Asymmetrical arrest of the proximal tibial physis and genu recurvatum deformity

We are reporting six cases of premature asymmetrical closure of the proximal tibial physis and associated genu recurvatum deformity and have reviewed the fourteen cases reported in the English-language literature. No single etiological factor could be implicated as the cause of the physeal arrest. Trauma, prolonged immobilization, tibial wire traction, and a surgical procedure involving the proximal tibial physis were observed risk factors among our patients. In our patients, established genu recurvatum due to deformity of the proximal end of the tibia and associated tibial length discrepancy were managed successfully by an opening-wedge osteotomy through the proximal one-third of the tibia and bone-grafting. Epiphyseodesis in the contralateral extremity may be required in patients with significant shortening of the tibia.     

Unbalanced expression of Fas and CD40 in mantle cell lymphoma

B cells are characterized by the dual expression of CD40 and Fas receptors, which can mediate their survival and death, respectively. The balance between the dynamically opposing functions of these two receptors is important for B-cell selection, maturation and homeostasis. We found that mantle cell lymphoma (MCL) cells had a high level of CD40 and low or absent level of Fas, therefore favouring the CD40 cell survival pathway. Exogenous Fas ligand had no effect on MCL cells, whereas exogenous CD40 ligand enhanced their survival and rescued them from fludarabine-induced apoptosis. Our data raise the possibility that the prolonged survival of MCL cells in vivo may be explained by the unbalanced expression of Fas and CD40.     

Autozygome maps dispensable DNA and reveals potential selective bias against nullizygosity

PurposeCopy number variants are an important source of human genome diversity. The widespread distribution of hemizygous copy number variants in the DNA of healthy humans suggests that haploinsufficiency is largely tolerated. However, little is known about the extent to which corresponding nullizygosity (two-copy deletion) is similarly tolerated.MethodsWe analyzed a cohort of first cousin unions to enrich for shared parental hemizygous events and tested their Mendelian inheritance in offspring.ResultsAnalysis of autozygous DNA blocks (autozygome) in the offspring not only proved an efficient method of mapping “dispensable” DNA but also revealed potential selective bias against the occurrence of nullizygous changes. This bias was not restricted to genic copy number variants and was not accounted for by a high rate of miscarriages.ConclusionsThe autozygome is an efficient way to map dispensable segments of DNA and may reveal selective bias against nullizygosity in healthy individuals.Genet Med 2012:14(5):515–519     

Clinical development of panobinostat in classical Hodgkin's lymphoma

Deacetylase (DAC) inhibitors are promising new anticancer drugs that have complex mechanisms of action, including induction of cell-cycle arrest and apoptosis, inhibition of angiogenesis and induction of a favorable anti-tumor immune response. Panobinostat, a potent inhibitor of DAC 1-11 enzymatic activity, has demonstrated a significant in vitro antiproliferative activity against classical Hodgkin's lymphoma (cHL) cell lines in addition to a promising clinical activity in early Phase I studies in patients with relapsed cHL. In a recently completed large Phase II study in patients with relapsed cHL, panobinostat reduced tumor measurements in 74% of patients, including 23% partial and 4% complete remissions. In this article, we review the status of panobinostat drug development and compare its activity to those of other DAC inhibitors in patients with relapsed cHL. Future investigations should focus on designing rational combination regimens and identifying predictive markers that will assist in selecting patients who are likely to benefit from this novel therapy.