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Interactions within the tumor microenvironment (TME) significantly influence tumor progression and treatment responses. While single-cell RNA sequencing (scRNA-seq) and spatial genomics facilitate TME exploration, many clinical cohorts are assessed at the bulk tissue level. Integrating scRNA-seq and bulk tissue RNA-seq data through computational deconvolution is essential for obtaining clinically relevant insights. Our method, ProM, enables the examination of major and minor cell types. Through evaluation against existing methods using paired single-cell and bulk RNA sequencing of human urothelial cancer (UC) samples, ProM demonstrates superiority. Application to UC cohorts treated with immune checkpoint inhibitors reveals pre-treatment cellular features associated with poor outcomes, such as elevated SPP1 expression in macrophage/monocytes (MM). Our deconvolution method and paired single-cell and bulk tissue RNA-seq dataset contribute novel insights into TME heterogeneity and resistance to immune checkpoint blockade.
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BACKGROUND: In the United States, Black men are at highest risk for being diagnosed with and dying from prostate cancer. Given this disparity, we examined relevant data to establish clinical prostate-specific antigen (PSA) screening guidelines for Black men in the United States. METHODS: A comprehensive literature search identified 1848 unique publications for screening. Of those screened, 287 studies were selected for full-text review, and 264 were considered relevant and form the basis for these guidelines. The numbers were reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Three randomized controlled trials provided Level 1 evidence that regular PSA screening of men 50 to 74 years of age of average risk reduced metastasis and prostate cancer death at 16 to 22 years of follow-up. The best available evidence specifically for Black men comes from observational and modeling studies that consider age to obtain a baseline PSA, frequency of testing, and age when screening should end. Cohort studies suggest that discussions about baseline PSA testing between Black men and their clinicians should begin in the early 40s, and data from modeling studies indicate prostate cancer develops 3 to 9 years earlier in Black men compared with non-Black men. Lowering the age for baseline PSA testing to 40 to 45 years of age from 50 to 55 years of age, followed by regular screening until 70 years of age (informed by PSA values and health factors), could reduce prostate cancer mortality in Black men (approximately 30% relative risk reduction) without substantially increasing overdiagnosis. CONCLUSIONS: These guidelines recommend that Black men should obtain information about PSA screening for prostate cancer. Among Black men who elect screening, baseline PSA testing should occur between ages 40 and 45. Depending on PSA value and health status, annual screening should be strongly considered. (Supported by the Prostate Cancer Foundation.).
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Negro o Afroamericano , Detección Precoz del Cáncer , Antígeno Prostático Específico , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/etnología , Neoplasias de la Próstata/sangre , Antígeno Prostático Específico/sangre , Estados Unidos/epidemiología , Persona de Mediana Edad , Anciano , Guías de Práctica Clínica como Asunto , Tamizaje MasivoRESUMEN
BACKGROUND: There is currently limited literature assessing the real-world treatment patterns and clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) mutations. METHODS: Medical charts were abstracted for mCRPC patients with ≥ 1 of 12 HRR somatic gene alterations treated at US oncology centers participating in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange. Treatment patterns and clinical outcomes were assessed from the initiation of first-line or later (1L+) mCRPC therapy received on or after July 1, 2014. RESULTS: Among 138 patients included in the study, the most common somatic HRR mutations were CDK12 (47.8%), BRCA2 (22.5%), and ATM (21.0%). Novel hormonal therapy and taxane chemotherapy were most commonly used in 1L; taxane use increased in later lines. Median overall survival (95% confidence interval [CI]) was 36.3 (30.7-47.8) months from initiation of 1L therapy and decreased for subsequent lines. Similarly, there was a trend of decreasing progression-free survival and prostate-specific antigen response from 1L to 4L+ therapy. CONCLUSIONS: Treatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature.
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Proteína BRCA2 , Mutación , Neoplasias de la Próstata Resistentes a la Castración , Reparación del ADN por Recombinación , Humanos , Masculino , Anciano , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteína BRCA2/genética , Persona de Mediana Edad , Proteínas de la Ataxia Telangiectasia Mutada/genética , Taxoides/uso terapéutico , Taxoides/administración & dosificación , Quinasas Ciclina-Dependientes/genética , Resultado del Tratamiento , Anciano de 80 o más Años , Antígeno Prostático Específico/sangre , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Retrospectivos , Metástasis de la NeoplasiaRESUMEN
OBJECTIVES: Androgen receptor-targeted therapies (ARTs) improve survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC); however, a significant portion of patients discontinue treatment for various reasons including treatment-related toxicity. We aim to describe reasons for ART treatment discontinuation and identify predictors associated with increased risk of treatment discontinuation due to toxicity. METHODS: We performed a single-institution retrospective review of patients with mCRPC receiving ART between 2010 and 2021. Our primary aim was to identify risk factors for treatment discontinuation due to toxicity. Our secondary aim was to describe ART discontinuation patterns among patients with mCRPC. RESULTS: One hundred thirty-three patients with mCRPC started and discontinued ARTs. Fourteen patients (10.5%) discontinued treatment due to toxicity. Common reasons for treatment discontinuation include Prostate Specific Antigen test progression, radiographic progression, toxicity, and death. Significant predictors of treatment discontinuation due to toxicity on bivariate analysis and multivariate analysis included patient-reported falls (odds ratio [OR]: 7.67, CI: [1.31-40.42]; P =0.016), rash (OR: 13.4, CI: [1.35-134.81]; P =0.026), and weakness (OR: 4.16, CI: [1.15-15.0]; P =0.019). CONCLUSIONS: Our work presents the first description of ART treatment discontinuation and its causes in the real-world setting, as well as patient-reported side effects. Most patients with mCRPC discontinued treatment due to the progression of disease and a minority of patients discontinued secondary to treatment toxicity. Initial multivariable analysis suggests that patient-reported weakness, falls, and rash were associated with a higher likelihood of treatment discontinuation due to toxicity. Early monitoring of this population can prolong the duration of treatment and prevent unnecessary treatment burden.
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Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Estudios Retrospectivos , Anciano , Factores de Riesgo , Persona de Mediana Edad , Privación de Tratamiento/estadística & datos numéricos , Receptores Androgénicos , Anciano de 80 o más Años , Antagonistas de Receptores Androgénicos/uso terapéutico , Antagonistas de Receptores Androgénicos/efectos adversos , Terapia Molecular Dirigida/efectos adversosRESUMEN
BACKGROUND: In the phase III SPARC trial, satraplatin, an oral platinum analogue, demonstrated anticancer activity in men with metastatic castration-resistant prostate cancer (mCRPC). Repeat biopsies are uncommon in mCRPC, limiting the feasibility of tissue-based biomarkers. This phase II study sought to evaluate the feasibility and utility of blood-based biomarkers to identify platinum-sensitive mCRPC. METHODS: Patients with mCRPC who had progressed on docetaxel were enrolled at a single center from 2011 to 2013. Subjects received satraplatin 80 mg/m2 by mouth daily on days 1-5 and prednisone 5 mg PO twice daily, on a 35-day cycle. Serial peripheral blood samples were collected for biomarker assessment. RESULTS: Thirteen docetaxel-refractory mCRPC patients were enrolled, with a median age of 69 years (range 54-77 years) and median PSA of 71.7 ng/mL (range 0.04-3057). Four of 13 patients (31%) responded to satraplatin (defined as a PSA decline of ≥30%). Responders demonstrated improved time to disease progression (206 vs. 35 days, HR 0.26, 95% CI, 0.02-0.24, P = .003). A 6-gene peripheral blood RNA signature and serum tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were assessed as biomarkers, but neither was significantly associated with response to satraplatin. CONCLUSION: In this small series, one-third of mCRPC patients responded to platinum-based chemotherapy. Peripheral blood biomarker measurement is feasible in mCRPC, though the biomarkers we investigated were not associated with platinum response. Other biomarkers, such as DNA damage repair mutations, should be evaluated.
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Persona de Mediana Edad , Anciano , Docetaxel , Neoplasias de la Próstata Resistentes a la Castración/patología , Antígeno Prostático Específico , Inhibidor Tisular de Metaloproteinasa-1/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: Stress-induced adrenergic signaling can suppress the immune system. In animal models, pharmacological beta-blockade stimulates CD8 + T-cell activity and improves clinical activity of immune checkpoint blockade (ICB) in inhibiting tumor growth. Herein, we investigated the effect of BB on clinical outcomes of patients receiving ICB in advanced solid tumors. METHODS: We retrospectively evaluated patients with solid tumors treated with ICB at our institution from January 1, 2011 to April 28, 2017. The primary clinical outcome was disease control. Secondary clinical outcomes were overall survival (OS), and duration of therapy (DoT). The primary predictor was use of BB. Association between disease control status and BB use was assessed in univariable and multivariable logistic regression. OS was calculated using hazard ratios of BB-recipient patients vs. BB non-recipient patients via Cox proportional hazards regression models. All tests were two-sided at a significance level of 0.05. RESULTS: Of 339 identified patients receiving ICB, 109 (32%) also received BB. In covariate-adjusted analysis, odds of disease control were significantly higher among BB recipients compared to BB-non-recipients (2.79; [1.54-5.03]; P = 0.001). While we did not observe significant association of OS with the use of BB overall, significant association with better OS was observed for the urothelial carcinoma cohort (HR: 0.24; [0.09, 0.62]; P = 0.0031). CONCLUSIONS: Concurrent use of BB may enhance the clinical activity of ICB and influence overall survival, particularly in patients with urothelial carcinoma. Our findings warrant further investigation to understand the interaction of beta adrenergic signaling and antitumor immune activity and explore a combination strategy.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Retrospectivos , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Upfront docetaxel or novel hormonal agents (NHA) such as abiraterone and enzalutamide have become the standard of care for metastatic hormone sensitive prostate cancer (mHSPC). We evaluated real-world management of patients treated with these agents at a single center. PATIENTS AND METHODS: Patients with de novo mHSPC treated with upfront docetaxel or an NHA between January 2014 and April 2019 at Mount Sinai Health System were included. We evaluated time to next treatment (TTNT), PSA progression free survival (PFS) and overall survival (OS) after initial treatment with these drugs. Kaplan Meier method and multivariable Cox proportional hazards models were used for analysis. We additionally assessed the prognostic value of post-treatment PSA. RESULTS: We identified 94 de novo mHSPC patients; 52 and 42 treated with upfront docetaxel and NHAs, respectively. NHAs were associated with a median TTNT of 20.7 months compared to 10.1 months with docetaxel (log-rank p = 0.023). We also observed median PSA PFS of 19 months for NHAs and 13.2 months for docetaxel (p = 0.069). However, OS between the two treatment groups was unchanged. Among docetaxel treated patients, TTNT was shorter among those with high metastasis burden (9.63 vs 25.5 months, p = 0.026) which was not observed among NHA treated patients (25.1 vs 20.7 months, p = 0.79). Regardless of treatment, lower post-treatment PSA levels were associated with improved TTNT (58.95 vs. 11.57 vs. 9.4 months for PSA ≤0.2, 0.2-0.4, >0.4ng/ml, respectively; p<0.001). CONCLUSION: Real world data demonstrated a shorter duration of treatment with docetaxel than NHAs, reflecting the time-limited nature of docetaxel regimens compared to the treat-till-progression approach of NHAs. While TTNT was generally longer for NHAs than docetaxel, some docetaxel-treated patients achieved significant periods of time off treatment. In addition, the depth of PSA response following combination treatment may hold prognostic value for mHSPC outcomes.
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Antineoplásicos , Neoplasias de la Próstata Resistentes a la Castración , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Docetaxel/uso terapéutico , Hormonas/uso terapéutico , Humanos , Masculino , Antígeno Prostático Específico/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVES: Response to immune checkpoint inhibitor (ICI) remains limited to a subset of patients and predictive biomarkers of response remains an unmet need, limiting our ability to provide precision medicine. Using real-world data, we aimed to identify potential clinical prognosticators of ICI response in solid tumor patients. METHODS: We conducted a retrospective analysis of all solid tumor patients treated with ICIs at the Mount Sinai Hospital between January 2011 and April 2017. Predictors assessed included demographics, performance status, co-morbidities, family history of cancer, smoking status, cancer type, metastatic pattern, and type of ICI. Outcomes evaluated include progression free survival (PFS), overall survival (OS), overall response rate (ORR) and disease control rate (DCR). Univariable and multivariable Cox proportional hazard models were constructed to test the association of predictors with outcomes. RESULTS: We identified 297 ICI-treated patients with diagnosis of non-small cell lung cancer (N = 81, 27.3%), melanoma (N = 73, 24.6%), hepatocellular carcinoma (N = 51, 17.2%), urothelial carcinoma (N = 51, 17.2%), head and neck squamous cell carcinoma (N = 23, 7.7%), and renal cell carcinoma (N = 18, 6.1%). In multivariable analysis, good performance status of ECOG ≤ 2 (PFS, ORR, DCR and OS) and family history of cancer (ORR and DCR) associated with improved ICI response. Bone metastasis was associated with worse outcomes (PFS, ORR, and DCR). CONCLUSIONS: Mechanisms underlying the clinical predictors of response observed in this real-world analysis, such as genetic variants and bone metastasis-tumor microenvironment, warrant further exploration in larger studies incorporating translational endpoints. Consistently positive clinical correlates may help inform patient stratification when considering ICI therapy.
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PURPOSE: Data quality and standardization remain a challenge when analyzing real-world clinical data. We built a clinical research database, using machine learning and natural learning processing, and investigated factors influencing testosterone recovery (T-recovery) in patients with localized prostate cancer (LPC) after initial androgen deprivation therapy (ADT). METHODS: Medication and treatment-associated dates missing in structured tables were extracted from patient notes using ConceptMapper, an automated data extraction tool, standardized and curated in Sema4 clinical research database. ADT usage duration was evaluated, and T-recovery in patients with LPC was analyzed by the Kaplan-Meier method and multivariable Cox proportional hazards models. We assessed the prognostic value of post-ADT T-recovery with prostate-specific antigen progression-free survival and failure-free survival. RESULTS: In total, 4,125 of 30,832 (13.4%) patients with prostate cancer had medication exclusively from notes with high precision and recall, F1 score ≥ 0.95. Association of dates with medication usage had a F1 score of 0.76. ADT duration estimation had higher accuracy combining information from notes to tables from electronic medical record (70% v 45%). Baseline testosterone was the strongest predictor of T-recovery in these patients. Patients with a baseline testosterone ≥ 300 ng/dL recovered in 9.79 versus 38 months for patients with baseline testosterone < 300 ng/dL (P < .0001). Shorter prostate-specific antigen progression-free interval was observed for patients with T-recovery (≥ 300 ng/dL) at 6 months after ADT cessation compared with patients without T-recovery (< 300 ng/dL; 13.7 v 25.1 months; P = .055). CONCLUSION: We augmented structured electronic medical record data with data extracted from notes and improved the accuracy of medication information for patients. ADT exposure and T-recovery in patients with LPC produced results consistent with the literature and clinical experience and illustrates the power of applying machine learning methods to enhance the quality of real-world evidence in answering clinically relevant questions.
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Antígeno Prostático Específico , Neoplasias de la Próstata , Antagonistas de Andrógenos/efectos adversos , Antagonistas de Andrógenos/uso terapéutico , Registros Electrónicos de Salud , Humanos , Masculino , Antígeno Prostático Específico/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Testosterona/uso terapéuticoRESUMEN
BACKGROUND: TMPRSS2, a cell surface protease regulated by androgens and commonly upregulated in prostate cancer (PCa), is a necessary component for SARS-CoV-2 viral entry into respiratory epithelial cells. Previous reports suggested a lower risk of SARS-CoV-2 among PCa patients on androgen deprivation therapy (ADT). However, the impact of ADT on severe COVID-19 illness is poorly understood. METHODS: We performed a multicenter study across 7 US medical centers and evaluated patients with PCa and SARS-CoV-2 detected by polymerase-chain-reaction between March 1, 2020, and May 31, 2020. PCa patients were considered on ADT if they had received appropriate ADT treatment within 6 months of COVID-19 diagnosis. We used multivariable logistic and Cox proportional-hazard regression models for analysis. All statistical tests were 2-sided. RESULTS: We identified 465 PCa patients (median age = 71 years) with a median follow-up of 60 days. Age, body mass index, cardiovascular comorbidity, and PCa clinical disease state adjusted overall survival (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 0.68 to 1.98, P = .59), hospitalization status (HR = 0.96, 95% CI = 0.52 to 1.77, P = .90), supplemental oxygenation (HR 1.14, 95% CI = 0.66 to 1.99, P = .64), and use of mechanical ventilation (HR = 0.81, 95% CI = 0.25 to 2.66, P = .73) were similar between ADT and non-ADT cohorts. Similarly, the addition of androgen receptor-directed therapy within 30 days of COVID-19 diagnosis to ADT vs ADT alone did not statistically significantly affect overall survival (androgen receptor-directed therapy: HR = 1.27, 95% CI = 0.69 to 2.32, P = .44). CONCLUSIONS: In this retrospective cohort of PCa patients, the use of ADT was not demonstrated to influence severe COVID-19 outcomes, as defined by hospitalization, supplemental oxygen use, or death. Age 70 years and older was statistically significantly associated with a higher risk of developing severe COVID-19 disease.
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Tratamiento Farmacológico de COVID-19 , Neoplasias de la Próstata , Anciano , Antagonistas de Andrógenos/uso terapéutico , Andrógenos/uso terapéutico , Prueba de COVID-19 , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/uso terapéutico , Estudios Retrospectivos , SARS-CoV-2RESUMEN
Prostate cancer is the most common cancer affecting men in the United States. A significant proportion of men have nonmetastatic castration-resistant prostate cancer (CRPC), in which biochemical progression is evidenced by rising levels of prostate-specific antigen without radiographic progression in the setting of castrate levels of testosterone. Historically, the preferred treatment for these patients has been observation and continued treatment with androgen deprivation therapy (ADT). The standard of care has recently evolved to include the addition of androgen receptor (AR) inhibitors to ADT. The US Food and Drug Administration has approved 3 next-generation AR inhibitors for nonmetastatic CRPC: apalutamide, enzalutamide, and darolutamide. These agents were approved based on data from phase 3 randomized trials. There is now a significant amount of data from these trials. All 3 agents improve metastasis-free survival and overall survival. Selection of treatment can be guided by factors such as the patient's overall health and frailty, potential drug-drug interactions, and the safety profile associated with each agent.
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Neoplasias de la Próstata Resistentes a la Castración , Antagonistas de Andrógenos/uso terapéutico , Antagonistas de Receptores Androgénicos/efectos adversos , Humanos , Masculino , Nitrilos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genéticaAsunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Antagonistas de Andrógenos/uso terapéutico , Antagonistas de Receptores Androgénicos/uso terapéutico , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores AndrogénicosAsunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Antagonistas de Andrógenos/uso terapéutico , Antagonistas de Receptores Androgénicos/uso terapéutico , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genéticaAsunto(s)
ADN Tumoral Circulante , Células Neoplásicas Circulantes , Neoplasias de la Próstata , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Humanos , Masculino , Células Neoplásicas Circulantes/patología , Antígeno Prostático Específico , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence. OBJECTIVE: To present the voting results from APCCC 2021. DESIGN, SETTING, AND PARTICIPANTS: The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process. RESULTS AND LIMITATIONS: The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material. CONCLUSIONS: These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making.
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Neoplasias de la Próstata , Consenso , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapiaRESUMEN
BACKGROUND: Treatment options have been historically limited for cisplatin-ineligible patients with advanced urothelial carcinoma (UC). Given the need for alternatives to platinum-based chemotherapy, including non-chemotherapy regimens for patients with both impaired renal function and borderline functional status, in 2010 (prior to the immune checkpoint blockade era in metastatic UC), we initiated a phase II trial to test the activity of everolimus or everolimus plus paclitaxel in the cisplatin-ineligible setting. METHODS: This was an open-label phase II trial conducted within the US-based Hoosier Cancer Research Network (ClinicalTrials.gov number: NCT01215136). Patients who were cisplatin-ineligible with previously untreated advanced UC were enrolled. Patients with both impaired renal function and poor performance status were enrolled into cohort 1; patients with either were enrolled into cohort 2. Patients received everolimus 10 mg daily alone (cohort 1) or with paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle (cohort 2). The primary outcome was clinical benefit at 4 months. Secondary outcomes were adverse events, progression-free survival (PFS), and 1-year overall survival (OS). Exploratory endpoints included genomic correlates of outcomes. The trial was not designed for comparison between cohorts. RESULTS: A total of 36 patients were enrolled from 2010 to 2018 (cohort 1, N = 7; cohort 2, N = 29); the trial was terminated due to slow accrual. Clinical benefit at 4 months was attained by 0 (0%, 95% confidence interval [CI] 0-41.0%) patients in cohort 1 and 11 patients (37.9%, 95% CI 20.7-57.7%) in cohort 2. Median PFS was 2.33 (95% CI 1.81-Inf) months in cohort 1 and 5.85 (95% CI 2.99-8.61) months in cohort 2. Treatment was discontinued due to adverse events for 2 patients (29%) in cohort 1 and 11 patients (38%) in cohort 2. Molecular alterations in microtubule associated genes may be associated with treatment benefit but this requires further testing. CONCLUSION: Everolimus plus paclitaxel demonstrates clinical activity in cisplatin-ineligible patients with metastatic UC, although the specific contribution of everolimus cannot be delineated. Patients with both impaired renal function and borderline functional status may be difficult to enroll to prospective trials. (ClinicalTrials.gov Identifier NCT01215136).
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Transicionales/tratamiento farmacológico , Cisplatino , Everolimus/uso terapéutico , Humanos , Paclitaxel/uso terapéutico , Estudios Prospectivos , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Patients with advanced prostate cancer (APC) may be at greater risk for severe illness, hospitalisation, or death from coronavirus disease 2019 (COVID-19) due to male gender, older age, potential immunosuppressive treatments, or comorbidities. Thus, the optimal management of APC patients during the COVID-19 pandemic is complex. In October 2021, during the Advanced Prostate Cancer Consensus Conference (APCCC) 2021, the 73 voting members of the panel members discussed and voted on 13 questions on this topic that could help clinicians make treatment choices during the pandemic. There was a consensus for full COVID-19 vaccination and booster injection in APC patients. Furthermore, the voting results indicate that the expert's treatment recommendations are influenced by the vaccination status: the COVID-19 pandemic altered management of APC patients for 70% of the panellists before the vaccination was available but only for 25% of panellists for fully vaccinated patients. Most experts (71%) were less likely to use docetaxel and abiraterone in unvaccinated patients with metastatic hormone-sensitive prostate cancer. For fully vaccinated patients with high-risk localised prostate cancer, there was a consensus (77%) to follow the usual treatment schedule, whereas in unvaccinated patients, 55% of the panel members voted for deferring radiation therapy. Finally, there was a strong consensus for the use of telemedicine for monitoring APC patients. PATIENT SUMMARY: In the Advanced Prostate Cancer Consensus Conference 2021, the panellists reached a consensus regarding the recommendation of the COVID-19 vaccine in prostate cancer patients and use of telemedicine for monitoring these patients.
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COVID-19 , Neoplasias de la Próstata , Antagonistas de Andrógenos/uso terapéutico , Vacunas contra la COVID-19 , Humanos , Masculino , Pandemias/prevención & control , Neoplasias de la Próstata/patologíaRESUMEN
INTRODUCTION: Historically, high rates of actionable driver mutations have been reported in never-smokers with lung adenocarcinoma (ADC). In the era of modern, comprehensive cancer mutation sequencing, this relationship necessitates a more detailed analysis. METHODS: All Mount Sinai patients between January 1, 2015, and June 1, 2020, with a diagnosis of ADC of any stage with known smoking status who received genomic testing were included. Most patients were analyzed using the Sema4 hotspot panel or the Oncomine Comprehensive Assay version 3 next-generation sequencing (NGS) panel conducted at Sema4. Patients were considered fully genotyped if they were comprehensively analyzed for alterations in EGFR, KRAS, MET, ALK, RET, ROS1, BRAF, NTRK1-3, and ERBB2, otherwise they were considered partially genotyped. RESULTS: Two hundred and thirty-six never-smokers and 671 smokers met the above criteria. Of the never-smokers, 201 (85%) had a driver mutation with 167 (71%) considered actionable (ie, those with US Food and Drug Administration-approved agents). Among smokers, 439 (65%) had an identified driver mutation with 258 (38%) actionable (P < .0001). When comprehensively sequenced, 95% (70/74) of never-smokers had a driver mutation with 78% (58/74) actionable; whereas, for smokers, 75% (135/180) had a driver with only 47% (74/180) actionable (P < .0001). Within mutations groups, EGFR G719X and KRAS G12Cs were more common to smokers. For stage IV patients harboring EGFR-mutant tumors treated with EGFR-directed therapies, never-smokers had significantly improved OS compared to smokers (hazard ratio = 2.71; P = .025). In multivariable analysis, Asian ancestry and female sex remained significant predictors of (1) OS in stage IV patients and (2) likelihood of harboring a receptor of fusion-based driver. CONCLUSION: Comprehensive NGS revealed driver alterations in 95% of never-smokers, with the majority having an associated therapy available. All efforts should be exhausted to identify or rule out the presence of an actionable driver mutation in all metastatic lung ADC.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , FumadoresRESUMEN
Apha-1-adrenergic receptor antagonists (α1-blockers) can suppress pro-inflammatory cytokines, thereby potentially improving outcomes among patients with COVID-19. Accordingly, we evaluated the association between α1-blocker exposure (before or during hospitalization) and COVID-19 in-hospital mortality. We identified 2,627 men aged 45 or older who were admitted to Mount Sinai hospitals with COVID-19 between February 24 and May 31, 2020, in New York. Men exposed to α1-blockers (N = 436) were older (median age 73 vs. 64 years, P < 0.001) and more likely to have comorbidities than unexposed men (N = 2,191). Overall, 777 (29.6%) patients died in hospital, and 1,850 (70.4%) were discharged. Notably, we found that α1-blocker exposure was independently associated with improved in-hospital mortality in a multivariable logistic analysis (OR 0.699; 95% CI, 0.498-0.982; P = 0.039) after adjusting for patient demographics, comorbidities, and baseline vitals and labs. The protective effect of α1-blockers was stronger among patients with documented inpatient exposure to α1-blockers (OR 0.624; 95% CI 0.431-0.903; P = 0.012). Finally, age-stratified analyses suggested variable benefit from inpatient α1-blocker across age groups: Age 45-65 OR 0.483, 95% CI 0.216-1.081 (P = 0.077); Age 55-75 OR 0.535, 95% CI 0.323-0.885 (P = 0.015); Age 65-89 OR 0.727, 95% CI 0.484-1.092 (P = 0.124). Taken together, clinical trials to assess the therapeutic value of α1-blockers for COVID-19 complications are warranted.