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1.
Chronobiol Int ; 32(10): 1359-66, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26540634

RESUMEN

Seasonal variation of baseline diagnosis (or clinical suspect) of stage I-III colorectal cancer patients has been repeatedly reported as an independent variable influencing overall survival. However, data are conflicting and no information is available about such a rhythm in advanced stage patients. To test whether a circannual rhythm of efficacy outcomes can be detected in this setting, we collected data about response rate (RR), progression-free survival (PFS), and overall survival (OS) to first-line chemotherapy of 1610 newly diagnosed metastatic patients treated at four independent centers. Responses to first-line chemotherapy were available for 1495 patients. A strong circannual rhythm in RR was evident, with the higher proportion of responding patients in the subgroup diagnosed in January (acrophase). At the time of data cutoff, 1322 patients progressed and 986 died, with median PFS and OS of 11 and 25.6 months, respectively. A circannual rhythmicity of the proportion of patients progressing at 6 months and surviving at 1 year was demonstrated, with acrophases located both in winter (February and January, respectively), similar to what reported for RR. Several interpretations about the genesis of this cyclic variation could be claimed: the rhythm in sunlight exposure and, as a consequence, of vitamin D serum levels and folate degradation, the variability in toxic effect intensity of chemotherapy, and the rhythm in the biological behavior of tumor cells. This observation is worth of further investigation both in preclinical and in clinical settings in order to better elucidate the underlying mechanisms.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ritmo Circadiano/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Camptotecina/administración & dosificación , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , Resultado del Tratamiento
2.
Ann Oncol ; 25(8): 1597-603, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24827133

RESUMEN

BACKGROUND: Biliary tract cancer (BTC) is a highly lethal disease for which the best available therapy remains undetermined. The mammalian target of rapamycin (mTOR) pathway is up-regulated in several cancers, including BTC, and preclinical evidence indicates that mTOR inhibition may be effective in the treatment of BTC. We sought to evaluate the activity and tolerability of the mTOR inhibitor RAD001-everolimus-in patients with BTC progressing after prior chemotherapy. PATIENTS AND METHODS: This was an open-label, single-arm, phase II study (EUDRACT 2008-007152-94) conducted in eight sites in Italy. Patients with locally advanced, metastatic or recurrent BTC progressing despite previous chemotherapy received a daily oral dose of everolimus 10 mg administered continuously in 28-day cycles. The two primary end points were disease control rate (DCR) and objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS) and time-to-progression (TTP). RESULTS: Thirty-nine patients were enrolled. The DCR was 44.7%, and the ORR was 5.1%. One patient showed a partial response at 2 months and one patient showed a complete response sustained up to 8 months. The median (95% confidence interval) PFS was 3.2 (1.8-4.0) months, and the median OS was 7.7 (5.5-13.2) months. The median TTP was 2.0 (1.7-3.7) months. Most common toxicities were asthenia (43.6%), thrombocytopenia (35.9%), pyrexia (30.8%) and erythema, mainly of mild-to-moderate severity. Two patients required dose reduction due to adverse events. CONCLUSION: Everolimus demonstrated a favourable toxicity profile and encouraging anti-tumour activity. Further trials are needed to establish the role of everolimus in the treatment of BTC. EUDRACT 2008-007152-94.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Sirolimus/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/mortalidad , Neoplasias del Sistema Biliar/patología , Quimioterapia Adyuvante , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Everolimus , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/uso terapéutico , Calidad de Vida , Sirolimus/uso terapéutico , Análisis de Supervivencia
3.
Br J Cancer ; 108(8): 1743-9, 2013 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-23558893

RESUMEN

BACKGROUND: As epidermal growth factor receptor (EGFR) is involved in the pathogenesis of malignant pleural mesotheliomas (MPMs), the anti-EGFR drugs may be effective in treating MPM patients. Mutations of the EGFR gene or its downstream effectors may cause constitutive activation leading to cell proliferation, and the inhibition of apoptosis and metastases. Consequently, molecular profiling is essential for select patients with MPM who may respond to anti-EGFR therapies. METHODS: After manual macrodissection, genomic DNA was extracted from 77 histological samples of MPM: 59 epithelioid, 10 biphasic, and 8 sarcomatoid. Epidermal growth factor receptor gene mutations were sought by means of real-time polymerase chain reaction (PCR) and direct sequencing, KRAS gene mutations by mutant-enriched PCR, and PIK3CA and BRAF gene mutations by direct sequencing. RESULTS: Gene mutations were identified in nine cases (12%): five KRAS, three BRAF, and one PI3KCA mutation; no EGFR gene mutations were detected. There was no difference in disease-specific survival between the patients with or without gene mutations (P=0.552). CONCLUSIONS: Mutations in EGFR downstream pathways are not rare in MPM. Although none of those found in this study seemed to be prognostically significant, they may support a more specific selection of patients for future trials.


Asunto(s)
Receptores ErbB/genética , Mesotelioma/genética , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Formaldehído , Humanos , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Adhesión en Parafina , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras) , Transducción de Señal , Fijación del Tejido , Factores de Transcripción/genética , Proteínas ras/genética
4.
Clin Lab ; 58(11-12): 1211-8, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23289191

RESUMEN

BACKGROUND: The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultra-metabolizers, UMs). The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects. METHODS: 61 women with ER+ breast cancer receiving tamoxifen monotherapy were investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genotyping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology. RESULTS: A highly significant difference was detected (41.2% of difference, 95% CI 6 - 61%, Fisher's exact test, p = 0.030) between the numbers of Ultrarapid Metabolizer patients (UM; high activity) with two or more adverse drug reactions to tamoxifen (7/9; 77.8%), compared to the number of Extensive Metabolizers (EM; normal activity), Intermediate Metabolizers (IM; reduced activity), and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5%). A similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM/EM/IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005). CONCLUSIONS: Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence.


Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Citocromo P-450 CYP2D6/genética , Tamoxifeno/uso terapéutico , Neoplasias de la Mama/diagnóstico , Diagnóstico Precoz , Femenino , Genotipo , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos
5.
Int J Oncol ; 34(1): 69-77, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19082479

RESUMEN

p27Kip1 is a nuclear member of the Kip/Cip family of cyclin-dependent kinase inhibitors and is a negative cell cycle regulator that is thought to play a role in tumour suppression. Reduced levels of p27Kip1 are frequent in human cancers and these have been associated with poor prognosis. We have analysed p27Kip1 expression and intracellular localization in 70 human colorectal cancers by western blotting and immunohistochemistry and the results related to Akt expression and clinical pathological parameters. p27Kip1 protein expression, as evaluated by western blotting, was absent or reduced in about 63% of colorectal cancers compared with both peritumoral and normal tissue. Cytoplasmic p27Kip1 was detected, by immunohistochemical analysis, in 30% (21 of 70) of cases indicating that translocation of p27Kip1 protein into the cytoplasm may be responsible for p27Kip1 inactivation. The analysis of phosphorylated Akt by western blotting indicated that it was expressed in 38% (8 of 21) of tumours showing cytoplasmic p27Kip1. Patients whose cancer presented accumulation of cytoplasmic p27Kip1 showed poorer outcomes for cancer-related relapse and survival. These results suggest that cytoplasmic p27Kip1 localization, associated or not with Akt activation, may contribute to colorectal tumorigenesis and metastasis and it may be useful as a negative prognostic factor for the outcome of patients with colorectal cancer.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Citoplasma/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Núcleo Celular/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/secundario , Activación Enzimática , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Fosforilación , Pronóstico , Tasa de Supervivencia
6.
Radiol Med ; 114(1): 1-17, 2009 Feb.
Artículo en Inglés, Italiano | MEDLINE | ID: mdl-19082787

RESUMEN

PURPOSE: The aim of this pilot study was to compare positron emission tomography computed tomography (PET-CT) and whole-body DWIBS in staging oncological patients to determine the staging accuracy of whole-body DWIBS. MATERIALS AND METHODS: We initiated a prospective, blinded investigation on 29 patients affected by oncological diseases (n=14) or lymphoma (n=15), who underwent fluorodeoxyglucose (FDG)-based PET-CT and whole-body DWIBS for restaging purposes. Magnetic resonance (MR) imaging was conducted with a multistack (n=4) DWIBS pulse sequence. Images were read independently by two experienced radiologists and one nuclear physician. Statistical analysis assessed interobserver agreement and diagnostic accuracy. RESULTS: Whole-body DWIBS had a room occupation time of 20 min. Mean postprocessing time was 15 min (range 10-17 min). Mean reading time was 20 min for reader 1 (range 15-25 min) and 18 min for reader 2 (range 13-22 min). Interobserver agreement was almost perfect (=0.93). Reader 1 had a sensitivity of 89.07%, a specificity of 98.5%, and an accuracy of 97.65%, with a positive predictive value (PPV) of 85.48% and a negative predictive value (NPV) of 98.91%. Reader 2 had a sensitivity of 87.39%, a specificity of 98.39% and a diagnostic accuracy of 97.8%, with a PPV of 88.13% and a NPV of 98.75%. CONCLUSIONS: The whole-body DWIBS protocol provided a fast whole-body examination with high specificity and NPV. One major bias of the study was the inclusion of patients with diffuse disease and advanced disease stage and the heterogeneity of the neoplastic diseases included.


Asunto(s)
Imagen de Difusión por Resonancia Magnética/métodos , Neoplasias/diagnóstico , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Imagen de Cuerpo Entero/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Interpretación Estadística de Datos , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Variaciones Dependientes del Observador , Proyectos Piloto , Programas Informáticos
7.
Eur J Cancer ; 44(17): 2615-22, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18805000

RESUMEN

AIM: To describe the healthcare resource consumption of metastatic colorectal cancer (MCRC) patients in the Italian healthcare setting. METHODS: A retrospective chart analysis estimating direct medical costs of first-line infusional 5-Fluorouracil (5-FU) or oral Capecitabine (CAP), associated or not with other chemotherapies, from the Italian Healthcare Service (IHCS) and Hospital (H) perspectives. RESULTS: 202 subjects were analysed. CAP patients (N=66) were older, with a more compromised clinical status and received less chemotherapy agents in association than 5-FU patients (N=136). From the IHCS perspective, mean total costs per patient were 12,029 euro and 5,781 euro in the 5-FU and CAP arms respectively; 7,338 euro and 4,688 euro from the H perspective. The infusional administration route of 5-FU was a cost driver from both perspectives. Sensitivity analyses found the results to be robust to variations in base case parameters. CONCLUSIONS: Management of MCRC by oral chemotherapies may be an economically advantageous option to both IHCS and hospitals.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/economía , Neoplasias Colorrectales/tratamiento farmacológico , Costos de los Medicamentos , Administración Oral , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina , Neoplasias Colorrectales/economía , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/economía , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Fluorouracilo/economía , Humanos , Infusiones Intravenosas , Italia , Leucovorina/administración & dosificación , Leucovorina/economía , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven
8.
Ann Oncol ; 19(2): 370-3, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18156144

RESUMEN

BACKGROUND: The aim of this study was to evaluate the activity and toxicity of pemetrexed and carboplatin combination as first-line chemotherapy in malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with measurable advanced MPM and a zero to two Eastern Cooperative Oncology Group (ECOG) performance status (PS) were enrolled. The schedule was pemetrexed 500 mg/m(2) in combination with carboplatin area under the curve 5, every 21 days. In all, 76 patients were treated. Median age was 65 years; median ECOG PS was zero. RESULTS: Grade 3 hematological toxicity according to World Health Organization criteria was seen in 36 (47.3%) patients; grade 4 hematological toxicity in 5 (6.5%) patients. There were 16 (21%) partial responses and 3 (4%) complete responses, for an overall response rate of 19 (25%) [95% confidence interval (CI) 15.3-34.7]. In all, 29 (39%) (95% CI 28-48) patients reported stable disease. The median survival was estimated at 14 months. CONCLUSION: This combination of carboplatin and pemetrexed is moderately active and the toxicity is acceptable.


Asunto(s)
Carboplatino/administración & dosificación , Glutamatos/administración & dosificación , Guanina/análogos & derivados , Mesotelioma/tratamiento farmacológico , Mesotelioma/patología , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/patología , Adulto , Anciano , Carboplatino/efectos adversos , Intervalos de Confianza , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Glutamatos/efectos adversos , Guanina/administración & dosificación , Guanina/efectos adversos , Historia Antigua , Humanos , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Mesotelioma/mortalidad , Persona de Mediana Edad , Estadificación de Neoplasias , Pemetrexed , Neoplasias Pleurales/mortalidad , Probabilidad , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento
9.
J Biol Regul Homeost Agents ; 21(1-2): 13-20, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-18211746

RESUMEN

The aim of the study was to correlate tumoral DNA ploidy and Ki-67 expression with therapy response, Overall Survival (OS), Disease Specific Survival (DSS) and Disease Free Survival (DFS). Three samples of colorectal cancer were collected from each patient. One sample of normal tissue was our internal control. DNA ploidy was evaluated by FACSCalibur cytometer and Ki-67 by immunohistochemistry. We studied 67 patients and we found aneuploidy in 65,7 percent of carcinoma with a Ki-67 median expression of 55 percent. After surgery and chemotherapy in 35 percent of the patients with aneuploid carcinoma and high proliferative activity (Ki-67 greater than 55 percent) there were no evidence of disease versus 100 percent of patients with DNA diploidy and low proliferative activity (Ki-67 less than 55 percent). Tumoral aneuploidy significantly correlated with lower OS, DSS and DFS (18 percent vs 86 percent at 30 months). Univariated analysis demonstrated a significant correlation between aneuploidy and develop disease progression (p=0,033, odd ratio=5.7), while the cut-off of 55 percent for Ki-67 expression did not correlate with OS, DSS and DFS. Preliminary results (the study is still in progress) seemed to suggest that DNA ploidy has a prognostic and predictive significance in colorectal carcinoma.


Asunto(s)
Neoplasias Colorrectales/diagnóstico , Antígeno Ki-67/análisis , Ploidias , Adulto , Anciano , Anciano de 80 o más Años , Aneuploidia , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , ADN/análisis , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos
10.
Br J Cancer ; 95(1): 13-20, 2006 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-16773070

RESUMEN

The purpose of the study was to evaluate the influence of baseline haemoglobin level in predicting response to 5-fluorouracil (5FU)-based first-line chemotherapy in advanced colorectal cancer patients. Data from 631 patients were collected from three different institutions. Globally, overall response rate was 35.8% (226 out of 631). Factors influencing response rate were 5FU dose intensity (high: 43.1%, low: 34.0%, P = 0.03); oxaliplatin (yes: 45.8%, no: 22.9%, P < 0.0001), performance status (PS 0: 46.1%, 1: 28.8%, 2: 26.7%, P < 0.0001), and haemoglobin levels (> or = 12 g dl(-1): 40.4%, < 12 g dl(-1): 29.2%, P = 0.004). In subgroup analysis significant differences in response rate between anaemic and nonanaemic patients were recorded in those patients treated with infusional chemotherapies (45.7 vs 25.5%, P < 0.0001), with high 5FU dose intensity (50.3 vs 32.7%, P = 0.005), with PS = 0 (49.8 vs 37.9%, P = 0.03), and with liver metastases (44.8 vs 33.8%, P = 0.002), whereas no difference was evident in those subjects treated with bolus schedules or according to gender. Anaemia was a strong predictor for activity of first-line 5FU-based chemotherapy especially in those groups that showed the best responses, for example high performance status, infusionally treated, higher 5FU dose and those with liver secondaries. Patients with higher haemoglobin levels recorded a greater response rate and a longer time to progression and survival than anaemic subjects. Prospective evaluation of role of correcting anaemia on response to therapy is justified by these results.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Hemoglobinas/análisis , Adulto , Anciano , Anciano de 80 o más Años , Anemia/complicaciones , Antimetabolitos Antineoplásicos/efectos adversos , Neoplasias Colorrectales/diagnóstico , Bases de Datos Factuales , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluorouracilo/efectos adversos , Estudios de Seguimiento , Hemoglobinas/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Análisis de Regresión , Tasa de Supervivencia , Resultado del Tratamiento
11.
Oncology ; 69(5): 408-13, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16319512

RESUMEN

BACKGROUND: Treating patients with anthracycline- and taxane-pretreated metastatic breast cancer is challenging. This study evaluated the activity and safety of a combination of cisplatin and capecitabine in this setting. PATIENTS AND METHODS: Thirty-nine consecutive patients entered the study. All had experienced failures or relapse after previous treatment with anthracyclines and taxanes plus/minus other chemotherapeutic regimens. The present treatment consisted of intravenous cisplatin 20 mg/m(2) every week for 6 weeks, followed by 1 week of rest, and oral capecitabine 1,000 mg/m(2) twice daily for 14 days, followed by a 7-day rest period. RESULTS: Objective response was obtained in 14 patients (35.9%), with complete remission in 3 (7.7%). Median time to progression was 5.2 months and survival was 10.9 months in the entire population and 8.7 and 16.5 months in the responding patients, respectively. The dose-limiting toxicity for the regimen was leucopenia, while gastrointestinal discomfort was the most frequent cause of capecitabine reduction or delay. CONCLUSIONS: The cisplatin and capecitabine combination regimen is active and manageable. It seems to be non-cross resistant to anthracyclines and taxanes.


Asunto(s)
Antraciclinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Cisplatino/administración & dosificación , Desoxicitidina/análogos & derivados , Inmunoterapia/métodos , Taxoides/uso terapéutico , Células Presentadoras de Antígenos/citología , Capecitabina , Células Dendríticas/citología , Desoxicitidina/administración & dosificación , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Fluorouracilo/análogos & derivados , Genes Reporteros , Proteínas Fluorescentes Verdes/metabolismo , Antígenos HLA-A/inmunología , Antígeno HLA-A24 , Humanos , Interferón gamma/metabolismo , Leucocitos Mononucleares/metabolismo , Microscopía Fluorescente , Metástasis de la Neoplasia , ARN Mensajero/metabolismo , Inducción de Remisión , Factores de Tiempo , Transcripción Genética , Resultado del Tratamiento
14.
Panminerva Med ; 43(4): 243-8, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11677418

RESUMEN

BACKGROUND: Advanced and relapsed tumors remain a challenging disease with a poor and dismal prognosis. Our choice for inoperable tumors consists in a percutaneous treatment strategy involving intra-arterial chemotherapy and hemofiltration, with previous blood stop-flow, which allows high doses of Cisplatin-cisplatinum, cis-diammine-dichloroplatinum (CDDP) and Mitomycin C (MMC) in the tumor-bearing area with minimal systemic toxicity. METHODS: We analyse the morbidity and mortality associated with stop-flow in 20 patients with unresectable and/or metastatic thoraco- abdominal tumors, non responders to prior systemic chemotherapy. RESULTS: In our experience, the rate of major side effects of the procedure was 31% with a mortality of 5%. The side effects were related to the radiological procedure and to the chemotherapic treatment. A 74-year-old patient died for acute kidney toxicity within 15 days after the procedure. The other transient toxicity symptoms recorded were: nausea, vomiting, increasing of creatinine levels, diplopia and appearance of necrotic ulcer associated to chemotherapic drugs. Concerning the complications related to the radiological technique, the main problem was the rupture of the balloon stop-flow catheter in four patients. CONCLUSIONS: Stop-flow is a new procedure that could develop in the future, thanks to the possibility of obtaining a higher dose intensity of chemotherapic drugs in districts or organs affected by advanced tumors, with less systemic side effects. Unfortunately, the uncertain results in terms of increasing survival and the default of effective devices are to be resolved for a wider application of the procedure.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Catéteres de Permanencia/efectos adversos , Femenino , Hemofiltración/efectos adversos , Humanos , Infusiones Intraarteriales/efectos adversos , Masculino , Persona de Mediana Edad
15.
Am J Clin Oncol ; 24(4): 354-9, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11474260

RESUMEN

From February 1996 to December 1998, 95 patients affected with colorectal liver metastases underwent the positioning of an intraarterial hepatic catheter by a transcutaneous subclavian access, under local anesthesia. All patients were evaluated for catheter implantation complications. Moreover, 61 patients of 95 treated at our center were retrospectively evaluated for results of chemotherapy performed with two different schedules of hepatic artery infusion (HAI) combined with systemic chemotherapy (SC). Eleven patients (group A) were treated with combined SC (5-fluorouracil continuous infusion) and HAI (floxuridine). A subsequent 50 patients underwent HAI (floxuridine, 4 cycles) followed, if a response or stable disease were observed, by combined SC and HAI (group B). Three cases of aneurysm of subclavian artery occurred, which were treated by the positioning of a radiologic arterial stent and the reimplantation of the catheter by a femoral access. Thrombosis of the hepatic artery was registered in four cases. We observed 10.5% occurrence of dislocation of the catheter, which was always moved again in the hepatic artery. In group A, with 45% clinical objective response rate and 10% stable disease rate, median survival time and median time to extrahepatic progression were 9 and 6 months, respectively. In group B, we observed 44% clinical objective responses and 26% stable disease after HAI. Patients without disease progression and therefore submitted to sequential SC and HAI had a median survival time of 21 months and a median time to extrahepatic progression of 16 months. The development of the mini-invasive technique of implantation of an arterial port can avoid laparotomy for HAI. Percutaneous implantation of an arterial port has a low rate of technical complications. HAI followed by combined systemic and regional chemotherapy has good results in terms of survival and time to extrahepatic progression.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Catéteres de Permanencia , Arteria Hepática , Infusiones Intraarteriales/métodos , Neoplasias Hepáticas/tratamiento farmacológico , Arteria Subclavia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Catéteres de Permanencia/efectos adversos , Neoplasias Colorrectales/patología , Femenino , Humanos , Infusiones Intraarteriales/efectos adversos , Infusiones Intravenosas , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia
16.
Int J Pancreatol ; 27(3): 225-33, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10952405

RESUMEN

BACKGROUND: Systemic chemotherapy does not satisfactorily improve the poor prognosis of pancreas and biliary tract cancer unresectable or metastatic to the liver. Intra-arterial infusion of antineoplastic agents can give higher concentrations to the tumor and slighter concentrations to the whole body, with a potential of efficacy and lower toxicity, due to the hepatic clearance. METHODS: Based on a safe and ambulatorial technique of transcutaneous arterial port implantation, this study was designed to evaluate feasibility and toxicity of 5-fluorouracil (5-FU) intra-arterial continuous infusion combined with systemic gemcitabine with dose escalation. Seventeen patients affected by pancreatic (14) or biliary tract (3) cancer received up to six cycles of treatment. Treatment consisted of intravenous gemcitabine on d 1 and 8 and intra-arterial 5-FU continuous infusion on d 1-14 every 21 d. Dose-escalation levels were 900 and 1000 mg/m2 for gemcitabine and 8, 10, 12, 15, and 17 mg/kg/d for 5-FU. Consecutive cohorts of three patients were planned at each dose level. RESULTS: Gastrointestinal toxicity (vomiting and diarrhea [3rd-4th degree] and gastritis), constituted the dose-limiting toxicity, with a maximum-tolerated dose of 1000 mg/m2 for gemcitabine and 15 mg/kg/d for 5-FU. Hematological toxicity was present in a minority of patients. No patient had acute or later complications such as arterial thrombosis related to the implanted arterial port, sclerosis cholangitis, or chemical cholecistitis. CONCLUSION: 5-Fluorouracil intra-arterial continuous infusion, combined with systemic gemcitabine, seems to be a feasible and safe regimen that could give interesting results in pancreatic cancer.


Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias del Sistema Biliar/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Fluorouracilo/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Anciano , Desoxicitidina/administración & dosificación , Femenino , Fluorouracilo/efectos adversos , Humanos , Infusiones Intraarteriales , Masculino , Persona de Mediana Edad , Gemcitabina
17.
Clin Cancer Res ; 6(6): 2448-55, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10873098

RESUMEN

We report here that the progression of pancreatic carcinomas in tumor patients is associated with increased serum levels of both the soluble forms of CD95 ligand (CD95L/FasL) and its receptor, CD95 (Fas). Shedding of proteolytically processed soluble CD95L was also observed in pancreatic carcinoma cells in vitro, thus identifying one possible source of CD95L in patients' sera. Because the secreted forms of both CD95 and CD95L have been implicated previously in protection of cells from CD95-mediated cell death, we assessed the effect of soluble CD95L in supernatants of pancreatic carcinoma cells on viability of Jurkat T lymphocytes. We describe that (a) supernatants derived from cultured pancreatic carcinoma cells caused apoptosis of Jurkat cells; (b) soluble tumor-derived CD95L contributed significantly to this effect; and (c) in comparison to Jurkat cells, pancreatic carcinoma cells themselves revealed increased resistance to apoptosis induction by autocrine soluble CD95L. These results are consistent with the notion that in the microenvironment of pancreatic tumors, tumor-derived shed CD95L exerts paracrine pro-apoptotic effects. In addition, because it is released at high levels into the bloodstream, soluble CD95L may have systemic effects in tumor patients that reach beyond the microenvironment of the tumor site.


Asunto(s)
Apoptosis , Carcinoma/metabolismo , Glicoproteínas de Membrana/biosíntesis , Neoplasias Pancreáticas/metabolismo , Receptor fas/biosíntesis , Adulto , Anciano , Carcinoma/sangre , Separación Celular , Técnicas de Cocultivo , Medios de Cultivo Condicionados , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Proteína Ligando Fas , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Proteínas Fluorescentes Verdes , Humanos , Immunoblotting , Inmunohistoquímica , Células Jurkat , Proteínas Luminiscentes/metabolismo , Masculino , Glicoproteínas de Membrana/sangre , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/metabolismo , Linfocitos T/patología , Células Tumorales Cultivadas , Receptor fas/sangre
18.
Cancer Chemother Pharmacol ; 44(6): 505-10, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10550572

RESUMEN

PURPOSE: The incorrect positioning of the arterial Port-a-Cath or the presence of anatomic or functional hepatic arteriovenous shunting may explain the occurrence of systemic toxicity of hepatic arterial infusion of floxuridine in patients with liver metastases. The aim of our study was to predict the occurrence of systemic toxic effects from this treatment using a scintigraphic and pharmacokinetic approach. METHODS: A group of 26 patients were studied. Before treatment, Tc-99m-labelled macroaggregated albumin arterial perfusion scintigraphy was performed to verify the correct positioning of the catheter, to evaluate the percentage of pulmonary uptake of the tracer, reflecting intrahepatic arteriovenous anatomic shunting, and to qualitatively assess the perfusion pattern of the metastases with respect to the normal liver parenchyma (SPECT images). Hepatic arteriovenous functional shunting was assessed through the bioavailability of intraarterially administered D-sorbitol. Treatment was then started and systemic toxic effects were evaluated according to WHO recommendations. RESULTS: No correlation was found between anatomic shunting (

Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Disponibilidad Biológica , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Cateterismo Periférico , Quimioterapia del Cáncer por Perfusión Regional , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Femenino , Arteria Hepática , Humanos , Infusiones Intraarteriales , Hígado/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Sorbitol/farmacocinética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Tomografía Computarizada de Emisión de Fotón Único
19.
J Hepatol ; 30(6): 1112-8, 1999 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10406191

RESUMEN

BACKGROUND/AIM: Hepatic arteriovenous shunting in the metastatic liver reduces the advantages of intraarterial infusion of chemotherapeutic agents because of the passage of drugs into the systemic circulation. The aim of this study was to quantitatively assess spontaneous functional hepatic arteriovenous shunting in patients with liver metastases and to determine its implication in the increase in systemic toxic effects of intra-arterial infusion chemotherapy with floxuridine. METHODS: Twenty-five patients who underwent implantation of arterial ports for regional chemotherapy of liver metastases were studied. Functional hepatic arterio-venous shunting was evaluated through the bioavailability of intra-arterially administered D-sorbitol, a safe, natural compound whose kinetic features make its hepatic clearance flow dependent. In addition, D-sorbitol hepatic clearance (a parameter reflecting functional liver blood flow) and common liver function tests were evaluated for each studied patient. Patients were then grouped with respect to the percentage of medically-assessed liver occupation by metastases and with respect to systemic toxicity of the chemotherapeutic treatment. Both univariate and multivariate analyses by Student's t-test and stepwise logistic regression, respectively, were performed in both groups for each of the evaluated parameters (age, liver function tests, D-sorbitol hepatic clearance and arterial bioavailability). RESULTS: Arterial bioavailability of D-sorbitol ranged between 0.05 and 0.72 and was significantly greater in patients with more than 50% liver occupation (0.39+/-0.19) compared with those with minor liver involvement (0.17+/-0.13; p = 0.003); it was also significantly greater in patients experiencing high-grade systemic toxicity (0.40+/-0.19) compared with those with low-grade toxicity (0.16+/-0.11; p<0.001). Multivariate analysis showed that arterial bioavailability of D-sorbitol was the only parameter among those evaluated which was able to predict systemic toxicity of this kind of chemotherapy. CONCLUSIONS: Our results show that, in the metastatic liver, arterial bioavailability of D-sorbitol, an index of functional arteriovenous shunting, varies widely, is significantly greater in patients with massive liver occupation and it is a good predictor of systemic toxicity of intra-arterial regional chemotherapy with floxuridine.


Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Floxuridina/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Sorbitol/metabolismo , Adulto , Anciano , Análisis de Varianza , Antimetabolitos Antineoplásicos/efectos adversos , Derivación Arteriovenosa Quirúrgica , Disponibilidad Biológica , Femenino , Floxuridina/efectos adversos , Humanos , Infusiones Intraarteriales , Hígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad
20.
Am J Clin Oncol ; 22(3): 315-9, 1999 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10362345

RESUMEN

The purpose of this study was to verify the applicability of nuclear techniques with technetium-99m labeled macroaggregated albumin (Tc-99m-MAA) in extrahepatic regional chemotherapy. Of 98 patients in whom arterial Port-a-caths were implanted by transcutaneous access, 13 were treated by regional extrahepatic chemotherapy (breast, one; pancreas, four; kidney, one; uterus, three; vagina, two; bladder, two). In all 13 patients, Tc-99m-MAA was slowly infused intraarterially. The examination showed the perfusion of the area with the neoplasm and excluded the presence of important misperfusions of Tc-99m-MAA to the nearest areas. To detect the presence of an arteriovenous shunt with systemic misperfusion, an anterior image of the thorax was obtained in all patients and an index of misperfusion was calculated. In 12 patients, the index was < 5%; in one patient it was about 40%. In conclusion, our preliminary experience concerns the monitoring of intraarterial infusion chemotherapy of extrahepatic districts. In all 13 patients, we evaluated the correct positioning of the intraarterial catheter and the distribution pattern of the arterial flow, with a semiquantitative indication of arteriovenous shunting. This method gave us an instrument of study that was inexpensive, harmless, and free of collateral complications.


Asunto(s)
Quimioterapia del Cáncer por Perfusión Regional/métodos , Infusiones Intraarteriales/métodos , Radiofármacos , Agregado de Albúmina Marcado con Tecnecio Tc 99m , Anciano , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Neoplasias Renales/irrigación sanguínea , Neoplasias Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias Uterinas/irrigación sanguínea , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Vaginales/irrigación sanguínea , Neoplasias Vaginales/tratamiento farmacológico
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