Therapeutic potential of new B cell-targeted agents in the treatment of elderly and unfit patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is primarily a disease of the elderly, with most patients ≥65 years of age and having at least one major comorbidity. Aggressive chemoimmunotherapy regimens recommended to achieve remission and improve survival in young, fit patients are often poorly tolerated in elderly and/or less physiologically fit (“unfit”) patients, necessitating alternative treatment options. Although patient age, fitness, and comorbidities are key considerations in the selection of a treatment regimen, historically, clinical trials have been limited to young, fit patients by virtue of the ethical concerns associated with potential end organ toxic effects that could worsen comorbidities. However, the availability of new therapies promises a shift to a research paradigm that encompasses the identification of optimal treatments for elderly and unfit patients. Anti-CD20 monoclonal antibody therapy, which overall has improved response rates and survival in patients with CLL, has only recently been evaluated elderly and unfit patients. B cell-targeted agents such as the Bruton’s tyrosine kinase inhibitor ibrutinib and the phosphatidylinositol 3-kinase inhibitor idelalisib are the first of a new generation of oral agents for CLL. Available clinical data suggest that these therapies have the potential to address the unmet need in elderly and unfit patients with CLL and result in clinical remission, and not merely symptom palliation and improved quality of life, which, by themselves, are also a reasonable goal

The results of arthroscopic versus mini-open repair for rotator cuff tears at mid-term follow-up

<p>Abstract</p> <p>Background</p> <p>To prospectively evaluate patients who underwent a "mini-open" repair versus a completely arthroscopic technique for small to large size rotator cuff tears.</p> <p>Methods</p> <p>Fifty-two patients underwent "mini-open" or all arthroscopic repair of a full thickness tear of the rotator cuff. Patients who complained of shoulder pain and/or weakness and who had failed a minimum of 6 weeks of physical therapy and had at least one sub-acromial injection were surgical candidates. Pre and post-operative clinical evaluations included the following: 1) demographics; 2) Simple Shoulder Test (SST); 3) University of California, Los Angeles (UCLA) rating scale; 4) visual analog pain assessment (VAS); and 5) pre-op SF12 assessment. Descriptive analysis was performed for patient demographics and for all variables. Pre and post outcome scores, range of motion and pain scale were compared using paired t-tests. Analysis of variance (ANOVA) was used to evaluate any effect between dependent and independent variables. Significance was set at p is less than or equal to 0.05.</p> <p>Results</p> <p>There were 31 females and 21 males. The average follow-up was 50.6 months (27 – 84 months). The average age was similar between the two groups [arthroscopic x = 55 years/mini-open x = 58 years, p = 0.7]. Twenty-seven patients underwent arthroscopic repair and 25 underwent repair with a mini-open incision. The average rotator cuff tear size was 3.1 cm (range: 1–5 centimeters). There was no significant difference in tear size between the two groups (arthroscopic group = 2.9 cm/mini-open group = 3.2 cm, p = 0.3). Overall, there was a significant improvement from pre-operative status in shoulder pain, shoulder function as measured on the Simple Shoulder test and UCLA Shoulder Form. Visual analog pain improved, on average, 4.4 points and the most recent Short Shoulder Form and UCLA scores were 8 and 26 respectively. Both active and passive glenohumeral joint range of motion improved significantly from pre-operatively.</p> <p>Conclusion</p> <p>Based upon the number available, we found no statistical difference in outcome between the two groups, indicating that either procedure is efficacious in the treatment of small and medium size rotator cuff tears.</p> <p>Level of Evidence</p> <p>Type III</p

TGFβ activated kinase 1 (TAK1) at the crossroad of B cell receptor and toll-like receptor 9 signaling pathways in human B cells

B cell development and activation are regulated by combined signals mediated by the B cell receptor (BCR), receptors for the B-cell activating factor of the tumor necrosis factor family (BAFF-R) and the innate receptor, Toll-like receptor 9 (TLR9). However, the underlying mechanisms by which these signals cooperate in human B cells remain unclear. Our aim was to elucidate the key signaling molecules at the crossroads of BCR, BAFF-R and TLR9 mediated pathways and to follow the functional consequences of costimulation.Therefore we stimulated purified human B cells by combinations of anti-Ig, B-cell activating factor of the tumor necrosis factor family (BAFF) and the TLR9 agonist, CpG oligodeoxynucleotide. Phosphorylation status of various signaling molecules, B cell proliferation, cytokine secretion, plasma blast generation and the frequency of IgG producing cells were investigated. We have found that BCR induced signals cooperate with BAFF-R- and TLR9-mediated signals at different levels of cell activation. BCR and BAFF- as well as TLR9 and BAFF-mediated signals cooperate at NFκB activation, while BCR and TLR9 synergistically costimulate mitogen activated protein kinases (MAPKs), ERK, JNK and p38. We show here for the first time that the MAP3K7 (TGF beta activated kinase, TAK1) is responsible for the synergistic costimulation of B cells by BCR and TLR9, resulting in an enhanced cell proliferation, plasma blast generation, cytokine and antibody production. Specific inhibitor of TAK1 as well as knocking down TAK1 by siRNA abrogates the synergistic signals. We conclude that TAK1 is a key regulator of receptor crosstalk between BCR and TLR9, thus plays a critical role in B cell development and activation

B-lymphocyte tolerance and effector function in immunity and autoimmunity

B-lymphocytes are integral to host defense against microbial pathogens and are associated with many autoimmune diseases. The B-cell receptor implements B-cell self-tolerance based on the antigen specificity, and B-cell-activating factor receptor (BAFF-R) imposes homeostatic control. While shaping the repertoire, the immune tolerance process also culls mature B cells into distinct populations. The activation response of B cells is tailored to the type of pathogen attack and is facilitated by T-cell help via CD40/CD40L interaction and/or innate cell help via toll-like receptors in conjunction with BAFF receptors and ligands. Activated effector B cells not only produce antibodies, but also produce a variety of cytokines to enhance and suppress the immune response. Not surprisingly, B cells play multiple roles in both humoral and cellular immune responses during infection and autoimmune pathogenesis. Here, we discuss how gene expression and signaling networks regulate peripheral B-cell tolerance, B-cell effector functions and emerging therapies targeting B-cell signaling in autoimmune diseases