RESUMO
BACKGROUND: No evidence-based treatment options are available for patients with advanced colorectal cancer (CRC) progressing after standard therapies. MGMT is involved in repair of DNA damage and MGMT promoter methylation may predict benefit from alkylating agents such as temozolomide. The aim of our study was to evaluate the activity of temozolomide in terms of response rate in patients with metastatic CRC and MGMT methylation, after failure of approved treatments. PATIENTS AND METHODS: Patients were enrolled in a monocentre, open-label, phase II study and treated with temozolomide at a dose of 150 mg/m2/day for 5 consecutive days in 4-weekly cycles. The treatment was continued for at least six cycles or until progressive disease. RESULTS: Thirty-two patients were enrolled from August 2012 to July 2013. Treatment was well tolerated with one grade 4 thrombocytopenia and no other grade≥3 toxicities. No complete response occurred. The objective response rate was 12%, reaching the pre-specified level for promising activity. Median progression-free survival and overall survival were 1.8 and 8.4 months, respectively. Patients with KRAS, BRAF and NRAS wild-type CRC showed significantly higher response when compared with those with any RAS or BRAF mutation (44% versus 0%; P=0.004). TP53 status had no influence on the primary end point. CONCLUSIONS: Temozolomide is tolerable and active in heavily pre-treated patients with advanced CRC and MGMT promoter methylation. Further studies in biomolecularly enriched populations or in a randomized setting are necessary to demonstrate the efficacy of temozolomide after failure of standard treatments.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina/análogos & derivados , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Antineoplásicos Alquilantes/farmacologia , Neoplasias Colorretais/mortalidade , Metilação de DNA , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Temozolomida , Resultado do TratamentoAssuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Transplante de Fígado , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologiaRESUMO
OBJECTIVE: To assess the influence of passive and light active smoking on the reduction of intrauterine growth of the foetus and on modifications in the body composition of the newborn. DESIGN: Random. SETTING: Full term newborn infants at the Department of the Pediatric and Gynaecological Divisions of the City Major Hospital, Chair of Paediatrics, Verona University. SUBJECTS: One hundred and twelve mothers selected after having completed a questionnaire on smoking habits during pregnancy. One hundred and twelve newborn infants were divided into three groups: Group 1: non-smoking and non-exposed mothers; Group 2: non-smoking but exposed mothers; Group 3: light smoking mothers (under 10 cigarettes/d, whether or not also exposed to passive smoking). Examination within 24 h of birth established the anthropometric measurements and estimates of body composition through indices or equations. RESULTS: Newborns of groups 2 and 3 had a statistically significant reduction of fat mass and most anthropometric measurements: fat mass according to Dauncey (P < 0.001), birth-weight (P < 0.013), crownheel length (P < 0.000), upper- and lower-arm length (P < 0.000) and circumference (P < 0.002), triceps skinfold and sum of all skinfolds (P < 0.004). Student t-test, between groups 2 and 3, did not evidence intergroup differences. CONCLUSIONS: Exposure of the foetus to passive and/or light active smoking involves a reduction of most auxiological parameters and not only weight. As regards body composition, smoking appears to reduce fat mass. The prevention of smoking during pregnancy is therefore extremely important, as intrauterine growth seems to be negatively influenced not only by active smoking, but also by passive and light active smoking.
Assuntos
Composição Corporal , Desenvolvimento Embrionário e Fetal , Fumar/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Tecido Adiposo , Antropometria , Peso ao Nascer , Índice de Massa Corporal , Feminino , Humanos , Recém-Nascido , Tamanho do Órgão , Placenta/anatomia & histologia , Gravidez , Dobras Cutâneas , Aumento de PesoRESUMO
There is conflicting evidence on the predictive role of KRAS status when cetuximab is added to oxaliplatin-based regimens. This study investigated the impact of KRAS, NRAS, BRAF, PI3KCA and TP53 status on outcome of elderly metastatic colorectal cancer patients enrolled in TEGAFOX-E (cetuximab, oxaliplatin and oral uracil/ftorafur--UFT) phase II study. Twenty-eight patients were enrolled and all were evaluable for safety and activity. Twenty-three specimens were analysed for KRAS, BRAF, NRAS, PI3KCA and TP53 mutational status by means of polymerase chain reaction and correlated with objective response, progression-free survival and overall survival. An evident increase of response rate was noted in KRAS/NRAS wild-type cases (70 versus 33%, P = 0.198). KRAS/NRAS wild-type status showed an independent association with a longer progression-free survival (44 versus 9 weeks, P = 0.009). Considering the combined assessment of BRAF, KRAS/NRAS and TP53, a trend towards an increase of response rate was noted in patients without mutations (83 versus 33%, P = 0.063). Moreover, patients with all wild-type genes had significantly longer progression-free survival than patients with any mutation (48 versus 10 weeks, P = 0.007). As a single biomarker, only KRAS/NRAS proteins maintained an independent value for outcome prediction. Patients with KRAS/NRAS, BRAF and TP53 wild-type tumours could derive the maximal benefits from treatment with cetuximab, oxaliplatin and UFT.
Assuntos
Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cetuximab , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Proteínas de Membrana/genética , Mutação , Proteínas Nucleares/genética , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tegafur/administração & dosagem , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Uracila/administração & dosagem , Proteínas ras/genéticaRESUMO
BACKGROUND: Currently, first-line chemotherapy in advanced colorectal cancer is not tailored on predictive biomarkers. Bax proapoptotic protein may correlate to chemosensitivity and differential response to irinotecan or oxaliplatin-based combinations. METHODS: Bax expression was assessed by immunohistochemistry in 49 advanced colorectal cancer patients enrolled at our institution from 2002 to 2004 within a multicenter, phase II, randomized trial of first-line UFT/leucovorin/irinotecan (TEGAFIRI) versus UFT/leucovorin/oxaliplatin (TEGAFOX). RESULTS: Bax-positive and negative samples were 49 and 51 %. Response was significantly lower in Bax positive (25 %) as compared to Bax negative (56 %) (Odds ratio = 0.26; p = 0.03). No significant difference was noted in TEGAFOX subgroup; in TEGAFIRI arm, responses were lower in Bax positive (18 %) than Bax negative (67 %) (Odds ratio = 0.11; p = 0.03). No difference in terms of progression-free and overall survival was observed according to Bax. CONCLUSION: Bax-negative colorectal cancer may identify a specific phenotype of patients with significantly higher chance to respond to doublet irinotecan-based chemotherapy.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Proteína X Associada a bcl-2/metabolismo , Adulto , Idoso , Antineoplásicos/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Irinotecano , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-IdadeAssuntos
Adenocarcinoma Papilar , Neoplasias das Tubas Uterinas , Adenocarcinoma Papilar/diagnóstico , Adenocarcinoma Papilar/etiologia , Adenocarcinoma Papilar/patologia , Idoso , Terapia Combinada , Neoplasias das Tubas Uterinas/diagnóstico , Neoplasias das Tubas Uterinas/etiologia , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , PrognósticoRESUMO
Estrogen and progesterone receptor status was reviewed in 405 patients from prior adjuvant breast cancer trials at the University of Verona. Only 233 patients were actually examined with respect to hormone status and outcome. No relationship between hormone receptor status and most of the commonly followed prognostic signs, i.e. tumor size, nodal status, and age, was found. Overall survival was correlated with hormone receptor positivity for patients with more than 4 positive axillary nodes. Disease-free survival was correlated only with PgR positivity, in premenopausal and in T1 groups.
Assuntos
Neoplasias da Mama/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Feminino , Humanos , Metástase Linfática , Menopausa , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
The antiemetic efficacy of metoclopramide and lorazepam (MTC + L) versus alizapride and lorazepam (ALZ + L) was compared in 100 patients receiving chemotherapy, in a prospective randomized double-blind study. In highly emetogenic (HE) regimen (including platinum) patients received MTC 1 mg/kg or ALZ 3 mg/kg x 4 doses, and lorazepam 2.5 mg 30 min before therapy. In moderately emetogenic (ME) regimen patients received MTC 0.5 mg/kg or ALZ 1.5 mg kg x 3 doses, and lorazepam 2.5 mg 30 min before therapy. In both HE and ME regimen groups there was no statistically significant difference between MTC + L and ALZ + L treatments as regards the number of vomiting episodes, the duration of emesis and nausea, the intensity of nausea and side effects, but a statistically significant difference between treatments was found in the HE group where MTC-L was superior to ALZ + L in obtaining complete protection from vomiting (37 vs 11%, p = 0.05). No significant difference in side effects was observed.
Assuntos
Antieméticos/administração & dosagem , Antineoplásicos/efeitos adversos , Lorazepam/administração & dosagem , Metoclopramida/administração & dosagem , Pirrolidinas/administração & dosagem , Vômito/prevenção & controle , Adolescente , Adulto , Idoso , Antieméticos/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Lorazepam/uso terapêutico , Masculino , Metoclopramida/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Pirrolidinas/uso terapêuticoRESUMO
BACKGROUND: Currently, first-line chemotherapy in advanced colorectal cancer is not tailored on predictive biomarkers. Bax proapoptotic protein may correlate to chemosensitivity and differential response to irinotecan or oxaliplatin-based combinations. METHODS: Bax expression was assessed by immunohistochemistry in 49 advanced colorectal cancer patients enrolled at our institution from 2002 to 2004 within a multicenter, phase II, randomized trial of first-line UFT/leucovorin/irinotecan (TEGAFIRI) versus UFT/leucovorin/oxaliplatin (TEGAFOX). RESULTS: Bax-positive and negative samples were 49 and 51 %. Response was significantly lower in Bax positive (25 %) as compared to Bax negative (56 %) (Odds ratio = 0.26; p = 0.03). No significant difference was noted in TEGAFOX subgroup; in TEGAFIRI arm, responses were lower in Bax positive (18 %) than Bax negative (67 %) (Odds ratio = 0.11; p = 0.03). No difference in terms of progression-free and overall survival was observed according to Bax. CONCLUSION: Bax-negative colorectal cancer may identify a specific phenotype of patients with significantly higher chance to respond to doublet irinotecan-based chemotherapy (AU)