissue is increasing to the level of studying the impact of larger volume removed around the kidney and the histopathology of that non-neoplastic tissue to predict kidney function behavior postoperatively., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether heterogeneity of tumor grade affects the response to Bacillus Calmette-Guérin (BCG) treatment for patients with non-muscle-invasive bladder cancer (NMIBC)., Methods: Patients with Ta or T1 NMBIC receiving a 6-week induction course of intravesical BCG therapy after transurethral resection were divided according to the tumor grade. Clinical and pathological variables were compared. Advanced intervention-free survival (AIFS), defined as duration of freedom from advanced intervention (including non-BCG intravesical agents or cystectomy) or metastasis, was plotted using Kaplan-Meier methods. The effect of grade on survival duration was assessed by multivariate Cox proportional hazards modeling., Results: One hundred and fifty-three patients were identified: 17 with mixed low- and high-grade (MG) and 136 with pure high-grade (PHG) NMIBC. Demographic and additional pathologic variables were comparable between groups (p > 0.05). Five-year AIFS was 88.2% for MG patients, compared to 48.5% for PHG patients (p = 0.030 by log-rank test). On multivariate analysis, PHG was an independent risk factor for worse AIFS (HR 4.4, 95% CI 1.1-18.4, p = 0.040). Among patients failing to respond to primary BCG induction, who underwent a secondary induction of BCG with interferon, MG patients had better response than PHG patients (100 vs. 26.3%, p = 0.035)., Conclusions: Mixed low- and high-grade NMIBC exhibits a significantly better response profile to intravesical BCG therapy compared to PHG NMIBC. The implications of these results are that less aggressive treatment strategies for this unique cancer entity may be needed and that there is a benefit to the reporting of tumor heterogeneity in transurethral resection of bladder tumor specimens.

Background: To determine the effect of statins and metformin in combination on biochemical recurrence (BCR) among diabetic men undergoing radical prostatectomy (RP)., Methods: Diabetic men undergoing RP at our institution from January 1995 to March 2012 were retrospectively reviewed. Recipients of adjuvant radiation or hormonal therapy were excluded. Statin and/or metformin use was determined through review of electronic records. BCR-free survival was plotted using Kaplan-Meier analysis, and the effect of statins and metformin on BCR was assessed via a multivariate Cox proportional hazards model., Results: Seven hundred and sixty-seven men met the inclusion criteria. Seventy-six (9.9%) were users of statins only, 56 (7.3%) were users of metformin only and 42 (5.5%) were dual users. Median follow-up time was 27 months. Dual users were less likely than nonusers or users of either medication alone to have a biopsy Gleason sum of 8-10 (P=0.033), and tended towards a lower rate of pathological T stage of pT3 or higher (P=0.064). Dual users had the highest 2-year and 5-year BCR-free survival, although this was not statistically significant (P=0.205). On multivariate regression, neither statin nor metformin use alone was significantly associated with BCR-free survival. However, their interaction led to a significantly lower BCR risk than would be expected from each medication's independent effects (hazard ratio=0.2; P=0.037)., Conclusions: The combination of statins and metformin in men undergoing RP for prostate cancer (PCa) may be associated with a lower BCR risk than would be predicted based on the independent effects of both medications. A synergism between these two agents is biologically plausible based on our current understanding of their diverse molecular pathways of action. The results of future clinical trials involving the use of either medication in men with PCa should be carefully assessed for confirmatory evidence of such a relationship.

Objective: To identify the effect of the 2012 United States Preventive Services Task Force (USPSTF) prostate-specific antigen (PSA) recommendation statement on primary care referral patterns and urologists' decision making., Methods: Men referred to our institution for newly elevated PSA level from June 2011 to June 2013 were identified. Patients with a prior history of prostate cancer or biopsy were excluded. Clinical and management parameters were compared between those presenting in the year before vs the year after the USPSTF statement. Factors predictive of receiving a prostate biopsy were identified using multivariate regression analysis., Results: A total of 201 men were identified in the pre-USPSTF period and 212 men, thereafter. The groups were comparable in age, race, prostate cancer family history, PSA values, and digital rectal examination findings. At the initial evaluation, patients presenting after the statement were more likely to undergo PCA3 testing (27% vs 11%; P <.01) and repeat PSA testing (82% vs 72%; P = .02) and less likely to undergo immediate biopsy (16% vs 24%; P = .03). The proportion of patients ultimately receiving a biopsy was equivalent. The groups were similar in the percentage of positive biopsies, Gleason distribution, and D'Amico risk. African American race and family history were predictors for receiving a biopsy in the post-USPSTF group but not in the pre-USPSTF group., Conclusion: The 2012 USPSTF recommendation statement has not affected the number or clinical characteristics of patients referred to a tertiary center for elevated PSA level. After recommendation, urologists ordered significantly more PCA3 and repeat PSA tests and recommended fewer biopsies at the initial visit. The fraction of patients ultimately receiving a biopsy remained the same., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Response rates to current second line intravesical therapies for recurrent nonmuscle invasive bladder cancer range between 10% and 30%. Nanoparticle albumin bound (nab-)paclitaxel has increased solubility and lower toxicity compared to other taxanes. Results of the phase I intravesical trial of this compound demonstrated minimal toxicity during dose escalation. We now report the results of a phase II trial to assess efficacy., Materials and Methods: This study was an investigator initiated, single center, single arm, phase II trial investigating the use of nab-paclitaxel in patients with recurrent Tis, T1 and Ta urothelial carcinoma in whom at least 1 prior regimen of intravesical bacillus Calmette-Guérin failed. Patients received 500 mg/100 ml nab-paclitaxel administered in 6 weekly intravesical instillations. Efficacy was evaluated with cystoscopy, biopsy, cytology and imaging. If complete response was achieved, patients were treated with full dose monthly maintenance treatments for 6 months., Results: A total of 28 patients were enrolled in the study. Of these patients 10 (35.7%) exhibited a complete response after initial treatment. At 1 year all of these responses remained durable after maintenance therapy. At a mean followup of 21 months (range 5 to 47) 19 of 28 (67.8%) patients retained their bladders without progression or distant metastases. A single patient had progression to muscle invasive disease at radical cystectomy. Treatment related adverse events were noted in 9 of 28 (32.1%) patients and were limited to grade 1 or 2., Conclusions: Intravesical nab-paclitaxel has minimal toxicity and a 35.7% response rate in patients with nonmuscle invasive bladder cancer and previous bacillus Calmette-Guérin failure. Complete response remained durable at 1 year followup in this heavily pretreated patient population., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine the costs of treatment and the duration of survival, adjusted for quality of life, for patients with muscle-invasive bladder cancer treated with immediate radical cystectomy (RC) or with neoadjuvant chemotherapy (NAC) with intent for subsequent RC., Methods and Materials: A retrospective review of our institutional review board-approved database identified patients with muscle-invasive bladder cancer treated at our institution from 2004 to 2011. Patients were divided into those receiving RC alone and those receiving NAC before planned RC. Patients who refused RC following NAC were included in an intention-to-treat analysis. Survival duration was converted to quality-adjusted life years (QALYs), and costs of treatment per QALY were determined., Results: A total of 119 patients (65.4%) received RC alone and 63 (34.6%) received NAC, 38 of whom proceeded to cystectomy as planned. Mean total costs were $42,890 and $52,429 for RC and NAC, respectively (P = 0.005). The 5-year overall survival was 31.7% and 42.5% for the RC-only group and the NAC group, respectively (P = 0.034). The 5-year overall survival measured in QALYs was 21.9% and 42.9% for the RC-only and the NAC groups, respectively (P = 0.021). The increased cost for NAC was $5,840 per additional life year gained (95% CI: $1,772-$9,909) and $6,187 per additional QALY gained (95% CI: $1,877-$10,498)., Conclusions: The use of NAC is associated with a significant increase in quality-adjusted survival. The additional cost per QALY gained is approximately $6,000. The cost-utility analysis of NAC compares favorably with other cancer-specific therapies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Brite adipocytes are inducible energy-dissipating cells expressing UCP1 which appear within white adipose tissue of healthy adult individuals. Recruitment of these cells represents a potential strategy to fight obesity and associated diseases., Methods/results: Using human Multipotent Adipose-Derived Stem cells, able to convert into brite adipocytes, we show that arachidonic acid strongly inhibits brite adipocyte formation via a cyclooxygenase pathway leading to secretion of PGE2 and PGF2α. Both prostaglandins induce an oscillatory Ca(++) signaling coupled to ERK pathway and trigger a decrease in UCP1 expression and in oxygen consumption without altering mitochondriogenesis. In mice fed a standard diet supplemented with ω6 arachidonic acid, PGF2α and PGE2 amounts are increased in subcutaneous white adipose tissue and associated with a decrease in the recruitment of brite adipocytes., Conclusion: Our results suggest that dietary excess of ω6 polyunsaturated fatty acids present in Western diets, may also favor obesity by preventing the "browning" process to take place.

Purpose of Review: Radical cystectomy is the standard of care for patients who fail intravesical bacillus Calmette-Guérin (BCG) for nonmuscle invasive bladder cancer (NMIBC). For patients unwilling or unable to undergo cystectomy, numerous local therapies exist, although few are approved by the Food and Drug Administration. This review describes available therapies for this challenging clinical entity., Recent Findings: Combination intravesical chemotherapy, targeted therapy, and drug delivery enhancement have all been under recent investigation and are promising, although none has proven superior as of yet., Summary: While BCG is standard treatment for intermediate and high-risk NMIBC, many patients fail therapy with recurrence or progression. Early cystectomy is the standard of care for BCG failure; however, many patients are unwilling or unable to undergo cystectomy. Multiple intravesical therapies have been used in this BCG failure population with moderate success, and, recently, technologies to improve drug delivery or create novel drugs have also been applied. Comparing efficacy of these therapies remain challenging as study cohorts are heterogeneous and study designs are variable. However, there are an increasing number of novel treatment options that can be offered to patients faced with recurrent NMIBC after BCG who seek bladder-sparing therapy.

Objective: To determine whether socioeconomic status (SES) predicts the size and local extent of tumors at presentation, and if this association leads to differences in survival., Materials and Methods: The National Cancer Institute's Survival, Epidemiology, and End Results registry was queried for patients diagnosed with renal cancers between 2004 and 2010. Demographic, tumor, survival, and socioeconomic data were obtained. Cancers with T0 classification, nonrenal cell histology, or missing clinical or pathologic data were excluded. An SES measure was created from available metrics. Outcomes analyzed were tumor size, TNM classifications at diagnosis, tumor grade and histology subtype, and survival duration., Results: A total of 40,212 cases were identified. On regression modeling, lower SES was an independent risk factor for tumor size ≥ 4 cm (P = .003) and for T classification ≥ T2 (P = .040) at presentation, but did not predict histology subtype, positive lymph nodes, or metastasis. Lower SES predicted high-grade disease on univariate analysis (P = .012) but lost significance in the multivariate model. Lower SES was also independently predictive of shortened cancer-specific survival on multivariate analysis after adjusting for available cofactors (lowest vs highest SES quartile; P = .001)., Conclusion: This study suggests that low SES is correlated with poorer survival outcomes in renal cancer, and this may be related to a tendency toward larger and more locally advanced tumors at diagnosis. Additional investigation is needed to ascertain whether these effects could be mediated by relatively lower rates of incidental detection via abdominal imaging in disadvantaged populations., (Copyright © 2014 Elsevier Inc. All rights reserved.)