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1.
Oncoimmunology ; 9(1): 1844403, 2020 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-33299655

RESUMEN

In head and neck squamous cell carcinoma (HNSCC), data from studies using checkpoint-inhibiting antibodies that target programmed death 1 (PD-1) or its ligand the programmed death ligand 1 (PD-L1) demonstrated outstanding clinical activity. Translational investigations also suggested some correlations between therapeutic response and PD-L1 expression in tumor tissue. We comprehensively summarize results that have evaluated PD-L1 expression in HNSCC. We discuss flaws and strength of current PD-1/PD-L1 detection, quantification methods and the evaluation of PD-L1 as a prognostic and theragnostic biomarker. Understanding tumor microenvironment may help understanding resistance to checkpoint inhibitors, designing clinical trials that can exploit drug combinations.


Asunto(s)
Antígeno B7-H1 , Neoplasias de Cabeza y Cuello , Antígeno B7-H1/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Microambiente Tumoral
2.
Clin Transl Gastroenterol ; 10(7): e00056, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31295152

RESUMEN

INTRODUCTION: Inhibition of tumor growth factor-ß (TGF-ß) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-ß1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment. METHODS: The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-ß1, safety, overall survival (OS), response rate, and pharmacokinetics (PK). RESULTS: Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-ß1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038). DISCUSSION: The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/patología , Pirazoles/uso terapéutico , Quinolinas/uso terapéutico , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Progresión de la Enfermedad , Quimioterapia Combinada/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Quinolinas/administración & dosificación , Quinolinas/farmacocinética , Seguridad , Sorafenib/administración & dosificación , Sorafenib/uso terapéutico , Factor de Crecimiento Transformador beta1/sangre , Factor de Crecimiento Transformador beta1/efectos de los fármacos , Resultado del Tratamiento , alfa-Fetoproteínas/efectos de los fármacos
3.
Encephale ; 45(5): 376-383, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30885444

RESUMEN

OBJECTIVES: The main objective of the study was to assess 25-hydroxyvitamin D (25(OH)D) status in a psychiatric population in France according to psychiatric diagnoses. The secondary objective was to investigate a correlation between 25(OH)D and CRP. METHODS: A retrospective study from February 1st, 2014 to January 31, 2016, was carried out in a French psychiatric hospital. Inpatients with a 25(OH)D measure were included. Variables including ethnic origin, BMI, psychiatric diagnoses, medical history and CRP were collected. Factors associated with 25(OH)D and CRP were studied in univariate and multivariate analyses, as was the correlation between 25(OH)D and CRP. RESULTS: Among 604 patients included, 80.6% presented 25(OH)D deficiency of which 46.9% with 25(OH)D<50nmol/L. 25(OH)D varied with age, ethnic origin, BMI, season, CRP and medical history. It was associated with schizophrenia in univariate analysis but not in multivariate analyses considering age and BMI. CRP varied with age, BMI and medical conditions but not with psychiatric diagnoses. 25(OH)D was inversely correlated with CRP. CONCLUSION: This psychiatric population was significantly more deficient in 25(OH)D than the French population in general. 25(OH)D was inversely correlated with CRP as observed in the general population.


Asunto(s)
Proteína C-Reactiva/metabolismo , Trastornos Mentales/sangre , Deficiencia de Vitamina D/sangre , Vitamina D/análogos & derivados , Adulto , Correlación de Datos , Estudios Transversales , Femenino , Francia , Hospitales Psiquiátricos/estadística & datos numéricos , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Inflamación/epidemiología , Inflamación/psicología , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/epidemiología , Trastornos Mentales/psicología , Valores de Referencia , Estudios Retrospectivos , Factores de Riesgo , Esquizofrenia/sangre , Esquizofrenia/epidemiología , Psicología del Esquizofrénico , Vitamina D/sangre , Deficiencia de Vitamina D/diagnóstico , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/psicología
6.
Crit Rev Oncol Hematol ; 111: 39-51, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28259294

RESUMEN

c-MET is a membrane spanning receptor tyrosine kinase for hepatocyte growth factor (HGF) also termed scatter factor. Transmitting signals from mesenchymal to epithelial cells, the HGF/c-MET axis mediates a range of biological processes that stimulate proliferation, motility, invasiveness, morphogenesis, apoptosis, and angiogenesis. Aberrant c-MET signal transduction favours tumorigenesis with the acquisition of invasive and metastatic phenotypes. Biological functions of c-MET may strongly vary according to microenvironmental changes, which occur at different stages of tumorigenesis and include also HGF/c-MET activation in stromal cells. In this review, we focused on abnormalities in non-nasopharyngeal squamous cell carcinoma of the head & neck. While the prevalence of c-MET mutations and amplifications ranges 0-25%, c-MET upregulation can be found in the majority of squamous head & neck carcinomas. Despite marked heterogeneity in published scoring methods, immunohistochemical overexpression of c-MET has been typically linked to advanced stages and associated with impaired survival and/or resistance to radiotherapy, chemoradiotherapy, and cetuximab. Experimental studies in cell lines and patient-derived xenografts using various c-MET antagonists (both as single-agents and in combination with cytotoxic and epidermal growth factor receptor [EGFR]-directed agents) yielded promising results, albeit benefit in clinical trials remains to be demonstrated. Consequently, selecting more active agents and integrating them effectively in studies, which incorporate predictive biomarkers such as c-MET gene mutations, amplifications, and overexpression, remains challenging. Further investigations should increase emphasis on disentangling the role of tumour-stromal interactions and analyse their potential as modifiers of drug response.


Asunto(s)
Carcinoma de Células Escamosas/enzimología , Neoplasias de Cabeza y Cuello/enzimología , Proteínas Proto-Oncogénicas c-met/metabolismo , Animales , Humanos , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello
7.
Ann Oncol ; 28(2): 339-343, 2017 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-27836885

RESUMEN

BACKGROUND: In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan-Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses. RESULTS: Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1-20.6) months for sunitinib and 5.8 (3.8-7.2) months for placebo (HR, 0.32; 95% CI 0.18-0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (HR, 0.73; 95% CI 0.50-1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib. CONCLUSIONS: BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib. TRIAL REGISTRATION NUMBER: NCT00428597.


Asunto(s)
Indoles/administración & dosificación , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Pirroles/administración & dosificación , Antineoplásicos/administración & dosificación , Estudios Transversales , Supervivencia sin Enfermedad , Método Doble Ciego , Humanos , Estimación de Kaplan-Meier , Tumores Neuroendocrinos/diagnóstico por imagen , Neoplasias Pancreáticas/diagnóstico por imagen , Modelos de Riesgos Proporcionales , Sunitinib , Tasa de Supervivencia
9.
Rev Med Suisse ; 11(475): 1149-51, 2015 May 20.
Artículo en Francés | MEDLINE | ID: mdl-26152091

RESUMEN

In hepatocellular carcinoma, sorafenib is the only active medical treatment validated to date. Sorafenib is a targeted therapy mainly blocking tumor vascularisation. Sorafenib is currently used for inoperable or advanced stages of hepatocellular carcinoma, as well for hepatocellular carcinoma recurrence when the disease is diffuse or multifocal. Current clinical trials are designed to identify new antitumor molecules active in hepatocellular carcinoma that could enrich the therapeutic armamentarium in addition to sorafenib.


Asunto(s)
Carcinoma Hepatocelular/terapia , Ensayos Clínicos como Asunto , Neoplasias Hepáticas/terapia , Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Carcinoma Hepatocelular/patología , Ensayos Clínicos como Asunto/estadística & datos numéricos , Progresión de la Enfermedad , Humanos , Neoplasias Hepáticas/patología , Niacinamida/análogos & derivados , Selección de Paciente , Compuestos de Fenilurea , Sorafenib
10.
Br J Cancer ; 112(1): 86-94, 2015 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-25422908

RESUMEN

BACKGROUND: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus. METHODS: In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence. RESULTS: Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis. CONCLUSIONS: In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/irrigación sanguínea , Carcinoma de Células Renales/patología , Diferenciación Celular/efectos de los fármacos , Esquema de Medicación , Everolimus , Femenino , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Neoplasias Renales/irrigación sanguínea , Neoplasias Renales/patología , Ratones , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Pirroles/administración & dosificación , Pirroles/efectos adversos , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sirolimus/análogos & derivados , Sunitinib , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Curr Oncol ; 21(6): 309-17, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25489258

RESUMEN

Molecular strategies to improve outcomes for patients with pancreatic neuroendocrine tumours (nets) have focused on targeting vascular endothelial growth factor, platelet-derived growth factor, and mtor (the mammalian target of rapamycin). This approach has led to the regulatory approval of two molecularly targeted agents for advanced pancreatic nets: sunitinib, a multi-targeted tyrosine kinase inhibitor, and everolimus, an mtor inhibitor. Initial experience with sunitinib in advanced pancreatic net was gained from the phase iii registration trial, which used a continuous daily dosing (cdd) schedule instead of daily drug administration for 4 consecutive weeks every 6 weeks (schedule 4/2), the approved schedule for advanced renal cell carcinoma (rcc) and gastrointestinal stromal tumour (gist). Clinical experience gained with schedule 4/2 in rcc and gist shows that, using a therapy management approach, patients can start and be maintained on the recommended dose and schedule, thus optimizing treatment outcomes. Here, we discuss challenges that can potentially be faced by physicians who use sunitinib on the cdd schedule, and we use clinical data and real-life clinical experience to present therapy management approaches that support cdd in advanced pancreatic net.

12.
Cancer Metastasis Rev ; 33(1): 361-6, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24452757

RESUMEN

The systemic management of patients with pancreatic neuroendocrine tumors includes chemotherapy and targeted agents such as everolimus and sunitinib. Which treatment to favor in a particular patient is not known. The most commonly used chemotherapy agents are streptozocin and temozolamide, often prescribed in combination with fluoropyrimidines. A potential biomarker for selection of temozolomide-based chemotherapy is O-6-methylguanine-DNA-methyltrasferase expression. Chemotherapy yields higher response rates and may be preferable in patients with higher-grade tumors and those who are symptomatic. The mammalian target of rapamycin inhibitor everolimus has shown improvement in progression-free survival (PFS) in a robust, well-conducted phase III study. Everolimus, however, can induce limiting toxicities that may result in treatment discontinuation and does not improve survival. However, the objective response rate is very low. Sunitinib, likewise, increases PFS but the data comes from a smaller trial which was terminated early. Sunitinib displays a different toxicity profile and is associated with a trend towards improved overall survival. It is clear that biomarkers to properly select the most effective agents in an individual patient are needed.


Asunto(s)
Indoles/uso terapéutico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Pirroles/uso terapéutico , Sirolimus/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Supervivencia sin Enfermedad , Everolimus , Humanos , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/enzimología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/enzimología , Sirolimus/uso terapéutico , Sunitinib , Resultado del Tratamiento , Proteínas Supresoras de Tumor/metabolismo
13.
Invest New Drugs ; 32(1): 94-103, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23539344

RESUMEN

INTRODUCTION: MSC1992371A is an aurora kinase inhibitor with potential antitumor activity. METHODS: This trial established the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral MSC1992371A given before or after gemcitabine (1,000 mg/m(2)) in a 21-day cycle in patients with advanced malignancies. In schedule 1 (n = 31), gemcitabine was administered on days 1 and 8 followed by escalating doses of MSC1992371A on days 2 and 9. In schedule 2 (n = 35), MSC1992371A was given on days 1 and 8 followed by gemcitabine on days 2 and 9. Patients had a range of solid tumors, the most frequent of which was colorectal (n = 19). RESULTS: In both schedules, the 37 mg/m(2) dose level was defined as the MTD. The main DLT was grade 4 neutropenia. Adverse events consisted of neutropenia, thrombocytopenia, asthenia, fatigue, nausea, vomiting, anorexia, and diarrhea. Administration of MSC1992371A prior to gemcitabine had no effect on the metabolism or elimination of gemcitabine. Time to reach maximum plasma concentration and area under the plasma concentration-time curve for MSC1992371A increased proportionally with dose. Exploration of drug-target-related and tumor biomarkers did not identify predictors of biologic activity or response. Two patients (1 with lung carcinoma and 1 with hepatocellular carcinoma) had durable partial responses in schedule 2, and 5 patients had stable disease (SD) lasting 6 - 14 months. CONCLUSION: Oral MSC1992371A can be administered at a MTD of 37 mg/m(2) in combination with the standard 1,000 mg/m(2) dose of gemcitabine, but hematologic toxicity requires careful monitoring. Preliminary signs of efficacy were indicated by durable responses and SD.


Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Norbornanos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Demografía , Desoxicitidina/análogos & derivados , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/sangre , Norbornanos/efectos adversos , Norbornanos/sangre , Norbornanos/farmacocinética , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/sangre , Pirimidinas/farmacocinética , Adulto Joven , Gemcitabina
14.
Dig Dis ; 30 Suppl 2: 143-9, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23207947

RESUMEN

Surgery remains the best curative treatment for resectable patients with colorectal liver metastases. In patients initially considered unresectable, both refinements in surgical technique using portal vein occlusion or two-step resections and increased efficiency of chemotherapy regimen with the adjunction of antiangiogenics now allow secondary resection. Recent evidence suggests almost identical long-term survival in case of secondary downstaged lesions advocating an aggressive approach. However, these data lie on disparate and nonconsensual criteria for unresectability, which often do not gather technical and oncologic components together. Furthermore, both impaired general status and damaged underlying parenchyma as a consequence of prolonged chemotherapy to achieve resectability as well as the technical challenge required to perform adequate carcinologic resection could increase the operative risk in such patients. In our experience, a subgroup of slow chemo-responding initially unresectable patients who required preoperative liver volume modulation after ≥ 12 cycles of chemotherapy to achieve sufficient response experienced dramatically high operative risk which jeopardized postoperative chemotherapy and subsequently put these patients at increased risk of recurrence. Whether all patients preoperatively amenable to surgery using intensive chemotherapy and complex surgical strategy actually benefit from such an aggressive approach is a matter of ongoing debate, which needs a reappraisal.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/patología , Hepatectomía , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Antineoplásicos/efectos adversos , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Estadificación de Neoplasias , Resultado del Tratamiento
15.
Br J Cancer ; 105(11): 1640-5, 2011 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-22027711

RESUMEN

BACKGROUND: BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1-3, platelet-derived growth factor receptors α and ß, and fibroblast growth factor receptors 1-3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients. METHODS: This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m(-2), every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity. RESULTS: Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ≥50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone. CONCLUSION: Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m(-2) of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Administración Oral , Anciano , Antígenos/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Progresión de la Enfermedad , Docetaxel , Relación Dosis-Respuesta a Droga , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Indoles/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Hormono-Dependientes/metabolismo , Neoplasias Hormono-Dependientes/patología , Prednisona/administración & dosificación , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Taxoides/administración & dosificación , Taxoides/farmacocinética
16.
Br J Cancer ; 104(2): 272-80, 2011 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-21179031

RESUMEN

BACKGROUND: Pralatrexate is a dihydrofolate reductase (DHFR) inhibitor with high affinity for reduced folate carrier 1 (RFC-1) and folylpolyglutamate synthetase (FPGS), resulting in extensive internalization and accumulation in tumour cells. Pralatrexate is approved in the US for the treatment of relapsed or refractory peripheral T-cell lymphoma and is being investigated in various malignancies. Here, we evaluated molecular correlates of sensitivity to pralatrexate and explored combinations with a variety of anticancer agents. METHODS: Antiproliferative effects of pralatrexate were evaluated in 15 human-cancer cell lines using the MTT assay. Gene expression was evaluated using qRT-PCR. RESULTS: Pralatrexate and methotrexate had a similar pattern of cytotoxicity, pralatrexate being more potent. Pralatrexate potentiated the effects of platinum drugs, antimetabolites and EGFR inhibitors. Dose- and time-dependent cytotoxicity of pralatrexate correlated with high mRNA expression of FPGS. Acquired resistance to pralatrexate was associated with decreased RFC-1 expression, whereas methotrexate resistance correlated with increased DHFR expression, suggesting different mechanisms of acquired resistance. CONCLUSION: Pralatrexate was more potent than methotrexate in a panel of solid tumour lines. Our findings support the further clinical development of pralatrexate in combination with certain cytotoxics and targeted therapies, and suggest that RFC-1, FPGS and DHFR may be potential biomarkers of outcome.


Asunto(s)
Aminopterina/análogos & derivados , Antineoplásicos/farmacología , Antagonistas del Ácido Fólico/farmacología , Aminopterina/administración & dosificación , Aminopterina/farmacología , Antineoplásicos/administración & dosificación , Apoptosis , Western Blotting , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Antagonistas del Ácido Fólico/administración & dosificación , Humanos , Metotrexato/administración & dosificación , Metotrexato/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
17.
Bull Cancer ; 96(10): 989-1004, 2009 Oct.
Artículo en Francés | MEDLINE | ID: mdl-19793686

RESUMEN

Basaloid squamous cell carcinomas (SCC) are a rare variant of SCC of the head and neck. Their histological characteristics have been described by Wain in 1986 and are reported in the 2005 WHO classification. A poorer prognosis of BSCC has been reported. Two recent case-control studies have shown a higher rate of distant metastases (15-40%, mean over 30%). Conversely, BSCC have similar or better locoregional control rates, a relatively good radiosensitivity and locoregional control. The role of chemotherapy in the neoadjuvant, concomitant or adjuvant setting needs to be redefined due to high metastatic failure rates; chest CT or PET CT are recommended at baseline and every 6-month during follow-up. Some subgroups of BSCC (oropharynx in particular) are more likely to be associated with oncogenic human papilloma virus HPV16. The determination of BSCC head and neck subgroups by HPV status is critical for the prognosis. The basaloid sub-type of squamous cell carcinomas owing to its particular behavior, should be taken into account while deciding the optimal therapeutic strategy.


Asunto(s)
Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virología , Terapia Combinada/métodos , Diagnóstico Diferencial , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/virología , Humanos , Infecciones por Papillomavirus/complicaciones , Vacunas contra Papillomavirus/administración & dosificación , Pronóstico , Radioterapia
18.
Bull Cancer ; 96(5): 553-61, 2009 May.
Artículo en Francés | MEDLINE | ID: mdl-19467986

RESUMEN

Hepatocellular carcinoma (HCC) is one of the 5th most common cancers around the world with a limited number of systemic therapeutic options. Cytotoxic agents, hormonotherapy and immunotherapy have failed to demonstrate benefit compared to best supportive care in patients with advanced HCC. The recent development of targeted therapies provided hope for the treatment of advanced HCC. We reviewed phases II-III trials presented in 2007 and 2008. Results are promising with a clinical benefit reported with molecular therapies targeting EGF/EGFR and VEGF/VEGFR pathways.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Receptores ErbB/antagonistas & inhibidores , Neoplasias Hepáticas/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Carcinoma Hepatocelular/irrigación sanguínea , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Predicción , Humanos , Neoplasias Hepáticas/irrigación sanguínea , Inhibidores de Proteínas Quinasas/uso terapéutico
19.
Bull Cancer ; 96(4): 405-15, 2009 Apr.
Artículo en Francés | MEDLINE | ID: mdl-19357015

RESUMEN

Cholangiocarcinoma represents the second most common primary hepatobiliary cancer. Although few patients are candidates for surgery, surgical resection represents the only potential curative option. The prognosis for patients remains poor, despite advances in the understanding of mechanisms involved in carcinogenesis. This review aims to assess clinicopathological factors and biological markers for the ability to predict prognosis. Clinicopathologic factors most often cited are tumor size, lymph node involvement, resecability and surgical margins involvement. Molecular biomarkers have been examined and a number of these, including mdm2, p27, matrix metalloproteinases and vitamin D receptor appear to have prognostic utility. The advent of 'omic'-based profiling offers the potential to assess many different biomarkers at the same time. This 'protein/gene signature' could open the way for developing valid and reproducible predictors of survival based on protein or gene profiles.


Asunto(s)
Neoplasias de los Conductos Biliares , Conductos Biliares Intrahepáticos , Colangiocarcinoma , Apoptosis/genética , Neoplasias de los Conductos Biliares/clasificación , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Adhesión Celular , Ciclo Celular , Colangiocarcinoma/clasificación , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Receptores ErbB/metabolismo , Humanos , Metástasis Linfática/patología , Invasividad Neoplásica , Proteínas de Neoplasias/metabolismo , Estadificación de Neoplasias , Neoplasia Residual , Neovascularización Patológica/complicaciones , Pronóstico , Receptor ErbB-2/metabolismo
20.
Rev Med Interne ; 30(5): 416-24, 2009 May.
Artículo en Francés | MEDLINE | ID: mdl-19299048

RESUMEN

Targeted therapies are widely used in cancer because of their effectiveness, even in tumours that are resistant to conventional chemotherapy such as kidney or hepatocellular carcinomas. There are different families classified according to their mode of action. The antiangiogenics block tumor angiogenesis by acting on VEGF or its receptor. The main molecules are bevacizumab, sunitinib, and sorafinib. HER inhibitors work by blocking these receptors, which control different signaling intracellular pathways, and include an inhibitor of HER2, trastuzumab, and various inhibitors of HER1, or EGFR, including cetuximab, erlotinib, and gefitinib. Inhibitors of KIT, a membrane receptor, are mainly represented by imatinib, an inhibitor of tyrosine kinase. Finally, mTOR inhibitors act on the signaling pathway PI3K/AKT/mTOR, and key molecules are temsirolimus, everolimus, and deforolimus.


Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptores ErbB/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Bencenosulfonatos/administración & dosificación , Bevacizumab , Clorhidrato de Erlotinib , Everolimus , Gefitinib , Humanos , Indoles/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/administración & dosificación , Pirroles/administración & dosificación , Quinazolinas/administración & dosificación , Receptor ErbB-2/efectos de los fármacos , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Sorafenib , Sunitinib
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