RESUMO
BACKGROUND: There is a high unmet clinical need for treatments of advanced/metastatic biliary tract cancers after progression on first-line chemotherapy. Regorafenib has demonstrated efficacy in some gastrointestinal tumors that progress on standard therapies. PATIENTS AND METHODS: REACHIN was a multicenter, double-blind, placebo-controlled, randomized phase II study designed to evaluate the safety and efficacy of regorafenib in patients with nonresectable/metastatic biliary tract cancer that progressed after gemcitabine/platinum chemotherapy. Patients were randomly assigned 1 : 1 to best supportive care plus either regorafenib 160 mg once daily 3 weeks on/1 week off or placebo until progression or unacceptable toxicity. No crossover was allowed. The primary objective was progression-free survival (PFS). Secondary objectives were response rate, overall survival, and translational analysis. RESULTS: Sixty-six patients with intrahepatic (n = 42), perihilar (n = 6), or extrahepatic (n = 9) cholangiocarcinoma, or gallbladder carcinoma (n = 9) were randomized, 33 to each treatment group (33 per group). At a median follow-up of 24 months, all patients had progressed and six patients were alive. Median treatment duration was 11.0 weeks [95% confidence interval (CI): 6.0-15.9] in the regorafenib group and 6.3 weeks (95% CI: 3.9-7.0) in the placebo group (P = 0.002). Fourteen of 33 patients (42%) in the regorafenib group had a dose reduction. Stable disease rates were 74% (95% CI: 59-90) in the regorafenib group and 34% with placebo (95% CI: 18-51; P = 0.002). Median PFS in the regorafenib group was 3.0 months (95% CI: 2.3-4.9) and 1.5 months (95% CI: 1.2-2.0) in the placebo group (hazard ratio 0.49; 95% CI: 0.29-0.81; P = 0.004) and median overall survival was 5.3 months (95% CI: 2.7-10.5) and 5.1 months (95% CI: 3.0-6.4), respectively (P = 0.28). There were no unexpected/new safety signals. CONCLUSION: Regorafenib significantly improved PFS and tumor control in patients with previously treated metastatic/unresectable biliary tract cancer in the second- or third-line setting. CLINICAL TRIAL REGISTRATION: The trial is registered in the European Clinical Trials Register database (EudraCT 2012-005626-30) and at ClinicalTrials.gov (NCT02162914).
Assuntos
Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ductos Biliares Intra-Hepáticos , Neoplasias do Sistema Biliar/tratamento farmacológico , Desoxicitidina/análogos & derivados , Método Duplo-Cego , Humanos , Compostos de Fenilureia , Platina/uso terapêutico , Piridinas , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: The vagus nerve may slow tumor progression because it inhibits inflammation. This study examined the relationship between a new vagal neuroimmunomodulation (NIM) index and survival in fatal cancers. METHOD: We retroactively derived markers of vagal nerve activity indexed by heart rate variability (HRV), specifically the root mean square of successive differences (RMSSD), from patients' electrocardiograms near diagnosis. The NIM index was the ratio of RMSSD to C-reactive protein levels (RMSSD/CRP). Sample 1 included 202 Belgian patients with advanced pancreatic cancer (PC), while sample 2 included 71 Belgian patients with non-small cell lung cancer (NSCLC). In both samples, we examined the overall survival, while in sample 2, we additionally examined the survival time in deceased patients. RESULTS: In PC patients, in a multivariate Cox regression controlling for confounders, the NIM index had a protective relative risk (RR) of 0.68 and 95% confidence interval (95% CI) of 0.51-0.92. In NSCLC patients, the NIM index also had a protective RR of 0.53 and 95% CI of 0.32-0.88. Finally, in NSCLC, patients with a higher NIM index survived more days (475.2) than those with lower NIM (285.1) (p < 0.05). CONCLUSIONS: The NIM index, reflecting vagal modulation of inflammation, may be a new independent prognostic biomarker in fatal cancers.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neuroimunomodulação , Neoplasias Pancreáticas/diagnóstico , Nervo Vago/fisiologia , Idoso , Idoso de 80 Anos ou mais , Bélgica , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Frequência Cardíaca , Humanos , Imunomodulação , Inflamação , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
BACKGROUND: There is an increasing interest for Notch signalling pathway and particularly Delta-like ligand 4 (DLL4) as potential therapeutic target to improve outcome for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Using immunohistochemistry (IHC) and tissue microarray (TMA), we assessed the expression patterns of DLL4, Notch1 and Notch3 in 151 patients from two independent cohorts of resected PDAC. We investigated the prognostic and the predictive significance of these proteins. RESULTS: High IHC DLL4 expression in cancer cells was associated with worse overall survival (OS) and disease-free survival (DFS) than low DLL4 expression (median OS: 12.9 vs 30.4 months, P=0.004 and median DFS: 8.8 vs 17.4 months, P=0.02). High DLL4 expression remained a significant negative prognostic factor in multivariate analysis (HR for OS: 2.1, P=0.02 and HR for DFS: 2.0, P=0.02). Low DLL4 abundance was associated with a longer OS-only for patients who received an adjuvant gemcitabine-based chemotherapy (P<0.001) but not for patients who did not receive gemcitabine (P=0.72). Furthermore, the interaction test for adjuvant gemcitabine therapy was statistically significant (P<0.001). The validating cohort recapitulated the findings of the training cohort. CONCLUSIONS: Low DLL4 abundance in tumour cells may predict the benefit from adjuvant gemcitabine therapy after PDAC resection.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Desoxicitidina/análogos & derivados , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação ao Cálcio , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Quimioterapia Adjuvante/métodos , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica/métodos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Pancreáticas/patologia , Prognóstico , Receptor Notch1/metabolismo , Receptor Notch3/metabolismo , GencitabinaRESUMO
Pancreatic ductal adenocarcinoma is characterized by a high rate of early metastatic relapse. Surgical resection is still recognized as the cornerstone upfront therapy. However, reported 5 years survival rates are inferior to 20-25% even when surgery is followed by chemotherapy. Margins involvement on the surgical specimen (50 to 85%) and lymph node involvement (around 70%) both strongly impact survival. Median survivals are close to those of locally advanced diseases treated by chemotherapy or chemoradiotherapy, 15 to 16 months. This review focuses on adverse prognostic factors, post-operative outcomes and their impact on multimodality therapy completion rates and survivals in patients undergoing upfront surgery. Current data and emerging results from neoadjuvant series could lead to a change in the therapeutic strategy.
Assuntos
Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Humanos , Neoplasias PancreáticasRESUMO
AIMS: To help cells to better resist the stressful conditions associated with the freeze-drying process during starter production, we investigated the effect of various osmotic conditions on growth, survival and acidification activity of Lactobacillus buchneri R1102, after freeze-drying and during storage for 3 months at 25°C. METHODS AND RESULTS: High survival rates during freeze-drying, but not during storage, were obtained when 0·1 mol l(-1) KCl was added at the beginning of fermentation, without any change in membrane properties and betaine accumulation. This condition made it possible to maintain a high acidification rate throughout the process. In contrast, the addition of 0·6 mol l(-1) KCl concentrations at the beginning of fermentation led to a high survival rate during storage that was related to high intracellular betaine levels, low membrane fluidity and high cycC19:0 concentrations. However, these modifications induced the degradation of acidification activity during storage. When a moderate stress was applied by combining 0·1 mol l(-1) KCl at the beginning and 0·6 mol l(-1) KCl at the end of fermentation, betaine accumulated in the cells without any membrane alteration, allowing them to maintain high acidification activity and survival rate during storage. CONCLUSION: Specific osmotic conditions during fermentation induced intracellular betaine accumulation and modifications of membrane character-istics, thus affecting stress resistance of Lact. buchneri R1102. A slight osmotic stress made it possible to maintain a high acidification activity, whereas a high osmotic stress at the end of fermentation led to the preservation of cell survival during freeze-dried storage. SIGNIFICANCE AND IMPACT OF THE STUDY: This study revealed that the survival and preservation of acidification activity of freeze-dried Lact. buchneri R1102 during starter production can be improved by using appropriate osmotic conditions.
Assuntos
Betaína/metabolismo , Lactobacillus/efeitos dos fármacos , Fluidez de Membrana/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Preservação Biológica/métodos , Fermentação , Liofilização , Concentração de Íons de Hidrogênio , Lactobacillus/fisiologia , Viabilidade Microbiana/efeitos dos fármacos , Pressão OsmóticaRESUMO
Pancreatic ductal adenocarcinoma has a high mortality rate, which is generally related to the initial diagnosis coming at late stage disease combined with a lack of effective treatment options. Gemcitabine has been the most commonly used drug over the past decade and is still the cornerstone of therapy in adjuvant and metastatic settings. Intrinsic or acquired resistance of tumours to gemcitabine is, however, a major clinical problem. New therapeutic strategies are urgently needed whereas we also need to identify new prognostic and predictive biomarkers. This article focuses on gemcitabine resistance, on the role of chemokines and chemokine receptors in pancreatic carcinoma initiation and progression, and on stellate cells as partners in crime with neoplastic epithelial cells.
Assuntos
Adenocarcinoma/tratamento farmacológico , Terapia de Alvo Molecular , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/metabolismo , Antineoplásicos/uso terapêutico , Quimiocina CXCL12/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pancreáticas/metabolismo , Células Estreladas do Pâncreas/metabolismo , Receptores CXCR4/metabolismo , GencitabinaRESUMO
BACKGROUND: Prognosis of patients with pancreatic adenocarcinoma is poor. Many prognostic biomarkers have been tested, but most studies included heterogeneous patients. We aimed to investigate the prognostic and/or predictive values of four relevant biomarkers in a multicentric cohort of patients. PATIENTS AND METHODS: A total of 471 patients who had resected pancreatic adenocarcinoma were included. Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-ß receptor, CXCR4, and LKB1. RESULTS: High CXCR4 expression was found to be the only independent negative prognostic biomarker [hazard ratio (HR) = 1.74; P < 0.0001]. In addition, it was significantly associated with a distant relapse pattern (HR = 2.19; P < 0.0001) and was the strongest prognostic factor compared with clinicopathological factors. In patients who did not received adjuvant treatment, there was a trend toward decrease in the overall survival for negative Smad4 expression. Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy (CT) benefit (HR = 0.59; P = 0.002). CONCLUSIONS: CXCR4 is a strong independent prognostic biomarker associated with distant metastatic recurrence and appears as an attractive target to be evaluated in pancreatic adenocarcinoma. Negative SMAD4 expression should be considered as a potential predictor of adjuvant CT benefit.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores CXCR4/metabolismo , Proteína Smad4/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Resultado do TratamentoRESUMO
Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.
Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Projetos de Pesquisa , Antineoplásicos/farmacologia , Europa (Continente) , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa/normas , Projetos de Pesquisa/tendênciasRESUMO
BACKGROUND: Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. RESULTS: Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. CONCLUSIONS: Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.
Assuntos
Adenocarcinoma/terapia , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/administração & dosagem , Neoplasias Retais/terapia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Procedimentos Cirúrgicos do Sistema Digestório , Feminino , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Dosagem Radioterapêutica , Neoplasias Retais/patologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Adulto JovemAssuntos
Benzenossulfonatos/uso terapêutico , Neoplasias do Sistema Biliar , Procedimentos Cirúrgicos do Sistema Biliar/efeitos adversos , Carcinoma Hepatocelular , Hemobilia/etiologia , Neoplasias Hepáticas , Piridinas/uso terapêutico , Stents/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Benzenossulfonatos/efeitos adversos , Neoplasias do Sistema Biliar/complicações , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/secundário , Neoplasias do Sistema Biliar/cirurgia , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Progressão da Doença , Evolução Fatal , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , SorafenibeRESUMO
Chemokines and their receptors are involved in tumourigenicity and clinicopathological significance of chemokines receptor expression in pancreatic adenocarcinoma (PA) is not fully understood. This study was conducted to determine patients' outcome according to the expressions of CXCR4, CXCR7 and HIF-1alpha after resection of PA. Immunohistochemistry for CXCR4, CXCR7 and HIF-1alpha expressions as well as cell proliferative index (Ki-67) was conducted in 71 resected (R0) PA and their 48 related lymph nodes (LN) using tissue microarray. CXCR4 and CXCR7 expressions were positively correlated to HIF-1alpha suggesting a potential role of HIF-1alpha in CXCR4 and CXCR7 transcription activation. Patients with CXCR4(high) tumour expression had shorter OS than those with low expression (median survival: 9.7 vs 43.2 months, P=0.0006), a higher risk of LN metastases and liver recurrence. In multivariate analysis, high CXCR4 expression, LN metastases and poorly differentiated tumour are independent negative prognosis factors. In a combining analysis, patients with a CXCR7(high)/CXCR4(high) [corrected] tumour had a significantly shorter DFS and OS than patients with a CXCR4(low)/CXCR7(low) [corrected] tumour. CXCR4 in resected PA may represent a valuable prognostic factor as well as an attractive target for therapeutic purpose.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/cirurgia , Regulação Neoplásica da Expressão Gênica , Pancreatectomia/estatística & dados numéricos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Receptores CXCR4/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Receptores CXCR/genética , Estudos Retrospectivos , Análise de Sobrevida , SobreviventesRESUMO
BACKGROUND: Gemcitabine monotherapy is the cornerstone of the treatment of patients suffering from advanced pancreatic cancer (PC). For a few years, new chemotherapeutic agents and combinations have been under validation. The use of such treatment makes it necessary to determine factors that could predict survival time. PATIENTS AND METHODS: To identify factors that predict survival time in chemonaïve patients with advanced PC and after gemcitabine failure, a retrospective analysis was performed on patients with advanced PC coming from phase II and III studies and treated with gemcitabine-based first-line chemotherapy. RESULTS: Ninety-nine patients (median age 66 years, range 27-87) suffering from pathologically proven unresectable or metastatic adenocarcinoma of the pancreas were reviewed. Median overall survival time for the whole population was 251 days and progression-free survival in first- and second-line treatment was 108 and 67 days, respectively. The Cox regression analysis identified aspartate transaminase >53 IU/l, weight loss > or =10% and Karnofsky performance status <90 as significant independent negative prognostic factors in first-line and CA 19-9 >400 IU/ml and albumin < or =3.5 mg/dl in second-line chemotherapy. A prognostic index was calculated from the regression coefficients for each independent prognostic factor and used to classify the patients in 3 different groups with good, intermediate and poor prognosis. The prognosis index in chemonaïve and gemcitabine-refractory patients was (Karnofsky performance status x 0.52) + (weight loss x 1.10) + (aspartate transaminase x 0.82) and (albumin x 1.40) + (CA 19-9 x 0.74), respectively. CONCLUSIONS: Predictive factors could be identified in first- and second-line treatments, although they require prospective validation before they could be used in the design and analysis of future clinical trials.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Desoxicitidina/análogos & derivados , Avaliação de Estado de Karnofsky , Neoplasias Pancreáticas/tratamento farmacológico , Redução de Peso , Análise Atuarial , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/metabolismo , Aspartato Aminotransferases/sangue , Antígeno CA-19-9/sangue , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de Sobrevida , GencitabinaRESUMO
Gemcitabine and oxaliplatin (GEMOX) are active as first-line therapy against advanced pancreatic cancer. This study aims to evaluate the activity and tolerability of this combination in patients refractory to standard gemcitabine (GEM). A total of 33 patients (median age of 57) were included with locally advanced and metastatic evaluable diseases, who had progressed during or following GEM therapy. The GEMOX regimen consisted of 1000 mg m(-2) of GEM at a 100-min infusion on day 1, followed on day 2 by 100 mg m(-2) of oxaliplatin at a 2-h infusion; a cycle that was given every 2 weeks. All patients received at least one cycle of GEMOX (median 5; range 1-29). Response by 31 evaluable patients was as follows: PR: 7/31(22.6%), s.d. > or = 8 weeks: 11/31(35.5%), s.d. < 8 weeks: 1/31(3.2%), PD: 12/31(38.7%). Median duration of response and TTP were 4.5 and 4.2 months, respectively. Median survival was 6 months (range 0.5-21). Clinical benefit response was observed in 17/31 patients (54.8%). Grade III/IV non-neurologic toxicities occurred in 12/33 patients (36.3%), and grade I, II, and III neuropathy in 17(51%), 3(9%), and 4(12%) patients, respectively. GEMOX is a well-tolerated, active regimen that may provide a benefit to patients with advanced pancreatic cancer after progression following standard gemcitabine treatment.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Neoplasias Pancreáticas/patologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
Actually, the Fournier's gangrene is described as a dermohypodermitis of the perineal, genital and/or perianal regions which can affect both sexes and a wide range of ages. The diagnosis of the disease is essentially made on clinical grounds. Imagery can be interesting in case of an intra-abdominal suspected source of the infection, uncertain diagnosis and good available trechniques. Surgery is the only potential curative therapy and the delay between its application and the beginning of the symptoms is the most predictive prognostic factor. Adjuvant treatments consist of broad spectrum antibiotherapy, hyperbaric oxygenotherapy and topical treatments have been proposed in order to improve the prognosis of these patients, which has remained relatively dark and unchanged for thirty years. The efficiency of such therapeutics are difficult to assess because all available studies do not meet the classical criteria of evidence-based medicine.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Gangrena de Fournier/cirurgia , Doenças dos Genitais Femininos/cirurgia , Comorbidade , Feminino , Gangrena de Fournier/diagnóstico , Gangrena de Fournier/epidemiologia , Gangrena de Fournier/fisiopatologia , Doenças dos Genitais Femininos/diagnóstico , Doenças dos Genitais Femininos/epidemiologia , Doenças dos Genitais Femininos/fisiopatologia , Humanos , Hospedeiro Imunocomprometido , Pessoa de Meia-IdadeRESUMO
The combination of 5-fluorouracil (5-FU) modulated by folinic acid (FA) and cisplatin is commonly used in advanced digestive non-colon cancers (ADNCC). In order to simplify treatment administration by avoiding cisplatin-related hydration, we investigated a weekly regimen of 5-FU/FA/cisplatin. Patients with ADNCC were treated with 5-FU 2.0 g/m2, FA 500 mg/m2 and cisplatin 25 mg/m2 day 1, for 6 weeks with a 2-week rest, and were assessed for toxicity, tumor response and disease-free survival. Forty-three patients with measurable ADNCC were treated with this weekly regimen. Primary tumor sites were mainly esophagus (n = 17), stomach (n = 12) and pancreas (n = 9). Results were as follows. Toxicity was mostly hematological, with 16% grade 3/4 neutropenia (seven of 43) and 4% febrile neutropenia (two of 43). Objective response (OR) was observed in 19 of 43 (44%) patients including four complete responses (9%) and 15 partial responses (35%). Another 18 patients (42%) experienced stable disease. Time to progression was 6.5 months. The median response and stable disease durations were 4.3 (range 3-34) and 5 (range 2-16) months, respectively. We conclude that weekly administration of 5-FU/FA/cisplatin is an active and well-tolerated regimen. Toxicity is manageable and allows chemotherapy on an outpatient basis without hydration program as required when cisplatin is used at the dose of 50 mg/m2.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Digestório/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Neoplasias do Sistema Digestório/patologia , Progressão da Doença , Esquema de Medicação , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologiaRESUMO
A 47-year-old man with acute lymphocytic leukemia was admitted in intensive care unit (ICU) because of respiratory failure. He had febrile neutropenia and probable invasive pulmonary aspergillosis (IA). Amphotericin B renal toxicity and clinical deterioration prompted a shift to caspofungin and resulted in a successful response.
Assuntos
Antifúngicos/administração & dosagem , Antineoplásicos/efeitos adversos , Aspergilose , Pneumopatias Fúngicas , Neutropenia/complicações , Peptídeos Cíclicos , Peptídeos/administração & dosagem , Terapia de Salvação , Antineoplásicos/administração & dosagem , Aspergilose/tratamento farmacológico , Aspergilose/imunologia , Linfoma de Burkitt/tratamento farmacológico , Caspofungina , Equinocandinas , Humanos , Lipopeptídeos , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/imunologia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Indução de Remissão , Fatores de Tempo , Resultado do TratamentoRESUMO
In a 56-year-old man with metastatic small-cell lung cancer, a persistent hiccup was refractory to classic treatments. Hyponatremia, neoplasic mediastinal involvement and liver metastases were though to be potential causative factors. Methylphenidate (MTP), a mild central nervous system (CNS) stimulant that is most commonly used for the treatment of attention deficit hyperactivity disorder, was started at a daily dose of 10 mg. It was rapidly efficient and well tolerated. This report suggests a potential advantage of MTP in the treatment of intractable hiccup in cancer patients.
Assuntos
Carcinoma de Células Pequenas/complicações , Estimulantes do Sistema Nervoso Central/farmacologia , Soluço/tratamento farmacológico , Soluço/etiologia , Neoplasias Pulmonares/complicações , Metilfenidato/farmacologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Oenococcus oeni is a lactic acid bacterium which is able to grow in wine and perform malolactic fermentation. To survive and grow in such a harsh environment as wine, O. oeni uses several mechanisms of resistance including stress protein synthesis. The molecular characterisation of three stress genes hsp18, clpX, trxA encoding for a small heat shock protein, an ATPase regulation component of ClpP protease and a thioredoxin, respectively, allow us to suggest the existence in O. oeni of multiple regulation mechanisms as is the case in Bacillus subtilis. One common feature of these genes is that they are expressed under the control of housekeeping promoters. The expression of these genes as a function of growth is significantly different. Surprisingly, the clpX gene, which is induced by heat shock, was highly expressed in the early phase of growth. In addition to stress protein synthesis, adaptation to the acid pH of wine requires efficient cellular systems to extrude protons. Using inhibitors specific for different types of ATPases, we demonstrated the existence of H+-ATPase and P-type ATPase.
Assuntos
Proteínas de Bactérias , Cocos Gram-Positivos/fisiologia , Adenosina Trifosfatases/metabolismo , Proteínas de Choque Térmico/genética , Concentração de Íons de Hidrogênio , Leuconostoc/fisiologia , Regiões Promotoras Genéticas , Transcrição GênicaRESUMO
Mutants of Oenococcus oeni were isolated as spontaneous neomycin-resistant mutants. Three of these mutants harbored a significantly reduced ATPase activity that represented 50% of that of the wild-type strain. Their growth rates were also impaired at pH 5.3 (46-86% of the wild-type level). However, the profiles of sugar consumption appeared identical to those of the parental strain. At pH 3.2, all the mutant strains failed to grow and a drastic decrease in viability was observed after an acid shock. Surprisingly, all the isolated mutants were devoid of malolactic activity. These results suggest that the ATPase and malolactic activities of O. oeni are linked to each other and play a crucial role in the mechanism of resistance to an acid stress.
Assuntos
Adenosina Trifosfatases/metabolismo , Antibacterianos/farmacologia , Cocos Gram-Positivos/efeitos dos fármacos , Ácido Láctico/metabolismo , Malatos/metabolismo , Neomicina/farmacologia , Resistência Microbiana a Medicamentos , Cocos Gram-Positivos/genética , Cocos Gram-Positivos/metabolismo , Proteínas de Choque Térmico/metabolismo , Resposta ao Choque Térmico , Concentração de Íons de Hidrogênio , Leuconostoc/efeitos dos fármacos , Leuconostoc/genética , Leuconostoc/metabolismoRESUMO
The effect of the ingestion of the carcinogenic substance DAB on the density and distribution of organic free radicals in rat liver is studied by the electron spin resonance method. There is a remarkable parallelism between what is known about the evolution of the activity of mitochondria and the concentration variations of free radicals.