Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 330
Filtrar
1.
Oncologist ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712304

RESUMO

BACKGROUND: Somatic alterations in circulating tumor DNA (ctDNA) may be associated with treatment response or prognosis in prostate cancer (PCa). The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in ctDNA from patients with PCa and to further understand the somatic genetic heterogeneity of advanced prostate cancer. PATIENTS AND METHODS: This study included a heterogeneous group of 892 patients with advanced PCa (predominantly castrate-resistant prostate cancer) with AR alterations detected in ctDNA that underwent next-generation sequencing of 54 to 73 genes via Guardant360 testing (Guardant Health, Inc., Redwood City, CA). Distribution and summary of AR alterations detected, the association of AR alterations with other genes, and a pathway analysis are reported. RESULTS: The median absolute plasma copy number of AR amplifications was 3.3 (range, 1.2-165.2). Many patients had multiple AR mutations; a total of 112 unique mutations were identified in AR, including L702H (25%), T878A (14%), H875Y (11%), W742C (8%), W742L (4%), F877L (2%), and T878S (2%). Other ctDNA gene alterations in the Guardant assays included TP53 (50%), MYC (34%), BRAF (32%), PIK3CA (29%), MET (25%), CDK6 (26%), EGFR (24%), FGFR1 (21%), and APC (12%). Many of these non-AR alterations are not tissue verified in other studies. AR amplification cosegregated with alterations in MYC (p < .001), BRAF (p < .001), PIK3CA (p < .001), MET (p < .001), CDK6 (p < .001), EGFR (p < .001), FGFR1 (p = .391), and more. Alterations in APC were significantly associated with mutations in AR (p < .001). CONCLUSION: Several AR alterations and concomitant non-AR alterations that associate with drug resistance were detected. These findings provide additional insights into the heterogeneity of advanced prostate cancer. IMPLICATIONS FOR PRACTICE: The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in circulating tumor DNA (ctDNA) from patients with prostate cancer in relation to non-AR gene alterations detected in the ctDNA landscape. The study included 892 patients with prostate cancer with AR alterations in ctDNA. AR alterations were significantly associated with other gene alterations detected in ctDNA. The common AR mutations found are linked to resistance to abiraterone, enzalutamide, or bicalutamide. Characterization of the circulating AR landscape and gene alterations provides potential additional insight into the somatic genetic heterogeneity of advanced prostate cancer.

3.
J Immunother Cancer ; 7(1): 273, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640776

RESUMO

Following publication of the original article [1], the author reported that the current funding section "Kidney Cancer Association Young Investigator Grant provided funding for this project" should be replaced with "Kidney Cancer Association Young Investigator Grant and Bucks County Board provided funding for this project."

4.
Urology ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31586570

RESUMO

OBJECTIVE: To examine the use of in-hospital pharmacologic thromboprophylaxis (PTP) in patients undergoing radical cystectomy between 2004 and 2014 and to assess the risk of venous thromboembolism (VTE) across the study period. MATERIAL AND METHODS: We identified 8322 patients without contraindications to PTP undergoing radical cystectomy in the US using the Premier Healthcare Database. Nonparametric Wilcoxon type test for trend was employed to examine the trend of PTP utilization across the study period. Ensuing, we employed multivariable logistic regression and generalized linear regression models to examine the odds of receiving PTP and the risk of being diagnosed with VTE, respectively. RESULTS: Based on VTE risk-stratification, the majority of patients (87.8%) qualified as "high-risk." Across the study period the use of PTP increased (Odds ratio 1.02, 95% confidence interval (CI) 1.00-1.03, P = .044), but remained underutilized as the maximum percentage of patients receiving in-hospital PTP did not exceed 58.6%. The risk of VTE did not vary across the study period (risk ratio 0.97, 95%CI 0.92-1.02, P = .178). CONCLUSION: Utilization of PTP increased throughout the study period, while the risk of VTE did not change. Future studies are necessary to improve implementation of guideline-driven care, as PTP remained underutilized throughout the study period.

5.
Expert Opin Investig Drugs ; 28(10): 821-826, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31526130

RESUMO

Introduction: The conventional management of most patients with metastatic urothelial carcinoma (UC) is platinum-based chemotherapy followed by immunotherapy. Erdafitinib is an option in post-platinum patients with activating mutations in fibroblast growth factor receptor (FGFR)-3 and -2. Salvage therapy with taxanes or vinflunine has demonstrated minimal efficacy. Enfortumab Vedotin (EV), a monoclonal antibody-drug conjugate (ADC) targeting nectin-4 is under investigation in patients with advanced UC. Areas covered: This review describes the epidemiology and unmet needs of patients with metastatic UC and is focused specifically on heavily treated patients. We explore the rationale for targeting nectin 4 and the clinical development of EV; efficacy and safety data from the completed phase I and II studies are examined. Ongoing trials to definitively assess clinical outcomes in comparison to current therapy and trials exploring EV in combination are also highlighted. Expert opinion: There is an unmet need for new therapies in most patients with advanced UC and who progress after platinum and immunotherapy. EV has shown promising efficacy and safety in this population in phase 1 and 2 trials including those with poor prognostic factors such as liver metastases. Ongoing trials exploring this agent in combination will continue to advance the treatment of UC.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/imunologia , Moléculas de Adesão Celular/imunologia , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacologia , Imunoterapia/métodos , Metástase Neoplásica , Oligopeptídeos/imunologia , Prognóstico , Neoplasias Urológicas/imunologia
6.
Expert Opin Investig Drugs ; 28(10): 851-860, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31554440

RESUMO

Introduction: Renal cell carcinoma (RCC) consists of distinct clinical and biologic entities, with an urgent need for novel therapies targeting histology-specific molecular drivers of cancer growth. The MET pathway is now being targeted by multiple novel agents in clinical development. This review highlights the upcoming role of MET inhibition in the treatment of RCC. Areas covered: The HGF-MET axis is now recognized as playing a vital role in the growth of papillary histology and in driving VEGF inhibitor resistance. The heterogeneity of MET alterations influences sensitivity to MET inhibition and we need predictive biomarkers for improving patient selection. In this review, we highlight the role of the MET pathway in both clear cell and non-clear cell RCC and  provide a comprehensive review of preclinical and early clinical data on multiple drugs targeting the MET pathway. Expert opinion: MET alterations can act as primary or secondary drivers of tumor growth in RCC and represents a viable therapeutic target. Combination strategies of VEGF and MET inhibitors could lead to sustained and deep responses even in non-MET driven RCC by inhibiting pathways of VEGF resistance. Addition of checkpoint inhibitors to MET inhibition has also demonstrated promising signs of early efficacy.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Drogas em Investigação/farmacologia , Humanos , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Seleção de Pacientes , Inibidores de Proteínas Quinases/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
7.
Transl Oncol ; 12(11): 1416-1424, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31401334

RESUMO

Cancer cells utilize vitamin folate to fulfill their excessive demand for nucleotides and amino acids. Dihydrofolate reductase (DHFR), an enzyme involved in folate metabolism converts dihydrofolate into tetrahydrofolate, which is required for the de novo synthesis of purines, and certain amino acids. DHFR inhibitors are used as a chemotherapeutic agent. Cancer sequencing analysis has identified additional enzymes in folate metabolism that are dysregulated in cancer. Methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L), one such enzyme is overexpressed in bladder cancer. MTHFD1L is a mitochondrial enzyme involved in the folate cycle by catalyzing the reaction of formyl-tetrahydrofolate to formate and tetrahydrofolate (THF). THF is crucial for de novo purine and thymidylate synthesis and is also involved in the regeneration of methionine. Cancer cells rely on purines derived from the de novo pathway for the nucleotides whereas normal cells favor the salvage pathway. In this study we examined MTHFD1L expression in bladder cancer. By using publicly available cancer transcriptome data analysis web-portal UALCAN, we found overexpression of MTHFD1L in bladder cancer and expression was associated with overall survival. RT-PCR and immunoblot analysis confirmed the overexpression of MTHFD1L in muscle invasive bladder cancer tissues compared to normal urothelium. Furthermore, our investigations suggested a critical role for MTHFD1L in bladder cancer cell proliferation, colony formation and invasion. Thus, in this study, we show the significance of the folate metabolic enzyme MTHFD1L in aggressive bladder cancers and suggest that being an enzyme, MTHFD1L serves as a valuable therapeutic target.

8.
Eur Urol Oncol ; 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-31412003

RESUMO

BACKGROUND: Reliable biomarkers to predict the response of metastatic urothelial cancer (mUC) to programmed death-1 and programmed death-ligand 1 (PD-1/PD-L1) inhibitors are being investigated. Texture analysis represents tumor heterogeneity and may serve as a predictor of response in mUC. OBJECTIVE: To assess the predictive ability of computed tomography (CT) texture analysis for progression-free survival (PFS) in patients with mUC treated with PD-1/PD-L1 inhibitors. DESIGN, SETTING, AND PARTICIPANTS: Forty-two postplatinum patients with mUC treated with PD-1/PD-L1 inhibitors from 2013 to 2018, including those with measurable disease per RECIST 1.1 who had contrast-enhanced baseline or first follow-up CT within 3mo after starting treatment, were included. PFS was calculated based on serial follow-up CT scans. Eleven patients with follow-up of <12mo without progression were excluded. Texture features of measurable lesions on baseline and first follow-up CT were extracted using commercially available software (TexRAD; Feedback Plc, Cambridge, UK) using different spatial scaling factors (0, 2-6). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Stepwise logistic regression analysis was conducted to identify patients with PFS <12mo, and performance was assessed using receiver operator characteristic curves. RESULTS AND LIMITATIONS: Of 31 included patients, 18 had PFS <12mo. Twenty-five baseline CT and 29 first follow-up CT scans met the inclusion criteria. In patients with PFS <12mo, entropy and mean were higher on first follow-up CT (p=0.02 and p=0.005, respectively). A predictive model including mean and entropy on first follow-up CT yielded 95% sensitivity, 80% specificity, 90% positive predictive value, 89% negative predictive value, and 90% accuracy (area under the curve=0.963) to identify patients with PFS <12mo. Limitations include retrospective nature and small sample size. CONCLUSIONS: CT texture analysis can help predict early progression with high accuracy soon after starting PD-1/PD-L1 inhibitors. Studies investigating the correlation of texture analysis with survival endpoints may help validate texture analysis as a biomarker of PD-1/PD-L1 inhibitors' treatment response. PATIENT SUMMARY: Computed tomography texture analysis can help predict durability of response in patients with metastatic urothelial cancer early during treatment with programmed death-1 and programmed death-ligand 1 (PD-1/PD-L1) inhibitors.

9.
Eur Urol Oncol ; 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-31412004

RESUMO

Cell-free circulating DNA (cfDNA) can be used for noninvasive profiling of tumor genomic aberrations. We hypothesized that molecular alterations may inform prognostication in advanced urothelial carcinoma (aUC). We evaluated 124 aUC patients who underwent cfDNA analysis using a 73-gene sequencing panel (Guardant360). The association of molecular alterations and clinical factors with overall survival (OS) and failure-free-survival (FFS) was evaluated using the Kaplan-Meier method and Cox proportional-hazards regression. The median age was 72yr, and 65 patients (52.4%) received prior therapy with platinum, 21 (17.1%) with a taxane, and ten (8.1%) with a PD-1/PD-L1 inhibitor. At least one genomic alteration was detected in 112 patients (90.3%). The median number of alterations per sample was four (range 0-80). Commonly altered genes included TP53 (54.8%), PIK3CA (24.2%), ARID1A (22.6%), ERBB2 (19.4%), EGFR (16.1%), NF1 (13.7%), RB1 (12.9%), FGFR3 (11.3%), BRAF (10.5%), BRCA1 (10.5%), and RAF1 (8.9%). BRCA1 and RAF1 alterations were associated with worse OS (hazard ratio [HR] 2.48; p=0.07; HR 4.87; p=0.007) and FFS (HR 2.35; p=0.016; HR 2.40; p=0.047). Poor Eastern Cooperative Oncology Group performance status and the presence of visceral metastasis were associated with shorter OS; genomic evolution was observed. In conclusion, cfDNA molecular alterations were detected in most aUC patients. BRCA1 and RAF1 alterations were negatively prognostic, supporting further evaluation of DNA damage response and RAF kinase inhibitors. PATIENT SUMMARY: Noninvasive testing of cell-free circulating DNA in advanced urothelial carcinoma identifies clinically relevant molecular aberrations. Alterations in BRCA1 and RAF1 genes appear to be negatively associated with clinical outcomes, supporting further study of DNA damage response and RAF kinase inhibitors in selected patients.

10.
Abdom Radiol (NY) ; 44(12): 3858-3873, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31363813

RESUMO

The recent genomic characterization of urothelial carcinoma by the Cancer Genome Atlas Project, made possible by the introduction of high throughput, reduced cost, and sequence analysis, has shed new insights on the biology of advanced disease. In addition, studies on imaging of advanced urothelial carcinoma have widened the knowledge on disease presentation and on pattern of metastatic spread and their correlation with the underlying biology of urothelial carcinoma. The wide range of treatments for advanced urothelial cancer, including combined chemotherapy regimens and immune checkpoint inhibitors, each result in treatment class-specific patterns of response and adverse events. Results of studies point to the need for a reliable biomarker, perhaps with imaging, that predicts prognosis and treatment response to systemic treatment, and can be used to select the most effective treatment while minimizing toxicity. This review of advanced urothelial cancer introduces the latest advances in genetic profiling, the current role of imaging, the radiographic appearance of treatment response and their toxicities, and details potential future areas of imaging research.

11.
Am Soc Clin Oncol Educ Book ; 39: 284-300, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31099684

RESUMO

Platinum-based chemotherapy has been the standard of care in advanced urothelial cancer, but long-term outcomes have remained poor. Immune checkpoint inhibitors, with their favorable toxicity profiles and noteworthy efficacy, have steered a new era in advanced urothelial cancer, with five agents targeting the PD-1/PD-L1 pathway approved by the U.S. Food and Drug Administration (FDA). However, most patients do not achieve response, whereas immunotherapy-related adverse events may cause morbidity, increased health care use, and-rarely-mortality. Therefore, there is an urgent need for additional therapeutic modalities across the disease spectrum. A plethora of clinical trials are ongoing in various disease settings, including chemotherapy regimens, radiotherapy, antibody-drug conjugates, agents targeting additional immune checkpoint pathways, vaccine, cytokines, adoptive cell therapies, as well as targeted and anti-angiogenic agents. Two agents, enfortumab vedotin and erdafitinib, have breakthrough designation by the FDA but are not approved yet (at the time of this paper's preparation). Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials. Evaluation of new treatments has met with substantial challenges for many reasons, for example, molecular heterogeneity, clonal evolution, and genomic instability. In the era of precision molecular medicine, and because patients do not respond uniformly to current therapies, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. Here, we review current updates and future directions of experimental therapeutics in urothelial cancer, including examples (but not an exhaustive list) of ongoing clinical trials.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Terapia de Alvo Molecular , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Uretrais/metabolismo , Neoplasias Uretrais/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Resultado do Tratamento , Neoplasias Uretrais/imunologia
12.
J Immunother Cancer ; 7(1): 139, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138299

RESUMO

BACKGROUND: The tumor immune microenvironment has become the focus of research in clear cell renal cell carcinoma (ccRCC) due to its important role in immune surveillance post nephrectomy. This study investigates the correlation of tumor infiltrating immune cell characteristics with rates of recurrence following surgery in localized ccRCC. METHODS: We morphologically identified and scored tumor infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) stained slides of patients with localized ccRCC (stage ≥T1b excluding stage IV). The University of Alabama at Birmingham (UAB) dataset (n = 159) was used to discover and the Fox Chase Cancer Center (FCCC) dataset (n = 198) was used to validate the results of morphologic immune cell analysis. We then performed gene expression analysis using the Immune Profile panel by NanoString in the UAB cohort and identified immune cells and pathways associated with recurrence, followed by validation in the Cancer Genome Atlas (TCGA) ccRCC dataset. Infiltrating immune cell types were identified by gene expression deconvolution. RESULTS: The presence of TILs identified by morphology correlated with higher T cell, Th1, CD8+ T and Treg gene signatures. Recurrence was associated with lower T cells and higher neutrophils. Higher Teffector (Teff)/Treg ratio correlated with lower rate of recurrence and was validated in the TCGA dataset. Genes associated with adaptive immune response were downregulated in tumors that recurred. Unsupervised hierarchical clustering identified a subset of patients with over-expression of adaptive response genes including CD8, CD3, GZMA/B, PRF1, IDO1, CTLA4, PDL1, ICOS and TIGIT. These patients had higher morphologic lymphocyte infiltration and T cell gene expression. Higher levels of TILs identified by morphology correlated with higher rates of recurrence in our discovery dataset but not in our validation set. CONCLUSIONS: Recurrence of ccRCC following surgery was associated with lower T cell infiltrate, lower adaptive immune response and higher neutrophil gene expression. Presence of higher Teff/Treg ratio correlated with lower recurrence.

13.
Cancer Lett ; 454: 1-13, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974114

RESUMO

Molecular reprogramming in response to chemotherapeutics leads to poor therapeutic outcomes for prostate cancer (PCa). In this study, we demonstrated that CXCR6-CXCL16 axis promotes DTX resistance and acts as a counter-defense mechanism. After CXCR6 activation, cell death in response to DTX was inhibited, and blocking of CXCR6 potentiated DTX cytotoxicity. Moreover, in response to DTX, PCa cells expressed higher CXCR6, CXCL16, and ADAM-10. Furthermore, ADAM-10-mediated release of CXCL16 hyper-activated CXCR6 signaling in response to DTX. Activation of CXCR6 resulted in increased GSK-3ß, NF-κB, ERK1/2 phosphorylation, and survivin expression, which reduce DTX response. Finally, treatment of PCa cells with anti-CXCR6 monoclonal antibody synergistically or additively induced cell death with ∼1.5-4.5 fold reduction in the effective concentration of DTX. In sum, our data imply that co-targeting of CXCR6 would lead to therapeutic enhancement of DTX, leading to better clinical outcomes for PCa patients.

14.
World J Urol ; 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30993426

RESUMO

BACKGROUND: Basophils, eosinophils and monocytes may be involved in BCG-induced immune responses and be associated with outcomes of bladder cancer patients receiving intravesical BCG. Our objective was to explore the association of baseline counts of basophils, eosinophils and monocytes with outcomes of patients with high-grade T1 bladder cancer receiving a standard course of intravesical BCG. METHODS: We retrospectively reviewed medical records of patients with primary T1 HG/G3 bladder cancer. After re-TURBT, patients were treated with a 6-week course of intravesical BCG induction followed by intravesical BCG every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months from initiation of therapy The analysis of potential risk factors for recurrence, muscle invasion and cancer-specific and overall survival was performed using univariable Cox regression models. Those factors that presented, at univariate analysis, an association with the event at a liberal p < 0.1, have been selected for the development of a multivariable model. RESULTS: A total of 1045 patients with primary T1 HG/G3 were included. A total of 678 (64.9%) recurrences, 303 (29.0%) progressions and 150 (14.3%) deaths were observed during follow-up. Multivariate analysis showed that logarithmic transformation of basophils count was associated with a 30% increment in the hazard of recurrence per unit increase of logarithmic basophils count (HR 1.30; 95% confidence interval 1.09-1.54; p = 0.0026). Basophil count modeled by quartiles was also significantly associated with time to recurrence [second vs. lower quartile HR 1.42 (1.12-1.79); p = 0.003, third vs. lower quartile HR 1.26 (1.01-1.57); p = 0.041; upper vs. lower quartile HR 1.36 (1.1-1.68); p = 0.005]. The limitations of a retrospective study are applicable. CONCLUSION: Baseline basophil count may predict recurrence in BCG-treated HG/G3 T1 bladder cancer patients. External validation is warranted.

15.
AJR Am J Roentgenol ; : 1-10, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30860885

RESUMO

OBJECTIVE: The purpose of this study was to determine whether quantitative T2-weighted imaging and apparent diffusion coefficient (ADC) texture features of bladder cancer and extravesical fat are predictive of muscle invasive bladder cancer (category ≥ T2) and extravesical (category ≥ T3) disease after transurethral resection of a bladder tumor (TURBT). MATERIALS AND METHODS: In this retrospective study, 36 patients (27 men, nine women; mean age, 71 years) were identified who underwent post-TURBT MRI followed by cystectomy without intervening treatment from August 2011 through October 2016. Texture features of bladder cancer and extravesical fat adjacent to the tumor on T2-weighted and ADC images were extracted and compared between category ≤ T2 versus ≥ T3 and category T1 versus ≥ T2 tumors by means of Kruskal-Wallis or Mann-Whitney U test. Multivariate logistic regression analysis was performed, and ROC curves were calculated. RESULTS: Twenty-six of the 36 (72%) tumors were ≥ T2, and 53% (19/36) were ≥ T3. In multivariate analysis, bladder cancer entropy on T2-weighted images (p = 0.006; odds ratio [OR], 4.56; 95% CI, 1.49-20.41; AUC, 0.85) and ADC maps (p = 0.019; OR, 2.24; 95% CI, 1.13-5.31; AUC, 0.80) and extravesical fat entropy on T2-weighted images (p = 0.005; OR, 17.50; 95% CI, 3.01-200.80; AUC, 0.84) and ADC maps (p = 0.002; OR, 6.54; 95% CI, 1.90-32.40; AUC, 0.82) remained greater for ≥ T3 than for ≤ T2 tumors. In multivariate analysis, bladder cancer entropy on ADC maps (p = 0.027; OR, 2.11; 95% CI, 1.08-5.03; AUC, 0.76) and extravesical fat entropy on T2-weighted images (p = 0.010; OR, 5.33; 95% CI, 1.25-3.79; AUC, 0.78) and ADC maps (p = 0.029; OR, 3.80; 95% CI, 1.25-16.97; AUC, 0.74) remained greater for category ≥ T2 compared with category T1 tumors. CONCLUSION: Greater entropy of primary bladder cancers and extravesicular fat was observed in category ≥ T3 than in category ≤ T2 and in category ≥ T2 than in category T1 tumors. MRI texture analysis can help with local bladder cancer staging in patients who have undergone TURBT and may serve as a biomarker for higher local category bladder cancers.

16.
Eur Urol Focus ; 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30910391

RESUMO

Treatment options for rare genitourinary malignancies, including adrenocortical carcinoma, bladder/upper tract cancers of variant histology, penile squamous cell carcinoma, and chemotherapy-refractory germ cell tumors, are limited, often with a poor response to systemic therapy. Given preclinical data and efficacy across multiple malignancies, immunotherapy has been and continues to be explored in this challenging setting. In this report, we explore the data for immunotherapy in these tumors and highlight ongoing clinical trials. International collaborations and innovative trials will be critical to advancing treatment for these rare tumors. PATIENT SUMMARY: In this report, we explore the data for immunotherapy in rare genitourinary malignancies and highlight ongoing clinical trials. International collaborations and innovative trials will be critical to advancing treatment for these rare tumors.

17.
Curr Treat Options Oncol ; 20(2): 12, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30741358

RESUMO

OPINION STATEMENT: Cisplatin has been established as an important agent in the neoadjuvant setting prior to radical cystectomy (RC) surgery for muscle-invasive urothelial cancer (MIUC) as well as in the unresectable or metastatic urothelial carcinoma (mUC) setting. Unfortunately, many patients in practice are felt to be "cisplatin-ineligible." Thus, it is vital that we develop treatment approaches and novel therapeutics for this population. We evaluate therapeutic alternatives to cisplatin-based treatment. For patients undergoing RC, there is no recommended alternative to neoadjuvant cisplatin-based combination therapy, and upfront RC or clinical trials are preferable. For patients receiving "bladder-sparing" radiation, concurrent radiosensitizing chemotherapies may be used, and several trials are also underway. For cisplatin-ineligible patients with mUC who are eligible for chemotherapy, carboplatin-based or split-dose cisplatin-based regimens may be employed. Pembrolizumab and atezolizumab offer options as first-line therapy for cisplatin-ineligible patients with high PD-L1 expression. The results of trials combining checkpoint inhibitors or platinum-based chemotherapy plus PD1/PD-L1 inhibitors are eagerly awaited. For platinum or chemotherapy-ineligible patients with mUC, immune checkpoint inhibitors such as inhibitors of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) are approved regardless of PD-L1 expression. However, given limited effectiveness of first-line PD-1/PD-L1 inhibitor monotherapy in tumors with low PD-L1 expression, trials in this space are critical.

18.
Cancer Res ; 79(7): 1413-1425, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30733194

RESUMO

Although c-MYC and mTOR are frequently activated proteins in prostate cancer, any interaction between the two is largely untested. Here, we characterize the functional cross-talk between FOXP3-c-MYC and TSC1-mTOR signaling during tumor progression. Deletion of Tsc1 in mouse embryonic fibroblasts (MEF) decreased phosphorylation of c-MYC at threonine 58 (pT58) and increased phosphorylation at serine 62 (pS62), an observation validated in prostate cancer cells. Conversely, inhibition of mTOR increased pT58 but decreased pS62. Loss of both FOXP3 and TSC1 in prostate cancer cells synergistically enhanced c-MYC expression via regulation of c-Myc transcription and protein phosphorylation. This crosstalk between FOXP3 and TSC1 appeared to be mediated by both the mTOR-4EBP1-c-MYC and FOXP3-c-MYC pathways. In mice, Tsc1 and Foxp3 double deletions in the prostate led to prostate carcinomas at an early age; this did not occur in these mice with an added c-Myc deletion. In addition, we observed synergistic antitumor effects of cotreating mice with inhibitors of mTOR and c-MYC in prostate cancer cells and in Foxp3 and Tsc1 double-mutant mice. In human prostate cancer, loss of nuclear FOXP3 is often accompanied by low expression of TSC1. Because loss of FOXP3 transcriptionally induces c-Myc expression and loss of TSC1 activates mTOR signaling, these data suggest cross-talk between FOXP3-c-MYC and TSC1-mTOR signaling that converges on c-MYC to regulate tumor progression. Coadministration of c-MYC and mTOR inhibitors may overcome the resistance to mTOR inhibition commonly observed in prostate cancer cells. SIGNIFICANCE: These results establish the principle of a synergistic action of TSC1 and FOXP3 during prostate cancer progression and provide new therapeutic targets for patients who have prostate cancer with two signaling defects.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1413/F1.large.jpg.

19.
J Biol Chem ; 294(16): 6621-6634, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30792308

RESUMO

Nuclear localization of androgen receptor (AR) directs transcriptional regulation of a host of genes, referred to as genomic signaling. Additionally, nonnuclear or nongenomic activities of the AR have long been described, but understanding of these activities remains elusive. Here, we report that AR is imported into and localizes to mitochondria and has a novel role in regulating multiple mitochondrial processes. Employing complementary experimental approaches of AR knockdown in AR-expressing cells and ectopic AR expression in AR-deficient cells, we demonstrate an inverse relationship between AR expression and mitochondrial DNA (mtDNA) content and transcription factor A, mitochondrial (TFAM), a regulator of mtDNA content. We show that AR localizes to mitochondria in prostate tissues and cell lines and is imported into mitochondria in vitro We also found that AR contains a 36-amino-acid-long mitochondrial localization sequence (MLS) capable of targeting a passenger protein (GFP) to the mitochondria and that deletion of the MLS abolishes the import of AR into the mitochondria. Ectopic AR expression reduced the expression of oxidative phosphorylation (OXPHOS) subunits. Interestingly, AR also controlled translation of mtDNA-encoded genes by regulating expression of multiple nuclear DNA-encoded mitochondrial ribosomal proteins. Consistent with these observations, OXPHOS supercomplexes were destabilized, and OXPHOS enzymatic activities were reduced in AR-expressing cells and restored upon AR knockdown. Moreover, mitochondrial impairment induced AR expression and increased its translocation into mitochondria. We conclude that AR localizes to mitochondria, where it controls multiple mitochondrial functions and mitonuclear communication. Our studies also suggest that mitochondria are novel players in nongenomic activities of AR.


Assuntos
Mitocôndrias/metabolismo , Fosforilação Oxidativa , Sinais Direcionadores de Proteínas , Receptores Androgênicos/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Células PC-3 , Transporte Proteico/genética , Receptores Androgênicos/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
20.
Cancer ; 125(8): 1319-1329, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30633323

RESUMO

BACKGROUND: There are race-based differences in bladder cancer survival. To better understand this phenomenon, this study was designed to assess the statistical contributions of tumor, treatment, and access variables to race-based differences in survival. METHODS: Data were extracted from the National Cancer Data Base on black and white adults with muscle-invasive bladder cancer from 2004 to 2015. The impact of tumor, access, and treatment variables on differences in survival was inferred by the performance of sequential propensity score-weighted analyses in which black and white patients were balanced with respect to demographics and health status (comorbidities) tumor characteristics, treatment, and access-related variables. The propensity score-weighted hazard of death (black vs white) was calculated after each iteration. RESULTS: This study identified 44,577 patients with a median follow-up of 77 months. After demographics and health status were balanced, black race was associated with 18% worse mortality (hazard ratio, 1.18; 95% confidence interval [CI], 1.12-1.25; P < .001). Balancing by tumor characteristics reduced this to 16%, balancing by treatment reduced this to 10%, and balancing by access-related variables resulted in no difference. Access-related variables explained 40% (95% CI, 22.9%-57.0%) of the excess risk of death in blacks, whereas treatment factors explained 35% (95% CI, 22.2%-46.9%). The contribution of tumor characteristics was not significant. CONCLUSIONS: In the models, differences in survival for black and white patients with bladder cancer are best explained by disparities in access and treatment, not tumor characteristics. Access to care is likely a key factor in racial disparities in cancer.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA