Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis.

Abstract Introduction Emerging epidemiological evidence suggests that proton pump inhibitor (PPI) acid-suppression therapy is associated with an increased risk of Clostridium difficile infection (CDI). Methods Ovid MEDLINE, EMBASE, ISI Web of Science, and Scopus were searched from 1990 to January 2012 for analytical studies that reported an adjusted effect estimate of the association between PPI use and CDI. We performed random-effect meta-analyses. We used the GRADE framework to interpret the findings. Results We identified 47 eligible citations (37 case-control and 14 cohort studies) with corresponding 51 effect estimates. The pooled OR was 1.65, 95% CI (1.47, 1.85), I2 = 89.9%, with evidence of publication bias suggested by a contour funnel plot. A novel regression based method was used to adjust for publication bias and resulted in an adjusted pooled OR of 1.51 (95% CI, 1.26–1.83). In a speculative analysis that assumes that this association is based on causality, and based on published baseline CDI incidence, the risk of CDI would be very low in the general population taking PPIs with an estimated NNH of 3925 at 1 year. Conclusions In this rigorously conducted systemic review and meta-analysis, we found very low quality evidence (GRADE class) for an association between PPI use and CDI that does not support a cause-effect relationship

Quantitative analysis of tumor-specific BCL2 expression in DLBCL: refinement of prognostic relevance of BCL2

BCL2 overexpression has been reported to be associated with poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL). However, currently there is no consensus on the evaluation of BCL2 expression and only the proportion of BCL2 positive cells are evaluated for the determination of BCL2 positivity. This study aimed to define BCL2 positivity by quantitative analysis integrating both the intensity and proportion of BCL2 expression. BCL2 expression of 332 patients (221 patients for the training set and 111 patients for the validation set) with newly diagnosed DLBCL who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) were analyzed using the tumor-specific automated quantitative analysis (AQUA) scoring method based on multiplex immunofluorescence. In the training set, high BCL2 AQUA score (N = 86, 38.9%) was significantly associated with poor prognosis (p = 0.01, HR 2.00; 95% CI [1.15-3.49]) independent of international prognostic index, cell of origin, and MYC expression. The poor prognostic impact of the high BCL2 AQUA score was validated in the validation set. AQUA scoring of BCL2 expression incorporating both the intensity and proportion of BCL2 positive cells was independently associated with survival outcomes of patients with primary DLBCL treated with R-CHOP

Changes in osteoblastic activity in patient who received bortezomib as second line treatment for plasma cell myeloma: a prospective multicenter study

We conducted a prospective multicenter study identifying the role of bortezomib in patients with relapsed or refractory plasma cell myeloma (PCM) in bone resorption and formation via bone turnover markers. A total of 104 patients received at least 1 cycle of bortezomib. Most of them had advanced disease (n = 89). Among them, 75 patients completed 4 cycles of treatment. Most of the patients (81.7%) were treated in combination with steroid. After the 4th cycle treatment, 47 of 75 patients achieved CR, nCR, VGPR, and PR (64.4%), while 26 patients achieved less than PR (35.6%). The proportion of patients who achieved >/= PR increased as patients received more treatment cycles, reaching 90% after the 8th cycle. DKK-1 levels decreased significantly posttreatment. Bone formation markers (bALP and OC) and osteoclast regulator such as sRANKL also decreased significantly. These findings were observed primarily in patients who received steroid and who had a longer disease duration. While sRANKL demonstrated significant reduction posttreatment, osteoprotegerin (OPG) level did not significantly change posttreatment, resulting in a decreased sRANKL/OPG ratio (P = 0.037). In conclusion, our clinical data suggest that treatment with bortezomib and steroid may rearrange the metabolic balance between osteoblast and osteoclast activities in PCM

Clinical outcomes and prognostic factors in patients with breast diffuse large B cell lymphoma; Consortium for Improving Survival of Lymphoma (CISL) study

<p>Abstract</p> <p>Background</p> <p>The breast is a rare extranodal site of non-Hodgkin lymphoma, and primary breast lymphoma (PBL) has been arbitrarily defined as disease localized to one or both breasts with or without regional lymph nodes involvement. The aim of this study was to evaluate the clinical outcomes in patients with diffuse large B cell lymphoma (DLBCL) and breast involvement, and to find the criteria of PBL reflecting the outcome and prognosis.</p> <p>Methods</p> <p>We retrospectively analyzed data from 68 patients, newly diagnosed with DLBCL and breast involvement at 16 Korean institutions between January 1994 and June 2009.</p> <p>Results</p> <p>Median age at diagnosis was 48 years (range, 20-83 years). Forty-three (63.2%) patients were PBL according to previous arbitrary criteria, sixteen (23.5%) patients were high-intermediate to high risk of international prognostic index. The patients with one extranodal disease in the breast (OED) with or without nodal disease were 49 (72.1%), and those with multiple extranodal disease (MED) were 19 (27.9%). During median follow-up of 41.5 months (range, 2.4-186.0 months), estimated 5-year progression-free survival (PFS) was 53.7 ± 7.6%, and overall survival (OS) was 60.3 ± 7.2%. The 5-year PFS and OS was significantly higher for patients with the OED group than those with the MED group (5-year PFS, 64.9 ± 8.9% vs. 27.5 ± 11.4%, p = 0.001; 5-year OS, 74.3 ± 7.6% vs. 24.5 ± 13.0%, p < 0.001). In multivariate analysis, MED (hazard ratio [HR], 3.61; 95% confidence interval [CI], 1.07-12.2) and fewer than four cycles of systemic chemotherapy with or without local treatments (HR, 4.47; 95% CI, 1.54-12.96) were independent prognostic factors for worse OS. Twenty-five (36.8%) patients experienced progression, and the cumulative incidence of progression in multiple extranodal sites or other than breasts and central nervous system was significantly different between the OED group and the MED group (5-year cumulative incidence, 9.7 ± 5.4% vs. 49.0 ± 15.1%, p = 0.001).</p> <p>Conclusions</p> <p>Our results show that the patients included in OED group, reflecting different treatment outcome, prognosis and pattern of progression, should be considered as PBL in the future trial. Further studies are warranted to validate our suggested criteria.</p

Lessons from non-canonical splicing

Recent improvements in experimental and computational techniques that are used to study the transcriptome have enabled an unprecedented view of RNA processing, revealing many previously unknown non-canonical splicing events. This includes cryptic events located far from the currently annotated exons and unconventional splicing mechanisms that have important roles in regulating gene expression. These non-canonical splicing events are a major source of newly emerging transcripts during evolution, especially when they involve sequences derived from transposable elements. They are therefore under precise regulation and quality control, which minimizes their potential to disrupt gene expression. We explain how non-canonical splicing can lead to aberrant transcripts that cause many diseases, and also how it can be exploited for new therapeutic strategies