Association Between Symptom Burden and Early Lymphatic Abnormalities After Regional Nodal Irradiation for Breast Cancer.

PURPOSE: Dermal backflow visualized on near-infrared fluorescence lymphatic imaging (NIRF-LI) signals preclinical lymphedema that precedes the development of volumetrically defined lymphedema. We sought to evaluate whether dermal backflow correlates with patient-reported lymphedema outcomes (PRLO) surveys in breast cancer patients treated with regional nodal irradiation (RNI). METHODS AND MATERIALS: Patients with breast cancer planned for axillary dissection and RNI prospectively underwent perometry, NIRF-LI, and PRLOs (the Lymphedema Symptom Intensity and Distress Survey [LSIDS] and QuickDASH) at baseline, after surgery, and at 6, 12, and 18 months after radiation. Clinical lymphedema was defined as an arm volume increase ≥5% over baseline. Trends over time were assessed using analysis of variance testing. The association between survey responses and both dermal backflow and lymphedema was assessed using a linear mixed-effects model. RESULTS: Sixty participants completed at least 2 sets of measurements and surveys and were eligible for analysis. Fifty-four percent of patients had cT3-T4 disease, 53% cN3 disease, and 75% had a body mass index >25. Dermal backflow and clinical lymphedema increased from 10% to 85% and from 0% to 40%, respectively, from baseline to 18 months. In the adjusted model, soft tissue sensation, neurologic sensation, and functional LSIDS subscale scores were associated with presence of dermal backflow (all P < .05). Both dermal backflow and lymphedema were associated with QuickDASH score (P < .05). CONCLUSIONS: In this high-risk cohort, we found highly prevalent early signs of lymphedema, with increased symptom burden from baseline. Presence of dermal backflow correlated with PRLO measures, highlighting a potential NIRF-LI use to identify patients for early intervention trials after RNI.

Definitive Liver Radiotherapy for Intrahepatic Cholangiocarcinoma with Extrahepatic Metastases.

Introduction: Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT. Methods: We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by propensity score and a National Cancer Database (NCDB) cohort by frequency technique. The median biologically effective dose was 97.5 Gy (interquartile range 80.5-97.9 Gy) for L-RT. Patients treated with other local therapies or supportive care alone were excluded. We analyzed survival with Cox proportional hazard modeling. Results: We identified 61 patients who received L-RT and 220 who received chemotherapy alone. At median follow-up of 11 months after diagnosis, median OS was 9 months (95% confidence interval [CI] 8-11) and 21 months (CI: 17-26) for patients receiving chemotherapy alone and L-RT, respectively. TRLF was the cause of death more often in the patients who received chemotherapy alone compared to those who received L-RT (82% vs. 47%; p = 0.001). On multivariable propensity score-matched analysis, associations with lower risk of death included duration of upfront chemotherapy (hazard ratio [HR] 0.82; p = 0.005) and receipt of L-RT (HR: 0.40; p = 0.002). The median OS from diagnosis for NCDB chemotherapy alone cohort was shorter than that of the institutional L-RT cohort (9 vs. 22 months; p < 0.001). Conclusion: For M1 ICC, L-RT associated with a lower rate of death due to TRLF and longer OS versus those treated with chemotherapy alone. Prospective studies of L-RT in this setting are warranted.

Characteristics of the Association of Residents in Radiation Oncology Educator of the Year Award Recipients.

PURPOSE: The Association of Residents in Radiation Oncology (ARRO) presents the Educator of the Year Award to outstanding faculty members at each participating institution every year. The aim of this study was to characterize the recipients of this award. METHODS AND MATERIALS: The recipients of the annual ARRO Educator of the Year Award were identified from the years 2008 to 2019. Publicly available website domains were accessed to obtain data regarding clinical treatment site, number of sites treated, whether they were at the same institution where they trained, academic rank, sex, American Society for Radiation Oncology fellow status, repeat awardee status during the period, and number of years since board certification. H- and m-indices were obtained from Scopus and calculated based on the time of the award. General workforce data were obtained from American Society for Radiation Oncology and recently published articles. The authors performed correlative analyses stratified by sex and logistic regression to determine predictors of repeat awardee status. RESULTS: There were a total of 607 ARRO educator awards from the years 2008 to 2019. The majority of recipients were male (77.6%) and assistant professors (39.0%). The median number of years from board certification was 7 (interquartile range, 3-17) and the median h- and m-indices were 14 and 1, respectively. When stratified by sex, publication metrics were significantly higher for men (P < .05), and men were more likely to be repeat awardees (P < .001) and have higher academic rank (P = .007). On multivariate analysis, those of higher rank were more likely to be repeat awardees (associate odds ratio [OR], 3.55; P < .001; full professor OR, 2.04; P = .046) and less likely to be women (OR, 0.41; P = .002), and h- and m-indices were not associated with repeat awardee status. CONCLUSIONS: Recipients of the ARRO educator award appear to be diverse in rank and experience; however, associate professor rank and sex were associated with continued recognition of educational excellence.

Proton radiotherapy for recurrent or metastatic sarcoma with palliative quad shot.

Patients with previously treated, recurrent or metastatic sarcomas who have progressed on multiples lines of systemic therapy may have limited options for local control. We evaluated outcomes of palliative proton therapy with the quad shot regimen to unresectable disease for patients with recurrent and/or metastatic sarcoma. From 2014 to 2018, 28 patients with recurrent or metastatic sarcomas were treated to 40 total sites with palliative proton RT with quad shot (14.8 Gy/4 twice daily). Outcomes included toxicity, ability to receive further systemic therapy, and subjective palliative response. Univariate analysis was performed for local progression-free survival (LPFS) and overall survival (OS). Of the 40 total sites, 25 (62.5%) received ≥3 cycles with median follow up of 12 months (IQR 4-19). The most common histologies were GIST (9; 22.5%) and leiomyosarcoma (7; 17.5%). A total of 27 (67.5%) sites were located in the abdomen or pelvis. Seventeen (42.5%) treatments involved concurrent systemic therapy and 13 (32.5%) patients received further systemic therapy following proton therapy. Overall subjective palliative response was 70%. Median LPFS was 11 months and 6-month LPFS was 66.1%. On univariate analysis, receipt of four cycles of quad shot (HR 0.06, p = 0.02) and receipt of systemic therapy after completion of radiation therapy (HR 0.17, p = 0.02) were associated with improved LPFS. Three grade 3 acute toxicities were observed. The proton quad shot regimen serves as a feasible alternative for patients with previously treated, recurrent or metastatic sarcomas where overall treatment options may be limited.

To ban or not to ban tanning bed use for minors: A cost-effectiveness analysis from multiple US perspectives for invasive melanoma.

BACKGROUND: Tanning bed use is common among US adolescents, but is associated with increased melanoma risk. The decision to ban tanning bed use by adolescents should be made in consideration of the potential health benefits and costs. METHODS: The US population aged 14 to 17 years was modeled by microsimulation, which compared ban versus no ban strategies. Lifetime quality-adjusted life years (QALYs) and costs were estimated from a health care sector perspective and two societal perspectives: with and without the costs of policy enforcement and the economic losses of the indoor-tanning bed industry. RESULTS: Full adherence to the ban prevented 15,102 melanoma cases and 3299 recurrences among 17.1 million minors, saving $61in formal and informal health care costs per minor and providing an increase of 0.0002 QALYs. Despite the intervention costs of the ban and the economic losses to the indoor-tanning industry, banning was still the dominant strategy, with a savings of $12 per minor and $205.4 million among 17.1 million minors. Findings were robust against varying inspection costs and ban compliance, but were sensitive to lower excess risk of melanoma with early exposure to tanning beds. CONCLUSIONS: A ban on tanning beds for minors potentially lowers costs and increases cost effectiveness. Even after accounting for the costs of implementing a ban, it may be considered cost effective. Even after accounting for the costs of implementing a ban and economic losses in the indoor-tanning industry, a tanning bed ban for US minors may be considered cost effective. A ban has the potential to reduce the number of melanoma cases while decreasing health care costs. LAY SUMMARY: Previous meta-analyses have linked tanning bed use with an increased risk of melanoma, particularly with initial use at a young age. Yet, it remains unclear whether a ban of adolescents would be cost effective. Overall, a ban has the potential to reduce the number of melanoma cases while promoting a decrease in health care costs. Even after accounting for the costs of implementing a ban and the economic losses incurred by the indoor-tanning industry, a ban would be cost effective.

Neoadjuvant therapy for gastrointestinal stromal tumors: A propensity score-weighted analysis.

Retrospective and single-arm prospective studies have reported clinical benefit with neoadjuvant imatinib for GISTs. In the absence of randomized Phase III data, the impact of neoadjuvant systemic therapy (NAT) on survival compared to upfront resection (UR) remains unknown. We identified N = 16 308 patients within the National Cancer Database (2004-2016) who underwent resection of localized GIST of the stomach, esophagus, small bowel and colorectum, with or without ≥3 months of NAT. Inverse probability of treatment weighting adjusted for covariable imbalance among treatment groups. We estimated the effect of NAT on overall survival with a weighted time-dependent Cox proportional hazards model, and on 90-day postoperative mortality and R0 resection with weighted logistic regressions. Eight hundred sixty-five (5.3%) patients received NAT compared to 15 443 (94.7%) who underwent UR. Median NAT duration was 6.3 months. 53.7% of NAT patients were male vs 48.6% of UR patients, 67.3% vs 65.1% had primary gastric GIST and 72.8% vs 49.7% were at high risk. NAT patients had larger tumors and higher mitotic index. >3 months of NAT was associated with a significant survival benefit (weighted HR 0.85 [0.80-0.91]). 90-day postoperative mortality rate was 4/865 (0.5%) among NAT patients vs 346/15443 (2.2%). NAT was associated with lower odds of 90-day postoperative mortality. R0 resection rate was not significantly different between groups. In conclusion, despite higher risk features among NAT patients, this analysis suggests that NAT for localized GIST is associated with a modest survival benefit and lower risk of 90-day postoperative mortality, with no difference in likelihood of achieving an R0 resection.

Cost-Effectiveness Analysis of Selective Internal Radiotherapy With Yttrium-90 Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma.

PURPOSE: The recent sorafenib versus radioembolization in advanced hepatocellular carcinoma (SARAH) and selective internal radiation therapy versus sorafenib in locally advanced hepatocellular carcinoma (SIRveNIB) trials showed no statistically significant difference in overall survival for randomization to selective internal radiotherapy (SIRT) versus sorafenib for locally advanced hepatocellular carcinoma, although SIRT was better tolerated. Given the high cost of both treatments, we investigated their comparative cost-effectiveness from a US healthcare sector perspective. PATIENTS AND METHODS: We constructed a state-transition microsimulation model to simulate patients allocated to SIRT versus sorafenib according to an intention-to-treat principle. Hazard rates of disease progression and death were based on pooled individual patient data generated from the SARAH and SIRveNIB trials' Kaplan-Meier curves. Inputs for adverse events, treatment adherence, and quality of life utility weights were derived from trial data as well. Costs were based on Medicare reimbursement rates and literature. We performed probabilistic sensitivity analysis and estimated costs and quality-adjusted life years (QALYs) over a 5-year time horizon. We evaluated sensitivity to uncertainty of key model parameters. RESULTS: Costs were $78,859 v $58,397 (difference $20,462; 95% uncertainty interval $14,444 to 27,205) and QALYs were 0.88 v 0.87 (difference 0.02, -0.02 to 0.05) for sorafenib versus SIRT, respectively. The incremental cost-effectiveness ratio (ICER) of sorafenib was $1,280,224/QALY. The likelihood that sorafenib would be cost effective did not exceed 1%, assuming cost-effectiveness thresholds up to $200k/QALY. If the monthly price of sorafenib decreased from $16,390 to below $7,000, the ICER of sorafenib fell below $200k/QALY, and an ICER < $100k/QALY was reached if the monthly price fell below $6,600. CONCLUSION: Sorafenib is unlikely to provide a gain in quality-adjusted survival compared with SIRT at an acceptable cost for the US healthcare sector. Only if the current price decreased by more than 50% would sorafenib be considered economically attractive.

The prognostic significance of human papilloma virus in sinonasal squamous cell carcinoma.

BACKGROUND: Human papilloma virus (HPV) has been implicated in the pathology of oropharyngeal head and neck cancers, but its role in sinonasal squamous cell carcinoma (SNSCC) has not been well established. METHODS: Thirty-two patients with SNSCC diagnosed between 2011 and 2018 were identified and stratified by HPV status and viral serotype, as determined by PCR. Endpoints including recurrence, metastases and survival were analyzed using the Kaplan-Meier method. RESULTS: Seventeen (53%) patients were HPV-positive and 15 (47%) were HPV-negative. The median follow-up time of living patients was 30.7 months (range 4-123 months). Survival did not differ by HPV status, but HPV+ tumors were more likely to locally recur and metastasize. When stratifying by treatment type, the lowest rate of recurrence occurred in patients receiving surgery and chemoradiation. CONCLUSION: A significant proportion of sinonasal tumors appear to be associated with HPV. Testing for HPV might be justified in all cases of sinonasal cancers. Further investigation is warranted to better understand the role of HPV in SNSCC.

Estimated Costs Associated With Radiation Therapy for Positive Surgical Margins During Radical Prostatectomy.

Importance: Prostate cancer is the most common malignant neoplasm among men and is the one with the highest positive surgical margin (PSM) rate. This high rate is due to the difficulty in balancing the risk of extraprostatic disease and excising periprostatic structures, which ultimately affects patients' quality of life. In the case of a PSM, the appropriateness of adjuvant radiation therapy (aRT) should be discussed. The financial burden of PSMs on health systems has not been investigated. Objective: To estimate the financial costs associated with a PSM during radical prostatectomy on the basis of the odds of undergoing aRT. Design, Setting, and Participants: This cohort study used data on men with prostate cancer from the US National Cancer Database (January 1, 2010, through December 31, 2015). Data were requested in March 2019, accessed in April 2019, and analyzed in August 2019. Exposure: Treatment with radical prostatectomy followed by aRT, if indicated. Main Outcomes and Measures: The attributable risk fraction of PSMs on undergoing aRT was estimated from a logistic regression with aRT administration as the outcome. The analysis was adjusted for patients' socioeconomic and demographic characteristics and tumor characteristics. The aRT cost for the year 2019 was calculated using the Medicare Physician Fee Schedule and the Hospital Outpatient Prospective Payment System. The fraction of this cost attributable to a PSM was estimated according to its attributable risk fraction. Results: In total, 230 175 men were identified (median [interquartile range] age at diagnosis, 62.0 [56.0-67.0] years). Overall, 22.8% of the patients had a PSM. Patients with PSMs were more likely than those without PSMs to be older (median [interquartile range] age, 62.0 [56.0-66.0] years vs 62.0 [57.0-67.0] years) and nonwhite (9320 patients [17.8%] vs 29 872 patients [16.8%]), to have higher comorbidity scores (1604 patients [3.1%] vs 4884 patients [2.7%] with a Charlson-Deyo Comorbidity Index score ≥2) and worse tumor characteristics (category T3 and T4 disease, 26 394 patients [50.3%] vs 36 040 patients [20.3%]), and to have lower socioeconomic indicators (median annual income <$30 000, 5708 patients [10.9%] vs 17 874 patients [10.1%]; proportion of individuals without a high school degree in the area ≥29%, 6925 patients [13.2%] vs 22 648 patients [12.7%]). In addition, PSMs were documented more frequently at nonacademic institutions than academic ones (31 702 patients [60.5%] vs 20 714 patients [39.5%]). A total of 11 585 patients (5.0%) underwent aRT, and 7698 of them (3.3%) had a PSM at the final pathology examination. When controlling for patients' socioeconomic and demographic characteristics and tumor characteristics, men with PSMs were more likely than those with negative margins to undergo aRT, with an odds ratio of 3.79 (95% CI, 3.63-3.96; P < .001). The attributable risk fraction of the presence of a PSM on aRT was 44% (95% CI, 42%-45%). The attributable cost of a PSM was calculated as $17 356 (95% CI, $16 567-$17 751). Assuming 60 000 prostatectomies in 2019 and similar trends of PSM and aRT, the overall health burden attributable to PSMs was calculated to be $52 068 000 (95% CI, $49 701 000-$53 253 000). Conclusions and Relevance: The estimated aRT cost attributable to the presence of a PSM was $17 356, resulting in $52 068 000 in spending on aRT in 2019. Strategies to reduce PSMs could be associated with a reduction in the overall health costs of surgically treated PCa.

Prolonged hormonal therapy and external beam radiation independently increase the risk of Persistent Hypogonadism in men treated with prostate brachytherapy.

PURPOSE: To identify variables that predict persistent hypogonadism and castration in patients with prostate cancer (PCa) treated with brachytherapy (BT). MATERIALS AND METHODS: A retrospective analysis was performed on 1,053 patients receiving BT ± external beam radiation therapy (EBRT) ± hormone therapy (HT) for NCCN low, intermediate, or high-risk PCa between 1990 and 2011. Patients were categorized as not receiving HT (n = 438, 41.6%), ≤6 months (n = 317, 31.1%) or > 6 months (n = 298, 28.3%) of HT. 572 (54.3%) received BT alone, and 481 had combination therapy. The five- and 10-year freedom from persistent hypogonadism (T < 280 ng/dL) and castration (T < 50 ng/dL) for each group was evaluated with Kaplan-Meier estimates. Multivariable cox proportional hazards models were used to compare the risk of persistent hypogonadism and castration at a median followup of 6.5 years (posttreatment to final T) (IQR: 4.3-9.1 years; range: 1.0-19.2 years). RESULTS: The 5-year freedom from hypogonadism rates were 92.4%, 88.9%, and 87.0% for patients with no HT, ≤ 6 months and >6 months of HT, respectively (10-year rates: 66.7%, 55.3%, 40.5%); p < 0.01. The 5-year freedom from castration rates were 99.2%, 98.0%, and 98.4%, respectively (10-year rates: 97.9%, 95.5%, 90.9%); p = 0.078. Number of months of HT (HR = 1.04, p = 0.030) and BT with EBRT vs. BT alone (HR = 1.56, p = 0.010) significantly increased the risk of persistent hypogonadism. Number of months of HT was the only variable which increased the risk of persistent castration (HR = 1.09, p = 0.014). CONCLUSIONS: The addition of EBRT to BT is an independent risk factor for persistent hypogonadism. Prolonged HT additionally increases the risk of persistent hypogonadism and castration.

"Lipase Only, Please": Reducing Unnecessary Amylase Testing.

BACKGROUND: Serum amylase testing is not recommended for the workup of acute pancreatitis; yet it is commonly ordered in acute care settings. METHODS: This was a student-led quality improvement initiative with application of a pre-post study design at two urban hospitals: Mount Sinai Hospital, a 1,134-bed academic hospital, and Mount Sinai Queens, a 235-bed community hospital. The multifaceted intervention combined a targeted educational and awareness campaign with the decoupling of amylase from electronic order sets (at the academic hospital only), as well as a nonintrusive electronic medical record (EMR) advisory statement (at both hospitals). Monthly amylase orders were tracked for all emergency department visits and hospital admissions between January 2016 and May 2018 for both hospitals RESULTS: There was a significant and sustained decrease in amylase ordering at both the academic hospital (from 3,214 orders per month to 2,348 orders per month; p = 0.011) and the community hospital (from 100 orders per month to 23 orders per month; p = 0.001). Specifically, the nonintrusive EMR order advisory statement was independently associated with a significant reduction in serum amylase ordering. There was an estimated net annual cost reduction of $44,999. CONCLUSIONS: This student-led initiative was successful in reducing unnecessary amylase ordering across two diverse institutions through a combination of education, publicity, and EMR changes.

Programmed Death-1 or Programmed Death Ligand-1 Blockade in Patients with Platinum-resistant Metastatic Urothelial Cancer: A Systematic Review and Meta-analysis.

CONTEXT: Several anti-programmed death-1 (anti-PD-1) and anti-programmed death ligand-1 (anti-PD-L1) antibodies have been approved by regulatory authorities for treatment of platinum-resistant metastatic urothelial cancer (mUC). The impact of these therapies on survival, and comparability of PD-1 versus PD-L1 blockade are unknown. OBJECTIVE: To determine the restricted mean survival time (RMST) of patients with platinum-resistant mUC treated with PD-1/PD-L1 inhibitors and to compare RMSTs in patients treated with PD-1 versus PD-L1 inhibitors. EVIDENCE ACQUISITION: We searched for phase 1, 2, and 3 clinical trials that assessed PD-1 or PD-L1 inhibition for patients with platinum-resistant mUC. Literature review and study selection, data abstraction, and risk of bias assessment were performed by two reviewers. Survival data were reconstructed using an algorithm that derives individual time-to-event data from published Kaplan-Meier curves. The RMST with 95% confidence interval (CIs) was calculated. EVIDENCE SYNTHESIS: From 836 references, six clinical trials were included. Survival data were reconstructed for 1315 and 736 patients treated with PD-1/PD-L1 inhibitors and chemotherapy, respectively. The RMSTs with PD-1/PD-L1 blockade up to 12 and 18mo of follow-up were 7.8mo (95% CI 7.6, 8.1) and 10mo (95% CI 9.7, 10.5), respectively. A network meta-analysis of two randomized trials revealed no significant difference in the RMST up to 18mo with PD-1 versus PD-L1 blockade (1.0mo; 95% CI -0.5, 2.3mo). Using reconstructed survival data from all six trials, the RMSTs with PD-1 versus PD-L1 blockade up to 12 and 18mo follow-up were 7.8mo (95% CI 7.7, 8.2) versus 7.8mo (95% CI 7.5, 8.2) and 10.1mo (95% CI 9.6, 10.7) versus 10mo (95% CI 9.5, 10.6), respectively. CONCLUSIONS: Our RMST estimates may be used as benchmarks to contextualize survival outcomes and inform future trial design with PD-1/PD-L1 inhibitors. PD-1 versus PD-L1 blockade in patients with mUC yields comparable survival outcomes. PATIENT SUMMARY: In this study, we found that outcomes for patients with metastatic bladder cancer treated with programmed death-1 and programmed death ligand-1 inhibitors, who received prior platinum-based chemotherapy, were similar.

The impact of pathologic response to neoadjuvant chemotherapy on conditional survival among patients with muscle-invasive bladder cancer.

PURPOSE: Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with a favorable prognosis. Patients with pathologic residual disease (pRD) generally have poor outcomes. However, prognosis after radical cystectomy (RC) improves with ongoing survivorship. Our objective was to determine whether the difference in prognosis of patients with pCR and pRD changes over time. MATERIALS AND METHODS: We queried the National Cancer Database for patients who received NAC and RC for localized MIBC (cT2-T4aN0M0) between 1998 and 2012. pCR was defined as ≤Tis disease. Kaplan-Meier analysis was used to estimate conditional survival to 5 years given survival to 1, 2, 3, and 4 years post-RC. Cox proportional hazard modeling was used to estimate the effect of pRD vs. pCR on overall survival. RESULTS: The cohort comprised 1,553 patients (pCR: 314 and pRD: 1,239). With median follow-up 2.65 years (range 0.01-9.97), median survival was 2.5 years (95% confidence interval 2.2-2.9) and not reached for pRD and pCR, respectively. All patients had improved conditional survival with each additional year of survivorship. Patients with pCR had improved overall survival relative to those with pRD. The effect of pRD vs. pCR on conditional survival did not differ over time (P = 0.7). CONCLUSIONS: MIBC patients with pCR after NAC have improved conditional survival relative to those with pRD post-RC. This survival advantage does not significantly change over time. These findings may inform patient counseling, surveillance intensity, and novel adjuvant approaches for patients with pRD.

Effectiveness of Transurethral Resection plus Systemic Chemotherapy as Definitive Treatment for Muscle Invasive Bladder Cancer in Population Level Data.

PURPOSE: We investigated the characteristics and outcomes of patients with muscle invasive bladder cancer treated with transurethral resection plus chemotherapy alone in a large observational cohort reflecting the continuum of practice settings in the United States. MATERIALS AND METHODS: In the National Cancer Database from 2004 to 2015 we identified 1,538 patients treated with transurethral resection plus multi-agent chemotherapy as definitive treatment of cT2-T4aN0M0 urothelial carcinoma of the bladder. For comparison purposes we included in study 17,866 patients treated with radical cystectomy with or without perioperative chemotherapy. Baseline characteristics were compared between the 2 groups by multivariable logistic regression. Treatment outcomes were assessed using Kaplan-Meier analysis and a Cox regression model. RESULTS: On multivariate analysis several variables, including patient demography (older age, African American race, prior malignancy and lack of insurance), tumor characteristics (higher cT stage) and facility type (nonacademic facilities and lower radical cystectomy volume) were associated with a higher probability of transurethral resection plus chemotherapy for muscle invasive bladder cancer compared to the standard of care. Two and 5-year survival rates in all patients treated with transurethral resection plus chemotherapy were 49.0% and 32.9%, and in patients with cT2 disease the rates were 52.6% and 36.2%, respectively. CONCLUSIONS: This large population level cohort of unselected patients shows that long-term survival can be achieved in a subset of patients treated with transurethral resection plus chemotherapy alone for muscle invasive bladder cancer. However, the best candidates for this approach remain to be defined. Ongoing clinical trials are now being launched to evaluate the ability of biomarkers to accurately select patients who could be treated with this bladder sparing strategy.

Early Mortality in Patients With Muscle-Invasive Bladder Cancer Undergoing Cystectomy in the United States.

BACKGROUND: Although radical cystectomy (RC) is a standard treatment for muscle-invasive bladder cancer (MIBC), for many patients the risks versus benefits of RC may favor other approaches. We sought to define the landscape of early postcystectomy mortality in the United States and identify patients at high risk using pretreatment variables. METHODS: We identified patients with MIBC (cT2-T4aN0M0) who underwent RC without perioperative chemotherapy within the National Cancer Database (2003-2012). Using multistate multivariable modeling, we calculated time spent in three health states: hospitalized, discharged, and death more than 90 days postcystectomy. Cross-validation was performed by geographic region. Time spent in each state was weighted by utility to determine 90-day quality-adjusted life days (QALDs). RESULTS: Among 7922 patients, 90-day mortality was 7.6% (8.0% for lower and 6.7% for higher volume hospitals). Increasing age, clinical T stage, Charlson Comorbidity Index, and lower volume were associated with higher 90-day mortality and were included in the model. Cross-validation revealed appropriate performance (C-statistics of 0.53-0.74; calibration slopes of 0.50-1.67). The model predicted 25% of patients had a 90-day mortality risk higher than 10%, and observed 90-day mortality in this group was 14.0% (95% CI = 12.5% to 15.6%). Mean quality-adjusted life days (QALDs) was 63 (range = 44-68). CONCLUSIONS: RC is associated with relatively high early mortality risk. Pretreatment variables may identify patients at particularly high risk, which may inform clinical trial design, facilitate shared decision making, and enhance quality improvement initiatives.

Liver-specific cholesteryl ester hydrolase deficiency attenuates sterol elimination in the feces and increases atherosclerosis in ldlr-/- mice.

OBJECTIVE: Liver is the major organ responsible for the final elimination of cholesterol from the body either as biliary cholesterol or as bile acids. Intracellular hydrolysis of lipoprotein-derived cholesteryl esters (CEs) is essential to generate the free cholesterol required for this process. Earlier, we demonstrated that overexpression of human CE hydrolase (Gene symbol CES1) increased bile acid synthesis in human hepatocytes and enhanced reverse cholesterol transport in mice. The objective of the present study was to demonstrate that liver-specific deletion of its murine ortholog, Ces3, would decrease cholesterol elimination from the body and increase atherosclerosis. APPROACH AND RESULTS: Liver-specific Ces3 knockout mice (Ces3-LKO) were generated, and Ces3 deficiency did not affect the expression of genes involved in cholesterol homeostasis and free cholesterol or bile acid transport. The effects of Ces3 deficiency on the development of Western diet-induced atherosclerosis were examined in low density lipoprotein receptor knock out(-/-) mice. Despite similar plasma lipoprotein profiles, there was increased lesion development in low density lipoprotein receptor knock out(-/-)Ces3-LKO mice along with a significant decrease in the bile acid content of bile. Ces3 deficiency significantly reduced the flux of cholesterol from [(3)H]-CE-labeled high-density lipoproteins to feces (as free cholesterol and bile acids) and decreased total fecal sterol elimination. CONCLUSIONS: Our results demonstrate that hepatic Ces3 modulates the hydrolysis of lipoprotein-delivered CEs and thereby regulates free cholesterol and bile acid secretion into the feces. Therefore, its deficiency results in reduced cholesterol elimination from the body, leading to significant increase in atherosclerosis. Collectively, these data establish the antiatherogenic role of hepatic CE hydrolysis.

Macrophage-specific transgenic expression of cholesteryl ester hydrolase attenuates hepatic lipid accumulation and also improves glucose tolerance in ob/ob mice.

Cellular cholesterol homeostasis is increasingly being recognized as an important determinant of the inflammatory status of macrophages, and a decrease in cellular cholesterol levels polarizes macrophages toward an anti-inflammatory or M2 phenotype. Cholesteryl ester hydrolase (CEH) catalyzes the hydrolysis of stored intracellular cholesteryl esters (CE) and thereby enhances free cholesterol efflux and reduces cellular CE content. We have reported earlier reduced atherosclerosis as well as lesion necrosis and improved insulin sensitivity (due to decreased adipose tissue inflammation) in macrophage-specific CEH transgenic (CEHTg) mice in the LDLR(-/-) background. In the present study, we examined the effects of reduced intracellular accumulation of CE in CEHTg macrophages in an established diabetic mouse model, namely the leptin-deficient ob/ob mouse. Macrophage-specific transgenic expression of CEH improved glucose tolerance in ob/ob-CEHTg mice significantly compared with ob/ob nontransgenic littermates, but with no apparent change in macrophage infiltration into the adipose tissue. However, there was a significant decrease in hepatic lipid accumulation in ob/ob-CEHTg mice. Consistently, decreased [(14)C]acetate incorporation into total lipids and triglycerides was noted in precision-cut liver slices from ob/ob-CEHTg mice. In the primary hepatocyte-macrophage coculture system, macrophages from CEHTg mice significantly reduced the incorporation of [(14)C]acetate into triglycerides in hepatocytes, indicating a direct effect of macrophages on hepatocyte triglyceride biosynthesis. Kupffer cells isolated from ob/ob-CEHTg mice were polarized toward an anti-inflammatory M2 (Ly6C(lo)) phenotype. Taken together, these studies demonstrate that transgenic overexpression of CEH in macrophages polarizes hepatic macrophages (Kupffer cells) to an anti-inflammatory M2 phenotype that attenuates hepatic lipid synthesis and accumulation.