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1.
Cell ; 170(5): 875-888.e20, 2017 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-28757253

RESUMEN

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.


Asunto(s)
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Elementos de Facilitación Genéticos , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 3-alfa del Hepatocito/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Epigenómica , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Metástasis de la Neoplasia , Organoides/metabolismo , Páncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología
2.
Nature ; 618(7964): 374-382, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37225988

RESUMEN

Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.


Asunto(s)
Vesículas Extracelulares , Ácidos Grasos , Hígado Graso , Hígado , Neoplasias Pancreáticas , Animales , Ratones , Sistema Enzimático del Citocromo P-450/genética , Vesículas Extracelulares/metabolismo , Ácidos Grasos/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Hígado Graso/metabolismo , Hígado Graso/prevención & control , Hígado/metabolismo , Hígado/patología , Hígado/fisiopatología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Microambiente Tumoral , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo , Neoplasias Hepáticas/secundario , Humanos , Inflamación/metabolismo , Ácido Palmítico/metabolismo , Macrófagos del Hígado , Fosforilación Oxidativa , Proteínas rab27 de Unión a GTP/deficiencia
3.
J Natl Compr Canc Netw ; 22(6): 366-375, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-39151454

RESUMEN

The determination of an optimal treatment plan for an individual patient with rectal cancer is a complex process. In addition to decisions relating to the intent of rectal cancer surgery (ie, curative or palliative), consideration must also be given to the likely functional results of treatment, including the probability of maintaining or restoring normal bowel function/anal continence and preserving genitourinary functions. Particularly for patients with distal rectal cancer, finding a balance between curative-intent therapy while having minimal impact on quality of life can be challenging. Furthermore, the risk of pelvic recurrence is higher in patients with rectal cancer compared with those with colon cancer, and locally recurrent rectal cancer is associated with a poor prognosis. Careful patient selection and the use of sequenced multimodality therapy following a multidisciplinary approach is recommended. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Rectal Cancer, including the addition of endoscopic submucosal dissection as an option for early-stage rectal cancer, updates to the total neoadjuvant therapy approach based on the results of recent clinical trials, and the addition of a "watch-and-wait" nonoperative management approach for clinical complete responders to neoadjuvant therapy.


Asunto(s)
Neoplasias del Recto , Humanos , Neoplasias del Recto/terapia , Neoplasias del Recto/diagnóstico , Neoplasias del Recto/patología , Terapia Neoadyuvante/métodos , Terapia Neoadyuvante/normas , Terapia Combinada/métodos , Estadificación de Neoplasias , Oncología Médica/normas , Oncología Médica/métodos
4.
J Natl Compr Canc Netw ; 22(2 D)2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38862008

RESUMEN

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.


Asunto(s)
Neoplasias del Colon , Humanos , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/terapia , Neoplasias del Colon/patología , Neoplasias del Colon/tratamiento farmacológico , Oncología Médica/normas , Oncología Médica/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estados Unidos
5.
J Natl Compr Canc Netw ; 21(6): 653-677, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37308125

RESUMEN

This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.


Asunto(s)
Neoplasias del Ano , Carcinoma de Células Escamosas , Humanos , Biopsia , Oncología Médica
6.
J Natl Compr Canc Netw ; 20(10): 1139-1167, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36240850

RESUMEN

This selection from the NCCN Guidelines for Rectal Cancer focuses on management of malignant polyps and resectable nonmetastatic rectal cancer because important updates have been made to these guidelines. These recent updates include redrawing the algorithms for stage II and III disease to reflect new data supporting the increasingly prominent role of total neoadjuvant therapy, expanded recommendations for short-course radiation therapy techniques, and new recommendations for a "watch-and-wait" nonoperative management technique for patients with cancer that shows a complete response to neoadjuvant therapy. The complete version of the NCCN Guidelines for Rectal Cancer, available online at NCCN.org, covers additional topics including risk assessment, pathology and staging, management of metastatic disease, posttreatment surveillance, treatment of recurrent disease, and survivorship.


Asunto(s)
Neoplasias del Recto , Humanos , Oncología Médica , Terapia Neoadyuvante , Neoplasias del Recto/diagnóstico , Neoplasias del Recto/patología , Neoplasias del Recto/terapia
7.
J Natl Compr Canc Netw ; 19(3): 329-359, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33724754

RESUMEN

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.


Asunto(s)
Neoplasias del Colon , Biosimilares Farmacéuticos , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/genética , Neoplasias del Colon/terapia , Reparación de la Incompatibilidad de ADN , Humanos , Inestabilidad de Microsatélites , Mutación
8.
J Natl Compr Canc Netw ; 18(7): 806-815, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32634771

RESUMEN

The NCCN Guidelines for Rectal Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with rectal cancer. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines. These updates include clarifying the definition of rectum and differentiating the rectum from the sigmoid colon; the total neoadjuvant therapy approach for localized rectal cancer; and biomarker-targeted therapy for metastatic colorectal cancer, with a focus on new treatment options for patients with BRAF V600E- or HER2 amplification-positive disease.


Asunto(s)
Neoplasias del Colon , Neoplasias del Recto , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/terapia , Humanos , Terapia Neoadyuvante , Guías de Práctica Clínica como Asunto , Neoplasias del Recto/diagnóstico , Neoplasias del Recto/terapia
9.
J Natl Compr Canc Netw ; 17(9): 1109-1133, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31487687

RESUMEN

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced stage, outcomes for SBA are worse on average than for other related malignancies, including colorectal cancer. Due to the rarity of this disease, few studies have been done to direct optimal treatment, although recent data have shown that SBA responds to treatment differently than colorectal cancer, necessitating a separate approach to treatment. The NCCN Guidelines for Small Bowel Adenocarcinoma were created to establish an evidence-based standard of care for patients with SBA. These guidelines provide recommendations on the workup of suspected SBA, primary treatment options, adjuvant treatment, surveillance, and systemic therapy for metastatic disease. Additionally, principles of imaging and endoscopy, pathologic review, surgery, radiation therapy, and survivorship are described.


Asunto(s)
Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Neoplasias Intestinales/diagnóstico , Neoplasias Intestinales/terapia , Intestino Delgado/patología , Guías de Práctica Clínica como Asunto , Adenocarcinoma/etiología , Adenocarcinoma/mortalidad , Terapia Combinada , Diagnóstico Diferencial , Humanos , Neoplasias Intestinales/etiología , Neoplasias Intestinales/mortalidad , Estadificación de Neoplasias , Factores de Riesgo , Supervivencia , Resultado del Tratamiento , Espera Vigilante
10.
Cancer ; 124(4): 688-697, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29211295

RESUMEN

BACKGROUND: The authors hypothesized that patients with metastatic colorectal cancer (mCRC) who had tumors with low thymidylate synthase (TS-L) expression would have a higher response rate to combined 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab (FOLFOX/Bev) than those with high TS (TS-H) expression and that combined irinotecan and oxaliplatin (IROX) plus bevacizumab (IROX/Bev) would be more effective than FOLFOX/Bev in those with TS-H tumors. METHODS: TS protein expression was determined in mCRC tissue. Patients who had TS-L tumors received FOLFOX/Bev, and those who had TS-H tumors were randomly assigned to receive either FOLFOX/Bev or IROX/Bev. The primary endpoint was the response rate (complete plus partial responses). RESULTS: In total, 211 of 247 patients (70% TS-H) were registered to the treatment phase. Efficacy analyses included eligible patients who had started treatment (N = 186). The response rates for patients who received IROX/Bev (TS-H), FOLFOX/Bev (TS-H), and FOLFOX/Bev (TS-L) were 33%, 38%, and 49%, respectively (P = nonsignificant). The median progression-free survival (PFS) was 10 months (95% confidence interval [CI], 9-12 months; 10 months in the IROX/Bev TS-H group, 9 months in the FOLFOX/Bev TS-H group, and 13 months in the FOLFOX/Bev TS-L group). The TS-L group had improved PFS compared with the TS-H group that received FOLFOX/Bev (hazard ratio, 1.6; 95% CI, 1.0%-2.4%; P = .04; Cox regression). The median overall survival (OS) was 22 months (95% CI, 20 29 months; 18 months in the IROX/Bev TS-H group, 21 months in the FOLFOX/Bev TS-H group, and 32 months in the TS-L group). OS comparisons for the 2 TS-H arms and for the FOLFOX/Bev TS-H versus TS-L arms were not significantly different. CONCLUSIONS: TS expression was prognostic: Patients with TS-L tumors who received FOLFOX/Bev had a longer PFS than those with TS-H tumors, along with a trend toward longer OS. Patients with TS-H tumors did not benefit more from IROX/Bev than from FOLFOX/Bev. Cancer 2018;124:688-97. © 2017 American Cancer Society.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Timidilato Sintasa/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab/administración & dosificación , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Oxaliplatino/administración & dosificación , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del Tratamiento
11.
J Natl Compr Canc Netw ; 16(4): 359-369, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29632055

RESUMEN

The NCCN Guidelines for Colon Cancer provide recommendations regarding diagnosis, pathologic staging, surgical management, perioperative treatment, surveillance, management of recurrent and metastatic disease, and survivorship. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel discussions for the 2018 update of the guidelines regarding risk stratification and adjuvant treatment for patients with stage III colon cancer, and treatment of BRAF V600E mutation-positive metastatic colorectal cancer with regimens containing vemurafenib.


Asunto(s)
Neoplasias del Colon/diagnóstico , Neoplasias del Colon/terapia , Neoplasias del Colon/etiología , Humanos
12.
J Natl Compr Canc Netw ; 16(7): 852-871, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-30006428

RESUMEN

The NCCN Guidelines for Anal Carcinoma provide recommendations for the management of patients with squamous cell carcinoma of the anal canal or perianal region. Primary treatment of anal cancer usually includes chemoradiation, although certain lesions can be treated with margin-negative local excision alone. Disease surveillance is recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is essential for optimal patient care.


Asunto(s)
Neoplasias del Ano/terapia , Carcinoma de Células Escamosas/terapia , Oncología Médica/normas , Recurrencia Local de Neoplasia/terapia , Sociedades Médicas/normas , Canal Anal/patología , Canal Anal/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Ano/diagnóstico , Neoplasias del Ano/epidemiología , Neoplasias del Ano/patología , Biopsia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/patología , Quimioradioterapia/métodos , Quimioradioterapia/normas , Colostomía/normas , Supervivencia sin Enfermedad , Humanos , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Grupo de Atención al Paciente/normas , Ensayos Clínicos Controlados Aleatorios como Asunto , Estados Unidos/epidemiología
13.
J Natl Compr Canc Netw ; 16(7): 874-901, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-30006429

RESUMEN

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Rectal Cancer address diagnosis, staging, surgical management, perioperative treatment, management of recurrent and metastatic disease, disease surveillance, and survivorship in patients with rectal cancer. This portion of the guidelines focuses on the management of localized disease, which involves careful patient selection for curative-intent treatment options that sequence multimodality therapy usually comprised of chemotherapy, radiation, and surgical resection.


Asunto(s)
Oncología Médica/normas , Recurrencia Local de Neoplasia/terapia , Neoplasias del Recto/terapia , Sociedades Médicas/normas , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Quimioradioterapia/métodos , Quimioradioterapia/normas , Supervivencia sin Enfermedad , Humanos , Incidencia , Quimioterapia de Inducción/métodos , Terapia Neoadyuvante/métodos , Terapia Neoadyuvante/normas , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Selección de Paciente , Proctectomía/métodos , Proctectomía/normas , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias del Recto/diagnóstico , Neoplasias del Recto/epidemiología , Neoplasias del Recto/patología , Recto/patología , Recto/cirugía , Estados Unidos/epidemiología , Espera Vigilante/métodos , Espera Vigilante/normas
14.
J Natl Compr Canc Netw ; 15(3): 370-398, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28275037

RESUMEN

This portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease. Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy have included treatment history, extent of disease, goals of treatment, the efficacy and toxicity profiles of the regimens, KRAS/NRAS mutational status, and patient comorbidities and preferences. Location of the primary tumor, the BRAF mutation status, and tumor microsatellite stability should also be considered in treatment decisions.


Asunto(s)
Neoplasias del Colon/diagnóstico , Neoplasias del Colon/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/etiología , Neoplasias del Colon/mortalidad , Terapia Combinada , Manejo de la Enfermedad , Progresión de la Enfermedad , Humanos , Metástasis de la Neoplasia , Estadificación de Neoplasias , Retratamiento , Factores de Tiempo , Resultado del Tratamiento
15.
Pharm Res ; 34(3): 564-578, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27995525

RESUMEN

PURPOSES: To determine the pharmacokinetic parameters and biodistribution of GDC-0449 loaded polymeric micelles after systemic administration into common bile duct ligation (CBDL) induced liver fibrotic mice. METHODS: We used GDC-0449 encapsulated methoxy poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylene carbonate)-graft-dodecanol (PEG-PCD) non-targeted polymeric micelles for GDC-0449 delivery to normal and liver fibrotic mice. To maximize GDC-0449 delivery to hepatic stellate cells (HSCs), mixed micelles formulations with 10, 20 and 30% w/w mannose-6-phosphate (M6P)-conjugated micelles were administered to normal and liver fibrotic mice for targeting M6P/IGF-IIR overexpressed on activated HSCs and biodistribution of GDC-0449 was determined at 30 and 120 min post systemic administration. RESULTS: GDC-0449 distributed to all major organs after systemic administration of drug loaded micelles, with higher accumulation in the liver of both normal and fibrotic mice. The plasma concentration versus time profiles suggest rapid clearance of GDC-0449 after systemic administration of drug loaded micelles in both normal and fibrotic mice, with similar plasma clearance (CL), area under the curve (AUCint) and volume of distribution at steady state (Vss). However, there is significant increase in GDC-0449 accumulation in the liver when M6P-conjugated mixed micelles were injected, with the highest GDC-0449 concentration in the liver with mixed micelles carrying 30% M6P-conjugated polymer. HSCs accounted for 14.19% of GDC-0449 accumulation for M6P-targeted micelles in fibrotic mice compared to 5.62% of non-targeted micelles in the liver uptake study. CONCLUSION: M6P-conjugated GDC-0449 loaded mixed micelles may be used as a potential drug delivery vehicle for treating liver fibrosis.


Asunto(s)
Anilidas/farmacocinética , Cirrosis Hepática/metabolismo , Piridinas/farmacocinética , Anilidas/administración & dosificación , Anilidas/química , Animales , Química Farmacéutica , Portadores de Fármacos , Liberación de Fármacos , Células Estrelladas Hepáticas/metabolismo , Humanos , Hígado/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Masculino , Manosafosfatos/química , Ratones Endogámicos C57BL , Micelas , Poliésteres/química , Polietilenglicoles/química , Piridinas/administración & dosificación , Piridinas/química , Propiedades de Superficie , Distribución Tisular
16.
Cancer ; 121(21): 3862-8, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-26242208

RESUMEN

BACKGROUND: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU). METHODS: Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m(2) on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m(2) /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase. RESULTS: Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity. CONCLUSIONS: The recommended dose of PDX was 148 mg/m(2) . A subset of heavily pretreated patients had PFS durations of ≥6 months with this regimen.


Asunto(s)
Aminopterina/análogos & derivados , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Aminopterina/administración & dosificación , Aminopterina/efectos adversos , Aminopterina/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Antagonistas del Ácido Fólico/administración & dosificación , Antagonistas del Ácido Fólico/efectos adversos , Antagonistas del Ácido Fólico/uso terapéutico , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Mucositis/inducido químicamente , Mucositis/epidemiología , Polimorfismo Genético/genética , Tetrahidrofolato Deshidrogenasa/sangre , Tetrahidrofolato Deshidrogenasa/genética , Timidilato Sintasa/sangre , Timidilato Sintasa/genética , Factores de Tiempo , Resultado del Tratamiento
17.
Cancer Invest ; 33(5): 172-9, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25844818

RESUMEN

PURPOSE: To evaluate the maximum tolerated dose, safety profile, pharmacokinetics, and pharmacodynamics of pegaspargase (PEG-ASP) in combination with gemcitabine in patients with advanced metastatic solid tumors and lymphoma. METHODS: We conducted a multicenter, open label, nonrandomized, Phase 1 dose escalation study designed to evaluate up to 10 cohorts of patients with advanced or metastatic solid tumors and lymphoma. Seventeen patients were treated with of PEG-ASP in combination with gemcitabine. RESULTS: The study was terminated early because the doses for PEG-ASP suggested for de-escalation were predicted not to provide desired sustained asparaginase concentrations based on the analysis of treated patients.


Asunto(s)
Asparaginasa/administración & dosificación , Desoxicitidina/análogos & derivados , Linfoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Asparaginasa/antagonistas & inhibidores , Asparaginasa/farmacocinética , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Linfoma/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias/patología , Polietilenglicoles/farmacocinética , Gemcitabina
18.
J Natl Compr Canc Netw ; 13(6): 719-28; quiz 728, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26085388

RESUMEN

The NCCN Guidelines for Rectal Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Rectal Cancer Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize major discussion points from the 2015 NCCN Rectal Cancer Panel meeting. Major discussion topics this year were perioperative therapy options and surveillance for patients with stage I through III disease.


Asunto(s)
Neoplasias del Recto/terapia , Terapia Combinada , Humanos , Guías de Práctica Clínica como Asunto , Neoplasias del Recto/diagnóstico
19.
Br J Clin Pharmacol ; 80(2): 267-75, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25752914

RESUMEN

AIM: This study evaluated the influence of CYP2C19 polymorphisms on the pharmacokinetics of nelfinavir and its metabolite M8 in patients with pancreatic cancer. METHODS: Nelfinavir was administered orally to patients for over 10 days. The plasma concentrations of nelfinavir and M8 were measured by HPLC. The genotypes of CYP2C19*1, CYP2C19*2 and CYP2C19*3 were determined by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: Pharmacokinetic profiles of nelfinavir and M8 were characterized by wide interindividual variability. The mean Cmax of nelfinavir in CYP2C19*1/*1 patients was 3.89 ± 0.40 (n = 3) and 5.12 ± 0.41 (n = 30) µg ml(-1) , while that of CYP2C19*1/*2 patients was 3.60 (n = 1) and 6.14 ± 0.31 (n = 5) µg ml(-1) at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. For the M8 metabolite, the mean Cmax of CYP2C19*1/*1 patients was 1.06 ± 0.06 (n = 3) and 1.58 ± 0.27 (n = 30) µg ml(-1) , while those of CYP2C19*1/*2 patients were 1.01 (n = 1) and 1.23 ± 0.15 (n = 5) µg ml(-1) at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The area under the plasma concentration-time curve (AUC(0,12 h)) values of nelfinavir for CYP2C19*1/*1 patients were 28.90 ± 1.27 and 38.90 ± 4.99 µg ml(-1) ·h and for CYP2C19*1/*2 patients, AUC(0,12 h) was 28.20 (n = 1) and 40.22 ± 3.17 (n = 5) µg ml(-1) ·h at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The Cmax of nelfinavir was significantly higher (P <0.05) in CYP2C19*1/*2 patients but there was no statistical difference in AUC(0,12 h). CONCLUSION: CYP2C19*1/*2 genotype modestly affected the pharmacokinetic profiles of nelfinavir and M8 in patients with locally advanced pancreatic cancer.


Asunto(s)
Antineoplásicos/farmacocinética , Citocromo P-450 CYP2C19/genética , Nelfinavir/farmacocinética , Neoplasias Pancreáticas/tratamiento farmacológico , Polimorfismo de Longitud del Fragmento de Restricción , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nelfinavir/administración & dosificación , Nelfinavir/sangre , Nelfinavir/uso terapéutico , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/enzimología
20.
J Natl Compr Canc Netw ; 12(7): 1028-59, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24994923

RESUMEN

The NCCN Guidelines for Colon Cancer address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease,and survivorship. This portion of the guidelines focuses on the use of systemic therapy in metastatic disease. The management of metastatic colorectal cancer involves a continuum of care in which patients are exposed sequentially to a variety of active agents, either in combinations or as single agents. Choice of therapy is based on the goals of treatment, the type and timing of prior therapy, the different efficacy and toxicity profiles of the drugs, the mutational status of the tumor, and patient preference.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/cirugía , Neoplasias Hepáticas/secundario , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Capecitabina , Cetuximab , Neoplasias del Colon/patología , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Progresión de la Enfermedad , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , GTP Fosfohidrolasas/genética , Humanos , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Proteínas de la Membrana/genética , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Oxaloacetatos , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras) , Resultado del Tratamiento , Proteínas ras/genética
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