Identification of non-actionable mutations with prognostic and predictive value in patients with advanced or metastatic non-small cell lung cancer.

INTRODUCTION: Lung cancer is one of the most prevalent cancers and the leading cause of cancer death. Advanced non-small cell lung cancer (aNSCLC) patients frequently harbor mutations that impact their survival outcomes. There are limited data regarding the prognostic and predictive significance of these mutations on survival outcomes in the real-world setting. METHODS: This observational retrospective study analyzed de-identified electronic medical records from the Flatiron Health Clinico-Genomic and FoundationCore® databases to identify patients with aNSCLC who initiated first-line immune checkpoint inhibitors (ICI; alone or in combination) or chemotherapy under routine care between 2016 and 2021. The primary objectives were to assess the prevalence of non-actionable mutations and to determine their association with overall survival (OS). Real-world progression-free survival (rwPFS) and real-world response (rwR) were investigated as secondary exploratory outcomes. RESULTS: Based on an assessment of 185 non-actionable mutations in 2999 patients, the most prevalent mutations were TP53 (70%), KRAS (42%), CDKN2A/B (31%), and STK11 (21%). STK11, KEAP1, and CDKN2A/B mutations were significantly associated with lower rwR, shorter rwPFS and OS. KRAS mutations were clinically associated with shorter rwPFS in CIT-treated patients. Subgroup analysis revealed that fast progressors were significantly more likely to harbor STK11, KEAP1, and CDKN2A/B mutations. Accordingly, long-term survivors (LTS) showed a significantly lower prevalence of these mutations. CONCLUSION: Our results provide evidence on the prognostic value of STK11, KEAP1, and CDKN2A/B mutations in patients with aNSCLC. Further research is required to better understand the implications of these findings on patient management and future trial design and treatment selection.

The effect of menopause on metabolic syndrome: cross-sectional results from the Canadian Longitudinal Study on Aging.

OBJECTIVES: Data were examined from women surveyed in the Canadian Longitudinal Study on Aging to evaluate whether menopause is an independent risk factor for the development of metabolic syndrome (MetS) or its components, including hypertension, central obesity, dyslipidemia, or elevated glycated hemoglobin. METHODS: We conducted a cross-sectional analysis of women aged 45-85 years old that participated in the baseline data of the Canadian Longitudinal Study on Aging Comprehensive Cohort collected from 2012 to 2015. Modified Poisson regression with robust error variance was used to estimate the crude and adjusted relative risks (aRRs) of MetS in postmenopausal women compared to premenopausal women. RESULTS: Among 12,611 women analyzed, 10,035 (79.6%) had undergone menopause and 2,576 (20.4%) were premenopausal. Postmenopausal women were more likely to meet criteria for MetS compared to premenopausal women (32.6% vs 20.5%, P < 0.001). Using the MetS criteria with a lower waist circumference threshold, the prevalence of MetS was higher at 38.2% among postmenopausal women and 23.2% among premenopausal women (P < 0.001). After adjusting for age, body mass index, and other covariates, the occurrence of menopause was not associated with a significantly higher relative risk of MetS, using the unified criteria for MetS (aRR 1.09 [95% CI: 0.99-1.19]). Women with menopause had a significantly higher relative risk of MetS when using criteria with a lower waist circumference (aRR 1.10 [95% CI: 1.01-1.19]). Menopause was also associated with a higher risk of impaired glucose tolerance (aRR 1.42 [95% CI: 1.26-1.59]), elevated blood pressure (aRR 1.12 [95% CI: 1.03-1.21]), and elevated triglycerides (aRR 1.17 [95% CI: 1.08-1.26]). CONCLUSION: Menopause is associated with an increased risk of MetS, independent of age. Lifestyle interventions targeted at women with MetS are known to prevent type 2 diabetes mellitus and cardiovascular risk. Perimenopause may be an important preventative care opportunity to assess metabolic risk factors and improve health and longevity of Canadian women.

Impact of diabetes, obesity and hypertension on preterm birth: Population-based study.

OBJECTIVE: To determine the impact of pre-pregnancy diabetes mellitus (D), obesity (O) and chronic hypertension (H) on preterm birth (PTB). METHODS: Retrospective population-based cohort study in Ontario, Canada between 2012-2016. Women who had a singleton livebirth or stillbirth at > 20 weeks gestation were included in the cohort. Exposures of interest were D, O and H, individually, and in various combinations. The primary outcome was PTB at 241/7 to 366/7 weeks. PTB was further analyzed by spontaneous or provider-initiated, early (< 34 weeks) or late (34-37 weeks), and the co-presence of preeclampsia, large for gestational age (LGA), and small for gestational age (SGA). Multivariable Poisson regression models with robust error variance were used to generate relative risks (RR), further adjusted for maternal age and parity (aRR). Population attributable fractions (PAF) were calculated for each of the outcomes by exposure state. RESULTS: 506,483 women were eligible for analysis. 30,139 pregnancies (6.0%) were complicated by PTB < 37 weeks, of which 7375 (24.5%) had D or O or H. Relative to women without D or O or H, the aRR for PTB < 37 weeks was higher for D (3.51; 95% CI 3.26-3.78) and H (3.81; 95% CI 3.55-4.10) than O (1.14; 95% CI 1.10-1.17). The combined state of DH was associated with a significantly higher aRR of PTB < 37 weeks (6.34; 95% CI 5.14-7.80) and < 34 weeks (aRR 10.33, 95% CI 6.96-15.33) than D alone. The risk of provider initiated PTB was generally higher than that for spontaneous PTB. Pre-pregnancy hypertension was associated with the highest risk for PTB with preeclampsia (aRR 45.42, 95% CI 39.69-51.99) and PTB with SGA (aRR 9.78, 95% CI 7.81-12.26) while pre-pregnancy diabetes was associated with increased risk for PTB with LGA (aRR 28.85, 95% CI 24.65-33.76). CONCLUSION: Combinations of DOH significantly magnify the risk of PTB, especially provider initiated PTB, and PTB with altered fetal growth or preeclampsia.

The relationship between maternal body mass index and pregnancy outcomes in twin compared with singleton pregnancies.

OBJECIVE: Women with twins have an a priori increased risk for many of the complications associated with maternal obesity. Thus, the impact of maternal obesity in twins may differ from that reported in singletons. In addition, given the increased metabolic demands in twin pregnancies, the impact of maternal underweight may be greater in twin compared with singleton gestations. Our objective was to test the hypothesis that the relationship between maternal pre-pregnancy body mass index (BMI) and adverse pregnancy outcomes differ between twin and singleton gestations. METHODS: This was a retrospective population-based study of all women who had a singleton or twin hospital birth in Ontario, Canada, between April 2012 and March 2016. Data were obtained from the Better Outcomes Registry & Network (BORN) Ontario. The relationship between maternal BMI category and pregnancy complications was assessed separately in twin and singleton gestations. The primary outcome was a composite variable that included any of the following complications: preeclampsia, gestational diabetes, or preterm birth before 320/7 weeks. Relative risk (aRR) and 95% confidence intervals (CI) for adverse outcomes for each BMI category as defined by WHO (using normal weight category as reference) were generated using modified Poisson regression, adjusting for maternal age, nulliparity, smoking, previous preterm birth, and fetal sex. RESULTS: A total of 487,870 women with singleton (n = 480,010) and twin (n = 7860) pregnancies met the inclusion criteria. The risk of the composite primary outcome, preeclampsia, gestational diabetes, and cesarean delivery increased with high maternal BMI in both singleton and twin gestations, but these associations were weaker in twin compared with singleton gestations (association of BMI ≥ 40.0 kg/m2 with primary outcome: aRR = 3.10, 95%-CI 2.96-3.24 in singletons compared with aRR = 1.74, 95%-CI 1.37-2.20 in twins). In singleton pregnancies the risk of preterm birth at < 320/7 weeks increased with maternal BMI, mainly due to an increased risk of provider-initiated preterm birth. In twin gestations, however, underweight (but not overweight or obesity) was associated with the greatest risk of preterm birth at < 32 weeks (aRR 1.67, 95%-CI 1.17-2.37), mainly due to an increased risk of spontaneous preterm birth (aRR 2.10, 95%-CI 1.44-3.08). CONCLUSION: In healthy women with twin pregnancies, underweight is associated with the greatest risk for preterm birth, while the association of maternal obesity with adverse pregnancy outcomes is weaker than that observed in singletons.

Trial of labor versus elective repeat cesarean delivery in twin pregnancies after a previous cesarean delivery-A systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review of success rates of trial of labor after cesarean (TOLAC) and maternal and neonatal outcomes in twin pregnancy versus elective repeat cesarean delivery (ERCD). METHODS: We searched MEDLINE, EMBASE, and Web of Science from data inception to May 2018 with no language or regional restrictions, to identify all studies that compared twin TOLAC and ERCD for maternal and/or neonatal outcomes. The Newcastle-Ottawa Scale was used to assess the methodological quality of the included studies. We assessed the pooled relative risk and mean difference using a random-effects model. The pooled event rates for successful VBAC, cesarean delivery for twin B after vaginal delivery of twin A, and uterine rupture were determined. RESULTS: Of the 841 citations identified, 10 were eligible for analysis (2336 TOLAC cases and 5763 ERCD cases). The pooled event rates for successful VBAC and uterine rupture during TOLAC were 72.2% (95% CI 59.7%-83.2%) and 0.87% (95% CI 0.51%-1.31%), respectively. TOLAC was associated with a significantly higher risk of neonatal death (RR 3.02 [95% CI 1.07-8.54]) with no significant differences in mean gestational age at birth, NICU admission rates, or 5-minute Apgar <7. Although the risk for maternal infectious morbidity was significantly lower with TOLAC (RR 0.48 [95% CI 0.25-0.90]), risks of uterine dehiscence, blood transfusions, and hysterectomy were comparable. CONCLUSIONS: Twin TOLAC is associated with a relatively high rate of successful vaginal delivery and a low risk of uterine rupture. The finding of higher neonatal mortality rates may be influenced by prematurity, but requires further investigation.

Weight gain during pregnancy: Does the antenatal care provider make a difference? A retrospective cohort study.

BACKGROUND: The primary aim of this study was to examine weight gain during pregnancy and associated adverse outcomes across different types of antenatal health care providers. Our research question examined whether type of antenatal health care provider (family physician, obstetrician, midwife, or family physician plus obstetrician) was associated with differing rates of excess or inadequate weight gain and associated adverse outcomes including being large for gestational age, being small for gestational age, cesarean delivery and preterm birth. METHODS: This retrospective cohort study used data from the Better Outcomes Registry & Network Information System, 2014-2016, for singleton hospital births at 20-42 weeks' gestation in Ontario. We calculated descriptive statistics to summarize patient characteristics and outcomes by antenatal health care provider. We calculated crude and adjusted relative risks with 95% confidence intervals (CIs) for the exposure (weight gain during pregnancy) relative to each secondary outcome by health care provider. We calculated population attributable fractions with 95% CIs to assess the proportion of secondary outcomes that could be prevented if inadequate or excess weight gain (according to the 2009 Institute of Medicine guidelines) were removed by health care provider. RESULTS: The final cohort consisted of 231 697 pregnancies, of which 26 043 (11.2%), 136 994 (59.1%), 32 262 (13.9%) and 36 298 (15.7%) were managed by a family physician, obstetrician, midwife, and family physician plus obstetrician, respectively. Rates of weight gain below, within or above recommended levels were 31 742 (13.7%), 71 826 (31.0%) and 128 128 (55.3%), respectively, and did not differ across health care provider groups. No difference was observed in rates of secondary outcomes according to weight gain across health care providers. Excess weight gain was associated with a significant risk of being large for gestational age and cesarean delivery, and inadequate weight gain was associated with an increased risk of being small for gestational age and preterm birth. The population attributable fractions indicated a pronounced contribution of excess weight gain to being large for gestational age across all health care provider groups. INTERPRETATION: Weight gain during pregnancy and rates of associated secondary outcomes did not differ according to antenatal health care provider. This suggests a need for further research exploring counselling techniques and strategies for all types of antenatal health care providers to use in order to promote optimal weight gain during pregnancy.

Prevalence of Pre-Pregnancy Diabetes, Obesity, and Hypertension in Canada.

OBJECTIVE: Pre-existing diabetes mellitus (D), obesity (O), and chronic hypertension (H) can each alter the natural course of pregnancy, especially when they cluster together. Because the prevalence of various combinations of D, O, and H is unknown, the current study was undertaken. METHODS: This population-based cross-sectional study included 506 483 singleton and twin live birth and stillbirth deliveries in Ontario, occurring at ≥20 weeks gestation. All hospital births from 2012 to 2016 were identified in the Better Outcomes Registry and Network information system. The prevalence per 1000 births (95% confidence interval [CI]) of D, O, and H and their combinations were calculated. Prevalence estimates were stratified by twin and singleton gestations, maternal age, parity, and ethnicity (Canadian Task Force Classification II-2). RESULTS: During the study period, 5493 women (10.8 per 1000 births; 95% CI 10.6-11.1) had D, 90,177 (178.2; 95% CI 177.0-179.3) had O, and 5667 (11.2; 95% CI 10.9-11.5) had H. The prevalence per 1000 of DO was 4.8, DH 1.0, and OH 5.5, whereas 359 women (0.71 per 1000) had all three. D and H each linearly increased with rising maternal age, along with their combinations, and to some degree with higher parity. The combination of O and H was highest among women of Black ancestry (14.5 per 1000) and lowest among those of Asian ancestry (3.0 per 1000). CONCLUSION: D, O, and H are common conditions in pregnancy, both alone and in various combinations. These data can be used to assess the impact of each state on perinatal health.

Utility of the number needed to treat in paediatric haematological cancer randomised controlled treatment trials: a systematic review.

OBJECTIVES: The primary objective was to assess the utility of the number needed to treat (NNT) to inform decision-making in the context of paediatric oncology and to calculate the NNT in all superiority, parallel, paediatric haematological cancer, randomised controlled trials (RCTs), with a comparison to the threshold NNT as a measure of clinical significance. DESIGN: Systematic review DATA SOURCES: MEDLINE, EMBASE and the Cochrane Childhood Cancer Group Specialized Register through CENTRAL from inception to August 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Superiority, parallel RCTs of haematological malignancy treatments in paediatric patients that assessed an outcome related to survival, relapse or remission; reported a sample size calculation with a delta value to allow for calculation of the threshold NNT, and that included parameters required to calculate the NNT and associated CI. RESULTS: A total of 43 RCTs were included, representing 45 randomised questions, of which none reported the NNT. Among acute lymphoblastic leukaemia (ALL) RCTs, 29.2% (7/24) of randomised questions were found to have a NNT corresponding to benefit, in comparison to acute myeloid leukaemia (ALM) RCTs with 50% (3/6), and none in lymphoma RCTs (0/13). Only 28.6% (2/7) and 33.3% (1/3) had a NNT that was less than the threshold NNT for ALL and AML, respectively. Of these, 100% (2/2 ALL and 1/1 AML) were determined to be possibly clinically significant. CONCLUSIONS: We recommend that decision-makers in paediatric oncology use the NNT and associated confidence limits as a supportive tool to evaluate evidence from RCTs while placing careful attention to the inherent limitations of this measure.

Gestational diabetes mellitus is associated with adverse outcomes in twin pregnancies.

BACKGROUND: Among singleton pregnancies, gestational diabetes mellitus is associated with adverse outcomes. In twin pregnancies, this association may be attenuated, given the higher rate of prematurity and the a priori increased risk of some of these complications. OBJECTIVE: Our aim was to test the hypothesis that gestational diabetes mellitus is less likely to be associated with adverse pregnancy outcomes in twin compared with singleton gestations. METHODS: This retrospective cohort study comprised all twin and singleton live births in Ontario, Canada, 2012-2016. Pregnancy outcomes were compared between women with vs without gestational diabetes mellitus, analyzed separately for twin and singleton births. Adjusted risk ratios and 95% confidence intervals were generated using modified Poisson regression, adjusting for maternal age, nulliparity, smoking, race, body mass index, preexisting hypertension, and assisted reproductive technology. RESULTS: A total of 270,843 women with singleton (n = 266,942) and twin (n = 3901) pregnancies met the inclusion criteria. In both the twin and singleton groups, gestational diabetes mellitus was associated with (adjusted risk ratio, [95% confidence interval]) cesarean delivery (1.11 [1.02-1.21] and 1.20 [1.17-1.23], respectively) and preterm birth at <370/7 weeks (1.21 [1.08-1.37] and 1.48 [1.39-1.57]) and at <340/7 weeks (1.45 [1.03-2.04] and 1.25 [1.06-1.47]). In singletons, but not twins, gestational diabetes mellitus was associated with gestational hypertension (1.66 [1.55-1.77]) and preeclampsia. With respect to neonatal outcomes, gestational diabetes mellitus was associated with birthweight greater than the 90th percentile in both twins and singletons, with the risk being 2-fold higher in twins (2.53 [1.52-4.23] vs 1.18 [1.13-1.23], respectively, P = .004). Gestational diabetes mellitus was associated with jaundice in both twins (1.56 [1.10-2.21]) and singletons (1.49 [1.37-1.62) but was associated with the following complications only in singletons: neonatal intensive care unit admission (1.44 [1.38-1.50]), respiratory morbidity (1.09 [1.02-1.16]), and neonatal hypoglycemia (3.20 [3.01-3.40]). CONCLUSION: In contrast to singleton pregnancies, gestational diabetes mellitus in twins was not associated with hypertensive complications and certain neonatal morbidities. Still, the current study highlights that gestational diabetes mellitus is associated with some adverse pregnancy outcomes including accelerated fetal growth also in twin pregnancies.

Clinical significance in pediatric oncology randomized controlled treatment trials: a systematic review.

BACKGROUND: Clinical significance in a randomized controlled trial (RCT) can be determined using the minimal clinically important difference (MCID), which should inform the delta value used to determine sample size. The primary objective was to assess clinical significance in the pediatric oncology randomized controlled trial (RCT) treatment literature by evaluating: (1) the relationship between the treatment effect and the delta value as reported in the sample size calculation, and (2) the concordance between statistical and clinical significance. The secondary objective was to evaluate the reporting of methodological attributes related to clinical significance. METHODS: RCTs of pediatric cancer treatments, where a sample size calculation with a delta value was reported or could be calculated, were systematically reviewed. MEDLINE, EMBASE, and the Cochrane Childhood Cancer Group Specialized Register through CENTRAL were searched from inception to July 2016. RESULTS: RCTs (77 overall; 11 and 66), representing 95 (13 and 82) randomized questions were included for non-inferiority and superiority RCTs (herein, respectively). The minority (22.1% overall; 76.9 and 13.4%) of randomized questions reported conclusions based on clinical significance, and only 4.2% (15.4 and 2.4%) explicitly based the delta value on the MCID. Over half (67.4% overall; 92.3 and 63.4%) reported a confidence interval or standard error for the primary outcome experimental and control values and 12.6% (46.2 and 7.3%) reported the treatment effect, respectively. Of the 47 randomized questions in superiority trials that reported statistically non-significant findings, 25.5% were possibly clinically significant. Of the 24 randomized questions in superiority trials that were statistically significant, only 8.3% were definitely clinically significant. CONCLUSIONS: A minority of RCTs in the pediatric oncology literature reported methodological attributes related to clinical significance and a notable portion of statistically insignificant studies were possibly clinically significance.

Timing of Delivery in Women With Chronic Hypertension.

OBJECTIVE: To assess whether routine induction of labor at 38 or 39 weeks in women with chronic hypertension is associated with the risk of superimposed preeclampsia or cesarean delivery. METHODS: We conducted a retrospective population-based study of women with chronic hypertension who had a singleton hospital birth at 38 0/7 weeks of gestation of gestation in Ontario, Canada, between 2012 and 2016. Women who underwent induction of labor at 38 0/7 to 38 6/7 weeks of gestation for chronic hypertension (n=281) were compared with those who were managed expectantly during that week and remained undelivered at 39 0/7 weeks of gestation (n=1,606). Separately, women who underwent induction of labor at 39 0/7 to 39 6/7 weeks of gestation for chronic hypertension (n=259) were compared with women who remained undelivered at 40 0/7 weeks of gestation (n=801). RESULTS: Of 534,529 women gave birth during the study period, 6,054 (1.1%) had chronic hypertension and 2,420 met the inclusion criteria. Women managed expectantly at 38 or 39 weeks of gestation were at risk of new-onset superimposed preeclampsia (19.2% [308/1,606] and 19.0% [152/801], respectively) and eclampsia (0.6% [10/1,606] and 0.7% [6/801], respectively), and more than half underwent induction of labor later in gestation (56.8% and 57.8%, respectively). The risk of cesarean delivery in the induction groups was lower (38 weeks of gestation) or similar (39 weeks of gestation) to that observed in women managed expectantly at the corresponding weeks (38 weeks of gestation: 17.1% vs 24.0%, adjusted relative risk 0.74 [95% CI 0.57-0.95]; 39 weeks of gestation: 20.1% vs 26.0%, adjusted relative risk 0.90 [95% CI 0.69-1.17]). CONCLUSION: Our findings suggest that in women with isolated chronic hypertension, induction of labor at 38 or 39 weeks of gestation may prevent severe hypertensive complications without increasing the risk of cesarean delivery.

Incidence and risk factors for gestational diabetes mellitus in twin versus singleton pregnancies.

OBJECTIVE: To compare the incidence and risk factors for gestational diabetes mellitus (GDM) between women with twin and singleton pregnancies. METHODS: Retrospective study of all women who had a twin or singleton birth in Ontario (2012-2016). Risk ratios (RR) and 95% CIs for GDM (stratified by type of treatment) were adjusted for relevant confounding variables. Multivariable Poisson regression analysis was used to identify risk factors for GDM in twin and singleton gestations. RESULTS: Of 270,843 women who met inclusion criteria, 266,942 (98.6%) and 3901 (1.4%) had a singleton and a twin pregnancy, respectively. Women with twins had a significantly higher risk for overall GDM (aRR = 1.13, 95% CI 1.01-1.28) and diet-treated GDM (aRR = 1.20, 95% CI 1.01-1.42) while the association with insulin-treated GDM was not significant (aRR = 1.07, 95% CI 0.89-1.28). Maternal age ≥ 35 years, non-Caucasian ethnicity and BMI > 30 kg/m2 were independent risk factors for GDM among women with twins and singletons, and the magnitude of the association of these factors with GDM was similar. CONCLUSIONS: Women with twins are at increased risk of GDM, mainly due to a higher rate of diet-treated GDM. Despite higher baseline risk of GDM in women with twins, the effect of known risk factors for GDM is similar to that observed in singletons.

Healthcare system barriers to long-term follow-up for adult survivors of childhood cancer in British Columbia, Canada: a qualitative study.

PURPOSE: Risk-stratified life-long follow-up care is recommended for adult childhood cancer survivors (CCS) to ensure appropriate prevention, screening, and management of late effects. The identification of barriers to long-term follow-up (LTFU), particularly in varying healthcare service contexts, is essential to develop and refine services that are responsive to survivor needs. We aimed to explore CCS and healthcare professionals (HCP) perspectives of healthcare system factors that function as barriers to LTFU in British Columbia, Canada. METHODS: We analyzed data from 43 in-depth interviews, 30 with CCS and 13 with HCP, using qualitative thematic analysis and constant comparative methods. RESULTS: Barriers to accessible, comprehensive, quality LTFU were associated with the following: (1) the difficult and abrupt transition from pediatric to adult health services, (2) inconvenient and under-resourced health services, (3) shifting patient-HCP relationships, (4) family doctor inadequate experience with late effects management, and (5) overdue and insufficient late effects communication with CCS. CONCLUSIONS: Structural, informational, and interpersonal/relational healthcare system factors often prevent CCS from initially accessing LTFU after discharge from pediatric oncology programs as well as adversely affecting engagement in ongoing screening, surveillance, and management of late effects. IMPLICATIONS FOR CANCER SURVIVORS: Understanding the issues faced by adult CCS will provide insight necessary to developing patient-centered healthcare solutions that are key to accessible, acceptable, appropriate, and effective healthcare.

"Assessing the methodological quality of systematic reviews in radiation oncology: A systematic review".

OBJECTIVE: The objective of our study was to evaluate the methodological quality of systematic reviews and meta-analyses in Radiation Oncology. METHODS: A systematic literature search was conducted for all eligible systematic reviews and meta-analyses in Radiation Oncology from 1966 to 2015. Methodological characteristics were abstracted from all works that satisfied the inclusion criteria and quality was assessed using the critical appraisal tool, AMSTAR. Regression analyses were performed to determine factors associated with a higher score of quality. RESULTS: Following exclusion based on a priori criteria, 410 studies (157 systematic reviews and 253 meta-analyses) satisfied the inclusion criteria. Meta-analyses were found to be of fair to good quality while systematic reviews were found to be of less than fair quality. Factors associated with higher scores of quality in the multivariable analysis were including primary studies consisting of randomized control trials, performing a meta-analysis, and applying a recommended guideline related to establishing a systematic review protocol and/or reporting. CONCLUSIONS: Systematic reviews and meta-analyses may introduce a high risk of bias if applied to inform decision-making based on AMSTAR. We recommend that decision-makers in Radiation Oncology scrutinize the methodological quality of systematic reviews and meta-analyses prior to assessing their utility to inform evidence-based medicine and researchers adhere to methodological standards outlined in validated guidelines when embarking on a systematic review.

Long-term Outcomes and Complications in Pediatric Ewing Sarcoma.

OBJECTIVES: The objective of this study was to determine treatment outcomes and long-term complications in pediatric patients with Ewing Sarcoma treated at the British Columbia Cancer Agency (BCCA). METHODS: A retrospective chart review of 101 pediatric patients (<19 y old) with Ewing Sarcoma diagnosed between 1960 and 2005 was performed. The Kaplan-Meier survival analysis and Cox regression multivariate analysis were used to assess prognostic factors for overall survival (OS) and event-free survival (EFS). RESULTS: The median age at diagnosis was 11 years and the median follow-up for nondeceased patients was 13.5 years. The most common primary tumor locations were lower extremity (33%), pelvis (24%), and thorax (18%). Fifty percent of patients received surgery, 79% radiotherapy and 94% chemotherapy. The 5-year OS and EFS for patients with localized disease was 85% and 73% and for metastatic disease was 27% (P<0.0001) and 28% (P<0.0001), respectively. Metastatic disease was an independent predictor of lower OS (hazard ratio [HR], 9.5; 95% confidence interval [CI],4.7-19.4; P<0.0001) and EFS (HR, 4.9; 95% CI, 2.7-8.8; P<0.0001). Extremity tumor location was an independent predictor for improved OS (HR, 0.4; 95% CI, 0.2-0.9; P=0.03). The majority (77%) of long-term survivors (≥5 y) had long-term complications; the most common were musculoskeletal abnormalities (50%) and cardiac toxicity (28%). The actuarial second neoplasm risk was 5% at 10 years. CONCLUSIONS: Ewing sarcoma patients with localized disease had excellent treatment outcomes at the BCCA. However, the majority of patients had chronic complications from treatment. This study validates the need for long-term follow-up of Ewing Sarcoma survivors for management of late effects.

Comparison of hypersensitivity rates to intravenous and intramuscular PEG-asparaginase in children with acute lymphoblastic leukemia: A meta-analysis and systematic review.

BACKGROUND: Pegylated-asparaginase (PEG-ASP) is a critical treatment for pediatric acute lymphoblastic leukemia (ALL) and has traditionally been delivered via intramuscular (IM) injection. In an attempt to reduce pain and anxiety, PEG-ASP has increasingly been delivered via intravenous (IV) administration. The study objective was to perform a meta-analysis and systematic review to compare and generate pooled hypersensitivity rates for IM and IV PEG-ASP. METHODS: A systematic literature search was conducted for all epidemiological studies that investigated IV and IM hypersensitivity rates for pediatric ALL. Included studies were critically appraised using the GRACE checklist. Pooled estimates and odds ratios with 95% confidence intervals (CIs) for IM and IV hypersensitivity rates were derived based on either a random or fixed effects model. RESULTS: Four studies satisfied the inclusion criteria and were of adequate quality. The random effects pooled hypersensitivity rates were 23.5% (95% CI 14.7-33.7) and 8.7% (95% CI 5.4-12.8) for IV and IM, respectively. The fixed effects pooled odds ratio after adjusting for publication bias was 2.49 (95% CI 1.62-3.83), indicating a significantly higher risk of hypersensitivity for IV over IM PEG-ASP. This risk is far more pronounced for high-risk (HR) patients compared with standard-risk (SR) patients (IV vs. IM: HR ↑35.2% and SR ↓2.9%). CONCLUSIONS: Although administering PEG-ASP through IV is preferable for patients, it poses a significantly higher risk of hypersensitivity when compared with IM administration, especially for HR patients. We recommend pediatric oncologists consider treating patients with HR pediatric ALL with IM PEG-ASP to reduce the risk of hypersensitivity.

A Cross-Sectional Cohort Study of Cerebrovascular Disease and Late Effects After Radiation Therapy for Craniopharyngioma.

BACKGROUND: The study objective was to describe radiation-induced vascular abnormalities, stroke prevalence, and stroke risk factors in survivors of childhood craniopharyngioma. PROCEDURE: Twenty survivors of childhood craniopharyngioma who received radiotherapy (RT) were included in the study. A clinical history, quality of life assessment, cognitive functioning assessment, magnetic resonance angiogram or computed tomography angiogram, fasting lipid profile, and fasting glucose or hemoglobin A1c test were obtained. RESULTS: Median age at diagnosis was 10.3 years and median age at time of study was 29.0 years. Vascular abnormalities were detected in six (32%) of 19 patients' angiograms (vascular stenosis, decreased artery size, aneurysm, cavernoma, and small vessel disease). Five (25%) of 20 patients experienced a stroke after RT. Median time since RT was 27.8 versus 9.1 years in patients with versus without vascular abnormalities (P = 0.02). A low level of high-density lipoproteiin (HDL) was present in 100% (5/5) of patients who had a post-RT stroke as compared with 13% (2/15) of patients who did not have any post-RT stroke (P = 0.02). Previous stroke had occurred in 0% (0/5) of patients receiving growth hormone (GH) replacement at the time of study, compared to 40% (6/15) of patients who were not receiving GH replacement (P = 0.09). CONCLUSIONS: Patients with craniopharyngioma treated with RT have a high prevalence of stroke and vascular abnormalities, particularly those with low HDL and longer duration of time since RT. There is a trend to suggest that continual GH replacement may reduce the risk of stroke. These patients should undergo careful monitoring and aggressive modification of stroke risk factors.

Methodologic Quality of Systematic Reviews Published in the Plastic and Reconstructive Surgery Literature: A Systematic Review.

BACKGROUND: Well-conducted systematic reviews have a critical role in informing evidence-based decision-making in plastic surgery. The authors' objective was to assess the methodologic quality of systematic reviews in the plastic surgery literature. METHODS: The authors systematically assessed all systematic reviews in 10 high-impact plastic surgery journals using MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from 2003 to 2013. These were evaluated for methodologic quality using A Measurement Tool to Assess Systematic Reviews (AMSTAR), a validated 11-point instrument. RESULTS: After removal of duplicates and screening titles and abstracts, 190 systematic reviews met eligibility criteria. The majority of systematic reviews were published in Plastic and Reconstructive Surgery (n = 88). The most common domain covered was reconstruction (17.9 percent). Using AMSTAR, the median score was 4 (interquartile range, 2.25 to 6.00) on a scale of 1 to 11. No increase in AMSTAR score was observed with time (p = 0.18). Almost half of all systematic reviews (48.4 percent) included at least two independent data extractors, and less than one-third of them (15.3 percent) searched unpublished studies or provided a list of both included and excluded studies (14.8 percent). The methodologic quality of included primary studies was evaluated in 35.3 percent. CONCLUSIONS: Systematic reviews in plastic surgery demonstrated inadequate adherence to methodologic standards of quality, which raises concerns about validity. There has been an increase in the number of systematic reviews published in plastic surgery over the past decade, yet there has been no significant improvement observed in methodologic quality.

Assessing the accuracy of death records and pre-mortem clinical diagnoses in children diagnosed with brain tumors: A retrospective chart review of children in British Columbia, Canada.

The advantages of autopsy have been demonstrated in pediatric oncology; however, it is unknown to what extent the utility of autopsy is in deceased children diagnosed with a pediatric brain tumor (PBT). The purpose of this study was to describe the frequency of autopsy, prevalence of clinical discrepancies, and accuracy of cancer registry death records for deceased children diagnosed with a PBT in British Columbia, Canada. A retrospective chart review was performed of medical records and autopsy reports of pediatric patients diagnosed with a PBT that died between 1982 and 2012 in British Columbia. Clinical discrepancies between pre- and post-mortem findings were classified based on a modified classification system of the Goldman Criteria. The overall autopsy rate was 15.5% (32 of 206) during 1982-2012, with a significant (P=0.001) decrease of 22.4% observed between decade 1 (32.8%) and decade 2 (10.4%) and a further slight decrease (4.5%) between decade 2 (10.4%) and decade 3 (5.9%) (P=0.379). A third of patients had discrepancies between pre-mortem and post-mortem clinical diagnoses, with slightly over 10% of these cases revealing information that would have altered the probability of survival had it been known prior to death. More than half (59.3%) of cases had discordant cause of death as recorded in the cancer registry when compared to autopsy findings. Autopsy for children diagnosed with a PBT can provide health care professionals with important information about the accuracy of their diagnoses and evaluate the efficacy of therapy.