Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma.

To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signaling pathways in the lymphomagenesis of MCL and the biologic basis for ibrutinib sensitivity of these tumors are unknown. Here, we demonstrate activation of B-cell receptor (BCR) and canonical NF-κB signaling specifically in MCL cells in the lymph node. Quantification of BCR signaling strength, reflected in the expression of BCR regulated genes, identified a subset of patients with inferior survival after cytotoxic therapy. Tumor proliferation was highest in the lymph node and correlated with the degree of BCR activation. A subset of leukemic tumors showed active BCR and NF-κB signaling apparently independent of microenvironmental support. In one of these samples, we identified a novel somatic mutation in RELA (E39Q). This sample was resistant to ibrutinib-mediated inhibition of NF-κB and apoptosis. In addition, we identified germ line variants in genes encoding regulators of the BCR and NF-κB pathway previously implicated in lymphomagenesis. In conclusion, BCR signaling, activated in the lymph node microenvironment in vivo, appears to promote tumor proliferation and survival and may explain the sensitivity of this lymphoma to BTK inhibitors.

Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL.

Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, tissue-resident CLL cells show prominent activation of both B-cell receptor (BCR) and NF-κB pathways. We evaluated the in vivo effects of ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor on tumor cell activation and proliferation in the blood, lymph node, and bone marrow of patients with CLL. Applying validated pathway-specific gene signatures, we detected a rapid and sustained downregulation of BCR and NF-κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment. Ibrutinib reduced phosphorylation of PLCγ2 and ERK and decreased nuclear protein expression of NF-κB p50. Ibrutinib significantly decreased tumor proliferation and expression of surface activation markers CD69 and CD86, independent of prognostic factors such as IGHV mutational status, chromosome 17p deletion, or prior treatment history. Interestingly, stronger inhibition of BCR signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2. Together, these data validate on-target effects of BTK inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo. This study is registered at www.clinicaltrials.gov as #NCT01500733.

Epidemiology and visual outcomes of ocular injuries in a low resource country.

BACKGROUND: Ocular injury is a major cause of ocular morbidity and unilateral visual impairment and represents a considerable public health concern especially in low resource societies. OBJECTIVE: To evaluate the epidemiology and visual outcomes of ocular injuries in southern Ghana. METHODS: A retrospective hospital-based case series was conducted. Information on new cases of ocular injuries were retrieved and parameters including time between injury occurrence and reporting to the clinic, presenting visual acuity (VA), and the best corrected final VA were investigated and visual outcomes were assessed Results: Most (50.2%) of the patients reported to the hospital after a day of sustaining an ocular injury; workplace injuries, older patients and farm-related injuries were most likely to report after a day of sustaining an injury. A significant proportion (40.4%) of patients reported with good presenting vision (6/6-6/18) which increased to 56.7% after treatment; 45.3% of patients reported with visual impairment (<6/18) and reduced to 42.4% after treatment. Farming (AOR = 4.5, p = 0.02), reporting after a day of sustaining injury (AOR = 78, p< 0.001), workplace injuries (AOR = 3.1, p = 0.007) and roadside injuries (AOR = 3.1, p = 0.02) were associated with poor visual outcomes. Initial VA 6/18 or better was the highest predictor of good visual outcome. CONCLUSION: There is a shift in the pattern of ocular injury occurrence from work-related to home- related.