John Carson Allen

A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer

Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor–mutated non–small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individuals response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism–associated TKI resistance.

Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria.

Objective:To compare microvascular invasion (McVI) with parameters defined by the Milan criteria in predicting tumor recurrence and overall survival (OS) in patients with surgical resection (SR) for hepatocellular carcinoma (HCC). Summary Background Data:Although the Milan criteria is discriminatory for selecting patients with good outcomes in liver transplantation and SR for HCC, it neither adequately predict tumor recurrence nor explain differences in survival for patients with good liver function. McVI is a strong indicator of intrahepatic metastasis in HCC, but its relative significance for predicting clinical outcomes compared to the Milan criteria is unclear. Methods:Patients undergoing SR with curative intent from January 2000 to March 2009 at the Singapore General Hospital were followed up for long-term outcomes till January 1, 2010. They were stratified first by the Milan criteria and then by the presence of McVI and compared relative to OS. Results:Altogether, 454 of the 515 patients received curative SR. There were stratified into 4 groups (Milan+, McVI−), (Milan+, McVI+), (Milan−, McVI−), and (Milan−, McVI+). All pair-wise comparisons between groups relative to OS were significant except (Milan+, McVI−) (OS, 90%, 73%, and 60% at 1, 3, and 5 years) with (Milan−, McVI−) (OS, 86%, 71%, and 61% at 1, 3, 5 years) and (Milan+, McVI+) with (Milan−, McVI+). Multivariate Cox regression analysis showed that McVI was predictive of OS, after which Milan status did not add additional discriminative information. Conclusions:McVI is a better predictor of tumor recurrence and OS than the Milan criteria after SR for HCC. Assessment of McVI should aid in patient selection for adjuvant treatments to improve outcomes after SR.

Systematic review of outcomes of liver resection for early hepatocellular carcinoma within the Milan criteria

Long‐term overall survival after liver resection in patients with hepatocellular carcinoma (HCC) within the Milan criteria has been reported to improve in recent years. This study systematically reviewed the outcomes of surgical resection for HCC in patients with good liver function and meeting the Milan criteria for early HCC, published in the past 10 years.

Efficacy and safety of esmolol vs propranolol in the treatment of supraventricular tachyarrhythmias: A multicenter double-blind clinical trial

The efficacy and safety of intravenous esmolol infusion was compared to that of intravenous propranolol injection in patients with supraventricular tachyarrhythmias (SVT) in a multicenter double-blind parallel study. A total of 127 patients were randomized to either the esmolol (n = 64) or propranolol (n = 63) group. Therapeutic response was achieved in 72% of esmolol and 69% of propranolol patients (p = NS). The average dose of esmolol in responders was 115 +/- 11 micrograms/kg/min. Therapeutic response was sustained in the 4-hour maintenance period in 67% of esmolol and 58% of propranolol patients (p = NS). Rate of conversion to normal sinus rhythm was similar in the two treatment groups. After discontinuation, rapid recovery from beta blockade (decrease in heart rate reduction) was observed in esmolol patients (within 10 minutes) compared to propranolol patients (no change in heart rate up to 4.3 hours). The principal adverse effect was hypotension, reported in 23 esmolol (asymptomatic in 19) and four propranolol (asymptomatic in three) patients. In the majority of esmolol patients, hypotension resolved quickly (within 30 minutes) after esmolol was discontinued. It was concluded that esmolol was comparable in efficacy and safety to propranolol in the treatment of patients with SVT. Unlike propranolol, because of the short half-life of esmolol, rapid control of beta blockade is possible with esmolol in clinical conditions when required.

Evaluation of the NS1 Rapid Test and the WHO Dengue Classification Schemes for Use as Bedside Diagnosis of Acute Dengue Fever in Adults

Because healthcare facilities in many dengue endemic countries lack laboratory support, early dengue diagnosis must rely on either clinical recognition or a bedside diagnostic test. We evaluated the sensitivity and specificity of the 1997 and 2009 World Health Organization (WHO) dengue classification schemes and the NS1 strip test in acute sera from 154 virologically confirmed dengue patients and 200 patients with other febrile illnesses. Both WHO classification schemes had high sensitivity but lacked specificity. The NS1 strip test had high specificity, but its sensitivity was significantly lower in secondary compared with primary dengue infections. Differences in viral serotypes did not affect the performance of any of the three diagnostic approaches. Taken collectively, our findings indicate that the 1997 WHO dengue case definition can be used to exclude dengue, and the NS1 strip test can be used to confirm dengue infection, although the latter should be interpreted with caution in regions where secondary dengue infection is prevalent.

Determinants of Angle Width in Chinese Singaporeans

PURPOSE To investigate determinants of angle width and derive mathematic models to best predict angle width. DESIGN Population-based, cross-sectional study. PARTICIPANTS A total of 1067 Chinese subjects aged ≥40 years. METHODS Participants underwent gonioscopy, A-scan biometry, and imaging by anterior segment optical coherence tomography (ASOCT, Carl Zeiss Meditec, Dublin, CA). Customized software (Zhongshan Angle Assessment Program, Guangzhou, China) was used to measure ASOCT parameters. Linear regression modeling was performed with trabecular-iris space area at 750 μm (TISA750) and angle opening distance at 750 μm (AOD750) from the scleral spur as the 2 dependent angle width variables. By using a combination of ASOCT and biometric parameters, an optimal model that was predictive of angle width was determined by a forward selection regression algorithm. Validation of the results was performed in a separate set of community-based clinic study of 1293 persons aged ≥50 years. MAIN OUTCOME MEASURES Angle width and biometric parameters. RESULTS The mean age (standard deviation) of the population-based subjects was 56.9 (8.5) years, and 50.2% were male. For TISA750, the strongest determinants among ASOCT and A-scan independent variables were anterior chamber volume (ACV, R(2)=0.51), followed by anterior chamber area (ACA, R(2)=0.49) and lens vault (LV, R(2)=0.47); for AOD750, these were LV (R(2)=0.56), ACA (R(2)=0.55), and ACV (R(2)=0.54). The R(2) values for anterior chamber depth and axial length were 0.39 and 0.27 for TISA750, respectively, and 0.46 and 0.30 for AOD750, respectively. An optimal model consisting of 6 variables (ACV, ACA, LV, anterior chamber width [ACW], iris thickness at 750 μm, and iris area) explained 81.4% of the variability in TISA750 and 85.5% of the variability in AOD750. The results of the population-based study were validated in the community-based clinic study, where the strongest determinants of angle width (ACA, ACV, and LV) and the optimal model with 6 variables were similar. CONCLUSIONS Angle width is largely dependent on variations in ACA, ACV, and LV. A predictive model comprising 6 quantitative ASOCT parameters explained more than 80% of the variability of angle width and may have implications for screening for angle closure.

The Effects of Exposure to General Anesthesia in Infancy on Academic Performance at Age 12

BACKGROUND: Recent evidence from juvenile animal models has shown that exposure to anesthetic drugs above threshold doses during a critical neurodevelopmental window causes widespread neuronal apoptosis, resulting in irreversible brain damage and subsequent learning difficulties. The relevance of this to human infants having general anesthesia for minor surgery is unknown. In this pilot observational cohort study, we sought to determine whether children exposed to general anesthesia for minor surgery during infancy exhibited differences in academic achievement at age 12 years, as evidenced by (1) lower aggregate scores in the Singapore standardized Primary School Leaving Examination (PSLE) and (2) formally diagnosed learning disability, compared with children who were never exposed to anesthesia or sedation. METHODS: We compared 100 full-term, apparently healthy children aged 12 years who were exposed to general anesthesia for minor surgery before age 1 at our institution with an age-matched cohort of 106 children who were never exposed to anesthesia or sedation. Parents of children completed a 20-minute telephone interview with questions regarding their children’s medical history, school environment, and home environment. RESULTS: The difference in mean PSLE aggregate scores (3.0; 95% confidence interval [CI], −8.3 to 14.3) between exposed (197.0; 95% CI, 185.6–208.4) and control groups (194.0; 95% CI, 182.9–205.1) was not statistically significant (P = 0.603). The presence of formally diagnosed learning disability was 15% (15 of 100) in the exposed group compared with 3.77% (4 of 106) in the control group (P < 0.001). The odds ratio for a formal diagnosis of learning disability in those exposed to general anesthesia relative to controls was 4.5 (95% CI, 1.44–14.1). CONCLUSION: The odds of a formal diagnosis of learning disability by age 12 years in apparently healthy children exposed to general anesthesia for minor surgery during infancy were 4.5 times greater than their peers who had never been exposed to anesthesia. However, study precision was inadequate to detect a clinically relevant difference in PSLE scores.

Determinants of Anterior Chamber Depth: The Singapore Chinese Eye Study

PURPOSE Recent advances in anterior segment imaging have enabled the measurement of novel ocular biometric parameters, such as lens vault (LV), posterior corneal arc length (PCAL), and iris area. The aims of this study were to identify the determinants of anterior chamber depth (ACD) and to ascertain the relative importance of these determinants in Chinese persons in Singapore. DESIGN Population-based, cross-sectional study. PARTICIPANTS One thousand sixty Chinese participants recruited from the Singapore Chinese Eye Study. METHODS All subjects underwent AS optical coherence tomography (OCT; Carl Zeiss Meditec, Dublin, CA). Customized software (Zhongshan Angle Assessment Program, Guangzhou, China) was used to measure the AS-OCT parameters. Anterior chamber depth was determined using IOLMaster (Carl Zeiss Meditec). Univariate and multivariate regression analyses were performed to assess the association between ACD with ocular biometric and systemic parameters. A stepwise selection algorithm was used to identify sequentially the contribution of each independent variable. MAIN OUTCOME MEASURES Anterior chamber depth and ocular biometric parameters. RESULTS The mean age (±standard deviation) of participants was 56.9±8.57 years and 50.5% were men. The mean ACD was 3.24±0.35 mm. The strongest determinants of ACD were LV (R(2) = 0.582; P<0.001) and PCAL (partial R(2) = 0.186; P<0.001). For every 10-μm increase in LV and every 1-mm increase in PCAL, ACD changed by -0.008 mm (95% confidence interval [CI], -0.009 to -0.008 mm; P<0.001) and 0.525 mm (95% CI, 0.468-0.583 mm; P<0.001), respectively. The 8 most highly associated variables (including LV, PCAL, axial length, age, and iris area) explained 80.5% of the variability in ACD, but when excluding LV and PCAL, the other 6 variables explained only 3.7% of the variability in ACD. After controlling for LV and PCAL, axial length was a poor determinant of ACD (partial R(2) = 0.006), whereas lens thickness was not associated independently with ACD. CONCLUSIONS Lens vault and PCAL explained 76.8% of the variability in ACD. When information about LV and PCAL were available, axial length was a poor determinant of ACD, whereas lens thickness was not associated independently with ACD. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Clinical evolution of Parkinson's disease and prognostic factors affecting motor progression: 9‐year follow‐up study

There have been few long‐term studies that have characterized and charted the clinical progression of Parkinsons disease (PD). This study was therefore undertaken to understand the natural clinical evolution of treated PD patients and to identify the variables that predict greater progression in these patients.

Mortality of bullous pemphigoid in Singapore: risk factors and causes of death in 359 patients seen at the National Skin Centre.

Bullous pemphigoid (BP) is the most common autoimmune‐mediated subepidermal blistering skin disease and is associated with significant morbidity and mortality.