RESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy. PATIENTS AND METHODS: KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study. RESULTS: On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes. CONCLUSIONS: This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/terapia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Imunoterapia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação , Fator 2 Relacionado a NF-E2 , Ensaios Clínicos Controlados Aleatórios como Assunto , Microambiente TumoralRESUMO
OBJECTIVE: The purpose of this study is to evaluate the clinical determinants of complete response in locally advanced basal cell carcinoma (laBCC) patients receiving Sonidegib in a real-life, retrospective, observational study. Hedgehog pathway inhibitors (Vismodegib and Sonidegib) are approved for the systemic treatment of locally advanced basal cell carcinoma (laBCC). The objective response rate was the primary endpoint of the trials for both drugs. PATIENTS AND METHODS: Adult patients with laBCC treated with Sonidegib at the Dermato-Oncology Unit of IFO San Gallicano between June 2020 and September 2022 were included in the study. Patient, tumor, and treatment characteristics were recorded. The complete response rate was the primary outcome. The median time to the best response and complete response were the secondary outcomes. Treatment-related adverse events (TRAEs) and dose adjustments were recorded. RESULTS: Of the 19 patients included in the study, eight (42.1%) achieved a complete response, seven (36.8%) had a partial response, and four experienced progressive disease (21%). The median time to the best response was 3 months in the group of patients with partial response (range 2.0-4.0, with three patients not evaluable) and 3.5 months in the group of patients with complete response (range 2-5). TRAEs occurred in 14 (73.6%) patients, with 8 (57.1%) reporting ≤2 TRAE categories and 6 (42.8%) >2. A total of 78.9% of patients received a modified treatment schedule; 12.5% of patients who achieved a complete response received full dosage from the beginning to the end of treatment, compared with 27.3% of those with a partial response. CONCLUSIONS: The associations between the clinical outcome of interest (objective response rate) and the clinicopathological and treatment characteristics were evaluated. No statistically significant association was observed. Our analysis confirms the observation that no statistically significant correlation exists between clinical response and Sonidegib alternate dose regimen.
Assuntos
Antineoplásicos , Compostos de Bifenilo , Carcinoma Basocelular , Piridinas , Neoplasias Cutâneas , Adulto , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/patologia , Proteínas Hedgehog , Piridinas/farmacologia , Piridinas/uso terapêutico , Estudos Retrospectivos , Neoplasias Cutâneas/patologiaRESUMO
OBJECTIVE: Lichen sclerosus is a chronic, inflammatory, progressive skin disease predominantly affecting anogenital areas. Vulvar lichen sclerosus (VLS) is one of the most common conditions treated in vulvar clinics; most patients report distressing symptoms of itching, burning, stinging, and pain (particularly during or after sexual intercourse). A preliminary, prospective, single-center study was performed to investigate the efficacy of hyaluronan hybrid cooperative complex (HCC) comprising high and low molecular weight hyaluronic acid to treat menopausal women with VLS. PATIENTS AND METHODS: Patients (N = 30) received two HCC injections at 32 mg/ml (one month apart). At baseline and one and six months after treatment, patients completed validated psychometric questionnaires to assess their self-reported pain, itching, and dryness using the Visual Analogue Scale (VAS) and sexual function by the Female Sexual Function Index (FSFI). RESULTS: After treatment with HCC, no side effects or complications were reported. VAS scores showed a trend towards reduced pain and itching intensity, and there was a statistically significant reduction in median VAS score for dryness at follow-up vs. baseline (p=0.038). For sexual function, there was a statistically significant improvement in lubrication (p=0.001) and orgasm (p=0.001) FSFI domains. CONCLUSIONS: Overall, this preliminary study demonstrated the promising efficacy of HCC in menopausal women with VLS without side effects.
Assuntos
Dermatopatias , Líquen Escleroso Vulvar , Humanos , Feminino , Líquen Escleroso Vulvar/tratamento farmacológico , Líquen Escleroso Vulvar/complicações , Estudos Prospectivos , Vulva , Prurido/complicações , DorRESUMO
BACKGROUND: We investigated pretreatment fasting glucose as a predictor of patients' important outcomes in breast and colorectal cancers undergoing targeted therapies. PATIENTS AND METHODS: In a historic cohort of 202 breast and 218 colorectal cancers treated with targeted agents from 1998 to 2009, we used the Kaplan-Meier method and the log-rank test to estimate survival through tertiles of fasting glucose and the Cox proportional hazards model for multivariate analysis stratified by primary site of cancer and including gender, age and body mass index. RESULTS: The median follow-up was 20 months (1-128). At 60 months, 65% of patients in the lowest tertile of fasting glucose did not experiment disease progression compared with 34% in the highest tertile (P=0.001). Seventy-six percent of females in the lowest tertile showed no progression compared with 49% in the top tertiles (P=0.015). In multivariate analysis, fasting glucose was a significant predictor of time to disease progression only in breast cancer patients in the first tertile compared with the third (P=0.017). CONCLUSIONS: We found evidence of a predictive role of pretreatment fasting glucose in the development of resistance in breast cancer patients treated with targeted agents. Prospective studies are warranted to confirm our findings.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Glicemia , Neoplasias da Mama/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Bevacizumab , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Cetuximab , Neoplasias Colorretais/sangue , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Jejum , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Trastuzumab , Resultado do TratamentoRESUMO
We conducted a prospective, observational study to verify the efficacy, tolerability and impact on quality of life, mood and global neurocognitive performances of oxcarbazepine monotherapy in patients with brain tumor-related epilepsy (BTRE). Patients were followed for 12 months. We recruited 25 patients (11 females 14 males; mean age 49.7) affected with BTRE (17 de novo patients and 7 in monotherapy with other antiepileptics) and introduced oxcarbazepine monotherapy because of uncontrolled seizures and/or side effects. At first visit, patients underwent neurological examination, Qolie 31P V2, EORTC QLQC30, Zung self-depression rating scale (ZSDRS) and adverse events profile. A seizure diary was given to each patient. Follow-up duration was 1-12 months (mean 7.1 months, 5 patients died and 10 dropped out). Totals of 16 patients underwent both chemotherapy and radiotherapy, 4 chemotherapy only, 1 radiotherapy only, and 4 did not undergo any systemic therapy. Mean dosage of oxcarbazepine was 1,230 mg/day (min 600, max 2,100 mg/day). McNemar's test showed a significant difference in seizure freedom rate (P = 0.002) between baseline and final follow-up in the intent-to-treat population. Six patients (24%) had serious side effects and one patient (4%) mild. Logistic regression revealed that, in our study, chemotherapy and radiotherapy did not affect the efficacy of OXC in seizure outcome (P = 0.658). The test evaluation at final follow-up showed a significant improvement in ZSDRS (P = 0.011) and no change over time. Oxcarbazepine seems to be efficacious in controlling seizures and in improving mood in patients with BTRE, but special caution should be taken when it is administered during radiotherapy.
Assuntos
Anticonvulsivantes/uso terapêutico , Carbamazepina/análogos & derivados , Epilepsia/tratamento farmacológico , Epilepsia/psicologia , Qualidade de Vida , Adulto , Idoso , Neoplasias Encefálicas/complicações , Carbamazepina/uso terapêutico , Epilepsia/etiologia , Feminino , Glioma/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Testes Neuropsicológicos , Oxcarbazepina , Projetos Piloto , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
The aim of the study was to evaluate efficacy, safety and impact on life expectancy of levetiracetam (LEV), oxcarbazepine (OXC) and topiramate (TPM) monotherapy in patients with seizures related to brain metastases. We conducted a prospective observational study on 70 patients with brain metastases. Thirteen patients were excluded because they were in prophylactic therapy with antiepileptics, nine patients did not return to our Center. A total of 48 patients with epilepsy related to brain metastases were enrolled. Patients were treated with LEV, OXC and TPM in monotherapy and followed until their death. Eighteen patients dropped out. Therefore, we followed 30 patients. Mean duration of follow-up was 6.1 months. Upon visiting the patients prior to their death (i.e. last visit preceding the death of the patients), we observed a significant reduction (P < 0.001) in the mean monthly seizure frequency; with 19 patients (63.3%) obtaining complete seizure control in the whole population. A significant improvement of seizure frequency was also observed considering each antiepileptic treatment group separately. Median survival time was similar among the three groups of patients and was similar to Class I of prognostic factors of Radiation Therapy Oncology Group. Logistic regression showed that systemic treatments did not influence the antiepileptics' efficacy on seizure control (P = 0.614). In conclusion, regarding the use of newer antiepileptics in patients with seizures related to brain metastases, our data indicate that LEV, OXC and TPM significantly reduce seizure frequency (independently of systemic treatment), produce few side effects and appear not to affect life expectancy.
Assuntos
Anticonvulsivantes/uso terapêutico , Neoplasias Encefálicas/complicações , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Expectativa de Vida , Adulto , Idoso , Anticonvulsivantes/efeitos adversos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Avaliação de Medicamentos/métodos , Epilepsia/mortalidade , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Cancer increases the risk of thromboembolic events and the risk of recurrent thromboembolic events while on anticoagulation. OBJECTIVES: To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants (vitamin K antagonist (VKA) and ximelagatran) for the long term treatment of venous thromboembolism (VTE) in patients with cancer. SEARCH STRATEGY: A comprehensive search was undertaken including a January 2007 search of electronic databases; Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library 2007, Issue 1). MEDLINE (1966 onwards; accessed via OVID), EMBASE (1980 onwards; accessed via OVID) and ISI the Web of Science. Hand search of the proceedings of the American Society of Clinical Oncology and of the American Society of Hematology. Checking of references of included studies, relevant papers and related systematic reviews. Use of "related article" feature in PubMed; and (5) search of ISI the Web of Science for papers citing landmark studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing long term treatment with LMWH versus oral anticoagulants (VKA or ximelagatran) in patients with cancer and symptomatic objectively confirmed VTE. DATA COLLECTION AND ANALYSIS: Using a standardized data form we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia and postphlebitic syndrome. MAIN RESULTS: Of 3986 identified citations, eight RCTs were eligible and reported data for patients with cancer. Their overall methodological quality was moderate. Meta-analysis of six RCTs showed that LMWH, compared to VKA provided no statistically significant survival benefit (Hazard ratio (HR) = 0.96; 95% CI 0.81 to 1.14) but a statistically significant reduction in VTE (HR = 0.47; 95% (Confidence Interval (CI) = 0.32 to 0.71). There was no statistically significant difference between LMWH and VKA in bleeding outcomes (RR = 0.91; 95% CI = 0.64 to 1.31) or thrombocytopenia (RR = 1.02; 95% CI = 0.60 to 1.74). One RCT compared tinzaparin and dalteparin and showed no differences in the outcomes of interest. One RCT compared a six months extension of anticoagulation with 18 months Ximelagatran 24mg twice daily versus placebo. It showed a reduction in VTE (HR = 0.16; 95% CI 0.09 to 0.30) with no apparent effect on survival or bleeding. AUTHORS' CONCLUSIONS: For the long term treatment of VTE in patients with cancer, LMWH compared to VKA reduces venous thromboembolic events but not death. The decision for a patient with cancer and VTE to start long term LMWH versus oral anticoagulation should balance the benefits and downsides and integrate the patient's values and preferences for the important outcomes and alternative management strategies.
Assuntos
Anticoagulantes/uso terapêutico , Neoplasias/complicações , Tromboembolia Venosa/tratamento farmacológico , Azetidinas/uso terapêutico , Benzilaminas/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina K/antagonistas & inibidoresRESUMO
BACKGROUND: Compared to patients without cancer, patients with cancer receiving anticoagulant treatment for venous thromboembolism are more likely to develop recurrent venous thromboembolism (VTE). OBJECTIVES: To compare the efficacy and safety of three types of anticoagulants (i.e. low molecular weight heparin (LMWH), unfractionated heparin (UFH), and fondaparinux) for the initial treatment of VTE in patients with cancer. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients including a January 2007 electronic search of : Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI the Web of Science. SELECTION CRITERIA: Randomized clinical trials (RCTs) comparing LMWH, UFH, and fondaparinux in patients with cancer and objectively confirmed VTE. DATA COLLECTION AND ANALYSIS: Using a standardized data form data was extracted in duplicate on methodological quality, participants, interventions and outcomes of interest that included all cause mortality, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia and postphlebitic syndrome. MAIN RESULTS: Of 3986 identified citations, 26 RCTs including cancer patients as subgroups fulfilled the inclusion criteria. Cancer subgroup data was obtained for 15 of the 26 RCTs. Thirteen studies compared a LMWH to UFH while one study compared fondaparinux to UFH and one study compared dalteparin to tinzaparin. Meta-analysis of 11 studies showed a statistically significant mortality reduction in patients treated with LMWH compared with those treated with UFH (Relative risk (RR) = 0.71; 95% confidence interval (CI) 0.52 to 0.98). There was little change in the results after excluding studies of lower methodological quality (RR = 0.72; 95% CI 0.52 to 1.00). A meta-analysis of three studies comparing LMWH with UFH in reducing recurrent VTE was inconclusive (RR = 0.78; 95% CI 0.29 to 2.08). No data was available for bleeding outcomes, thrombocytopenia or postphlebitic syndrome. Compared to UFH, fondaparinux showed a non-statistically significant benefit for the outcome of death (RR = 0.52; 95% CI 0.26 to 1.05). The one study comparing dalteparin to tinzaparin showed a non-statistically significant mortality reduction with dalteparin (RR = 0.86; 95% CI 0.43 to 1.73). AUTHORS' CONCLUSIONS: Based on the included trials, LMWH is likely to be superior to UFH in the initial treatment of VTE in patients with cancer. However, there is a need for more trials to better address this research question in cancer patients. Moreover, researchers should consider making the raw data of RCTs available for individual patient data meta-analyses.
Assuntos
Anticoagulantes/uso terapêutico , Neoplasias/complicações , Tromboembolia Venosa/tratamento farmacológico , Fondaparinux , Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Polissacarídeos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Tromboembolia Venosa/mortalidadeRESUMO
BACKGROUND: A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumour effect in addition to their antithrombotic effect. OBJECTIVES: To evaluate the effectiveness and safety of oral anticoagulation (including vitamin K antagonists and ximelagatran) as an intervention to improve survival of patients with cancer. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients including (1) a January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed. SELECTION CRITERIA: Randomized clinical trials (RCTs) comparing vitamin K antagonist or ximelagatran to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism. DATA COLLECTION AND ANALYSIS: Using a standardized data form we extracted data on methodological quality, participants, interventions and outcome of interest that included all cause mortality, symptomatic deep venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding. MAIN RESULTS: Of 3986 identified citations five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The overall methodological quality of these RCTs was acceptable. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.95; 95% CI 0.86 to 1.05) at 2 years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). In the subgroup of patients with small cell lung cancer (SCLC), warfarin reduced mortality at six months (RR = 0.69; 95% CI 0.50 to 0.96) but not at one year (RR = 0.88; 95% CI 0.77 to 1.01). This six month mortality benefit was statistically significant in the subgroup of extensive SCLC (RR = 0.65; 95% CI 0.45 to 0.93) but not in the subgroup of limited SCLC (RR = 0.68; 95% CI 0.36 to 1.28). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (p = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74). Warfarin increased the risk of major bleeding (RR 5.46; 95% CI 3.04 to 9.81) and minor bleeding (RR 4.01; 95% CI 1.30 to 12.42) also in patients with SCLC. There was no evidence for a significant reduction in mortality in any other cancer subtype. AUTHORS' CONCLUSIONS: Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer. In patients with SCLC, the evidence suggests a survival benefit at six months from warfarin particularly when the disease is extensive. The decision for a patient with extensive SCLC to start warfarin for survival benefit should balance that benefit with the downsides of increased bleeding risk in light of patient values for these outcomes.
Assuntos
Anticoagulantes/administração & dosagem , Neoplasias/mortalidade , Varfarina/administração & dosagem , Administração Oral , Anticoagulantes/efeitos adversos , Carcinoma de Células Pequenas/mortalidade , Hemorragia/induzido quimicamente , Humanos , Neoplasias Pulmonares/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Tromboembolia/prevenção & controle , Varfarina/efeitos adversosRESUMO
BACKGROUND: Central venous catheter (CVC) placement increases the risk of thrombosis in cancer patients. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis related morbidity and mortality. OBJECTIVES: To evaluate the efficacy and safety of anticoagulation in reducing venous thromboembolic (VTE) events in cancer patients with CVC. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients up to January 2006 was conducted in the following databases: The Cochrane Central Register of Controlled Trials ( CENTRAL), MEDLINE, EMBASE and ISI the Web of Science. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonists (VKA), fondaparinux or ximelagatran to no intervention or placebo in cancer patients with a CVC or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS: Data was extracted on methodological quality, patients, interventions and outcomes including all cause mortality (primary outcome), premature CVC removal, catheter-related infections, CVC site and non CVC site deep venous thrombosis (DVT), pulmonary embolism (PE), major and minor bleeding and thrombocytopenia. MAIN RESULTS: Of 3986 identified citations nine RCTs were included in the meta-analysis including one published as an abstract and one focusing on paediatric patients not included in the meta-analysis. None of these RCTs tested fondaparinux or ximelagatran. The use of heparin in cancer patients with CVC was associated with a trend towards a reduction in symptomatic DVT (Relative Risk (RR) = 0.43; 95% Confidence Interval (CI): 0.18 to 1.06), but the data did not show any statistically significant effect on mortality (RR = 0.74; 95% CI: 0.40 to 1.36), infection (RR = 0.91; 95% CI: 0.36 to 2.28), major bleeding (RR = 0.68; 95% CI: 0.10 to 4.78) or thrombocytopenia (RR = 0.85; 95% CI: 0.49 to 1.46). The effect warfarin on symptomatic DVT was not statistically significant (RR = 0.62; 95% CI: 0.30 to 1.27). When studies assessing different types of anticoagulants were pooled, symptomatic DVT rates were significantly reduced (RR = 0.56; 95% CI: 0.34 to 0.92). AUTHORS' CONCLUSIONS: Cancer patients with CVC considering anticoagulation, should consider the possible benefit of reduced incidence of thromboembolic complications with the burden and harms of anticoagulation. Future studies should be adequately powered and evaluate the effects of newer anticoagulants such as fondaparinux and ximelagatran in cancer patients with CVC.
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Anticoagulantes/uso terapêutico , Cateterismo Venoso Central/efeitos adversos , Neoplasias , Trombose Venosa/prevenção & controle , Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombose Venosa/etiologia , Vitamina K/antagonistas & inibidoresRESUMO
To evaluate the effectiveness and safety of oral anticoagulants in improving survival of cancer patients. We conducted in January 2007 a comprehensive search for relevant randomized clinical trials (RCTs). We extracted data on methodological quality, participants, interventions and outcomes using a standardized form. Five RCTs fulfilled the inclusion criteria and all compared warfarin to either placebo or no intervention. Their overall methodological quality was acceptable. The effect of warfarin on mortality was not statistically significant at 6 months (RR = 0.96; 95% CI 0.80-1.16), at 1 year (RR = 0.95; 95% CI 0.86-1.05), at 2 years (RR = 0.97; 95% CI 0.87-1.08) or at 5 years (RR 0.91; 95% CI 0.83-1.01). In the subgroup of patients with small cell lung cancer (SCLC), warfarin reduced mortality at 6 months (RR = 0.69; 95% CI 0.50-0.96) but not at 1 year (RR = 0.88; 95% CI 0.77-1.01). This 6 months mortality benefit was statistically significant in the subgroup of extensive SCLC (RR = 0.65; 95% CI 0.45-0.93) but not in the subgroup of limited SCLC (RR = 0.68; 95% CI 0.36-1.28). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85-9.68) and minor bleeding (RR = 3.34; 95% CI 1.66-6.74). The evidence suggests a survival benefit from warfarin in patients with extensive SCLC, but not in other patient groups. This survival benefit should be weighed against the increased risk for hemorrhage.
Assuntos
Anticoagulantes/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Varfarina/administração & dosagem , Administração Oral , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/mortalidade , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Varfarina/efeitos adversos , Varfarina/uso terapêuticoRESUMO
UNLABELLED: We aimed at describing the epidemiology of femur fracture in elderly hospitalized for femur fracture in Lazio (Italy), and evaluating the association between patient's and hospital characteristics on in-hospital mortality. We conducted a population- and hospital-based study (Lazio region: 5.233.233 inhabitants) among people 65+ years aged. SOURCE OF DATA: regional hospital register 2002-2003; ICD-9-CM codes for patients' selection 820 e 821. Direct standardization (rate x 1000) and logistic regression analysis (OR, 95% CI) were performed. Overall hospitalization rate in elderly was 7.5%o (10.l%o females vs. 3.9%0 males). 12.033 patients with femur fractures were enrolled in the study period; 21,6% were not treated surgically: in comparison with those who underwent surgery, they were males, residents out of Rome, older and with worst health status. In-hospital mortality rate was 7,97%. In-hospital mortality determinants were: male gender (OR=0.56), older age (85+, OR=3.30), living out of Rome (OR=0.50), comorbidities (Charlson 'index 3: OR=4.44), "others and unspecified parts of femur" as site of fracture (OR=1.84), admission to a private hospital (OR=O. 79) and a surgical treatment (OR=0.20). In conclusion, this study showed the effect of selected individual characteristics on in hospital mortality and suggested a role of early surgical treatment and access to private sector. Regional hospital information systems represent useful tools to address epidemiological impact of hip fracture and its health care resources utilization.
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Fraturas do Colo Femoral/mortalidade , Hospitalização/estatística & dados numéricos , Hospitais Gerais , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Fraturas do Fêmur/mortalidade , Fraturas do Colo Femoral/epidemiologia , Fraturas do Colo Femoral/cirurgia , Mortalidade Hospitalar , Humanos , Lactente , Recém-Nascido , Classificação Internacional de Doenças , Itália/epidemiologia , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Estudos Retrospectivos , Cidade de Roma/epidemiologia , Distribuição por SexoRESUMO
Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.
Assuntos
Neoplasias da Mama/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metástase Neoplásica/genética , Recidiva Local de Neoplasia/genética , Animais , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Camundongos , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas , Transativadores , Fatores de Transcrição , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Lacosamide (LCM) is an antiepileptic drug (AED) that has demonstrated a good efficacy in controlling seizures as an add-on in adult epilepsy. To date, there have been no studies on LCM in patients with brain tumor-related epilepsy (BTRE). To evaluate efficacy and tolerability of LCM as an add-on in BTRE, we followed 14 patients suffering from BTRE who had already been treated with other AEDs and who had not experienced adequate seizure control. Eleven patients underwent chemotherapy while being treated with LCM. Mean duration of follow up was 5.4 months (min < 1 max 10 months). Mean seizure number in the last month prior to the introduction of LCM had been 15.4. At last follow-up, the mean seizure number was reduced to 1.9/month. Lacosamide mean dosage was of 332.1 mg/day (min 100 max 400 mg/day). Responder rate was 78.6%. One patient discontinued LCM because of side-effects. There were no other reported side-effects. Preliminary data on the use of LCM in add-on in patients with BTRE indicate that this drug may represent a valid alternative as an add-on in this particular patient population. However, larger samples are necessary in order to draw definitive conclusions.