Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
Circulation ; 139(13): e579-e602, 2019 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-30786722

RESUMEN

Cardio-oncology has organically developed as a new discipline within cardiovascular medicine as a result of the cardiac and vascular adverse sequelae of the major advances in cancer treatment. Patients with cancer and cancer survivors are at increased risk of vascular disease for a number of reasons. First, many new cancer therapies, including several targeted therapies, are associated with vascular and metabolic complications. Second, cancer itself serves as a risk factor for vascular disease, especially by increasing the risk for thromboembolic events. Finally, recent data suggest that common modifiable and genetic risk factors predispose to both malignancies and cardiovascular disease. Vascular complications in patients with cancer represent a new challenge for the clinician and a new frontier for research and investigation. Indeed, vascular sequelae of novel targeted therapies may provide insights into vascular signaling in humans. Clinically, emerging challenges are best addressed by a multidisciplinary approach in which cardiovascular medicine specialists and vascular biologists work closely with oncologists in the care of patients with cancer and cancer survivors. This novel approach realizes the goal of providing superior care through the creation of cardio-oncology consultative services and the training of a new generation of cardiovascular specialists with a broad understanding of cancer treatments.


Asunto(s)
Cardiología , Enfermedades Cardiovasculares , Oncología Médica , Neoplasias , American Heart Association , Humanos , Estados Unidos
2.
Lancet Oncol ; 19(4): 451-460, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29530667

RESUMEN

BACKGROUND: The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. METHODS: The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751. FINDINGS: Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54-100) of six patients in the dose-finding phase and 26 (53%, 38-68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44-71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily. INTERPRETATION: The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy. FUNDING: Pfizer and Merck.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Anciano , Alanina Transaminasa/sangre , Amilasas/sangre , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Enfermedades Autoinmunes/inducido químicamente , Axitinib/administración & dosificación , Axitinib/efectos adversos , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/cirugía , Esquema de Medicación , Femenino , Síndrome Mano-Pie/etiología , Humanos , Hipertensión/inducido químicamente , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Lipasa/sangre , Masculino , Persona de Mediana Edad , Miocarditis/inducido químicamente , Datos Preliminares , Proteinuria/inducido químicamente , Criterios de Evaluación de Respuesta en Tumores Sólidos , Resultado del Tratamiento
3.
Br J Cancer ; 119(7): 801-807, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30293995

RESUMEN

BACKGROUND: The majority of urothelial cancers (UC) harbor alterations in retinoblastoma (Rb) pathway genes that can lead to loss of Rb tumour suppressor function. Palbociclib is an oral, selective inhibitor of CDK 4/6 that restores Rb function and promotes cell cycle arrest. METHODS: In this phase II trial, patients with metastatic platinum-refractory UC molecularly selected for p16 loss and intact Rb by tumour immunohistochemistry received palbociclib 125 mg p.o. daily for 21 days of a 28-day cycle. Primary endpoint was progression-free survival at 4 months (PFS4) using a Simon's two-stage design. Next-generation sequencing including Rb pathway alterations was conducted. RESULTS: Twelve patients were enrolled and two patients (17%) achieved PFS4 with insufficient activity to advance to stage 2. No responses were seen. Median PFS was 1.9 months (95% CI 1.8-3.7 months) and median overall survival was 6.3 months (95% CI 2.2-12.6 months). Fifty-eight percent of patients had grade ≥3 hematologic toxicity. There were no CDKN2A alterations found and no correlation of Rb pathway alterations with clinical outcome. CONCLUSIONS: Palbociclib did not demonstrate meaningful activity in selected patients with platinum-refractory metastatic UC. Further development of palbociclib should only be considered with improved integral biomarker selection or in rational combination with other therapies.


Asunto(s)
Carcinoma de Células Transicionales/tratamiento farmacológico , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Piperazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/administración & dosificación , Neoplasias Urológicas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Carcinoma de Células Transicionales/genética , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Piperazinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Piridinas/efectos adversos , Análisis de Secuencia de ADN , Resultado del Tratamiento , Neoplasias Urológicas/genética
4.
Oncologist ; 23(6): 686-692, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29487220

RESUMEN

BACKGROUND: Pazopanib is an oral tyrosine-kinase inhibitor that is approved by the U.S. Food and Drug Administration for treatment of metastatic renal cell carcinoma (mRCC). Pharmacokinetic data have shown that concomitant administration of pazopanib and esomeprazole, a proton pump inhibitor (PPI), leads to decreased area under the curve and thus decreased exposure of pazopanib by 40%. Despite the pharmacokinetic data published to date, the clinical significance and impact on patient outcomes resulting from decreased pazopanib exposure remains unknown. MATERIALS AND METHODS: In this retrospective, observational, cohort study, 90 patients with mRCC who either received pazopanib in combination with a PPI or histamine 2 receptor antagonist (H2RA; concurrent PPI/H2RA group) or who did not take concurrent pH-elevating medications (no PPI/H2RA group) were compared to determine if there was an impact on progression-free survival (PFS), the primary endpoint, and secondary endpoints, overall survival (OS) and safety. RESULTS: The differences between the PFS of 9.0 months and OS of 28.0 months for the concomitant PPI/H2RA group versus 11.0 months and 30.1 months, respectively, for the no PPI/H2RA group were not statistically significant. Rates of adverse events were similar between the concomitant PPI/H2RA and no PPI/H2RA groups. CONCLUSION: Concomitant PPI or H2RA usage was not shown to be associated with a reduction in PFS or OS for patients receiving pazopanib for mRCC, with a similar toxicity profile in each group. Based on the results of this retrospective cohort study and the palliative nature of the treatment of patients with mRCC, clinicians should consider allowing patients to remain on concomitant pazopanib and acid-reducing therapy. IMPLICATIONS FOR PRACTICE: Pazopanib is a preferred category-one first-line treatment for predominant clear cell metastatic renal cell carcinoma (mRCC). However, because of an aging demographic, coupled with patients with mRCC presenting with multiple comorbidities, including symptomatic dyspepsia or gastroesophageal reflux disease, patients are commonly required to take pazopanib concomitantly with a proton pump inhibitor (PPI) or a histamine 2 receptor antagonist (H2RA). Despite earlier pharmacokinetic reports suggesting that an alkaline pH may result in poorer absorption, this institutional retrospective study found no effect on clinical outcomes. These data suggest that concurrent treatment of mRCC with pazopanib and a PPI or H2RA may be safe in everyday practice.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/farmacología , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Estudios de Cohortes , Femenino , Humanos , Indazoles , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Pirimidinas/farmacología , Estudios Retrospectivos , Sulfonamidas/farmacología , Análisis de Supervivencia
5.
J Natl Compr Canc Netw ; 15(10): 1277-1284, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28982752

RESUMEN

With the advent of platinum-based chemotherapy, survival rates for metastatic urothelial carcinoma have plateaued, giving way to the modern immunotherapy paradigm. Although immunotherapy as an effective treatment dates back to the live, attenuated bacillus Calmette-Guérin vaccine, the recent impact of immune checkpoint inhibitors targeting programmed death/programmed death-ligand 1 (PD-1/PD-L1) coupled with the promise of both anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies and indoleamine-2, 3-dioxygenase-1 (IDO-1) inhibitors have provided a resurgence. To date, pembrolizumab, a PD-1 inhibitor, has been granted full FDA approval based on its high antitumor activity, tolerability, and efficacy, with notable prolonged durable responses in the second-line setting. Nivolumab (a PD-1 inhibitor) and atezolizumab, durvalumab, and avelumab (PD-L1 inhibitors) have also gained accelerated drug approval in the second-line setting. In addition, atezolizumab and pembrolizumab have been approved for platinum-ineligible patients in the first-line setting. Effective 2-drug combinations reported include nivolumab plus the CTLA-4 antibody ipilimumab and pembrolizumab plus the IDO-1 inhibitor epacadostat. Further expansion of immunotherapy will hinge in part on the ability to define responders versus nonresponders through the use of biomarkers like PD-L1 or mutational load. Clinical trials with immunotherapy for metastatic disease as single agents or in combination are ongoing. This review explores the rise of immunotherapy and presents the current treatments and challenges posed with development of biomarkers, and provides a summary of ongoing phase III clinical trials.


Asunto(s)
Carcinoma/terapia , Inmunoterapia , Neoplasias de la Vejiga Urinaria/terapia , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Biomarcadores de Tumor , Carcinoma/etiología , Carcinoma/patología , Ensayos Clínicos como Asunto , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Estadificación de Neoplasias , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/etiología , Neoplasias de la Vejiga Urinaria/patología
6.
Proc Natl Acad Sci U S A ; 111(8): 3110-5, 2014 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-24520177

RESUMEN

We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of high-grade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed "luminal" and "basal-like," which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtype-specific therapies, will be of interest.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Modelos Biológicos , Neoplasias de la Vejiga Urinaria/clasificación , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Mama/clasificación , Análisis por Conglomerados , Perfilación de la Expresión Génica/métodos , Humanos , Análisis por Micromatrices , Valor Predictivo de las Pruebas
7.
Clin Cancer Res ; 30(1): 63-73, 2024 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-37861407

RESUMEN

PURPOSE: Effective treatment of locally advanced or metastatic urothelial carcinoma (mUC) remains an unmet need. Antibody-drug conjugates (ADC) providing targeted drug delivery have shown antitumor activity in this setting. AGS15E is an investigational ADC that delivers the cytotoxic drug monomethyl auristatin E to cells expressing SLITRK6, a UC-associated antigen. PATIENTS AND METHODS: This was a multicenter, single-arm, phase I dose-escalation and expansion trial of AGS15E in patients with mUC (NCT01963052). During dose escalation, AGS15E was administered intravenously at six levels (0.10, 0.25, 0.50, 0.75, 1.00, 1.25 mg/kg), employing a continual reassessment method to determine dose-limiting toxicities (DLT) and the recommended phase II dose (RP2D) for the dose-expansion cohort. The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in patients with and without prior chemotherapy and with prior checkpoint inhibitor (CPI) therapy. Best overall response was also examined. RESULTS: Ninety-three patients were recruited, including 33 patients previously treated with CPI. The most common treatment-emergent adverse events were fatigue (54.8%), nausea (37.6%), and decreased appetite (35.5%). Peripheral neuropathy and ocular toxicities occurred at doses of ≥0.75 mg/kg. AGS15E increased in a dose-proportional manner after single- and multiple-dose administration; accumulation was low. Five DLT occurred from 0.50 to 1.25 mg/kg. The RP2D was assessed at 1.00 mg/kg; the objective response rate (ORR) was 35.7% at this dose level. The ORR in the total population and CPI-exposed subgroup were 18.3% and 27.3%, respectively. CONCLUSIONS: DLT with AGS15E were observed at 0.75, 1.00, and 1.25 mg/kg, with an RP2D of 1.00 mg/kg being determined.


Asunto(s)
Carcinoma de Células Transicionales , Inmunoconjugados , Neoplasias de la Vejiga Urinaria , Humanos , Antineoplásicos , Carcinoma de Células Transicionales/tratamiento farmacológico , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacocinética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico
8.
Oncologist ; 18(8): 933-40, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23883869

RESUMEN

Neoadjuvant cisplatin-based combination chemotherapy for muscle-invasive bladder cancer (MIBC) has been shown to confer a survival advantage in two randomized clinical trials and a meta-analysis. Despite level 1 evidence supporting its benefit, utilization remains dismal with nearly one-half of patients ineligible for cisplatin-based therapy because of renal dysfunction, impaired performance status, and/or coexisting medical problems. This situation highlights the need for the development of novel therapies for the management of MIBC, a disease with a lethal phenotype. The neoadjuvant paradigm in bladder cancer offers many advantages for accelerated drug development. First, there is a greater likelihood of successful therapy at an earlier disease state that may be characterized by less genomic instability compared with the metastatic setting, with an early readout of activity with results determined in months rather than years. Second, pre- and post-treatment tumor tissue collection in patients with MIBC is performed as the standard of care without the need for research-directed biopsies, allowing for the ability to perform important correlative studies and to monitor tumor response to therapy in "real time." Third, pathological complete response (pT0) predicts for improved outcome in patients with MIBC. Fourth, there is a strong biological rationale with rapidly accumulating evidence for actionable targets in bladder cancer. This review focuses on the neoadjuvant paradigm for accelerated drug development using bladder cancer as the ideal model.


Asunto(s)
Cisplatino/uso terapéutico , Descubrimiento de Drogas , Terapia Neoadyuvante , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inestabilidad Genómica , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología
9.
JAMA Netw Open ; 5(3): e224304, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35344045

RESUMEN

Importance: Non-Hispanic Black individuals experience a higher burden of COVID-19 than the general population; hence, there is an urgent need to characterize the unique clinical course and outcomes of COVID-19 in Black patients with cancer. Objective: To investigate racial disparities in severity of COVID-19 presentation, clinical complications, and outcomes between Black patients and non-Hispanic White patients with cancer and COVID-19. Design, Setting, and Participants: This retrospective cohort study used data from the COVID-19 and Cancer Consortium registry from March 17, 2020, to November 18, 2020, to examine the clinical characteristics and outcomes of COVID-19 in Black patients with cancer. Data analysis was performed from December 2020 to February 2021. Exposures: Black and White race recorded in patient's electronic health record. Main Outcomes and Measures: An a priori 5-level ordinal scale including hospitalization intensive care unit admission, mechanical ventilation, and all-cause death. Results: Among 3506 included patients (1768 women [50%]; median [IQR] age, 67 [58-77] years), 1068 (30%) were Black and 2438 (70%) were White. Black patients had higher rates of preexisting comorbidities compared with White patients, including obesity (480 Black patients [45%] vs 925 White patients [38%]), diabetes (411 Black patients [38%] vs 574 White patients [24%]), and kidney disease (248 Black patients [23%] vs 392 White patients [16%]). Despite the similar distribution of cancer type, cancer status, and anticancer therapy at the time of COVID-19 diagnosis, Black patients presented with worse illness and had significantly worse COVID-19 severity (unweighted odds ratio, 1.34 [95% CI, 1.15-1.58]; weighted odds ratio, 1.21 [95% CI, 1.11-1.33]). Conclusions and Relevance: These findings suggest that Black patients with cancer experience worse COVID-19 outcomes compared with White patients. Understanding and addressing racial inequities within the causal framework of structural racism is essential to reduce the disproportionate burden of diseases, such as COVID-19 and cancer, in Black patients.


Asunto(s)
COVID-19 , Neoplasias , Anciano , Población Negra , COVID-19/epidemiología , Prueba de COVID-19 , Femenino , Humanos , Neoplasias/epidemiología , Estudios Retrospectivos
10.
JAMA Netw Open ; 5(1): e2142046, 2022 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-34982158

RESUMEN

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 250 000 (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.


Asunto(s)
COVID-19/epidemiología , Neoplasias/epidemiología , Pandemias , Población Rural , Vulnerabilidad Social , Población Urbana , Anciano , Causas de Muerte , Censos , Femenino , Instituciones de Salud , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Sistema de Registros , Respiración Artificial , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Análisis Espacial , Estados Unidos/epidemiología
11.
JAMA Oncol ; 4(12): 1721-1728, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30242316

RESUMEN

Importance: Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data. Objective: To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects. Design, Setting, and Participants: We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally. Exposures: Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab). Main Outcomes and Measures: Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects. Results: Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4). Conclusions and Relevance: In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/mortalidad , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Bases de Datos Factuales/estadística & datos numéricos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Genes cdc/efectos de los fármacos , Genes cdc/inmunología , Humanos , Factores Inmunológicos/efectos adversos , Inmunoterapia/efectos adversos , Incidencia , Neoplasias/mortalidad , Neoplasias/terapia , Farmacovigilancia , Estudios Retrospectivos
12.
Kidney Cancer ; 1(1): 83-88, 2017 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-30334008

RESUMEN

We report a case of severe type B lactic acidosis (LA) in a 51-year-old male, 12 days after he received his first dose of nivolumab for metastatic Von Hippel Lindau (VHL)-mutated, clear cell renal cell carcinoma. Throughout his hospital course, infection, hypoperfusion, and tissue necrosis were not identified. We propose that his LA may have resulted from either inherent tumor glycolysis or immune activation and enhanced metabolism. The patient's course was complicated by acute renal failure, and his LA rose progressively, eventually necessitating daily hemodialysis (HD). After receiving five consecutive days of HD, the patient started everolimus daily with the intent of reducing glycolytic metabolism. Subsequently, the rate of lactic acid production slowed, and HD was no longer required after two doses of everolimus. To our knowledge, this is the first reported case of type B LA following nivolumab administration, and the use of everolimus to treat type B LA in a patient with renal cancer.

13.
Fertil Steril ; 83 Suppl 1: 1125-33, 2005 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15831285

RESUMEN

OBJECTIVE: To treat experimental human endometrial cancers based on targeted chemotherapy with the cytotoxic luteinizing hormone-releasing hormone (LHRH) analogues AN-152 and AN-207. DESIGN: Experimental study using athymic nude mice bearing xenografts of HEC-1A and RL-95-2 human endometrial cancers to assess the efficacy and toxicity of AN-152 and AN-207. The expression of LHRH receptors in HEC-1A and RL-95-2 cancers was determined by reverse transcription-polymerase chain reaction, Western blot analysis, and radioligand binding assays. SETTING: Experimental laboratory research. ANIMAL(S): Female athymic nude mice (Ncr, nu/nu). INTERVENTION(S): Animals were treated with IV injections of the cytotoxic LHRH analogues AN-152 and AN-207 and their respective cytotoxic radicals doxorubicin (DOX) and AN-201 (2-pyrrolinodoxorubicin) on a control vehicle solution. MAIN OUTCOME MEASURE(S): Tumor volume, final tumor weight, tumor doubling time, body weight, white blood cell count, and LHRH receptor expression. RESULT(S): AN-152 significantly inhibited the growth of HEC-1A tumors. AN-207 also significantly suppressed the proliferation in vivo of HEC-1A and RL-95-2 cancers. The cytotoxic radicals DOX and AN-201 had no effect. Furthermore, mRNA for LHRH receptors, LHRH receptor protein, and high-affinity binding sites for LHRH were demonstrated on tumors. CONCLUSION(S): Targeted chemotherapy with AN-152 and AN-207 strongly inhibits the growth of human endometrial cancers, which express LHRH receptors, and could provide a new treatment modality for women with advanced endometrial carcinoma.


Asunto(s)
Antineoplásicos/farmacología , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacología , Neoplasias Endometriales/tratamiento farmacológico , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/metabolismo , Hormona Liberadora de Gonadotropina/farmacología , Animales , Western Blotting , Línea Celular Tumoral , Neoplasias Endometriales/metabolismo , Femenino , Humanos , Ratones , Ratones Desnudos , Unión Proteica/efectos de los fármacos , ARN Mensajero/análisis , Receptores LHRH/genética , Receptores LHRH/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Case Rep Pathol ; 2015: 459318, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26351608

RESUMEN

A 33-year-old male with a history of left testis Leydig cell tumor (LCT), 3-month status after left radical orchiectomy, presented with a rapidly enlarging (0.6 cm to 3.7 cm) right testicular mass. He underwent a right radical orchiectomy, sections interpreted as showing a similar Leydig cell-like oncocytic proliferation, with a differential diagnosis including metachronous bilateral LCT and metachronous bilateral testicular tumors associated with congenital adrenal hyperplasia (a.k.a. "testicular adrenal rest tumors" (TARTs) and "testicular tumors of the adrenogenital syndrome" (TTAGS)). Additional workup demonstrated a markedly elevated serum adrenocorticotropic hormone (ACTH) and elevated adrenal precursor steroid levels. He was diagnosed with congenital adrenal hyperplasia, 3ß-hydroxysteroid dehydrogenase deficiency (3BHSD) type, and started on treatment. Metachronous bilateral testicular masses in adults should prompt consideration of adult presentation of CAH. Since all untreated CAH patients are expected to have elevated serum ACTH, formal exclusion of CAH prior to surgical resection of a testicular Leydig-like proliferation could be accomplished by screening for elevated serum ACTH.

15.
Clin Cancer Res ; 20(7): 1721-3, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24634386

RESUMEN

Renal cell carcinoma is a heterogeneous disease, and tissue investigations provide clues that may predict treatment response. Oncogenomic analysis of five outliers, who achieved a sustained response with rapalogs, implicates alterations of the TSC1 and mTOR genes and reveals insights into the conserved evolution of tumors.


Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Serina-Treonina Quinasas TOR/biosíntesis , Humanos , Masculino
16.
Expert Rev Anticancer Ther ; 14(11): 1369-78, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24927631

RESUMEN

After initial response to androgen receptor (AR) targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand-binding domain of AR may confer resistance to enzalutamide. Emergence of AR splice variants lacking the ligand-binding domain may mediate resistance to abiraterone and enzalutamide. Steroid receptors such as glucocorticoid receptor may substitute for AR. Drugs with novel mechanisms of action or combination therapy, along with biomarkers for patient selection, may be needed to improve the therapy of castration resistant prostate cancer.


Asunto(s)
Antagonistas de Receptores Androgénicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Resistencia a Antineoplásicos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/metabolismo , Sistemas de Liberación de Medicamentos/tendencias , Resistencia a Antineoplásicos/genética , Humanos , Masculino
18.
Am J Physiol Lung Cell Mol Physiol ; 282(4): L847-53, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11880312

RESUMEN

Human airway smooth muscle (HASM) cells express interleukin (IL)-13 and IL-4 receptors and respond to these cytokines with signal transducer and activator of transcription-6 and extracellular signal-regulated kinase (ERK) activation. The purpose of this study was to determine whether IL-13 and/or IL-4 influence eotaxin release in HASM cells and whether the ERK mitogen-activated protein (MAP) kinase pathway is involved in these events. Eotaxin release into HASM cell supernatants was assayed by ELISA, and eotaxin mRNA expression was determined by Northern blot analysis. Pretreatment with either IL-13 or IL-4 resulted in a concentration- and time-dependent release of eotaxin, although IL-4 was more effective. Eotaxin release was approximately twice baseline after treatment with 50 ng/ml IL-13 or IL-4 (P < 0.001). IL-13 and IL-4 also acted synergistically with tumor necrosis factor (TNF)-alpha to induce eotaxin release: TNF-alpha alone (10 ng/ml for 24 h) resulted in an approximately fourfold increase in eotaxin release, whereas TNF-alpha in combination with IL-13 or IL-4 resulted in 10- or 20-fold increases (P < 0.05). Similar results were obtained for eotaxin mRNA expression. Pretreatment with either U-0126 (10 microM) or PD-98059 (30 microM), both inhibitors of MAP/ERK kinase, the enzyme upstream of ERK, inhibited IL-13- or IL-4-induced eotaxin release (P < 0.05). U-0126 also inhibited IL-13, and TNF-alpha induced mRNA expression. Our results indicate that IL-13 and IL-4 cause eotaxin release in HASM cells through a mechanism that, in part, involves ERK activation and suggest that the smooth muscle may be an important source of chemokines leading to eosinophil recruitment in asthma.


Asunto(s)
Antineoplásicos/farmacología , Quimiocinas CC/metabolismo , Interleucina-13/farmacología , Interleucina-4/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso/metabolismo , Asma/inmunología , Asma/metabolismo , Butadienos/farmacología , Células Cultivadas , Quimiocina CCL11 , Quimiocinas CC/genética , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Humanos , Nitrilos/farmacología , ARN Mensajero/análisis , Tráquea/citología , Factor de Necrosis Tumoral alfa/farmacología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA