Germline variant analysis from a cohort of patients with severe hypertriglyceridemia in Brazil.

Hypertriglyceridemia (HTG) is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. It is well stablished that the severe cases of disease often present with an underlying genetic cause. In this study, we determined the frequency and variation spectrum of genes involved in the triglyceride metabolism in a series of Brazilian patients with severe HTG. A total of 212 patients with very high HTG, defined with fasting triglycerides (TG) ≥ 880 mg/ dL, that underwent a multi-gene panel testing were included in this research. Germline deleterious variants (i.e. Pathogenic/Likely Pathogenic (P/LP) variants) were identified in 28 out of 212 patients, reflecting an overall diagnostic yield of 13% in our cohort. Variants of unknown significance (VUS) were identified in 87 patients, and represent 80% of detected variants in this dataset. We confirm the LPL as the most frequently mutated gene in patients with severe HTG, and we had only one suspected case of familial chylomicronemia syndrome, caused by a homozygous variant in LMF1, in our cohort. Notably, we report 16 distinct and novel variants (P/LP and VUS), each of them representing a single case, not previously reported in any public databases or other studies. Our data expand our knowledge of genetic variation spectrum in patients with severe HTG in the Brazilian population, often underrepresented in public genomic databases, being also a valuable clinical resource for genetic counseling and healthcare programs in the country.

Hydroxychloroquine plus azithromycin early treatment of mild COVID-19 in an outpatient setting: a randomized, double-blinded, placebo-controlled clinical trial evaluating viral clearance.

BACKGROUND: Hydroxychloroquine has shown potential to block viral replication of SARS-CoV-2 in some in vitro studies. This randomised, double-blinded, placebo controlled clinical trial evaluated the efficacy of hydroxychloroquine plus azithromycin (HCQ/AZT) in reducing viral loads in patients with early and mild SARS-CoV-2 infection. METHODS: A single-centre randomised placebo-controlled clinical trial was conducted with outpatients with early and mild SARS-CoV-2 infection. Inclusion criteria were: patients aged 18-65 years with symptoms suggestive of COVID-19 for < 5 days, no significant comorbidities, and positive nasopharyngeal/oropharyngeal swab screening tests (POCT-PCR). Randomised patients received either hydroxychloroquine for 7 days plus azithromycin for 5 days or placebo. The primary endpoint was viral clearance within a 9-day period. Secondary endpoints included viral load reduction, clinical evolution, hospitalization rates, chest computed tomography evolution, and adverse effects. RESULTS: From 107 potential trial participants, 84 were enrolled following predetermined criteria. Statistical analyses were performed on an intention-to-treat (N = 84) and per-protocol (PP) basis (N = 70). On the PP analysis, the treatment (N = 36) and placebo (N = 34) groups displayed similar demographic characteristics. At 95% CI, no statistically significant between-group differences were found in viral clearance rates within 9 days following enrolment (P = 0.26). CONCLUSIONS: This randomised, double-blinded, placebo-controlled clinical trial evaluating outpatients with early and mild COVID-19 showed that viral clearance rates within a 9-day period from enrolment did not change with HCQ/AZT treatment compared with placebo, although no major cardiovascular events were observed in participants without comorbidities. Secondary outcomes were also not significantly improved with HCQ/AZT treatment compared with placebo. These findings do not support use of HCQ/AZT in this setting.

Results of a randomized, prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high-grade, operable osteosarcomas of the extremities: A report from the Latin American Group of Osteosarcoma Treatment.

BACKGROUND: Metronomic chemotherapy (MC) consists of the administration of a low dose of chemotherapy on a daily or weekly basis without a long break to achieve an antitumoral effect through an antiangiogenic effect or stimulation of the immune system. The potential effect of MC with continuous oral cyclophosphamide and methotrexate in patients with high-grade operable osteosarcomas (OSTs) of the extremities was investigated. METHODS: Patients with high-grade OSTs who were 30 years old or younger were eligible for registration at diagnosis. Eligibility for randomization included 1) nonmetastatic disease and 2) complete resection of the primary tumor. The study design included a backbone of 10 weeks of preoperative therapy with methotrexate, adriamycin, and platinum (MAP). After surgery, patients were randomized between 2 arms to complete 31 weeks of MAP or receive 73 weeks of MC after MAP. The primary endpoint was event-free survival (EFS) from randomization. RESULTS: There were 422 nonmetastatic patients registered (May 2006 to July 2013) from 27 sites in 3 countries (Brazil, Argentina and Uruguay), and 296 were randomized to MAP plus MC (n = 139) or MAP alone (n = 157). At 5 years, the EFS cumulative proportions surviving in the MAP-MC group and the MAP-alone group were 61% (standard error [SE], 0.5%) and 64% (SE, 0.5%), respectively, and they were not statistically different (Wilcoxon [Gehan] statistic = 0.724; P =.395). The multivariate analysis showed that necrosis grades 1 and 2, tumor size, and amputation were associated with shorter EFS. CONCLUSIONS: According to the current follow-up, EFS with MAP plus MC is not statistically superior to EFS with MAP alone in patients with high-grade, resectable OSTs of the extremities. Cancer 2017;123:1003-10. © 2016 American Cancer Society.

Trends in incidence of primary cutaneous malignancies in children, adolescents, and young adults: a population-based study.

BACKGROUND: Skin cancer incidence among young adults is rising; however, the epidemiological characteristics of primary cutaneous lymphomas and cutaneous soft tissue sarcomas (CSTS) in individuals <30 years old has not been investigated. We analyzed the incidence and time-trends of primary cutaneous malignancies in children and adolescents/young adults (AYA). PROCEDURE: SEER-17 and -13 data were used to assess the descriptive epidemiology and time-trends in incidence of primary cutaneous malignancies in children and AYA. SEERStat and Joinpoint softwares were utilized to estimate annual percent changes (APC) in incidence. RESULTS: In total, 7,814 cases (ASR = 25.66/1,000,000 habitants) of primary skin cancers in <30 years old were diagnosed in 2000-2008. Females had a higher incidence of melanoma (risk ratio (RR) = 1.95; P < 0.001) and a lower risk of developing CSTS (RR = 0.64, P < 0.001). Compared to whites, blacks have a lower incidence of melanoma (RR = 0.03, P < 0.001), and higher risk of CSTS (RR = 2.28, P < 0.001). Melanoma increased in females over a 15-year period (1992-2006) (APC = 2.5, 95%CI = 1.8; 3.2), and the incidence of cutaneous T-cell lymphomas increased over the period 1992-2008 (APC = 9.5, 95% CI = 6.7; 12.4). CSTS incidence decreased among males over the period 1992-1999 (APC = -21.4, 95% CI -27.2; -15.1), particularly due to a decrease in Kaposi sarcoma incidence (AAPC 1992-2008 = -13.6, 95% CI = -22.4;-3.8), although with a notable racial disparity (whites, AAPC = -15.2, 95% CI = -23.2;-6.4; blacks, AAPC = -10.6, 95% CI = -13.2;-7.9). CONCLUSIONS: Non-melanoma skin cancer is very rare in children and AYA. We have shown variation in time-trends in incidence as well as in incidence patterns by race, sex, age, and histologic type, highlighting the importance of descriptive epidemiology to better understand the characteristics of these malignancies.