RESUMEN
BACKGROUND: Pre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and ß, RET, KIT). PATIENTS AND METHODS: Patients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). RESULTS: Thirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6-32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31-69%); DCR was 76% (95% CI: 59-88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients. All the cases showed expression of PDGFRß in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRß, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRß immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%). CONCLUSIONS: Sorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRß-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carcinoma Adenoide Quístico/tratamiento farmacológico , Carcinoma Mucoepidermoide/tratamiento farmacológico , Mioepitelioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/secundario , Adulto , Anciano , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , Carcinoma Adenoide Quístico/secundario , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/patología , Carcinoma Mucoepidermoide/secundario , Diarrea/inducido químicamente , Supervivencia sin Enfermedad , Erupciones por Medicamentos/etiología , Fatiga/inducido químicamente , Síndrome Mano-Pie/etiología , Humanos , Hipertensión/inducido químicamente , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mioepitelioma/metabolismo , Mioepitelioma/patología , Mioepitelioma/secundario , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/metabolismo , Niacinamida/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/metabolismo , Proteínas Proto-Oncogénicas c-ret/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/patología , Sorafenib , Tasa de Supervivencia , Resultado del Tratamiento , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Data on preoperative chemotherapy in resectable oral cavity cancer are conflicting. We present the long-term results of a randomized trial of induction chemotherapy in resectable oral cavity cancer. PATIENTS AND METHODS: A randomized, parallel, multicentre trial evaluated the impact of three cycles of cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2 (120-h infusion administered every 21 days) in stage T2-T4, N0-N2, previously untreated patients with advanced disease. Control group received upfront surgery. Postoperative radiation was offered to both arms when pathologic risk features were identified. The co-primary end points were the occurrence of locoregional or distant tumour relapse, and death. RESULTS: Among the 198 enrolled patients, with a median follow-up of 11.5 years, there was no difference in the incidence of locoregional relapse between chemotherapy and control group (P=0.6337), nor in distant metastasis development (P=0.1527). There was also no difference between groups in overall survival (P=0.3402). Patients with a pathological complete response (pCR) had higher probability of survival than those without (10-year OS: 76.2% versus 41.3%, P=0.0004). Late toxicities in patients with a minimum follow-up of 60 months (42 in each group) were similar between arms, except from fibrosis (cumulative incidence 40% versus 22% in chemotherapy arm) and grade 2 dysphagia (14% versus 5%). CONCLUSIONS: Long-term follow-up of this randomized trial confirmed the absence of survival benefit with preoperative chemotherapy in oral cavity cancer. Late toxicity was similar in the two arms except for fibrosis and dysphagia, which were less in the chemotherapy arm. The survival benefit for patients achieving a pCR was maintained.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Neoplasias de la Boca/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/mortalidad , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Neoplasias de la Boca/mortalidad , Periodo Preoperatorio , Modelos de Riesgos Proporcionales , Resultado del TratamientoRESUMEN
BACKGROUND: Pazopanib achieved the end point of clinical activity in pretreated patients with urothelial cancer in a single-group, phase 2 trial. The objective was to identify biological predictors of clinical benefit to pazopanib in these patients. METHODS: EDTA blood samples were collected at baseline (T0) and after 4 weeks (T1) of treatment, together with radiological imaging in all 41 patients to analyse plasma circulating angiogenic factor levels by multiplex ELISA plates. Changes from T0 to T1 in marker levels were matched with response with the covariance analysis. Univariable and multivariable analyses evaluated the association with overall survival (OS), adjusted for prespecified clinical variables. Net reclassification improvement (NRI) tested the performance of the recognised Cox model. RESULTS: Increasing IL8(T1) level associated with lower response probability at covariance analysis (P=0.010). Both IL8(T0) (P=0.019) and IL8(T1) (P=0.004) associated with OS and the prognostic model, including clinical variables and IL8(T1) best-predicted OS after backward selection. The NRI for this model was 39%.When analysed as a time-varying covariate, IL8(T1) level<80 pg ml(-1) portended significantly greater response (â¼80%) and 6-month OS (â¼60%) probability than level ≥ 80. CONCLUSION: IL8-level changes during pazopanib allowed for a prognostic improvement and were associated with response probability.
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Inductores de la Angiogénesis/sangre , Citocinas/sangre , Interleucina-8/sangre , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Neoplasias Urológicas/sangre , Neoplasias Urológicas/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Biomarcadores de Tumor/sangre , Carcinoma de Células Transicionales/sangre , Carcinoma de Células Transicionales/tratamiento farmacológico , Ensayo de Inmunoadsorción Enzimática , Humanos , Indazoles , Imagen Multimodal , Tomografía de Emisión de Positrones , Pronóstico , Modelos de Riesgos Proporcionales , Tomografía Computarizada por Rayos XRESUMEN
AIM: Loop ileostomy is a suitable procedure for transitory faecal diversion after colorectal or coloanal anastomosis. We describe here an easy alternative technique for ileostomy construction that does not require reintervention for the closure. METHOD: In twenty patients undergoing anterior resection of the extraperitoneal rectum with colorectal and/or coloanal anastomosis, loop ileostomy was performed using a modified jejunotomy tube inflated with 10 ml of normal saline. The tube was deflated on the eighth post-operative day and removed on day 11 after a radiological contrast enema of the anastomosis. RESULTS: Radiological control carried out on day 11 evidenced a premature dislocation of the jejunostomy tube in 1 patient, thus the tube was correctly removed without any complications. In another patient a delayed closure of the ileo cutaneous fistula was recorded that required simple medication over 15 days in the out patient clinic. No signs of anastomotic leakage, either clinical or radiological were evidenced. CONCLUSION: We have described here a safe alternative technique for loop ileostomy with negligible complications related to construction as demonstrated in our results.
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Anastomosis Quirúrgica/métodos , Ileostomía/métodos , Neoplasias del Recto/cirugía , Anciano , Anciano de 80 o más Años , Fuga Anastomótica , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIM: Evaluate the vitamin D serum status in a population of white and black mothers who live in the same geographic area of northern Italy (45 degrees 8' N of latitude) and its correlation with vitamin D serum concentrations of the respective newborns at birth, at 2 and 12 months. METHODS: Twelve white woman-infant pairs and 12 black woman-infant pairs were recruited from January through March 2006. The study population had no pre-existing disease and delivered at term of pregnancy (37-41 weeks of gestational age). Only black infants were given vitamin D supplementation from birth to 1 year of age. RESULTS: Eleven black and 12 white women had low vitamin D serum levels at term of pregnancy. Similarly, black and white newborns were both vitamin D deficient at birth. After 12 months white women re-gained physiological vitamin D serum levels, whereas black women maintained a status of vitamin D deficiency. Black newborns who were given supplementation showed lower vitamin D serum concentrations as compared with white newborns at 1 year of age. CONCLUSION: These data showed that all the women living in the same region of northern Italy without any supplementation are equally vitamin D deficient at term of pregnancy regardless of their skin pigmentation. Consequently, every woman should be supplied with additional vitamin D during pregnancy and lactation, though such supplementation seems to exert the most beneficial effects in black women.
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Población Negra , Lactancia/sangre , Vitamina D/sangre , Población Blanca , Femenino , Humanos , Lactante , Recién Nacido , Italia , EmbarazoRESUMEN
This study reports the tolerability and feasibility of capecitabine, an oral fluoropyrimidine, chemoradiation as postoperative treatment. Stage II-III rectal cancer patients received 2 cycles of bolus 5-FU (425 mg/m2) and leucovorin (LV) (20 mg/m2) on days 1-5 q3w followed by oral capecitabine (800 mg/m2 bid) continuously during pelvic radiotherapy (total 50.4 Gy). Two additional cycles of 5-FU/LV were finally administered. Forty-one radically resected patients (median age: 61 years) were enrolled. All patients were evaluable for safety. Grade 3 adverse events included: proctitis (n = 3, 7%), diarrhea (n = 5, 12%), and leukopenia (n = 1, 2%). The overall rate of grade 3 diarrhea and leukopenia was 15% (95% confidence interval, 5-29%). Capecitabine chemoradiation in the adjuvant setting is well tolerated and is convenient to administer. These results support the use and further study of capecitabine chemoradiation in radically resected rectal cancer patients.
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Antimetabolitos Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/radioterapia , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Adenocarcinoma/cirugía , Administración Oral , Adulto , Anciano , Capecitabina , Terapia Combinada , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Fluorouracilo/análogos & derivados , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Profármacos , Dosificación Radioterapéutica , Neoplasias del Recto/cirugíaRESUMEN
AIMS: We report the effects of cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP) in the treatment of advanced/recurrent epithelial ovarian cancer (EOC) on survival, morbidity and mortality. PATIENTS: Forty EOC patients were studied. Median age was 52.5 years (range: 30-68) and median follow-up 26.1 months (range: 0.3-117.6). Most patients presented advanced disease (stage III/IV). Previous systemic chemotherapy included cisplatin-based, taxol-based or taxol/platinum containing regimens. RESULTS: After the CRS, 33 patients presented no macroscopic residual disease. Five-year overall survival was 15%; the mean overall and progression-free survivals were 41.4 and 23.9 months, respectively. The morbidity, toxicity and mortality rates were 5%, 15% and 0%, respectively. CONCLUSION: Our results suggest that CRS + IPHP merits further evaluation by a formal prospective trial.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hipertermia Inducida , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Adulto , Anciano , Cisplatino/administración & dosificación , Terapia Combinada , Doxorrubicina/administración & dosificación , Femenino , Humanos , Infusiones Parenterales , Persona de Mediana Edad , Mitomicina/administración & dosificación , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Vulvar vestibulitis syndrome, which represents one of the major cause of dyspareunia, is a puzzling clinical entity. Although many treatment options have been employed, a rationale therapeutic strategy is still not stated. The present article reviews the most popular medical approaches of such entity (biofeedback, tricyclic antidepressants, interferon psychologic-behavioural therapy, diet modification), as well as those to avoid. Tricyclic antidepressants and biofeedback of the pelvic floor muscles represents the first line effective therapy. Moreover, psychological counselling must support any treatment options.
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Antidepresivos Tricíclicos/uso terapéutico , Vulvitis/psicología , Vulvitis/terapia , Biorretroalimentación Psicológica , Femenino , Humanos , Interferones/uso terapéutico , Vulvitis/dietoterapia , Vulvitis/etiologíaRESUMEN
PURPOSE: In modern management of rectal carcinoma, the preoperative evaluation of disease parameters is important for selection of therapeutic options. Such parameters are currently defined through endorectal ultrasonography or endoscopic ultrasonography. A retrospective analysis of the parameters obtained with double-contrast barium enema (DCBE) and endorectal balloon computed tomography (CT) was conducted to verify the diagnostic reliability of the radiological techniques and to establish whether there is still an indication for their use. METHODS: 53 consecutive patients with adenocarcinoma of the distal half of the rectal ampulla underwent double contrast barium enema examination and CT of the pelvis with endorectal balloon. On the basis of the DCBE and CT assessment we evaluated: 1) the distance between the cranial extremity of the anal canal and the distal margin of the neoplasm; 2) the radial diffusion of the tumor; 3) the metastatic involvement of the perirectal and inferior mesenteric lymph nodes. RESULTS: 1) CT and DBCE measurements of the distal margin tended to coincide, but both tended to overestimate the measurement when compared to the pathologic examination; 2) in the identification of neoplastic infiltration of perirectal fat (T3) CT had 100% sensitivity, 78.7% specificity and 86.8% accuracy; 3) the CT sensitivity for detecting lymph node metastasis was 52.6%, specificity 85.3% and accuracy 73.6%. CONCLUSIONS: The diagnostic information provided by the radiological examinations is comparable to that of clinical and instrumental methods currently employed for staging of rectal carcinoma, although the latter are preferred because they are more readily accessible and less costly. DCBE and CT can therefore be usefully employed for staging of cancer of the rectum in those cases in which there are limitations of the current standard methods.
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Adenocarcinoma/diagnóstico por imagen , Sulfato de Bario , Enema , Cuidados Preoperatorios/métodos , Neoplasias del Recto/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adenocarcinoma/patología , Medios de Contraste , Diagnóstico Diferencial , Humanos , Estadificación de Neoplasias , Neoplasias del Recto/patología , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: There currently is no agreement regarding the appropriate treatment of elderly patients with advanced breast carcinoma (ABC). Doxifluridine (5-dFUR), a prodrug of 5-fluorouracil, has been found to be effective in this entity, but its use is limited by neurotoxicity and cardiotoxicity that are not observed when the oral formulation is used. The objective of this Phase II trial was to evaluate the effectiveness and tolerability of oral 5-dFUR, biomodulated with levoleucovorin (1-leucovorin), in elderly patients (age > 70 years) with ABC. METHODS: 5-dFUR was administered orally at 600 mg/m2 twice daily for 4 consecutive days every 12 days, and oral 1-leucovorin was administered as 25 mg 2 hours before each 5-dFUR administration. Response was assessed every five cycles according to the World Health Organization criteria. In the presence of response or stable disease, the patients were treated for a maximum of 15 cycles. RESULTS: Seventy-three eligible patients were enrolled, 27 of whom had been pretreated with chemotherapy and/or hormonotherapy; all were assessable for response and toxicity after a median follow-up of 15 months. The objective response rate was 26% (95% confidence interval, 17.4-45.4). Regression predominantly occurred in the presence of soft tissue involvement (skin, lymph nodes, and breast). The median time to response was 2 months (range, 1-2 months) and the median response duration was 7 months (range, 2-17+ months). The median survival was 24 months (range, 2-42+ months). The treatment was very well tolerated, and the side effects were manageable and always reversible. CONCLUSIONS: The results of the current study show that 5-dFUR plus 1-leucovorin, both given orally, are associated with excellent patient compliance. Although the results are suboptimal in terms of an objective response, this characteristic could allow 5-dFUR to be used in elderly patients considered unsuitable for "aggressive" chemotherapy.
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Antídotos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Leucovorina/uso terapéutico , Administración Oral , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Femenino , Floxuridina/administración & dosificación , Floxuridina/efectos adversos , Fluorouracilo/administración & dosificación , Humanos , Metotrexato/administración & dosificación , Estadificación de NeoplasiasRESUMEN
Using L1210 and a subline resistance to chloroethylnitrosoureas (L1210/BCNU), we found that the resistance to 1-(2-chloroethyl)-1-nitrosourea (CNU) or to diethyl-1-3-(2-chloroethyl)-3-nitrosoureido ethyl phosphonate (fotemustine) can be reversed by a pretreatment with O6-methyl Guanine (O6-mGua) or temozolomide. In L1210/BCNU but not in L1210 the pretreatment with O6mGua caused an increased peak level of CNU-induced DNA-interstrand crosslinks. We then evaluated whether the resistance to BCNU could be counteracted in vivo by i.p. O6mGua treatment of L1210/BCNU bearing mice. The results were negative due to the fact that O6mGua, which was not toxic when given alone, caused a high toxicity when associated with BCNU.
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Antineoplásicos/farmacología , Carmustina/farmacología , Dacarbazina/análogos & derivados , Etilnitrosourea/análogos & derivados , Guanina/análogos & derivados , Leucemia L1210/tratamiento farmacológico , Compuestos de Nitrosourea/farmacología , Compuestos Organofosforados/farmacología , Animales , Carmustina/uso terapéutico , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos , Etilnitrosourea/farmacología , Etilnitrosourea/uso terapéutico , Guanina/farmacología , Guanina/uso terapéutico , Cinética , Ratones , Ratones Endogámicos DBA , Compuestos de Nitrosourea/uso terapéutico , Compuestos Organofosforados/uso terapéutico , TemozolomidaRESUMEN
The Authors report about the results of 23 clinical trials carried out in Italy with oral formulations of BAY o 9867 (ciprofloxacin) in the treatment of infections in various sites of the body. Altogether 644 patients were evaluated for therapeutic efficacy; positive clinical results were obtained in 95 to 100% of the treated patients, according to the site of the infection. The bacteriological examinations performed on 575 cases show eradication in 89.22%, eradication with relapse or reinfection in 2.26%, and persistence in 6.09%. Adverse reactions were observed in 38 out of 646 patients (5.89%); none of them, however, were severe or irreversible.