Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort.

BACKGROUND: Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse. METHODS: We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes. RESULTS: Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01). CONCLUSION: We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.

Advances in the clinical management of high-risk Wilms tumors.

Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors' view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.

Advances in the clinical management of high-risk Wilms tumors.

Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors' view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.

Background sensitivity to chemotherapy-induced nausea and vomiting and response to antiemetics in paediatric patients: a genetic association study.

Chemotherapy-induced nausea and vomiting (CINV) remains a common adverse effect for children with cancer. In children, chemotherapy emetogenicity and patient factors such as susceptibility to motion sickness and age group determine a patient's risk of CINV. Besides known risk factors, genetic factors may play a role in interindividual variation in the occurrence of CINV. We investigated the influence of candidate gene polymorphisms on the efficacy of antiemetics and on the background sensitivity to CINV in children. This prospective study included 100 children with cancer (median age 6.4 years, range 0.8-17.9) who received moderately to highly emetogenic chemotherapy. Participants registered nausea and vomiting episodes in a mobile app. Genotypes were determined by whole-genome sequencing (n = 79) or Sanger sequencing (n = 21) for 71 genetic polymorphisms involved in motion sickness and antiemetic pathways. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate associations between acute CINV and genotypes adjusting for susceptibility to motion sickness and age group. Rs3782025 in the 5-hydroxytryptamine type 3 (5-HT3) receptor gene (HTR3B) [minor allele frequency (MAF): 0.48] affected response to 5-HT3 receptor antagonists; acute CINV occurred in 76% of patients with GA/AA genotypes and in 41% of patients with GG genotype (OR 5.59; 95% CI 1.74-17.9, dominant genetic model). Rs2975226 in the dopamine transporter gene (SLC6A3) (MAF: 0.54) was associated with acute CINV (OR 5.79; 95% CI 1.09-30.67, recessive genetic model). Polymorphisms in HTR3B and SLC6A3 may contribute to the variability in response to antiemetic prophylaxis for CINV in children.

The clinical impact of observer variability in lung nodule classification in children with Wilms tumour.

OBJECTIVES: To investigate the extent to which observer variability of computed tomography (CT) lung nodule assessment may affect clinical treatment stratification in Wilms tumour (WT) patients, according to the recent Société Internationale d'Oncologie Pédiatrique Renal Tumour Study Group (SIOP-RTSG) UMBRELLA protocol. METHODS: I: CT thoraces of children with WT submitted for central review were used to estimate size distribution of lung metastases. II: Scans were selected for blinded review by five radiologists to determine intra- and inter-observer variability. They assessed identical scans on two occasions 6 months apart. III: Monte Carlo simulation (MCMC) was used to predict the clinical impact of observer variation when applying the UMBRELLA protocol size criteria. RESULTS: Lung nodules were found in 84 out of 360 (23%) children with WT. For 21 identified lung nodules, inter-observer limits of agreement (LOA) for the five readers were ±2.4 and ±1.4 mm (AP diameter), ±1.9 and ±1.8 mm (TS diameter) and ±2.0 and ±2.4 mm (LS diameter) at assessments 1 and 2. Intra-observer LOA across the three dimensions were ±1.5, ±2.2, ±3.5, ±3.1 and ±2.6 mm (readers 1-5). MCMC demonstrated that 17% of the patients with a 'true' nodule size of ≥3 mm will be scored as <3 mm, and 21% of the patients with a 'true' nodule size of <3 mm will be scored as being ≥3 mm. CONCLUSION: A significant intra-inter observer variation was found when measuring lung nodules on CT for patients with WT. This may have significant implications on treatment stratification, and thereby outcome, when applying a threshold of ≥3 mm for a lung nodule to dictate metastatic status.

Long-term kidney function in children with Wilms tumour and constitutional WT1 pathogenic variant.

BACKGROUND: Wilms tumour (WT) survivors, especially patients with associated syndromes or genitourinary anomalies due to constitutional WT1 pathogenic variant, have increased risk of kidney failure. We describe the long-term kidney function in children with WT and WT1 pathogenic variant to inform the surgical strategy and oncological management of such complex children. METHODS: Retrospective analysis of patients with WT and constitutional WT1 pathogenic variant treated at a single centre between 1993 and 2016, reviewing genotype, phenotype, tumour histology, laterality, treatment, patient survival, and kidney outcome. RESULTS: We identified 25 patients (60% male, median age at diagnosis 14 months, range 4-74 months) with WT1 deletion (4), missense (2), nonsense (8), frameshift (7), or splice site (4) pathogenic variant. Thirteen (52%) had bilateral disease, 3 (12%) had WT-aniridia, 1 had incomplete Denys-Drash syndrome, 11 (44%) had genitourinary malformation, and 10 (40%) had no phenotypic anomalies. Patient survival was 100% and 3 patients were in remission after relapse at median follow-up of 9 years. Seven patients (28%) commenced chronic dialysis of which 3 were after bilateral nephrectomies. The overall kidney survival for this cohort as mean time to start of dialysis was 13.38 years (95% CI: 10.3-16.4), where 7 patients experienced kidney failure at a median of 5.6 years. All of these 7 patients were subsequently transplanted. In addition, 2 patients have stage III and stage IV chronic kidney disease and 12 patients have albuminuria and/or treatment with ACE inhibitors. Four patients (3 frameshift; 1 WT1 deletion) had normal blood pressure and kidney function without proteinuria at follow-up from 1.5 to 12 years. CONCLUSIONS: Despite the known high risk of kidney disease in patients with WT and constitutional WT1 pathogenic variant, nearly two-thirds of patients had sustained native kidney function, suggesting that nephron-sparing surgery (NSS) should be attempted when possible without compromising oncological risk. Larger international studies are needed for accurate assessment of WT1genotype-kidney function phenotype correlation.

The diagnostic accuracy and clinical utility of pediatric renal tumor biopsy: Report of the UK experience in the SIOP UK WT 2001 trial.

INTRODUCTION: The International Society of Paediatric Oncology (SIOP) protocols recommend preoperative chemotherapy appropriate for Wilms tumors (WTs) in children with renal tumors aged ≥6 months, reserving biopsy for "atypical" cases. The Children's Cancer and Leukaemia Group (CCLG) joined the SIOP-WT-2001 study but continued the national practice of biopsy at presentation. METHOD: Retrospective study of concordance between locally reported renal tumor biopsies and central pathology review nephrectomy diagnoses of children enrolled by CCLG centers in the SIOP-WT-2001 study. RESULTS: Biopsy reports were available for 552/787 children with unilateral tumors. 36 of 552 (6.5%) were nondiagnostic: 2 normal tissue, 12 necrotic, 9 insufficient sample, and 13 indeterminate results (disproportionately non-WTs). The sensitivity and specificity of biopsy to identify tumors that did not require SIOP empirical preoperative chemotherapy were 86.0% and 99.6%, respectively. 13 of 548 (2.4%) biopsy results were discordant with nephrectomy; non-WTs other than renal cell carcinoma and clear cell sarcoma of the kidney (CCSK) were poorly recognized. In children aged 6-119 months, 480 of 518 (91.6%) had WT or nephroblastomatosis. 5 of 518 (1%) had benign tumors, and only one diagnosed on biopsy. Biopsy results correctly changed clinical management in 25 of 518 (4.8%), including identifying 19 of 20 CCSKs, but would have led to overtreatment in 5 of 518 (1%) or undertreatment in 4 of 518 (0.8%). In children aged ≥10 years, biopsy correctly changed management in 5 of 19 (26%) cases with no discordance. CONCLUSION: Biopsy is less effective at identifying non-WTs than WTs and rarely changes management in younger children. Biopsy should be reserved in SIOP protocols for children ≥10 years and in younger children with clinical or radiological features inconsistent with WT.

Relapse of Wilms' tumour and detection methods: a retrospective analysis of the 2001 Renal Tumour Study Group-International Society of Paediatric Oncology Wilms' tumour protocol database.

BACKGROUND: Wilms' tumour is the most common renal cancer in childhood and about 15% of patients will relapse. There is scarce evidence about optimal surveillance schedules and methods for detection of tumour relapse after therapy. METHODS: The Renal Tumour Study Group-International Society of Paediatric Oncology (RTSG-SIOP) Wilms' tumour 2001 trial and study is an international, multicentre, prospective registration, biological study with an embedded randomised clinical trial for children with renal tumours aged between 6 months and 18 years. The study covers 243 different centres in 27 countries grouped into five consortia. The current protocol of SIOP surveillance for Wilms' tumour recommends that abdominal ultrasound and chest x-ray should be done every 3 months for the first 2 years after treatment and be repeated every 4-6 months in the third and fourth year and annually in the fifth year. In this retrospective cohort study of the protocol database, we analysed data from participating institutions on timing, anatomical site, and mode of detection of all first relapses of Wilms' tumour. The primary outcomes were how relapse of Wilms' tumour was detected (ie, at or between scheduled surveillance and with or without clinical symptoms, scan modality, and physical examination) and to estimate the number of scans needed to capture one subclinical relapse. The RTSG-SIOP study is registered with Eudra-CT, number 2007-004591-39. FINDINGS: Between June 26, 2001, and May 8, 2015, of 4271 eligible patients in the 2001 RTSG-SIOP Wilms' tumour database, 538 (13%) relapsed. Median follow-up from surgery was 62 months (IQR 32-93). The method used to detect relapse was registered for 410 (76%) of 538 relapses. Planned surveillance imaging captured 289 (70%) of these 410 relapses. The primary imaging modality used to detect relapse was reported for 251 patients, among which relapse was identified by abdominal ultrasound (80 [32%] patients), chest x-ray (78 [31%]), CT scan of the chest (64 [25%]) or abdomen (20 [8%]), and abdominal MRI (nine [4%]). 279 (68%) of 410 relapses were not detectable by physical examination and 261 (64%) patients did not have clinical symptoms at relapse. The estimated number of scans needed to detect one subclinical relapse during the first 2 years after nephrectomy was 112 (95% CI 106-119) and, for 2-5 years after nephrectomy, 500 (416-588). INTERPRETATION: Planned surveillance imaging captured more than two-thirds of predominantly asymptomatic relapses of Wilms' tumours, with most detected by abdominal ultrasound, chest x-ray, or chest CT scan. Beyond 2 years post-nephrectomy, a substantial number of surveillance scans are needed to capture one relapse, which places a burden on families and health-care systems. FUNDING: Great Ormond Street Hospital Children's Charity, the European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment, The Danish Childhood Cancer Foundation, Cancer Research UK, the UK National Cancer Research Network and Children's Cancer and Leukaemia Group, Société Française des Cancers de l'Enfant and Association Leon Berard Enfant Cancéreux and Enfant et Santé, Gesellschaft für Pädiatrische Onkologie und Hämatologie and Deutsche Krebshilfe, Grupo Cooperativo Brasileiro para o Tratamento do Tumor de Wilms and Sociedade Brasileira de Oncologia Pediátrica, the Spanish Society of Pediatric Haematology and Oncology and the Spanish Association Against Cancer, and SIOP-Netherlands.

Irinotecan for relapsed Wilms tumor in pediatric patients: SIOP experience and review of the literature-A report from the SIOP Renal Tumor Study Group.

While irinotecan has been studied in various pediatric solid tumors, its potential role in Wilms tumor (WT) is less clear. We evaluated response and outcome of irinotecan-containing regimens in relapsed WT and compared our results to the available literature. Among 14 evaluable patients, one complete response (CR) and two partial responses (PRs) were observed in patients with initial intermediate-risk (CR and PR) and blastemal-type histologies (PR). Two patients were alive at last follow-up showing no evidence of disease. Our results and the reviewed literature suggest some effectiveness of irinotecan in the setting of relapsed WT.

Interventions for paracetamol (acetaminophen) overdose.

BACKGROUND: Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various interventions to treat paracetamol poisoning, depending on the clinical status of the person. These interventions include inhibiting the absorption of paracetamol from the gastrointestinal tract (decontamination), removal of paracetamol from the vascular system, and antidotes to prevent the formation of, or to detoxify, metabolites. OBJECTIVES: To assess the benefits and harms of interventions for paracetamol overdosage irrespective of the cause of the overdose. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2017), CENTRAL (2016, Issue 11), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), and Science Citation Index Expanded (1900 to January 2017). We also searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov database (US National Institute of Health) for any ongoing or completed trials (January 2017). We examined the reference lists of relevant papers identified by the search and other published reviews. SELECTION CRITERIA: Randomised clinical trials assessing benefits and harms of interventions in people who have ingested a paracetamol overdose. The interventions could have been gastric lavage, ipecacuanha, or activated charcoal, or various extracorporeal treatments, or antidotes. The interventions could have been compared with placebo, no intervention, or to each other in differing regimens. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included trials. We used fixed-effect and random-effects Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of the review outcomes. We used the Cochrane 'Risk of bias' tool to assess the risks of bias (i.e. systematic errors leading to overestimation of benefits and underestimation of harms). We used Trial Sequential Analysis to control risks of random errors (i.e. play of chance) and GRADE to assess the quality of the evidence and constructed 'Summary of findings' tables using GRADE software. MAIN RESULTS: We identified 11 randomised clinical trials (of which one acetylcysteine trial was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol, or acetylcysteine. There were no randomised clinical trials of agents that inhibit cytochrome P-450 to decrease the activation of the toxic metabolite N-acetyl-p-benzoquinone imine.Of the 11 trials, only two had two common outcomes, and hence, we could only meta-analyse two comparisons. Each of the remaining comparisons included outcome data from one trial only and hence their results are presented as described in the trials. All trial analyses lack power to access efficacy. Furthermore, all the trials were at high risk of bias. Accordingly, the quality of evidence was low or very low for all comparisons. Interventions that prevent absorption, such as gastric lavage, ipecacuanha, or activated charcoal were compared with placebo or no intervention and with each other in one four-armed randomised clinical trial involving 60 participants with an uncertain randomisation procedure and hence very low quality. The trial presented results on lowering plasma paracetamol levels. Activated charcoal seemed to reduce the absorption of paracetamol, but the clinical benefits were unclear. Activated charcoal seemed to have the best risk:benefit ratio among gastric lavage, ipecacuanha, or supportive treatment if given within four hours of ingestion. There seemed to be no difference between gastric lavage and ipecacuanha, but gastric lavage and ipecacuanha seemed more effective than no treatment (very low quality of evidence). Extracorporeal interventions included charcoal haemoperfusion compared with conventional treatment (supportive care including gastric lavage, intravenous fluids, and fresh frozen plasma) in one trial with 16 participants. The mean cumulative amount of paracetamol removed was 1.4 g. One participant from the haemoperfusion group who had ingested 135 g of paracetamol, died. There were no deaths in the conventional treatment group. Accordingly, we found no benefit of charcoal haemoperfusion (very low quality of evidence). Acetylcysteine appeared superior to placebo and had fewer adverse effects when compared with dimercaprol or cysteamine. Acetylcysteine superiority to methionine was unproven. One small trial (low quality evidence) found that acetylcysteine may reduce mortality in people with fulminant hepatic failure (Peto OR 0.29, 95% CI 0.09 to 0.94). The most recent randomised clinical trials studied different acetylcysteine regimens, with the primary outcome being adverse events. It was unclear which acetylcysteine treatment protocol offered the best efficacy, as most trials were underpowered to look at this outcome. One trial showed that a modified 12-hour acetylcysteine regimen with a two-hour acetylcysteine 100 mg/kg bodyweight loading dose was associated with significantly fewer adverse reactions compared with the traditional three-bag 20.25-hour regimen (low quality of evidence). All Trial Sequential Analyses showed lack of sufficient power. Children were not included in the majority of trials. Hence, the evidence pertains only to adults. AUTHORS' CONCLUSIONS: These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available. Evidence from a single trial found activated charcoal seemed the best choice to reduce absorption of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best efficacy. Current management of paracetamol poisoning worldwide involves the administration of intravenous or oral acetylcysteine which is based mainly on observational studies. Results from these observational studies indicate that treatment with acetylcysteine seems to result in a decrease in morbidity and mortality, However, further evidence from randomised clinical trials comparing different treatments are needed.

Association Between Chronic Obstructive Pulmonary Disease and Type 2 Diabetes: A Systematic Review and Meta-Analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been associated with an increased risk of type 2 diabetes (T2D). However, the mechanisms linking COPD and T2D is not fully understood and contradicting results are reported in the literature. AIM: The aim of this study is to investigate whether COPD is associated with an increased risk of T2D. METHODS: A systematic review and meta-analysis of cohort and case-control studies were performed. Search for studies and data extraction was carried out by two authors independently. Study quality was assessed by NOS. Adjusted data were pooled using the random effects model to calculate summary odds ratios (ORs) with corresponding 95% confidence intervals (CIs). RESULTS: We identified four cohort studies and three case-control studies with a total of 1,369,560 participants of whom 42,716 were COPD patients. The quality of the studies was acceptable, with an average on 7.7 indicating overall good study quality. The meta-analysis on adjusted data from all seven studies showed that the COPD group had a higher risk of T2D compared with the non-COPD group: random effect OR = 1.17 (1.01-1.35), p = 0.03. No heterogeneity was found I2 = 0%. When including only studies diagnosing both COPD and T2D according to recommended guidelines the association did not remain statistically significant, OR =1.17 (0.96-1.42), p = 0.12. CONCLUSION: This systemic review and meta-analyses showed that the association between COPD and T2D might be influenced by the diagnostic method and should be further investigated in studies using diagnostic definition according to guidelines. Nevertheless, physicians should be aware of comorbidities in COPD patients.

Epidemiological study of paediatric germ cell tumours revealed the incidence and distribution that was expected, but a low mortality rate.

AIM: Germ cell tumours (GCTs) are a rare heterogeneous tumour group derived from primordial germ cells, which can be benign or malignant and occur in the gonads or extragonadally. This study mapped the paediatric GCTs in Denmark from 1984 to 2013 to study the incidence and outcome. METHODS: We identified paediatric GCTs from the Danish Childhood Cancer and National Pathology Registries and reviewed the case records for patient characteristics, tumour characteristics and clinical outcome. RESULTS: We identified 403 (71% female) paediatric GCTs and the crude incidence was 1.43 per 100 000. Of these, 79 (20%) were malignant, 39 (10%) were potentially malignant and 285 (70%) were benign. Extragonadal GCTs (39%) were mainly observed in early childhood and were predominately sacrococcygeal teratomas. Gonadal GCTs (61%) in late childhood were most frequently mature teratomas in the ovaries. Nearly all patients underwent surgery. Of the malignant tumours, 62% were treated with chemotherapy. Radiotherapy was only administered to intracranial GCTs. In the cohort, 12 patients died (3%). CONCLUSION: Paediatric GCTs in Denmark were mainly benign and mortality was low, even for malignant tumours. We identified a peak of extragonadal GCTs in early childhood and a peak of gonadal GCTs in late childhood, which was comparable to previous reports.

Role of CD56 in Normal Kidney Development and Wilms Tumorigenesis.

The cell-surface glycoprotein CD56 has three major isoforms that play important roles in cell adhesion and signaling, which may promote cell proliferation, differentiation, survival, or migration. It is an important molecule in normal kidney development and acts as a key marker in Wilms tumor stem and progenitor cells. Here, we review the structural and genetic features of the CD56 glycoprotein, and summarize its roles in the normal versus diseased metanephric blastema. We discuss areas of CD56-related research that may complement or improve existing Wilms tumor treatment strategies, including the antibody-drug conjugate lorvotuzumab mertansine that binds to CD56.

Quality of life in adolescents and young adults with CHD is not reduced: a systematic review and meta-analysis.

PURPOSE: We performed a systematic review and meta-analysis of observational studies assessing quality of life in adolescents and young adults born with CHD compared with age-matched controls. METHODS: We carried out a systematic search of the literature published in Medline, Embase, PsychINFO, and the Cochrane Library's Database (1990-2013); two authors independently extracted data from the included studies. We used the Newcastle-Ottawa scale for quality assessment of studies. A random effects meta-analysis model was used. Heterogeneity was assessed using the I2-test. RESULTS: We included 18 studies with 1786 patients. The studies were of acceptable-to-good quality. The meta-analysis of six studies on quality of life showed no significant difference - mean difference: -1.31; 95% confidence intervals: -6.51 to +3.89, I2=90.9% - between adolescents and young adults with CHD and controls. Similar results were found in 10 studies not eligible for the meta-analysis. In subdomains, it seems that patients had reduced physical quality of life; however, social functioning was comparable or better compared with controls. CONCLUSION: For the first time in a meta-analysis, we have shown that quality of life in adolescents and young adults with CHD is not reduced when compared with age-matched controls.

Age at menarche and risk of asthma: systematic review and meta-analysis.

BACKGROUND: Several studies have suggested a relationship between the age at menarche and risk of asthma development. OBJECTIVE: To conduct a systematic review and meta-analysis of the relationship between the age at menarche and the risk of asthma. METHODS: This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). A pre specified literature search strategy was used to identify studies of potential relevance and independent reviews were carried out by two authors. Raw data was pooled using the software package RevMan to calculate summary odds ratios. The risk of publication bias was assessed graphically by using a funnel plot and the robustness of the overall estimate obtained was assessed by using sensitivity analyses. RESULTS: The searches identified 61 potentially relevant articles of which seven articles, with a total of 22,859 subjects, matched the inclusion criteria for the meta-analysis. Pooling of the seven studies showed that girls with early menarche (<12 years) had an increased risk of asthma relative to girls with late menarche; random effects odds ratio = 1.37 (1.15-1.64), (p = 0.0005). Substantial heterogeneity was revealed (I(2) = 55%). Sensitivity analysis showed that the risk estimate was not markedly changed when excluding any of the studies. The funnel plot did not indicate publication bias. CONCLUSIONS: Early menarche appears to be associated with increased risk of asthma. Hormonal, immunological, genetic and environmental factors may act in a developmental context to explain this relationship. Future studies are warranted to further determine the mechanisms responsible for this observation.

Recent advances in understanding the etiology and pathogenesis of pediatric germ cell tumors.

Pediatric germ cell tumors (GCTs) are rare neoplasms arising predominantly in the gonads and sacrococcygeal, mediastinal, and intracranial localizations. In this article, we review current knowledge of pathogenesis of pediatric GCTs, which differs from adult/adolescent GCTs. One distinctive feature is the absence of a progenitor stage, such as carcinoma in situ or gonadoblastoma, which are seen in adult/adolescent GCTs, except spermatocytic seminoma. The primordial germ cell (PGC) is the suggested origin of all GCTs, with variations in histology reflecting differentiation stage. Expression of pluripotency transcription factors OCT-3/4, NANOG, and AP-2γ in germinomas/seminomas/dysgerminomas is consistent with retaining a germ cell phenotype. Teratomas, in contrast, develop through a pathway of aberrant somatic differentiation of immature germ cells, and the yolk sac tumors and choriocarcinomas result from abnormal extraembryonic differentiation. In pediatric GCTs, origin is suggested at an earlier developmental stage because of predisposing genetic factors, although responsible genes remain largely unknown. Some extragonadal GCTs have been linked to overexpression of the KIT/KITLG system, allowing for survival of aberrantly migrated ectopic PGCs. Infant gonadal/sacrococcygeal GCTs may be caused by apoptosis-related pathways, consistent with an association with polymorphisms in BAK1. Although recent advances have identified candidate pathways, further effort is needed to answer central questions of pathogenesis of these fascinating tumors.

Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C.

BACKGROUND: Pegylated interferon (peginterferon) plus ribavirin is the recommended treatment for patients with chronic hepatitis C, but systematic assessment of the effect of this treatment compared with interferon plus ribavirin is needed. OBJECTIVES: To systematically evaluate the benefits and harms of peginterferon plus ribavirin versus interferon plus ribavirin for patients with chronic hepatitis C. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index-Expanded, and LILACS. We also searched conference abstracts, journals, and grey literature. The last searches were conducted in September 2013. SELECTION CRITERIA: We included randomised clinical trials comparing peginterferon plus ribavirin versus interferon plus ribavirin with or without co-intervention(s) (e.g., other antiviral drugs) for chronic hepatitis C. Quasi-randomised and observational studies retrieved through the searches for randomised clinical trials were also considered for reports of harms. Our primary outcomes were liver-related morbidity, all-cause mortality, serious adverse events, adverse events leading to treatment discontinuation, other adverse events, and quality of life. Our secondary outcome was sustained virological response in serum, that is, undetectable hepatitis C virus RNA in serum by sensitive tests six months after the end of treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently used a standardised data collection form. We meta-analysed data with both fixed-effect and random-effects models. For each outcome, we calculated the odds ratio (OR) (for liver-related morbidity or all-cause mortality) or the risk ratio (RR) along with 95% confidence interval (CI) based on intention-to-treat analysis. We used domains of the trials to assess the risk of systematic errors (bias) and trial sequential analyses to assess the risk of random errors (play of chance).For each outcome, we calculated the RR with 95% CI based on intention-to-treat analysis. Effects of interventions on outcomes were assessed according to GRADE. MAIN RESULTS: We included 27 randomised trials with 5938 participants. All trials had high risk of bias. We considered that the risk of bias did not impact on the quality of evidence for liver-related mortality and adverse event outcomes, but it did for virological response. All trials compared peginterferon alpha-2a or peginterferon alpha-2b plus ribavirin versus interferon plus ribavirin for participants with chronic hepatitis C. Three trials administered co-interventions (amantadine hydrochloride 200 mg daily to both intervention groups), and 24 trials were conducted without co-interventions. The effect observed between the two intervention groups regarding liver-related morbidity plus all-cause mortality (5/907 (0.55%) versus 4/882 (0.45%) was imprecise: OR 1.14 ( 95% CI 0.38 to 3.42; five trials; low quality of evidence), as was the risk of adverse events leading to treatment discontinuation (332/2692 (12.3%) versus 409/2176 (18.8%); RR 0.86, 95% CI 0.68 to 1.09; 15 trials; low quality of evidence) or regarding adverse events leading to treatment discontinuation (332/2692 (12.3%) versus 409/2176 (18.8%); RR 0.86, 95% CI 0.66 to 1.12; 17 trials; low quality of evidence). However, peginterferon plus ribavirin versus interferon plus ribavirin significantly increased the risk of neutropenia (332/2202 (15.1%) versus 117/1653 (7.1%); RR 2.15, 95% CI 1.76 to 2.61; 13 trials), thrombocytopenia (65/1113 (5.8%) versus 23/1082 (2.1%); RR 2.63, 95% CI 1.68 to 4.11; 10 trials), arthralgia (517/1740 (29.7%) versus 282/1194 (23.6%); RR 1.19, 95% CI 1.05 to 1.35; four trials), injection site reaction (627/1168 (53.7%) versus 186/649 (28.7%); RR 1.71, 95% CI 1.50 to 1.93; four trials), and nausea (606/1784 (34.0%) versus 354/1239 (28.6%); RR 1.13, 95% CI 1.01 to 1.26; four trials). The most frequent adverse event was fatigue, which occurred in 57% of participants (2024/3608). No significant difference was noted between peginterferon plus ribavirin versus interferon plus ribavirin in terms of fatigue (1177/2062 (57.1%) versus 847/1546 (54.8%); RR 1.01, 95% CI 0.96 to 1.07; 12 trials). No significant differences were reported between the two treatment groups regarding anaemia, headache, rigours, myalgia, pyrexia, weight loss, asthenia, depression, insomnia, irritability, alopecia, pruritus, skin rash, thyroid malfunction, decreased appetite, or diarrhoea. We were unable to identify any data on quality of life. Peginterferon plus ribavirin versus interferon plus ribavirin seemed to significantly increase the number of participants achieving sustained virological response (1673/3300 participants (50.7%) versus 1081/2804 patients (36.7%); RR 1.39, 95% CI 1.25 to 1.56; I2 = 64%; 27 trials; very low quality of evidence). However, the risk of bias in the 13/27 (48.1%) trials reporting on this outcome was high and was considered only 'lower' in the remainder. Because the conventional meta-analysis did not reach its required information size (n = 14,486 participants), we used trial sequential analysis to control for risks of random errors. Again, in this analysis, the estimated effect was statistically significant in favour of peginterferon. Subgroup analyses according to risk of bias, viral genotype, baseline viral load, past treatment history, and type of intervention yielded similarly significant results favouring peginterferon over interferon on the outcome of sustained virological response. AUTHORS' CONCLUSIONS: Peginterferon plus ribavirin versus interferon plus ribavirin seems to significantly increase the proportion of patients with sustained virological response, as well as the risk of certain adverse events. However, we have insufficient evidence to recommend or reject peginterferon plus ribavirin for liver-related morbidity plus all-cause mortality compared with interferon plus ribavirin. The clinical consequences of achieved sustained virological response are unknown, as sustained virological response is still an unvalidated surrogate outcome. We found no evidence of the potential benefits on quality of life in patients with achieved sustained virological response. Further high-quality research is likely to have an important impact on our confidence in the estimate of patient-relevant outcomes and is likely to change our estimates.There is very low quality evidence that peginterferon plus ribavirin increases the proportion of patients with sustained virological response in comparison with interferon plus ribavirin. There is evidence that it also increases the risk of certain adverse events.