Polyneuropathy improvement following autologous stem cell transplantation for POEMS syndrome

OBJECTIVE: To study the evolution of the neuropathy and long-term disability in a large cohort of patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome following autologous stem cell transplantation (ASCT). METHODS: Retrospective chart review documenting the clinical, electrophysiologic, and laboratory characteristics of patients with POEMS syndrome undergoing ASCT at Mayo Clinic, Rochester. RESULTS: Sixty patients with a median follow-up time of 61 months were studied. All patients had peripheral polyneuropathy and demonstrated neurologic improvement after ASCT (apart from one patient who died early). Before ASCT, 27 patients (45%) required a wheelchair and 17 (29%) required a walker or foot brace. At the end of the follow-up period, no patient was using a wheelchair and 23 patients (38%) were using a foot brace. The median Neuropathy Impairment Score improved from 66 to 48 points at 12 months and to 30 points at most recent follow-up (p < 0.0001). Median Rankin Scale score improved from 3 to 1.5 (p < 0.0001). Vascular endothelial growth factor levels decreased from a median of 452 to 63.5 pg/mL (p < 0.0001). The ulnar compound motor action potential amplitude (median) improved from 4.3 to 7.6 mV (p < 0.0001) and ulnar compound motor action potential conduction velocity (median) improved from 34 to 51 m/s (p < 0.0001). Predicted forced vital capacity improved from 81% to 88% (p < 0.0001). Periengraftment syndrome occurred in 24 patients. Fourteen patients required additional chemotherapy and/or radiation following ASCT, but there was no clinical deterioration in the neuropathy in any of these patients. Six patients died: 1 due to POEMS, 1 due to failed engraftment, and 4 due to other malignancies (2 myelodysplastic syndrome, 1 lymphoma, 1 metastatic lung cancer). CONCLUSION: Patients with POEMS syndrome who undergo ASCT have a significant and meaningful improvement of their neuropathy by multiple measurements during both short and long-term follow-up, which corresponds to reduction in morbidity and disability (none are in wheelchair long-term). Periengraftment syndrome was common but manageable. Fatal complications, although rare, did occur, usually in association with other malignancies. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with POEMS syndrome, ASCT improves neuropathy-related function

The Enskog Process

The existence of a weak solution to a McKean-Vlasov type stochastic differential system corresponding to the Enskog equation of the kinetic theory of gases is established under natural conditions. The distribution of any solution to the system at each fixed time is shown to be unique. The existence of a probability density for the time-marginals of the velocity is verified in the case where the initial condition is Gaussian, and is shown to be the density of an invariant measure.Comment: 38 page

A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men

Background Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). Methods We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan® PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. Results The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32–4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50–6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. Conclusions To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD

Stochastic Reaction-diffusion Equations Driven by Jump Processes

We establish the existence of weak martingale solutions to a class of second order parabolic stochastic partial differential equations. The equations are driven by multiplicative jump type noise, with a non-Lipschitz multiplicative functional. The drift in the equations contains a dissipative nonlinearity of polynomial growth.Comment: See journal reference for teh final published versio

Evaluation of a chemoresponse assay as a predictive marker in the treatment of recurrent ovarian cancer: Further analysis of a prospective study

BACKGROUND: Recently, a prospective study reported improved clinical outcomes for recurrent ovarian cancer patients treated with chemotherapies indicated to be sensitive by a chemoresponse assay, compared with those patients treated with non-sensitive therapies, thereby demonstrating the assay's prognostic properties. Due to cross-drug response over different treatments and possible association of in vitro chemosensitivity of a tumour with its inherent biology, further analysis is required to ascertain whether the assay performs as a predictive marker as well. METHODS: Women with persistent or recurrent epithelial ovarian cancer (n=262) were empirically treated with one of 15 therapies, blinded to assay results. Each patient's tumour was assayed for responsiveness to the 15 therapies. The assay's ability to predict progression-free survival (PFS) was assessed by comparing the association when the assayed therapy matches the administered therapy (match) with the association when the assayed therapy is randomly selected, not necessarily matching the administered therapy (mismatch). RESULTS: Patients treated with assay-sensitive therapies had improved PFS vs patients treated with non-sensitive therapies, with the assay result for match significantly associated with PFS (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.50–0.91, P=0.009). On the basis of 3000 simulations, the mean HR for mismatch was 0.81 (95% range=0.66–0.99), with 3.4% of HRs less than 0.67, indicating that HR for match is lower than for mismatch. While 47% of tumours were non-sensitive to all assayed therapies and 9% were sensitive to all, 44% displayed heterogeneity in assay results. Improved outcome was associated with the administration of an assay-sensitive therapy, regardless of homogeneous or heterogeneous assay responses across all of the assayed therapies. CONCLUSIONS: These analyses provide supportive evidence that this chemoresponse assay is a predictive marker, demonstrating its ability to discern specific therapies that are likely to be more effective among multiple alternatives

Semi-Groups of Isometries and the Representation and Multiplicity of Weakly Stationary Stochastic Processes

1 online resource (PDF, 27 pages

Alcohol reversibly disrupts TNF-α/TACE interactions in the cell membrane

BACKGROUND: Alcohol abuse has long been known to adversely affect innate and adaptive immune responses and pre-dispose to infections. One cellular mechanism responsible for this effect is alcohol-induced suppression of TNF-α (TNF) by mononuclear phagocytes. We have previously shown that alcohol in part inhibits TNF-α processing by TNF converting enzyme (TACE) in human monocytes. We hypothesized that the chain length of the alcohol is critical for post-transcriptional suppression of TNF secretion. METHODS: Due to the complex transcriptional and post-transcriptional regulation of TNF in macrophages, to specifically study TNF processing at the cell membrane we performed transient transfections of A549 cells with the TNF cDNA driven by the heterologous CMV promoter. TNF/TACE interactions at the cell surface were assessed using fluorescent resonance energy transfer (FRET) microscopy. RESULTS: The single carbon alcohol, methanol suppressed neither TNF secretion nor FRET efficiency between TNF and TACE. However, 2, 3, and 4 carbon alcohols were potent suppressors of TNF processing and FRET efficiency. The effect of ethanol, a 2-carbon alcohol was reversible. CONCLUSION: These data show that inhibition of TNF-α processing by acute ethanol is a direct affect of ethanol on the cell membrane and is reversible upon cessation or metabolism

Investigation of the Role of TNF-α Converting Enzyme (TACE) in the Inhibition of Cell Surface and Soluble TNF-α Production by Acute Ethanol Exposure

Toll-like receptors (TLRs) play a fundamental role in the immune system by detecting pathogen associated molecular patterns (PAMPs) to sense host infection. Ethanol at doses relevant for humans inhibits the pathogen induced cytokine response mediated through TLRs. The current study was designed to investigate the mechanisms of this effect by determining whether ethanol inhibits TLR3 and TLR4 mediated TNF-α secretion through inhibition of transcription factor activation or post-transcriptional effects. In NF-κB reporter mice, activation of NF-κB in vivo by LPS was inhibited by ethanol (LPS alone yielded 170,000±35,300 arbitrary units of light emission; LPS plus ethanol yielded 56,120±16880, p = 0.04). Inhibition of protein synthesis by cycloheximide revealed that poly I:C- or LPS-induced secreted TNF-α is synthesized de novo, not released from cellular stores. Using real time RT-PCR, we found inhibition of LPS and poly I:C induced TNF-α gene transcription by ethanol. Using an inhibitor of tumor necrosis factor alpha converting enzyme (TACE), we found that shedding caused by TACE is a prerequisite for TNF-α release after pathogen challenge. Flow cytometry was used to investigate if ethanol decreases TNF-α secretion by inhibition of TACE. In cells treated with LPS, ethanol decreased both TNF-α cell surface expression and secretion. For example, 4.69±0.60% of untreated cells were positive for cell surface TNF-α, LPS increased this to 25.18±0.85%, which was inhibited by ethanol (86.8 mM) to 14.29±0.39% and increased by a TACE inhibitor to 57.88±0.62%. In contrast, cells treated with poly I:C had decreased secretion of TNF-α but not cell surface expression. There was some evidence for inhibition of TACE by ethanol in the case of LPS, but decreased TNF-α gene expression seems to be the major mechanism of ethanol action in this system