Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma.

BACKGROUND: More than 80% of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients harbor the (nucleophosmin) NPM1-ALK fusion gene t(2;5) chromosomal translocation. We evaluated the preclinical and clinical efficacy of ceritinib treatment of this aggressive lymphoma. MATERIALS AND METHODS: We studied the effects of ceritinib treatment in NPM1-ALK+ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALK+ ALCL patient with ceritinib. We reviewed all hematologic malignancies profiled by a large hybrid-capture next-generation sequencing (NGS)-based comprehensive genomic profiling assay for ALK alterations. RESULTS: In our in vitro experiments, ceritinib inhibited constitutive activation of the fusion kinase NPM1-ALK and downstream effector molecules STAT3, AKT, and ERK1/2, and induced apoptosis of these lymphoma cell lines. Cell cycle analysis following ceritinib treatment showed G0/G1 arrest with a concomitant decrease in the percentage of cells in S and G2/M phases. Further, treatment with ceritinib in the NPM1-ALK+ ALCL xenograft model resulted in tumor regression and improved survival. Of 19 272 patients with hematopoietic diseases sequenced, 58 patients (0.30%) harbored ALK fusions that include histiocytic disorders, multiple myeloma, B-cell neoplasms, Castleman's disease, and juvenile xanthogranuloma. A multiple relapsed NPM1-ALK+ ALCL patient treated with ceritinib achieved complete remission with ongoing clinical benefit to date, 5 years after initiation of therapy. CONCLUSIONS: This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.

Knowledge, attitudes and practices regarding tuberculosis in two districts of Punjab, Pakistan.

SETTING: Pakistan ranks eighth among the world's highest tuberculosis (TB) burden countries, and Punjab province accounts for 60% of TB cases nationally. OBJECTIVE: To explore knowledge, attitudes and practices regarding TB in the general population of two districts of Punjab province, and the effect of socio-economic determinants. DESIGN: In a cross-sectional survey, subjects aged > or =20 years were randomly selected using multistage cluster sampling and interviewed. A knowledge score was formulated based on nine questions. Bivariate analysis using the chi(2) test was employed to independently correlate socio-economic factors with understanding of disease and information sources. Attitudes, practices and information sources were also compared with TB knowledge. RESULTS: Forty-two per cent of the surveyed population had good knowledge about TB, which was associated with better education, high income and good housing (all P < 0.001). Despite the fact that the majority (82.2%) knew about correct treatment, less than half (48.8%) were aware that diagnosis and treatment were free. Intended health-seeking behaviour was determined by better education (P = 0.011), good housing (P = 0.004) and good knowledge about TB (P < 0.001). Television (69.4%) and health workers (43.6%) were the main sources of information. CONCLUSION: Socio-economic factors should be considered when designing communication strategies and prioritising TB prevention and control interventions.