RESUMO
BACKGROUND: The World Health Organization (WHO) 2021 classification of central nervous system (CNS) tumors classified astrocytoma isocitrate dehydrogenase-mutant (A IDHm) with either microvascular proliferation and/or necrosis or homozygous deletion of CDKN2A/B as CNS grade 4 (CNS WHO G4), introducing a distinct entity and posing new challenges to physicians for appropriate management and prognostication. PATIENTS AND METHODS: We retrospectively collected information about patients diagnosed with A IDHm CNS WHO G4 at three reference neuro-oncological Italian centers and correlated them with survival. RESULTS: A total of 133 patients were included. Patients were young (median age 41 years) and most received post-operative treatment including chemo-radiation (n = 101) and/or temozolomide maintenance (n = 112). With a median follow-up of 51 months, the median overall survival (mOS) was 31.2 months, with a 5-year survival probability of 26%. In the univariate analysis, complete resection (mOS: 40.2 versus 26.3 months, P = 0.03), methyl-guaninemethyltransferase (MGMT) promoter methylation (mOS: 40.7 versus 18 months, P = 0.0136), and absence of telomerase reverse transcriptase (TERT) promoter mutation (mOS: 40.7 versus 18 months, P = 0.0003) correlated with better prognosis. In the multivariate models, lack of TERT promoter mutation [hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.07-0.82, P = 0.024] and MGMT methylation (HR 0.40, 95% CI 0.20-0.81, P = 0.01) remained associated with improved survival. CONCLUSIONS: This is the largest experience in Western countries exploring the prognostic signature of patients with A IDHm CNS G4. Our results show that MGMT promoter methylation and TERT promoter mutation may impact clinical outcomes. This may support physicians in prognostication, clinical management, and design of future studies of this distinct diagnostic entity.
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Astrocitoma , Isocitrato Desidrogenase , Mutação , Humanos , Estudos Retrospectivos , Isocitrato Desidrogenase/genética , Astrocitoma/genética , Astrocitoma/mortalidade , Astrocitoma/terapia , Masculino , Feminino , Adulto , Prognóstico , Pessoa de Meia-Idade , Adulto Jovem , Neoplasias Encefálicas/genética , Enzimas Reparadoras do DNA/genética , Metilases de Modificação do DNA/genética , Idoso , Telomerase/genética , Adolescente , Gradação de Tumores , Metilação de DNA , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: In the randomized phase II REGOMA trial, regorafenib showed promising activity in patients with recurrent glioblastoma. We conducted a large, multicenter, prospective, observational study to confirm the REGOMA data in a real-world setting. PATIENTS AND METHODS: The major inclusion criteria were histologically confirmed diagnosis of glioblastoma according to the World Health Organization (WHO) 2016 classification and relapse after radiotherapy with concurrent/adjuvant temozolomide treatment, good performance status [Eastern Cooperative Oncology Group performance status (ECOG PS 0-1)] and good liver function. Regorafenib was administered at the standard dose of 160 mg/day for 3 weeks on/1 week off. Brain magnetic resonance imaging was carried out within 14 days before starting regorafenib and every 8-12 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate, disease control rate (DCR), safety and health-related quality of life. The Response Assessment in Neuro-Oncology (RANO) criteria were used for response evaluation and Common Terminology Criteria for Adverse Events (CTCAE) version 5 for assessment of adverse events (AEs). RESULTS: From September 2020 to October 2022, 190 patients with recurrent glioblastoma were enrolled from 30 cancer centers in Italy: their median age was 58.5 years [interquartile range (IQR) 53-67 years], 68% were male and 85 (44.7%) were in optimal clinical condition (ECOG PS 0). The number of patients taking steroids at baseline was 113 (60%); the second surgery was carried out in 39 (20.5%). O6-methylguanine-DNA methyltransferase (MGMT) was methylated in 80 patients (50.3%) and 147 (92.4%) of the patients analyzed had isocitrate dehydrogenase (IDH) wild type. The median follow-up period was 20 months (IQR 15.6-25.5 months). The median OS was 7.9 months ([95% confidence interval (CI) 6.5-9.2 months] and the median PFS was 2.6 months (95% CI 2.3-2.9 months). Radiological response was partial response and stable disease in 13 (7.3%) and 26 (14.6%) patients, respectively, with a DCR of 21.9%. The median number of regorafenib cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 drug-related adverse events were reported in 22.6% of patients. A dose reduction due to AEs was required in 36% of patients. No deaths were considered as treatment-related AEs. CONCLUSIONS: This large, real-world observational study showed similar OS with better tolerability of regorafenib in patients with relapsed glioblastoma compared with the REGOMA study.
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Neoplasias Encefálicas , Glioblastoma , Recidiva Local de Neoplasia , Compostos de Fenilureia , Piridinas , Humanos , Glioblastoma/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Piridinas/uso terapêutico , Piridinas/farmacologia , Idoso , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Itália , Adulto , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). RESULTS: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. CONCLUSIONS: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antígeno B7-H1/metabolismo , Fatores de Transcrição Forkhead , Microambiente TumoralRESUMO
Background: Safety and efficacy of pembrolizumab, a humanized programmed death 1 monoclonal antibody, was assessed in KEYNOTE-028, a multicohort, phase Ib trial for patients with programmed death ligand 1 (PD-L1)-positive advanced solid tumors. We report results for the cohort of patients with advanced anal carcinoma. Patients and methods: Patients with PD-L1-positive tumors (≥1%) received intravenous pembrolizumab 10 mg/kg once every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter per Response Evaluation Criteria In Solid Tumors, version 1.1. Primary endpoints were safety and overall response rate per investigator review. Secondary endpoints included progression-free survival, overall survival, and response duration. Data cutoff date was 1 July 2015. Results: Of the 43 patients with advanced anal carcinoma evaluable for PD-L1 expression, 32 (74%) had PD-L1-positive tumors as assessed with the 22C3 prototype assay, of whom 25 were enrolled between April and September 2014. Sixteen patients (64%) experienced treatment-related adverse events; the most common ones were diarrhea and fatigue in four patients (16%) each and nausea in three patients (12%). There were no treatment-related deaths or discontinuations as of the data cutoff date. Among the 24 patients with squamous cell carcinoma histology, four had confirmed partial response, for an overall response rate of 17% [95% confidence interval (CI), 5%-37%) and 10 (42%) had confirmed stable disease, for a disease control rate of 58%. One additional patient with non-squamous histology had confirmed stable disease. Conclusion: In this population of patients with PD-L1-positive advanced squamous cell anal carcinoma, pembrolizumab demonstrated a manageable safety profile and encouraging antitumor activity. These data support further study of pembrolizumab for this patient population. ClinicalTrials.gov: NCT02054806.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Canal Anal/patologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias do Ânus/mortalidade , Carcinoma de Células Escamosas/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Resultado do TratamentoRESUMO
BACKGROUND: This expansion cohort of a multicenter, dose-escalation, phase I study (NCT00557856) evaluated safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamic effects of the anti-activin receptor-like kinase-1 (ALK-1) monoclonal antibody PF-03446962 in advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with HCC and disease progression after prior antiangiogenic therapy or intolerance to treatment received PF-03446962 7 mg/kg intravenously biweekly, as recommended in the dose-escalation part of the study. RESULTS: Twenty-four patients received PF-03446962. The most frequent treatment-related adverse events (AEs) were thrombocytopenia (33.3%), asthenia (29.2), and chills (16.7%). Two patients experienced treatment-related telangiectasia, suggesting an in vivo knockout of ALK-1 function through ALK-1 pathway inhibition. Overall, treatment-related grade 3-4 AEs were reported in eight patients (33.3%). Treatment-related grade 3-4 thrombocytopenia was noted in four patients. No complete or partial responses were reported. Twelve (50%) patients achieved stable disease, which lasted ≥12 weeks in seven (29.2%) patients. The median time to progression was 3 months. Biomarker analyses showed higher mean tumor expression of c-tumor mesenchymal-epithelial transition factor and higher mean serum levels of bone morphogenetic protein-9 in patients with disease control (DC) for ≥12 weeks versus patients with disease progression. Conversely, lower mean serum transforming growth factor-ß and vascular endothelial growth factor receptor-3 levels were detected in patients with DC versus patients with progression. CONCLUSIONS: The observed safety, tolerability, pharmacokinetic profile, and clinical activity support further evaluation of PF-03446962 in patients with HCC and other solid malignancies, as single agent or in combination with other antiangiogenic, chemotherapeutic, or immunotherapeutic agents. TRIAL REGISTRATION NUMBER: NCT00557856.
Assuntos
Receptores de Activinas Tipo II/imunologia , Anticorpos Monoclonais/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Activinas Tipo II/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/imunologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
The aim of the present retrospective controlled study was to analyse and compare risk factors for tracheocutaneous fistula in patients who received tracheostomy after supracricoid partial laryngectomy with those who received tracheostomy for other causes. We enrolled 39 patients with tracheocutaneous fistulas who were divided into two groups. The first received temporary tracheostomy for supracricoid partial laryngectomies (n = 21), while the control group consisted of patients who received temporary tracheostomy for other causes (n = 18). Risk factors believed to play a role in the pathogenesis of tracheocutaneous fistula were examined including advanced age, cardiopathy, local infections, radiotherapy, elevated body mass index, malnutrition, decannulation time and aspiration grade. The Leipzig and Pearson scale score was significantly higher in the supracricoid partial laryngectomy group (p = 0.006 and 0.031 for univariate and multivariate analyses, respectively). The penetration/aspiration scale score was significantly higher in the supracricoid partial laryngectomy group as determined by univariate analysis (p = 0.014). The decannulation time was significantly lower in the supracricoid partial laryngectomy group (p = 0.004 and 0.0004 for univariate and multivariate analyses, respectively). The number of surgical closures for tracheocutaneous fistula was significantly higher in the supracricoid partial laryngectomy group by univariate analysis (p = 0.027). These results suggest that chronic aspiration and related cough may be important pathogenic factors for tracheocutaneous fistula and could be responsible for the significantly higher rates of closure failure in patients after supracricoid partial laryngectomy.
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Fístula Cutânea/etiologia , Laringectomia/efeitos adversos , Laringectomia/métodos , Aspiração Respiratória/complicações , Fístula do Sistema Respiratório/etiologia , Doenças da Traqueia/etiologia , Traqueostomia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Cartilagem Cricoide , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. There are no specific guidelines for their management. METHODS: The clinical records of elderly patients (⩾70 years old) with MPM referred from January 2005 to November 2011 to six Italian Centres were reviewed. Age, gender, histology, International Mesothelioma Interest Group (IMIG) stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), Charlson Comorbidity Index (CCI) and treatment modalities were analysed and correlated to overall survival (OS). RESULTS: In total, 241 patients were identified. Charlson Comorbidity Index was ⩾1 in 92 patients (38%). Treatment was multimodality therapy including surgery in 18, chemotherapy alone in 180 (75%) and best supportive care in 43 cases (18%). Chemotherapy was mainly pemetrexed based. Median OS was 11.4 months. Non-epithelioid histology (HR 2.32; 95% CI 1.66-3.23, P<0.001), age ⩾75 years (HR 1.44; 95% CI 1.08-1.93, P=0.014), advanced (III-IV) stage (HR 1.47; 95% CI 1.09-1.98, P=0.011) and CCI⩾1 (HR 1.38; 95% CI 1.02-1.85, P=0.034) were associated to a shorter OS. Treatment with pemetrexed was associated with improved OS (HR 0.40; 95% CI 0.28-0.56, P<0.001). CONCLUSIONS: Non-epithelioid histology, age ⩾75 years, advanced IMIG stage and presence of comorbidities according to CCI were significant prognostic factors in elderly patients with MPM. Treatment with pemetrexed-based chemotherapy was feasible in this setting. Prospective dedicated trials in MPM elderly patients selected according to prognostic factors including comorbidity scales are warranted.
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Neoplasias Pulmonares/mortalidade , Mesotelioma/mortalidade , Neoplasias Pleurais/mortalidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Humanos , Itália/epidemiologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Mesotelioma/patologia , Mesotelioma/terapia , Mesotelioma Maligno , Neoplasias Pleurais/patologia , Neoplasias Pleurais/terapia , Prognóstico , Análise de Sobrevida , Resultado do TratamentoRESUMO
This study evaluated the intra- and inter-rater reliability of the Pooling score (P-score) in clinical endoscopic evaluation of severity of swallowing disorder, considering excess residue in the pharynx and larynx. The score (minimum 4 - maximum 11) is obtained by the sum of the scores given to the site of the bolus, the amount and ability to control residue/bolus pooling, the latter assessed on the basis of cough, raclage, number of dry voluntary or reflex swallowing acts (< 2, 2-5, > 5). Four judges evaluated 30 short films of pharyngeal transit of 10 solid (1/4 of a cracker), 11 creamy (1 tablespoon of jam) and 9 liquid (1 tablespoon of 5 cc of water coloured with methlyene blue, 1 ml in 100 ml) boluses in 23 subjects (10 M/13 F, age from 31 to 76 yrs, mean age 58.56±11.76 years) with different pathologies. The films were randomly distributed on two CDs, which differed in terms of the sequence of the films, and were given to judges (after an explanatory session) at time 0, 24 hours later (time 1) and after 7 days (time 2). The inter- and intra-rater reliability of the P-score was calculated using the intra-class correlation coefficient (ICC; 3,k). The possibility that consistency of boluses could affect the scoring of the films was considered. The ICC for site, amount, management and the P-score total was found to be, respectively, 0.999, 0.997, 1.00 and 0.999. Clinical evaluation of a criterion of severity of a swallowing disorder remains a crucial point in the management of patients with pathologies that predispose to complications. The P-score, derived from static and dynamic parameters, yielded a very high correlation among the scores attributed by the four judges during observations carried out at different times. Bolus consistencies did not affect the outcome of the test: the analysis of variance, performed to verify if the scores attributed by the four judges to the parameters selected, might be influenced by the different consistencies of the boluses, was not significant. These initial data validate the clinical use of the P-score in the management of patients with deglutition disorders by a multidisciplinary team.
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Transtornos de Deglutição/diagnóstico , Esofagoscopia/estatística & dados numéricos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Índice de Gravidade de DoençaRESUMO
Grade inflation presents pedagogical and safety concerns for nursing educators and is defined as a "greater percentage of excellent scores than student performances warrant" (Speer et al., 2000, p. 112). This descriptive correlational study evaluated the relationship of licensure exam-style final written exams and faculty assigned clinical grades from undergraduate students (N = 281) for evidence of grade inflation at a private undergraduate nursing program in the Northeast of the United States and developed a new measurement of grade inflation, the clinical grade discrepancy score. This measurement can be used in programs where clinical competency is graded on a numeric scale. Evidence suggested grade inflation was present and the clinical grade discrepancy score was an indicator of the severity of grade inflation. The correlation between licensure-style final written exams and faculty assigned clinical grades was moderate to low at 0.357. The clinical grade discrepancy scores were 98% positive indicating likely grade inflation. Some 70% of clinical grade discrepancy scores indicated a difference of student licensure-style final written exams and faculty assigned clinical grades of at least one full letter grade (10 points out of 100). Use of this new measure as a tool in exploring the prevalence of grade inflation and implications for patient safety are discussed.
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Logro , Competência Clínica/normas , Bacharelado em Enfermagem/organização & administração , Avaliação Educacional/normas , Docentes de Enfermagem , Licenciamento/normas , Estudantes de Enfermagem , Adolescente , Feminino , Humanos , Masculino , New England , Valores de Referência , Estatística como Assunto , Adulto JovemRESUMO
BACKGROUND: Pemetrexed-platinum chemotherapy is the standard first-line treatment of unresectable malignant pleural mesothelioma (MPM). At progression, patients are generally selected to experimental trials, when available, or, in every-day clinical practice, they are offered second-line chemotherapy. The optimal treatment has not yet been defined. The aim of this retrospective, single-center study was to evaluate the activity and toxicity of vinorelbine administered to a consecutive series of pemetrexed-pretreated MPM patients. METHODS: Vinorelbine 25 mg/m(2) was administered intravenously as a single agent on days 1, 8 every three weeks, either as second-line (2L) or further-line (>2L) therapy. Treatment was repeated for a maximum of 6 cycles, until progression, or unacceptable toxicity. RESULTS: Fifty-nine patients were included in this analysis. Vinorelbine was given to 34 patients as 2L, and to 25 as > 2L treatment. The median age was 69 years (range 45-80). Forty-two patients (71.2%) had a good EORTC prognostic score. Partial response was observed in 9 (15.2%) cases, stable disease in 20 (33.9%). The overall disease control rate (DCR) was 49.1%. Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.2 months, respectively. ECOG performance status (PS) (HR(0 vs. 1-2) 0.50; 95%CI: 0.3-0.8; p = 0.014) and PFS ≥ 6 months following first-line (FL) chemotherapy (HR(FL-PFS>6 ms vs. <6 ms) 0.50; 95%CI: 0.3-0.9; p = 0.031) were significantly associated to OS in multivariate analysis. No difference was observed in terms of DCR, PFS, and OS in relation to age, histology, sex, line of vinorelbine therapy, or response to FL treatment. Hematological toxicity was acceptable, with grade 3/4 neutropenia occurring in 5 (8.4%) patients, and there were no cases of febrile neutropenia. The main non-hematological toxicities were grade 2 fatigue in 17 (28.8%) and constipation in 7 (11.8%) patients. CONCLUSIONS: Vinorelbine was moderately active in pemetrexed-pretreated MPM patients, with an acceptable toxicity profile, particularly in patients with ECOG-PS0 and FL-PFS ≥ 6 months.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Terapia de Salvação/métodos , Vimblastina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Feminino , Glutamatos/uso terapêutico , Guanina/análogos & derivados , Guanina/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Mesotelioma/mortalidade , Mesotelioma Maligno , Pessoa de Meia-Idade , Pemetrexede , Neoplasias Pleurais/mortalidade , Estudos Retrospectivos , Vimblastina/uso terapêutico , VinorelbinaRESUMO
BACKGROUND: The WHO-classification was shown to be an independent prognostic marker in some but not all retrospective studies possibly due to lack of reproducibility. We investigated the reproducibility of the WHO-classification and its prognostic implication using a large series of resected thymomas. METHODS: Four independent pathologists histologically classified a surgical series of 129 thymic tumors in a blinded fashion. Fleiss' kappa-coefficient was used to assess the pathologists' overall agreement, and Cohen-Kappa to assess the agreement between two observers. Disease-related-survival (DRS) and progression-free-survival (PFS) curves were generated by Kaplan-Meier method and compared by log-rank test. RESULTS: In 63/129 (48.8%) cases there was a complete agreement; in 43/129 (33.3%) cases 3/4 pathological diagnoses were identical; in 15/129 (11.6%) cases the diagnoses were identical by pair; in 8/129 (6.2%) cases three different pathological diagnoses were on record. The Kappa-correlation coefficient was only moderate (0.53). A following web review carried out on the 23 cases with at least two different diagnoses reached a complete consensus. The histotype showed a statistically significant impact on PFS and DRS in the classification provided by only two pathologists. CONCLUSIONS: In this study, the agreement on WHO classification of thymomas was only moderate and this impacted on patients management. Web consensus conference on the diagnosis, more stringent diagnostic criteria or the adoption of referral diagnostic centres may substantially reduce discrepancies.
Assuntos
Timoma/classificação , Timoma/patologia , Organização Mundial da Saúde , Adulto , Idoso , Idoso de 80 Anos ou mais , Consenso , Conferências de Consenso como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Prognóstico , Reprodutibilidade dos Testes , Timoma/mortalidade , Adulto JovemRESUMO
BACKGROUND: The mesenchymal-epithelial transition factor (MET) receptor is dysregulated in hepatocellular carcinoma (HCC), and tivantinib (ARQ 197) is an oral, selective, MET inhibitor. METHODS: This Phase-1b study assessed tivantinib safety as primary objective in patients with previously treated HCC and Child-Pugh A or B liver cirrhosis. Patients received oral tivantinib 360 mg twice daily until disease progression or unacceptable toxicity. RESULTS: Among 21 HCC patients, common drug-related adverse events (AEs) were neutropaenia, anaemia, asthenia, leucopaenia, anorexia, diarrhoea, and fatigue. No drug-related worsening of liver function or performance status occurred, but one Child-Pugh B patient experienced drug-related bilirubin increase. Four patients had drug-related serious AEs, including one neutropaenia-related death. Haematologic toxicities were more frequent than in previous tivantinib studies but were manageable with prompt therapy. Best response was stable disease (median, 5.3 months) in 9 of 16 evaluable patients (56%). Median time to progression was 3.3 months. CONCLUSION: Tivantinib demonstrated a manageable safety profile and preliminary antitumour activity in patients with HCC and Child-Pugh A or B cirrhosis.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Cirrose Hepática/complicações , Neoplasias Hepáticas/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/complicações , Feminino , Humanos , Neoplasias Hepáticas/complicações , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirrolidinonas/efeitos adversos , Quinolinas/efeitos adversos , RetratamentoRESUMO
BACKGROUND: NGR-hTNF exploits the peptide asparagine-glycine-arginine (NGR) for selectively targeting tumour necrosis factor (TNF) to CD13-overexpressing tumour vessels. Maximum-tolerated dose (MTD) of NGR-hTNF was previously established at 45 µg m(-2) as 1-h infusion, with dose-limiting toxicity being grade 3 infusion-related reactions. We explored further dose escalation by slowing infusion rate (2-h) and using premedication (paracetamol). METHODS: Four patients entered each of 12 dose levels (n=48; 60-325 µg m(-2)). Pharmacokinetics, soluble TNF receptors (sTNF-R1/sTNF-R2), and volume transfer constant (K(trans)) by dynamic imaging (dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)) were assessed pre- and post-treatment. RESULTS: Common related toxicity included grade 1/2 chills (58%). Maximum-tolerated dose was not reached. Both C(max) (P<0.0001) and area under the plasma concentration-time curve (P=0.0001) increased proportionally with dose. Post-treatment levels of sTNF-R2 peaked significantly higher than sTNF-R1 (P<0.0001). Changes in sTNF-Rs, however, did not differ across dose levels, suggesting a plateau effect in shedding kinetics. As best response, 12/41 evaluable patients (29%) had stable disease. By DCE-MRI, 28/37 assessed patients (76%) had reduced post-treatment K(trans) values (P<0.0001), which inversely correlated with NGR-hTNF C(max) (P=0.03) and baseline K(trans) values (P<0.0001). Lower sTNF-R2 levels and greater K(trans) decreases after first cycle were associated with improved survival. CONCLUSION: asparagine-glycine-arginine-hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Fator de Necrose Tumoral alfa/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Fator de Necrose Tumoral alfa/efeitos adversos , Adulto JovemRESUMO
The pemetrexed-cisplatin chemotherapy is standard of care in first-line (FL) treatment of malignant pleural mesothelioma (MPM). The second-line (SL) chemotherapy is considered, but the optimal treatment has not been defined yet. The aim of this study was to evaluate the clinical outcomes of SL-therapy in a series of MPM-patients included in a retrospective multicenter database. Clinical records of MPM-patients who received SL-treatment from 1996 to 2008 were reviewed. Study endpoints were response, overall-survival (OS), and progression-free-survival (PFS) for SL, stratified for patient characteristics, FL-outcomes, and type of SL. Out of 423 patients, 181 with full clinical data were identified. Patients' characteristics: median-age 64 years (range: 36-85); male gender 115 (63.5%); good EORTC-score 109 (60.2%); epithelial histology 135 (74.6%). After FL, 147 (81.2%) patients achieved disease-control (DC) and 45 had a time-to-progression≥12 months (TTP≥12). After SL, 95 patients (52.6%) achieved DC (21 response; 74 stable-disease); median PFS and OS were 4.3 and 8.7 months, respectively. According to multivariate analysis, DC after SL-therapy was significantly related to pemetrexed-based treatment (OR: 2.46; p=0.017) and FL-TTP≥12 (OR: 3.50; p=0.006). PFS was related to younger age (<65 years) (HR: 0.70; p=0.045), ECOG-PS0 (HR: 0.67; p=0.022), and FL-TTP≥12 (HR: 0.45; p<0.001). OS was significantly related to ECOG-PS0 (HR: 0.43; p<0.001) and to FL-TTP≥12 (HR: 0.54; p=0.005). In pemetrexed pre-treated patients, re-treatment with a pemetrexed/platinum combination significantly reduced the risk-of-death than pemetrexed alone (HR: 0.11; p<0.001). In conclusion, SL-chemotherapy seems to be active in MPM-patients, particularly in younger patients with ECOG-PS0 and prolonged TTP after FL-pemetrexed-based chemotherapy. In selected patients, re-challenge with pemetrexed-based regimens, preferentially associated with platinum-compound, appears to be an option for SL-setting. Considering the important limitations of this study, due to retrospective nature and the possible selection bias, prospective clinical trials are warranted to clarify these issues.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cisplatino/administração & dosagem , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Masculino , Mesotelioma/mortalidade , Pessoa de Meia-Idade , Análise Multivariada , Pemetrexede , Compostos de Platina/uso terapêutico , Neoplasias Pleurais/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Based on the high chemosensitivity of germ-cell tumors (GCTs), the concept of high-dose chemotherapy (HDCT) has been developed worldwide and investigated through many clinical trials. It has been carried out in different clinical settings, ranging from resistant or absolute refractory disease to chemosensitive relapse. HDCT with stem-cell support has been also explored as a part of first-line strategy for poor-prognosis patients. PATIENTS AND METHODS: Our review summarized results from clinical trials evaluating the role of HDCT in patients with advanced GCTs. So far available data were obtained through a Medline search of English-language literature. RESULTS: Several phase II trials and retrospective series have shown a possible benefit for GCT patients with recurrent disease as well as in first-line setting. Despite these results, data derived from randomized phase III studies failed to demonstrate any survival advantage for HDCT over conventional chemotherapy. CONCLUSIONS: The role of HDCT in GCTs remains controversial. We need new prospective studies based on prognostic factors with multiple transplants of carboplatin and etoposide as the preferred high dose regimen. At present, based mainly on retrospective and phase II studies, HDCT may represent a therapeutic option for patients with primary refractory disease or for those with a second or further relapse.
Assuntos
Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Transplante de Células-Tronco , Resistencia a Medicamentos Antineoplásicos , Humanos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/mortalidade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Terapia de SalvaçãoRESUMO
Malignant pleural mesothelioma is a highly aggressive cancer with a very poor prognosis. Although the mechanism of carcinogenesis is not fully understood, approximately 80% of malignant pleural mesothelioma can be attributed to asbestos fiber exposure. This disease is largely unresponsive to conventional chemotherapy or radiotherapy, and most patients die within 10-17 months of their first symptoms. Currently, malignant pleural mesothelioma therapy is guided by clinical stage and patient characteristics rather than by the histological or molecular features of the tumor. Several molecular pathways involved in malignant pleural mesothelioma have been identified; these include cell cycle regulation, apoptosis, growth factor pathways, and angiogenesis. Unfortunately, several agents targeting these processes, including erlotinib, gefitinib, and imatinib, have proven ineffective in clinical trials. A greater understanding of the molecular pathways involved in malignant pleural mesothelioma is needed to develop better diagnostics, therapeutics, and preventative measures. Moreover, understanding the biological basis of mesothelioma progression may facilitate personalized treatment approaches, and early identification of poor prognostic indicators may help reduce the heterogeneity of the clinical response. This paper reviews advances in the molecular biology of malignant pleural mesothelioma in terms of pathogenesis, the major molecular pathways and the associated therapeutic strategies, and the roles of biomarkers.
Assuntos
Antineoplásicos/uso terapêutico , Mesotelioma/metabolismo , Proteínas de Neoplasias/metabolismo , Derrame Pleural Maligno/metabolismo , Neoplasias Pleurais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Derrame Pleural Maligno/tratamento farmacológico , Derrame Pleural Maligno/patologia , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/patologiaAssuntos
Expansão das Repetições de DNA/genética , Demência/diagnóstico , Demência/genética , Diagnóstico Precoce , Mutação Puntual/genética , Príons/genética , Adulto , Encéfalo/metabolismo , Códon/genética , Fluordesoxiglucose F18/farmacocinética , Genótipo , Humanos , Itália , Imageamento por Ressonância Magnética , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Tomografia por Emissão de Pósitrons , Proteínas Priônicas , Compostos Radiofarmacêuticos/farmacocinéticaRESUMO
Although the design of the study we undertook was randomized, the groups were statistically similar, the intervention was based on evidence of previous efficacy, and the treatment was delivered exactly as planned, this pilot study on an intervention to promote motivation for weight loss in new mothers failed to produce an effect. A closer examination using criteria for intervention fidelity revealed a number of weaknesses. Both treatment integrity and differentiation merit careful consideration in intervention design.
Assuntos
Pesquisa em Avaliação de Enfermagem/normas , Projetos Piloto , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa/normas , Adulto , Aconselhamento/organização & administração , Feminino , Promoção da Saúde/organização & administração , Necessidades e Demandas de Serviços de Saúde , Serviços de Assistência Domiciliar/organização & administração , Humanos , Entrevistas como Assunto/métodos , Estilo de Vida , Motivação , Obesidade/prevenção & controle , Obesidade/psicologia , Educação de Pacientes como Assunto/organização & administração , Cuidado Pós-Natal/métodos , Cuidado Pós-Natal/psicologia , Transtornos Puerperais/prevenção & controle , Transtornos Puerperais/psicologia , Telefone , Falha de Tratamento , Redução de PesoRESUMO
The concept of relapse has had many and varied applications in research literature. Great confusion exists in the application of the term to scientific measurement within the various studies. Therefore, an in-depth analysis of the generic term relapse was undertaken through the evolutionary approach offered by Rodgers and Knafl.
Assuntos
Comportamentos Relacionados com a Saúde , Abandono do Hábito de Fumar/psicologia , Feminino , Humanos , Recidiva , AutoeficáciaRESUMO
OBJECTIVE: It is known that the placenta acts as an immunological barrier between the mother and fetal "graft" allowing two antigenically different organisms to tolerate one another. Preeclampsia may be considered as a fetal rejection consequent to severe damage at placental endothelial and syncytiotrophoblast level. In order to verify this placental barrier damage we undertook the present study by electron microscopy. STUDY DESIGN: 14 placentae from preeclaptic women, and the same number of placentae from healthy controls were examined. RESULTS: The results showed that endothelial cells from preeclamptic placentae express various and severe alterations, consisting of swollen and bulbous cytoplasm, degenerated inter-endothelial junctions with consequent crossing of fetal blood cells outside the vessels. CONCLUSIONS: These lesions could be the ultrastructural evidence of the placental barrier breakage leading to rejective reaction we presumed to be basis of preeclampsia.