Characteristics and Survival Outcomes of Children With Hodgkin Lymphoma Treated Primarily With Chemotherapy.

BACKGROUND: Hodgkin disease is a malignant tumor of the lymphatic system that comprises ∼6% of childhood cancers. In developing countries, efforts are made to ensure adherence to standard protocol/regimens, study patients' outcomes, and compare with that in developed world. MATERIALS AND METHODS: We conducted a retrospective medical records' review of 212 children younger than 20 years presenting to The Indus Hospital in Pakistan with previously untreated Hodgkin lymphoma between August 2000 and December 2012. We collected demographic and other epidemiologic variables such as age, sex, stage, subtype of disease, and survival outcomes. RESULTS: The mean±SD age of patients at time of diagnosis was 9.0±3.8 years with a male to female ratio of ∼4.7:1. In total, 44 (20.8%) patients were 5 years of age or above at presentation. Overall, 131 (61.8%) patients presented with B-symptoms and mixed cellularity was the most frequently diagnosed subtype in 65.1% of cases. In total, 170 (80.2%) achieved full remission after completion of chemotherapy. Patients were treated with alternating cycles of ABVD (Adriamycin, Bleomycin, Vincristine, and Dacarbazine) and COPDAC (Cyclophosphamide, Vincristine, Prednisolone, and Dacarbazine). The majority (n=114, 59.1%) received 6 cycles of chemotherapy, 44 (22.8%) received ≤4 cycles followed by 24 (12.4%) receiving 8 cycles. Radiotherapy was administered only to those patients with significant residual disease at the end of chemotherapy (n=20, 10%). The 5-year overall survival and event-free survival in our cohort was 89.6% and 82.1%, respectively. CONCLUSION: Our findings suggest that treatment with 4 to 8 alternating cycles of ABVD/COPDAC has an excellent outcome in childhood Hodgkin disease.

Evaluation of Baseline Cardiac Function by Echocardiography and its Association With Nutritional Status in Pediatric Cancer Patients at The Indus Hospital in Karachi, Pakistan.

INTRODUCTION: Evidence on conducting baseline echocardiogram before starting chemotherapy in pediatric cancer patients is limited from developing countries where malnutrition and infections are common and which may result in cardiac dysfunction. MATERIALS AND METHODS: A prospective, observational study was conducted from October 2016 to May 2017 at The Indus Hospital, Karachi, Pakistan, among children 1 to 16 years of age suffering from cancer. Echocardiography was performed before starting chemotherapy. Associations between body mass index and cardiac abnormalities were studied. RESULTS: A total of 384 children met the inclusion criteria. The median (interquartile range) age was 8.0 (5.0 to 12.0) years and 62.0% (n=238) were male individuals. Twenty-two of 384 (5.7%) children had systolic dysfunction. Four of 22 had moderate-systolic and one of 22 had mild systolic dysfunction, for whom the therapy was altered, and they were treated without anthracyclines. Four of these 5 patients died, and only 1 of 5 survived through high-risk protocol. Seventeen of 22 children had low-normal systolic dysfunction. We found no evidence of an association between body mass index for age and abnormal left ventricular ejection fraction and abnormal fractional shortening (P-trend=0.587; 0.487, respectively). No associations were found of weight-for-age and height-for-age with these outcomes. CONCLUSIONS: In developing countries, echocardiograms should be expeditiously performed and technology made more accessible to rule out cardiac dysfunction and avoid delay in chemotherapy. Malnutrition was not associated with cardiac dysfunction.

Vitamin D supplementation for preventing infections in children under five years of age.

BACKGROUND: Vitamin D is a micronutrient important for bone growth and immune function. Deficiency can lead to rickets and has been linked to various infections, including respiratory infections. The evidence on the effects of supplementation on infections in children has not been assessed systematically. OBJECTIVES: To evaluate the role of vitamin D supplementation in preventing pneumonia, tuberculosis (TB), diarrhoea, and malaria in children under five years of age. This includes high-, middle-, and low-income countries. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, MEDLINE, EMBASE, LILACS, the WHO International Clinical Trials Registry Platform (ICTRP; http://www.who.int/ictrp/en/) , ClinicalTrials.gov and the ISRCTN registry (http://www.isrctn.com/) up to 16 June 2016. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated preventive supplementation of vitamin D (versus placebo or no intervention) in children under five years of age. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts, extracted the data, and assessed the risk of bias of included trials. MAIN RESULTS: Four trials met the inclusion criteria, with a total of 3198 children under five years of age, and were conducted in Afghanistan, Spain, and the USA. Prevalence of vitamin D deficiency varied widely in these populations (range: 73.1% in Afghanistan, 10 to 12% in USA, and 6.2% in Spain). The included trials evaluated mortality (two trials), pneumonia incidence (two trials), diarrhoea incidence (two trials), hospitalization (two trials), and mean serum vitamin D concentrations (four trials).We do not know whether vitamin D supplementation impacts on all-cause mortality because this outcome was underpowered due to few events (risk ratio (RR) 1.43, 95% confidence interval (CI) 0.54 to 3.74; one trial, 3046 participants, low quality evidence).For pneumonia, episodes of 'radiologically confirmed' first or only episode of pneumonia were little different in the supplemented and unsupplemented group (Rate Ratio: 1.06, 95% confidence interval (CI) 0.89 to 1.26; two trials, 3134 participants, moderate quality evidence), and similarly for children with confirmed or unconfirmed pneumonia (RR 0.95, 95% CI 0.87 to 1.04; one trial, 3046 participants). In these two trials there were no obvious differences between supplemented and unsupplemented children regarding episodes of diarrhoea.In the single large trial from Afghanistan, the trial authors reported that vitamin D supplementation was associated with an increase in repeat episodes of pneumonia confirmed by chest radiograph (RR 1.69, 95% CI 1.28 to 2.21; one trial, 3046 participants), but not reflected in the outcome of confirmed or unconfirmed pneumonia (RR 1.06, 95% CI 1.00 to 1.13; one trial, 3046 participants).For hospital admission measured in one small trial, there was no difference detected (RR 0.86, 95% CI 0.20 to 3.62; one trial, 88 participants; very low quality evidence).The mean serum vitamin D concentrations were higher in supplemented compared to unsupplemented children at the end of supplementation (MD 7.72 ng/mL, 95% CI 0.50 to 14.93; four trials, 266 participants, low quality evidence). These results were driven primarily by two smaller trials with large magnitudes of effect. In the other two bigger trials, serum vitamin D concentrations were elevated in the intervention group for most of the trial duration but not at the end of supplementation. This may be due to time elapsed at measurement from the last dose, incomplete compliance, or increased need of vitamin D with infant age.We did not find any trial that reported on the incidence of TB, malaria or febrile illness, duration of pneumonia, duration of diarrhoea, severity of infection, and cause-specific mortality (due to TB, diarrhoea, or malaria). AUTHORS' CONCLUSIONS: Evidence from one large trial did not demonstrate benefit of vitamin D supplementation on the incidence of pneumonia or diarrhoea in children under five years. To our knowledge, trials that evaluated supplementation for preventing other infections, including TB and malaria, have not been performed.

Impact of Dietary and Metabolic Risk Factors on Cardiovascular and Diabetes Mortality in South Asia: Analysis From the 2010 Global Burden of Disease Study.

OBJECTIVES: To quantify cardiovascular disease and diabetes deaths attributable to dietary and metabolic risks by country, age, sex, and time in South Asian countries. METHODS: We used the 2010 Global Burden of Disease national surveys to characterize risk factor levels by age and sex. We derived etiological effects of risk factors-disease endpoints, by age, from meta-analyses. We defined optimal levels. We combined these inputs with cause-specific mortality rates to compute population-attributable fractions as a percentage of total cardiometabolic deaths. RESULTS: Suboptimal diet was the leading cause of cardiometabolic mortality in 4 of 5 countries, with population-attributable fractions from 40.7% (95% uncertainty interval = 37.4, 44.1) in Bangladesh to 56.9% (95% uncertainty interval = 52.4, 61.5) in Pakistan. High systolic blood pressure was the second leading cause, except in Bangladesh, where it superseded suboptimal diet. This was followed in all nations by high fasting plasma glucose, low fruit intake, and low whole grain intake. Other prominent burdens were more variable, such as low intake of vegetables, low omega-3 fats, and high sodium intake in India, Nepal, and Pakistan. CONCLUSIONS: Important similarities and differences are evident in cardiometabolic mortality burdens of modifiable dietary and metabolic risks across these countries, informing health policy and program priorities.

ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies.

IMPORTANCE: The role of ω-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers. OBJECTIVE: To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20:5ω-3), docosapentaenoic acid (DPA; 22:5ω-3), and docosahexaenoic acid (DHA; 22:6ω-3) and plant-derived α-linolenic acid (ALA; 18:3ω-3) for incident CHD. DATA SOURCES: A global consortium of 19 studies identified by November 2014. STUDY SELECTION: Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue ω-3 biomarkers and ascertained CHD. DATA EXTRACTION AND SYNTHESIS: Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, ω-6 levels, and FADS desaturase genes. MAIN OUTCOMES AND MEASURES: Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI). RESULTS: The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with ω-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baseline was 59 years (range, 18-97 years), and 28 660 (62.8%) were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the ω-3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses. CONCLUSIONS AND RELEVANCE: On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived ω-3 fatty acids are associated with a modestly lower incidence of fatal CHD.

Circulating Biomarkers of Dairy Fat and Risk of Incident Diabetes Mellitus Among Men and Women in the United States in Two Large Prospective Cohorts.

BACKGROUND: In prospective studies, the relationship of self-reported consumption of dairy foods with risk of diabetes mellitus is inconsistent. Few studies have assessed dairy fat, using circulating biomarkers, and incident diabetes mellitus. We tested the hypothesis that circulating fatty acid biomarkers of dairy fat, 15:0, 17:0, and t-16:1n-7, are associated with lower incident diabetes mellitus. METHODS AND RESULTS: Among 3333 adults aged 30 to 75 years and free of prevalent diabetes mellitus at baseline, total plasma and erythrocyte fatty acids were measured in blood collected in 1989 to 1990 (Nurses' Health Study) and 1993 to 1994 (Health Professionals Follow-Up Study). Incident diabetes mellitus through 2010 was confirmed by a validated supplementary questionnaire based on symptoms, diagnostic tests, and medications. Risk was assessed by using Cox proportional hazards, with cohort findings combined by meta-analysis. During mean±standard deviation follow-up of 15.2±5.6 years, 277 new cases of diabetes mellitus were diagnosed. In pooled multivariate analyses adjusting for demographics, metabolic risk factors, lifestyle, diet, and other circulating fatty acids, individuals with higher plasma 15:0 had a 44% lower risk of diabetes mellitus (quartiles 4 versus 1, hazard ratio, 0.56; 95% confidence interval, 0.37-0.86; P-trend=0.01); higher plasma 17:0, 43% lower risk (hazard ratio, 0.57; 95% confidence interval, 0.39-0.83; P-trend=0.01); and higher t-16:1n-7, 52% lower risk (hazard ratio, 0.48; 95% confidence interval, 0.33-0.70; P-trend <0.001). Findings were similar for erythrocyte 15:0, 17:0, and t-16:1n-7, although with broader confidence intervals that only achieved statistical significance for 17:0. CONCLUSIONS: In 2 prospective cohorts, higher plasma dairy fatty acid concentrations were associated with lower incident diabetes mellitus. Results were similar for erythrocyte 17:0. Our findings highlight the need to better understand the potential health effects of dairy fat, and the dietary and metabolic determinants of these fatty acids.

Impact of complications on long-term survival after resection of intrahepatic cholangiocarcinoma.

BACKGROUND: The impact of postoperative complications on the long-term outcomes of patients undergoing surgery for cancer is unclear. The objective of the current study was to define the incidence of complications among patients undergoing surgery for intrahepatic cholangiocarcinoma (ICC) and identify the association between morbidity and long-term outcomes. METHODS: A total of 583 patients undergoing surgery with curative intent for ICC between 1990 and 2013 at 1 of 12 participating institutions were identified. The association between the occurrence and severity of postoperative complications on long-term survival was analyzed. RESULTS: The median age of the patients was 59.9 years and the majority of patients were male (52.3%). A total of 91 patients (15.6%) and 153 patients (26.2%) developed a major and minor postoperative complication, respectively; 18 patients (3.5%) died within 90 days of surgery. Median, 1-year, 3-year, and 5-year recurrence-free survival were 10.0 months, 43.3%, 16.7%, and 11.1%, respectively. Postoperative complications (hazard ratio [HR], 1.37, 95% confidence interval [95% CI], 1.08-1.73 [P = .01]) and severity of complications (major vs none: HR, 1.55; 95% CI, 1.14-2.11 [P = .01]; minor vs none: HR, 1.30; 95% CI, 0.99-1.70 [P = .06]) independently predicted shorter recurrence-free survival. Median, 1-year, 3-year, and 5-year overall survival was 27.8 months, 76.8%, 39.0%, and 23.4%, respectively. Postoperative complications (HR, 1.64; 95% CI, 1.30-2.08 [P<.001]) and severity of complications (major vs none: HR, 1.79; 95% CI, 1.31-2.44 [P<.001]; minor vs none: HR, 1.50; 95% CI, 1.15-1.95 [P<.01]) independently predicted shorter overall survival. CONCLUSIONS: Postoperative complications were found to be independent predictors of worse long-term outcomes. The prevention and management of postoperative complications is crucial to increase both short-term and long-term survival.

The Impact of Surgical Margin Status on Long-Term Outcome After Resection for Intrahepatic Cholangiocarcinoma.

BACKGROUND: The influence of margin status on long-term outcome of patients undergoing liver resection for intrahepatic cholangiocarcinoma (ICC) remains controversial. We sought to study the impact of surgical tumor margin status on recurrence-free survival (RFS) and overall survival (OS) of patients undergoing resection for ICC. METHODS: From a multi-institutional database, 583 patients who underwent hepatic resection for ICC were identified. Demographics data, operative details, pathologic margin status, and long-term outcomes were collected and analyzed. RESULTS: Margin status was positive (R1) in 95 (17.8 %) patients; among patients who underwent an R0 resection (80.9 %), margin width was negative by 1-4 mm in 166 (31.0 %) patients, 5-9 mm in 100 (18.7 %) patients, and ≥1 cm in 174 (32.5 %) patients. Overall, 379 (65.0 %) patients had a recurrence: 61.5 % intrahepatic, 13.5 % extrahepatic, and 25.0 % both intra- and extrahepatic. Median and 5-year RFS and OS was 10.0 months and 9.2 %, and 26.4 months and 23.0 %, respectively. Patients who had an R1 resection had a higher risk of recurrence (hazard ratio [HR] 1.61, 95 % CI 1.15-2.27; p = 0.01) and shorter OS (HR 1.54, 95 % CI 1.12-2.11). Among patients with an R0 resection, margin width was also associated with RFS (1-4 mm: HR 1.32, 95 % CI 0.98-1.78 vs. 5-9 mm: HR 1.21, 95 % CI 0.89-1.66) and OS (1-4 mm: HR 1.95, 95 % CI 0.45-2.63 vs. 5-9 mm: HR 1.21, 95 % CI 0.88-1.68) (referent ≥1 cm; both p ≤ 0.002). Margin status and width remain independently associated with RFS and OS on multivariable analyses. CONCLUSIONS: For patients undergoing resection of ICC, R1 margin status was associated with an inferior long-term outcome. Moreover, there was an incremental worsening RFS and OS as margin width decreased.

Circulating biomarkers of dairy fat and risk of incident stroke in U.S. men and women in 2 large prospective cohorts.

BACKGROUND: Previous observational studies of self-reported dairy product consumption and stroke risk have reported mixed findings. Few studies have used circulating biomarkers that provide objective measures of dairy fat intake. OBJECTIVES: We tested the hypothesis that the circulating biomarkers of dairy fat, pentadecanoic acid (15:0), heptadecanoic acid (17:0), and trans palmitoleate (trans 16:1n-7), were associated with lower incidence of stroke, especially ischemic stroke. Secondarily, we evaluated 14:0, which is obtained from dairy products and beef, and also endogenously synthesized. DESIGN: In participants from 2 large US cohorts (the Health Professionals Follow-Up Study: 51,529 men; the Nurses' Health Study: 121,700 women) with stored blood samples in 1993-1994 (n = 18,225) and 1989-1990 (n = 32,826), respectively, we prospectively identified 594 incident stroke cases (median follow-up: 8.3 y) and matched them 1:1 to risk-set-sampled control subjects by age, sex, race, and smoking. Total plasma and red blood cell (RBC) fatty acids were measured by using gas-liquid chromatography. Covariates were assessed by using validated questionnaires. Stroke events and subtypes were adjudicated by using medical records or other supporting documentation. We used conditional logistic regression to estimate associations of fatty acids with incident stroke, and cohort-specific findings were combined by inverse-variance weights. RESULTS: After adjustment for demographic characteristics, lifestyle, cardiovascular disease risk factors, diet, and other circulating fatty acids, no significant associations with total stroke were seen for plasma 15:0 (pooled HR for highest compared with lowest quartiles: 0.85; 95% CI: 0.54, 1.33), 17:0 (0.99; 0.67, 1.49), trans 16:1 n-7 (0.89; 0.55, 1.45), or 14:0 (1.05; 0.62, 1.78). Results were similar for ischemic and hemorrhagic stroke subtypes, for RBC fatty acids, and in several different sensitivity analyses. CONCLUSION: In 2 large prospective cohorts, circulating biomarkers of dairy fat were not significantly associated with stroke.

The risk of congenital malformations associated with exposure to ß-blockers early in pregnancy: a meta-analysis.

ß-blockers are commonly used during the first trimester of pregnancy. Data about risks of congenital anomalies in offspring have not been summarized. We performed a meta-analysis to determine teratogenicity of ß-blockers in early pregnancy. A systematic literature search was performed using PubMed, EMBASE, Cochrane Clinical Trials, and hand search. Meta-analyses were performed using random-effects models based on odds ratios (ORs). Prespecified subgroup analyses were performed to explore heterogeneity. Randomized controlled trials or observational studies examining risks of congenital malformations associated with first trimester ß-blocker exposure compared with no exposure were included. Thirteen population-based case-control or cohort studies were identified. Based on meta-analyses, first-trimester oral ß-blocker use showed no increased odds of all or major congenital anomalies (OR=1.00; 95% confidence interval, 0.91-1.10; 5 studies). However, in analyses examining organ-specific malformations, increased odds of cardiovascular defects (OR=2.01; 95% confidence interval, 1.18-3.42; 4 studies), cleft lip/palate (OR=3.11; 95% confidence interval, 1.79-5.43; 2 studies), and neural tube defects (OR=3.56; 95% confidence interval, 1.19-10.67; 2 studies) were observed. The effects on severe hypospadias were nonsignificant (1 study). Causality is difficult to interpret given the small number of heterogeneous studies and possibility of biases. Given the frequency of this exposure in pregnancy, further research is needed.

The association of maternal race and ethnicity and the risk of postpartum hemorrhage.

BACKGROUND: There are profound racial and ethnic disparities in obstetric outcomes in the United States, but little is known about disparities in risk of postpartum hemorrhage (PPH). We explored the association of race and ethnicity on the risk of PPH due to uterine atony with sequential adjustment for possible mediating factors. METHODS: This analysis was based on the Nationwide Inpatient Sample, from between 2005 and 2008. The frequencies of atonic PPH and atonic PPH resulting in transfusion or hysterectomy were estimated. We developed multivariable logistic regression models to estimate the odds of these outcomes in maternal racial/ethnic groups by sequentially adding potential mediators. RESULTS: Hispanic ethnicity and Asian/Pacific Islander race were associated with a statistically significant increased odds of atonic PPH in comparison with Caucasians, despite adjustment for potential mediators (adjusted odds ratio [OR] for Hispanics: 1.21, 99% confidence interval [1.18, 1.25]; for Asians/Pacific Islanders: 1.31 [1.25, 1.38], with Caucasians as reference). Similar results were observed for these racial/ethnic groups for atonic PPH resulting in transfusion or hysterectomy. CONCLUSION: Hispanic ethnicity and Asian/Pacific Islander race are significant risk factors for atonic PPH independent of measured potential mediators; biological differences may play a role.