Tyrosine kinase-targeting drugs-associated heart failure.

BACKGROUND: The impact of cancer therapies on cardiac disease in the general adult cancer survivor population is largely unknown. Our objective was to evaluate which tyrosine kinase-targeting drugs are associated with greater risk for new-onset heart failure (HF). METHODS: A nested case-control analysis was conducted within a cohort of 27 992 patients of Clalit Health Services, newly treated with a tyrosine kinase-targeting, and/or chemotherapeutic drug, for a malignant disease, between 1 January 2005 and 31 December 2012. Each new case of HF was matched to up to 30 controls from the cohort on calendar year of cohort entry, age, gender, and duration of follow-up. Main outcome measure was odds ratio (OR) with 95% confidence interval (CI) of new-onset HF. RESULTS: There were 936 incident cases of HF during 71 742 person-years of follow-up. Trastuzumab (OR 1.90, 95% CI 1.46-2.49), cetuximab (OR 1.72, 1.10-2.69), panitumumab (OR 3.01, 1.02-8.85), and sunitinib (OR 3.39, 1.78-6.47) were associated with increased HF risk. Comorbidity independently associated with higher risk in a multivariable conditional regression model was diabetes mellitus, hypertension, chronic renal failure, ischaemic heart disease, valvular heart disease, arrhythmia, and smoking. CONCLUSIONS: Trastuzumab, cetuximab, panitumumab, and sunitinib are associated with increased risk for new-onset HF.

The role of CHADS2 and CHA2 DS2 -VASc scores in the prediction of stroke in individuals without atrial fibrillation: a population-based study.

UNLABELLED: Essentials CHADS2 and CHA2 DS2 -VASc scores are used to predict stroke in atrial fibrillation (AF). These scores were calculated for a large cohort from the largest healthcare provider in Israel. The risk of stroke gradually increased with an increase in the scores in individuals without AF. Both scores have a relatively high performance for stroke prediction in individuals without AF. Click to hear Prof. Lowe's perspective on Arterial Thrombosis, Pathogenesis and Epidemiology SUMMARY: Background CHADS2 and CHA2 DS2 -VASc are validated scores used to predict stroke in patients with atrial fibrillation (AF). We aimed to examine the performance of these scores in predicting stroke in individuals without AF. Methods Using the computerized database of the largest HMO in Israel, we identified all not-anticoagulated adults, aged 50 years or older on 1 January 2012. The cohort was followed for the occurrence of stroke or transient ischemic attack (TIA) until 31 December 2014. Results Of 1 053 871 individuals without AF at baseline, 34 215 developed stroke/TIA during a follow-up of 3 014 002 person-years (stroke/TIA incidence rate, 1.14 per 100 person-years). The incidence rate of stroke/TIA increased in a graded manner with increasing CHADS2 score: 0.36, 0.89, 1.89, 2.96, 4.31, 5.37 and 6.62 per 100 person-years for CHADS2 scores of 0 to 6 points, respectively (P < 0.001). Results were similar for the CHA2 DS2 -VASc score. A similar graded increasing trend in the stroke/TIA incidence rate was observed in a cohort of 46 657 patients with AF at baseline; however, stroke/TIA rates were higher in each score stratum compared with the rates of individuals without AF. The area under the receiver operating characteristic curve was 0.718 (95% CI, 0.715-0.721) and 0.714 (0.711-0.717) for CHADS2 and CHA2 DS2 -VASc scores, respectively, in individuals without AF, and 0.606 (0.598-0.614) and 0.610 (0.602-0.618), respectively, in individuals with AF. Conclusions CHADS2 and CHA2 DS2 -VASc scores have a relatively high performance for prediction of stroke/TIA in individuals without AF, which is comparable to their performance in patients with AF.

Clinical outcome of low-grade NHL patients with bone marrow involvement.

BACKGROUND: Bone marrow (BM) involvement in low-grade non-Hodgkin's lymphoma (NHL) has a clear impact on patients' survival. The standard practice is morphological examination of BM biopsy at diagnosis. The clinical significance of flow cytometry (FC) analysis of BM aspirates is largely unknown. MATERIALS AND METHODS: The medical charts of 70 low-grade NHL patients, who underwent BM biopsy and FC analysis between 1994 and 2004, were reviewed. RESULTS: Forty-three patients (61.4%) were BM+ by morphology, while in those without morphological involvement by lymphoma FC was positive in 9 (BM-FC+, 12.9%) and negative in 18 (BM-FC-, 25.7%). The median treatment-free period was shorter in the BM+ and BM-FC+ groups compared with the BM-FC- group (1 and 4 months vs. 31 months, respectively) (log-rank test, P = 0.0195). The median survival time was not reached for the BM-FC- patients, whereas for BM+ and BM-FC+ patients it was 129 and 89 months, respectively, with no significant difference between them [the difference between the BM-FC- and the two other groups was statistically significant (log-rank test, P = 0.029)]. CONCLUSIONS: The outcome of low grade NHL in patients who had BM involvement by FC alone or by morphology was similar. If confirmed, these findings suggest a modification in the workup and management of localized low grade NHL.

The influence of different chromosomal aberrations on molecular cytogenetic parameters in chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia of adults in Western countries. The most frequent recurring chromosomal aberrations identified in B-CLL patients are trisomy 12 and deletions of 13q, 17p, and 11q. Cases with deletions of 11q and 17p have a poor prognosis, whereas cases with deletions in 13q have a favorable prognosis. It was previously shown that CLL patients with trisomy 12 and del(13)(q14) have a higher rate of asynchronous replication of normal structural genes when compared to those with normal karyotypes. We studied the replication pattern of the structural locus 21q22 and the imprinted gene SNRPN and its telomere (15qter) and the random aneuploidy of chromosomes 9 and 18 in CLL patients with trisomy 12 and deletions of 11q and 17p, and compared the results to those of CLL patients without these aberrations and to healthy controls. Random aneuploidy rate was higher in the group of patients with trisomy 12 as compared to all other groups. The replication pattern with higher asynchronous pattern was found in both aberration groups compared to the CLL patients without the aberrations and to the control group with involvement of 21q22 and 15qter, whereas the highest synchronous group was found in the 2 aberrations CLL patient groups compared to the other groups with the imprinted locus SNRPN. The existence and significance of chromosomal aberrations in CLL have a deleterious effect on the processes of cell cycle and gene replication and may have biological and prognostic implications.

Random aneuploidy in neoplastic and pre-neoplastic diseases, multiple myeloma, and monoclonal gammopathy.

In this study we evaluated the aneuploidy rate of cells from patients considered to have a premalignant condition (monoclonal gammopathy or MGUS) and patients with multiple myeloma, as well as healthy controls. By applying a fluorescence situ hybridization technique, we estimated the random aneuploidy rate of alpha-satellite (centromeres) probes from chromosomes 9 and 18. The monosomy and total aneuploidy rates were higher in the two study groups compared to the control group. The monosomy rate was significantly higher in the MGUS group compared to the group with chromosome 18 alpha-satellite probes, a finding that was reported before in preneoplastic conditions. Our results support the cancer aneuploidy theory that carcinogenesis is initiated by a random aneuploidy, which is induced either spontaneously or by a carcinogen. The resulting karyotype instability sets a chain reaction of aneuploidization, which generates even more abnormal and eventually cancer-specific combinations and rearrangements of chromosomes.