A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial.

BACKGROUND: While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance. PATIENTS AND METHODS: BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS: Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively. CONCLUSIONS: No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination.

Accuracy of radiographer comment following a two-month experiential and blended learning in appendicular skeleton X-ray interpretation: The Singapore experience.

INTRODUCTION: The value of combined blended and experiential learning on radiographer diagnostic comment has not been explored. This study aims to examine the accuracy of image interpretation comment of radiographers who received a period of blended and experiential learning in Radiographer Abnormality Detection Systems (RADS). METHODS: We evaluated the diagnostic opinions of 13 radiographers who received a blended training and experiential learning (a process of self-learning and reflection) in RADS. Radiographers' opinions on 16,483 images were examined using the final radiologists' report as a reference standard. For each radiographer, we recorded the number of true positive, true negative, false positive and false negative opinions and MedCal® was used to calculate diagnostic performance and error rates. A t-test was used to assess whether the number of images read was associated with performance and whether the radiographers retained performance over time. RESULTS: Sensitivity ranged from 87.4 (84.0-90.2) to 98.9 (97.5-99.7) with a mean of 94.3 (93.6-94.8). Specificity varied from 96.4 (94.8-97.5) to 99.9 (99.41-100.0) with a mean of 98.2 (97.9-98.4). Diagnostic accuracy ranged from 93.1 (91.5-94.4) to 99.5 (98.9-99.8) with a mean of 96.9 (96.6-97.1). The mean false positive rate was 0.018 (range: 0.010-0.031) with a false negative rate of 0.057 (range: 0.026-0.11). There were no differences in performance between the first and latter nine months of providing opinions and the number of images reviewed was not associated with performance. CONCLUSION: Radiographers who received blended and experiential learning in RADS provide accurate diagnostic comments on plain emergency appendicular skeleton radiographs. IMPLICATION FOR PRACTICE: A combined blended and experiential learning can equip radiographers to provide diagnostic opinion on plain appendicular skeleton radiographs.

The impact of impulsivity on weight loss after bariatric surgery: a systematic review.

BACKGROUND: Impulsivity has been shown to be associated with obesity through links to pathological eating behavior such as binge eating. The recent literature suggests that impulsivity is linked to poorer outcomes post-bariatric surgery. Impulsivity can be measured in various ways and comprises of three broad domains: impulsive choice, impulsive action, and impulsive personality traits. The aim of this systematic review is to synthesize the current evidence on the impact of impulsivity on post-bariatric surgery weight loss. METHODS: A literature review was performed in February 2020. Original studies investigating the relationship between impulsivity and weight loss post-bariatric surgery were evaluated. RESULTS: Ten studies with a total of 1246 patients were analyzed. There were four case-control, four prospective observational and two retrospective observational studies. The postoperative follow-up ranged from 0.5 to 12 years. Eight studies measuring trait impulsivity did not show any association with weight loss post-bariatric surgery, although two studies reported an indirect effect of impulsivity on weight loss mediated via pathological eating behavior. Assessment of impulsive action by two studies showed that post-bariatric surgery weight loss is affected by impulsive action. CONCLUSION: Impulsivity may adversely affect postoperative outcomes after bariatric surgery. However, this may be specific to state impulsivity or impulsive action rather than trait impulsivity. Patients with a higher state impulsivity may benefit from closer follow-up post-bariatric surgery, as well as cognitive behavioral therapies targeting cognitive control over food. LEVEL OF EVIDENCE: Level I, systematic review.

Accuracy of parent-reported ages and stages questionnaire in assessing the motor and language skills of preterm infants.

BACKGROUND: Parent-completed tools like the Ages and Stages Questionnaire Third Edition (ASQ-3) are important in developmental screening. As a screening tool, a high negative predictive value (NPV) is critical to avoid missing the diagnosis of developmental delay. This study evaluated the NPV and accuracy of the ASQ-3 in assessing the development of preterm infants. METHODS: Infants born at <32 weeks and/or <1250 grams, presenting to the Neonatal Neurodevelopmental Clinic at the Singapore General Hospital for follow-up from January 2014 to June 2017, at 6, 12, and 18 months corrected age, were included. The ASQ-3 and standardized tests - Peabody Developmental Motor Scale-Second Edition (PDMS-2) and Preschool Language Scale, Fourth Edition UK (PLS-4 UK) - were administered. ASQ-3 gross motor and fine motor scores were compared to PDMS-2 at 6 and 12 months, and ASQ-3 communication scores to PLS-4 UK at 18 months. RESULTS: At 6 months (n = 145), NPV for gross motor and fine motor were 96.4% (accuracy 80.0%) and 95.4% (accuracy 77.2%) respectively. At 12 months (n = 127), NPV for gross motor and fine motor were 88.9% (accuracy 79.8%) and 82.8% (accuracy 74.0%) respectively. At 18 months (n = 113), NPV for language was 56.9% (accuracy 63.7%). CONCLUSIONS: The ASQ-3 showed high NPV and accuracy in screening gross motor and fine motor skills at 6 and 12 months, but not in screening language skills at 18 months. Judicious use of the ASQ-3 may allow for more effective utilization of resources.

Effect of direct defect closure during laparoscopic inguinal hernia repair ("TEP/TAPP plus" technique) on post-operative outcomes.

PURPOSE: Seroma formation and recurrence in large inguinal hernia still remain an important clinical complication despite decades since the advent of mesh repair. METHODS: In our prospective comparative analysis, we want to evaluate the effect of direct hernia defect closure on surgical outcomes in patients undergoing laparoscopic inguinal hernia repair in two tertiary care institutions in Singapore. The direct hernia defects were closed with non-absorbable sutures incorporating the pseudosac. RESULTS: A group of 241 patients underwent laparoscopic inguinal hernia mesh repair for a total of 378 direct defects from April 2014 to July 2018. Of these patients, 98 (40.6%) patients underwent hernia repair without closure of their direct defect while 143 (59.4%) patients underwent direct defect closure. No significant differences were observed between the two patient populations' demographic information and the mean operative time. A total of 219 direct defects were closed and 159 direct defects were not repaired. Compared to the group that did not undergo direct defect closure, the group that had closure of the direct defects demonstrated a statistically significant reduction in recurrence (4.4% versus 0.9%, p = 0.036) and seroma formation (12.6% versus 6.4%, p = 0.045). CONCLUSION: Direct defect closure has proven to be effective in reducing recurrence and seroma formation post-operatively in patients undergoing laparoscopic inguinal hernia repair. Randomized controlled trials will be required to further evaluate these outcomes.

Early entrapment of fourth ventricle following Pseudomonas meningitis in extreme prematurity: Case report.

Trapped fourth ventricle (TFV) as a complication of post-hemorrhagic hydrocephalus (PHH) is widely reported in the pediatric population with a prior history of ventriculo-peritoneal (VP) shunt placement. Characterized by disproportionate dilatation of the fourth ventricle on serial neuro-imaging, it is rarely encountered in the early course of preterm infants and the differentiating clinical features are subtle and non-specific. Clinical alertness and sonographic correlation hold the key to early diagnosis. We report an early emergence of TFV in an extremely low gestational age newborn (ELGAN) following fulminant Pseudomonas aeruginosa meningitis, approach to management, and the neurological outcome. Fourth ventricle entrapment as a complication of perinatally acquired Pseudomonas aeruginosa meningitis in a surviving ELGAN is extremely rare.

Diffuse Speckle Contrast Analysis Assisted Intraoperative Blood Flow Monitoring in the Rat Model of Femoral Arterial Occlusion.

The rodent model has been largely used for understanding specific disease pathophysiology, with low cost and the large spectrum from genetic strains. Here, we present a diffuse speckle contrast analysis (DSCA) system to measure blood flow changes non-invasively in rat's thigh and paw during femoral arterial occlusion (FAO) surgery which is the procedure for inducing peripheral arterial disease. The blood flow index in rat's paw showed significant decrease according to arterial occlusion. Moreover, we analyzed cross-correlation between two measurement positions. The results showed the affinity with hemodynamic response. In conclusion, the DSCA system secured the intraoperative blood flow monitoring during FAO surgery in a rat model.

Angiosome based time series analysis of deep tissue perfusion using diffuse speckle contrast analysis.

An angiosome is a three dimensional volume of biological tissue which a specific artery governs. Although proven useful for vascular surgery, the direct relationship between arterial flow and microcirculation in specific angiosome remains controversial. Here, we present new optical approach, a four-channel diffuse speckle contrast analysis (DSCA) which can simultaneously measure blood perfusion at different foot area. Based on the hypothesis that same angiosome will support similar low frequency oscillation, we investigated cross-correlation among different DSCA channels. Our preliminary results show that the LFO signal from the channel closest to posterior tibial artery is leading the signal from the other channels.

The mRNA-binding protein HuR promotes hypoxia-induced chemoresistance through posttranscriptional regulation of the proto-oncogene PIM1 in pancreatic cancer cells.

Previously, it has been shown that pancreatic ductal adenocarcinoma (PDA) tumors exhibit high levels of hypoxia, characterized by low oxygen pressure (pO2) and decreased O2 intracellular perfusion. Chronic hypoxia is strongly associated with resistance to cytotoxic chemotherapy and chemoradiation in an understudied phenomenon known as hypoxia-induced chemoresistance. The hypoxia-inducible, pro-oncogenic, serine-threonine kinase PIM1 (Proviral Integration site for Moloney murine leukemia virus 1) has emerged as a key regulator of hypoxia-induced chemoresistance in PDA and other cancers. Although its role in therapeutic resistance has been described previously, the molecular mechanism behind PIM1 overexpression in PDA is unknown. Here, we demonstrate that cis-acting AU-rich elements (ARE) present within a 38-base pair region of the PIM1 mRNA 3'-untranslated region mediate a regulatory interaction with the mRNA stability factor HuR (Hu antigen R) in the context of tumor hypoxia. Predominantly expressed in the nucleus in PDA cells, HuR translocates to the cytoplasm in response to hypoxic stress and stabilizes the PIM1 mRNA transcript, resulting in PIM1 protein overexpression. A reverse-phase protein array revealed that HuR-mediated regulation of PIM1 protects cells from hypoxic stress through phosphorylation and inactivation of the apoptotic effector BAD and activation of MEK1/2. Importantly, pharmacological inhibition of HuR by MS-444 inhibits HuR homodimerization and its cytoplasmic translocation, abrogates hypoxia-induced PIM1 overexpression and markedly enhances PDA cell sensitivity to oxaliplatin and 5-fluorouracil under physiologic low oxygen conditions. Taken together, these results support the notion that HuR has prosurvival properties in PDA cells by enabling them with growth advantages in stressful tumor microenvironment niches. Accordingly, these studies provide evidence that therapeutic disruption of HuR's regulation of PIM1 may be a key strategy in breaking an elusive chemotherapeutic resistance mechanism acquired by PDA cells that reside in hypoxic PDA microenvironments.

Isolated fallopian tube torsion in prepubertal females.

Isolated fallopian tube torsion is an uncommon diagnosis. It is particularly rare in the paediatric and post-menopausal age groups. It lacks pathognomonic symptoms, signs and imaging findings, yet each of these diagnostic steps plays a crucial role in early diagnosis. We describe two cases of isolated fallopian tube torsion in prepubertal females.

Measurement of vital sign in chick embryo using multi-channel diffuse speckle contrast analysis.

In poultry industry which is avian breeding program, the determination whether chick embryos survive in the artificial incubation periods or not is essential to reduce the financial resources. We developed the multi-channel diffuse speckle contrast analysis (DSCA) system composed of four optical fiber detectors enabling to achieve in-vivo measurements of deep tissue flow noninvasively. The system could confirm vital sign of the chick embryo in early incubation stage. Moreover, it demonstrates the change of relative blood flow index and depth information with simplicity, low cost, and flexibility.

Development of the dual SMART micro-surgical system using common-path swept source optical coherence tomography.

Manual micro-surgical tasks are fundamentally divided into grasping, cutting and injecting maneuvers performed on biological tissues. Efficient dissection of fibrous tissue from the surface of the retina often requires grasping and cutting maneuvers carried out simultaneously. True bimanual surgery requires that the surgeon contend with the innate hand tremor of two hands at once as well as unpredicted patient's movement. In this study, we develop and test a dual SMART micro-surgical system to suppress bimanual hand tremor during micro-surgical dissection.

Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz.

The purpose of this study was to determine the demographic and pharmacogenetic covariates that influence the disposition of efavirenz (EFV) and its major metabolites. A population pharmacokinetic (PK) model was developed from a randomized, cross-over, drug-interaction study in healthy male Korean subjects (n = 17). Plasma concentrations of EFV and its hydroxy-metabolites (0-120 hours) were measured by LC/MS/MS. Genomic DNA was genotyped for variants in the cytochrome P450 (CYP) 2A6, 2B6, 3A5, and MDR1 genes. A PK model was built in a stepwise procedure using nonlinear mixed effect modeling in NONMEM 7. The covariate model was built using the generalized additive modeling and forward selection-backward elimination. Model-based simulations were performed to predict EFV steady-state concentrations following 200, 400, and 600 mg daily oral dose among different CYP2B6 genotypes. The final model included only CYP2B6 genotype as a covariate that predicts EFV clearance through the formation of 8-OH EFV that represented 65% to 80% of EFV clearance. The total clearance of EFV in CYP2B6*6/*6 genotype was ∼30% lower than CYP2B6*1/*1 or CYP2B6*1/*6 alleles (P < .001). Clopidogrel reduced both formation and elimination clearances of 8-OH EFV by 22% and 19%, respectively (P = .033 and .041). Other demographics and genotype of accessory CYP pathways did not predict EFV or metabolites PK. CYP2B6 genotype was the only significant predictor of EFV disposition. The developed model may serve as the foundation for further exploration of pharmacogenetic-based dosing of EFV.

Cervical sparganosis: case reports with focus on radiological findings.

BACKGROUND: Cervical sparganosis is a rare condition that presents as a lateral neck mass. Its radiological findings have not previously been investigated. Thus, the important radiological findings of cervical sparganosis are presented herein. METHODS: We report two patients with cervical sparganosis who presented with cervical masses, and we review the relevant head and neck literature. Computed tomography was performed three times over 13 months of follow up for one patient. RESULTS: On follow-up radiological examination, a migratory lesion with a tubular appearance, seen on serial images, should be considered significant for cervical sparganosis. CONCLUSION: Radiologically, a migratory cervical mass in the head and neck area with a tubular appearance is suggestive of cervical sparganosis.

Ministry of Health clinical practice guidelines: depression.

The Ministry of Health (MOH) have updated the clinical practice guidelines on Depression to provide doctors and patients in Singapore with evidence-based treatment for depression. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on Depression, for the information of readers of the Singapore Medical Journal. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/home/Publications/guidelines/cpg/2012/depression.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Prospective audit and feedback on antibiotic prescription in an adult hematology-oncology unit in Singapore.

We evaluated the impact of a prospective audit and feedback antimicrobial stewardship program (ASP) on antibiotic prescription and resistance trends in a hematology-oncology unit in a university hospital (National University Cancer Institute, Singapore [NCIS]). A prospective interrupted time-series study comprising 11-month pre-intervention (PIP) and intervention evaluation phases (IEP) flanking a one-month implementation phase was carried out. Outcome measures included defined daily dose per 100 (DDD/100) inpatient-days of ASP-audited and all antibiotics (encompassing audited and non-audited antibiotics), and the incidence-density of antibiotic-resistant microorganisms at the NCIS. Internal and external controls were DDD/100 inpatient-days of paracetamol at the NCIS and DDD/100 inpatient-days of antibiotics prescribed in the rest of the hospital. There were 580 ASP recommendations from 1,276 audits, with a mean monthly compliance of 86.9%. Significant reversal of prescription trends towards reduced prescription of audited (coefficient = -2.621; 95% confidence interval [CI]: -4.923, -0.319; p = 0.026) and all evaluated antibiotics (coefficient = -4.069; 95% CI: -8.075, -0.063; p = 0.046) was observed. No changes were seen for both internal and external controls, except for the reversal of prescription trends for cephalosporins hospital-wide. Antimicrobial resistance did not change over the time period of the study. Adverse outcomes-the majority unavoidable-occurred following 5.5% of accepted ASP recommendations. Safe and effective ASPs can be implemented in the complex setting of hematology-oncology inpatients.