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Cancer Gene Ther ; 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31155611


Effective chimeric antigen receptor-modified T-cell (CAR-T) therapy for liver metastases (LM) will require innovative solutions to ensure efficient delivery and minimization of systemic toxicity. We previously demonstrated the safety of CAR-T hepatic artery infusions (HAI). We subsequently conducted the phase 1b HITM-SIR trial, in which six patients (pts) with CEA+ LM received anti-CEA CAR-T HAIs and selective internal radiation therapy (SIRT). The primary endpoint was safety with secondary assessments of biologic activity. Enrolled pts had a mean LM size of 6.4 cm, 4 pts had >10 LM, and pts received an average of two lines of prior systemic therapy. No grade 4 or 5 toxicities were observed, and there were no instances of severe cytokine-release syndrome (CRS) or neurotoxicity. The mean transduction efficiency was 60.4%. Following CAR-T HAI, reduced levels of GM-CSF-R, IDO, and PD-L1 were detected in LM, and serum CEA levels were stable or decreased in all subjects. Median survival time was 8 months (mean 11, range 4-31). Anti-CEA CAR-T HAI with subsequent SIRT was well tolerated, and biologic responses were demonstrated following failure of conventional therapy. HAI of CAR-T was once again confirmed not to be associated with severe CRS or neurotoxicity.

J Natl Compr Canc Netw ; 16(4): 370-376, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29632056


Background: Cholangiocarcinoma (CCA) includes cancers arising from the intrahepatic and extrahepatic bile ducts. The etiology and pathogenesis of CCA remain poorly understood. This is the first study investigating both incidence patterns of CCA from 1973 through 2012 and demographic, clinical, and treatment variables affecting survival of patients with CCA. Patients and Methods: Using the SEER database, age-adjusted incidence rates were evaluated from 1973-2012 using SEER*Stat software. A retrospective cohort of 26,994 patients diagnosed with CCA from 1973-2008 was identified for survival analysis. Cox proportional hazards models were used to perform multivariate survival analysis. Results: Overall incidence of CCA increased by 65% from 1973-2012. Extrahepatic CCA (ECC) remained more common than intrahepatic CCA (ICC), whereas the incidence rates for ICC increased by 350% compared with a 20% increase seen with ECC. Men belonging to non-African American and non-Caucasian ethnicities had the highest incidence rates of CCA. This trend persisted throughout the study period, although African Americans and Caucasians saw 50% and 59% increases in incidence rates, respectively, compared with a 9% increase among other races. Median overall survival (OS) was 8 months in patients with ECC compared with 4 months in those with ICC. Our survival analysis found Hispanic women to have the best 5-year survival outcome (P<.0001). OS diminished with age (P<.0001), and ECC had better survival outcomes compared with ICC (P<.0001). Patients who were married, were nonsmokers, belonged to a higher income class, and underwent surgery had better survival outcomes compared with others (P<.0001). Conclusions: This is the most up-to-date study of CCA from the SEER registry that shows temporal patterns of increasing incidence of CCA across different races, sexes, and ethnicities. We identified age, sex, race, marital status, income, smoking status, anatomic location of CCA, tumor grade, tumor stage, radiation, and surgery as independent prognostic factors for OS in patients with CCA.

J Immunother Cancer ; 5(1): 97, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29254501


BACKGROUND: There has been a significant improvement in survival of advanced malignancies with the advent of checkpoint inhibitors. These newer treatment modalities come with a wide spectrum of unique side effects, termed immune related adverse events (irAE), ranging from mild skin rash to severe colitis. Included in that spectrum is the rare side effect of autoimmune diabetes mellitus. Despite a few case reports illustrating the incidence of autoimmune diabetes associated with immunotherapy, there has not been much mentioned about exacerbation or acceleration of hyperglycemia in non-autoimmune settings leading to de novo diagnosis of type 2 diabetes mellitus. CASE PRESENTATION: We report the case of a 42 year old man with metastatic melanoma and no prior history of diabetes mellitus, who presented with diabetic ketoacidosis (DKA) after 3 cycles of combination checkpoint inhibitor therapy using nivolumab and ipilimumab. New onset diabetes mellitus was diagnosed on the basis of elevated hemoglobin A1c, in the absence of prior personal or family history. Autoimmune or type 1 diabetes mellitus was ruled out with normal levels of anti-glutamic acid decarboxylase 65 (GAD65) antibody, zinc transporter 8 (ZnT8) antibody, and islet antigen-2 (IA-2) antibody. CONCLUSIONS: This case report highlights the importance of recognizing rare but serious adverse events related to immunotherapy and incorporation of appropriate tools for early identification and management in national cancer treatment guidelines.

Antineoplásicos Imunológicos/efeitos adversos , Diabetes Mellitus Tipo 2/diagnóstico , Cetoacidose Diabética/induzido quimicamente , Melanoma/tratamento farmacológico , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetoacidose Diabética/etiologia , Humanos , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Masculino , Metástase Neoplásica , Nivolumabe
Cureus ; 9(5): e1238, 2017 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-28620568


Multiple myelomas is a neoplastic plasma cell disorder that accounts for one percent of all cancers and 13% of hematologic malignancies. Although primarily known to be a bone marrow disorder, it can metastasize to extramedullary sites or it can present as a solitary extramedullary plasmacytoma. Primary pleural effusion from myeloma is rare, occurring in less than one percent of the patients. The following case report highlights a case of bilateral pleural effusion, directly attributable to multiple myeloma after other causes were ruled out. The diagnosis was made using cytology and immunohistochemical (IHC) staining of the pleural fluid. Myelomatous pleural effusion (MPE) is a poor prognostic feature heralding an aggressive underlying disease state, as represented in this case.

J Clin Oncol ; 31(32): 4060-6, 2013 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-24081946


PURPOSE: Etirinotecan pegol (NKTR-102) is a unique, long-acting topoisomerase-I inhibitor with prolonged systemic exposure to SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan. This randomized phase II trial investigated two dosing schedules of etirinotecan pegol in patients with platinum-resistant/refractory ovarian carcinoma. PATIENTS AND METHODS: A total of 71 eligible patients were randomly assigned to receive etirinotecan pegol 145 mg/m(2) every 14 or 21 days until progression or unacceptable adverse events (AEs). The primary end point was objective response rate (ORR) by RECIST (version 1.0). Secondary end points included response by Gynecologic Cancer Intergroup criteria, duration of ORR, progression-free survival (PFS), and overall survival (OS). RESULTS: The overall confirmed ORR was 20% (95% CI, 10% to 30%): 20% for once every 14 days, and 19% for once every 21 days. Median response duration was 4.1 months for once every 14 days and 4.0 months for once every 21 days. Median PFS for every 14 and every 21 days was 4.1 and 5.3 months, respectively, and median OS was 10.0 and 11.7 months, respectively. Etirinotecan pegol was well tolerated, with the most common grade 3 to 4 AEs being dehydration (24%) and diarrhea (23%). Diarrhea, dehydration, nausea, and neutropenia were less frequent with the schedule of once every 21 days than with that of once every 14 days. CONCLUSION: Both schedules of etirinotecan pegol showed activity in patients with heavily pretreated ovarian cancer, with encouraging ORR and PFS rates. The schedule of once every 21 days was better tolerated and had slightly longer PFS and OS rates. The treatment schedule of etirinotecan pegol 145 mg/m(2) once every 21 days was selected for the expanded phase II study and is preferred for future phase III studies. These findings provide support to directly compare etirinotecan pegol versus one of the approved drugs (eg, pegylated liposomal doxorubicin or topotecan) in platinum-resistant ovarian cancer.

Antineoplásicos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Compostos de Platina/uso terapêutico , Polietilenoglicóis/efeitos adversos , Resultado do Tratamento