Benjamin Adam Haaland
Email Address
gmsbenah@nus.edu.sg
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Publication Non-communicable diseases and injuries in Pakistan: Strategic priorities(2013) Jafar, T.H.; Haaland, B.A.; Rahman, A.; Razzak, J.A.; Bilger, M.; Naghavi, M.; Mokdad, A.H.; Hyder, A.A.; DUKE-NUS GRADUATE MEDICAL SCHOOL S'PORENon-communicable diseases, including cardiovascular diseases, cancers, respiratory diseases, diabetes, and mental disorders, and injuries have become the major causes of morbidity and mortality in Pakistan. Tobacco use and hypertension are the leading attributable risk factors for deaths due to cardiovascular diseases, cancers, and respiratory diseases. Pakistan has the sixth highest number of people in the world with diabetes; every fourth adult is overweight or obese; cigarettes are cheap; antismoking and road safety laws are poorly enforced; and a mixed public-private health-care system provides suboptimum care. Furthermore, almost three decades of exposure to sociopolitical instability, economic uncertainty, violence, regional conflict, and dislocation have contributed to a high prevalence of mental health disorders. Projection models based on the Global Burden of Disease 2010 data suggest that there will be about 3•87 million premature deaths by 2025 from cardiovascular diseases, cancers, and chronic respiratory diseases in people aged 30-69 years in Pakistan, with serious economic consequences. Modelling of risk factor reductions also indicate that Pakistan could achieve at least a 20% reduction in the number of these deaths by 2025 by targeting of the major risk factors. We call for policy and legislative changes, and health-system interventions to target readily preventable non-communicable diseases in Pakistan.Publication A systematic review and network meta-analysis of immunotherapy and targeted therapy for advanced melanoma(2017) da Silveira Nogueira Lima, J.P; Georgieva, M; Haaland, B; de Lima Lopes, G; DUKE-NUS MEDICAL SCHOOLImmune and BRAF-targeted therapies have changed the therapeutic scenario of advanced melanoma, turning the clinical decision-making a challenging task. This Bayesian network meta-analysis assesses the role of immunotherapies and targeted therapies for advanced melanoma. We retrieved randomized controlled trials testing immune, BRAF- or MEK-targeted therapies for advanced melanoma from electronic databases. A Bayesian network model compared therapies using hazard ratio (HR) for overall survival (OS), progression-free survival (PFS), and odds ratio (OR) for response rate (RR), along with 95% credible intervals (95% CrI), and probabilities of drugs outperforming others. We assessed the impact of PD-L1 expression on immunotherapy efficacy. Sixteen studies evaluating eight therapies in 6849 patients were analyzed. For OS, BRAF-MEK combination and PD-1 single agent ranked similarly and outperformed all other treatments. For PFS, BRAF-MEK combination surpassed all other options, including CTLA-4-PD-1 dual blockade hazard ratio (HR: 0.56; 95% CrI: 0.33–0.97; probability better 96.2%), whereas BRAF single agent ranked close to CTLA-4-PD-1 blockade. For RR, BRAF-MEK combination was superior to all treatments including CTLA-4-PD-1 (OR: 2.78; 1.18–6.30; probability better 97.1%). No OS data were available for CTLA-4-PD-1 blockade at the time of systematic review, although PFS and RR results suggested that this combination could also bring meaningful benefit. PD-L1 expression, as presently defined, failed to inform patient selection to PD-1-based immunotherapy. BRAF-MEK combination seemed an optimal therapy for BRAF-mutated patients, whereas PD-1 inhibitors seemed optimal for BRAF wild-type patients. Longer follow-up is needed to ascertain the role of CTLA-4-PD-1 blockade. Immunotherapy biomarkers remain as an unmet need. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.Publication Bosutinib inhibits migration and invasion via ack1 in kras mutant non-small cell lung cancer(2014) Tan, D.S.W; Haaland, B; Gan, J.M; Tham, S.C; Sinha, I; Tan, E.H; Lim, K.H; Takano, A; Krisna, S.S; Thu, M.M.M; Liew, H.P; Ullrich, A; Lim, W.-T; Chua, B.T; DUKE-NUS MEDICAL SCHOOLThe advent of effective targeted therapeutics has led to increasing emphasis on precise biomarkers for accurate patient stratification. Here, we describe the role of ACK1, a non-receptor tyrosine kinase in abrogating migration and invasion in KRAS mutant lung adenocarcinoma. Bosutinib, which inhibits ACK1 at 2.7 nM IC50, was found to inhibit cell migration and invasion but not viability in a panel of non-small cell lung cancer (NSCLC) cell lines. Knockdown of ACK1 abrogated bosutinib-induced inhibition of cell migration and invasion specifically in KRAS mutant cells. This finding was further confirmed in an in vivo zebrafish metastatic model. Tissue microarray data on 210 Singaporean lung adenocarcinomas indicate that cytoplasmic ACK1 was significantly over-expressed relative to paired adjacent non-tumor tissue. Interestingly, ACK1 expression in " normal" tissue adjacent to tumour, but not tumour, was independently associated with poor overall and relapse-free survival. In conclusion, inhibition of ACK1 with bosutinib attenuates migration and invasion in the context of KRAS mutant NSCLC and may fulfil a therapeutic niche through combinatorial treatment approaches. © 2014 Tan et al.; licensee BioMed Central Ltd.Publication Prediction of adverse cardiac events in emergency department patients with chest pain using machine learning for variable selection(2014) Liu, N; Koh, Z.X; Goh, J; Lin, Z; Haaland, B; Ting, B.P; Ong, M.E.H; DUKE-NUS MEDICAL SCHOOLBackground: The key aim of triage in chest pain patients is to identify those with high risk of adverse cardiac events as they require intensive monitoring and early intervention. In this study, we aim to discover the most relevant variables for risk prediction of major adverse cardiac events (MACE) using clinical signs and heart rate variability.Methods. A total of 702 chest pain patients at the Emergency Department (ED) of a tertiary hospital in Singapore were included in this study. The recruited patients were at least 30 years of age and who presented to the ED with a primary complaint of non-traumatic chest pain. The primary outcome was a composite of MACE such as death and cardiac arrest within 72 h of arrival at the ED. For each patient, eight clinical signs such as blood pressure and temperature were measured, and a 5-min ECG was recorded to derive heart rate variability parameters. A random forest-based novel method was developed to select the most relevant variables. A geometric distance-based machine learning scoring system was then implemented to derive a risk score from 0 to 100.Results: Out of 702 patients, 29 (4.1%) met the primary outcome. We selected the 3 most relevant variables for predicting MACE, which were systolic blood pressure, the mean RR interval and the mean instantaneous heart rate. The scoring system with these 3 variables produced an area under the curve (AUC) of 0.812, and a cutoff score of 43 gave a sensitivity of 82.8% and specificity of 63.4%, while the scoring system with all the 23 variables had an AUC of 0.736, and a cutoff score of 49 gave a sensitivity of 72.4% and specificity of 63.0%. Conventional thrombolysis in myocardial infarction score and the modified early warning score achieved AUC values of 0.637 and 0.622, respectively.Conclusions: It is observed that a few predictors outperformed the whole set of variables in predicting MACE within 72 h. We conclude that more predictors do not necessarily guarantee better prediction results. Furthermore, machine learning-based variable selection seems promising in discovering a few relevant and significant measures as predictors. © 2014 Liu et al.; licensee BioMed Central Ltd.Publication Randomized clinical trial of cutting balloon angioplasty versus high-pressure balloon angioplasty in hemodialysis arteriovenous fistula stenoses resistant to conventional balloon angioplasty(2014-02) Aftab, S.A.; Tay, K.H.; Irani, F.G.; Gong Lo, R.H.; Gogna, A.; Haaland, B.; Tan, S.G.; Chng, S.P.; Pasupathy, S.; Choong, H.L.; Tan, B.S.; MEDICINE; DUKE-NUS GRADUATE MEDICAL SCHOOL S'POREPurpose To compare the efficacy and safety of cutting balloon angioplasty (CBA) versus high-pressure balloon angioplasty (HPBA) for the treatment of hemodialysis autogenous fistula stenoses resistant to conventional percutaneous transluminal angioplasty (PTA). Materials and Methods In a prospective, randomized clinical trial involving patients with dysfunctional, stenotic hemodialysis arteriovenous fistulas (AVFs), patients were randomized to receive CBA or HPBA if conventional PTA had suboptimal results (ie, residual stenosis > 30%). A total of 516 patients consented to participate in the study from October 2008 to September 2011, 85% of whom (n = 439) had technically successful conventional PTA. The remaining 71 patients (mean age, 60 y; 49 men) with suboptimal PTA results were eventually randomized: 36 to the CBA arm and 35 to the HPBA arm. Primary and secondary target lesion patencies were determined by Kaplan-Meier analysis. Results Clinical success rates were 100% in both arms. Primary target lesion patency rates at 6 months were 66.4% and 39.9% for CBA and HPBA, respectively (P =.01). Secondary target lesion patency rates at 6 months were 96.5% for CBA and 80.0% for HPBA (P =.03). There was a single major complication of venous perforation following CBA. The 30-day mortality rate was 1.4%, with one non-procedure-related death in the HPBA group. Conclusions Primary and secondary target lesion patency rates of CBA were statistically superior to those of HPBA following suboptimal conventional PTA. For AVF stenoses resistant to conventional PTA, CBA may be a better second-line treatment given its superior patency rates. © 2014 SIR.Publication A fit-fat index for predicting incident diabetes in apparently healthy men: A prospective cohort study(Public Library of Science, 2016) Sloan R.A.; Haaland B.A.; Sawada S.S.; Lee I.-M.; Sui X.; Lee D.-C.; Ridouane Y.; Müller-Riemenschneider F.; Blair S.N.; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; DUKE-NUS MEDICAL SCHOOLBackground: The purpose of this study was to examine the impact of combined cardiorespiratory fitness and waist-to-height ratio in the form of a fit-fat index on incident diabetes risk. Additionally, the independent predictive performance of cardiorespiratory fitness, waist-to-height ratio, and body mass index also were estimated and compared. Methods: This was a prospective cohort study of 10,381 men who had a normal electrocardiogram and no history of major chronic disease at baseline from 1979 to 2005. Random survival forest models and traditional Cox proportional hazards models were used to predict diabetes at 5-, 10-, and 15-year incidence horizons. Results: Overall, 4.8% of the participants developed diabetes. Receiver operating characteristic curve analyses for incidence risk demonstrated good discrimination using random survival forest models across fitness and fatness measures; Cox models were poor to fair. The differences between fitness and fatness measures across horizons were clinically negligible. Smoothed random survival forest estimates demonstrated the impact of each fitness and fatness measure on incident diabetes was intuitive and graded. Conclusions: Although fitness and fatness measures showed a similar discriminative ability in predicting incident diabetes, unique to the study was the ability of the fit-fat index to demonstrate a better indication of incident risk when compared to fitness or fatness alone. A single index combining cardiorespiratory fitness and waist-to-height ratio may be more useful because it can indicate improvements in either or both of the measures. © 2016 Sloan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Publication Meta-analysis of first-line therapies with maintenance regimens for advanced non-small-cell lung cancer (NSCLC) in molecularly and clinically selected populations(2017) Tan, P.S; Bilger, M; Lopes, G.L; Acharyya, S; Haaland, B; DUKE-NUS MEDICAL SCHOOLEvidence has suggested survival benefits of maintenance for advanced NSCLC patients not progressing after first-line chemotherapy. Additionally, particular first-line targeted therapies have shown survival improvements in selected populations. Optimal first-line and maintenance therapies remain unclear. Here, currently available evidence was synthesized to elucidate optimal first-line and maintenance therapy within patient groups. Literature was searched for randomized trials evaluating first-line and maintenance regimens in advanced NSCLC patients. Bayesian network meta-analysis was performed within molecularly and clinically selected groups. The primary outcome was combined clinically meaningful OS and PFS benefits. A total of 87 records on 56 trials evaluating first-line treatments with maintenance were included. Results showed combined clinically meaningful OS and PFS benefits with particular first-line with maintenance treatments, (1) first-line intercalated chemotherapy+erlotinib, maintenance erlotinib in patients with EGFR mutations, (2) first-line afatinib, maintenance afatinib in patients with EGFR deletion 19, (3) first-line chemotherapy + bevacizumab, maintenance bevacizumab in EGFR wild-type patients, (4) chemotherapy+conatumumab, maintenance conatumumab in patients with squamous histology, (5) chemotherapy+cetuximab, maintenance cetuximab or chemotherapy + necitumumab, maintenance necitumumab in EGFR FISH-positive patients with squamous histology, and (6) first-line chemotherapy+bevacizumab, maintenance bevacizumab or first-line sequential chemotherapy+gefitinib, maintenance gefitinib in patients clinically enriched for EGFR mutations with nonsquamous histology. No treatment showed combined clinically meaningful OS and PFS benefits in patients with EGFR L858R or nonsquamous histology. Particular first-line with maintenance treatments show meaningful OS and PFS benefits in patients selected by EGFR mutation or histology. Further research is needed to achieve effective therapy for patients with EGFR mutation L858R or nonsquamous histology. © 2017 The Authors.Publication A meta-analysis of anastrozole in combination with fulvestrant in the first line treatment of hormone receptor positive advanced breast cancer(2013-04) Tan, P.S.; Haaland, B.; Montero, A.J.; Lopes, G.; DUKE-NUS GRADUATE MEDICAL SCHOOL S'POREFulvestrant is a highly active systemic therapy in patients with metastatic hormone receptor positive breast cancer. Preclinical work suggested potential synergy of fulvestrant in combination with aromatase inhibitor therapy and delayed development of endocrine resistance. The purpose of this meta-analysis is to evaluate the effectiveness of fulvestrant plus anastrozole, compared to anastrozole alone, as first line treatment of postmenopausal stage IV hormone receptor positive, HER2-negative breast cancer. The literature search was performed using PubMed, Google Scholar, Embase, ASCO, and ESMO to search for abstracts published during the last 10 years using relevant keywords. Two prospective randomized clinical trials were found to fulfill the search criteria for combination of anastrozole plus fulvestrant versus anastrozole alone. Meta-estimates were calculated by combining study estimates using the DerSimonian and Laird random effects model. The linear mixed-effects model was used to generate 95 % prediction intervals (PIs) for study-specific hazard and odds ratios. Pooled hazard ratio for progression-free survival is 0.88 (95 % CI 0.72-1.09, 95 % PI 0.65-1.21), overall survival 0.88 (95 % CI 0.72-1.08, 95 % PI 0.68-1.14) and pooled odds ratio for response rate is 1.13 (95 % CI 0.79-1.63, 95 % PI 0.78-1.65). A non-significant trend was observed with anastrozole plus fulvestrant being only marginally better than anastrozole alone in the endpoints of: progression-free survival, overall survival, and response rates. Based on these data, there is not solid evidence that the addition of fulvestrant at a dose of 250 mg monthly is better than anastrozole alone as first line therapy in women with postmenopausal hormone receptor positive breast cancer. © 2013 Springer Science+Business Media New York.Publication Meta-analysis of first-line therapies in advanced non-small-cell lung cancer harboring EGFR-activating mutations(2014) Haaland, B.; Tan, P.S.; De Castro Jr., G.; Lopes, G.; DUKE-NUS GRADUATE MEDICAL SCHOOL S'POREINTRODUCTIONPublication Design and baseline characteristics of participants in the TRial of Economic Incentives to Promote Physical Activity (TRIPPA): A randomized controlled trial of a six month pedometer program with financial incentives(Elsevier, 2015) Finkelstein, Eric Andrew; Aarti Sahasranaman; John Geraldine; Benjamin Adam Haaland; Marcel Bilger; Sloan, Robert A.; Nang, Ei Ei Khaing; Evenson, Kelly R.; DUKE-NUS GRADUATE MEDICAL SCHOOL S'PORE
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