Characteristics and treatment of acute myeloid neoplasms with cutaneous involvement in infants up to 6 months of age: A retrospective study.

BACKGROUND: Myeloid neoplasms account for 50% of cases of pediatric leukemias in infants. Approximately 25%-50% of patients with newborn leukemia have cutaneous extramedullary disease (EMD). In less than 10% of patients, aleukemic leukemia cutis or isolated extramedullary disease with cutaneous involvement (cEMD) occurs when skin lesions appear prior to bone marrow involvement and systemic symptoms. Interestingly, in acute myeloid leukemia with cutaneous EMD (AML-cEMD) and cEMD, spontaneous remissions have been reported. METHOD: This is a multicentric retrospective cohort study aiming to describe characteristics, treatment, and outcome of infants with either cEMD or presence of cutaneous disease with involvement of the bone marrow (AML-cEMD). This study included patients born between 1990 and 2018 from Italy, the Netherlands, Switzerland, and the United States, diagnosed between 0 and 6 months of life with cEMD or AML-cEMD. Descriptive statistics, Fisher's exact test, Kaplan-Meier method, and log rank test were applied. RESULTS: The cohort consisted of n = 50 patients, including 42 AML-cEMD and eight cEMD patients. The most common genetic mutation found was a KMT2A rearrangement (n = 26, 52%). Overall 5-year event-free survival (EFS) and overall survival (OS) were 66% [confidence interval (CI): 51-78] and 75% [CI: 60-85], respectively. In two patients, complete spontaneous remission occurred without any therapy. Central nervous system (CNS) involvement was found in 25% of cEMD patients. No difference in outcomes was observed between the AML-cEMD and cEMD groups, but none of the latter patients included in the study died. KMT2A rearrangements were not associated with poorer prognosis. CONCLUSION: In the largest cohort to date, our study describes the characteristics of infants with cutaneous involvement of myeloid neoplasms including cytomolecular findings and survival rates. Further prospective biologic and clinical studies of these infants with myeloid neoplasms will be required to individualize therapy for this rare patient population.

Screening for genital chlamydia infection.

BACKGROUND: Genital infections caused by Chlamydia trachomatis are the most prevalent bacterial sexually transmitted infection worldwide. Screening of sexually active young adults to detect and treat asymptomatic infections might reduce chlamydia transmission and prevent reproductive tract morbidity, particularly pelvic inflammatory disease (PID) in women, which can cause tubal infertility and ectopic pregnancy. OBJECTIVES: To assess the effects and safety of chlamydia screening versus standard care on chlamydia transmission and infection complications in pregnant and non-pregnant women and in men. SEARCH METHODS: We searched the Cochrane Sexually Transmitted Infections Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, CINAHL, DARE, PsycINFO and Web of Science electronic databases up to 14 February 2016, together with World Health Organization International Clinical Trials Registry (ICTRP) and ClinicalTrials.gov. We also handsearched conference proceedings, contacted trial authors and reviewed the reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) in adult women (non-pregnant and pregnant) and men comparing a chlamydia screening intervention with usual care and reporting on a primary outcome (C. trachomatis prevalence, PID in women, epididymitis in men or incidence of preterm delivery). We included non-randomised controlled clinical trials if there were no RCTs for a primary outcome. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data and assessed the risk of bias. We resolved disagreements by consensus or adjudication by a third reviewer. We described results in forest plots and conducted meta-analysis where appropriate using a fixed-effect model to estimate risk ratios (RR with 95% confidence intervals, CI) in intervention vs control groups. We conducted a pre-specified sensitivity analysis of the primary outcome, PID incidence, according to the risks of selection and detection bias. MAIN RESULTS: We included six trials involving 359,078 adult women and men. One trial was at low risk of bias in all six specific domains assessed. Two trials examined the effect of multiple rounds of chlamydia screening on C. trachomatis transmission. A cluster-controlled trial in women and men in the general population in the Netherlands found no change in chlamydia test positivity after three yearly invitations (intervention 4.1% vs control 4.3%, RR 0.96, 95% CI 0.84 to 1.09, 1 trial, 317,304 participants at first screening invitation, low quality evidence). Uptake of the intervention was low (maximum 16%). A cluster-randomised trial in female sex workers in Peru found a reduction in chlamydia prevalence after four years (adjusted RR 0.72, 95% CI 0.54 to 0.98, 1 trial, 4465 participants, low quality evidence).Four RCTs examined the effect of chlamydia screening on PID in women 12 months after a single screening offer. In analysis of four trials according to the intention-to-treat principle, the risk of PID was lower in women in intervention than control groups, with little evidence of between-trial heterogeneity (RR 0.68, 95% CI 0.49 to 0.94, I2 7%, 4 trials, 21,686 participants, moderate quality evidence). In a sensitivity analysis, the estimated effect of chlamydia screening in two RCTs at low risk of detection bias (RR 0.80, 95% CI 0.55 to 1.17) was compatible with no effect and was lower than in two RCTs at high or unclear risk of detection bias (RR 0.42, 95% CI 0.22 to 0.83).The risk of epididymitis in men invited for screening, 12 months after a single screening offer, was 20% lower risk for epididymitis than in those not invited; the confidence interval was wide and compatible with no effect (RR 0.80, 95% CI 0.45 to 1.42, 1 trial, 14,980 participants, very low quality evidence).We found no RCTs of the effects of chlamydia screening in pregnancy and no trials that measured the harms of chlamydia screening. AUTHORS' CONCLUSIONS: Evidence about the effects of screening on C. trachomatis transmission is of low quality because of directness and risk of bias. There is moderate quality evidence that detection and treatment of chlamydia infection can reduce the risk of PID in women at individual level. There is an absence of RCT evidence about the effects of chlamydia screening in pregnancy.Future RCTs of chlamydia screening interventions should determine the effects of chlamydia screening in pregnancy, of repeated rounds of screening on the incidence of chlamydia-associated PID and chlamydia reinfection in general and high risk populations.

Changes in chlamydia control activities in Europe between 2007 and 2012: a cross-national survey.

BACKGROUND: In 2012, the levels of chlamydia control activities including primary prevention, effective case management with partner management and surveillance were assessed in 2012 across countries in the European Union and European Economic Area (EU/EEA), on initiative of the European Centre for Disease Control (ECDC) survey, and the findings were compared with those from a similar survey in 2007. METHODS: Experts in the 30 EU/EEA countries were invited to respond to an online questionnaire; 28 countries responded, of which 25 participated in both the 2007 and 2012 surveys. Analyses focused on 13 indicators of chlamydia prevention and control activities; countries were assigned to one of five categories of chlamydia control. RESULTS: In 2012, more countries than in 2007 reported availability of national chlamydia case management guidelines (80% vs. 68%), opportunistic chlamydia testing (68% vs. 44%) and consistent use of nucleic acid amplification tests (64% vs. 36%). The number of countries reporting having a national sexually transmitted infection control strategy or a surveillance system for chlamydia did not change notably. In 2012, most countries (18/25, 72%) had implemented primary prevention activities and case management guidelines addressing partner management, compared with 44% (11/25) of countries in 2007. CONCLUSION: Overall, chlamydia control activities in EU/EEA countries strengthened between 2007 and 2012. Several countries still need to develop essential chlamydia control activities, whereas others may strengthen implementation and monitoring of existing activities.

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome.

BACKGROUND: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients. METHODS: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated. RESULTS: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively). CONCLUSIONS: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.

Cancer predisposition syndromes as a risk factor for early second primary neoplasms after childhood cancer - A national cohort study.

BACKGROUND: Childhood cancer patients are at increased risk of second primary neoplasms (SPNs). We assessed incidence and risk factors for early SPNs with a focus on cancer predisposition syndromes (CPSs). PATIENTS AND METHODS: This cohort study used data from the Swiss Childhood Cancer Registry. We included patients with first primary neoplasms (FPNs) diagnosed before age 21 years from 1986 to 2015 and identified SPNs occurring before age 21. We calculated standardised incidence ratios (SIRs) and absolute excess risks (AERs) using Swiss population cancer incidence data, and cumulative incidence of SPNs. We calculated hazard ratios (HRs) of risk factors for SPNs using Fine and Gray competing risk regression. RESULTS: Among 8074 childhood cancer patients, 304 (4%) were diagnosed with a CPS and 94 (1%) developed early SPNs. The incidence of SPNs was more than 10-fold higher in childhood cancer patients than the incidence of neoplasms in the general population (SIR = 10.6, 95% confidence interval [CI]: 8.7-13.1) and the AER was 179/100,000 person-years (CI: 139-219). Cumulative incidence of SPNs 20 years after FPN diagnosis was 23% in patients with CPSs (CI: 12-41%) and 2.7% in those without (CI: 2.0-3.6%). Risk factors for SPNs were CPSs (HR = 7.8, CI: 4.8-12.7), chemotherapy (HR = 2.2, CI: 1.1-4.6), radiotherapy (HR = 1.9, CI = 1.2-2.9), haematopoietic stem cell transplantation (HR = 1.8, CI: 1-3.3), and older age (15-20 years) at FPN diagnosis (HR = 1.9, CI: 1.1-3.2). CONCLUSION: CPSs are associated with a high risk of SPNs before age 21 years. Identification of CPSs is important for appropriate cancer surveillance and targeted screening.

Temporal trends in incidence of childhood cancer in Switzerland, 1985-2014.

BACKGROUND: Incidence of childhood cancer increased in most countries worldwide, but reasons are unclear. This study investigates trends of childhood cancer incidence in Switzerland from 1985 to 2014. METHODS: We extracted data on all childhood cancer cases diagnosed at ages 0-14 years in Switzerland from the Swiss Childhood Cancer Registry. We included ICCC-3 main groups I-XII and calculated age-standardised, cumulative, and age-specific incidence for different diagnostic groups. We analysed trends of annual age-standardised incidence using JoinPoint regression models. RESULTS: Over the study period from 1985 to 2014, 5104 of 5486 cancer diagnoses (93%) were microscopically verified. The proportion of children treated in paediatric cancer centres increased from 84% during 1985-1994 to 93% in 1995-2004 and 98% in 2005-2014 (p < 0.001). Using the World standard population, age-standardised incidence was 143 in 1985-1994, 154 in 1995-2004, and 162 per million in 2005-2014. Incidence increased by 0.7% (95% confidence interval (CI) 0.5; 1.0) per year for all cancers from 1985 to 2014, 0.8% (95% CI 0.2%-1.4%) for leukaemias over the same period, 3.0% (95% CI 0.2%-1.4%) for CNS tumours during 1985-2002, and 3.8% (95% CI 1.7%-6.0%) for epithelial neoplasms and melanomas over the period 1985-2014. CONCLUSION: Trends in incidence were driven mostly by increases among leukaemias and CNS tumours. For CNS tumours, observed trends may be explained at least partially by diagnostic changes and improved registration. For leukaemias, rising incidence may be real and due to risk factors that experience similar increases in trends.

Two-dose schedules for human papillomavirus vaccine: Systematic review and meta-analysis.

Simpler schedules for human papillomavirus (HPV) vaccine delivery could improve vaccine coverage and the effectiveness of cervical cancer prevention. The objective of this study was to systematically review evidence about the effects of two-dose compared with three-dose schedules for human papillomavirus (HPV) vaccine and to describe the uptake of two-dose HPV vaccination schedules globally. We searched PubMed, the Cochrane Central Registry of Controlled Trials, trials registers, and manufacturers' databases from their earliest date to February 2016. We selected randomised controlled trials and controlled clinical trials that directly compared HPV vaccine schedules with two or three doses. We extracted data on immunological and clinical outcomes and used meta-analysis where appropriate. We also described the use of two-dose HPV vaccine schedules globally. We screened 1464 items and included seven eligible noninferiority trials in 11 countries. In randomised comparisons amongst adolescent girls (three trials), geometric mean concentrations (GMC) of antibodies against HPV16 and HPV18 were non-inferior or inconclusive, up to 24months after a two-dose compared with a three-dose schedule. One trial with a clinical outcome found no persistent HPV infections occurred after either two or three doses. In non-randomised comparisons, GMC were non-inferior or superior in adolescent girls receiving the two-dose schedule compared with women receiving the three-dose schedule for at least 21months after vaccination. By February 2017, 23 low and middle income and 25 high income countries had adopted a two-dose HPV vaccination schedule. A two-dose HPV vaccine schedule provides satisfactory immunological outcomes in adolescent girls, but uptake globally is limited, particularly in countries with the highest burden of cervical cancer.

Genital chlamydia prevalence in Europe and non-European high income countries: systematic review and meta-analysis.

BACKGROUND: Accurate information about the prevalence of Chlamydia trachomatis is needed to assess national prevention and control measures. METHODS: We systematically reviewed population-based cross-sectional studies that estimated chlamydia prevalence in European Union/European Economic Area (EU/EEA) Member States and non-European high income countries from January 1990 to August 2012. We examined results in forest plots, explored heterogeneity using the I² statistic, and conducted random effects meta-analysis if appropriate. Meta-regression was used to examine the relationship between study characteristics and chlamydia prevalence estimates. RESULTS: We included 25 population-based studies from 11 EU/EEA countries and 14 studies from five other high income countries. Four EU/EEA Member States reported on nationally representative surveys of sexually experienced adults aged 18-26 years (response rates 52-71%). In women, chlamydia point prevalence estimates ranged from 3.0-5.3%; the pooled average of these estimates was 3.6% (95% CI 2.4, 4.8, I² 0%). In men, estimates ranged from 2.4-7.3% (pooled average 3.5%; 95% CI 1.9, 5.2, I² 27%). Estimates in EU/EEA Member States were statistically consistent with those in other high income countries (I² 0% for women, 6% for men). There was statistical evidence of an association between survey response rate and estimated chlamydia prevalence; estimates were higher in surveys with lower response rates, (p = 0.003 in women, 0.018 in men). CONCLUSIONS: Population-based surveys that estimate chlamydia prevalence are at risk of participation bias owing to low response rates. Estimates obtained in nationally representative samples of the general population of EU/EEA Member States are similar to estimates from other high income countries.

Cohort study of trials submitted to ethics committee identified discrepant reporting of outcomes in publications.

OBJECTIVES: To identify factors associated with discrepant outcome reporting in randomized drug trials. STUDY DESIGN AND SETTING: Cohort study of protocols submitted to a Swiss ethics committee 1988-1998: 227 protocols and amendments were compared with 333 matching articles published during 1990-2008. Discrepant reporting was defined as addition, omission, or reclassification of outcomes. RESULTS: Overall, 870 of 2,966 unique outcomes were reported discrepantly (29.3%). Among protocol-defined primary outcomes, 6.9% were not reported (19 of 274), whereas 10.4% of reported outcomes (30 of 288) were not defined in the protocol. Corresponding percentages for secondary outcomes were 19.0% (284 of 1,495) and 14.1% (334 of 2,375). Discrepant reporting was more likely if P values were <0.05 compared with P ≥ 0.05 [adjusted odds ratio (aOR): 1.38; 95% confidence interval (CI): 1.07, 1.78], more likely for efficacy compared with harm outcomes (aOR: 2.99; 95% CI: 2.08, 4.30) and more likely for composite than for single outcomes (aOR: 1.48; 95% CI: 1.00, 2.20). Cardiology (aOR: 2.34; 95% CI: 1.44, 3.79) and infectious diseases (aOR: 1.77; 95% CI: 1.01, 3.13) had more discrepancies compared with all specialties combined. CONCLUSION: Discrepant reporting was associated with statistical significance of results, type of outcome, and specialty area. Trial protocols should be made freely available, and the publications should describe and justify any changes made to protocol-defined outcomes.

Comparing Haemophilus influenzae type b conjugate vaccine schedules: a systematic review and meta-analysis of vaccine trials.

BACKGROUND: The optimal schedule and the need for a booster dose are unclear for Haemophilus influenzae type b (Hib) conjugate vaccines. We systematically reviewed relative effects of Hib vaccine schedules. METHODS: We searched 21 databases to May 2010 or June 2012 and selected randomized controlled trials or quasi-randomized controlled trials that compared different Hib schedules (3 primary doses with no booster dose [3p+0], 3p+1 and 2p+1) or different intervals in primary schedules and between primary and booster schedules. Outcomes were clinical efficacy, nasopharyngeal carriage and immunological response. Results were combined in random-effects meta-analysis. RESULTS: Twenty trials from 15 countries were included; 16 used vaccines conjugated to tetanus toxoid (polyribosylribitol phosphate conjugated to tetanus toxoid). No trials assessed clinical or carriage outcomes. Twenty trials examined immunological outcomes and found few relevant differences. Comparing polyribosylribitol phosphate conjugated to tetanus toxoid 3p+0 with 2p+0, there was no difference in seropositivity at the 1.0 µg/mL threshold by 6 months after the last primary dose (combined risk difference -0.02; 95% confidence interval: -0.10, 0.06). Only small differences were seen between schedules starting at different ages, with different intervals between primary doses, or with different intervals between primary and booster doses. Individuals receiving a booster were more likely to be seropositive than those at the same age who did not. CONCLUSIONS: There is no clear evidence from trials that any 2p+1, 3p+0 or 3p+1 schedule of Hib conjugate vaccine is likely to provide better protection against Hib disease than other schedules. Until more data become available, scheduling is likely to be determined by epidemiological and programmatic considerations in individual settings.

Vaginal practices as women's agency in sub-Saharan Africa: a synthesis of meaning and motivation through meta-ethnography.

This paper reports on a systematic review of qualitative research about vaginal practices in sub-Saharan Africa, which used meta-ethnographic methods to understand their origins, their meanings for the women who use them, and how they have evolved in time and place. We included published documents which were based on qualitative methods of data collection and analysis and contained information on vaginal practices. After screening, 16 texts were included which dated from 1951 to 2008. We found that practices evolve and adapt to present circumstances and that they remain an important source of power for women to negotiate challenges that they face. Recent evidence suggests that some practices may increase a woman's susceptibility to HIV and other sexually transmitted infections. The success of new female-controlled prevention technologies, such as microbicides, might be determined by whether they can and will be used by women in the course of their daily life.

Intravaginal practices, vaginal infections and HIV acquisition: systematic review and meta-analysis.

BACKGROUND: Intravaginal practices are commonly used by women to manage their vaginal health and sexual life. These practices could, however, affect intravaginal mucosal integrity. The objectives of this study were to examine evidence for associations between: intravaginal practices and acquisition of HIV infection; intravaginal practices and vaginal infections; and vaginal infections and HIV acquisition. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a systematic review of prospective longitudinal studies, searching 15 electronic databases of journals and abstracts from two international conferences to 31(st) January 2008. Relevant articles were selected and data extracted in duplicate. Results were examined visually in forest plots and combined using random effects meta-analysis where appropriate. Of 2120 unique references we included 22 publications from 15 different studies in sub-Saharan Africa and the USA. Seven publications from five studies examined a range of intravaginal practices and HIV infection. No specific vaginal practices showed a protective effect against HIV or vaginal infections. Insertion of products for sex was associated with HIV in unadjusted analyses; only one study gave an adjusted estimate, which showed no association (hazard ratio 1.09, 95% confidence interval, CI 0.71, 1.67). HIV incidence was higher in women reporting intravaginal cleansing but confidence intervals were wide and heterogeneity high (adjusted hazard ratio 1.88, 95%CI 0.53, 6.69, I(2) 83.2%). HIV incidence was higher in women with bacterial vaginosis (adjusted effect 1.57, 95%CI 1.26, 1.94, I(2) 19.0%) and Trichomonas vaginalis (adjusted effect 1.64, 95%CI 1.28, 2.09, I(2) 0.0%). CONCLUSIONS/SIGNIFICANCE: A pathway linking intravaginal cleaning practices with vaginal infections that increase susceptibility to HIV infection is plausible but conclusive evidence is lacking. Intravaginal practices do not appear to protect women from vaginal infections or HIV and some might be harmful.