RESUMEN
The use of immune checkpoint inhibitors in solid organ malignancies has become widespread in the last decade. Accumulating evidence shows broad survival benefit as compared to traditional chemotherapies. At the same time, a need has emerged to stratify these drugs in various patient populations and histologies. Consequently, various immune biomarkers have been proposed to help in selecting patients for these therapies. Here, we review the evidence pertaining to biomarkers including programmed death-ligand 1, defective mismatch repair, tumor mutational burden, tumor-infiltrating lymphocytes, gene expression profiles, circulating blood cells, circulating DNA and the gut microbiome. The value of PD-L1 testing in certain malignancies, such as lung and urothelial cancer is highlighted as well as emerging data from trials such as GARNET and CheckMate142.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Biomarcadores de Tumor/genéticaRESUMEN
PURPOSE: Germline testing (GT) for prostate cancer (PCA) is now central to treatment and hereditary cancer assessment. With rising demand for and shortage of genetic counseling (GC), tools to deliver pretest informed consent across practice settings are needed to improve access to GT and precision care. Here, we report on Evaluation and Management for Prostate Oncology, Wellness, and Risk (EMPOWER), a patient-choice study for pretest video-based genetic education (VBGE) versus GC to inform urgent practice needs. PATIENTS AND METHODS: Men with PCA or at risk for PCA (family history of PCA) were eligible and could choose pretest VBGE or GC. Outcomes included decisional conflict for GT, change in genetics knowledge, satisfaction, and intention to share results with family and/or providers. Descriptive statistics summarized results with counts and percentages for categorical variables and mean ± standard deviation for continuous variables. Data were compared with Fisher's exact, chi-squared, or Wilcoxon two-sample tests. Mean change in genetics knowledge was compared with t tests. The significance level was set a priori at .05. RESULTS: Data on the first 127 participants were analyzed. Characteristics were White (85.8%), bachelor's degree (66.9%), and PCA diagnosis (90.6%). The majority chose VBGE (71%) versus GC (29%; P < .001). No differences were observed in decisional conflict for GT or satisfaction. Cancer genetics knowledge improved in both groups without significant difference (+0.9 VBGE, +1.8 GC, P = .056). Men who chose VBGE had higher intention to share GT results (96.4% VBGE v 86.4% GC, P = .02). Both groups had high rates of GT uptake (VBGE 94.4%, GC 92%). CONCLUSION: A substantial proportion of men opted for pretest VBGE, with comparable patient-reported outcomes and uptake of GT. The results support the use of pretest video to address the critical GC shortage in the precision era.
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Conducta de Elección , Educación del Paciente como Asunto/normas , Neoplasias de la Próstata/diagnóstico , Anciano , Distribución de Chi-Cuadrado , Asesoramiento Genético/métodos , Asesoramiento Genético/psicología , Asesoramiento Genético/normas , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Educación del Paciente como Asunto/métodos , Neoplasias de la Próstata/genética , Encuestas y CuestionariosRESUMEN
PURPOSE: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.
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Pruebas Genéticas/métodos , Mutación de Línea Germinal/genética , Neoplasias de la Próstata/genética , Historia del Siglo XX , Humanos , Masculino , Neoplasias de la Próstata/patologíaRESUMEN
OBJECTIVES: There is no study published regarding the benefit of radiation therapy (RT) in combination with immune checkpoint inhibitors (ICIs) for the treatment of metastatic renal cell cancer (mRCC). This report is part of an exploratory study aiming to determine the immunomodulatory activity of RT alone or in combination with pembrolizumab in solid tumors. MATERIALS AND METHODS: mRCC patients were treated with a combination of RT (8 Gy×1 or 4 Gy×5) followed by pembrolizumab with or without lead-in dose of pembrolizumab. Treatment response was measured based on the modified Response Evaluation Criteria in Solid Tumors criteria. Adverse events were monitored and graded. Pre-RT and post-RT tumor biopsies were obtained to evaluate programmed death-ligand 1 expression. Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. RESULTS: Twelve mRCC patients who progressed on prior antiangiogenic therapy were enrolled. Half had 2 lines of prior therapy. Two patients (16.7%) had partial responses and were on study for 12.4 and 14.5 months. Three patients had stable disease for a period ranging from 4.2 to 10.4 months, whereas 7 patients had progressive disease. Median progression-free survival was 8.6 months and median overall survival was 32.3 months. Three patients had grade ≥3 events (hyperglycemia, thrombocytopenia, transaminitis). Biopsied tissue programmed death-ligand 1 expression and tumor-infiltrating lymphocytes were numerically higher in responders comparing to nonresponders (Modified Proportion Score 45% vs. 30.45%; tumor-infiltrating lymphocytes odds ratio 4.92). CONCLUSION: Combining RT with pembrolizumab in pretreated mRCC is well-tolerated and appears to have comparable efficacy with single-agent nivolumab.
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Neoplasias de las Glándulas Suprarrenales/terapia , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/terapia , Quimioradioterapia/métodos , Neoplasias Renales/patología , Neoplasias Hepáticas/terapia , Neoplasias de las Glándulas Suprarrenales/secundario , Adulto , Anciano , Anciano de 80 o más Años , Alanina Transaminasa , Inhibidores de la Angiogénesis/uso terapéutico , Aspartato Aminotransferasas , Carcinoma de Células Renales/secundario , Femenino , Humanos , Hiperglucemia/inducido químicamente , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Proyectos Piloto , Supervivencia sin Progresión , Neoplasias de los Tejidos Blandos/secundario , Neoplasias de los Tejidos Blandos/terapia , Trombocitopenia/inducido químicamente , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
PURPOSE/OBJECTIVES: Radium-223 is a first-in-class radiopharmaceutical recently approved for the treatment of castration-resistant prostate cancer in patients with symptomatic bone metastases. Initial studies investigating Radium-223 primarily used nonsteroidal first-generation antiandrogens. Since that time, newer antiandrogen therapies have demonstrated improved survival in patients with castration-resistant prostate cancer. It has been suggested that the rational combination of these newly approved agents with Radium-223 may lead to improved response rates and clinical outcomes. Currently, there is lack of information regarding the safety of concurrent administration of these agents with radiopharmaceuticals. Here, we report on hematologic toxicity findings from our institution in patients receiving concurrent Radium-223 and next-generation antiandrogen therapies with either enzalutamide or abiraterone. MATERIALS/METHODS: In a retrospective study, we analyzed patients who received Radium-223 as part of an early-access trial, and following FDA approval in May 2013, patients receiving Radium-223 as part of standard care. Radium-223 was given at standard dosing of 50 kBq/kg each month for 6 total cycles. Complete blood counts were performed before treatment monthly and following each injection. Blood counts from patients receiving Radium alone and concurrently with next-generation antiandrogens were compared. To date, 25 total patients were analyzed, with a median of 5 monthly doses received per patient. Fourteen patients received concurrent therapy during monthly Radium-223 with either enzalutamide (n=8) or abiraterone (n=6). RESULTS: Six patients expired due to disease progression. Two patients discontinued treatment due to grade 3 myelosuppression. For patients receiving either Radium alone and with concurrent next-generation antiandrogen therapy, there did not appear to be any statistically significant differences between initial and nadir blood counts. Mean change from initial neutrophil count to nadir was 1.9×10/L in patients receiving Radium alone, versus 2.3×10/L in patients receiving concurrent therapy (P=0.77). Mean change from initial hemoglobin value to nadir was 1.5 g/L in patients receiving Radium alone, versus 1.8 g/L in patients receiving concurrent therapy (P=0.31). Mean change from initial platelet count to nadir was 52.3×10 cells/L in patients receiving Radium alone versus 70.6×10 cells/L in patients receiving concurrent therapy (P=0.39). Individual blood counts for each measured laboratory are included in the supplemental data. PSA was stable or decreased in 22% of patients receiving Radium alone versus 35% of patients receiving combination treatment (P=0.24). CONCLUSIONS: Concurrent administration of Radium-223 and next-generation antiandrogen therapies appears to be well tolerated with similar toxicities to standard administration of Radium-223 alone. This particular cohort of patients represents a high-risk, heavily pretreated group of patients with advanced metastatic disease and significant marrow burden. Despite these risk factors, hematologic toxicity was modest and was in the range expected for this risk group based on previous trials. To date, this is the first study investigating the toxicity of combination treatment. Further studies investigating the safety and efficacy of combination treatments are warranted.
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Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Radio (Elemento)/efectos adversos , Anciano , Antagonistas de Andrógenos/administración & dosificación , Androstenos/administración & dosificación , Androstenos/uso terapéutico , Antineoplásicos/uso terapéutico , Benzamidas , Células Sanguíneas/efectos de los fármacos , Terapia Combinada , Humanos , Masculino , Nitrilos , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/sangre , Radio (Elemento)/administración & dosificación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Within the last decade, fully disposable centrifuge technologies, fluidized-bed centrifuges (FBC), have been introduced to the biologics industry. The FBC has found a niche in cell therapy where it is used to collect, concentrate, and then wash mammalian cell product while continuously discarding centrate. The goal of this research was to determine optimum FBC conditions for recovery of live cells, and to develop a mathematical model that can assist with process scaleup. Cell losses can occur during bed formation via flow channels within the bed. Experimental results with the kSep400 centrifuge indicate that, for a given volume processed: the bed height (a bed compactness indicator) is affected by RPM and flowrate, and dead cells are selectively removed during operation. To explain these results, two modeling approaches were used: (i) equating the centrifugal and inertial forces on the cells (i.e., a force balance model or FBM) and (ii) a two-phase computational fluid dynamics (CFD) model to predict liquid flow patterns and cell retention in the bowl. Both models predicted bed height vs. time reasonably well, though the CFD model proved more accurate. The flow patterns predicted by CFD indicate a Coriolis-driven flow that enhances uniformity of cells in the bed and may lead to cell losses in the outflow over time. The CFD-predicted loss of viable cells and selective removal of the dead cells generally agreed with experimental trends, but did over-predict dead cell loss by up to 3-fold for some of the conditions. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1520-1530, 2016.
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Reactores Biológicos , Separación Celular , Centrifugación , Línea Celular , HumanosRESUMEN
PURPOSE: To provide a descriptive overview of international medical school graduates (IMGs), U.S. and non-U.S. citizens, who obtained their medical degrees outside of the United States and Canada, with a focus on where U.S. citizens received their medical education and how this choice has changed over time. METHOD: The study group included all IMGs (n = 143,926) certified by the Educational Commission for Foreign Medical Graduates (ECFMG) from 1983-2002. Descriptive statistics were calculated, including historical certification rates for non-U.S. citizen and U.S. citizen IMGs. For IMGs who were U.S. citizens (n = 18,762), the data were summarized by medical school and country of medical school. RESULTS: U.S. citizens who attended medical schools abroad were more likely to attend schools in Central America and the Caribbean than in any other geographic region. There was a steady decrease in the number of U.S. citizens graduating from European medical schools. Conversely, the number graduating from medical schools in India and Israel rose. Over the period studied, the regions of Africa, Oceania, and South America graduated relatively few U.S. citizens. CONCLUSIONS: From 1983-2002, U.S. citizens graduated from medical schools in Central America and the Caribbean more than any other geographic region. Studying the characteristics of medical schools in this region and their similarities to U.S. medical schools, such as a four-year curriculum, may explain why U.S. citizens are attracted to this region in large numbers. Additional studies focusing on the characteristics of medical schools that train IMGs, the performance of the graduates, and their posttraining practice patterns are warranted.