RESUMEN
BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangitis Esclerosante , Anciano , Australia/epidemiología , Neoplasias de los Conductos Biliares/diagnóstico , Conductos Biliares Intrahepáticos/patología , Colangitis Esclerosante/diagnóstico , Colangitis Esclerosante/tratamiento farmacológico , Colangitis Esclerosante/patología , Diagnóstico Diferencial , Humanos , Inmunoglobulina G , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Estudios RetrospectivosRESUMEN
Fe2+, Mg2+ and Mn2+ are enzyme cofactors in terpenoids biosynthesis. Effects of pre-harvest spray of FeSO4, MgSO4 and MnSO4 (0.2% and 0.3%) 30â¯d prior to harvest on the levels of terpenoids and phenolic compounds in ripe mango fruit were investigated. All treatments significantly increased lupeol in the peel compared to control and it was highest in pulp of 0.3% FeSO4-treated fruit. Spray of each nutrient (0.3%) increased total carotenoids in the pulp. Mangiferin in pulp was significantly higher in the fruit treated with 0.2% FeSO4, MgSO4 and MnSO4 compared to control and 0.3%. Concentrations of gallic, ferulic and caffeic acids in the peel and chlorogenic acid in pulp and peel were highest in fruit sprayed with 0.2% FeSO4. In conclusion, pre-harvest spray of FeSO4, MgSO4 and MnSO4 regulates concentrations of terpenoids and phenolic compounds in the pulp and peel of ripe mango fruit.
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Compuestos Ferrosos/química , Hidroxibenzoatos/análisis , Sulfato de Magnesio/química , Compuestos de Manganeso/química , Mangifera/crecimiento & desarrollo , Sulfatos/química , Terpenos/análisis , Xantonas/análisis , Cromatografía Líquida de Alta Presión , Compuestos Ferrosos/metabolismo , Frutas/química , Frutas/metabolismo , Sulfato de Magnesio/metabolismo , Compuestos de Manganeso/metabolismo , Espectrofotometría , Sulfatos/metabolismoRESUMEN
Liquid chromatography-high resolution mass spectrometry (LC-HRMS) was used to investigate the degradation of ß-casomorphin 5 (ß-CM5) and ß-casomorphin 7 (ß-CM7) by Streptococcus thermophilus and/or Lactobacillus delbrueckii ssp. bulgaricus, and to identify the degradation products forming during yoghurt processing. Bovine UHT milk was fermented with: (i) a single strain of L. delbrueckii ssp. bulgaricus, (ii) a single strain of S. thermophilus and (iii) the mixture of S. thermophilus and L. delbrueckii ssp. bulgaricus to pH4.5 and then stored at 4°C for 1 and 7days. Results showed that L. delbrueckii ssp. bulgaricus and/or S. thermophilus completely degraded ß-CM5 and ß-CM7 upon fermentation to pH4.5 and degradation products were significantly influenced by bacteria strains and storage time. Four peptides, ß-CNf60-61 (YP), ß-CNf62-63 (FP), ß-CNf64-66 (GPI) and ß-CNf62-66 (FPGPI) were tentatively identified through high resolution MS/MS experiments; however, it was not possible to confirm if either milk protein or ß-casomorphins was a source releasing these peptides. Nonetheless, in this study peptides YP and GPI were released by L. delbrueckii ssp. bulgaricus. This is the first time GPI has been identified and thus future investigation of its bioactivity is warranted.
Asunto(s)
Endorfinas/metabolismo , Fermentación , Lactobacillus delbrueckii/metabolismo , Leche/microbiología , Péptidos/análisis , Streptococcus thermophilus/metabolismo , Yogur/microbiología , Animales , Bovinos , Cromatografía Liquida/métodos , Manipulación de Alimentos , Microbiología de Alimentos , Almacenamiento de Alimentos , Calor , Humanos , Proteínas de la Leche , Fragmentos de Péptidos/metabolismo , Proteolisis , Espectrometría de Masas en Tándem/métodosRESUMEN
This study investigated beta-casomorphin 7 (BCM7) in yogurt by means of LC-tandem MS (MS/MS) and enzyme-linked immunosorbent assay (ELISA) and use LC-MS/MS as the "gold standard" method to evaluate the applicability of a commercial ELISA. The level of BCM7 in milk obtained from ELISA analysis was much lower than that obtained by LC-MS/MS analysis and trended to increase during fermentation and storage of yogurt. Meanwhile, the results obtained from LC-MS/MS showed that BCM7 degraded during stages of yogurt processing, and its degradation may have been caused by X-prolyl dipeptidyl aminopeptidase activity. As a result, the commercial sandwich ELISA kit was not suitable for the quantification of BCM7 in fermented dairy milk.
Asunto(s)
Endorfinas/análisis , Ensayo de Inmunoadsorción Enzimática/métodos , Fragmentos de Péptidos/análisis , Yogur/análisis , Animales , Bovinos , Cromatografía Liquida/métodos , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Endorfinas/metabolismo , Fragmentos de Péptidos/metabolismo , Extracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodosRESUMEN
BACKGROUND: There are limited treatment options available for patients with advanced pancreatic ductal adenocarcinoma (PDAC). We conducted a phase II study evaluating the efficacy and safety of capecitabine/oxaliplatin (CAPOX) in patients with locally advanced and metastatic PDAC treated in the first and second lines. METHODS: Forty subjects with advanced PDAC and ECOG performance status ≥2 were enrolled. Treatment consisted of capecitabine 2,000 mg/m2 orally in two divided doses daily for 14 days and oxaliplatin 130 mg/m2 intravenously day 1 every 21 days. The primary endpoint was response rate (RR); secondary endpoints included safety analysis, progression free survival (PFS) and overall survival (OS). RESULTS: The overall RR was 12.5% (N=3); the disease control rate was 67% (N=16). Due to the protocol definition for eligibility of response evaluation, only 60% (N=24) were evaluable for the primary endpoint. Median progression free survival (mPFS) was 3.8 months (95% CI: 1.3, 6.2); median OS (mOS) was 7.4 months (95% CI: 4.8, 12.2). The most common grade 3/4 toxicities included: fatigue (19%), nausea (17%), and diarrhea (14%). CONCLUSIONS: CAPOX is an active regimen in patients with advanced PDAC and is associated with acceptable toxicity. Careful consideration should be given to response endpoints and outcome measures when studying this characteristically ill population.
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Antivirales/uso terapéutico , Accesibilidad a los Servicios de Salud , Hepatitis C Crónica/tratamiento farmacológico , Australia/epidemiología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/prevención & control , Carcinoma Hepatocelular/virología , Hepatitis C Crónica/epidemiología , Humanos , Cirrosis Hepática/mortalidad , Cirrosis Hepática/prevención & control , Cirrosis Hepática/virología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/virologíaRESUMEN
Milk proteins including casein are sources of peptides with bioactivity. One of these peptides is beta-casomorphin (BCM) which belongs to a group of opioid peptides formed from ß-casein variants. Beta-casomorphin 7 (BCM7) has been demonstrated to be enzymatically released from the A1 or B ß-casein variant. Epidemiological evidence suggests the peptide BCM 7 is a risk factor for development of human diseases, including increased risk of type 1 diabetes and cardiovascular diseases but this has not been thoroughly substantiated by research studies. High performance liquid chromatography coupled to UV-Vis and mass spectrometry detection as well as enzyme-linked immunosorbent assay (ELISA) has been used to analyze BCMs in dairy products. BCMs have been detected in raw cow's milk and human milk and a variety of commercial cheeses, but their presence has yet to be confirmed in commercial yoghurts. The finding that BCMs are present in cheese suggests they could also form in yoghurt, but be degraded during yoghurt processing. Whether BCMs do form in yoghurt and the amount of BCM forming or degrading at different processing steps needs further investigation and possibly will depend on the heat treatment and fermentation process used, but it remains an intriguing unknown.
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Queso/análisis , Endorfinas/análisis , Manipulación de Alimentos/métodos , Leche , Yogur/análisis , Animales , Cromatografía Líquida de Alta Presión , Productos Lácteos/análisis , Ensayo de Inmunoadsorción Enzimática , Fermentación , Calor , Espectrometría de Masas , Proteínas de la Leche/análisisRESUMEN
PURPOSE: N(1),N(11)-diethylnorspermine (DENSPM), a synthetic analog of the naturally occurring polyamine spermine, can induce polyamine depletion and inhibit tumor cell growth. The objectives of this phase I study were to assess the safety, maximum-tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of DENSPM in advanced HCC. METHODS: Patients with measurable advanced HCC, Child-Pugh A or B cirrhosis, CLIP score ≤3, and Karnofsky score ≥60 % were eligible. DENSPM was given as a short intravenous infusion on days 1, 3, 5, 8, 10, and 12 of each 28-day cycle. The starting dose of 30 mg/m(2) was escalated at a fixed increment of 15 mg/m(2) until the MTD was identified. The plasma pharmacokinetics of DENSPM for the first and last doses given in cycle 1 was characterized. RESULTS: Thirty-eight patients (male 79 %; median age 61 years; Child-Pugh A 84 %; ≥1 prior systemic therapy 45 %) were enrolled and treated. The most common adverse events (AEs) ≥grade 1 were fatigue (53 %), nausea (34 %), diarrhea (32 %), vomiting (32 %), anemia (29 %), and elevated AST (29 %). The most common grade 3-4 AEs were fatigue/asthenia (13 %), elevated AST (13 %), hyperbilirubinemia (11 %), renal failure (8 %), and hyperglycemia (8 %). The MTD was 75 mg/m(2). There were no objective responses, although 7/38 (18 %) patients achieved stable disease for ≥16 weeks. The overall mean (±SD) total body clearance for the initial dose, 66.3 ± 35.9 L/h/m(2) (n = 16), was comparable to the clearance in patients with normal to near normal hepatic function. Drug levels in plasma decayed rapidly immediately after the infusion but remained above 10 nM for several days after dosing at the MTD. CONCLUSIONS: N(1),N(11)-diethylnorspermine treatment at the MTD of 75 mg/m(2), given intravenously every other weekday for two consecutive weeks of each 28-day cycle, was relatively well tolerated in patients with advanced HCC including those with mild-to-moderate liver dysfunction. This administration schedule provided prolonged systemic exposure to potentially effective concentrations of the drug. Stable disease was seen in 18 % of patients receiving DENSPM treatment. Further evaluation of DENSPM monotherapy for advanced HCC does not appear to be justified because of insufficient evidence of clinical benefit in the patients evaluated in this study.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Espermina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/patología , Femenino , Humanos , Infusiones Intravenosas , Estado de Ejecución de Karnofsky , Pruebas de Función Hepática , Neoplasias Hepáticas/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Espermina/efectos adversos , Espermina/farmacocinética , Espermina/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: To assess the efficacy and safety of the anti-VEGF receptor-2 (VEGFR-2) antibody ramucirumab as first-line therapy in patients with advanced hepatocellular carcinoma and explore potential circulating biomarkers. EXPERIMENTAL DESIGN: Adults with advanced hepatocellular carcinoma and no prior systemic treatment received ramucirumab 8 mg/kg every two weeks until disease progression or limiting toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and overall survival (OS). Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients. RESULTS: Forty-two patients received ramucirumab. Median PFS was 4.0 months [95% confidence interval (CI), 2.6-5.7], ORR was 9.5% (95% CI, 2.7-22.6; 4/42 patients had a partial response), and median OS was 12.0 months (95% CI, 6.1-19.7). For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95% CI, 0.5-9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95% CI, 6.1-23.5) for patients with Child-Pugh A cirrhosis. Treatment-related grade ≥ 3 toxicities included hypertension (14%), gastrointestinal hemorrhage and infusion-related reactions (7% each), and fatigue (5%). There was one treatment-related death (gastrointestinal hemorrhage). After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2. CONCLUSION: Ramucirumab monotherapy may confer anticancer activity in advanced hepatocellular carcinoma with an acceptable safety profile. Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and sVEGFR-2 that are consistent with those seen with other anti-VEGF agents.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Antineoplásicos/farmacología , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Factor de Crecimiento Placentario , Proteínas Gestacionales/sangre , Modelos de Riesgos Proporcionales , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , RamucirumabRESUMEN
BACKGROUND: Both everolimus and temozolomide are associated with single-agent activity in patients with pancreatic neuroendocrine tumor (NET). A phase 1/2 study was performed to evaluate the safety and efficacy of temozolomide in combination with everolimus in patients who have advanced pancreatic NET. METHODS: Patients were treated with temozolomide at a dose of 150 mg/m(2) per day on days 1 through 7 and days 15 through 21 in combination with everolimus daily in each 28-day cycle. In cohort 1, temozolomide was administered together with everolimus at 5 mg daily. Following demonstration of safety in this cohort, subsequent patients in cohort 2 were treated with temozolomide plus everolimus at 10 mg daily. The duration of temozolomide treatment was limited to 6 months. Patients were followed for toxicity, radiologic and biochemical response, and survival. RESULTS: A total of 43 patients were enrolled, including 7 in cohort 1 and 36 in cohort 2. Treatment was associated with known toxicities of each drug; no synergistic toxicities were observed. Among 40 evaluable patients, 16 (40%) experienced a partial response. The median progression-free survival duration was 15.4 months. Median overall survival was not reached. CONCLUSIONS: Temozolomide and everolimus can be safely administered together in patients with advanced pancreatic NET, and the combination is associated with encouraging antitumor activity. Future studies evaluating the efficacy of combination therapy compared to treatment with either agent alone are warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Anciano , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Supervivencia sin Enfermedad , Esquema de Medicación , Everolimus , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Estudios Prospectivos , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Temozolomida , Resultado del TratamientoRESUMEN
PURPOSE: Both tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor and bevacizumab, a monoclonal antibody targeting VEGF, have antitumor activity in neuroendocrine tumors (NETs). Temozolomide, an oral analog of dacarbazine, also has activity against NETs when administered alone or in combination with other agents. We performed a phase II study to evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally advanced or metastatic NETs. PATIENTS AND METHODS: Thirty-four patients (56% with carcinoid, 44% with pancreatic NETs) were treated with temozolomide 150 mg/m(2) orally per day on days 1 through 7 and days 15 through 21, together with bevacizumab at a dose of 5 mg/kg per day intravenously on days 1 and 15 of each 28-day cycle. All patients received prophylaxis against Pneumocystis carinii and varicella zoster. Patients were followed for toxicity, biochemical and radiologic response, and survival. RESULTS: The combination of temozolomide and bevacizumab was associated with anticipated grade 3 to 4 toxicities, including lymphopenia (53%) and thrombocytopenia (18%). Although the overall radiographic response rate was 15% (five of 34), response rates differed between patients with pancreatic NETs (33%; five of 15) and those with carcinoid tumors (zero of 19). The median progression-free survival was 11.0 months (14.3 months for pancreatic NETs v 7.3 months for carcinoid tumors). The median overall survival was 33.3 months (41.7 months for pancreatic NETs v 18.8 months for carcinoid tumors). CONCLUSION: Temozolomide and bevacizumab can be safely administered together in patients with advanced NETs, and the combination regimen appears promising for patients with pancreatic NETs. Studies evaluating the relative contributions of these two agents to the observed antitumor activity are warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dacarbazina/análogos & derivados , Dacarbazina/administración & dosificación , Tumores Neuroendocrinos/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/mortalidad , Radiografía , Temozolomida , Resultado del TratamientoRESUMEN
Pancreatic cancer is the tenth most common cancer in the United States and the fourth leading cause of cancer death. Afflicting approximately 37,000 Americans yearly, more than 80% of patients are unresectable and, therefore, incurable at the time of their diagnosis. Although surgical resection offers the only opportunity for cure, it remains largely unsuccessful; most patients who are candidates for surgical resection relapse and die in fewer than 5 years. This mortality leaves a 5-year overall survival of about 4% for patients diagnosed with pancreatic cancer. Perhaps the most daunting realization for physicians involved in the management of this disease is the understanding that these numbers have not changed in more than 30 years. As surgery remains the foundation of curative therapy for pancreatic cancer, this article reviews the data on adjuvant chemotherapy and adjuvant chemotherapy with radiotherapy as efforts to boost cure rates.
Asunto(s)
Pancreatectomía , Neoplasias Pancreáticas/cirugía , Antimetabolitos Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Humanos , Terapia Neoadyuvante , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/radioterapia , Radioterapia Adyuvante , Ensayos Clínicos Controlados Aleatorios como Asunto , Programa de VERF , Análisis de Supervivencia , GemcitabinaRESUMEN
PURPOSE: In some reports, 5-fluorouracil has been associated with modest activity in patients with neuroendocrine tumors. Pemetrexed is a multitargeted antifolate with activity in tumor types not significantly responsive to other antifolates. We evaluated the efficacy of pemetrexed in a phase II study of patients with advanced neuroendocrine tumors. METHODS: Patients with metastatic neuroendocrine tumors (excluding small-cell carcinoma) were treated with pemetrexed administered intravenously at a dose of 500 mg/m(2) every 21 days. To reduce potential toxicity, patients also received folic acid, vitamin B12 supplementation, and peri-infusional treatment with dexamethasone. Patients were followed for response, toxicity, and survival. RESULTS: The study was designed with a total accrual goal of 32 patients. Due to lack of radiographic responses in patients during the study period, accrual was terminated at 17. However, one patient achieved a delayed partial response following discontinuation of pemetrexed. Ten patients were evaluable for biochemical response; five (50%) experienced >50% decrease in plasma chromogranin A. Among the 17 patients, 5 (29%) discontinued therapy due to treatment-related toxicity. The median overall survival was 12.1 months. CONCLUSION: Pemetrexed does not appear to have significant antitumor activity in patients with advanced neuroendocrine tumors. The limited antitumor activity and potential toxicity associated with pemetrexed mirrors experience with the majority of other cytotoxic agents in patients with neuroendocrine tumors. Investigation of novel, molecularly targeted agents may offer more promise in this disease.
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Antimetabolitos Antineoplásicos/uso terapéutico , Glutamatos/uso terapéutico , Guanina/análogos & derivados , Tumores Neuroendocrinos/tratamiento farmacológico , Adulto , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Dexametasona/uso terapéutico , Femenino , Ácido Fólico/uso terapéutico , Glutamatos/efectos adversos , Guanina/efectos adversos , Guanina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Tumores Neuroendocrinos/patología , Pemetrexed , Sobrevida , Resultado del Tratamiento , Vitamina B 12/uso terapéutico , Complejo Vitamínico B/uso terapéuticoRESUMEN
BACKGROUND: Previous phase 2 studies have shown antitumour activity with gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary-tract cancers (BTCs). In this phase 2 study, we assessed the efficacy and safety of combined bevacizumab with GEMOX (GEMOX-B) in patients with advanced BTCs, and investigated how changes in 18-fluorodeoxyglucose ([(18)F]FDG)-PET correlate with clinical outcome. METHODS: Patients with advanced measurable BTCs were given the following treatment on days 1 and 15 of a 28-day cycle: bevacizumab 10 mg/kg, followed by gemcitabine 1000 mg/m(2) (10 mg/m(2) per min) and oxaliplatin 85 mg/m(2) (2-h infusion). [(18)F]FDG-PET scans were obtained at baseline and after completion of the second cycle. The primary endpoint was progression-free survival (PFS). Efficacy and safety analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00361231. FINDINGS: 35 patients were enrolled and evaluable for efficacy and toxicity. Median PFS was 7.0 months (95% CI 5.3-10.3), and PFS at 6 months was 63% (47-79), which was below the targeted rate of 70%. Grade 3-4 toxic effects included neutropenia (n=7), raised alanine aminotransferase concentrations (n=5), peripheral neuropathy (n=5), and hypertension (n=5). [(18)F]FDG-PET scans showed a significant decrease in maximum standardised uptake value (SUV(max)) after two cycles of treatment (5.72 [SD 2.01] at baseline; 3.73 [SD 1.88] after two cycles; p<0.0001). These changes were more pronounced in patients with partial response or stable disease than those with progressive disease (24 patients, -2.80 [SD 1.95] vs five patients, 1.41 [SD 3.13]; p=0.009). Change in SUV(max) was a significant predictor of PFS (HR 1.35, 1.14-1.60, p=0.0006) and overall survival (1.25, 1.05-1.50, p=0.01). INTERPRETATION: GEMOX-B showed antitumour activity with tolerable safety in patients with advanced BTCs. Decreases in SUV(max) on [(18)F]FDG-PET scans after treatment were associated with disease control and increases in PFS and overall survival. FUNDING: Genentech Oncology and Sanofi-Aventis.
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Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/diagnóstico por imagen , Neoplasias del Sistema Biliar/tratamiento farmacológico , Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Radiofármacos , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Neoplasias del Sistema Biliar/mortalidad , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: Recent studies suggest that temozolomide has activity in neuroendocrine tumors. Low levels of the DNA repair enzyme, O(6)-methylguanine DNA methyltransferase (MGMT), are associated with sensitivity to temozolomide in other tumor types. We evaluated the prevalence of MGMT deficiency in neuroendocrine tumors and correlated MGMT deficiency with treatment response to temozolomide-based regimens. EXPERIMENTAL DESIGN: The prevalence of MGMT deficiency, measured by immunohistochemistry, was assessed in 97 archival neuroendocrine tumor specimens. Rates of treatment response and survival were next evaluated in a cohort of 101 consecutive neuroendocrine tumor patients who had received treatment with a temozolomide-based regimen at one of three institutions. MGMT expression was directly correlated with treatment response in 21 patients who had available tumor tissue and response data. RESULTS: In archival specimens, MGMT deficiency was observed in 19 of 37 (51%) pancreatic neuroendocrine tumors and 0 of 60 (0%) carcinoid tumors (P < 0.0001). In the clinical cohort, 18 of 53 (34%) patients with pancreatic neuroendocrine tumors but only 1 of 44 (2%) patients with carcinoid tumors (P < 0.001) experienced a partial or complete response to temozolomide-based therapy. Among 21 patients with evaluable tumor tissue who had also received treatment with temozolomide, 4 of 5 patients with MGMT-deficient tumors (all pancreatic neuroendocrine tumors) and 0 of 16 patients with tumors showing intact MGMT expression responded to treatment (P = 0.001). CONCLUSIONS: MGMT deficiency, measured by immunohistochemistry, is more common in pancreatic neuroendocrine tumors than in carcinoid tumors as is treatment response to temozolomide-based therapy. Absence of MGMT may explain the sensitivity of some pancreatic neuroendocrine tumors to treatment.
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Dacarbazina/análogos & derivados , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/enzimología , O(6)-Metilguanina-ADN Metiltransferasa/deficiencia , Antineoplásicos Alquilantes/uso terapéutico , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/enzimología , Dacarbazina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/enzimología , Temozolomida , Resultado del TratamientoRESUMEN
Pancreatic cancer is the fifth most common cause of cancer-related death in the USA. However, the antepartum diagnosis of pancreatic adenocarcinoma in the pregnant patient is exceedingly rare, with only six cases previously reported in the literature. Optimizing both maternal and fetal health outcomes is particularly challenging when surgical procedures are necessary for staging and/or therapeutic purposes--as these interventions often pose significant risks to both the mother and the developing fetus. In this article, we report a case of pancreatic adenocarcinoma diagnosed during pregnancy and review the literature on the management issues confronted in this unique clinical situation.
Asunto(s)
Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Complicaciones Neoplásicas del Embarazo/diagnóstico , Complicaciones Neoplásicas del Embarazo/terapia , Adulto , Femenino , Humanos , EmbarazoRESUMEN
PURPOSE: Standard cytotoxic chemotherapy has limited efficacy in metastatic neuroendocrine tumor patients. Neuroendocrine tumors express vascular endothelial growth factor (VEGF) and its receptor (VEGFR). Sunitinib malate, an oral tyrosine kinase inhibitor, has activity against VEGFRs as well as platelet-derived growth factor receptors, stem-cell factor receptor, glial cell line-derived neurotrophic factor, and FMS-like tyrosine kinase-3. We evaluated the efficacy of sunitinib in a two-cohort, phase II study of advanced carcinoid and pancreatic neuroendocrine tumor patients. PATIENTS AND METHODS: Patients were treated with repeated 6-week cycles of oral sunitinib (50 mg/d for 4 weeks, followed by 2 weeks off treatment). Patients were observed for response, survival, and adverse events. Patient-reported outcomes were assessed. RESULTS: Among 109 enrolled patients, 107 received sunitinib (carcinoid, n = 41; pancreatic endocrine tumor, n = 66). Overall objective response rate (ORR) in pancreatic endocrine tumor patients was 16.7% (11 of 66 patients), and 68% (45 of 66 patients) had stable disease (SD). Among carcinoid patients, ORR was 2.4% (one of 41 patients), and 83% (34 of 41 patients) had SD. Median time to tumor progression was 7.7 months in pancreatic neuroendocrine tumor patients and 10.2 months in carcinoid patients. One-year survival rate was 81.1% in pancreatic neuroendocrine tumor patients and 83.4% in carcinoid patients. No significant differences from baseline in patient-reported quality of life or fatigue were observed during treatment. CONCLUSION: Sunitinib has antitumor activity in pancreatic neuroendocrine tumors; its activity against carcinoid tumors could not be definitively determined in this nonrandomized study. Randomized trials of sunitinib in patients with neuroendocrine tumors are warranted.
Asunto(s)
Antineoplásicos/uso terapéutico , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/patología , Indoles/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Pirroles/administración & dosificación , Calidad de Vida , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Tumor Carcinoide/mortalidad , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/mortalidad , Medición de Riesgo , Método Simple Ciego , Sunitinib , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
There is no standard chemotherapy option for patients with biliary tract cancers. These patients present fairly ill and can have a rapid progression of disease. We conducted a multi-center, phase-II trial for patients with locally unresectable or metastatic bile duct or gallbladder adenocarcinomas using a modified regimen of gemcitabine and cisplatin to potentially improve tolerability. Patients received a 21-day treatment cycle of gemcitabine at 1,000 mg/m2 and cisplatin at 30 mg/m2 on days 1 and 8. To participate, 33 patients signed informed consent, and 30 patients received at least one dose of chemotherapy. By intention-to-treat analyses, 7 patients (21%) experienced a partial response and another 12 (36%) had stable disease for at least 12 weeks. The median progression-free survival was 6.3 months and median overall survival was 9.7 months. After 1 year, 39% of patients were alive. Most common grade 3-4 toxicities included neutropenia (33%), thrombocytopenia (23%), anemia (20%), nausea (20%), emesis (13%) and fatigue (10%). Of note, 52% of patients withdrew from study treatment, principally due to treatment-related adverse events. We concluded that this modified regimen appeared to have comparable activity to other gemcitabine and cisplatin regimens against advanced bile duct and gallbladder cancers, but there was still moderate toxicity in this patient population.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos , Colangiocarcinoma/tratamiento farmacológico , Cisplatino/administración & dosificación , Desoxicitidina/análogos & derivados , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adulto , Anciano , Neoplasias de los Conductos Biliares/mortalidad , Colangiocarcinoma/mortalidad , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Femenino , Neoplasias de la Vesícula Biliar/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , GemcitabinaRESUMEN
BACKGROUND AND AIMS: The life expectancy of patients with cystic fibrosis (CF) has been increasing and the associated liver disease has emerged as a significant medical issue. Our aim was to describe the clinical features, course and effect of ursodeoxycholic acid (UDCA) on liver disease in an adult CF population. STUDY: From 1983 to 2005, 278 patients with CF were followed up at the Alfred Hospital, an adult tertiary referral centre. Twenty-seven patients (9.7%) satisfied the criteria for liver disease and their clinico-pathological features were assessed. The effect of UDCA on hepatobiliary symptoms and biochemical parameters was determined. RESULTS: The mean age at liver disease diagnosis was 23 years (range 8-47 years). Portal hypertension was present in 18 (67%) patients. During a median follow-up of 7 years (range 1.5-15), variceal haemorrhage occurred in two patients and ascites in three (one spontaneously). Nine (33%) patients died and five (19%) underwent lung transplantation. There was no encephalopathy, liver transplantation or liver-related deaths. UDCA was taken by 22 patients and was associated with a significant improvement in hepatobiliary symptoms [11/22 (50%) in the pre-UDCA period vs 1/22 (4%) in the post-UDCA period; P=0.0003] and a significant reduction in aspartate aminotransferase (P=0.005); alanine aminotransferase (P<0.001); gamma-glutamyltranspeptidase (P=0.021); and alkaline phosphatase (P<0.001). CONCLUSIONS: Liver disease in adults with CF is commonly complicated by portal hypertension, but morbidity and mortality associated with this in our small patient population were low. UDCA is associated with improvement in hepatobiliary symptoms and liver function tests.