Does the Diagnosis of Bladder Cancer Lead to Higher Rates of Smoking Cessation? Findings from the Medicare Health Outcomes Survey.

PURPOSE: Smoking is the most common risk factor for bladder cancer and it is associated with adverse clinical outcomes. The bladder cancer diagnosis represents a teachable moment for smoking cessation. We investigated the likelihood of smoking cessation after bladder cancer diagnosis in a population database. MATERIALS AND METHODS: We evaluated the 1998 to 2013 SEER (Surveillance, Epidemiology and End Results)-MHOS (Medicare Health Outcomes Survey) data on all patients diagnosed with incident bladder cancer on whom survey data were available before and after diagnosis. We compared these patients to propensity matched noncancer controls and to a cohort of patients with incident renal cell carcinoma. Differences in smoking cessation were compared between the groups and multivariate logistic regression was performed to assess the likelihood of smoking cessation. RESULTS: We propensity matched 394 patients with newly diagnosed bladder cancer to 1,970 noncancer controls and compared them with 169 patients with incident renal cell carcinoma. Baseline smoking prevalence was more common in patients diagnosed with bladder cancer compared to renal cell carcinoma (16% vs 11%) but the difference was not significant. The smoking cessation rate in patients with bladder cancer was 27% compared with 21% in noncancer controls and 26% in patients with renal cell carcinoma (p = 0.30 and 0.90, respectively). There was no significant difference in the adjusted OR of quitting smoking in patients with bladder cancer vs those with renal cell carcinoma compared to noncancer controls (OR 1.3, 95% CI 0.7-2.5 vs OR 1.2, 95% CI 0.4-3.6). Independent predictors of smoking cessation in patients with bladder cancer included age (p = 0.03), African American race (p = 0.03) and college education (p = 0.01). CONCLUSIONS: Compared to propensity matched noncancer controls smoking cessation did not significantly differ after a diagnosis of bladder cancer. The proportion of individuals who quit was low overall, suggesting that improved efforts are needed to use this teachable moment in patients with bladder cancer.

Health Related Quality of Life Following Radical Cystectomy: Comparative Analysis from the Medicare Health Outcomes Survey.

PURPOSE: Health related quality of life after radical cystectomy and ileal conduit is not well quantified at the population level. We evaluated health related quality of life in patients with bladder cancer compared with noncancer controls and patients with colorectal cancer using data from SEER (Surveillance, Epidemiology and End Results)-MHOS (Medicare Health Outcomes Survey). MATERIALS AND METHODS: SEER-MHOS data from 1998 to 2013 were used to identify patients with bladder cancer and those with colorectal cancer who underwent extirpative surgery with ileal conduit or colostomy creation, respectively. A total of 166 patients with bladder cancer treated with radical cystectomy were propensity matched 1:5 to 830 noncancer controls and compared with 154 patients with colorectal cancer. Differences in Mental and Physical Component Summary scores as well as component subscores were determined between patients with bladder cancer, patients with colorectal cancer and noncancer controls. RESULTS: SEER-MHOS patients were more commonly male and white with a mean ± SD age of 77 ± 6 years. Patients treated with radical cystectomy had significantly lower Physical Component Summary scores, select physical subscale scores and all mental subscale scores compared with noncancer controls. These findings were similar in the subset of 40 patients treated with radical cystectomy who had available preoperative and postoperative survey data. Global Mental Component Summary scores did not differ significantly between the groups. No significant differences were observed in global Mental Component Summary, Physical Component Summary or subscale scores between patients with bladder cancer and patients with colorectal cancer. CONCLUSIONS: Patients with bladder cancer who undergo radical cystectomy have significant declines in multiple components of physical and mental health related quality of life vs noncancer controls, which mirror those of patients with colorectal cancer. Further longitudinal study is required to better codify the effectors of poor health related quality of life after radical cystectomy to improve patient expectations and outcomes.

Characterizing the molecular features of ERG-positive tumors in primary and castration resistant prostate cancer.

BACKGROUND: The TMPRSS2-ERG gene fusion is detected in approximately half of primary prostate cancers (PCa) yet the prognostic significance remains unclear. We hypothesized that ERG promotes the expression of common genes in primary PCa and metastatic castration-resistant PCa (CRPC), with the objective of identifying ERG-associated pathways, which may promote the transition from primary PCa to CRPC. METHODS: We constructed tissue microarrays (TMA) from 127 radical prostatectomy specimens, 20 LuCaP patient-derived xenografts (PDX), and 152 CRPC metastases obtained immediately at time of death. Nuclear ERG was assessed by immunohistochemistry (IHC). To characterize the molecular features of ERG-expressing PCa, a subset of IHC confirmed ERG+ or ERG- specimens including 11 radical prostatectomies, 20 LuCaP PDXs, and 45 CRPC metastases underwent gene expression analysis. Genes were ranked based on expression in primary PCa and CRPC. Common genes of interest were targeted for IHC analysis and expression compared with biochemical recurrence (BCR) status. RESULTS: IHC revealed that 43% of primary PCa, 35% of the LuCaP PDXs, and 18% of the CRPC metastases were ERG+ (12 of 48 patients [25%] had at least one ERG+ metastasis). Based on gene expression data and previous literature, two proteins involved in calcium signaling (NCALD, CACNA1D), a protein involved in inflammation (HLA-DMB), CD3 positive immune cells, and a novel ERG-associated protein, DCLK1 were evaluated in primary PCa and CRPC metastases. In ERG+ primary PCa, a weak association was seen with NCALD and CACNA1D protein expression. HLA-DMB association with ERG was decreased and CD3 cell number association with ERG was changed from positive to negative in CRPC metastases compared to primary PCa. DCLK1 was upregulated at the protein level in unpaired ERG+ primary PCa and CRPC metastases (P = 0.0013 and P < 0.0001, respectively). In primary PCa, ERG status or expression of targeted proteins was not associated with BCR-free survival. However, for primary PCa, ERG+DCLK1+ patients exhibited shorter time to BCR (P = 0.06) compared with ERG+DCLK1- patients. CONCLUSIONS: This study examined ERG expression in primary PCa and CRPC. We have identified altered levels of inflammatory mediators associated with ERG expression. We determined expression of DCLK1 correlates with ERG expression and may play a role in primary PCa progression to metastatic CPRC. Prostate 76:810-822, 2016. © 2016 Wiley Periodicals, Inc.

Sarcomatoid Urothelial Carcinoma Is Associated With Limited Response to Neoadjuvant Chemotherapy and Poor Oncologic Outcomes After Radical Cystectomy.

INTRODUCTION: To examine oncologic outcomes and response to neoadjuvant chemotherapy (NAC) in patients with sarcomatoid urothelial carcinoma (SUC) treated with radical cystectomy (RC). MATERIALS AND METHODS: We retrospectively queried our institutional database (2003-18) and Surveillance, Epidemiology, and End Results (SEER)-Medicare (2004-2015) for patients with cT2-4, N0-2, M0 SUC and conventional UC (CUC) treated with RC. Clinicopathologic characteristics were described using descriptive statistics (t test, χ2-test and log-rank-test for group comparison). Overall (OS) and recurrence-free-survival (RFS) after RC were estimated with the Kaplan Meier method and associations with OS were evaluated with Cox proportional hazards models. RESULTS: We identified 38 patients with SUC and 287 patients with CUC in our database, and 190 patients with SUC in SEER-Medicare. In the institutional cohort, patients with SUC versus CUC had higher rates of pT3/4 stage (66% vs. 35%, P < 0.001), lower rates of ypT0N0 (6% vs. 35%, P = .02), and worse median OS (17.5 vs. 120 months, P < .001). Further, patients with SUC in the institutional versus SEER-Medicare cohort had similar median OS (17.5 vs. 21 months). In both cohorts, OS was comparable between patients with SUC undergoing NAC+RC vs. RC alone (17.5 vs. 18.4 months, P = .98, institutional cohort; 24 vs. 20 months, P = .56, SEER cohort). In Cox proportional hazards models for the institutional RC cohort, SUC was independently associated with worse OS (HR 2.3, CI 1.4-3.8, P = .001). CONCLUSION: SUC demonstrates poor pathologic response to NAC and worse OS compared with CUC, with no OS benefit associated with NAC. A unique pattern of rapid abdominopelvic cystic recurrence was identified.

Social and Clinical Correlates of Neoadjuvant Chemotherapy in Medicare Beneficiaries With Muscle Invasive Bladder Cancer From 2004-2015.

OBJECTIVE: To assess social and clinical correlates of neoadjuvant chemotherapy (NAC) utilization among Medicare beneficiaries. MATERIALS AND METHODS: A cohort of SEER-Medicare (2004-2015) patients with muscle-invasive bladder cancer treated by radical cystectomy were stratified into 3-groups: standard of care NAC (cisplatin-based combination), non-standard of care NAC, and upfront cystectomy. Multivariable logistic regression analysis was used to assess social, demographic and clinical correlates of each treatment category. Survival analyses were performed to compare propensity matched treatment groups. RESULTS: In total, 6214 patients were identified with a median follow-up of 21 [IQR 7-54] months. NAC utilization increased from 10.7% to 39.1%, between 2004 and 2015, largely due to increased use of standard of care regimens. The most commonly used nonstandard regimen was gemcitabine/carboplatin (50.2%). Older age, Hispanic and Black race, lower socioeconomic status, and contraindications to cisplatin were associated with increased odds of receiving nonstandard of care NAC compared to standard of care. Standard of care NAC was associated with improved overall survival HR 0.85 (95% CI 0.76, 0.94) and HR 0.75 (95% CI 0.63, 0.89) compared to both upfront cystectomy and nonstandard of care NAC, respectively. CONCLUSION: NAC utilization has increased to nearly 40%; however, the use of non-standard of care NAC regimen have persisted (~8%). Cisplatin-ineligibility, older age, race/ethnicity, and lower socioeconomic status were correlated with nonstandard of care NAC, which provided no clinical benefit at the risk of potential harm. In accordance with current clinical guidelines, cisplatin-ineligible patients should be considered for timely upfront cystectomy or novel clinical trials.

Nonmuscle Invasive Bladder Cancer Influences Physical Health Related Quality of Life and Urinary Incontinence.

OBJECTIVE: To evaluate the effects of nonmuscle invasive bladder cancer (NMIBC) on health-related quality of life (HRQOL) and urinary function within patients diagnosed with NMIBC as compared to the general population. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare Health Outcome Survey (SEER-MHOS) database (1998-2013), 325 patients diagnosed with NMIBC with baseline and postdiagnosis MHOS surveys were propensity-matched 1:5 to noncancer controls (NCC). Multivariate linear regression analysis compared NMIBC patients with matched NCC in terms of physical component summary (PCS), mental component summary (MCS), and health domain scales. Changes in urinary function were assessed using χ2 testing. RESULTS: Patients diagnosed with NMIBC experienced significant decline in PCS vs NCC (-3.0, 95% confidence interval [CI -4.1, -2.0] vs -1.5, 95%CI [-2.0, -1.0], P = .01), while the observed decline in MCS was not significantly different (P = .09) between groups. On sub-analysis, the significant decline in PCS was confined to patients with high-risk NMIBC (P = .01). NMIBC patients had significantly greater decline in role physical (P = .04), general health (P = .04) and role emotional (P <0.01) health domain scales. NMIBC patients were more likely to report worsened urinary leakage, require physician intervention, and receive new treatment for urinary leakage (P values all <.01). CONCLUSION: NMIBC diagnosis was associated with significant decreases in physical HRQOL and urinary function compared with NCC. Further study focused on NMIBC patients, and the inherent HRQOL factors to this diagnosis is needed to assess where improvements can be made in treating this patient population.

Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy.

BACKGROUND: Little is known about the genomic differences between metastatic urothelial carcinoma (LTUC) and upper tract urothelial carcinoma (UTUC). We compare genomic features of primary and metastatic UTUC and LTUC tumors in a cohort of patients with end stage disease. METHODS: We performed whole exome sequencing on matched primary and metastatic tumor samples (N=37) from 7 patients with metastatic UC collected via rapid autopsy. Inter- and intra-patient mutational burden, mutational signatures, predicted deleterious mutations, and somatic copy alterations (sCNV) were analyzed. RESULTS: We investigated 3 patients with UTUC (3 primary samples, 13 metastases) and 4 patients with LTUC (4 primary samples, 17 metastases). We found that sSNV burden was higher in metastatic LTUC compared to UTUC. Moreover, the APOBEC mutational signature was pervasive in metastatic LTUC and less so in UTUC. Despite a lower overall sSNV burden, UTUC displayed greater inter- and intra-individual genomic distances at the copy number level between primary and metastatic tumors than LTUC. Our data also indicate that metastatic UTUC lesions can arise from small clonal populations present in the primary cancer. Importantly, putative druggable mutations were found across patients with the majority shared across all metastases within a patient. CONCLUSIONS: Metastatic UTUC demonstrated a lower overall mutational burden but greater structural variability compared to LTUC. Our findings suggest that metastatic UTUC displays a greater spectrum of copy number divergence from LTUC. Importantly, we identified druggable lesions shared across metastatic samples, which demonstrate a level of targetable homogeneity within individual patients.

Is there a benefit to adjuvant radiation in stage III penile cancer after lymph node dissection? Findings from the National Cancer Database.

OBJECTIVE: The role of adjuvant radiation in advanced penile cancer (PC) is unknown. We used the National Cancer Database (NCDB) to determine factors associated with receiving adjuvant radiation (aXRT) and their influence on prognosis in men who underwent inguinal lymph node dissection (ILND) for stage III disease. MATERIALS AND METHODS: We queried the NCDB from 1998-2012 for all men with PC who had pathologic nodal status and aXRT data available. Clinical and pathologic variables associated with aXRT were examined using chi-square testing. Logistic regression evaluated the odds of receiving aXRT while multivariate Cox regression analysis evaluated the influence of aXRT on overall survival (OS). RESULTS: A total of 589 patients underwent ILND for stage III PC with 23% (N = 136) receiving aXRT. Mean age was 61.8 ±13.7 years. Factors associated with receiving aXRT included higher pathologic nodal stage (MV OR 1.85, 95% CI: 1.13-3.05), while greater distance of travel (MV OR 0.48, 95% CI: 0.25-0.92), and treatment in an academic setting (MV OR 0.53, 95% CI: 0.35-0.81) were inversely associated with receiving aXRT. On Cox regression analysis, aXRT improved OS (combined HR 0.58, 95% CI: 0.39-0.86), which appeared to have been driven by higher nodal burden (N2: HR 0.53, 95% CI: 0.32-0.88; N1: HR 1.36, 95% CI: 0.60-3.09). CONCLUSIONS: Determinants of aXRT delivery in stage III PC appear to be related to the proximity to community cancer centers and greater nodal burden. We find evidence of a survival benefit with the use of aXRT, particularly in those with higher nodal stage. Multi-institutional studies are needed to confirm these findings and improve treatment algorithms for high-stage PC.

Mechanistic target of rapamycin (MTOR) protein expression in the tumor and its microenvironment correlates with more aggressive pathology at cystectomy.

BACKGROUND: The mechanistic target of rapamycin (mTOR) has been implicated in driving tumor biology in multiple malignancies, including urothelial carcinoma (UC). We investigate how mTOR and phosphorylated mTOR (pmTOR) protein expression correlate with chemoresponsiveness in the tumor and its microenvironment at final pathologic staging after neoadjuvant chemotherapy (NAC). METHODS: A single-institution retrospective analysis was performed on 62 patients with cT2-4Nany UC undergoing NAC followed by radical cystectomy. Diagnostic (transurethral resection specimens, TURBT) and postchemotherapy radical cystectomy specimens were evaluated for mTOR and pmTOR protein expression using immunohistochemistry of the tumor, peritumoral stroma, and normal surrounding stroma. Protein expression levels were compared between clinical and pathologic stage. Whole transcriptome analysis was performed to evaluate mRNA expression relative to mTOR pathway activation. RESULTS: Baseline levels of mTOR and pmTOR within TURBT specimens were not associated with clinical stage and response to chemotherapy overall. Nonresponders with advanced pathologic stage at cystectomy (ypT2-4/ypTanyN+) had significantly elevated mTOR tumor staining (P = 0.006) and a sustained mTOR and pmTOR staining in the peritumoral and surrounding normal stroma (NS). Several genes relevant to mTOR activity were found to be up-regulated in the tumors of nonresponders. Remarkably, complete responders at cystectomy (ypT0) had significant decreases in both mTOR and pmTOR protein expression in the peritumoral and normal stroma (P = 0.01-0.03). CONCLUSIONS: Our results suggest that mTOR pathway activity is increased in tumor and sustained in its microenvironment in patients with adverse pathologic findings at cystectomy. These findings suggest the relevance of targeting this pathway in bladder cancer.

Predictors of Nodal Upstaging in Clinical Node Negative Patients With Penile Carcinoma: A National Cancer Database Analysis.

OBJECTIVE: To examine the risk factors associated with upstaging at inguinal lymph node dissection (ILND) in men with penile cancer and clinically negative lymph nodes (cN0) using a large US cancer database. METHODS: The National Cancer Data Base was queried from 1998 to 2012 to identify men with penile cancer who underwent ILND and had complete clinical or pathologic node status available. Lymphovascular invasion (LVI) was available after 2010. Multivariate logistic regression evaluated factors (cT stage, grade, LVI) associated with pathologic nodal upstaging in those with cN0 disease. Correlations between clinical and pathologic node status were also calculated with weighted kappa statistics. RESULTS: Complete clinical and pathologic LN status was available for 875 patients. Of these, 461 (53%) were cN0. Upstaging occurred in 111 (24%). When stratified by low, intermediate, and high-risk groups, the proportion with pathologically positive LNs was 16%, 20%, and 27%, respectively (P = .12). On multivariate analysis, limited to men with LVI data available (N = 206), LVI (odds ratio 3.10, 95% confidence interval 1.39-6.92), but not increasing stage (univariate only) or grade (univariate only), was significantly associated with upstaging at ILND. CONCLUSION: In this analysis, of 461 patients with node-negative penile cancer undergoing ILND, upstaging was observed in 24%. LVI was the strongest independent predictor of occult lymph node disease. These findings corroborate the presence of LVI as the significant risk factor for occult micrometastases and suggest a possible improvement in existing risk stratification groupings, with the presence of LVI, regardless of stage or grade, to be considered high-risk disease.

Extreme Gleason Upgrading From Biopsy to Radical Prostatectomy: A Population-based Analysis.

OBJECTIVE: To examine the risk factors associated with the odds of extreme Gleason upgrading at radical prostatectomy (RP) (defined as a Gleason prognostic group score increase of ≥2), we utilized a large, population-based cancer registry. MATERIALS AND METHODS: The Surveillance, Epidemiologic, and End Results database was queried (2010-2011) for all patients diagnosed with Gleason 3 + 3 or 3 + 4 on prostate needle biopsy. Available clinicopathologic factors and the odds of upgrading and extreme upgrading at RP were evaluated using multivariate logistic regression. RESULTS: A total of 12,459 patients were identified, with a median age of 61 (interquartile range: 56-65) and a diagnostic prostate-specific antigen (PSA) of 5.5 ng/mL (interquartile range: 4.3-7.5). Upgrading was observed in 34% of men, including 44% of 7402 patients with Gleason 3 + 3 and 19% of 5057 patients with Gleason 3 + 4 disease. Age, clinical stage, diagnostic PSA, and % prostate needle biopsy cores positive were independently associated with odds of any upgrading at RP. In baseline Gleason 3 + 3 disease, extreme upgrading was observed in 6%, with increasing age, diagnostic PSA, and >50% core positivity associated with increased odds. In baseline Gleason 3 + 4 disease, extreme upgrading was observed in 4%, with diagnostic PSA and palpable disease remaining predictive. Positive surgical margins were significantly higher in patients with extreme upgrading at RP (P < .001). CONCLUSION: Gleason upgrading at RP is common in this large population-based cohort, including extreme upgrading in a clinically significant portion.

Preliminary Comparative Effectiveness of Robotic Versus Open Radical Cystectomy in Elderly Patients.

INTRODUCTION: Treatment for muscle-invasive bladder cancer (MIBC) remains highly morbid despite improving surgical techniques. As the median age of diagnosis is 73, many patients are elderly at the time of cystectomy. We compare perioperative surgical outcomes in elderly patients undergoing robotic vs open radical cystectomy (RC). MATERIALS AND METHODS: Patients >75 years at time of RC were identified. Demographic, clinicopathologic, and perioperative variables were examined. Estimated blood loss (EBL) and length of stay (LOS) data were collected with multivariate linear regression analysis performed to assess whether technique was independently associated with outcomes. RESULTS: Eighty-seven patients >75 years of age underwent cystectomy for MIBC (58 open, 29 robotic). Mean age was 79.6 (±3.2) and 79.2 (±3.5) for open and robotic groups, respectively (p = 0.64). There were no significant differences in baseline comorbidities, clinical or pathologic stage, or use of neoadjuvant chemotherapy. The mean number of lymph nodes removed was similar (p = 0.08). Robotic cystectomy had significantly longer mean OR times (p < 0.001). On multivariate analyses, robotic surgery was associated with -389cc less EBL (95% CI -547 to -230, p < 0.001) and a -1.5-day-shortened LOS (95%CI -2.9 to -0.2, p = 0.02) compared with open surgery. There were no significant differences in surgical complications or 90-day readmission rates between the two groups. CONCLUSIONS: Robotic cystectomy is safe and feasible in an elderly population. We observed longer OR times with robotic surgery, but with decreased EBL, shorter hospital stays, and comparable complication and readmission rates with open RC. Larger prospective studies are required to confirm these findings.

Robotic total pelvic exenteration with laparoscopic rectus flap: initial experience.

Total pelvic exenteration is a highly morbid procedure performed for locally advanced pelvic malignancies. We describe our experience with three patients who underwent robotic total pelvic exenteration with laparoscopic rectus flap and compare perioperative characteristics to our open experience. Demographic, tumor, operative, and perioperative factors were examined with descriptive statistics reported. Mean operative times were similar between the two groups. When compared to open total pelvic exenteration cases (n = 9), median estimated blood loss, ICU stay, and hospital stay were all decreased. These data show robotic pelvic exenteration with laparoscopic rectus flap is technically feasible. The surgery was well tolerated with low blood loss and comparable operative times to the open surgery. Further study is needed to confirm the oncologic efficacy and the suggested improvement in surgical morbidity.

Cystic renal cell carcinoma carries an excellent prognosis regardless of tumor size.

INTRODUCTION: Cystic renal cell carcinoma (cystic RCC) is thought to carry an improved prognosis relative to clear cell RCC (CCRCC); however, this is based on small case series. We used a population-based tumor registry to compare clinicopathologic features and cancer-specific mortality (CSM) of cystic RCC with those of CCRCC. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database was queried for all patients diagnosed and treated for cystic RCC and CCRCC between 2001 and 2010. Clinical and pathologic factors were compared using t tests and chi-square tests as appropriate. Kaplan-Meier survival analysis compared CSM differences between cystic RCC and CCRCC. RESULTS: A total of 678 patients with cystic RCC and 46,677 with CCRCC were identified. The mean follow-up duration was 52 and 40 months, respectively. When compared with CCRCC patients, those with cystic RCC were younger (mean age 58 vs. 61 y, P < 0.001), more commonly black (22% vs. 9%, P < 0.001), and female (45% vs. 41%, P = 0.02). Cystic RCCs were more commonly T1a tumors (66% vs. 55%, P < 0.001), well differentiated (33% vs. 16%, P < 0.001), and smaller (mean size = 3.8 vs. 4.5 cm, P < 0.001). Cystic RCC was associated with a reduction in CSM when compared with CCRCC (P = 0.002). In a subset analysis, this reduction in CSM was seen only for those with T1b/T2 tumors (P = 0.01) but not for those with T1a RCCs lesions (P = 0.31). CONCLUSIONS: We report the largest series of cystic RCC and corroborate the findings of improved CSM when compared with CCRCC for larger tumors; however, no difference was noted in smaller tumors, suggesting that tumor biology becomes more relevant to prognosis with increasing size. These data may suggest a role for active surveillance in appropriately selected patients with small, cystic renal masses.

The epidemiology of male infertility.

The purpose of this review is to integrate understanding of epidemiology and infertility. A primer on epidemiologic science and an example disease for which the design of epidemiologic investigations is readily apparent are provided. Key features of infertility that limit epidemiologic investigation are described and a survey of available data on the epidemiology of infertility provided. Finally, the work that must be completed to move this area of research forward is proposed, and, with this new perspective of "infertility as a disease," improvements envisioned in public health that may be gained through improved understanding of the epidemiology of male infertility.

Systemic inflammation and insulin sensitivity in obese IFN-γ knockout mice.

Adipose tissue macrophages are important mediators of inflammation and insulin resistance in obesity. IFN-γ is a central regulator of macrophage function. The role of IFN-γ in regulating systemic inflammation and insulin resistance in obesity is unknown. We studied obese IFN-γ knockout mice to identify the role of IFN-γ in regulating inflammation and insulin sensitivity in obesity. IFN-γ-knockout C57Bl/6 mice and wild-type control litter mates were maintained on normal chow or a high fat diet for 13 weeks and then underwent insulin sensitivity testing then sacrifice and tissue collection. Flow cytometry, intracellular cytokine staining, and QRTPCR were used to define tissue lymphocyte phenotype and cytokine expression profiles. Adipocyte size was determined from whole adipose tissue explants examined under immunofluorescence microscopy. Diet-induced obesity induced systemic inflammation and insulin resistance, along with a pan-leukocyte adipose tissue infiltrate that includes macrophages, T-cells, and NK cells. Obese IFN-γ-knockout animals, compared with obese wild-type control animals, demonstrate modest improvements in insulin sensitivity, decreased adipocyte size, and an M2-shift in ATM phenotype and cytokine expression. These data suggest a role for IFN-γ in the regulation of inflammation and glucose homeostasis in obesity though multiple potential mechanisms, including effects on adipogenesis, cytokine expression, and macrophage phenotype.