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1.
ESMO Open ; 6(6): 100330, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34847382

RESUMEN

BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos de Fenilurea , Pronóstico , Quinolinas , Estudios Retrospectivos
2.
J Physiol Pharmacol ; 72(1)2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34272349

RESUMEN

The gold standard for the evaluation of liver fibrosis is histology. However, the heterogenous distribution of fibrosis limits the sensitivity of histology. The collection of two samples with a 16G needle is therefore recommended to reduce the risk of sampling error. The aim of this study was to investigate whether this standard is also applicable to patients with autoimmune hepatitis (AIH). This retrospective study included patients with AIH, who underwent mini-laparoscopic biopsy at our center between 2011 and 2020 (n = 32). Diagnosis was verified by usage of the simplified AIH score (≥ 6). Patients were categorized into three groups, based on the number of portal fields (PF) in the collected liver tissue (< 10 PF, 10 - 19 PF, ≥ 20 PF). We correlated the histological staging for these groups with the mini-laparoscopic fibrosis score (MLFS). Furthermore, non-invasive methods for the assessment of fibrosis were correlated with the histological staging (acoustic radiation force impulse (ARFI) and FIB-4 score). MLFS correlated well with histological staging (r = 0.649, p = 0.0001). The correlation between MLFS and histology improved with higher numbers of histologically analyzed portal fields (< 10 PF: r = 0.400, p = 0.378; 10 - 19 PF: r = 0.5467, p = 0.023; ≥ 20 PF: r = 0.956, p = 0.0002). The probability of collecting at least 10 or 20 portal fields was dependent on the number and diameter of the samples. For all patients with at least two 16G biopsies, 10 or more PF were available. With three 16G biopsies, at least 20 PF were obtained for all patients. ARFI correlated with MLFS and histological staging only in patients with low/moderate-grade inflammation as defined by ALT < 10xULN (upper limit of normal) (MLFS: r = 0.723; p = 0.004; histology: r = 0.619, p = 0.018). FIB-4 did not correlate with histological staging. The amount of liver tissue obtained by liver biopsy is crucial to minimalize the risk of sampling error and thus underestimation of fibrosis. This study was the first to investigate the amount of liver tissue required for histological staging in AIH. Our data suggest that diagnostic accuracy is likely to be higher with 20 PF compared to the generally recommended 10 PF. We therefore recommend to perform three biopsies with a 16G needle in (suspected) AIH patients. ARFI correlated well with histological staging unless inflammatory activity is high.


Asunto(s)
Hepatitis Autoinmune/diagnóstico , Cirrosis Hepática/diagnóstico , Hígado/patología , Adolescente , Adulto , Anciano , Biopsia/métodos , Femenino , Hepatitis Autoinmune/patología , Humanos , Inflamación/diagnóstico , Inflamación/patología , Laparoscopía , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Adulto Joven
3.
J Physiol Pharmacol ; 72(6)2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35485357

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) and cardiometabolic disorders are highly prevalent in obese individuals. Physical exercise is an important element in obesity and metabolic syndrome (MetS) treatment. However, the vast majority of individuals with obesity do not meet the general physical activity recommendations (i.e. 150 min of moderate activity per week). The present study aimed to investigate the impact of a highly time-saving high-intensity interval training (HIIT) protocol (28 min time requirement per week) on NAFLD fibrosis (NFS) and cardiometabolic risk scores in obese patients with MetS and elevated NFS values. Twenty-nine patients performed HIIT on cycle ergometers (5 x 1 min at an intensity of 80 - 95% maximal heart rate) twice weekly for 12 weeks and were compared to a control group without exercise (CON, n = 17). Nutritional counseling for weight loss was provided to both groups. NFS, cardiometabolic risk indices, MetS z-score, cardiorespiratory fitness (VO2max) and body composition were assessed before and after intervention. The HIIT (-4.3 kg, P < 0.001) and CON (-2.3 kg, P = 0.003) group significantly reduced body weight. There were no significant group differences in relative weight reduction (HIIT: -3.5%, CON: -2.4%). However, only the HIIT group improved NFS (-0.52 units, P = 0.003), MetS z-score (-2.0 units, P < 0.001), glycemic control (HbA1c: -0.20%, P = 0.014) and VO2max (+3.1 mL/kg/min, P < 0.001). Decreases in NFS (-0.50 units, P = 0.025) and MetS z-score (-1.4 units, P = 0.007) and the increment in VO2max (3.3 mL/kg/min, P < 0.001) were significantly larger in the HIIT than in the CON group. In conclusion, only 28 min of HIIT per week can elicit significant improvements in NFS and a several cardiometabolic health indices in obese MetS patients with increased NFS grades. Our results underscore the importance of exercise in NAFLD and MetS treatment and suggest that our low-volume HIIT protocol can be regarded as viable alternative to more time-consuming exercise programs.


Asunto(s)
Enfermedades Cardiovasculares , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Adulto , Fibrosis , Humanos , Síndrome Metabólico/terapia , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/terapia , Obesidad/complicaciones , Obesidad/terapia , Pérdida de Peso
4.
Support Care Cancer ; 28(5): 2431, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32056011

RESUMEN

The Acknowledgement Statement was incorrect in the original publication of this article [1] and the previous correction note [2]. The correct statement is as follows.

5.
J Physiol Pharmacol ; 71(5)2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33571964

RESUMEN

The systemic treatment of unresectable hepatocellular carcinoma (HCC) has been improved throughout the past years. Different tyrosine kinase inhibitors (TKI) and checkpoint inhibitors have approval for first- and second-line treatment. Still, data are missing about the choice for the right agent and senseful therapy sequences. Between 2017 and 2019 we treated 149 HCC patients. From those, we identified the patients, who received lenvatinib either as a first-line treatment or in a later treatment line. We investigated seven patients retrospectively, who received lenvatinib in second, third, or fourth treatment line regarding efficacy and safety. Besides that, we compared those patients with 13 patients, who received lenvatinib as a first-line treatment regarding duration of therapy, overall survivial (OS), side effects and best response to treatment. We discovered remission (PR) showed 4/7, stable disease (SD) 2/7 and 1/7 mixed response with an overall tolerable safety profile in patients with a later line lenvatinib treatment. The duration and overall survival for therapy is similar in first- and later treatment lines with comparable results. Most side effects are moderate in each treatment line. Remarkably, on patient diagnoses with HCC (the Barcelona Clinic Liver Cancer C algorithm), who received lenvatinib in fourth line reached 67 months OD since diagnosis. We conclude, that lenvatinib could be considered as a treatment option of HCC for later treatment lines.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/mortalidad , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Quinolinas/efectos adversos , Estudios Retrospectivos
6.
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
7.
Support Care Cancer ; 27(4): 1579, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30693392

RESUMEN

The "Acknowledgment Statement" of the published paper is incorrect. The correct statement should be the below: Acknowledgements We thank Sarah Vogel for her support in taste test realization and Yvonne Sauermann for preparation of the tastant solutions. The present work was carried out by Ms. Schalk in order to meet the requirements for the awarding of the title of Dr. med. at the FAU.

8.
Support Care Cancer ; 26(3): 843-851, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28948404

RESUMEN

PURPOSE: Cancer patients are at high risk of malnutrition and tumor cachexia further increasing morbidity and mortality. Reasons for cachexia are not clear yet, but inflammatory processes as well as the occurrence of taste disorders reducing nutrient uptake are discussed to play key roles. The purpose of this study was to gain insight into causative factors of taste disturbance in cancer patients. Does the cancer itself, inflammatory processes or cancer therapy influence taste disorders? METHODS: To capture an underlying taste disorder patients with cancer (n = 42), acutely hospitalized inflammatory disease patients (n = 57) and healthy controls (n = 39) were examined. To assess the influence of chemotherapy, patients with and without chemotherapy were compared. Taste tests were performed according to DIN ISO 3972:2011. Inflammation was recorded using laboratory parameters. Statistical evaluation was conducted using the Software R. RESULTS: Cancer patients showed significantly increased taste thresholds for sweet, salty, and umami compared to healthy controls. There were no significant differences in taste detection and recognition between patients with former, current, or without chemotherapeutical treatment. Patients with an acute inflammatory disease showed an increased taste threshold for umami compared to healthy controls. CONCLUSIONS: It could be shown that cancer patients suffer from taste disorders irrespective of an existing chemotherapeutical treatment. Cancer-related inflammation appears to have a greater impact on taste perception than an acute inflammatory process. Therefore, an adapted dietary adjustment should be carried out at an early stage for cancer patients in order to avoid nutritional disorders caused by a taste disorder.


Asunto(s)
Neoplasias/complicaciones , Trastornos del Gusto/etiología , Percepción del Gusto/fisiología , Enfermedad Aguda , Anciano , Femenino , Humanos , Inflamación , Masculino , Proyectos Piloto
9.
Eur J Surg Oncol ; 42(9): 1337-42, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27160353

RESUMEN

INTRODUCTION: In 2010, the seventh Tumour-Node-Metastasis (TNM) cancer staging system of the International Union for Cancer Control (UICC) and the American Joint Committee of Cancer (AJCC) introduced a subdivision of M1 in the TNM classification of colorectal carcinomas. For the eighth TNM edition which will be released in the autumn of 2016 and will become effective in January 2017 new proposals are appreciated. The aim of our study was to define a new and better proposal for M1 subclassification. METHODS: In a total of 814 patients with stage IV colorectal carcinoma treated between 1995 and 2013 prognostic factors were analysed in univariate and multivariate analyses. RESULTS: Advanced age, treatment in the earlier period 1995-2003, involvement of multiple metastatic sites, and non-curative resection were found to be independent prognostic factors. In patients with only one metastatic site, survival was good in patients with liver or lung metastasis, moderate in patients with metastasis of the peritoneum or non-regional lymph nodes and poor in patients with other rarely metastatic involved organs. The new proposal defines M1a, Metastasis confined to one organ: liver or lung (2-year survival 51.6%); M1b, Metastasis confined to one organ: peritoneum or non-regional lymph nodes, or Metastasis confined to liver plus lung (2-year survival 39.4%); and M1c, Metastasis confined to one organ: all other sites, or Metastasis in more than one organ, except liver plus lung (2-year survival 21.6%). CONCLUSION: The new proposal can identify three prognostic groups in stage IV colorectal carcinomas with significant differences in survival.


Asunto(s)
Carcinoma/secundario , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Ganglios Linfáticos/patología , Neoplasias Peritoneales/secundario , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Causas de Muerte , Niño , Femenino , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mortalidad , Análisis Multivariante , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Adulto Joven
10.
Ultraschall Med ; 36(6): 581-9, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26529354

RESUMEN

PURPOSE: Ultrasound is a well-established noninvasive test for assessing patients with liver disease. This study aims to prospectively compare ultrasound to the new technique elastography (ARFI) for the assessment of liver fibrosis/cirrhosis. MATERIALS AND METHODS: High-frequency B-mode ultrasound (liver surface/vein irregularity, liver homogeneity, spleen size), ARFI quantification, mini-laparoscopic liver evaluation including biopsy were prospectively obtained in compensated patients scheduled for liver biopsy. For the diagnosis of cirrhosis, a combined gold standard (cirrhosis at histology and/or at macroscopic liver evaluation) was used. RESULTS: Out of 157 patients, 35 patients were diagnosed cirrhotic. Ultrasound (combination of liver vein and/or surface irregularity) showed no significant difference compared to ARFI quantification for the diagnosis of significant liver fibrosis (Ishak> = 3) and cirrhosis. Diagnosis of cirrhosis had a sensitivity/specificity/PPV/NPV of 83 %(±â€Š12) / 82 %(±â€Š7) / 57 %(±â€Š14) / 94 %(±â€Š4), respectively, with ultrasound and 86 %(±â€Š12) / 81 %(±â€Š7) / 57 %(±â€Š13) / 95 %(±â€Š4), respectively, with ARFI quantification. The sensitivity/specificity/PPV/NPV for the detection of significant fibrosis were 68 %(±â€Š13) / 86 %(±â€Š7) / 71 %(±â€Š13) / 84 %(±â€Š7), respectively, for ultrasound and 70 %(±â€Š12) / 84 %(±â€Š7) / 69 %(±â€Š12) / 84 %(±â€Š7), respectively, for ARFI quantification. CONCLUSION: ARFI elastography and high-frequency B-mode ultrasound show similar and good results for the diagnosis of compensated liver cirrhosis and high-grade fibrosis. A key benefit of both methods is the high NPV suggesting them as noninvasive exclusion tests.


Asunto(s)
Diagnóstico por Imagen de Elasticidad/métodos , Laparoscopía/métodos , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/patología , Hígado/diagnóstico por imagen , Hígado/patología , Anciano , Biopsia/métodos , Medicina Basada en la Evidencia , Femenino , Venas Hepáticas/diagnóstico por imagen , Venas Hepáticas/patología , Humanos , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y Especificidad
12.
Br J Cancer ; 109(6): 1408-13, 2013 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-23963139

RESUMEN

BACKGROUND: Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer. METHODS: Two dose levels (I/II) were defined: capecitabine 850/1000 mg m(-2) twice daily on days 1-14; oxaliplatin 100/130 mg m(-2) on day 1; bevacizumab 7.5 mg kg(-1) on day 1; imatinib 300 mg day(-1) on days 1-21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS). RESULTS: Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities. CONCLUSION: The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Bevacizumab , Capecitabina , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Estudios Prospectivos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Resultado del Tratamiento
17.
Aliment Pharmacol Ther ; 33(11): 1183-93, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21457290

RESUMEN

BACKGROUND: Endocytoscopy (EC) enables in vivo microscopic imaging at 1400-fold magnification, thereby allowing the analysis of mucosal structures at the cellular level. In contrast to fluorescence imaging with confocal laser endomicroscopy which allows analysis of mucosal structures up to 250 µm in depth, EC is based on the principle of contact light microscopy and only allows visualisation of the very superficial mucosal layer. AIM: To systematically review the feasibility and diagnostic yield of EC for in vivo diagnosis of diseases. METHODS: A systematic search of the literature on diagnostic interventions in the gastrointestinal tract using EC was performed by searches in MEDLINE, Current Contents, PubMed, cross-references and references from relevant articles using the search terms 'endocytoscopy', 'endocytoscope', 'magnification endoscopy', 'endocytoscopic imaging', 'virtual histology' and 'optical biopsy'. Only full manuscripts and case reports published in English were included. RESULTS: Overall twenty-nine relevant reports were identified. EC was feasible to detect oesophageal squamous cell cancer with sensitivity, specificity and accuracy of 95%, 84% and 82%, respectively. Moreover, EC reached excellent sensitivity and specificity for in vivo diagnosis of colon polyps (91% and 100%, respectively). Other diagnostic applications of EC included diagnosis of Barrett's oesophagus, Helicobacter pylori, coeliac disease and small cell lung cancer. No serious complications of EC have yet been reported. CONCLUSIONS: Endocytoscopy is a safe and effective new endoscopic imaging technique to obtain in vivo histology and guided biopsies with high diagnostic accuracy. Therefore, endocytoscopy has the potential to facilitate both diagnosis and patient management.


Asunto(s)
Endoscopía Gastrointestinal/métodos , Enfermedades Gastrointestinales/diagnóstico , Tracto Gastrointestinal/ultraestructura , Enfermedades Gastrointestinales/patología , Humanos , Microscopía Confocal/métodos , Coloración y Etiquetado/métodos
18.
Gut ; 58(7): 1010-24, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19520891

RESUMEN

Gastrointestinal (GI) cancers are major health problems, being the most common cancers worldwide. Resistance to apoptosis is closely linked to carcinogenesis and enables malignant cells to evade therapy-induced cell death. In the recent past, the increasing understanding of molecular pathways of apoptosis has provided novel targets in cancer therapy. Several drugs, either inhibiting antiapoptotic signalling or actively inducing apoptosis in cancer cells, have already entered clinical trials. Until now, agents targeting apoptosis pathways are primarily being tested alone or in combination with chemotherapy. In the near future, personalized combination therapies will probably be beneficial for patients with GI cancer. In this review, the current knowledge on defects in apoptosis signalling in GI cancer is summarised and the focus is on the potential clinical efficacy of apoptosis targeting agents.


Asunto(s)
Apoptosis/fisiología , Neoplasias Gastrointestinales/terapia , Transducción de Señal/fisiología , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/inmunología , Regulación Neoplásica de la Expresión Génica , Humanos , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico
19.
Oncol Rep ; 15(1): 227-30, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16328060

RESUMEN

Hepatocellular carcinoma (HCC) is highly resistant to chemotherapy, leading to a poor prognosis of advanced disease. Inhibitors of histone deacetylase (HDACi) induce re-differentiation in tumor cells and thereby re-establish sensitivity towards apoptotic stimuli. HDACi are entering the clinical stage of tumor treatment, and several substances are currently being tested in clinical trials to prove their efficacy in the treatment of leukemias and solid tumors. In this study, we investigated the impact of the HDACi valproic acid (VA) on TRAIL- and CD95-mediated apoptosis in hepatoma cells, as well as its sensitizing effect on a chemotherapeutic agent. Treatment of HepG2 cells with VA increased sensitivity to CD95-mediated apoptosis (4% apoptosis vs. 42%), and treatment with epirubicin (74% vs. 90% viability). Caspase-3 activity was significantly enhanced in cells treated with VA plus anti-CD95 antibodies compared to cells treated with antibodies alone. In parallel, VA strongly augmented the effect of TNF-related apoptosis-inducing ligand (TRAIL or Apo2 ligand) on HepG2 cells (10% vs. 58% apoptosis). VA induced down-regulation of cellular FLICE-inhibitory protein (c-FLIP/CASH, also known as Casper/iFLICE/FLAME-1/CLARP/MRIT/usurpin), providing a possible molecular mechanism underlying the increased sensitivity towards cell death-mediated apoptosis. HDAC inhibitors are a promising class for the treatment of leukemias. In addition, among other class members, VA deserves further evaluation as a treatment option for patients with advanced HCC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis , Carcinoma Hepatocelular/tratamiento farmacológico , Inhibidores de Histona Desacetilasas , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Ácido Valproico/uso terapéutico , Proteínas Reguladoras de la Apoptosis/uso terapéutico , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Carcinoma Hepatocelular/enzimología , Caspasa 3 , Caspasas/metabolismo , Regulación hacia Abajo , Resistencia a Antineoplásicos/efectos de los fármacos , Epirrubicina/administración & dosificación , Epirrubicina/uso terapéutico , Humanos , Neoplasias Hepáticas/enzimología , Glicoproteínas de Membrana/uso terapéutico , Receptores del Factor de Necrosis Tumoral/agonistas , Ligando Inductor de Apoptosis Relacionado con TNF , Factor de Necrosis Tumoral alfa/uso terapéutico , Ácido Valproico/administración & dosificación , Receptor fas/metabolismo
20.
Br J Cancer ; 92(12): 2122-8, 2005 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-15942629

RESUMEN

An open-label randomised comparison of efficacy and tolerability of irinotecan plus high-dose 5-fluorouracil (5-FU) and leucovorin (LV) (ILF) with etoposide plus 5-FU/LV (ELF) in patients with untreated metastatic or locally advanced gastric cancer. One cycle of ILF comprised six once-weekly infusions of irinotecan 80 mg m(-2), LV 500 mg m(-2), 24-h 5-FU 2000 mg m(-2), and ELF comprised three once-daily doses of etoposide 120 mg m(-2), LV 300 mg m(-2), 5-FU 500 mg m(-2). In all, 56 patients received ILF and 58 ELF. Median age was 62 years, Karnofsky performance 90%, and disease status was comparable for both arms. The objective clinical response rates after 14 weeks treatment (primary end point) were 30% for ILF and 17% for ELF (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.29-1.13, P = 0.0766). Overall response rates over the entire treatment period for ILF and ELF were 43 and 24%, respectively (RR 0.56, 95% CI 0.33-0.97; P = 0.0467). For ILF and ELF, respectively, median progression-free survival was 4.5 vs 2.3 months, time to treatment failure was 3.6 vs 2.2 months (P = 0.4542), and overall survival was 10.8 vs 8.3 months (P = 0.2818). Both regimens were well tolerated, the main grade 3/4 toxicities being diarrhoea (18%, ILF) and neutropenia (57%, ELF). The data from this randomised phase II study indicate that ILF provides a better response rate than ELF, and that ILF should be investigated further for the treatment of metastatic gastric cancer.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/secundario , Adulto , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Unión Esofagogástrica , Etopósido/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Irinotecán , Leucovorina/administración & dosificación , Levoleucovorina , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Peritoneales/secundario , Neoplasias Gástricas/patología , Análisis de Supervivencia , Resultado del Tratamiento
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