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1.
Clin Epigenetics ; 14(1): 3, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34991708

RESUMO

BACKGROUND: DNA mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is not responsive to pembrolizumab monotherapy. DNA methyltransferase inhibitors can promote antitumor immune responses. This clinical trial investigated whether concurrent treatment with azacitidine enhances the antitumor activity of pembrolizumab in mCRC. METHODS: We conducted a phase 2 single-arm trial evaluating activity and tolerability of pembrolizumab plus azacitidine in patients with chemotherapy-refractory mCRC (NCT02260440). Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg SQ on days 1-5, every 3 weeks. A low fixed dose of azacitidine was chosen in order to reduce the possibility of a direct cytotoxic effect of the drug, since the main focus of this study was to investigate its potential immunomodulatory effect. The primary endpoint of this study was overall response rate (ORR) using RECIST v1.1., and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Tumor tissue was collected pre- and on-treatment for correlative studies. RESULTS: Thirty chemotherapy-refractory patients received a median of three cycles of therapy. One patient achieved partial response (PR), and one patient had stable disease (SD) as best confirmed response. The ORR was 3%, median PFS was 1.9 months, and median OS was 6.3 months. The combination regimen was well-tolerated, and 96% of treatment-related adverse events (TRAEs) were grade 1/2. This trial was terminated prior to the accrual target of 40 patients due to lack of clinical efficacy. DNA methylation on-treatment as compared to pre-treatment decreased genome wide in 10 of 15 patients with paired biopsies and was significantly lower in gene promoter regions after treatment. These promoter demethylated genes represented a higher proportion of upregulated genes, including several immune gene sets, endogenous retroviral elements, and cancer-testis antigens. CD8+ TIL density trended higher on-treatment compared to pre-treatment. Higher CD8+ TIL density at baseline was associated with greater likelihood of benefit from treatment. On-treatment tumor demethylation correlated with the increases in tumor CD8+ TIL density. CONCLUSIONS: The combination of pembrolizumab and azacitidine is safe and tolerable with modest clinical activity in the treatment for chemotherapy-refractory mCRC. Correlative studies suggest that tumor DNA demethylation and immunomodulation occurs. An association between tumor DNA demethylation and tumor-immune modulation suggests immune modulation and may result from treatment with azacitidine. Trial registration ClinicalTrials.gov, NCT02260440. Registered 9 October 2014, https://clinicaltrials.gov/ct2/show/NCT02260440 .


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Azacitidina/uso terapêutico , Biomarcadores/sangue , Neoplasias Colorretais/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Adulto , Idoso , Epigenômica , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade
2.
Clin Gastroenterol Hepatol ; 20(4): 886-897, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-33278573

RESUMO

BACKGROUND & AIMS: The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response. METHODS: For 340 treatment-naïve and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis. RESULTS: Among treatment-naïve PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8th edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using a ≥47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥47% was an independent prognostic factor for improved OS (P = .007). CONCLUSIONS: The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/cirurgia , Endossonografia , Humanos , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Pancreatectomia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos
4.
Ann Surg Oncol ; 28(5): 2438-2446, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33523364

RESUMO

AIMS: National studies have demonstrated disparities in the treatment and survival of pancreatic cancer patients based on socioeconomic status (SES). This study aimed to identify specific differences in perioperative management and outcomes based on patient SES and to study the role of a multidisciplinary clinic (MDC) in mitigating any variations. METHODS: The study analyzed patients undergoing pancreaticoduodenectomy for pancreatic ductal adenocarcinoma in a large hospital system. The patients were categorized into groups of high and low SES and whether they were managed by the authors' pancreatic cancer MDC or not. The study compared differences in disease characteristics, receipt of multimodality therapy, perioperative outcomes, and recurrence-free and overall survival. RESULTS: Of the 162 low-SES patients and 119 high-SES patients, 54% were managed in the MDC. Outside the MDC, low-SES patients were less likely to receive neoadjuvant chemotherapy and had less minimally invasive surgery, a longer OR time, less enhanced recovery participation, and more major complications (p < 0.05). No SES disparities were observed among the MDC patients. Despite similar tumor characteristics, the low-SES patients had inferior median overall survival (21 vs 32 months; p = 0.005), but the MDC appeared to eliminate this disparity. Low SES correlated with inferior survival for the non-MDC patients (17 vs 32 months; p < 0.001), but not for the MDC patients (24 vs 25 months; p = 0.33). These findings persisted in the multivariable analysis. CONCLUSION: A pancreatic cancer MDC standardizes treatment decisions, eliminates disparities in surgical outcomes, and improves survival for low-SES patients.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/cirurgia , Disparidades em Assistência à Saúde , Humanos , Recidiva Local de Neoplasia , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Classe Social
5.
Mod Pathol ; 33(9): 1832-1843, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32376853

RESUMO

Mutations in RAS occur in 30-50% of metastatic colorectal carcinomas (mCRCs) and correlate with resistance to anti-EGFR therapy. Consequently, mCRC biomarker guidelines state RAS mutational testing should be performed when considering EGFR inhibitor treatment. However, a small subset of mCRCs are reported to harbor RAS amplification. In order to elucidate the clinicopathologic features and anti-EGFR treatment response associated with RAS amplification, we retrospectively reviewed a large cohort of mCRC patients that underwent targeted next-generation sequencing and copy number analysis for KRAS, NRAS, HRAS, BRAF, and PIK3CA. Molecular testing was performed on 1286 consecutive mCRC from 1271 patients as part of routine clinical care, and results were correlated with clinicopathologic findings, mismatch repair (MMR) status and follow-up. RAS amplification was detected in 22 (2%) mCRCs and included: KRAS, NRAS, and HRAS for 15, 5, and 2 cases, respectively (6-21 gene copies). Patients with a KRAS-amplified mCRC were more likely to report a history of inflammatory bowel disease (p < 0.001). In contrast, mutations in KRAS were associated with older patient age, right-sided colonic origin, low-grade differentiation, mucinous histology, and MMR proficiency (p ≤ 0.017). Four patients with a KRAS-amplified mCRC and no concomitant RAS/BRAF/PIK3CA mutations received EGFR inhibitor-based therapy, and none demonstrated a clinicoradiographic response. The therapeutic impact of RAS amplification was further evaluated using a separate, multi-institutional cohort of 23 patients. Eight of 23 patients with KRAS-amplified mCRC received anti-EGFR therapy and all 8 patients exhibited disease progression on treatment. Although the number of KRAS-amplified mCRCs is limited, our data suggest the clinicopathologic features associated with mCRC harboring a KRAS amplification are distinct from those associated with a KRAS mutation. However, both alterations seem to confer EGFR inhibitor resistance and, therefore, RAS testing to include copy number analyses may be of consideration in the treatment of mCRC.


Assuntos
Adenocarcinoma/complicações , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Colo/complicações , Resistencia a Medicamentos Antineoplásicos/genética , Doenças Inflamatórias Intestinais/complicações , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Receptores ErbB/antagonistas & inibidores , Feminino , Amplificação de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Panitumumabe/uso terapêutico , Estudos Retrospectivos , Adulto Jovem
6.
J Clin Pharmacol ; 57(8): 947-955, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28614591

RESUMO

Biologicals are a rapidly expanding class of medications used in the treatment of many different conditions. This article reviews the common characteristics of this class and the requirements for safe and effective use in patients. Several vignettes are included to illustrate common challenges.


Assuntos
Produtos Biológicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Competência Clínica , Humanos , Internato e Residência , Farmacologia Clínica
8.
Oncologist ; 9(3): 302-11, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15169985

RESUMO

Head and neck squamous cell carcinoma is a devastating disease with a poor outcome in advanced stages, accounting for approximately 3% of all malignancies, with an estimated 37200 new cases and 11000 deaths annually in the U.S. Second primary tumors are estimated to occur at an annual rate of 3%-10% and are significant threats to long-term survivors. Chemoprevention is an appealing strategy, and its success has been demonstrated in breast cancer and familial adenomatous polyposis. High-dose retinoids have been shown to be active against oral premalignant lesions and in prevention of second primary tumors in the head and neck. New targets include the epidermal growth factor receptor, cyclooxygenase-2, and other molecular targets. Challenges in future head and neck cancer chemoprevention investigations include achieving long-lasting efficacy with retinoids and/or new agents, and determining the optimal dose and duration of therapy while maintaining acceptable toxicities.


Assuntos
Carcinoma de Células Escamosas/prevenção & controle , Neoplasias de Cabeça e Pescoço/prevenção & controle , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Humanos
9.
Expert Opin Emerg Drugs ; 9(1): 91-104, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15155138

RESUMO

Head and neck squamous cell carcinoma is a devastating disease with poor outcomes in advanced stages. For patients with locally advanced disease, a multi-modality approach with chemotherapy and radiotherapy has been used. Despite advances in diagnosis and treatment, including improvements in radiation therapy, surgical techniques, chemotherapy and prevention strategies, survival rates for patients with recurrent head and neck cancer are poor. Several cytotoxic drugs with significant activities as single agents and/or combination regimens have shown high response rates, but over the past several years, significant improvement in survival has not been achieved. New drugs, including those that target the epidermal growth factor receptor, the p53 gene, RAS protein post-translational modification, the proteosome, vascular endothelial growth factor, cyclooxygenase-2 and other molecular pathways, are promising agents in the management of head and neck cancer. Their potential is being tested in various settings, including chemoprevention, recurrent and metastatic disease and combination with radiation therapy and/or cytotoxic agents.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/classificação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/prevenção & controle , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/terapia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Terapia Combinada , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Terapia Genética , Inibidores do Crescimento/farmacologia , Inibidores do Crescimento/uso terapêutico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/prevenção & controle , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Cuidados Paliativos , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento
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