Phase II study of sorafenib in patients with relapsed or refractory lymphoma

The safety and activity of the multikinase inhibitor sorafenib were investigated in patients with relapsed or refractory lymphoproliferative disorders who received sorafenib (400 mg) twice daily until disease progression or appearance of significant clinical toxicity. The primary endpoint was overall response rate (ORR). Biomarkers of sorafenib activity were analysed at baseline and during treatment. Thirty patients (median age, 61 years; range, 18-74) received a median of 4 months of therapy. Grade 3-4 toxicities included hand/foot skin reactions (20%), infections (12%), neutropenia (20%) and thrombocytopenia (14%). Two patients achieved complete remission (CR), and two achieved partial remission (PR) for an ORR of 13%. Stable disease (SD) and progressive disease (PD) was observed in 15 (50%) and 11 patients (37%), respectively. The median overall survival (OS) for all patients was 16 months. For patients who achieved CR, PR and SD, the median time to progression and OS was 5 and 24 months, respectively. Compared with patients with PD, responsive patients had significantly higher baseline levels of extracellular signal-regulated kinase phosphorylation and autophagy and presented a significant reduction of these parameters after 1 month of therapy. Sorafenib was well tolerated and had a clinical activity that warrants development of combination regimens.     

Outbreak or coincidental cases of tuberculosis? Genotyping provides the clue

We illustrate how genotyping of mycobacterial strains contributed to the discovery of an undetected outbreak of tuberculosis in a hospital ward, ruling out misleading assumptions of transmission chains. Genotyping should be taken into account in routine tests for the control of tuberculosis.     

Renal insufficiency and vascular complications after primary angioplasty via femoral route. Impact of vascular closure devices use

Introduction and objectives

We sought to determine the incidence of vascular complications in patients with chronic kidney disease undergoing primary angioplasty via the femoral route; we also evaluated the safety and efficacy of the use of vascular closure devices in this setting.

Methods

Registry of 527 patients undergoing primary angioplasty via the femoral route from January 2003 to December 2008. Chronic kidney disease was defined as creatinine clearance less than 60 mL/min. The primary endpoint was the presence of major vascular complications.

Results

Baseline chronic kidney disease was observed in 166 (31.5%) patients. Patients with chronic kidney disease experienced higher rates of major vascular complications compared to those without worsening of renal function (8.4% vs 4.2%; P=.045), especially those requiring transfusion (6.6% vs 1.9%; P=.006). Among patients with chronic kidney disease, 129 (77.7%) received a vascular closure device and manual compression was used in 37 patients (22.3%). The risk of major vascular complications was significantly lower with vascular closure device use compared to manual compression (4.7% vs 21.6%; P=.003). Multivariable logistic regression analysis showed that the use of a vascular closure device was independently associated with a decreased risk of major vascular complications in patients with chronic kidney disease undergoing primary angioplasty (odds ratio=0.11; 95% confidence interval, 0.03-0.41; P=.001).

Conclusions

Patients with chronic kidney disease undergoing primary angioplasty via the femoral route experience higher rates of major vascular complications. The use of vascular closure devices in this group of patients is safe and is associated with lower rates of major vascular complications compared to manual compression.Full English text available from:www.revespcardiol.org     

Monoclonal B-cell lymphocytosis (MBL) with normal lymphocyte counts is associated with decreased numbers of normal circulating B-cell subsets

Monoclonal B-cell lymphocytosis (MBL) with normal lymphocyte counts is associated with decreased numbers of normal circulating B-cell subsets.Little is known about the distribution of normal lymphoid cells and their subsets in the peripheral blood (PB) of subjects with monoclonal B-cell lymphocytosis (MBL). In our study, we compared the absolute number of PB lymphoid cells and their subpopulations in 95 MBL cases with normal lymphocyte counts vs. 617 age-/sex-matched non-MBL healthy subjects (controls), using highly sensitive flow cytometry. MBL cases showed significantly reduced numbers of normal circulating B-cells, at the expense of immature and naive B-cells; in addition, CD4+CD8+ double-positive T-cells and CD8+ T-cells were significantly lower and higher vs. controls, respectively. Moreover, most normal B-cell subsets were significantly decreased in PB at >1% MBL-counts, vs. "low-count" MBL cases, and lower amounts of immature/naive B-cells were detected in biclonal (particularly in cases with coexisting CLL-like- and non-CLL-like B-cell clones) vs. monoclonal MBL subjects. In summary, our results show imbalanced (reduced) absolute numbers of recently produced normal circulating B-cells (e.g., immature and na?ve B-cells) in MBL, which becomes more pronounced as the MBL cell count increases.     

Suggestive evidence for association between L‐type voltage‐gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family‐based association study

Objectives: Through recent genome‐wide association studies (GWASs), several groups have reported significant association between variants in the calcium channel, voltage‐dependent, L‐type, alpha 1C subunit (CACNA1C) and bipolar disorder (BP) in European and European‐American cohorts. We performed a family‐based association study to determine whether CACNA1C is associated with BP in the Latino population. Methods: This study included 913 individuals from 215 Latino pedigrees recruited from the USA, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single‐nucleotide polymorphisms (SNPs) that spanned a 602.9‐kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family‐Based Association Test (version 2.0.3) and Haploview (version 4.2) software. Results: An eight‐locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). Conclusions: Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population.     

Glycosaminoglycan entrapment by fibrin in engineered heart valve tissues

Tissue engineered heart valves (TEHVs) may provide a permanent solution to congenital heart valve disease by permitting somatic valve growth in the pediatric patient. However, to date, TEHV studies have focused primarily on collagen, the dominant component of valve extracellular matrix (ECM). Temporal decreases in other ECM components, such as the glycosaminoglycans (GAGs), generally decrease as cells produce more collagen under mechanically loaded states; nevertheless, GAGs represent a key component of the valve ECM, providing structural stability and hydration to the leaflets. In an effort to retain GAGs within the engineered constructs, here we investigated the utility of the protein fibrin in combination with a valve-like, cyclic flexure and steady flow (flex–flow) mechanical conditioning culture process using adult human periodontal ligament cells (PLCs). We found both fibrin and flex–flow mechanical components to be independently significant (p < 0.05), and hence important in influencing the DNA, GAG and collagen contents of the engineered tissues. In addition, the interaction of fibrin with flex–flow was found to be significant in the case of collagen; specifically, the combination of these environments promoted PLC collagen production resulting in a significant difference compared to dynamic and statically cultured specimens without fibrin. Histological examination revealed that the GAGs were retained by fibrin entrapment and adhesion, which were subsequently confirmed by additional experiments on native valve tissues. We conclude that fibrin in the flex–flow culture of engineered heart valve tissues: (i) augments PLC-derived collagen production; and (ii) enhances retention of GAGs within the developing ECM.     

Primary hepatic lymphoma in a patient with previous rectal adenocarcinoma: a case report and discussion of etiopathogenesis and diagnostic tools

Primary hepatic lymphoma is an extremely rare malignancy accounting for 0.016% of all cases of non-Hodgkin lymphomas. Approximately 1–4% of histologies described show a follicular pattern. We report a case of primary hepatic non-Hodgkin lymphoma that developed in a middle-aged woman 3 years after radical treatment (neoadjuvant chemoradiotherapy and surgery) for a rectal adenocarcinoma. Abdomen ultrasound showed a single nodule in the liver, which raised the issue of differential diagnosis with a metastasis from rectal cancer. After surgical removal of the nodule, histology revealed a primary B cell, stage IE follicular non-Hodgkin lymphoma, confined to the liver; indeed, no foci of lymphoma were found elsewhere in the body.