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1.
J Urol ; : 101097JU0000000000004020, 2024 May 05.
Article in English | MEDLINE | ID: mdl-38704840

ABSTRACT

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

2.
BJU Int ; 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38658182

ABSTRACT

OBJECTIVES: To assess the effects of immunotherapy compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. METHODS: Based on a published protocol, we performed a systematic search of multiple databases. Two review authors independently performed the literature selection, identified relevant studies, assessed the eligibility of studies for inclusion, and extracted data. We performed statistical analyses using a random-effects model and assessed the quality of the evidence on a per-outcome basis according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We included five randomised controlled trials and also identified seven single-arm studies. When used as first-line therapy, immunotherapy probably has little to no effect on the risk of death from any cause compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87-1.07; moderate-certainty evidence). immunotherapy probably has little to no effect on health-related quality of life (mean difference [MD] 4.10, 95% CI 3.83-4.37; moderate). Immunotherapy probably reduces grade 3-5 adverse events (risk ratio [RR] 0.47, 95% CI 0.29-0.75; moderate). In the second-line setting immunotherapy may reduce the risk of death from any cause (HR 0.72, 95% CI 0.63-0.81; low). Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; low). Immunotherapy may reduce grade 3-5 adverse events (RR 0.89, 95% CI 0.81-0.97; low). CONCLUSIONS: Compared to chemotherapy, immunotherapy has little to no effect on the risk of death from any cause in a first-line setting. Nevertheless, it may reduce the risk of death from any cause when used as second-line therapy. The health-related quality of life of participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce grade 3-5 adverse events when used as first- and second-line therapy, respectively.

3.
Front Oncol ; 14: 1359725, 2024.
Article in English | MEDLINE | ID: mdl-38559556

ABSTRACT

Effective bladder-preserving therapeutic options are needed for patients with bacillus Calmette-Guérin unresponsive non-muscle-invasive bladder cancer. Nadofaragene firadenovec-vncg (Adstiladrin®) was approved by the US Food and Drug Administration as the first gene therapy in urology and the first intravesical gene therapy indicated for the treatment of adult patients with high-risk bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ with or without papillary tumors. The proposed mechanism of action underlying nadofaragene firadenovec efficacy is likely due to the pleiotropic nature of interferon-α and its direct and indirect antitumor activities. Direct activities include cell death and the mediation of an antiangiogenic effect, and indirect activities are those initiated through immunomodulation of the innate and adaptive immune responses. The sustained expression of interferon-α that results from this treatment modality contributes to a durable response. This review provides insight into potential mechanisms of action underlying nadofaragene firadenovec efficacy.

4.
Proc Biol Sci ; 291(2018): 20232840, 2024 Mar 13.
Article in English | MEDLINE | ID: mdl-38471557

ABSTRACT

Scientific knowledge is produced in multiple languages but is predominantly published in English. This practice creates a language barrier to generate and transfer scientific knowledge between communities with diverse linguistic backgrounds, hindering the ability of scholars and communities to address global challenges and achieve diversity and equity in science, technology, engineering and mathematics (STEM). To overcome those barriers, publishers and journals should provide a fair system that supports non-native English speakers and disseminates knowledge across the globe. We surveyed policies of 736 journals in biological sciences to assess their linguistic inclusivity, identify predictors of inclusivity, and propose actions to overcome language barriers in academic publishing. Our assessment revealed a grim landscape where most journals were making minimal efforts to overcome language barriers. The impact factor of journals was negatively associated with adopting a number of inclusive policies whereas ownership by a scientific society tended to have a positive association. Contrary to our expectations, the proportion of both open access articles and editors based in non-English speaking countries did not have a major positive association with the adoption of linguistically inclusive policies. We proposed a set of actions to overcome language barriers in academic publishing, including the renegotiation of power dynamics between publishers and editorial boards.


Subject(s)
Biological Science Disciplines , Publishing , Language , Linguistics
5.
Clin Genitourin Cancer ; 22(3): 102056, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38443295

ABSTRACT

INTRODUCTION: Baseline sarcopenia and postoperative changes in muscle mass are independently associated with overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy (CN). Here we examine the relationships between preoperative (baseline), postoperative changes in muscle quantity, and survival outcomes following CN as determined by linear segmentation, a clinic-friendly tool that rapidly estimates muscle mass. MATERIALS AND METHODS: Our nephrectomy database was reviewed for patients with metastatic disease who underwent CN for RCC. Linear segmentation of the bilateral psoas/paraspinal muscles was completed for baseline imaging within 60 days of surgery and imaging 30 to 365 days postoperatively. Kruskal-Wallis for numerical and Fisher's exact test for categorical variables were used to test for differences between groups according to percent change in linear muscle index (LMI, cm2/m2). Multivariable Cox proportional hazards models evaluated associations between LMI percent change and cancer-specific (CSM) and all-cause mortality (ACM). Kaplan Meier curves estimated cancer-specific (CSS) and overall survival (OS). RESULTS: From 2004-2020, 205 patients were included of whom 52 demonstrated stable LMI (25.4%; LMI change < 5% [0Δ]), 60 increase (29.3%; LMI +5% [+Δ]), and 92 decrease (44.9%; LMI -5% [-Δ]). Median time from baseline imaging to surgery was 18 days, and time from surgery to postoperative imaging was 133 days. Median CSS and OS were highest among patients with 0Δ LMI (CSS: 133.6 [0Δ] vs. 61.9 [+Δ] vs. 37.4 [-Δ] months; P = .0018 || OS: 67.2 [0Δ] vs. 54.8 [+Δ] vs. 29.5 [-Δ] months; P = .0007). Stable LMI was a protective factor for CSM (HR 0.48; P = .024) and ACM (HR 0.59; P = .040) on multivariable analysis. DISCUSSION: Change in muscle mass after CN, as measured by the linear muscle segmentation technique, is independently associated with OS and CSS in patients following CN. Of note, lack of change was associated with longer survival.


Subject(s)
Carcinoma, Renal Cell , Cytoreduction Surgical Procedures , Kidney Neoplasms , Nephrectomy , Sarcopenia , Humans , Carcinoma, Renal Cell/surgery , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/secondary , Kidney Neoplasms/surgery , Kidney Neoplasms/pathology , Kidney Neoplasms/mortality , Nephrectomy/methods , Female , Male , Cytoreduction Surgical Procedures/methods , Middle Aged , Aged , Sarcopenia/diagnostic imaging , Retrospective Studies , Prognosis , Psoas Muscles/diagnostic imaging , Psoas Muscles/pathology
6.
Urol Oncol ; 42(8): 223-228, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38307803

ABSTRACT

There are multiple ongoing and planned clinical trials that are evaluating novel therapies to treat patients with BCG-unresponsive high grade nonmuscle invasive bladder cancer (NMIBC). Importantly, there is considerable variation in surveillance strategies between these clinical trials, specifically with regards to the use of advanced imaging, enhanced cystoscopy, and mandatory biopsies, which could impact landmark efficacy assessments of investigational agents. To present guideline recommendations for the standardization of cystoscopic evaluation, surveillance, and efficacy assessments for patients with BCG-unresponsive NMIBC participating in clinical trials. On September 29, 2023 at the annual meeting of the International Bladder Cancer Network, a breakout session was convened, during which representatives from various disciplines discussed potential guidance statements with opportunity for discussion and comment. A set of statements regarding use of white light and enhanced cystoscopy were developed to help guide a pragmatic approach to surveillance and efficacy assessments of patients in clinical trials. The use of "for cause" and "mandatory" biopsies was also addressed. A standard approach to evaluation of patients within the context of clinical trials is necessary to accurately assess the efficacy of novel agents, especially within single arm trials that lack an appropriate comparator. Additionally, the utilization and timing of mandatory biopsies is critical, as these biopsies may impact both disease evaluations and the determination of duration of response.


Subject(s)
BCG Vaccine , Clinical Trials as Topic , Urinary Bladder Neoplasms , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/therapy , Urinary Bladder Neoplasms/drug therapy , Humans , BCG Vaccine/therapeutic use , Neoplasm Invasiveness , Neoplasm Grading , Cystoscopy/methods , Non-Muscle Invasive Bladder Neoplasms
7.
R Soc Open Sci ; 11(1): 231732, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38234441

ABSTRACT

Diet elicits varied effects on longevity across a wide range of animal species where dietary discordance between an organisms' evolutionary and developmental dietary history is increasingly recognized to play a critical role in shaping lifespan. However, whether such changes, predominantly assessed in a single generation, lead to evolutionary shifts in lifespan remains unclear. In this study, we used an experimental evolution approach to test whether changes in an organisms' evolutionary and developmental dietary history, specifically carbohydrate content, causes lifespan evolution in Drosophila serrata. After 30 generations, we investigated the evolutionary potential of lifespan in response to four novel diets that varied systematically in their ratio of carbohydrate-protein content. We also examined developmental plasticity effects using a set of control populations that were raised on the four novel environments allowing us to assess the extent to which plastic responses of lifespan mirrored adaptive responses observed following experimental evolution. Both high- and low-carbohydrate diets elicited plastic effects on lifespan; however, the plastic responses for lifespan to developmental diets bore little resemblance to the evolved responses on evolutionary diets. Understanding the dietary conditions regulating the match/mismatch of plastic and evolved responses will be important in determining whether a particular match/mismatch combination is adaptive for lifespan. While the differences in evolutionary diet by developmental diet interactions are only beginning to be elucidated, this study lays the foundation for future investigations of carbohydrate contributions to evolved and plastic effects on health and lifespan.

8.
Cancer ; 130(3): 453-466, 2024 02 01.
Article in English | MEDLINE | ID: mdl-37803521

ABSTRACT

BACKGROUND: The 2018 Leibovich prognostic model for nonmetastatic renal cell carcinoma (RCC) combines clinical, surgical, and pathologic factors to predict progression-free survival (PFS) and cancer-specific survival (CSS) for patients with clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC) histology. Despite high accuracy, <1% of the original cohort was Black. Here, the authors examined this model in a large population with greater Black patient representation. METHODS: By using a prospectively maintained RCC institutional database, patients were assigned Leibovich model risk scores. Survival outcomes included 5-year and 10-year PFS and CSS. Prognostic accuracy was determined using area under the curve (AUC) analysis and calibration plots. Black patient subanalyses were conducted. RESULTS: In total, 657 (29%) of 2295 patients analyzed identified as Black. Declines in PFS and CSS were observed as scores increased. Discrimination for ccRCC was strong for PFS (AUC: 5-year PFS, 0.81; 10-year PFS, 0.78) and for CSS (AUC: 5-year CSS, 0.82; 10-year CSS, 0.74). The pRCC AUC for PFS was 0.74 at 5 years and 0.71 at 10 years; and the AUC for CSS was 0.74 at 5 years and 0.70 at 10 years. In chRCC, better performance was observed for CSS (AUC at 5 years, 0.75) than for PFS (AUC: 0.66 at 5 years; 0.55 at 10 years). Black patient subanalysis revealed similar-to-improved performance for ccRCC at 5 years (AUC: PFS, 0.79; CSS, 0.87). For pRCC, performance was lower for PFS (AUC at 5 years, 0.63) and was similar for CSS (AUC at 5 years, 0.77). Sample size limited Black patient 10-year and chRCC analyses. CONCLUSIONS: The authors externally validated the 2018 Leibovich RCC prognostic model and found optimal performance for ccRCC, followed by pRCC, and then chRCC. Importantly, the results were consistent in this large representation of Black patients. PLAIN LANGUAGE SUMMARY: In 2018, a model to predict survival in patients with renal cell carcinoma (kidney cancer) was introduced by Leibovich et al. This model has performed well; however, Black patients have been under-represented in examination of its performance. In this study, 657 Black patients (29%) were included, and the results were consistent. This work is important for making sure the model can be applied to all patient populations.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/pathology , Prognosis , Kidney Neoplasms/pathology , Progression-Free Survival , Retrospective Studies
9.
JCO Clin Cancer Inform ; 7: e2300096, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37906722

ABSTRACT

PURPOSE: Treatment of non-muscle-invasive bladder cancer (NMIBC) is guided by risk stratification using clinical and pathologic criteria. This study aimed to develop a natural language processing (NLP) model for identifying patients with high-risk NMIBC retrospectively from unstructured electronic medical records (EMRs) and to apply the model to describe patient and tumor characteristics. METHODS: We used three independent EMR-derived data sets including adult patients with a bladder cancer diagnosis in 2011-2020 for NLP model development and training (n = 140), validation (n = 697), and application for the retrospective cohort analysis (n = 4,402). Deep learning methods were used to train NLP recognition of medical chart terminology to identify seven high-risk NMIBC criteria; model performance was assessed using the F1 score, weighted across features. An algorithm was then used to classify each patient as high-risk NMIBC (yes/no). Manually reviewed records served as the gold standard. RESULTS: The F1 scores after model training were >0.7 for all but one uncommon feature (prostatic urethral involvement). The highest area under the receiver operating curves (AUC) was observed for Ta (0.897) and T1 (0.897); the lowest AUC was for carcinoma in situ (CIS; 0.617). For high-risk NMIBC classification, positive predictive value was 79.4%, negative predictive value was 93.2%, and false-positive rate was 8.9%. Sensitivity and specificity were 83.7% and 91.1%, respectively. Of 748 patients manually confirmed as having high-risk NMIBC, 196 (26%) had CIS (of whom 19% also had T1 and 23% also had Ta disease); 552 tumors (74%) had no associated CIS. CONCLUSION: The NLP model, combined with a rule-based algorithm, identified high-risk NMIBC with good performance and will enable future work to study real-world treatment patterns and clinical outcomes for high-risk NMIBC.


Subject(s)
Non-Muscle Invasive Bladder Neoplasms , Urinary Bladder Neoplasms , Male , Adult , Humans , United States/epidemiology , Retrospective Studies , Natural Language Processing , Urinary Bladder Neoplasms/diagnosis , Urinary Bladder Neoplasms/epidemiology , Urinary Bladder Neoplasms/therapy , Cohort Studies
10.
Cochrane Database Syst Rev ; 10: CD013774, 2023 10 09.
Article in English | MEDLINE | ID: mdl-37811690

ABSTRACT

BACKGROUND: Immune checkpoint inhibitors are increasingly important in the treatment algorithm for locally advanced and metastatic bladder cancer. Numerous ongoing studies are investigating these agents as first- and second-line therapies, both alone and in combination with chemotherapy or in a maintenance therapy setting. OBJECTIVES: To assess the effects of immune checkpoint inhibitors compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. SEARCH METHODS: We performed a comprehensive search including the Cochrane Library, MEDLINE, Embase, three other databases, several trial registers, other sources of gray literature, and conference proceedings, with no restrictions on language of publication. We limited the search period to run from 2000 until August 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) using immunotherapy versus chemotherapy and would have considered non-randomized trials in the absence of randomized trial data. Participants had locally advanced inoperable (cT4b or N+, or both) or metastatic (M1) (or both) urothelial carcinoma of the bladder or upper urinary tract. We excluded studies of people in whom immunotherapy was used in combination with chemotherapy or in a surveillance setting. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies for inclusion and abstracted data from included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence on a per-outcome basis. MAIN RESULTS: We included five RCTs and identified seven single-armed studies. The RCTs included 3572 participants comparing immunotherapy versus chemotherapy for the treatment of locally advanced and metastatic bladder cancer. First-line therapy Immunotherapy probably has little to no effect on the risk of death from any cause when used as first-line therapy compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87 to 1.07; I2 = 0%; 3 studies, 2068 participants; moderate-certainty evidence). This corresponds to 750 deaths per 1000 participants with chemotherapy and 11 fewer (45 fewer to 26 more) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy probably has little to no effect on health-related quality of life (mean difference (MD) 4.10, 95% CI 3.83 to 4.37; 1 study, 393 participants; moderate-certainty evidence), when assuming a minimal clinically important difference (MCID) of at least 6 points (using the Functional Assessment of Cancer Therapy - Bladder [FACT-BL] tool; scale 0 to 156 with higher scores representing better quality of life). Immunotherapy probably reduces adverse events grade 3 to 5 (RR 0.47, 95% CI 0.29 to 0.75; I2 = 97%; 3 studies, 2046 participants; moderate-certainty evidence). This corresponds to 908 grade 3 to 5 adverse events per 1000 participants with chemotherapy, with 481 fewer (644 fewer to 227 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome time to death from bladder cancer. Immunotherapy probably increases the risk of time to disease progression (HR 1.33, 95% CI 1.17 to 1.50; I2 = 0%; 2 studies, 1349 participants; moderate-certainty evidence). This corresponds to 660 events per 1000 participants with chemotherapy and 102 more (57 more to 152 more) events per 1000 participants with immunotherapy at 36 months. Immunotherapy may reduce discontinuations due to adverse effects (RR 0.47, 95% CI 0.20 to 1.10; I2 = 94%; 3 studies, 2046 participants; low-certainty evidence). This corresponds to 338 discontinuations per 1000 participants with chemotherapy and 179 fewer (271 fewer to 34 more) discontinuations per 1000 participants with immunotherapy. Second-line therapy Immunotherapy may reduce the risk of death from any cause when used as second-line therapy (HR 0.72, 95% CI 0.63 to 0.81; I2 = 0%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 920 deaths per 1000 participants with chemotherapy (vinflunine, paclitaxel, docetaxel) and 59 fewer (95 fewer to 28 fewer) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; I2 = 85%; 2 studies, 727 participants; low-certainty evidence), assuming an MCID of at least 10 points (using the EORTC QLQ tool; scale 0 to 100 with higher scores representing better quality of life). Immunotherapy may reduce adverse events grade 3 to 5 in participants undergoing second-line therapy (RR 0.89, 95% CI 0.81 to 0.97; I2 = 9%; 2 studies, 1423 participants; low-certainty evidence). This corresponds to 630 grade 3 to 5 adverse events per 1000 participants with chemotherapy and 76 fewer (126 fewer to 25 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome of time to death from bladder cancer. We are very uncertain if immunotherapy reduces the risk of disease progression (HR 0.99, 95% CI 0.84 to 1.16; I2 = 0%; 2 studies, 1473 participants; very low-certainty evidence). Immunotherapy may reduce discontinuations due to adverse events in participants undergoing second-line therapy (RR 0.35, 95% CI 0.17 to 0.72; I2 = 69%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 110 discontinuations per 1000 participants with chemotherapy and 72 fewer (91 fewer to 31 fewer) discontinuations per 1000 participants with immunotherapy. AUTHORS' CONCLUSIONS: Compared to chemotherapy, immunotherapy for treating advanced or metastatic urothelial carcinoma probably has little to no effect on the risk of death from any cause when used as first-line therapy. Still, it may reduce the risk of death from any cause when used as second-line therapy. Health-related quality of life for participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce adverse events grade 3 to 5 when used as first- and second-line therapy, respectively.


Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Carcinoma, Transitional Cell/drug therapy , Disease Progression , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/adverse effects , Systematic Reviews as Topic , Urinary Bladder Neoplasms/drug therapy
11.
Oncologist ; 28(12): e1219-e1229, 2023 Dec 11.
Article in English | MEDLINE | ID: mdl-37540787

ABSTRACT

INTRODUCTION: Low creatinine to cystatin-C ratio (Cr/Cys-C) may be a biomarker for low-muscle mass. Furthermore, low Cr/Cys-C is associated with decreased overall survival (OS), but to date, has not been examined in patients with renal cell carcinoma (RCC). Our objective is to evaluate associations between low Cr/Cys-C ratio and OS and recurrence-free survival (RFS) in patients with RCC treated with nephrectomy. METHODS: We performed a retrospective review of patients with RCC treated with nephrectomy. Patients with end-stage renal disease and less than 1-year follow up were excluded. Cr/Cys-C was dichotomized at the median for the cohort (low vs. high). OS and RFS for patients with high versus low Cr/Cys-C were estimated with the Kaplan-Meier method, and associations with the outcomes of interest were modeled using Cox proportional Hazards models. Associations between Cr/Cys-C and skeletal muscle mass were assessed with correlations and logistic regression. RESULTS: A total of 255 patients were analyzed, with a median age of 64. Median (IQR) Cr/Cys-C was 1 (0.8-1.2). Low Cr/Cys-C was associated with age, female sex, Eastern Cooperative Oncology Group Performance Status ≥1, TNM stage, and tumor size. Kaplan-Meier and Cox regression analysis demonstrated an association between low Cr/Cys-C and decreased OS (HR = 2.97, 95%CI, 1.12-7.90, P =0.029) and RFS (HR = 3.31, 95%CI, 1.26-8.66, P = .015). Furthermore, a low Cr/Cys-C indicated a 2-3 increase in risk of radiographic sarcopenia. CONCLUSIONS: Lower Cr/Cys-C is associated with inferior oncologic outcomes in RCC and, pending validation, may have utility as a serum biomarker for the presence of sarcopenia in patients with RCC treated with nephrectomy.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Sarcopenia , Humans , Female , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/pathology , Creatinine , Prognosis , Biomarkers , Retrospective Studies
12.
bioRxiv ; 2023 Dec 04.
Article in English | MEDLINE | ID: mdl-37503266

ABSTRACT

Dietary restriction (DR) is a potent method to enhance lifespan and healthspan, but individual responses are influenced by genetic variations. Understanding how metabolism-related genetic differences impact longevity and healthspan are unclear. To investigate this, we used metabolites as markers to reveal how different genotypes respond to diet to influence longevity and healthspan traits. We analyzed data from Drosophila Genetic Reference Panel strains raised under AL and DR conditions, combining metabolomic, phenotypic, and genome-wide information. Employing two computational methods across species-random forest modeling within the DGRP and Mendelian randomization in the UK Biobank-we pinpointed key traits with cross-species relevance that influence lifespan and healthspan. Notably, orotate was linked to parental age at death in humans and counteracted DR effects in flies, while threonine extended lifespan, in a strain- and sex-specific manner. Thus, utilizing natural genetic variation data from flies and humans, we employed a systems biology approach to elucidate potential therapeutic pathways and metabolomic targets for diet-dependent changes in lifespan and healthspan.

13.
Oncologist ; 28(12): 1072-1078, 2023 Dec 11.
Article in English | MEDLINE | ID: mdl-37285524

ABSTRACT

BACKGROUND: In advanced urothelial cancers (UC), immune checkpoint inhibitors (ICI) show promise as a durable therapy. Immune-related adverse events (irAEs), a side effect of ICIs, may serve as an indicator of beneficial response. We investigated the relationship between irAEs and clinical outcomes in patients with advanced UC who received ICI. MATERIALS AND METHODS: In this retrospective study, we investigated 70 patients with advanced UC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on patients were collected through chart review. Cox's proportional hazard model and logistic regression were applied to estimate the association with overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). The possible lead-time bias was handled in extended Cox regression models. RESULTS: The median age of the cohort was 68. Over one-third (35%) of patients experienced an irAE, with skin being the most frequent organ involved (12.9%). Patients that experienced at least one irAE had significantly enhanced OS (HR: 0.38, 95% CI, 0.18-0.79, P = .009), PFS (HR: 0.27, 95% CI, 0.14-0.53, P < .001), and CB (OR: 4.20, 95% CI, 1.35-13.06, P = .013). Patients who experienced dermatologic irAEs also had significantly greater OS, PFS, and CB. CONCLUSION: Of patients with advanced UC that had undergone ICI therapy, those who had irAEs, especially dermatologic irAEs, had significantly greater OS, PFS, and CB. These results may suggest that irAE's may serve as an important marker of durable response to ICI therapy in urothelial cancer. The findings of this study need to be validated with larger cohort studies in the future.


Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Immune Checkpoint Inhibitors/adverse effects , Retrospective Studies , Patients
14.
Clin Genitourin Cancer ; 21(4): 475-482.e4, 2023 08.
Article in English | MEDLINE | ID: mdl-37210313

ABSTRACT

BACKGROUND: Renal cell carcinoma (RCC) with tumor thrombosis often requires nephrectomy and tumor thrombectomy. As an extensive and potentially morbid operation, patient preoperative functional reserve and body composition is an important consideration. Sarcopenia is a risk factor for increased postoperative complications, systemic therapy toxicity, and death solid organ tumors, including RCC. The influence of sarcopenia in RCC patients with tumor thrombus is not well defined. This study evaluates the prognostic ability of sarcopenia regarding surgical outcomes and complications in patients undergoing surgery for RCC with tumor thrombus. METHODS: We retrospectively analyzed patients with nonmetastatic RCC and tumor thrombus undergoing radical nephrectomy and tumor thrombectomy. Skeletal muscle index (SMI; cm2/m2) was measured on preoperative CT/MRI. Sarcopenia was defined using body mass index- and sex-stratified thresholds optimally fit via a receiver-operating characteristic analysis for survival. Associations between preoperative sarcopenia and overall (OS), cancer-specific survival (CSS), and 90-day major complications were determined using multivariable analysis. RESULTS: 115 patients were analyzed, with median (IQR) age and body mass index of 69 (56-72) and 28.6 kg/m2 (23.6-32.9), respectively. 96 (83.4%) of the cohort had ccRCC. Sarcopenia was associated with shorter median OS (P = .0017) and CSS (P = .0019) in Kaplan-Meier analysis. In multivariable analysis, preoperative sarcopenia was prognostic of shorter OS (HR = 3.38, 95% confidence interval [CI] 1.61-7.09) and CSS (HR = 5.15, 95% CI 1.46-18.18). Notably, 1 unit increases in SMI were associated with improved OS (HR = 0.97, 95% CI 0.94-0.999) but not CSS (HR = 0.95, 95% CI 0.90-1.01). No significant relationship between preoperative sarcopenia and 90-day major surgical complications was observed in this cohort (HR = 2.04, 95% CI 0.65-6.42). CONCLUSION: Preoperative sarcopenia was associated with decreased OS and CSS in patients surgically managed for nonmetastatic RCC and VTT, however, was not predictive of 90-day major postoperative complications. Body composition analysis has prognostic utility for patients with nonmetastatic RCC and venous tumor thrombus undergoing surgery.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Sarcopenia , Thrombosis , Humans , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/pathology , Sarcopenia/complications , Retrospective Studies , Vena Cava, Inferior/pathology , Thrombosis/complications , Thrombosis/pathology , Thrombosis/surgery , Prognosis , Nephrectomy , Risk Factors , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/surgery , Muscle, Skeletal/pathology , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/pathology
15.
Urol Pract ; 10(4): 345-351, 2023 07.
Article in English | MEDLINE | ID: mdl-37103557

ABSTRACT

INTRODUCTION: Bladder cancer patients represent a high-risk group for opioid dependence due to the frequency of surgical procedures. Using MarketScan insurance commercial claims and Medicare-eligible databases, we sought to identify whether filling an opioid prescription following initial transurethral resection of bladder tumor resulted in increased odds of prolonged opioid use. METHODS: We analyzed 43,741 commercial claims and 45,828 Medicare-eligible opioid-naïve patients with a new diagnosis of bladder cancer from 2009 to 2019. Multivariable analyses were completed to assess the odds of prolonged opioid use at 3-6 months based on initial exposure to opioids and initial opioid dose quartile. We performed subgroup analyses by sex and eventual treatment modality. RESULTS: Those who filled an opioid prescription following initial transurethral resection of bladder tumor had greater odds of persistent opioid use (commercial claims: 27% vs 12%, OR 2.14, 95% CI 1.84-2.45; Medicare-eligible: 24% vs 12%, OR 1.95, 95% CI 1.70-2.22). Increasing dosage quartile of opioids was associated with increased odds of prolonged opioid use. Those going on to radical therapy had the highest rates of an initial opioid prescription (31% commercial claims and 23% Medicare eligible). Men and women had similar rates of initial prescriptions, but female sex was associated with higher odds of persistent opioid use at 3-6 months in the Medicare-eligible group (OR 1.08, 95% CI 1.01-1.16). CONCLUSIONS: Opioids following initial transurethral resection of bladder tumor increase the odds of continued use at 3-6 months, with the greatest odds in those prescribed the highest initial doses. These data suggest that short-term prescriptions have long-term effects, and additional research on opioid use and bladder cancer outcomes is merited.


Subject(s)
Neoplasms , Opioid-Related Disorders , Male , Humans , Female , Aged , United States/epidemiology , Analgesics, Opioid/therapeutic use , Retrospective Studies , Medicare , Pain, Postoperative/drug therapy , Opioid-Related Disorders/epidemiology , Neoplasms/chemically induced
16.
BJU Int ; 131(1): 32-45, 2023 01.
Article in English | MEDLINE | ID: mdl-35696302

ABSTRACT

OBJECTIVES: To assess the effects of prostatic arterial embolisation (PAE) compared to other procedures for treatment of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). METHODS: We included randomised controlled trials (RCTs), as well as non-randomised studies (NRSs) enrolling men with BPH undergoing PAE vs other surgical interventions via a comprehensive search up until 8 November 2021. Two independent reviewers screened the literature, extracted data, assessed risk of bias, performed statistical analyses by using a random-effects model, and rated the certainty of evidence (CoE) of RCTs and NRSs. RESULTS: We found data to inform two comparisons: PAE vs transurethral resection of prostate (TURP; six RCTs and two NRSs), and PAE vs sham (one RCT). This abstract focuses on the primary outcomes in a comparison of PAE vs TURP. Short-term follow-up: based on RCT evidence, there may be little to no difference in urological symptom score improvement (mean difference [MD] 1.72, 95% confidence interval [CI] -0.37 to 3.81; low CoE) and quality of life (QoL; MD 0.28, 95% CI -0.28 to 0.84; low CoE) measured by International Prostatic Symptom Score. We are very uncertain about the effects of PAE on major adverse events (risk ratio [RR] 0.75, 95% CI 0.19-2.97; very low CoE). Long-term follow-up: based on RCT evidence, PAE may result in little to no difference in urological symptom scores (MD 2.58, 95% CI -1.54 to 6.71; low CoE) and QoL (MD 0.50, 95% CI -0.03 to 1.04; low CoE). We are very uncertain about major adverse events (RR 0.91, 95% CI 0.20-4.05; very low CoE). CONCLUSION: Compared to TURP, the impact on urological symptoms and QoL improvement as perceived by patients appears to be similar. This review did reveal major uncertainty as to how major adverse events compare.


Subject(s)
Embolization, Therapeutic , Lower Urinary Tract Symptoms , Prostatic Hyperplasia , Transurethral Resection of Prostate , Male , Humans , Prostatic Hyperplasia/therapy , Prostatic Hyperplasia/surgery , Prostate/surgery , Lower Urinary Tract Symptoms/therapy , Lower Urinary Tract Symptoms/surgery , Treatment Outcome
17.
Cancer Treat Res Commun ; 34: 100663, 2023.
Article in English | MEDLINE | ID: mdl-36527979

ABSTRACT

Urothelial carcinoma accounts for approximately 90% of all bladder cancer diagnoses. Localized, muscle-invasive disease is often managed with a multidisciplinary approach including either neoadjuvant chemotherapy (NAC) followed by radical cystectomy or concurrent chemoradiation, whereas multiple immunotherapies and novel antibody drug conjugates have recently joined platinum-based chemotherapy as standard of care therapy for metastatic disease. However, the clinical trials leading to these standards often require majority if not complete urothelial histology for eligibility. As many as one quarter of patients diagnosed with bladder cancer will have either divergent differentiation of their urothelial carcinoma or an alternate epithelial tumor such as squamous cell carcinoma, adenocarcinoma, or small cell carcinoma; even more rare are non-epithelial tumors such as sarcoma. The rarity of these diseases and their general exclusion from treatment within prospective clinical trials has created a challenging situation where treatment plans are often derived from case series or extrapolated from other disease types and outcomes are poor compared to pure urothelial carcinoma. In this review, we summarize the existing data on the diagnosis and treatment of epithelial, non-urothelial bladder cancers including adenocarcinoma, squamous cell carcinoma, and small cell carcinoma in their localized and advances stages. We will also review the current clinical trial landscape investigating novel approaches to these diseases.


Subject(s)
Adenocarcinoma , Carcinoma, Small Cell , Carcinoma, Squamous Cell , Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/therapy , Urinary Bladder Neoplasms/drug therapy , Carcinoma, Transitional Cell/therapy , Carcinoma, Transitional Cell/drug therapy , Prospective Studies , Carcinoma, Squamous Cell/pathology , Adenocarcinoma/therapy
18.
Front Oncol ; 12: 1068357, 2022.
Article in English | MEDLINE | ID: mdl-36505878

ABSTRACT

Purpose: Sarcopenia is associated with decreased survival and increased complications in patients with renal cell carcinoma. Readily identifying patients with low muscle composition that may experience worse outcomes or would benefit from preoperative intervention is of clinical interest. Traditional body composition analysis methods are resource intensive; therefore, linear segmentation with routine imaging has been proposed as a clinically practical alternative. This study assesses linear segmentation's prognostic utility in nonmetastatic renal cell carcinoma. Materials and Methods: A single institution retrospective analysis of patients that underwent nephrectomy for nonmetastatic renal cell carcinoma from 2005-2021 was conducted. Linear segmentation of the bilateral psoas/paraspinal muscles was completed on preoperative imaging. Total muscle area and total muscle index associations with overall survival were determined by multivariable analysis. Results: 532 (388 clear cell) patients were analyzed, with median (IQR) total muscle index of 28.6cm2/m2 (25.8-32.5) for women and 33.3cm2/m2 (29.1-36.9) for men. Low total muscle index was associated with decreased survival (HR=1.96, 95% CI 1.32-2.90, p<0.001). Graded increases in total muscle index were associated with better survival (HR=0.95, 95% CI 0.92-0.99, p=0.006). Conclusions: Linear segmentation, a clinically feasible technique to assess muscle composition, has prognostic utility in patients with localized renal cell carcinoma, allowing for incorporation of muscle composition analysis into clinical decision-making. Muscle mass determined by linear segmentation was associated with overall survival in patients with nonmetastatic renal cell carcinoma.

19.
Asian J Urol ; 9(4): 451-459, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36381596

ABSTRACT

Objective: Extramammary Paget's disease (EMPD) is a rare cutaneous malignant disease. Due to its rarity, there is a paucity of data regarding best treatment strategy. EMPD primarily affects apocrine gland-bearing skin areas such as the vulva, scrotum, and penis. Our objective was to provide a present-day rationale for diagnosis, pathogenesis, and treatment of EMPD with a focus on recent progress in workup and management of the disease. Methods: Literature on EMPD until February 2022 was assessed through PubMed, MEDLINE databases, and Google scholar. A narrative review of the most relevant articles was provided. Results: EMPD usually presents with indolent growth while usually being diagnosed primarily as carcinoma in situ. The foundation of EMPD treatment centers around prompt and accurate diagnosis, wide local or Mohs micrographic surgical excision with proper management towards the margin status, and careful consideration for lymphadenectomy in patients with regionally positive disease. Conventional chemotherapies are alternative treatments modality for patients with distant metastases; however, they sometimes have suboptimal efficacy. At present, there is no agreement regarding adjuvant or systemic therapies, although recent studies have shown several insights into the molecular pathogenesis, tumor biology, and genomics of the development and advancement of EMPD, which may lead to novel and targeted treatment approaches for metastatic EMPD in the future. Conclusion: Patients with EMPD should seek care from physicians with expertise in disease management and patient counseling. These patients should be surveilled with close follow-up to evaluate them for disease recurrence or progression. Global collaborations with groups such as the Global Society for Rare Genitourinary Tumors, and especially patient support groups are crucial in designing clinical trials to help elucidate more robust data in this orphan disease.

20.
Mol Ther Oncolytics ; 26: 141-157, 2022 Sep 15.
Article in English | MEDLINE | ID: mdl-35847448

ABSTRACT

Interferon alpha (IFNα) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNα have shown clinical efficacy treating bacillus Calmette-Guerin (BCG)-unresponsive bladder cancer (BLCA). However, transient transgene expression and adenoviral immunogenicity may limit therapeutic activity. Lentiviral vectors can achieve stable transgene expression and are less immunogenic. In this study, we evaluated lentiviral vectors expressing murine IFNα (LV-IFNα) and demonstrate IFNα expression by transduced murine BLCA cell lines, bladder urothelium, and within the urine following intravesical instillation. Murine BLCA cell lines (MB49 and UPPL1541) were sensitive to IFN-mediated cell death after LV-IFNα, whereas BBN975 was inherently resistant. Upregulation of interleukin-6 (IL-6) predicted sensitivity to IFN-mediated cell death mediated by caspase signaling, which when inhibited abrogated IFN-mediated cell killing. Intravesical therapy with LV-IFNα/Syn3 in a syngeneic BLCA model significantly improved survival, and molecular analysis of treated tumors revealed upregulation of apoptotic and immune-cell-mediated death pathways. In particular, biomarker discovery analysis identified three clinically actionable targets, PD-L1, epidermal growth factor receptor (EGFR), and ALDHA1A, in murine tumors treated with LV-IFNα/Syn3. Our findings warrant the comparison of adenoviral and LV-IFNα and the study of novel combination strategies with IFNα gene therapy for the BLCA treatment.

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