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INTRODUCTION: This study aimed to determine the predictors of quality of life (QOL) among persons with paraplegic spinal cord injury (SCI) after discharge from the hospital to the community in Pakistan, based on the International Classification of Functioning (ICF) components, including participation, impairments of body function/structures, personal factors, and environmental factors. MATERIALS AND METHODS: A cross-sectional study was conducted with, one hundred and forty individuals with paraplegic SCI, who met the inclusion and exclusion criteria and attended an outpatient rehabilitation clinic. The impairment of body function/structures of participants was assessed using the American Spinal Injury Association (ASIA) Scale, which classified them as A, B, C, D, or E. A set of questionnaire survey forms was used to collect sociodemographic information, occupational participation, environmental factors, and QOL by using a demographic questionnaire, World Health Organization Disability Assessment Schedule 2.0 (WHODAS-II), Craig Hospital Inventory of Environmental Factors (CHIEF) scale and World Health Organization Quality of Life (WHOQOL) BREF form respectively. RESULTS: The results showed that occupational participation was the strongest predictor of QOL among persons with paraplegic SCI (ß=-0.586, p<0.001). In the second step, variables representing body function/structure factors (ASIA-A, B, C, D, E) were added, and the overall model explained 40.7% of the variance in QOL. In the third step, personal factors (age groups, gender, marital status, level of education, and rehabilitation duration) were added, and the overall model explained 51.4% of the variance in QOL. In the final step, environmental factors (CHIEF 12 Items scale) were added, but they did not significantly explain the model. CONCLUSION: The findings suggest that occupational participation was found to be the most significant predictor of QOL among individuals with paraplegic SCI. Body function/structure factors, personal factors, and environmental factors were also significant predictors, but to a lesser extent. The findings of this study can inform healthcare professionals and policymakers in developing interventions and, policies targeting occupational participation, and personal factors that may be effective to improve the QOL of individuals with paraplegic SCI in Pakistan.
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Qualidade de Vida , Traumatismos da Medula Espinal , Humanos , Alta do Paciente , Estudos Transversais , Paquistão , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/reabilitação , HospitaisRESUMO
INTRODUCTION: Diabetic peripheral neuropathy (DPN) is one of the most prevalent chronic complications of diabetes mellitus (DM) that can significantly result in disability and impaired quality of life. The DPN of the foot has been extensively studied in diabetes care. Nevertheless, the DPN of hand has been the road less taken in research and clinical practice. Thus, a scoping review was conducted to identify all available standardized hand assessments which have been used, developed, or tested in individuals with DM. MATERIALS AND METHODS: This scoping review was reported in alignment with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Studies were identified through searches of five databases: Cochrane, Scopus, ProQuest, MEDLINE, and Web of Science (WoS). RESULTS: Of the 294 articles initially identified, 20 studies were included and analysed thematically after removing duplicates. The majority of these assessments measure body function and structure such as grip and pinch strength while the rest are measuring the activity and participation domain. Most of the hand assessments were performancebased measurements. It is suggestible to employ both types of assessments to obtain a comprehensive understanding of hand conditions in individuals with DM. While some validated hand assessments were identified, only the Duruöz Hand Index (DHI) has been validated as a reliable tool specifically for evaluating hand function in individuals with DM. CONCLUSION: There is a need to evaluate the measurement properties of existing instruments for assessing the hand function in individuals with DM, or to develop hand assessments specifically for the DM population. This scoping review was forging a new path, by discovering diabetes care through the utilisation of hand assessments.
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Neuropatias Diabéticas , Mãos , Humanos , Mãos/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Diabetes Mellitus/fisiopatologiaRESUMO
INTRODUCTION: With increased life expectancy among older adults in Malaysia, there is an increasing number of years of living after retirement. The role and lifestyle changes can significantly affect time use and participation in everyday life, influencing individuals' quality of life (QoL) and wellbeing. However, limited research has examined the healthrelated QoL and its relationship with time use, role participation and perceived social support among retirees in Malaysia. MATERIALS AND METHODS: In this cross-sectional study, we used the Malay versions of EuroQol 5 Dimensional (EQ-5D- 3L, Time Use Diary, Role Checklist Version 3 (RCv3) and Multidimensional Scale of Perceived Social Support (MSPSS) questionnaires among 362 purposively selected Malaysian retirees aged 55 and older. Regression analysis was employed to identify the predictor of health-related QoL using the Statistical Package for Social Sciences (SPSS) version 26. RESULTS: The results indicate a weak positive association between all determinants (time use, role participation, perceived social support) and health-related QoL among retirees. Only time use and role participation significantly influenced the health-related QoL of retirees. Our findings reveal no direct and substantial relationship between perceived social support and health-related QoL among Malaysian retirees. CONCLUSION: The results suggest active role involvement and effective time management can improve retirees' healthrelated QoL.
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Qualidade de Vida , Aposentadoria , Apoio Social , Humanos , Malásia , Masculino , Feminino , Estudos Transversais , Aposentadoria/psicologia , Idoso , Pessoa de Meia-Idade , Inquéritos e Questionários , Idoso de 80 Anos ou maisRESUMO
AIM: To assess the frequency of radiographically evident drug-induced sarcoidosis-like reaction (DISR) in patients treated with anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) therapy, anti-programmed cell death protein 1 (PD-1) therapy, or a combination of both in a single centre. MATERIALS AND METHODS: The images and medical records of 457 patients with metastatic melanoma or head and neck cancer treated with either anti-CTLA-4 therapy, anti-PD-1 therapy, or a combination of both at University of California medical centre were reviewed retrospectively and the incidence of radiological manifestations of DISR was assessed among these treatment groups. RESULTS: Radiological manifestations of DISR were found in 19/457 patients (4.1%). The mean interval from the initiation of immunotherapy to development of DISR was 5.5 months (range 2.3-13.5 months). Mean interval from radiological detection of DISR to imaging evidence of resolution was 5.8 months (range 1.6-18.3 months). Three patients out of 81 (3.7%), 11/297 (3.7%), and 5/79 (6.3%) developed sarcoidosis-like reaction after treatment with anti-CTLA-4 antibody, anti-PD-1 antibody, and a combination of both, respectively. Most patients with DISR were asymptomatic and did not require systemic therapy. Most patients did not demonstrate concomitant increased maximum standardised uptake value (SUVmax) in other organs on their integrated 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)/computed tomography (CT). CONCLUSIONS: In the present retrospective study of patients treated with immune checkpoint inhibitors (ICIs), DISR occurred in approximately 3.7% of patients treated with either anti-CTLA-4 or anti-PD-1 antibody and 6.3% of patients treated with a combination of both.
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Imunoterapia , Melanoma , Sarcoidose , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Incidência , Melanoma/tratamento farmacológico , Melanoma/patologia , Estudos Retrospectivos , Sarcoidose/diagnóstico por imagem , Sarcoidose/epidemiologia , Sarcoidose/etiologiaRESUMO
Highly porous membranes based on polyvinylidene fluoride (PVDF) with the addition of nanoscale particles of non-magnetic and magnetic iron oxides were synthesized using a combined method of non-solvent induced phase separation (NIPS) and thermo-induced phase separation (TIPS) based on the technique developed by Dr. Blade. The obtained membranes were characterized using SEM, EDS, XRD, IR, diffuse reflectance spectroscopy, and fluorescent microscopy. It was shown that the membranes possessed a high fraction of electroactive phase, which increased up to a maximum of 96% with the addition of 2 wt% of α-Fe2O3 and α/γ-Fe2O3 nanoparticles. It was demonstrated that doping PVDF with nanoparticles contributed to the reduction of pore size in the membrane. All membranes exhibited piezocatalytic activity in the degradation of Rhodamine B. The degree of degradation increased from 69% when using pure PVDF membrane to 90% when using the composite membrane. The nature of the additive did not affect the piezocatalytic activity. It was determined that the main reactive species responsible for the degradation of Rhodamine B were â¢OH and â¢O2-. It was also shown that under piezocatalytic conditions, composite membranes generated a piezopotential of approximately 2.5 V.
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BACKGROUND: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293). PATIENTS AND METHODS: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). RESULTS: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. CONCLUSIONS: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.
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Interleucina-12 , Melanoma , Neoplasias Cutâneas , Eletroporação , Humanos , Imunidade , Interleucina-12/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Plasmídeos , Estudos Prospectivos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genéticaRESUMO
BACKGROUND: Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed. PATIENTS AND METHODS: Patients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017). RESULTS: KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE. CONCLUSIONS: This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, NCT01295827.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Esquema de Medicação , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Melanoma/mortalidade , Melanoma/patologia , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment. PATIENTS AND METHODS: Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors. RESULTS: ORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib. CONCLUSION: Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01028222.
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Antineoplásicos/uso terapêutico , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Pirimidinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Dacarbazina/uso terapêutico , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pirimidinas/efeitos adversos , Análise de SobrevidaRESUMO
Previously, we reported the role of synergy between two flavonoids-namely, chrysin and kaempferol-in inhibiting the secretion of a few major proinflammatory mediators such as tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), and nitric oxide (NO) from lipopolysaccharide (LPS)-induced RAW 264.7 cells. The present study aims to evaluate the effects of this combination on a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Severe sepsis was induced in male ICR mice (n = 7) via the CLP procedure. The effects of chrysin and kaempferol combination treatment on septic mice were investigated using a 7-day survival study. The levels of key proinflammatory mediators and markers-such as aspartate aminotransferase (AST), TNF-α, and NO-in the sera samples of the septic mice were determined via ELISA and fluorescence determination at different time point intervals post-CLP challenge. Liver tissue samples from septic mice were harvested to measure myeloperoxidase (MPO) levels using a spectrophotometer. Moreover, intraperitoneal fluid (IPF) bacterial clearance and total leukocyte count were also assessed to detect any antibacterial effects exerted by chrysin and kaempferol, individually and in combination. Kaempferol treatment improved the survival rate of CLP-challenged mice by up to 16%. During this treatment, kaempferol expressed antibacterial, antiapoptotic and antioxidant activities through the attenuation of bacterial forming units, AST and NO levels, and increased polymorphonuclear leukocyte (PMN) count in the IPF. On the other hand, the chrysin treatment significantly reduced serum TNF-α levels. However, it failed to significantly improve the survival rate of the CLP-challenged mice. Subsequently, the kaempferol/chrysin combination treatment significantly improved the overall 7-day survival rate by 2-fold-up to 29%. Kaempferol and chrysin revealed some synergistic effects by acting individually upon multiple pathophysiological factors involved during sepsis. Although the kaempferol/chrysin combination did not exhibit significant antibacterial effects, it did exhibit anti-inflammatory and antioxidant activities, which translate to significant improvement in the survival rate of septic animals. These findings suggest the potential application of this combination treatment as a beneficial adjuvant supplement strategy in sepsis control.
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Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Flavonoides/farmacologia , Quempferóis/farmacologia , Sepse/tratamento farmacológico , Animais , Aspartato Aminotransferases/antagonistas & inibidores , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/genética , Biomarcadores/sangue , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Expressão Gênica , Contagem de Leucócitos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/sangue , Peroxidase/genética , Peroxidase/metabolismo , Sepse/sangue , Sepse/genética , Sepse/patologia , Análise de Sobrevida , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: Treatment options for sarcoma are limited. Histone deacetylase inhibitors increase the efficacy of topoisomerase II inhibitors by promoting access to chromatin and by down-regulating DNA repair. Thus, combined panobinostat and epirubicin therapy was evaluated to treat refractory sarcoma. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled in a 3 + 3 dose-escalation phase I trial of panobinostat given on days 1, 3, and 5 followed by 75 mg/m(2) of epirubicin on day 5 in 21-day cycles, with a dose expansion at maximum tolerated dose (MTD) in 20 sarcoma patients. Peripheral blood mononucleocyte histone acetylation was also evaluated. RESULTS: Forty patients received 20-60 mg panobinostat. Dose-limiting toxicities included thrombocytopenia, febrile neutropenia, and fatigue at 60 mg, defining a panobinostat MTD at 50 mg. Four responses were seen in 37 assessable patients, all after progression on prior topoisomerase II inhibitors. For those with sarcoma, 12 of 20 derived clinical benefit (1 partial response and 11 stable disease, median overall survival 8.3 months), including 8 of 14 previously progressed on topoisomerase II therapy. Treatment benefits correlated with increased histone acetylation and decreased neutrophil count on day 5. CONCLUSIONS: Panobinostat and epirubicin treatment is well tolerated and may reverse anthracycline resistance. Changes in histone acetylation and associated decrease in neutrophil count correlated with clinical benefit and warrant investigation as predictive biomarkers. CLINICAL TRIAL: This trial is registered at www.Clinicaltrials.gov, Identifier: NCT00878904.
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Quimioterapia Combinada , Epirubicina/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Indóis/administração & dosagem , Sarcoma/tratamento farmacológico , Adulto , Idoso , Cromatina/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Epirubicina/efeitos adversos , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Indóis/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Panobinostat , Sarcoma/genética , Sarcoma/patologia , Inibidores da Topoisomerase II/administração & dosagemRESUMO
OBJECTIVE: Efforts to improve patient safety are challenged by the lack of universally agreed upon terms. The International Classification for Patient Safety (ICPS) was developed by the World Health Organization for this purpose. This study aimed to test the applicability of the ICPS to a surgical population. DESIGN: A web-based safety debriefing was sent to clinicians involved in surgical care of abdominal organ transplant patients. A multidisciplinary team of patient safety experts, surgeons and researchers used the data to develop a system of classification based on the ICPS. Disagreements were reconciled via consensus, and a codebook was developed for future use by researchers. RESULTS: A total of 320 debriefing responses were used for the initial review and codebook development. In total, the 320 debriefing responses contained 227 patient safety incidents (range: 0-7 per debriefing) and 156 contributing factors/hazards (0-5 per response). The most common severity classification was 'reportable circumstance,' followed by 'near miss.' The most common incident types were 'resources/organizational management,' followed by 'medical device/equipment.' Several aspects of surgical care were encompassed by more than one classification, including operating room scheduling, delays in care, trainee-related incidents, interruptions and handoffs. CONCLUSIONS: This study demonstrates that a framework for patient safety can be applied to facilitate the organization and analysis of surgical safety data. Several unique aspects of surgical care require consideration, and by using a standardized framework for describing concepts, research findings can be compared and disseminated across surgical specialties. The codebook is intended for use as a framework for other specialties and institutions.
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Erros Médicos/classificação , Segurança do Paciente , Procedimentos Cirúrgicos Operatórios/normas , Humanos , Transplante de Rim/efeitos adversos , Transplante de Rim/normas , Transplante de Fígado/efeitos adversos , Transplante de Fígado/normas , Erros Médicos/prevenção & controle , Modelos Teóricos , Segurança do Paciente/normas , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Organização Mundial da SaúdeRESUMO
BACKGROUND: Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity. METHODS: We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0-1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1-14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m(-2)) was administered on day 1 starting with cycle 2. 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma. RESULTS: The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing (18)F-FLT-PET scans showed increases (23-92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAF(V600E/K) patients had significantly worse PFS than patients without these mutations. CONCLUSIONS: Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3'-Deoxy-3'-(18)F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Didesoxinucleosídeos , Feminino , Humanos , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Masculino , Melanoma/diagnóstico por imagem , Melanoma/genética , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Radiografia , Resultado do TratamentoRESUMO
BACKGROUND: Veliparib (ABT-888) is a potent, orally bioavailable, small-molecule inhibitor of the DNA repair enzymes poly ADP-ribose polymerase-1 and -2. Veliparib enhances the efficacy of temozolomide (TMZ) and other cytotoxic agents in preclinical tumor models. PATIENTS AND METHODS: In this multicenter, double-blind trial, adults with unresectable stage III or IV metastatic melanoma were randomized 1:1:1 to TMZ plus veliparib 20 or 40 mg, or placebo twice daily. Efficacy end points included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). RESULTS: Patients (N = 346) were randomized between February 2009 and January 2010. Median [95% confidence interval (CI)] PFS was 3.7 (3.0-5.5), 3.6 (1.9-4.1), and 2 (1.9-3.7) months in the 20-mg, 40-mg, and placebo arms, respectively. Median (95% CI) OS was 10.8 (9.0-13.1), 13.6 (11.4-15.9), and 12.9 (9.8-14.3) months, respectively; ORR was 10.3%, 8.7%, and 7.0%. Exploratory analyses showed patients with low ERCC1 expression had longer PFS when TMZ was combined with veliparib. Toxicities were as expected for TMZ. The frequencies of thrombocytopenia, neutropenia, and leukopenia were significantly increased in the veliparib groups. Grade 3 or 4 adverse events, mainly hematologic toxicities, were seen in 55%, 63%, and 41% of patients in the 20-mg, 40-mg, and placebo arms, respectively. CONCLUSIONS: Median PFS with 20 and 40 mg veliparib almost doubled numerically compared with placebo, but the improvements did not reach statistical significance. OS was not increased with veliparib. Toxicities were similar to TMZ monotherapy, but with increased frequency.
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Antineoplásicos Alquilantes/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Melanoma/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Dacarbazina/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Temozolomida , Adulto JovemRESUMO
BACKGROUND: Pyrexia is a frequent adverse event with combined dabrafenib and trametinib therapy (CombiDT), but little is known of its clinical associations, etiology, or appropriate management. PATIENTS AND METHODS: All patients on the BRF133220 phase I/II trial of CombiDT treated at the standard dose (150/2) were included for assessment of pyrexia (n = 201). BRAF and MEK inhibitor-naïve patients (n = 117) were included for efficacy analyses. Pyrexia was defined as temperature ≥38°C (≥100.4(°)F) or related symptoms. RESULTS: Fifty-nine percent of patients developed pyrexia during treatment, 24% of which had pyrexia symptoms without a recorded elevation in body temperature. Pyrexia was grade 2+ in 60% of pyrexia patients. Median time to onset of first pyrexia was 19 days, with a median duration of 9 days. Pyrexia patients had a median of two pyrexia events, but 21% had three or more events. Various pyrexia management approaches were conducted in this study. A trend was observed between dabrafenib and hydroxy-dabrafenib exposure and pyrexia. No baseline clinical characteristics predicted pyrexia, and pyrexia was not statistically significantly associated with treatment outcome. CONCLUSIONS: Pyrexia is a frequent and recurrent toxicity with CombiDT treatment. No baseline features predict pyrexia, and it is not associated with clinical outcome. Dabrafenib and metabolite exposure may contribute to the etiology of pyrexia. The optimal secondary prophylaxis for pyrexia is best studied in a prospective trial.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Febre/induzido quimicamente , Melanoma/tratamento farmacológico , Adulto , Idoso , Feminino , Febre/epidemiologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Mutação , Oximas/administração & dosagem , Oximas/efeitos adversos , Oximas/farmacocinética , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Piridonas/farmacocinética , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinéticaRESUMO
L-Glutamate plays a crucial role in neuronal cell death, which is known to be associated with various neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases. In this study, we investigated the protective effects of biochanin A, a phytoestrogen compound found mainly in Trifolium pratense, against L-glutamate-induced cytotoxicity in a PC12 cell line. Exposure of the cells to 10 mM L-glutamate was found to significantly increase cell viability loss and apoptosis, whereas pretreatment with various concentrations of biochanin A attenuated the cytotoxic effects of L-glutamate. Specifically, the pretreatment led to not only decreases in the release of lactate dehydrogenase, the number of apoptotic cells, and the activity of caspase-3 but also an increase in the total glutathione level in the L-glutamate-treated PC12 cells. These results indicate that biochanin A may be able to exert neuroprotective effects against L-glutamate-induced cytotoxicity. Furthermore, our findings also imply that biochanin A may act as an antiapoptotic agent in order to perform its protective function.
Assuntos
Apoptose/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Genisteína/farmacologia , Ácido Glutâmico/toxicidade , Fármacos Neuroprotetores/farmacologia , Animais , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , L-Lactato Desidrogenase/metabolismo , Células PC12 , RatosRESUMO
Creating stimulus-sensitive smart catalysts capable of decomposing organic dyes with high efficiency is a critical task in ecology. Combining the advantages of photoactive piezoelectric nanomaterials and ferroelectric polymers can effectively solve this problem by collecting mechanical vibrations and light energy. Using the electrospinning method, we synthesized hybrid polymer-inorganic nanocomposite fiber membranes based on polyvinylidene fluoride (PVDF) and bismuth ferrite (BFO). The samples were studied by scanning electron microscope (SEM), Fourier-transform infrared spectroscopy (FTIR), total transmittance and diffuse reflectance, X-ray photoelectron spectroscopy (XPS), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), vibrating-sample magnetometer (VSM), and piezopotential measurements. It has been demonstrated that the addition of BFO leads to an increase in the proportion of the polar phase from 86.5% to 96.1% due to the surface ion-dipole interaction. It is shown that the composite exhibits anisotropy of magnetic properties depending on the orientation of the magnetic field. The results of piezo-photocatalytic experiments showed that under the combined action of ultrasonic treatment and irradiation with both visible and UV light, the reaction rate increased in comparison with photolysis, sonolysis, and piezocatalysis. Moreover, for PVDF/BFO, which does not exhibit photocatalytic activity, under the combined action of light and ultrasound, the reaction rate increases by about 3× under UV irradiation and by about 6× under visible light irradiation. This behavior is explained by the piezoelectric potential and the narrowing of the band gap of the composite due to mechanical stress caused by the ultrasound.
RESUMO
BACKGROUND: Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma. METHODS: Patients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations. RESULTS: Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response. CONCLUSION: The recommended phase II dose is dasatinib 70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Metástase Neoplásica , Quinases da Família src/antagonistas & inibidores , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dacarbazina/efeitos adversos , Dasatinibe , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Análise de Sobrevida , Tiazóis/efeitos adversos , Resultado do TratamentoAssuntos
Ablação por Cateter/efeitos adversos , Endoscopia Gastrointestinal , Fístula Esofágica/diagnóstico por imagem , Fístula Esofágica/etiologia , Fístula/diagnóstico por imagem , Fístula/etiologia , Cardiopatias/diagnóstico por imagem , Cardiopatias/etiologia , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Tomografia Computadorizada por Raios X , Fibrilação Atrial/cirurgia , Evolução Fatal , Átrios do Coração , Hematemese/etiologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Increased COVID-19 vaccine hesitancy presents a major hurdle in global efforts to contain the COVID-19 pandemic. This study was designed to estimate the prevalence of adverse events after the first dose of the Covishield (AstraZeneca) vaccine among physicians in Bangladesh. A cross-sectional study was conducted using an online questionnaire for physicians (n = 916) in Bangladesh. Physicians who received at least one dose of the COVID-19 vaccine were included. The study was carried out from April 12 to May 31, 2021. More than 58% of respondents (n = 533) reported one or more adverse events. Soreness of the injected arm (71.9%), tiredness (56.1%), fever (54.4%), soreness of muscles (48.4%), headache (41.5%) and sleeping more than usual (26.8%) were the most commonly reported adverse events. Most vaccine-related reactogenicities were reported by the younger cohorts (<45 years). The majority of respondents reported severity of reactogenicity as "mild," experienced on the day of vaccination, and lasting for 1-3 days. The most common reactogenicity was pain at the injection site; the second most common was tiredness. Almost half (49.2%) of the physicians took acetaminophen (paracetamol) to minimize the effects of vaccine reactogenicity. Multivariate logistic regression analyses showed that physicians with diabetes and hypertension (OR = 2.729 95% CI: 1.282-5.089) and asthma with other comorbidities (OR = 1.885 95% CI: 1.001-3.551) had a significantly higher risk of vaccine-related reactogenicities than physicians without comorbidities. Further safety studies with larger cohorts are required to monitor vaccine safety and provide assurance to potential vaccine recipients.