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 relationship between obesity and the increase in serum 25(OH)D levels in response to vitamin D supplementation.

UNLABELLED: This study examines the relationship between obesity and the increase in serum 25(OH)D levels in response to vitamin D supplementation among adults with baseline serum 25(OH)D levels<50 nmol/L. This study revealed that the increase in serum 25(OH)D in response to vitamin D supplementation was higher in lean subjects as compared to obese subjects. INTRODUCTION: Serum 25(OH)D is lower among obese than non-obese. This study examines the relationship between obesity and the increase in serum 25(OH)D in response to vitamin D supplementation in a large sample of adults with baseline serum 25(OH)D<50 nmol/L, relatively long average treatment duration and large average daily cholecalciferol. METHODS: The computerized database of the Clalit Health Services, which the largest nonprofit health maintenance organization in Israel, was retrospectively searched for all subjects aged≥20 years who performed serum 25(OH)D test in 2011. Subjects with more than one test at different occasions in 2011 were identified and were included if the result of the first test was <50 nmol/L, and were treated with cholecalciferol between the first and the last test in 2011 (n=16,540 subjects). RESULTS: The mean increase in serum 25(OH)D level after treatment was 28.7 (95% confidence interval (CI), 28.0-29.4) nmol/L, 23.6 (23.0-24.2) nmol/L, and 20.1 (19.6-20.6) nmol/L in subject with BMI of <25, 25-29.9, and ≥30 kg/m2, respectively (P<0.001). The results were similar after adjustment for the potential confounders. Similarly, the proportion of subjects who achieved serum 25(OH)D≥50 nmol/L after treatment was inversely associated with BMI; 65.1, 58.3, and 49.1% for BMI of <25, 25-29.9, and ≥30 kg/m2, respectively. Compared to BMI of ≥30 kg/m2, the adjusted odds ratio for achieving levels of ≥50 nmol/L were 2.12 (95 % CI, 1.94-2.31) and 1.42 (1.31-1.54) for BMI of <25 kg/m2, and BMI of 25-29.9 kg/m2, respectively. CONCLUSIONS: BMI is inversely associated with the increase in serum 25(OH)D levels in response to vitamin D supplementation.

Total versus hemithyroidectomy for microscopic papillary thyroid cancer.

BACKGROUND: No increased mortality has been reported in patients with thyroid papillary microcarcinoma (PMC); however, neck recurrences and distant metastases have been described. In this study, we compare patients' outcomes after total thyroidectomy vs hemithyroidectomy for treatment of thyroid PMC. METHODS: Two hundred and ninety-three patients from two major medical centers in Israel were included. The mean follow-up period was 7.2±6.8 yr. RESULTS: Total thyroidectomy was performed in 214 patients and hemithyroidectomy in 79 patients. Mean tumor size was 6.3±3 mm. Lymph-node (LN) metastases and extraglandular extension were more frequent in the total thyroidectomy group than in the hemithyroidectomy group, 24.8% vs 1.3% (p<0.001) and 11.7% vs 3.8% (p=0.042), respectively. The cumulative incidence of recurrence at the end of follow-up was 13.2% in the total thyroidectomy group and 14.3% in the hemithyroidectomy group (p=ns). The incidence of recurrence was higher in patients with LN involvement in both groups. Considering low risk patients only (monofocal tumors, no LN involvement, no extraglandular extension; no.=63 in the total thyroidectomy group vs no.=60 in the hemithyroidectomy group) neck recurrence was found in 10% of patients in the hemithyroidectomy group but none in the total thyroidectomy group. In the hemithyroidectomy group, all locoregional recurrences were diagnosed using ultrasonography, compared to 47.6% in the total thyroidectomy group. CONCLUSION: For patients with monofocal disease within the thyroid gland and no LN involvement, hemithyroidectomy can be considered an option, bearing in mind a higher risk for recurrence. For all other patients with PMC, we propose total thyroidectomy as initial treatment.

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

The risk of developing uterine sarcoma after tamoxifen use.

The treatment of breast cancer with tamoxifen results in an increased risk of uterine cancer. The objective of this study was to evaluate the association between tamoxifen use and the risk of developing uterine sarcomas and endometrial carcinomas in a historical cohort of women diagnosed with breast cancer in 1987-1988. The medical records of all women diagnosed in Israel with breast cancer in the years 1987-1988 were sought. Clinical data, including use of hormone therapy, were extracted from oncology records. In 2004, patient identifiers were linked to the Israel Cancer Registry database to identify all uterine cancers that occurred within 15 years of the diagnosis of breast cancer. The records for 1507 breast cancer cases (84%) were retrieved. Among these cases, 32 uterine malignancies were identified; 11 occurred prior to the diagnosis of breast cancer and 21 occurred during the follow-up period. Eight hundred seventy-five women in the cohort had used tamoxifen (59%). There were 17 uterine cancers observed among the 875 exposed to tamoxifen (1.9%), compared to 4 uterine cancers among the 621 women (0.6%) who did not use tamoxifen (odds ratio = 3.1; 95% CI: 1.0-9.1; P = 0.04). There were four uterine sarcomas among the tamoxifen users, but none among nonusers (P = 0.15). Five of the 875 tamoxifen users (0.6%) died of uterine cancer, compared to no deaths among nonusers (P = 0.08). We conclude that in this national breast cancer cohort, tamoxifen use was associated with elevated risks of uterine cancer incidence and mortality. Uterine sarcomas appear to be overrepresented among women who use tamoxifen.

Does hysteroscopy affect prognosis in apparent early-stage endometrial cancer?

The objective of the study was to compare the outcome measures of patients with endometrial adenocarcinoma diagnosed by endometrial biopsy, uterine curettage, or hysteroscopy. Medical records of 392 women diagnosed with apparent early-stage endometrial adenocarcinoma were reviewed. Data concerning the mode of diagnosis, histologic type and grade, surgical stage, peritoneal washings and lymph nodes status, and patient's outcome were retrieved. During the study period, 99 (25.3%) cases were diagnosed by endometrial biopsy, 193 (49.2%) by uterine curettage, and 100 (25.5%) by hysteroscopy. There were 347 (88.5%) cases of endometrioid adenocarcinoma and 45 (11.5%) of poor histologic types, including serous papillary, clear cell, and small cell cancer. Three hundred and sixteen (80.6%) patients had stage I disease, 8 (2.0%) stage II, and 68 (17.4%) stage III. Peritoneal cytology was positive in only one case. Recurrent disease occurred in 6.9% patients, of which 50% had local recurrence and 50% had distant. Recurrent disease was found in 15.2% patients diagnosed by endometrial biopsy, in 4.7% where uterine curettage was used, and in 5% when hysteroscopy was applied. No statistically significant difference in the survival rate between the different diagnostic methods applied was found, although a higher recurrence rate was noted following endometrial biopsy. After a median follow-up time of 25 months for patients undergoing hysteroscopy, there was no difference in recurrence rates and/or overall survival compared to other diagnostic procedures implying that hysteroscopy can be safely used in the diagnosis of endometrial cancer.

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.

Neutrophil to lymphocyte ratio and risk of a first episode of stroke in patients with atrial fibrillation: a cohort study.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is associated with increased risk of cardiovascular morbidity and mortality. We aimed to assess the association between NLR and first episode of stroke in patients with atrial fibrillation. METHODS: Using the computerized database of the largest HMO in Israel, we identified a cohort of adults, aged 20 years or older, with atrial fibrillation diagnosed before 1 January 2012. Eligible subjects had no prior stroke or TIA, were not on anticoagulants at baseline, and had at least one blood cell count performed in 2011. The cohort (32,912 subjects) was followed for the first event of stroke or TIA until 31 December 2012. RESULTS: Overall 981 subjects developed stroke during a follow-up of 30,961 person-years (stroke rate, 3.17 per 100 person-years). The incidence rate of stroke increased across NLR quartiles: 2.27, 2.72, 3.26 and 4.54 per 100 person-years, respectively. Cox proportional hazard regression analysis adjusting for the individual CHA2 DS2 -VASc score risk factors showed that, compared with the lowest NLR quartile, the HR for stroke was 1.11 (95% CI, 0.91-1.35), 1.25 (1.03-1.51) and 1.56 (1.29-1.88) for the second, third and highest quartile, respectively. On stratified analysis, NLR refined the risk of stroke across all CHA2 DS2 -VASc score strata. Adding NLR to the CHA2 DS2 -VASc score increased the AUC from 0.627 (95% CI, 0.612-0.643) to 0.635 (0.619-0.651) (P = 0.037). CONCLUSIONS: The neutrophil to lymphocyte ratio is directly associated with the risk of stroke in patients with atrial fibrillation. Future studies are needed to replicate these findings.

Glycated hemoglobin and risk of first episode stroke in diabetic patients with atrial fibrillation: A cohort study.

BACKGROUND: Diabetes is associated with an increased risk of stroke in patients with atrial fibrillation. Whether glycemic control, evaluated by glycated hemoglobin, affects the risk of stroke in diabetic patients with atrial fibrillation remains unknown. OBJECTIVE: To examine the association between glycated hemoglobin and risk of first episode stroke in diabetic patients with atrial fibrillation. METHODS: By using the computerized database of the largest health maintenance organization in Israel, we identified a cohort of adults (age ≥20 years) in whom atrial fibrillation was diagnosed before January 1, 2012. Eligible subjects had no previous stroke or transient ischemic attack and were not on anticoagulants at baseline. The cohort (37,358 subjects) was followed for the first episode stroke or transient ischemic attack up to December 31, 2012. RESULTS: A total of 1052 subjects had stroke during 35,278 person-years of follow-up (stroke rate 2.98 per 100 person-years). Cox proportional hazards regression analysis adjusting for CHA2DS2-VASc score risk factors revealed that compared with subjects without diabetes, the hazard ratio for stroke was 1.04 (95% confidence interval [CI] 0.83-1.30) for the lowest glycated hemoglobin quartile (<6.35%), 1.14 (95% CI 0.92-1.42) for the second quartile (6.35%-6.90%), 1.46 (95% CI 1.19-1.79) for the third quartile (>6.90%-7.70%), and 1.63 (95% CI 1.33-2.00) for the highest quartile(>7.70%) (for trend, P < .001). In diabetic patients (n = 11,176), the hazard ratio for stroke was 1.17 (95% CI 1.09-1.26) for every 1% increment in glycated hemoglobin level. The area under the receiver operating characteristic curve was 0.585 for the CHA2DS2-VASc score, which increased to 0.604 when glycated hemoglobin was included in the model (P = .038). CONCLUSION: Glycated hemoglobin is directly associated with stroke risk, and it improves the predictive accuracy for stroke in diabetic patients with atrial fibrillation.

Statins use and risk of mortality in patient with Clostridium difficile infection.

Current evidence suggests that statins may improve outcome in infectious diseases. This study aims to assess whether statins use is associated with reduced risk of 30-day mortality in Clostridium difficile infection (CDI). Using the computerized database of Clalit, the largest healthcare provider in Israel, we identified a cohort of adult subjects (age ≥40 years) who tested positive on a C. difficile toxin assay performed between January 2011 and December 2012. Subjects were defined as current statins users if they filled at least one prescription during the 90 days before the laboratory assay date. Current users were classified into long-term users if at least one additional prescription was filled during the previous 91-180 days; otherwise they were defined as short-term users. A total 1888 patients with CDI were included. Of them, 340 (18.0%) died during the first 30 days after diagnosis. The 30-day mortality rate was lower among current statins users 89/669 (13.3%) compared with 251/1219 (20.6%) in non-users (p <0.001). A significant reduced risk of 30-day mortality existed after adjustment for potential confounders; adjusted OR = 0.57 (95% CI 0.42-0.79) and was unique to long-term users; 0.53 (0.38-0.73) but not short-term users; 1.15 (0.56-2.34). The risk of 30-day mortality decreased with increasing number of filled statins prescriptions; adjusted OR = 0.77 (95% CI 0.67-0.89) for each additional prescription. Current aspirin use was also independently associated with reduced mortality; adjusted OR = 0.64 (95% CI 0.43-0.88). In conclusion, current statins use, particularly long-term use, has a dose-response protective effect on mortality in patients with CDI.

Single measurement of serum 25(OH)D: is classification into month-specific cutpoints useful in accounting for seasonal variation?

Classification into month-specific cutpoints is used to minimize misclassification associated with single measurement of serum 25(OH)D. This study aims to evaluate this strategy, and to compare it with the widely used classification into overall cutpoints. For this purpose, we studied 69,553 subjects in whom serum 25(OH)D was tested on two different occasions. The level of agreement between the quartiles of the first and second tests was 43.8% between the month-specific quartiles and 43.1% between the overall quartiles. The level of agreement between the quartiles of the two approaches was 80.0% and 94.3% in the first and second test, respectively. The extent of seasonal variation (summer-autumn as compared with winter-spring) of serum 25(OH)D was higher in males and in Jews, inversely associated with baseline levels, body mass index and age, and directly associated with socioeconomic class. The month-specific cutpoint strategy does not seem to offer advantage over the overall cutpoints strategy.

The implementation of an anesthesia information management system.

BACKGROUND AND OBJECTIVE: Anaesthesia information management systems, though still not used widely, will inevitably replace handwritten records and may eventually serve as a core for the development of computerized decision support. We investigated staff expectations and the accuracy of data entry in a recently implemented commercially available anaesthesia information management system. METHODS: A structured questionnaire was administered to the staff before and 1 week and 3 months after implementation in order to assess their opinion. The quality of manual data entry, and of automatic data record was evaluated by looking for missing data and the prevalence of artefacts. RESULTS: Despite initial fears the users quickly accepted the system. Both automatic and manual data entry were found to be accurate and reliable while the prevalence of artefacts was relatively low. CONCLUSIONS: A commercially available anaesthesia information management system can be easily implemented and used instead of paper charts.