Fas (TNFRSF6/Apo-1/CD95) is a type I transmembrane receptor, which mediates apoptosis. Fas gene mutations, aberrant transcripts, and abundant expression of Fas have been reported in adult T cell leukemia (ATL). To further elucidate the role of Fas in ATL pathogenesis, we investigated whether the -670 FAS promoter A/G polymorphism (STAT1-binding site) might contribute to susceptibility and clinical outcome in ATL. Thirty-one patients with ATL, 33 healthy, human T lymphotropic virus type 1-infected individuals, and 70 healthy, uninfected controls were genotyped for the FAS -670 polymorphism by PCR-restriction fragment-length polymorphism. The AA genotype was significantly over-represented in ATL patients in comparison with healthy controls (P=0.006), as well as asymptomatics (P=0.037), corresponding to an odds ratio (OR) of 3.79 [95% confidence intervals (CI; 1.28-11.41)] and 4.58 [95% CI (1.13-20.03)], respectively. The AA group also comprised significantly more aggressive (acute and lymphoma) clinical subtypes [P=0.012; OR=8.40; 95% CI (1.60-44.12)]. In addition, we observed a statistically significant association between GG genotype and survival (log rank test, P=0.032). Finally, IFN-gamma-induced but not basal FAS mRNA levels were increased significantly (P=0.049) in PBMCs from AA versus GG individuals, demonstrating the IFN-dependent functionality of the -670 polymorphism. In conclusion, our results demonstrate that a functional Fas promoter polymorphism is significantly associated to susceptibility, clinical manifestation, and survival in ATL.

No abstract

Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) therapy model in EGFR mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibitor combinations. Importantly, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, we find durable responses to MLD therapy without associated toxicity. Our data support the notion that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibitor therapy.

The purpose of this study was to evaluate whether subdivision of adult T-cell leukemia/lymphoma (ATL) on the basis of clinical types, skin involvement, histologic features, cell size, and proliferative index (PI) was clinically relevant. Skin lesions were present in 47 cases (67%). Five cases were classified as primary cutaneous tumoral (PCT) type not included in the Shimoyama classification and characterized by skin tumors and absence of systemic involvement, lymphocytosis, and hypercalcemia. Mortality was high (61/70 [87%]). The overall median survival time (MST) was 12 months. The following variables were adversely related to survival: acute, lymphoma, and PCT types; absence of skin lesions; large cells; and PI more than 18%. The longer MST observed in cases with skin lesions was probably due to prolonged survival of the smoldering type (58 months). The MST of the PCT type (21 months) was shorter than that of the smoldering type, confirming the importance of clearly defining these 2 types of ATL.

No abstract

The juvenile HAM/TSP may occur very early and also presents marked female predominance. Progression of IDH to HAM/TSP before 19 years of age is frequent (54%). Rapid progressive form may also occur in early HAM/TSP. As juvenile IDH and HAM/TSP are due to vertical transmission through breastfeeding, it is very important to avoid this pathway of infection.

To determine the prevalence of sexually transmitted and blood-borne infections among incarcerated adolescents in Salvador, Brazil, we interviewed 300 incarcerated youth aged 11-18 years to participate in a physical examination and to provide a blood sample to test for HIV-1, hepatitis B and C viruses exposure, human T-cells lymphotrophic virus, and syphilis. Overall prevalence was anti-HIV, 0.34%; anti-HBc, 11.1%; HBsAg, 2.4%; anti-HCV, 6.4%; HTLV, 1.09%; and syphilis, 3.4%. The majority (86.3%) reported a history of sexual activity; 27% had never used condoms. Girls also reported previous pregnancy (35%), abortion (26%) and sexual abuse (74%). Many youth reported a family history of alcohol abuse (56%), illicit drug use (24.7%), or legal problems (38%). Serological results show that youth in Salvador are at high risk for blood-borne and sexually transmitted infections. Policies to reduce the risk and impact of these infections should be a requisite part of health care for incarcerated youth.

Adult t-cell leukemiA/lymphomA rev assoC med bras 2016; 62 (7):691-700 691