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BACKGROUND: Sarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases. METHODS: Germline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants. RESULTS: GPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (TP53, RB1, NF1, EXT1/2) but also in genes where that risk is still emerging/limited (ERCC2, TSC2 and BRCA2) or unknown (PALB2, RAD50, FANCM and others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%×6.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk. CONCLUSION: Our findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.
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Predisposição Genética para Doença , Sarcoma , Criança , Adulto Jovem , Adolescente , Humanos , Prevalência , Mutação em Linhagem Germinativa/genética , Sarcoma/epidemiologia , Sarcoma/genética , Células Germinativas , Proteína Grupo D do Xeroderma Pigmentoso/genética , DNA Helicases/genéticaRESUMO
Background: Endometrial cancer is of increasing concern in several countries, including Brazil, in part because of an ageing population, declines in fertility, and the increasing prevalence of obesity. Although endometrial tumors had lagged behind other cancer types in terms of treatment improvements, molecular characterization of these tumors is paving the way for novel therapies and an expansion of the therapeutic arsenal. We aimed to help medical oncologists who manage patients with recurrent or metastatic endometrial cancer in the Brazilian healthcare setting. Methods: The panel, composed of 20 medical oncologists, convened in November 2021 to address 50 multiple-choice questions on molecular testing and treatment choices. We classified the level of agreement among panelists as (1) consensus (≥75% choosing the same answer), (2) majority vote (50% to <75%), or (3) less than majority vote (<50%). Results: Consensus was present for 25 of the 50 questions, whereas majority vote was present for an additional 23 questions. Key recommendations include molecular testing for every patient with recurrent/metastatic endometrial cancer; choice of first-line treatment according to microsatellite instability and HER2, with the addition of programmed death ligand 1 (PD-L1) and hormone receptors (HRs) for second-line therapy; carboplatin and paclitaxel as the preferred option in first-line treatment of HER2-negative disease, with the addition of trastuzumab in HER2-positive disease; pembrolizumab plus lenvatinib as a key option in second line, regardless of HER2, PD-L1 or HRs; and various recommendations regarding treatment choice for patients with distinct comorbidities. Conclusion: Despite the existing gaps in the current literature, the vast majority of issues addressed by the panel provided a level of agreement sufficient to inform clinical practice in Brazil and in other countries with similar healthcare environments.
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Educational indicators are metrics that assist in assessing the quality of the educational system. They are often associated with economic and social factors suggested to contribute to good school performance, however there is no consensus on the impact of these factors. The main objective of this work was to evaluate the factors related to school performance. Using a data set composed by Brazilian schools' performance (IDEB), socioeconomic and school structure variables, we generated different models. The non-linear model predicted the best performance, measured by the error and determination coefficient metrics. The heterogeneity of the importance of the variable between school cycles and regions of the country was detected, this effect may contribute to the development of public educational policies.
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Desempenho Acadêmico/estatística & dados numéricos , Escolaridade , Política Pública , Instituições Acadêmicas/estatística & dados numéricos , Brasil , Interpretação Estatística de Dados , Ciência de Dados , Conjuntos de Dados como Assunto , Humanos , Dinâmica não Linear , Salários e Benefícios/estatística & dados numéricos , Professores Escolares/estatística & dados numéricos , Instituições Acadêmicas/economia , Instituições Acadêmicas/organização & administraçãoRESUMO
Targeted monoclonal antibodies have become an important therapeutic option for patients with cancer. Cetuximab, a chimeric mouse-human (30:70) immunoglobulin G1 monoclonal antibody against epidermal growth factor receptor, has been approved by the US Food and Drug Administration for the treatment of head and neck and metastatic colorectal cancer (mCRC). Severe (grade 3/4) hypersensitivity-infusion reactions (HIRs) occur in 2-3% of the patients, with fatal outcomes in 0.1%. It is recommended that patients showing severe HIRs to cetuximab should avoid further exposure to it, but in some cases there is no alternative treatment. Two options are currently available for patients with HIRs to cetuximab: desensitization protocol and panitumumab. We describe here two patients with mCRC who successfully underwent a cetuximab desensitization protocol following a severe HIR to cetuximab.
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Humanos , Anticorpos Monoclonais , Imunoglobulina G , Metástase Neoplásica , Neoplasias ColorretaisRESUMO
Patients with chronic obstructive pulmonary disease (COPD) have slowed pulmonary O(2) uptake (Vo(2)(p)) kinetics during exercise, which may stem from inadequate muscle O(2) delivery. However, it is currently unknown how COPD impacts the dynamic relationship between systemic and microvascular O(2) delivery to uptake during exercise. We tested the hypothesis that, along with slowed Vo(2)(p) kinetics, COPD patients have faster dynamics of muscle deoxygenation, but slower kinetics of cardiac output (Qt) following the onset of heavy-intensity exercise. We measured Vo(2)(p), Qt (impedance cardiography), and muscle deoxygenation (near-infrared spectroscopy) during heavy-intensity exercise performed to the limit of tolerance by 10 patients with moderate-to-severe COPD and 11 age-matched sedentary controls. Variables were analyzed by standard nonlinear regression equations. Time to exercise intolerance was significantly (P < 0.05) lower in patients and related to the kinetics of Vo(2)(p) (r = -0.70; P < 0.05). Compared with controls, COPD patients displayed slower kinetics of Vo(2)(p) (42 +/- 13 vs. 73 +/- 24 s) and Qt (67 +/- 11 vs. 96 +/- 32 s), and faster overall kinetics of muscle deoxy-Hb (19.9 +/- 2.4 vs. 16.5 +/- 3.4 s). Consequently, the time constant ratio of O(2) uptake to mean response time of deoxy-Hb concentration was significantly greater in patients, suggesting a slower kinetics of microvascular O(2) delivery. In conclusion, our data show that patients with moderate-to-severe COPD have impaired central and peripheral cardiovascular adjustments following the onset of heavy-intensity exercise. These cardiocirculatory disturbances negatively impact the dynamic matching of O(2) delivery and utilization and may contribute to the slower Vo(2)(p) kinetics compared with age-matched controls.
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Pressão Sanguínea/fisiologia , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Consumo de Oxigênio/fisiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Volume Sistólico/fisiologia , Idoso , Algoritmos , Limiar Anaeróbio/fisiologia , Eletrocardiografia , Teste de Esforço , Tolerância ao Exercício/fisiologia , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Troca Gasosa Pulmonar/fisiologia , Testes de Função Respiratória , Espectroscopia de Luz Próxima ao Infravermelho , EspirometriaRESUMO
Increased ventilatory response to the metabolic demand ("ventilatory inefficiency") is commonly found during dynamic exercise in patients with chronic obstructive pulmonary disease (COPD). However, the role of enhanced muscle ergoreflex activity on this phenomenon is yet unknown. Ten non-hypoxaemic patients with varying degrees of disease severity (median and range of post-bronchodilator FEV(1) = 37.5 (27 to 70%) predicted) and 7 age- and gender-matched controls were studied. Subjects were submitted to wrist flexion tests to the limit of tolerance (Tlim) with and without post-exercise regional circulatory occlusion (PE-RCO) for 3 min. The muscle ergoreflex activity was quantified as the difference in ventilation between PE-RCO and control recovery periods corrected for the resting values (ergoreflex Delta). In addition, the area under the ventilatory curve in the recovery period was calculated in both conditions. We found that Tlim and the physiological stress associated with localized exercise did not differ between patients and controls. However, patients had increased ventilatory response to a given metabolic demand (VCO(2)), either at rest or during exercise (P < 0.05). There were no significant differences in ergoreflex Delta in patients and controls (-2.2 to 2.4 (0.2) vs. -0.6 to 1.8 (0.3) l/min, respectively). In addition, the area under the ventilatory curve in the recovery period did not differ between control and PE-RCO tests in patients and healthy subjects (P > 0.05). We conclude that increased muscle ergoreflex activity did not contribute to an excessive ventilatory response to exercise in patients with COPD-at least in non-hypoxaemic and non-cachetic subjects.