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BACKGROUND: Transcatheter pulmonary valve implantation is usually performed from a femoral venous - transfemoral - approach, but this may not be the optimal vascular access option in some patients. This study aimed to determine which group of patients might benefit from an internal jugular - transjugular - approach for transcatheter pulmonary valve implantation. METHODS: This multicentre retrospective study included all patients who underwent attempted transcatheter pulmonary valve placement in the right ventricular outflow tract between April 2010 and June 2012 at two large congenital heart centres. Patients were divided into two groups based on venous access site - transfemoral or transjugular. Patient characteristics, procedural outcomes, and complications were compared between groups. RESULTS: Of 81 patients meeting the inclusion criteria (median age 16.4 years), the transjugular approach was used in 14 patients (17%). The transjugular group was younger (median age 11.9 versus 17.3 years), had lower body surface area (mean 1.33 versus 1.61 m2), more often had moderate or greater tricuspid regurgitation (29% versus 7%), and had a higher ratio of right ventricle-to-systemic systolic pressure (mean 82.4 versus 64.7). Patients requiring a transjugular approach after an unsuccessful transfemoral approach had longer fluoroscopic times and procedure duration. CONCLUSIONS: The transjugular approach for transcatheter pulmonary valve implantation is used infrequently but is more often used in younger and smaller patients. Technical limitations from a transfemoral approach may be anticipated if there is moderate or greater tricuspid regurgitation or higher right ventricular pressures. In these patients, a transjugular approach should be considered early.
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Cardiopatias Congênitas/complicações , Implante de Prótese de Valva Cardíaca/métodos , Próteses Valvulares Cardíacas/efeitos adversos , Veias Jugulares/cirurgia , Valva Pulmonar/anormalidades , Valva Pulmonar/cirurgia , Adolescente , Criança , Ecocardiografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento , Insuficiência da Valva Tricúspide/epidemiologia , Adulto JovemRESUMO
OBJECTIVES: To examine acute and mid-term patient outcomes following the hybrid approach to pulmonary atresia with intact ventricular septum (PA-IVS) compared with the standard surgical approach. BACKGROUND: A subset of PA-IVS patients with the prospect of biventricular circulation typically undergo surgical or transcatheter right ventricular (RV) outflow tract opening. A recently described hybrid procedure, involving perventricular pulmonary valve perforation, was shown to be safe and effective in single-center series. METHODS: A single-center retrospective review of all patient with PA-IVS who underwent either surgical or hybrid RV decompression between January 2002 and December 2011 was completed and acute and mid-term patient outcomes were compared between the surgical and hybrid cohorts. Additionally, a systematic literature review was completed to compare a transcatheter cohort to the hybrid cohort. RESULTS: Seven patients with PA-IVS underwent a hybrid procedure; the procedure was technically successful in all attempts, and none required CPB. No patients required surgical re-intervention prior to hospital discharge, and none died during the study period. Surgical RV decompression was performed in 17 patients with a median CPB time of 80 min. Patient outcomes were nearly identical between cohorts. By systematic review, the transcatheter approach has a procedural success of 75-95% but up to 75% of patients require operation in the neonatal period. CONCLUSIONS: The hybrid approach is a safe and feasible alternative to the standard surgical and transcatheter approaches to PA-IVS. Acute and mid-term patient outcomes are comparable with those treated with a standard surgical approach and neonatal CPB is completely avoided.
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Cateterismo Cardíaco , Procedimentos Cirúrgicos Cardíacos , Descompressão Cirúrgica , Cardiopatias Congênitas/terapia , Atresia Pulmonar/terapia , Cateterismo Cardíaco/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ponte Cardiopulmonar , Descompressão Cirúrgica/efeitos adversos , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/fisiopatologia , Cardiopatias Congênitas/cirurgia , Humanos , Recém-Nascido , Masculino , Michigan , Atresia Pulmonar/diagnóstico , Atresia Pulmonar/fisiopatologia , Atresia Pulmonar/cirurgia , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Despite progress, 2-year pancreatic cancer survival remains dismal. We evaluated a biomarker-driven, combination/N-of-one strategy in 18 patients (advanced/metastatic pancreatic cancer) (from Molecular Tumor Board). Targeted agents administered/patient = 2.5 (median) (range, 1-4); first-line therapy (N = 5); second line, (N = 13). Comparing patients (high versus low degrees of matching) (matching score ≥50% versus <50%; reflecting number of alterations matched to targeted agents divided by number of pathogenic alterations), survival was significantly longer (hazard ratio [HR] 0.24 (95% confidence interval [CI], 0.078-0.76, P = 0.016); clinical benefit rates (CBR) (stable disease ≥6 months/partial/complete response) trended higher (45.5 vs 0.0%, P = 0.10); progression-free survival, HR, 95% CI, 0.36 (0.12-1.10) (p = 0.075). First versus ≥2nd-line therapy had higher CBRs (80.0 vs 7.7%, P = 0.008). No grade 3-4 toxicities occurred. The longest responder achieved partial remission (17.5 months) by co-targeting MEK and CDK4/6 alterations (chemotherapy-free). Therefore, genomically matched targeted agent combinations were active in these advanced pancreatic cancers. Larger prospective trials are warranted.
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Germline testing is becoming increasingly relevant in prostate cancer (PCa) screening, prognosis, and management. A subset of patients with PCa harbor pathogenic/likely pathogenic variants (P/LPVs) in genes mediating DNA-repair processes, and these P/LPVs have implications for cancer screening, treatment, and cascade testing. As a result, it is recommended that all men with high-risk localized and metastatic PCa undergo routine germline testing. As more PCa patients undergo germline testing, it is important that clinicians and genetics experts recognize current disparities in germline testing rates among racial/ethnic minorities in the United States. The reasons for these disparities are multiple and require similarly manifold consideration to close the germline testing gap and reduce inequities in PCa screening, management, and treatment.
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Neoplasias da Próstata , Detecção Precoce de Câncer , Minorias Étnicas e Raciais , Células Germinativas/patologia , Mutação em Linhagem Germinativa , Humanos , Masculino , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: The introduction of tyrosine kinase inhibitor (TKI) therapy has dramatically improved outcomes for patients with chronic myeloid leukemia (CML); however, the prognosis for those who do not meet treatment milestones remains guarded. Here, we report our experience of patients with CML treated at a single center who did not achieve a complete cytogenetic response (CCyR) at 24 months. METHODS: We retrospectively evaluated 305 patients who were diagnosed with CML at the University of Michigan between 2001 and 2014 and were treated with TKIs. We assessed rates of CCyR at 24 months correlated to clinical outcomes. RESULTS: The majority of patients (79%) achieved CCyR at 24 months and were classified as responders. At a median follow-up of 8.1 years from TKI initiation, overall survival among responders was significantly greater than nonresponders (93% vs. 85%, P < .001). Progression to blast phase was more common in nonresponders (1.9% vs. 10.4%, P = .004). However, 34% of nonresponders (at 24 months) went on to achieve CCyR with continued TKI therapy. CONCLUSION: Here, we re-demonstrate the importance of early CCyR in predicting survival and prevention of progression to blast phase. In addition, late CCyR appears to have prognostic implications, and continued TKI therapy with the goal of achieving a later CCyR may be a reasonable strategy in patients with limited alternate treatment options.
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Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan-cancer data regarding the frequency of CDK12 alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real-world clinical-grade sequencing. METHODS: This was a single-center retrospective analysis of 4994 cancer patients who underwent tissue or blood genomic profiling, including CDK12 assessment, conducted as part of routine care from December 2012 to January 2020. Prevalence, clinical characteristics, and treatment outcomes of patients with tumors with pathogenic CDK12 alterations were described. RESULTS: In all, 39 (0.78%, n = 39/4994) patients had pathogenic CDK12 alterations. Among CDK12-altered tumors, the most common organ site was prostate (n = 9, 23.1%) followed by colorectal (n = 5, 12.8%). Adenocarcinoma was the most common histology (n = 26, 66.7%). Median follow-up from time of diagnosis was 4.02 years. Median overall survival from time of metastasis was 4.43 years (95% CI: 3.11-5.74). Ten patients with CDK12-altered tumors received at least one immune checkpoint inhibitor-containing regimen. The majority of patients (n = 6/10, 60%) experienced an objective response. Progression-free survival for patients who had metastatic disease and received a checkpoint inhibitor-containing regimen was 1.16 years (95% CI: 0.32-2.00). CONCLUSION: CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12-altered tumors.
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Quinases Ciclina-Dependentes , Neoplasias , Gerenciamento de Dados , Humanos , Masculino , Neoplasias/epidemiologia , Neoplasias/genética , Próstata , Estudos RetrospectivosRESUMO
INTRODUCTION: The homologous recombination repair (HRR) pathway is a frequently mutated pathway in advanced prostate cancer. The clinical course of patients with HRR gene alterations who have metastatic hormone sensitive prostate cancer (mHSPC) has not been fully characterized. Here, we examine the outcomes of men with mHSPC with HRR alterations. METHODS: We conducted a single-center retrospective analysis of men with mHSPC who underwent next generation sequencing. The primary objective was to assess the time from diagnosis of mHSPC to metastatic castrate resistance prostate cancer (mCRPC) in patients with pathogenic HRR alterations compared to individuals lacking these alterations. Key secondary objectives included time to mCRPC in prespecified cohorts, PSA response, and overall survival. RESULTS: 151 men with mHSPC were identified for the study. 24% (N = 37) had pathogenic HRR gene alterations detected with the most common alterations found in BRCA2 (n = 15), ATM (n = 10), and CDK12 (n = 7). Time to mCRPC was significantly decreased in patients with HRR gene alterations versus those without such alterations (12.7 vs. 16.1 months, HR 1.95, P = .02). In multivariate analysis, the effect of HRR gene alterations on time to CRPC remained significant when adjusting for age, mHSPC therapy, the volume of disease, the presence of visceral metastases, and PSA (adjusted HR 1.69, P = .02). Stratified by specific HRR gene alteration, patients with BRCA2 or CDK12 had significantly decreased time to mCRPC compared to other HRR alterations. CONCLUSION: HRR gene alterations are associated with the worse outcomes in mHSPC with significantly shorter time to mCRPC. Given the established role of Poly (ADP-ribose) Polymerase (PARP) inhibitors in mCRPC, these data highlight an opportunity to examine PARP inhibitors earlier in the clinical course for prostate cancer patients. Ongoing prospective studies will further validate the role of PARP inhibitors in mHSPC patients.
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Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Prognóstico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Antígeno Prostático Específico , Estudos Retrospectivos , Reparo de DNA por Recombinação/genética , Estudos Prospectivos , HormôniosRESUMO
BACKGROUND: Little is known about the true rate of pathogenic (P)/likely pathogenic (LP) germline alterations in Hispanic men with prostate cancer as most studies analyzing the prevalence of P/LP germline alterations were performed in a largely non-Hispanic white population (NHW). METHODS: We performed a retrospective analysis of two separate cohorts of men with prostate cancer: (1) a multicenter cohort of 17,256 men who underwent germline testing in a CLIA-certified laboratory and (2) a single-center cohort of all men eligible for germline testing between 2018 and 2020. The proportions of P/LP alterations and variants of uncertain significance (VUS) were computed. Fisher's exact test was used to compare germline alteration rates for significance. A multivariate logistic regression was performed adjusting for demographic and clinical factors to examine factors associated with germline testing. RESULTS: In the multicenter cohort, the rate of P/LP germline alterations among self-reported Hispanic men was 7.1%, which was lower than self-reported NHW men (9.7% vs. 7.1%, p = 0.058), but was not statistically significant. The VUS rate was significantly higher among the Hispanic cohort (21.5% vs. 16.6%, p = 0.005). In the single-center cohort, 136 Hispanic patients were eligible for testing of which 34 underwent germline testing (26.1%, N = 34/136). Of all prostate cancer patients in the single-center cohort undergoing germline testing (n = 173), the rate of P/LP alterations in Hispanic patients was not significantly different compared to NHW patients (14.7% vs. 12.2%, p = 0.77). The rate of VUS in Hispanic patients was significantly higher than that of NHW patients (20.6% vs. 7.2%, p = 0.047). CONCLUSION: The P/LP germline alteration rate in our cohorts was similar between Hispanic and NHW men. The rate of VUS was significantly higher in Hispanic men, a consequence of undertesting in minority populations. These data support that Hispanic men with prostate cancer should be screened for germline testing similar to NHW men.
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Neoplasias da Próstata , Estudos de Coortes , Células Germinativas , Hispânico ou Latino/genética , Humanos , Masculino , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Estudos RetrospectivosRESUMO
PURPOSE: Prostate cancer is a heterogeneous disease with variable clinical outcomes. Despite numerous recent approvals of novel therapies, castration-resistant prostate cancer remains lethal. A "real-world" clinical-genomic database is urgently needed to enhance our characterization of advanced prostate cancer and further enable precision oncology. METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) is a consortium whose aims are to establish a repository of de-identified clinical and genomic patient data that are linked to patient outcomes. The consortium structure includes a (1) bio-informatics committee to standardize genomic data and provide quality control, (2) biostatistics committee to independently perform statistical analyses, (3) executive committee to review and select proposals of relevant questions for the consortium to address, (4) diversity/inclusion committee to address important clinical questions pertaining to racial disparities, and (5) patient advocacy committee to understand patient perspectives to improve patients' quality of care. RESULTS: The PROMISE consortium was formed by 16 academic institutions in early 2020 and a secure RedCap database was created. The first patient record was entered into the database in April 2020 and over 1000 records have been entered as of early 2021. Data entry is proceeding as planned with the goal to have over 2500 patient records by the end of 2021. CONCLUSIONS: The PROMISE consortium provides a powerful clinical-genomic platform to interrogate and address data gaps that have arisen with increased genomic testing in the clinical management of prostate cancer. The dataset incorporates data from patient populations that are often underrepresented in clinical trials, generates new hypotheses to direct further research, and addresses important clinical questions that are otherwise difficult to investigate in prospective studies.
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Neoplasias da Próstata , Genômica , Humanos , Masculino , Oncologia , Medicina de Precisão , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapiaRESUMO
Importance: The COVID-19 pandemic has had a distinct spatiotemporal pattern in the United States. Patients with cancer are at higher risk of severe complications from COVID-19, but it is not well known whether COVID-19 outcomes in this patient population were associated with geography. Objective: To quantify spatiotemporal variation in COVID-19 outcomes among patients with cancer. Design, Setting, and Participants: This registry-based retrospective cohort study included patients with a historical diagnosis of invasive malignant neoplasm and laboratory-confirmed SARS-CoV-2 infection between March and November 2020. Data were collected from cancer care delivery centers in the United States. Exposures: Patient residence was categorized into 9 US census divisions. Cancer center characteristics included academic or community classification, rural-urban continuum code (RUCC), and social vulnerability index. Main Outcomes and Measures: The primary outcome was 30-day all-cause mortality. The secondary composite outcome consisted of receipt of mechanical ventilation, intensive care unit admission, and all-cause death. Multilevel mixed-effects models estimated associations of center-level and census division-level exposures with outcomes after adjustment for patient-level risk factors and quantified variation in adjusted outcomes across centers, census divisions, and calendar time. Results: Data for 4749 patients (median [IQR] age, 66 [56-76] years; 2439 [51.4%] female individuals, 1079 [22.7%] non-Hispanic Black individuals, and 690 [14.5%] Hispanic individuals) were reported from 83 centers in the Northeast (1564 patients [32.9%]), Midwest (1638 [34.5%]), South (894 [18.8%]), and West (653 [13.8%]). After adjustment for patient characteristics, including month of COVID-19 diagnosis, estimated 30-day mortality rates ranged from 5.2% to 26.6% across centers. Patients from centers located in metropolitan areas with population less than 250â¯000 (RUCC 3) had lower odds of 30-day mortality compared with patients from centers in metropolitan areas with population at least 1 million (RUCC 1) (adjusted odds ratio [aOR], 0.31; 95% CI, 0.11-0.84). The type of center was not significantly associated with primary or secondary outcomes. There were no statistically significant differences in outcome rates across the 9 census divisions, but adjusted mortality rates significantly improved over time (eg, September to November vs March to May: aOR, 0.32; 95% CI, 0.17-0.58). Conclusions and Relevance: In this registry-based cohort study, significant differences in COVID-19 outcomes across US census divisions were not observed. However, substantial heterogeneity in COVID-19 outcomes across cancer care delivery centers was found. Attention to implementing standardized guidelines for the care of patients with cancer and COVID-19 could improve outcomes for these vulnerable patients.
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COVID-19/epidemiologia , Neoplasias/epidemiologia , Pandemias , População Rural , Vulnerabilidade Social , População Urbana , Idoso , Causas de Morte , Censos , Feminino , Instalações de Saúde , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Razão de Chances , Sistema de Registros , Respiração Artificial , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Análise Espacial , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Older age is associated with poorer outcomes of SARS-CoV-2 infection, although the heterogeneity of ageing results in some older adults being at greater risk than others. The objective of this study was to quantify the association of a novel geriatric risk index, comprising age, modified Charlson comorbidity index, and Eastern Cooperative Oncology Group performance status, with COVID-19 severity and 30-day mortality among older adults with cancer. METHODS: In this cohort study, we enrolled patients aged 60 years and older with a current or previous cancer diagnosis (excluding those with non-invasive cancers and premalignant or non-malignant conditions) and a current or previous laboratory-confirmed COVID-19 diagnosis who reported to the COVID-19 and Cancer Consortium (CCC19) multinational, multicentre, registry between March 17, 2020, and June 6, 2021. Patients were also excluded for unknown age, missing data resulting in unknown geriatric risk measure, inadequate data quality, or incomplete follow-up resulting in unknown COVID-19 severity. The exposure of interest was the CCC19 geriatric risk index. The primary outcome was COVID-19 severity and the secondary outcome was 30-day all-cause mortality; both were assessed in the full dataset. Adjusted odds ratios (ORs) and 95% CIs were estimated from ordinal and binary logistic regression models. FINDINGS: 5671 patients with cancer and COVID-19 were included in the analysis. Median follow-up time was 56 days (IQR 22-120), and median age was 72 years (IQR 66-79). The CCC19 geriatric risk index identified 2365 (41·7%) patients as standard risk, 2217 (39·1%) patients as intermediate risk, and 1089 (19·2%) as high risk. 36 (0·6%) patients were excluded due to non-calculable geriatric risk index. Compared with standard-risk patients, high-risk patients had significantly higher COVID-19 severity (adjusted OR 7·24; 95% CI 6·20-8·45). 920 (16·2%) of 5671 patients died within 30 days of a COVID-19 diagnosis, including 161 (6·8%) of 2365 standard-risk patients, 409 (18·5%) of 2217 intermediate-risk patients, and 350 (32·1%) of 1089 high-risk patients. High-risk patients had higher adjusted odds of 30-day mortality (adjusted OR 10·7; 95% CI 8·54-13·5) than standard-risk patients. INTERPRETATION: The CCC19 geriatric risk index was strongly associated with COVID-19 severity and 30-day mortality. Our CCC19 geriatric risk index, based on readily available clinical factors, might provide clinicians with an easy-to-use risk stratification method to identify older adults most at risk for severe COVID-19 as well as mortality. FUNDING: US National Institutes of Health National Cancer Institute Cancer Center.
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COVID-19 , Neoplasias , Idoso , Teste para COVID-19 , Estudos de Coortes , Humanos , Pessoa de Meia-Idade , Fatores de Risco , SARS-CoV-2RESUMO
BACKGROUND: Little is known regarding the rate and clinical outcomes of asymptomatic carriers of SARS-CoV-2 among patients with cancer. Detection of asymptomatic carriers is important in this population given the use of myelosuppressive and immunomodulating therapies. Understanding the asymptomatic carrier rate will help to develop mitigation strategies in this high-risk cohort. METHODS: Retrospective cohort analysis of an asymptomatic screening protocol which required patients receiving infusional anti-cancer therapy to undergo a symptom/exposure screen and SARS-CoV-2 PCR testing 24-96 h prior to their infusion. The primary outcome of this analysis was the rate of asymptomatic SARS-CoV-2 infection. Secondary outcomes included the rate of COVID-19-related hospitalization and mortality and delays in oncologic therapy. RESULTS: Among a cohort of 2691 cancer patients who underwent asymptomatic screening, 1.6% (N = 43/2691) of patients were found to be SARS-CoV-2 positive on asymptomatic screening. 11.6% (N = 5/43) of the cohort ultimately developed COVID-19-related symptoms. Four patients required hospitalization for complications of COVID-19 infection. No patient died from COVID-related complications. 97.7% (N = 42/43) had their anti-cancer therapy delayed or deferred with a median delay of 21 days (range: 7-77 days). CONCLUSIONS: Overall, among a cohort of active cancer patients receiving anti-cancer therapy, an asymptomatic SARS-CoV2 PCR-based screening protocol detected a small cohort of asymptomatic carriers. The majority of these patients remained asymptomatic on long-term follow-up and outcomes were much more favorable compared to previously described outcomes of cancer patients with symptomatic COVID-19 infection.
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Infecções Assintomáticas , COVID-19/diagnóstico , Neoplasias/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , California , Feminino , Hospitalização , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Neoplasias/virologia , Estudos Retrospectivos , SARS-CoV-2 , Adulto JovemRESUMO
BACKGROUND: There has been considerable interest in ctDNA next generation sequencing platforms to assess genomic alterations in mCRPC given its accessibility and identification of temporal genomic data. PATIENTSAND METHODS: In this retrospective analysis, we analyzed 63 patients who underwent ctDNA genomic profiling during their mCRPC disease course using a CLIA-certified commercial assay. The primary objective was to assess the feasibility of commercial ctDNA analysis in a real world mCRPC cohort. Key secondary objectives included assessment of the landscape of pathogenic ctDNA alterations and the prognostic significance of ctDNA detection on overall survival (OS). RESULTS: Among the cohort, at the time of ctDNA collection, median age was 70 years, and 47.6% (N = 30/63) had bone-only metastases. ctDNA was detected in the majority of patients with at least 1 pathogenic alteration detected in 90.5% (N = 57/63) of individuals. The most common alterations detected were in AR, TP53, and PIK3CA. Actionable alterations with FDA-approved therapies were found in 15.8% (N = 10) of the cohort. The presence of ≤ 1 versus > 1 alteration on ctDNA analysis was strongly associated with inferior OS with a median OS of 26.1 versus 8.8 months, respectively (HR = 7.0, 95% CI, 2.2-23.1, P < .001). In multivariate analysis, the number of detected alterations remained a significant predictor for OS. Lastly, there was weak correlation between Prostate-Specific Antigen (PSA), and ctDNA characteristics. CONCLUSION: ctDNA is a viable next generation sequencing (NGS) platform in mCRPC and can be utilized to identify actionable alterations. The presence and extent of ctDNA alterations appear to be prognostic of OS in mCRPC.
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DNA Tumoral Circulante , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Idoso , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Humanos , Masculino , Mutação , Prognóstico , Neoplasias de Próstata Resistentes à Castração/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Pancreatic metastases (PM) are rare in renal cell carcinoma. It has been suggested that patients with metastases to the pancreas have a more favorable prognosis, but little is known about the long-term outcomes with systemic therapy. We sought to understand the outcomes of patients with metastatic renal cell carcinoma with PM treated with systemic therapy. PATIENTS AND METHODS: We conducted a pooled analysis of 4736 patients with metastatic renal cell carcinoma treated on phase II/III clinical trials. Systemic therapies included anti-vascular endothelial growth factor targeted therapy, mammalian target of rapamycin-targeted therapy, and cytokine therapy. RESULTS: The primary end point was overall survival (OS) in patients with versus without PM. Statistical analyses were performed using Kaplan-Meier analysis and Cox regression. Among 4736 patients, 235 (5.0%) were identified to have baseline PM at therapy initiation. The median OS in patients with PM was significantly prolonged with OS of 41.7 months versus 19.0 months (adjusted hazard ratio, 0.52; P < .0001). Similarly, progression-free survival was significantly prolonged in patients with PM (10.9 vs. 6.9 months; adjusted hazard ratio, 0.72; P = .004). The effect of PM on OS and progression-free survival was independent of other sites of metastasis or International mRCC Database Consortium risk group. CONCLUSION: The presence of PM in RCC is an independent positive predictor for survival and improved response to systemic therapy. These findings suggest RCC with PM is associated with favorable outcomes and further work to understand the underlying disease biology of these patients is warranted.
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Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Pancreáticas , Carcinoma de Células Renais/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Prognóstico , Estudos RetrospectivosRESUMO
PURPOSE: Cyclin and MAPK/MEK-related gene alterations are implicated in cell-cycle progression and cancer growth. Yet, monotherapy to target the cyclin (CDK4/6) or the MEK pathway has often yielded disappointing results. Because coalterations in cyclin and MEK pathway genes frequently cooccur, we hypothesized that resistance to CDK4/6 or MEK inhibitor monotherapy might be mediated via activation of oncogenic codrivers, and that combination therapy might be useful. EXPERIMENTAL DESIGN: Herein, we describe 9 patients with advanced malignancies harboring concomitant CDKN2A and/or CDKN2B alterations (upregulate CDK4/6) along with KRAS or BRAF alterations (activate the MEK pathway) who were treated with palbociclib (CDK4/6 inhibitor) and trametinib (MEK inhibitor) combination-based regimens. RESULTS: Two patients (with pancreatic cancer) achieved a partial remission (PR) and, overall, 5 patients (56%) had clinical benefit (stable disease ≥ 6 months/PR) with progression-free survival of approximately 7, 9, 9, 11, and 17.5+ months. Interestingly, 1 of these patients whose cancer (gastrointestinal stromal tumor) had progressed on MEK targeting regimen, did well for about 1 year after palbociclib was added. CONCLUSIONS: These observations suggest that cotargeting cyclin and MEK signaling can be successful when tumors bear genomic coalterations that activate both of these pathways. Further prospective studies using this matching precision strategy to overcome resistance are warranted.See related commentary by Groisberg and Subbiah, p. 2672.
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Ciclinas/genética , Variação Genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Neoplasias/genética , Biomarcadores Tumorais , Suscetibilidade a Doenças , Predisposição Genética para Doença , Humanos , Modelos Biológicos , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Importance: Androgen deprivation therapy (ADT) has been theorized to decrease the severity of SARS-CoV-2 infection in patients with prostate cancer owing to a potential decrease in the tissue-based expression of the SARS-CoV-2 coreceptor transmembrane protease, serine 2 (TMPRSS2). Objective: To examine whether ADT is associated with a decreased rate of 30-day mortality from SARS-CoV-2 infection among patients with prostate cancer. Design, Setting, and Participants: This cohort study analyzed patient data recorded in the COVID-19 and Cancer Consortium registry between March 17, 2020, and February 11, 2021. The consortium maintains a centralized multi-institution registry of patients with a current or past diagnosis of cancer who developed COVID-19. Data were collected and managed using REDCap software hosted at Vanderbilt University Medical Center in Nashville, Tennessee. Initially, 1228 patients aged 18 years or older with prostate cancer listed as their primary malignant neoplasm were included; 122 patients with a second malignant neoplasm, insufficient follow-up, or low-quality data were excluded. Propensity matching was performed using the nearest-neighbor method with a 1:3 ratio of treated units to control units, adjusted for age, body mass index, race and ethnicity, Eastern Cooperative Oncology Group performance status score, smoking status, comorbidities (cardiovascular, pulmonary, kidney disease, and diabetes), cancer status, baseline steroid use, COVID-19 treatment, and presence of metastatic disease. Exposures: Androgen deprivation therapy use was defined as prior bilateral orchiectomy or pharmacologic ADT administered within the prior 3 months of presentation with COVID-19. Main Outcomes and Measures: The primary outcome was the rate of all-cause 30-day mortality after COVID-19 diagnosis for patients receiving ADT compared with patients not receiving ADT after propensity matching. Results: After exclusions, 1106 patients with prostate cancer (before propensity score matching: median age, 73 years [IQR, 65-79 years]; 561 (51%) self-identified as non-Hispanic White) were included for analysis. Of these patients, 477 were included for propensity score matching (169 who received ADT and 308 who did not receive ADT). After propensity matching, there was no significant difference in the primary end point of the rate of all-cause 30-day mortality (OR, 0.77; 95% CI, 0.42-1.42). Conclusions and Relevance: Findings from this cohort study suggest that ADT use was not associated with decreased mortality from SARS-CoV-2 infection. However, large ongoing clinical trials will provide further evidence on the role of ADT or other androgen-targeted therapies in reducing COVID-19 infection severity.