Outcomes of adolescents with acute lymphoblastic leukaemia.

INTRODUCTION: Compared with young children who have acute lymphoblastic leukaemia (ALL), adolescents with ALL have unfavourable disease profiles and worse survival. However, limited data are available regarding the characteristics and outcomes of adolescents with ALL who underwent treatment in clinical trials. The aim of this study was to investigate the causes of treatment failure in adolescents with ALL. METHODS: We retrospectively analysed the outcomes of 711 children with ALL, aged 1-18 years, who were enrolled in five clinical trials of paediatric ALL treatment between 1993 and 2015. RESULTS: Among the 711 children with ALL, 530 were young children (1-9 years at diagnosis) and 181 were adolescents (including 136 younger adolescents [10-14 years] and 45 older adolescents [15-18 years]). Compared with young children who had ALL, adolescents with ALL were less likely to have favourable genetic features and more likely to demonstrate poor early response to treatment. The 10-year overall survival and event-free survival rates were significantly lower among adolescents than among young children (77.9% vs 87.6%, P=0.0003; 69.7% vs 76.5%, P=0.0117). There were no significant differences in the 10-year cumulative incidence of relapse, but the 10-year cumulative incidence of treatment-related death (TRD) was significantly greater among adolescents (7.2%) than among young children (2.3%; P=0.002). Multivariable analysis showed that both younger and older adolescents (vs young children) had worse survival and greater incidence of TRD. CONCLUSION: Adolescents with ALL had worse survival because they experienced a greater incidence of TRD. There is a need to investigate optimal treatment adjustments and novel targeted agents to achieve better survival rates (without excessive toxicity) among adolescents with ALL.

Prospective validation of a novel visual analogue uroflowmetry score (VAUS) in 1000 men with lower urinary tract symptoms (LUTS).

INTRODUCTION AND AIMS: Family physicians are limited by lack of tools to monitor benign prostate hyperplasia. VAUS provides a cost-effective, easily administered non-invasive tool. Our primary aim was to validate VAUS correlation with uroflowmetry measured maximal flow rate (Qmax), voided volume and International Prostate Symptom Scores (IPSS) symptom scores. Secondary aim was to study how the VAUS fared at predicting poor flow (Qmax < 10 ml/s) compared to age, voided volume and IPSS. Tertiary aim was to predict the best VAUS as a cutoff for poor flow. METHODS: After IRB approval, 1000 patients were prospectively recruited. They had VAUS, uroflowmetry and IPSS performed. VAUS is a novel five-point visual analogue scoring of urine flow, with one being the weakest and five the strongest. Data were analysed using SPSS where spearman's correlation coefficient and logistic regression analysis were performed looking for significance. Receiver operating curves (ROC) curves were used to identify best VAUS cutoff. RESULTS: 1000 patients were studied with mean age of 68.99 (50-95). VAUS showed good correlation with Qmaxp < 0.001, voided volume p = 0.006 and IPSS p <0.001. On multivariate analysis both VAUS and voided volume predicted poor flow significantly with p value of<0.001 and p =0.001, respectively. On ROC analysis VAUS of 2.5 was identified as best value for predicting poor flow with p value <0.001. CONCLUSION: VAUS is a validated tool for monitoring of lower urinary tract symptoms in our patients showing significant correlation with uroflowmetry, voided volume and IPSS.

Feature tracking for assessment of diastolic function by cardiovascular magnetic resonance imaging.

AIM: To assess the agreement of cardiovascular magnetic resonance imaging (CMRI) feature-tracking (FT) parameters with echocardiography to diagnose diastolic dysfunction; to determine whether a similar parameter to mitral inflow early diastolic velocity to early diastolic tissue velocity ratio (E/e') can increase accuracy of imaging by dividing the phase contrast (PC) mitral inflow E-wave (E) with a CMRI-FT parameter; to compare the agreement between CMRI-FT and PC diastolic function assessment using echocardiography. MATERIALS AND METHODS: Patients (n=71; 43 abnormal diastolic function) undergoing both CMRI and echocardiography independently were included. Echocardiography was the reference standard. CMRI-FT analysed the short and long axis cine contours. PC images of mitral inflow, tissue velocity, pulmonary vein flow, and left atrial area were assessed. RESULTS: Using CMRI-FT, the area under the curve (AUC) for identifying diastolic dysfunction was >0.80 for radial and circumferential strain, systolic strain rate (SSR), and early diastolic strain rate (DSR). For cases with CMRI-determined left ventricular ejection fraction (LVEF) ≥50% (n=38), circumferential DSR was the only parameter with good accuracy (AUC=0.87; cut-off 0.93/s). E/circumferential DSR ratio and longitudinal strain had high accuracy in all patients (AUC=0.88 and 0.93 respectively) and CMRI-determined LVEF ≥50% (AUC=0.81; cut-off 76.7). Circumferential DSR showed the highest agreement with echocardiography (higher than E/circumferential DSR and PC assessment) in all cases (kappa 0.75; p<0001) and cases with CMRI LVEF ≥50% (kappa 0.73; p<0.0001). CONCLUSIONS: CMRI-FT circumferential DSR showed the highest accuracy for determining diastolic dysfunction with good agreement with echocardiography. Circumferential DSR had higher accuracy than E/circumferential DSR and PC.

Salvaging the chemoport using catheter-assisted deflection during stenting of the superior vena cava.

Patients with malignancy who develop superior vena cava (SVC) obstruction may require stenting to relieve their symptoms. Some of these individuals also have an indwelling chemoport for concomitant chemotherapy. We present a case where stenting was accomplished after catheter-assisted deflection of the chemoport catheter tubing via a single groin access. It can save procedure time whilst salvaging the device.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic oesophageal cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and covered the management and treatment of local/locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of gastric cancer (GC) was published in 2016, and covered the management and treatment of local, locoregional, locally advanced and metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and The Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic GC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic GC representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Incidence and mortality of nasopharyngeal carcinoma: interim analysis of a cluster randomized controlled screening trial (PRO-NPC-001) in southern China.

BACKGROUND: Previous mass screening studies have shown that IgA antibodies against Epstein-Barr Virus (EBV) can facilitate early detection of nasopharyngeal carcinoma (NPC), but the impact of EBV-antibody screening for NPC-specific mortality remains unknown. PATIENTS AND METHODS: A prospective, cluster randomized, controlled trial for NPC screening (PRO-NPC-001) was conducted in 3 selected towns of Zhongshan City and 13 selected towns of Sihui City in southern China beginning in 2008. Serum samples of the screening group were tested for two previously selected anti-EBV antibodies. Subjects with serological medium risk were subsequently retested annually for 3 years, and those with serological high risk were referred to otorhinolaryngologists for diagnostic check-up. An interim analysis was carried out to evaluate the primary end points of the NPC-specific mortality and the early diagnostic rate, and the secondary end point of the NPC incidence, through linkage with the database of Zhongshan City. RESULTS: Among 70 296 total subjects, 29 413 screened participants (41.8% of the total subjects) in the screening group and 50 636 in the control group, 153 (43.3 per 100 000 person-year), 62 (55.3 per 100 000 person-year) and 99 (33.1 per 100 000 person-year) NPC cases were identified. The early diagnostic rates of NPC were significantly higher in the participants (79.0%, P < 0.0001) and the screening group (45.9%, P < 0.0001) compared with the control group (20.6%). Although no differences were found between NPC-specific mortality of the screening group and the control group [relative risk (RR)= 0.82, 95% confidence interval (CI) 0.37-1.79], lower NPC-specific mortality was noticed among participants from the screening group versus the control group (RR = 0.22, 95% CI 0.09-0.49). CONCLUSION: IgA antibodies against EBV can identify high-risk population and was effective in screening for early asymptomatic NPC. Although the mortality reduction was not significant in the primary end point, we noted encouraging evidence of a mortality reduction in screening participants in this interim analysis. CLINICAL TRIAL NUMBER: NCT00941538.

Tunneled catheter (PleurX) for long-term chest and abdominal drainages from 2012-2017 in a tertiary institution.

The PleurX catheter was developed to facilitate long-term intermittent drainage of malignant pleural effusion or ascites. For palliation, it is important that the process of insertion is safe and that this catheter remains complicationfree so as to improve end-of-life quality. We show that this catheter can be safely inserted and discuss methods to reduce infection, which was the most common complication. Our article hopes to enlighten clinicians, patients and their caregivers of this device as a treatment option in palliative patients. Proper case selection and caregiver training are essential in ensuring a successful outcome.

Validation of cardiac magnetic resonance tissue tracking in the rapid assessment of RV function: a comparative study to echocardiography.

AIM: To investigate the accuracy of cardiac magnetic resonance (CMR) tissue tracking (CMR-TT) and speckle tracking echocardiography (STE) against CMR determined right ventricular (RV) ejection fraction (RVEF) and to identify an optimal cut-off value for STE and CMR-TT to determine RVEF <45% and compare this to other conventional methods for estimating RVEF in dilated cardiomyopathy (DCM) patients. MATERIALS AND METHODS: Twenty-nine DCM patients were recruited prospectively. CMR and echocardiography were performed within 48 hours and four-chamber views were used for strain analysis. Contoured CMR short axis images provided RVEF. Intraclass correlation coefficient (ICC), bias, levels of agreement, and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: CMR-TT RV free-wall longitudinal strain (FLS) and STE RV global longitudinal strain (GLS) showed the best correlation with RVEF (r=-0.68, r=-0.82, p<0.001 respectively). There was moderate correlation between echocardiography RV GLS and CMR RV FLS (r=0.64, p<0.001). CMR-TT FLS showed excellent intra-observer and interobserver reliability (ICC=0.980; ICC=0.968 respectively). STE GLS correlated better with RVEF than with peak systolic annular velocity (S'; r=0.45), tricuspid annular plane systolic excursion (TAPSE; r=0.56), and fractional area change (FAC; r=0.78). CMR-TT RV FLS had better correlation with RVEF than CMR TAPSE (r=0.69 versus 0.40). ROC analysis demonstrated the optimal cut-off value for CMR-TT RV FLS and STE GLS in detection of RVEF <45% was ≥-24.4% (area under the curve=0.87, 100% sensitivity, 66.7% specificity) and ≥-20.9% (area under the curve=0.88, 100% sensitivity, 60% specificity) respectively. CONCLUSION: CMR-TT FLS and STE GLS showed potential to provide rapid assessment of RV function and had superior correlation with RVEF compared to conventional parameters.

Prioritising action on occupational carcinogens in Europe: a socioeconomic and health impact assessment.

BACKGROUND: Work-related cancer is an important public health issue with a large financial impact on society. The key European legislative instrument is the Carcinogens and Mutagens Directive (2004/37/EC). In preparation for updating the Directive, the European Commission commissioned a study to provide a socioeconomic, health and environmental impact assessment. METHODS: The evaluation was undertaken for 25 preselected hazardous substances or mixtures. Estimates were made of the number of cases of cancer attributable to workplace exposure, both currently and in the future, with and without any regulatory interventions, and these data were used to estimate the financial health costs and benefits. RESULTS: It was estimated that if no action is taken there will be >700 000 attributable cancer deaths over the next 60 years for the substances assessed. However, there are only seven substances where the data suggest a clear benefit in terms of avoided cancer cases from introducing a binding limit at the levels considered. Overall, the costs of the proposed interventions were very high (up to [euro ]34 000 million) and the associated monetised health benefits were mostly less than the compliance costs. CONCLUSIONS: The strongest cases for the introduction of a limit value are for: respirable crystalline silica, hexavalent chromium, and hardwood dust.

Glutamic acid decarboxylase and islet antigen 2 antibody profiles in people with adult-onset diabetes mellitus: a comparison between mixed ethnic populations in Singapore and Germany.

AIM: To gain insight into the presence of islet cell autoimmunity in an ethnic Asian compared with a white European population. METHODS: For this cross-sectional study we recruited people with adult-onset diabetes (age of diagnosis 20-60 years), at tertiary referral centres in Germany (n=1020) and Singapore (n=1088). Glutamic acid decarboxylase and islet antigen 2 antibodies were measured according to Islet Autoantibody Standardization Program protocols. RESULTS: The prevalence of glutamic acid decarboxylase antibody positivity was 13.9% (95% CI 12.1-16.0; P<0.001) in the white European cohort compared with 6.8% (95% CI 5.5-8.4; P<0.001) in the Asian cohort. Glutamic acid decarboxylase antibody positivity was 11.4% (95% CI 7.7-16.6) in Indian, 6.0% (95% CI 3.6-9.9) in Malay and 5.8% (95% CI 4.3-7.7; P<0.001) in Chinese participants. In the white European participants, the prevalence of islet antigen 2 antibody positivity was 7.8% (95% CI 6.4-9.4) compared with 14.8% (95% CI 12.8-17.0; P<0.001) in the Asian cohort as a whole, and among the three ethnicities in the Asian cohort it was 12.4% (95% CI 8.6-17.7) in Indian, 16.8% (95% CI 12.6-22.2) in Malay and 15.7% (95% CI 13.2-18.6) in Chinese participants. Double antibody positivity was seen in 5.7% (95% CI 4.5-7.1) of white European participants compared with 1.6% (95% CI 1.0-2.5; P<0.01) of Asian participants. In the white European cohort, those who were glutamic acid decarboxylase autoantibody-positive had a lower BMI than those who were autoantibody-negative, but this trend was absent in the Asian cohort. CONCLUSIONS: A marked prevalence of islet cell autoimmunity was observed in people with adult-onset diabetes. While glutamic acid decarboxylase antibodies were more frequent in the European cohort, islet antigen 2 antibody positivity was highest in the three ethnic groups in Singapore, suggesting ethnic-specific differences in antibody profiles.

High risk of conversion to diabetes in first-degree relatives of individuals with young-onset type 2 diabetes: a 12-year follow-up analysis.

AIM: Family history of diabetes is an established risk factor for Type 2 diabetes, but the impact of a family history of young-onset diabetes (onset < 40 years) on future risk of diabetes among first-degree relatives is unclear. In this prospective study, we examined the influence of family history of late- versus young-onset diabetes on the development of diabetes in a young to middle-aged Chinese population. METHODS: Some 365 siblings identified through probands with Type 2 diabetes and 452 participants from a community-based health awareness project (aged 18-55 years) who underwent metabolic assessment during the period 1998-2002 were followed to 2012-2013 to determine their glycaemic status. Multivariate logistic regression was performed to investigate the association of family history of diabetes presented at different age categories with development of diabetes. RESULTS: In this cohort, 53.4% (n = 167) of participants with a family history of young-onset diabetes, 30.1% (n = 68) of those with a family history of late-onset diabetes and 14.4% (n = 40) of those without a family history developed diabetes. Using logistic regression, family history of diabetes presented at ages ≥ 50, 40-49, 30-39 and < 30 years, increased conversion to diabetes with respective odds ratios of 2.4, 5.8, 9.4 and 7.0 (P < 0.001 for all), after adjustment for socio-economic status, smoking, obesity, hypertension and dyslipidaemia. Among participants without diabetes at baseline, risk association of family history of late-onset diabetes with incident diabetes was not sustained, whereas that of family history of young-onset diabetes remained robust on further adjustment for baseline glycaemic measurements. CONCLUSIONS: First-degree relatives of people with Type 2 diabetes, especially relatives of those with young-onset diabetes, are at high risk for diabetes.

Dogfish glucagon analogues counter hyperglycaemia and enhance both insulin secretion and action in diet-induced obese diabetic mice.

AIMS: To investigate the antidiabetic actions of three dogfish glucagon peptide analogues [known glucagon-like peptide-1 and glucagon receptor co-agonists] after chronic administration in diet-induced high-fat-diet-fed diabetic mice. MATERIALS AND METHODS: National Institutes of Health Swiss mice were pre-conditioned to a high-fat diet (45% fat) for 100 days, and control mice were fed a normal diet (10% fat). Normal diet control and high-fat-fed control mice received twice-daily intraperitoneal (i.p.) saline injections, while the high-fat-fed treatment groups (n = 8) received twice-daily injections of exendin-4(1-39), [S2a]dogfish glucagon, [S2a]dogfish glucagon exendin-4(31-39) or [S2a]dogfish glucagon-Lys(30) -γ-glutamyl-PAL (25 nmol/kg body weight) for 51 days. RESULTS: After dogfish glucagon analogue treatment, there was a rapid and sustained decrease in non-fasting blood glucose and an associated insulinotropic effect (analysis of variance, p < .05 to <.001) compared with saline-treated high-fat-fed controls. All peptide treatments significantly improved i.p. and oral glucose tolerance with concomitant increased insulin secretion compared with saline-treated high-fat-fed controls (p <.05 to <.001). After chronic treatment, no receptor desensitization was observed but insulin sensitivity was enhanced for all peptide-treated groups (p < .01 to <.001) except [S2a]dogfish glucagon. Both exendin-4 and [S2a]dogfish glucagon exendin-4(31-39) significantly reduced plasma triglyceride concentrations compared with those found in lean controls (p = .0105 and p = .0048, respectively). Pancreatic insulin content was not affected by peptide treatments but [S2a]dogfish glucagon and [S2a]dogfish glucagon exendin-4(31-39) decreased pancreatic glucagon by 28%-34% (p = .0221 and p = .0075, respectively). The percentage of ß-cell area within islets was increased by exendin-4 and peptide analogue treatment groups compared with high-fat-fed controls and the ß-cell area decreased (p < .05 to <.01). CONCLUSIONS: Overall, dogfish glucagon co-agonist analogues had several beneficial metabolic effects, showing therapeutic potential for type 2 diabetes.

Thymic carcinoma presenting with an unusual and delayed metastasis to the neural foramen, mimicking thoracic spinal radiculopathy.

We report a case of metastatic thymic carcinoma which presented as an enhancing mass located in the neural foramen of the thoracic spine. More common tumours which arise in the neural foramen would include a neurogenic tumour or developmental anomalies such as a foregut duplication cyst. This case is singular firstly because the lesion present as radiculopathy which mimics a neurogenic tumour. Secondly, the presentation was unusually delayed as the patient presented to our centre more than a decade after the resection of the primary tumour in another institution.

Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer.

BACKGROUND: Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ∼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort. METHODS: PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response. RESULTS: PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1ß, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002). CONCLUSIONS: In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.

Improved functional assessment of osteoarthritic knee joint after chondrogenically induced cell treatment.

OBJECTIVES: Our previous studies on osteoarthritis (OA) revealed positive outcome after chondrogenically induced cells treatment. Presently, the functional improvements of these treated OA knee joints were quantified followed by evaluation of the mechanical properties of the engineered cartilages. METHODS: Baseline electromyogram (EMGs) were conducted at week 0 (pre-OA), on the locomotory muscles of nine un-castrated male sheep (Siamese long tail cross) divided into controls, adipose-derived stem cells (ADSCs) and bone marrow stem cells (BMSCs), before OA inductions. Subsequent recordings were performed at week 7 and week 31 which were post-OA and post-treatments. Afterwards, the compression tests of the regenerated cartilage were performed. RESULTS: Post-treatment EMG analysis revealed that the control sheep retained significant reductions in amplitudes at the right medial gluteus, vastus lateralis and bicep femoris, whereas BMSCs and ADSCs samples had no further significant reductions (P < 0.05). Grossly and histologically, the treated knee joints demonstrated the presence of regenerated neo cartilages evidenced by the fluorescence of PKH26 tracker. Based on the International Cartilage Repair Society scores (ICRS), they had significantly lower grades than the controls (P < 0.05). The compression moduli of the native cartilages and the engineered cartilages differed significantly at the tibia plateau, patella femoral groove and the patella; whereas at the medial femoral condyle, they had similar moduli of 0.69 MPa and 0.40-0.64 MPa respectively. Their compression strengths at all four regions were within ±10 MPa. CONCLUSION: The tissue engineered cartilages provided evidence of functional recoveries associated to the structural regenerations, and their mechanical properties were comparable with the native cartilage.

Low Barrier Carbon Induced CO Dissociation on Stepped Cu.

Using x-ray photoelectron spectroscopy we observe the breaking of the strong interatomic bond in molecular CO at low temperature on a stepped Cu surface. Since the electronic structure of Cu does not allow for the splitting of CO at such low temperatures it suggests that there may be a less obvious pathway for the process. Through x-ray photoelectron spectroscopy we can clearly identify products associated with the dissociation of CO and the subsequent formation of stable graphitic carbon on the surface. However, the dissociation of CO can be inhibited when the stepped Cu surface is kept clean from surface carbon. These observations imply that the reaction is driven by the presence of small amounts of weakly bound carbon at the surface. Density-functional theory calculations confirm that carbon atoms on a stepped Cu surface indeed are the preferred adsorption sites for CO, which increases the stabilization of CO on the surface and weakens the C-O bond. This results in the breaking of the C-O bond at the step edge via the Boudouard reaction (2CO(ads)→C(ads)+CO(2)) with a barrier of 0.71 eV.