Effect of Rituximab on Pulmonary Function in Bronchiolitis Obliterans Syndrome due to Graft-Versus-Host-Disease

Purpose

Rituximab is an anti-CD20 monoclonal antibody that is used to suppress B-cell function in graft-versus-host-disease (GVHD). We sought to determine the effects of rituximab treatment on lung function in those patients with bronchiolitis obliterans syndrome (BOS) as a manifestation of GVHD.

Methods

Thirteen patients were treated with rituximab with a diagnosis of BOS and a significant reduction in the forced expiratory volume in 1 s (FEV1) after hematopoietic stem cell transplantation (HSCT). The changes in their pulmonary function for 12 months following treatment with rituximab were followed, along with other intervention performed and daily average dosing of prednisone.

Results

Following rituximab administration, there was an improvement in the slope of decline in lung function from ?5.12 ml/month prior to rituximab infusion to ?0.31 ml/month after 3 months and to +2.27 ml/month 12 months later. Seven of the 13 patients had an increase in their FEV1 after treatment with rituximab. Additionally, the mean daily dose of prednisone decreased from 27 mg prior to rituximab treatment to 11 mg 12 months after treatment. Nine out of 13 patients survived 12 months after rituximab treatment. All of the patients with improvement in FEV1 following rituximab treatment were receiving concomitant extracorporeal photopheresis.

Conclusion

Rituximab is safe with the potential to stabilize or improve lung function in patients with BOS after HSCT and should be considered as a treatment option in those patients.

     

Conditions for convergence of Monte Carlo EM sequences with an application to product diffusion modeling

Intractable maximum likelihood problems can sometimes be finessed with aMonte Carlo implementation of the EM algorithm. However, there appears to be little theory governing when Monte Carlo EM (MCEM) sequences converge. Consequently, in some applications, convergence is assumed rather than proved. Motivated by this problem in the context of modeling market penetration of new products and services over time, we develop (i) high-level conditions for rates of almost-sure convergence and convergence in distribution of any MCEM sequence and (ii) primitive conditions for almost-sure monotonicity and almost-sure convergence of an MCEM sequence when Monte Carlo integration is carried out using independent Gibbs runs. We verify the main primitive conditions for the Bass product diffusion model and apply the methodology to data on wireless telecommunication services.     

Cousins not twins: intratumoural and intertumoural heterogeneity in syndromic neuroendocrine tumours

Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma and medullary thyroid cancer, are caused by autosomal dominant mutations in several familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours, or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion, but have undergone independent clonal evolution. Such tumours provide an opportunity to discover common cooperative changes required for tumourigenesis, while controlling for the genetic background of the individual. We performed genomic analysis of synchronous and metachronous tumours from five patients bearing germline mutations in the genes SDHB, RET, and MAX. Using whole exome sequencing and high‐density single‐nucleotide polymorphism arrays, we analysed two to four primary tumours from each patient. We also applied multi‐region sampling, to assess intratumoural heterogeneity and clonal evolution, in two cases involving paraganglioma and medullary thyroid cancer, respectively. Heterogeneous patterns of genomic change existed between synchronous or metachronous tumours, with evidence of branching evolution. We observed striking examples of evolutionary convergence involving the same rare somatic copy‐number events in synchronous primary phaeochromocytoma/paraganglioma. Convergent events also occurred during clonal evolution of metastatic medullary thyroid cancer. These observations suggest that genetic or epigenetic changes acquired early within precursor cells, or pre‐existing within the genetic background of the individual, create contingencies that determine the evolutionary trajectory of the tumour. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Involvement of c-Myc in growth inhibition of Hep 3B human hepatoma cells by a vitamin K analog

BACKGROUND/AIMS: A synthetic vitamin K analog, compound 5 (Cpd 5), is a potent inhibitor of cell growth. The aim was to investigate whether c-Myc was involved in Cpd 5-induced cell growth inhibition. METHODS: Human hepotoma cells (Hep 3B) were cultured and treated with Cpd 5, and c-Myc protein expression and phosphorylation were investigated using Western blot analysis. RESULTS: Cpd 5 was found to inhibit c-Myc protein expression and induce c-Myc phosphorylation in Hep 3B cells. The phosphorylation of c-Myc was induced by both Cpd 5-mediated persistent extracellular signal-regulated kinase (ERK) phosphorylation and Cpd 5 increased glycogen synthase kinase-3 (GSK-3) activity. When using GSK-3 inhibitor, SB216763, c-Myc phosphorylation was significantly decreased and c-Myc levels were restored in Cpd 5 treated cells, suggesting that Cpd 5-mediated increase of GSK-3 activity enhanced c-Myc degradation and resulted in reduction of c-Myc levels. The lower c-Myc levels were found to cause altered expression of two c-Myc target genes, growth arrest gene gadd45 and ornithine decarboxylase (ODC). CONCLUSIONS: The results suggest that Cpd 5-mediated c-Myc phosphorylation resulted in enhanced c-Myc protein degradation and reduced c-Myc protein levels, which may contribute to cell growth inhibition by Cpd 5.