Beneficial effect of highly active antiretroviral therapy on the prognosis of AIDS-related systemic non-Hodgkin lymphomas

The influence of HAART on the survival of patients with AIDS-related lymphoma (ARL) was evaluated. A retrospective analysis of 73 HIV-1-infected patients with proven ARL diagnosed between 1992 and 2000 was conducted. Patients received uniformly the same chemotherapy regimen according to CD4 cell counts at NHL diagnosis:, patients with CD4 cells below or above 100 cells x 10(6)/liter received CHOP or ACVBP regimens, respectively. Event-free survival (EFS) and survival were estimated by the Kaplan-Meir method and a Cox model was used to evaluate the effect of different variables on survival. At diagnosis of ARL, the median age was 37 years and 22 patients (30%) had prior AIDS-defining events. Median CD4 cell count was 99 x 10(6)/liter. The median follow-up was 60 months. Ann Arbor stage 3-4 was noted in 60 patients (82%) and bone marrow or meningeal involvement was present in 13 (17%) and 12 (16%) patients, respectively. Two groups were identified: group 1 (n = 38) included patients who had never received HAART and group 2 (n = 35) included those who received HAART either before the diagnosis or following ARL. There was no statistical significant differences in lymphoma extensive stage, presence of B symptoms, meningeal involvement, CD4 cell count at diagnosis, prior AIDS events, or chemotherapy regimens between the two groups. Median survival (MS) of the whole cohort of patients was 8 months. Estimated EFS was significantly higher (30 months) in group 2 compared to group 1 (6.1 months) (p = 0.03). In the multivariate Cox model HAART has an independent significant effect on EFS (p = 0.0085). No influence on outcome was found for other variables except for prior AIDS and bone marrow involvement. HAART has significantly improved the survival and EFS in patients with ARL, independently of chemotherapy regimen.     

Constitutional thinness: unusual human phenotype of low bone quality

CONTEXT: Low fat mass and hormonal or nutritional deficiencies are often incriminated in bone loss related to thinness. Constitutional thinness has been described in young women with low body mass index (BMI) but close-to-normal body composition, physiological menstruation, no hormonal abnormalities, and no anorexia nervosa (AN) psychological profile. OBJECTIVE: Our objective was to determine whether constitutional thinness is associated with impaired bone quality. DESIGN, SETTING, AND PARTICIPANTS: This was an observational, cross-sectional study on 25 constitutionally thin and 44 AN young women with similar low BMI (<16.5 kg/m2) and 28 age-matched controls. MAIN OUTCOME MEASURES: Femoral and lumbar spine bone mineral density by dual-energy x-ray absorptiometry, distal tibia and radius bone architecture and breaking strength by three-dimensional peripheral quantitative computed tomography, and bone turnover markers were determined. RESULTS: Constitutionally thin subjects displayed a higher percentage of fat mass than AN subjects but had similar lumbar and femoral bone mineral density, which were significantly lower than in controls (P < 0.001). Constitutionally thin subjects displayed more markedly impaired trabecular and cortical bone parameters in the distal tibia than in the radius. AN bone structure was impaired only in subjects with a long history of disease. Calculated breaking strength was decreased in constitutional thinness and long-standing AN in both the radius and the tibia. Bone markers in constitutionally thin subjects were similar to those of controls. Osteoprotegerin to receptor activator of nuclear factor kappa B ligand ratio was higher in constitutionally thin subjects than in controls or AN women. CONCLUSIONS: Young women with constitutional thinness present an unexpectedly high prevalence of low bone mass (44%) associated with small bone size, overall diminished breaking strength, but normal bone turnover. Mechanisms related to insufficient skeletal load and/or genetics are proposed to explain this new phenotype of impaired bone quality.     

Novel pathogenic epitopes of myelin oligodendrocyte glycoprotein induce experimental autoimmune encephalomyelitis in C57BL/6 mice

Myelin oligodendrocyte glycoprotein (MOG), a minor protein of the central nervous system myelin, is recognized as a potential target in multiple sclerosis and neuromyelitis optica. The extracellular domain of MOG is commonly used in a wide range of mouse strains and other animals to induce experimental autoimmune encephalomyelitis (EAE), an autoimmune animal model of multiple sclerosis, because it is a target for antibody‐mediated attack. Previous studies, using selected peptides, have indicated that MOG^35–55 peptide is an encephalitogenic epitope in C57BL/6 (H‐2^b) mice. A more systematic analysis of both T‐cell and B‐cell responses following immunization of C57BL/6 mice with either recombinant extracellular mouse MOG protein (1–116) or with overlapping peptides spanning the whole sequence of MOG, before assessment of responses to 15 mer and 23 mer peptides was undertaken. The studies identified T‐cell responses within the MOG^35–55 (extracellular domain) but also two new immunogenic and encephalitogenic T‐cell epitopes within residues MOG^113–127, MOG^120–134 (localized in the transmembrane region) and MOG^183–197 (in the second hydrophobic MOG domain). In addition, residue MOG^113–127 was found to be a B‐cell epitope, suggesting that this may be a useful adjunct for the induction of EAE as well as for immunological studies in C57BL/6 mice, which are increasingly being used to study immune function through the use of transgenic and gene knockout technology.     

Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5

BackgroundHigh-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5–19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5.MethodsAll children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m²) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1–3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy).ResultsFifty-one patients (median age, 8 y; range, 5–19) were enrolled. The median follow-up was 7.1 years (range: 3.4–9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65–88) and 76% (63–86), and the 3 and 5-year OS were 84% (72–92) and 76% (63–86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated.ConclusionsThis treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.     

Mutations in the Genes Encoding the Transcription Factors Hepatocyte Nuclear Factor 1 Alpha and 4 Alpha in Maturity‐Onset Diabetes of the Young and Hyperinsulinemic Hypoglycemia

Maturity‐onset diabetes of the young (MODY) is a monogenic disorder characterized by autosomal dominant inheritance of young‐onset (typically <25 years), noninsulin‐dependent diabetes due to defective insulin secretion. MODY is both clinically and genetically heterogeneous with mutations in at least 10 genes. Mutations in the HNF1A gene encoding hepatocyte nuclear factor‐1 alpha are the most common cause of MODY in most adult populations studied. The number of different pathogenic HNF1A mutations totals 414 in 1,247 families. Mutations in the HNF4A gene encoding hepatocyte nuclear factor‐4 alpha are a rarer cause of MODY with 103 different mutations reported in 173 families to date. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The HNF4A MODY phenotype has been expanded by the reports of macrosomia in ～50% of babies, and more rarely, neonatal hyperinsulinemic hypoglycemia. The identification of an HNF1A or HNF4A gene mutation has important implications for clinical management in diabetes and pregnancy, but MODY is significantly underdiagnosed. Current research is focused on identifying biomarkers and developing probability models to identify those patients most likely to have MODY, until next generation sequencing technology enables cost‐effective gene analysis for all patients with young onset diabetes.