A prognostic index predicting survival in transformed Waldenström macroglobulinemia

Histological transformation into diffuse large B-cell lymphoma is a rare complication in patients with Waldenström macroglobulinemia (WM) usually associated with a poor prognosis. The objective of this study was to develop and validate a prognostic index for survival in transformed WM patients. Through this multicenter, international collaborative effort, we developed a scoring system based on data from 133 patients with transformed WM who were evaluated between 1995 and 2016 (training cohort). Univariate and multivariate analyses were used to propose a prognostic index with 2-year survival after transformation as an end-point. For external validation, a data set of 67 patients was used to evaluate the performance of the model (validation cohort). By multivariate analysis, three adverse covariates were identified as independent predictors of 2-year survival after transformation: elevated serum LDH (2 points), platelet count < 100 x 109/L (1 point) and any previous treatment for WM (1 point). Three risk groups were defined: low-risk (0-1 point, 24% of patients), intermediate-risk (2-3 points, 59%, hazard ratio (HR) = 3.4) and high-risk (4 points, 17%, HR = 7.5). Two-year survival rates were 81%, 47%, and 21%, respectively (P < 0.0001). This model appeared to be a better discriminant than the International Prognostic Index (IPI) and the revised IPI (R-IPI). We validated this model in an independent cohort. This easy-to-compute scoring index is a robust tool that may allow identification of groups of transformed WM patients with different outcomes and could be used for improving the development of risk-adapted treatment strategies

Variation in cytokine genes can contribute to severity of acetabular osteolysis and risk for revision in patients with ABG 1 total hip arthroplasty: a genetic association study

<p>Abstract</p> <p>Background</p> <p>The differences in total hip arthroplasty (THA) survivorship may be influenced by individual susceptibility to periprosthetic osteolysis. This may be driven by functional polymorphisms in the genes for cytokines and cytokine receptors involved in the development of osteolysis in THA, thereby having an effect on the individual's phenotype.</p> <p>Methods</p> <p>We performed a study on 22 single-nucleotide polymorphisms (SNPs) for 11 cytokines and two cytokine receptor candidate genes for association with severity of acetabular osteolysis and risk to failure in THA. Samples from 205 unrelated Caucasian patients with cementless type THA (ABG 1) were investigated. Distribution of investigated SNP variants between the groups of mild and severe acetabular osteolysis was determined by univariate and multivariate analysis. Time-dependent output variables were analyzed by the Cox hazards model.</p> <p>Results</p> <p>Univariate analysis showed: 1) <it>TNF</it>-238*A allele was associated with severe osteolysis (odds ratio, OR = 6.59, <it>p </it>= 0.005, population attributable risk, PAR 5.2%); 2) carriers of the <it>IL6</it>-174*G allele were 2.5 times more prone to develop severe osteolysis than non-carriers (OR = 2.51, <it>p </it>= 0.007, PAR = 31.5%); 3) the carriage of <it>IL2</it>-330*G allele was associated with protection from severe osteolysis (OR = 0.55, <it>p </it>= 0.043). Based on logistic regression, the alleles <it>TNF</it>-238*A and <it>IL6</it>-174*G were independent predictors for the development of severe acetabular osteolysis. Carriers of <it>TNF</it>-238*A had increased cumulative hazard of THA failure according to Cox model (<it>p </it>= 0.024). In contrast, <it>IL2</it>-330*G allele predicted lower cumulative hazard of THA failure (<it>p </it>= 0.019).</p> <p>Conclusion</p> <p>Genetic variants of proinflammatory cytokines TNF-alpha and IL-6 confer susceptibility to severe OL. In this way, presence of the minor <it>TNF </it>allele could increase the cumulative risk of THA failure. Conversely, SNP in the <it>IL2 </it>gene may protect carriers from the above THA complications.</p

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Compensatory Evolution of pbp Mutations Restores the Fitness Cost Imposed by β-Lactam Resistance in Streptococcus pneumoniae

The prevalence of antibiotic resistance genes in pathogenic bacteria is a major challenge to treating many infectious diseases. The spread of these genes is driven by the strong selection imposed by the use of antibacterial drugs. However, in the absence of drug selection, antibiotic resistance genes impose a fitness cost, which can be ameliorated by compensatory mutations. In Streptococcus pneumoniae, β-lactam resistance is caused by mutations in three penicillin-binding proteins, PBP1a, PBP2x, and PBP2b, all of which are implicated in cell wall synthesis and the cell division cycle. We found that the fitness cost and cell division defects conferred by pbp2b mutations (as determined by fitness competitive assays in vitro and in vivo and fluorescence microscopy) were fully compensated by the acquisition of pbp2x and pbp1a mutations, apparently by means of an increased stability and a consequent mislocalization of these protein mutants. Thus, these compensatory combinations of pbp mutant alleles resulted in an increase in the level and spectrum of β-lactam resistance. This report describes a direct correlation between antibiotic resistance increase and fitness cost compensation, both caused by the same gene mutations acquired by horizontal transfer. The clinical origin of the pbp mutations suggests that this intergenic compensatory process is involved in the persistence of β-lactam resistance among circulating strains. We propose that this compensatory mechanism is relevant for β-lactam resistance evolution in Streptococcus pneumoniae

Development of multivariable models to predict change in Body Mass Index within a clinical trial population of psychotic individuals

Many antipsychotics promote weight gain, which can lead to non-compliance and relapse of psychosis. By developing models that accurately identify individuals at greater risk of weight gain, clinicians can make informed treatment decisions and target intervention measures. We examined clinical, genetic and expression data for 284 individuals with psychosis derived from a previously published randomised controlled trial (IMPACT). These data were used to develop regression and classification models predicting change in Body Mass Index (BMI) over one year. Clinical predictors included demographics, anthropometrics, cardiac and blood measures, diet and exercise, physical and mental health, medication and BMI outcome measures. We included genetic polygenic risk scores (PRS) for schizophrenia, bipolar disorder, BMI, waist-hip-ratio, insulin resistance and height, as well as gene co-expression modules generated by Weighted Gene Co-expression Network Analysis (WGCNA). The best performing predictive models for BMI and BMI gain after one year used clinical data only, which suggests expression and genetic data do not improve prediction in this cohort

Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study

<p>Abstract</p> <p>Background</p> <p>Preoperative capecitabine-based chemoradiation is a standard treatment for locally advanced rectal cancer (LARC). Here, we explored the safety and efficacy of the addition of bevacizumab to capecitabine and concurrent radiotherapy for LARC.</p> <p>Methods</p> <p>Patients with MRI-confirmed stage II/III rectal cancer received bevacizumab 5 mg/kg i.v. 2 weeks prior to neoadjuvant chemoradiotherapy followed by bevacizumab 5 mg/kg on Days 1, 15 and 29, capecitabine 825 mg/m²twice daily on Days 1-38, and concurrent radiotherapy 50.4 Gy (1.8 Gy/day, 5 days/week for 5 weeks + three 1.8 Gy/day), starting on Day 1. Total mesorectal excision was scheduled 6-8 weeks after completion of chemoradiotherapy. Tumour regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was pathological complete response (pCR).</p> <p>Results</p> <p>61 patients were enrolled (median age 60 years [range 31-80], 64% male). Twelve patients (19.7%) had T3N0 tumours, 1 patient T2N1, 19 patients (31.1%) T3N1, 2 patients (3.3%) T2N2, 22 patients (36.1%) T3N2 and 5 patients (8.2%) T4N2. Median tumour distance from the anal verge was 6 cm (range 0-11). Grade 3 adverse events included dermatitis (n = 6, 9.8%), proteinuria (n = 4, 6.5%) and leucocytopenia (n = 3, 4.9%). Radical resection was achieved in 57 patients (95%), and 42 patients (70%) underwent sphincter-preserving surgery. TRG 4 (pCR) was recorded in 8 patients (13.3%) and TRG 3 in 9 patients (15.0%). T-, N- and overall downstaging rates were 45.2%, 73.8%, and 73.8%, respectively.</p> <p>Conclusions</p> <p>This study demonstrates the feasibility of preoperative chemoradiotherapy with bevacizumab and capecitabine. The observed adverse events of neoadjuvant treatment are comparable with those previously reported, but the pCR rate was lower.</p

C-Reactive Protein (CRP) Gene Polymorphisms, CRP Levels, and Risk of Incident Coronary Heart Disease in Two Nested Case-Control Studies

Background: C-reactive protein (CRP), an acute phase reactant and marker of inflammation, has been shown to predict risk of incident cardiovascular events. However, few studies have comprehensively examined six common single-nucleotide polymorphisms (SNPs) in the CRP gene, haplotypes, and plasma CRP levels with risk of coronary heart disease (CHD). Methods and Findings: We conducted parallel nested case-control studies within two ongoing, prospective cohort studies of U.S. women (Nurses' Health Study) and men (Health Professionals Follow-up Study). Blood samples were available in a subset of 32,826 women and 18,225 men for biomarker and DNA analyses. During 8 and 6 years of follow-up, 249 women and 266 men developed incident nonfatal myocardial infarction or fatal CHD, and controls (498 women, 531 men) were matched 2:1 on age, smoking, and date of blood draw from participants free of cardiovascular disease at the time the case was diagnosed. Among both women and men, minor alleles were significantly associated with higher CRP levels for SNPs 1919A greater than T and 4741G greater than C, but associated with lower CRP levels for SNPs 2667G greater than C and 3872C greater than T. SNP 2667G greater than C was individually associated with increased risk of CHD in both women [OR 1.57 (95% CI 1.01–2.44); p = 0.047] and men [1.93 (95% CI 1.30–2.88); p = 0.001]. Two of the five common haplotypes were associated with lower CRP levels, and Haplotype 4 which included minor alleles for 2667 and 3872 was associated with significantly lower CRP levels and an elevated risk of CHD. The remaining SNPs or haplotypes were not associated with CHD in both populations. Conclusions: Common variation in the CRP gene was significantly associated with plasma CRP levels; however, the association between common SNPs and CRP levels did not correspond to a predicted change in CHD risk. The underlying inflammatory processes which predict coronary events cannot be captured solely by variation in the CRP gene

One-year follow-up of patients of the ongoing Dutch Q fever outbreak: clinical, serological and echocardiographic findings

Contains fulltext : 89915.pdf (publisher's version ) (Open Access)PURPOSE: In 2007, a large goat-farming-associated Q fever outbreak occurred in the Netherlands. Data on the clinical outcome of Dutch Q fever patients are lacking. The current advocated follow-up strategy includes serological follow-up to detect evolution to chronic disease and cardiac screening at baseline to identify and prophylactically treat Q fever patients in case of valvulopathy. However, serological follow-up using commercially available tests is complicated by the lack of validated cut-off values. Furthermore, cardiac screening in the setting of a large outbreak has not been implemented previously. Therefore, we report here the clinical outcome, serological follow-up and cardiac screening data of the Q fever patients of the current ongoing outbreak. METHODS: The implementation of a protocol including clinical and serological follow-up at baseline and 3, 6 and 12 months after acute Q fever and screening echocardiography at baseline. RESULTS: Eighty-five patients with acute Q fever were identified (male 62%, female 38%). An aspecific, flu-like illness was the most common clinical presentation. Persistent symptoms after acute Q fever were reported by 59% of patients at 6 months and 30% at 12 months follow-up. We observed a typical serological response to Coxiella burnetii infection in both anti-phase I and anti-phase II IgG antibodies, with an increase in antibody titres up to 3 months and a subsequent decrease in the following 9 months. Screening echocardiography was available for 66 (78%) out of 85 Q fever patients. Cardiac valvulopathy was present in 39 (59%) patients. None of the 85 patients developed chronic Q fever. CONCLUSIONS: Clinical, serological and echocardiographic data of the current ongoing Dutch Q fever outbreak cohort are presented. Screening echocardiography is no longer part of the standard work-up of Q fever patients in the Netherlands.1 december 201