Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting.

PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR. An informative FCM-marker was found in 96.2% and only two patients (0.14%) had non-informative FCM and non-informative PCR-markers. The overall 5-year event-free survival was 86.1% with a cumulative incidence of relapse (CIR5y) of 9.5%. FCM-MRD levels on days 15 (HzR 4.0, p < 0.0001), 29 (HzR 2.7, p < 0.0001), and 79 (HzR 3.5, p < 0.0001) associated with hazard of relapse adjusted for age, cytogenetics, and WBC. The early (day 15) response associated with CIR5y adjusted for day 29 FCM-MRD, with higher levels in adults (median 2.4 × 10-2 versus 5.2 × 10-3, p < 0.0001). Undetectable FCM- and/or PCR-MRD on day 29 identified patients with a very good outcome (CIR5y = 3.2%). For patients who did not undergo transplantation, day 79 FCM-MRD > 10-4 associated with a CIR5y = 22.1%. In conclusion, FCM-MRD performed in a multicenter setting is a clinically useful method for MRD-based treatment stratification in BCP-ALL.

Correction: Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Multicenter randomized trial exploring effects of simulation-based ultrasound training on obstetricians' diagnostic accuracy: value for experienced operators.

OBJECTIVE: To explore the effects of simulation-based ultrasound training on the accuracy of fetal weight estimation in the third trimester among obstetricians with different levels of clinical experience. METHODS: This was a multicenter, randomized pre-post-test practical trial conducted between March 2016 and January 2018. Obstetricians with different levels of clinical experience were randomized to either simulation-based ultrasound training focusing on fetal weight scans or no intervention. Participants completed two scans in pregnant women at term to establish baseline accuracy of fetal weight estimation. Another two scans were performed at follow-up. Accuracy was defined by the percentage difference between estimated fetal weight and actual birth weight. Ultrasound image quality was rated by two expert raters. RESULTS: Seventy participants with different levels of clinical experience completed the study. Adjusting for clinical experience, the intervention group demonstrated an improvement in measurement accuracy of 31.9% (95% CI, 6.9-50.1%) (P = 0.02), whereas the control group did not improve (relative difference, 13.1% (95% CI, -17.9 to 55.9%); P = 0.45). The change in accuracy was significantly different between the groups (P = 0.02) and independent of clinical experience (P = 0.54). Image-quality scores improved by a mean of 1.2 (95% CI, 0.4-2.1) (P < 0.01) in the intervention group, with no change in the control group (mean difference, 0.1 (95% CI, -0.8 to 1.0); P = 0.78). There was a strong negative correlation between time spent using the simulator and clinical experience (r = -0.70, P = 0.0001). CONCLUSION: Simulation-based ultrasound training improved accuracy and image quality when performing fetal weight estimation in women at term, independent of obstetricians' clinical experience. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia.

Minimal residual disease (MRD) measured by PCR of clonal IgH/TCR rearrangements predicts relapse in T-cell acute lymphoblastic leukemia (T-ALL) and serves as risk stratification tool. Since 10% of patients have no suitable PCR-marker, we evaluated flowcytometry (FCM)-based MRD for risk stratification. We included 274 T-ALL patients treated in the NOPHO-ALL2008 protocol. MRD was measured by six-color FCM and real-time quantitative PCR. Day 29 PCR-MRD (cut-off 10-3) was used for risk stratification. At diagnosis, 93% had an FCM-marker for MRD monitoring, 84% a PCR-marker, and 99.3% (272/274) had a marker when combining the two. Adjusted for age and WBC, the hazard ratio for relapse was 3.55 (95% CI 1.4-9.0, p = 0.008) for day 29 FCM-MRD ≥ 10-3 and 5.6 (95% CI 2.0-16, p = 0.001) for PCR-MRD ≥ 10-3 compared with MRD < 10-3. Patients stratified to intermediate-risk therapy on day 29 with MRD 10-4-<10-3 had a 5-year event-free survival similar to intermediate-risk patients with MRD < 10-4 or undetectable, regardless of method for monitoring. Patients with day 15 FCM-MRD < 10-4 had a cumulative incidence of relapse of 2.3% (95% CI 0-6.8, n = 59). Thus, FCM-MRD allows early identification of patients eligible for reduced intensity therapy, but this needs further studies. In conclusion, FCM-MRD provides reliable risk prediction for T-ALL and can be used for stratification when no PCR-marker is available.

Transvaginal sonographic cervical length in first and second trimesters in a low-risk population: a prospective study.

OBJECTIVES: To assess cervical length (CL) longitudinally between the first and second trimesters and to determine the proportion of women with short CL. The study also aimed to assess if women with short CL at 19-24 weeks' gestation could be identified at the time of combined first-trimester screening (cFTS) at 11-14 weeks' gestation, in order to determine the potential value of implementation of CL screening for prediction of preterm delivery in a Danish population. METHODS: This was a prospective longitudinal study of women with singleton pregnancy attending three University Hospitals in Denmark for combined first-trimester screening from 1 November 2013 to 1 December 2014. Exclusion criteria were multiple pregnancy, uterine anomaly, cerclage or progesterone treatment at inclusion. CL was measured on transvaginal sonography at 11-14 weeks (Cx1), 19-21 weeks (Cx2) and 23-24 weeks (Cx3), by trained operators as a straight line from external to internal os. Women with CL ≤ 25 mm were referred to a maternal-fetal medicine specialist for treatment according to a standardized management protocol. RESULTS: Of the 4904 eligible women, 3477 (71%) participated and had Cx1 recorded. Of those, 3232 (93.0%) had CL measured on all three scans. Median Cx1 was 37 mm, and median Cx2 and Cx3 were 40 mm. The proportion of women with CL ≤ 25 mm increased with gestational age, from 0.41% (95% CI, 0.19-0.62%) at Cx1 to 1.79% (95% CI, 1.34-2.24%) at Cx3. In total, the proportion of women with second-trimester CL (Cx2 or Cx3) ≤ 25 mm was 2.0% (n = 67), of which 38.8% (n = 26) were detected at 19-21 weeks. The probability of short CL between 19 and 24 weeks was greater for those with shorter first-trimester CL. It was nearly nine-fold higher for women with Cx1 ≤ 25 mm compared with Cx1 ≥ 35 mm (17% vs 2%). The performance of Cx1 for prediction of short second-trimester CL was 50% at a 10% false-positive rate. It was found that more than 1500 women would need to be screened for short CL at 19-21 weeks to prevent one case of spontaneous preterm delivery before 34 weeks in a population such as the one in this study. CONCLUSIONS: There is an association between first-trimester CL and risk of short cervix in the second trimester. Once short CL was observed, risk of preterm delivery was greatly increased. However, whether universal CL screening should be implemented in this low-risk population depends on cost-benefit analysis taking into account the low proportions of women with short CL and at risk for preterm delivery. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Randomized trial to examine procedure-to-procedure transfer in laparoscopic simulator training.

BACKGROUND: Laparoscopic simulation has become a standard component of surgical training, but there is limited knowledge regarding skills transfer between procedural tasks. The objective was to investigate the specificity of procedural simulator training. METHODS: This was randomized single-centre educational superiority trial. Surgical novices practised basic skills on a laparoscopic virtual reality simulator. On reaching proficiency, participants were randomized to proficiency-based training. The intervention group practised two procedures on the simulator (appendicectomy followed by salpingectomy), whereas the control group trained on only one procedure (salpingectomy). The main outcomes were number of repetitions and time to proficiency for the second procedure. RESULTS: Ninety-six participants were randomized, of whom 74 per cent were women, with a median age of 26 years. The intervention group needed significantly fewer attempts than the control group to reach proficiency in the second procedure: median (i.q.r.) 22 (17-34) versus 32 (26-41) attempts, which corresponded to 24·1 per cent fewer attempts as assessed by multivariable analysis (P = 0·004). The intervention group required significantly less time than the control group to reach proficiency: median (i.q.r.) 88 (63-127) versus 131 (101-153) min respectively, corresponding to a difference of 31·1 min as assessed by multivariable analysis (P = 0·001). CONCLUSION: Practising two procedures, compared with only one, reduced the number of attempts and time to reach proficiency in the second procedure. Skills transfer is seen between two tasks in laparoscopic simulator training; however, task specificity is still present when practising procedures. REGISTRATION NUMBER: NCT02069951 (http://www.clinicaltrials.gov).

Crown-rump length discordance in the first trimester: a predictor of adverse outcome in twin pregnancies?

OBJECTIVES: To evaluate the usefulness of first-trimester crown-rump length (CRL) discordance in predicting adverse outcome in twin pregnancies. METHODS: This retrospective study included a large cohort retrieved from local ultrasound databases at 14 obstetric departments in Denmark, comprising all twin pregnancies with two live fetuses scanned between 11 and 14 weeks' gestation during the period 1 January 2004 to 31 December 2006. The association between CRL discordance ≥ 10 % and adverse outcome was evaluated. RESULTS: Among 1993 twin pregnancies, 1733 were dichorionic (156 (9%) discordant; 1577 (91%) concordant) and 260 were monochorionic (32 (12%) discordant; 228 (88%) concordant). In dichorionic twin pregnancies we found an association between CRL discordance ≥ 10% and preterm delivery before 34 weeks' gestation (P=0.007), birth weight discordance (P=0.001) and mean birth weight (P=0.033). In monochorionic twin pregnancies we found an association between CRL discordance ≥ 10% and birth weight discordance (P=0.02) and mean birth weight (P=0.03). To evaluate CRL discordance as a predictor of fetal loss and preterm delivery before 34 weeks' gestation, receiver-operating characteristics curves were created for each outcome. For CRL discordance ≥ 10% as a predictor of fetal loss and preterm delivery in dichorionic twin pregnancies, sensitivity was 0.17 (95% CI, 0.06-0.28) and 0.14 (95% CI, 0.10-0.18), respectively, and in monochorionic twin pregnancies it was 0.10 (95% CI, 0.03-0.22) and 0.16 (95% CI, 0.06-0.26), respectively. CONCLUSIONS: CRL discordance in twin pregnancies is associated with, but is not a strong predictor of, adverse outcome.

Physicians compliance during maintenance therapy in children with Down syndrome and acute lymphoblastic leukemia.

Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have an inferior prognosis compared with non-DS ALL patients. We reviewed methotrexate (MTX)/mercaptopurine (6MP) maintenance therapy data for children with DS treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL92 or the NOPHO ALL2000 protocols between 1992 and 2007. The 5-year event-free survival probability (pEFS(5 yr)) for the 66 DS patients was inferior to the 2602 non-DS patients (0.50 ± 0.07 vs 0.77 ± 0.01 (P<0.001)). The 48 DS patients in first remission at the beginning of maintenance therapy had pEFS(10 yr) below that of the 522 non-DS control patients (pEFS(10 yr): 0.58 (95% confidence interval (CI) 0.43-0.77) vs 0.83 (95% CI 0.80-0.86), respectively (P<0.0001)). The DS patients received lower median doses of MTX (median: 11.8 vs 15.4 (P<0.0001)) and 6MP (median: 43.6 vs 59.4 (P<0.0001)). In Cox regression analysis, male gender, presence of DS and high median maintenance therapy white blood cell levels (mWBC) were associated with increased risk for relapse. DS-ALL patients with mWBC above or below 3.5 × 10(9)/l (protocol target) had pEFS(10 yr) of 0.31 and 0.72 (P=0.02), and the mWBC hazard ratio for DS-ALL patients was 2.0 (P<0.0005). We conclude that insufficient treatment intensity during maintenance therapy of DS-ALL patients may contribute to their poor prognosis.

Risk factors of recurrent anal sphincter ruptures: a population-based cohort study.

OBJECTIVE: To determine the incidence and risk factors of recurrent anal sphincter rupture (ASR). DESIGN: Population-based retrospective cohort study. SETTING: Data were taken from the National Medical Birth Registry, Denmark. POPULATION: Patients with a first and a second vaginal delivery in the time period 1997-2010. METHODS: Univariate analysis and multivariate logistic regression were used to determine risk factors of recurrent ASR. MAIN OUTCOME MEASURES: The incidence of recurrent ASR and odds ratios for possible risk factors of recurrent ASR: age, body mass index, grade of ASR, birthweight, head circumference, gestational age, presentation, induction of labour, oxytocin augmentation, epidural, episiotomy, vacuum extraction, forceps, shoulder dystocia, delivery interval and year of second delivery. RESULTS: Out of 159 446 women, 7336 (4.6%) experienced an ASR at first delivery, and 521 (7.1%) had a recurrent ASR (OR 5.91). The risk factors of recurrent ASR in the multivariate analysis were: birthweight (adjusted OR, aOR, 2.94 per increasing kg, 95% CI 2.31-3.75); vacuum extraction (aOR 2.96, 95% CI 2.03-4.31); shoulder dystocia (aOR 1.98, 95% CI 1.11-3.54); delivery interval (aOR 1.08 by year, 95% CI 1.02-1.15); year of second delivery (aOR 1.06, 95% CI 1.03-1.09); and prior fourth-degree ASR (aOR 1.72, 95% CI 1.28-2.29). Head circumference was a protective factor (aOR 0.91 per increasing cm, 95% CI 0.85-0.98). CONCLUSIONS: The incidence of recurrent ASR was 7.1%. Risk factors of recurrent ASR were excessive birthweight, vacuum extraction, shoulder dystocia, delivery interval, year of second delivery and prior fourth-degree ASR. A larger head circumference reduced the risk of recurrent ASR.

Estimation of dynamic treatment strategies for maintenance therapy of children with acute lymphoblastic leukaemia: an application of history-adjusted marginal structural models.

Childhood acute lymphoblastic leukaemia is treated with long-term intensive chemotherapy. During the latter part of the treatment, the maintenance therapy, the patients receive oral doses of two cytostatics. The doses are tailored to blood counts measured on a weekly basis, and the treatment is therefore highly dynamic. In 1992-1996, the Nordic Society of Paediatric Haematology and Oncology (NOPHO) conducted a randomised study (NOPHO-ALL-92) to investigate the effect of a new and more sophisticated dynamic treatment strategy. Unexpectedly, the new strategy worsened the outcome for the girls, whereas there were no treatment differences for the boys. There are as yet no general guidelines for optimising the treatment. On basis of the data from this study, our goal is to formulate an alternative dosing strategy. We use recently developed methods proposed by van der Laan et al. to obtain statistical models that may be used in the guidance of how the physicians should assign the doses to the patients to obtain the target of the treatment. We present a possible strategy and discuss the reliability of this strategy. The implementation is complicated, and we touch upon the limitations of the methods in relation to the formulation of alternative dosing strategies for the maintenance therapy.

Vaccination associated thrombocytopenic purpura in children.

Patients who presented with purpura and blood platelets <30x10(9)/l within 1 month after vaccination were collected from a population based material of 506 consecutive pediatric patients with newly diagnosed ITP. Of the 35 such patients, 24 had thrombocytopenia after MMR vaccination giving an estimated ITP risk of approximately 1 in 30,000 MMR inoculations. Symptoms of the 35 patients were nearly always acute. Thrombocytopenia disappeared within a month in 74% of the study patients and lasted longer than 6 months in only 10%. Bleeding episodes were uncommon during the follow-up period. We conclude that the incidence of symptomatic thrombocytopenia after vaccinations is much lower than that after respective natural infections and that the outcome in most cases is excellent.

Impact of age and sex on sudden cardiovascular death following myocardial infarction.

OBJECTIVE: To evaluate and compare the risk of sudden cardiovascular death (SCD) and non-SCD after myocardial infarction (MI) associated with age and sex. DESIGN: Cohort study of patients admitted with an enzyme verified acute MI and discharged alive. Patients were followed up for up to four years. PATIENTS: 5983 consecutive hospital survivors of acute MI were enrolled in the TRACE (trandolapril cardiac evaluation) registry from 1990-92. Four age groups were prespecified: < 56, 56-65, 66-75, and > or = 76 years. MAIN OUTCOME MEASURES: SCD was defined as cardiovascular death within one hour of onset of symptoms. RESULTS: There were 536 SCD and 725 non-SCD. SCD mortality was 4.8% in the youngest and 15.7% in the oldest age groups. Non-SCD mortality was 3.5% and 25%, respectively. The ratio of SCD to non-SCD mortality varied from 1.44 in the youngest (< 56 years) to 0.55 in the oldest patients (> or = 76 years). Age significantly increased both SCD and non-SCD risk (p < 0.0001), but the increase in non-SCD risk was 40% higher (p < 0.0001). Male sex was associated with increased risk of SCD independently of age (risk ratio 1.34, p < 0.005). However, the absolute three year probability of SCD among women older than 66 years exceeded 10%. CONCLUSIONS: Compared with non-SCD the risk of SCD is relatively highest in the younger age groups, but the absolute risk of SCD is much higher among the upper age groups than the younger. The risk of SCD was slightly lower in women but not enough to warrant a different treatment strategy.

Antibacterial prophylaxis with trimethoprim-sulfamethoxazole during induction treatment for acute lymphoblastic leukemia.

BACKGROUND AND PURPOSE: Children with acute lymphoblastic leukemia are treated with intensive chemotherapy resulting in profound immuno suppression. Therefore treatment with trimethoprim-sulfamethoxazole (TMP-SMX) may be used for prophylaxis against infections both with bacteria and Pneumocystis carinii in some departments. The use of TMP-SMX for prophylaxis during the induction therapy is not uniform in the four departments of pediatric oncology in Denmark. This gave us the opportunity to describe the effect of TMP/SMX on bacterial infections in children with ALL during the induction therapy. MATERIAL AND METHODS: Between January 1st 1992 and December 31st 1997, 210 children were diagnosed with ALL in Denmark. Based on a retrospective review of the medical charts the number of children with fever (>38 degrees C), the number of febrile days, days of antibiotic treatment and the number of positive blood cultures were registered for every febrile episode. RESULTS: One hundred and fourteen children received TMP/SMX prophylaxis (10-30 mg/SMX/kg/day) and 76 did not. Children who received TMP/SMX prophylaxis had significantly fewer episodes of fever (66/114 (58%) v 60/76 (79%), p <0,01), and significantly fewer children who received TMP/SMX prophylaxis had positive blood cultures before start of antibiotic treatment compared with children who did not receive prophylaxis (23/114 (20%) vs 37/76 (49%), p<0.001)). Nineteen different species were isolated from the blood stream before start of antibiotic treatment. In the non-prophylaxis group there was a preponderance of isolates with Staph. aureus, Str. pneumoniae, E. coli and P. aeruginosa. There was no difference in the mortality between the two groups (p=0.44). There were no cases of P carinii pneumonia in the period of induction therapy. CONCLUSION: TMP/SMX prophylaxis during induction therapy for childhood ALL seems to reduce the risk of bacteremias and febrile illness.

[Granulosa cell tumors in children]. / Granulosacelletumorer hos børn.

Juvenile granulosa cell tumours (JGCT) are rare. They may develop in ovarian or testicular tissue. In childhood a special histological type called juvenile granulosa cell tumour (JGCT) is seen. Four cases are described: Congenital JGCT in a child with sex chromosomal abnormity (45 XO/46 XdicYq) and tumour arising from immature testicular tissue, JGCT in the testis of a four month old boy, JGCT associated with a hypothalmic hamartoma in a 18 month-old girl, and JGCT in an eight year-old girl. In all cases the tumours were benign.

The epidemiology of febrile malaria episodes in an area of unstable and seasonal transmission.

This study investigated the epidemiology of uncomplicated falciparum malaria in an area of unstable and seasonal transmission in eastern Sudan. About 90% of malaria morbidity in this region occurs in the months of September to November, and very few malaria cases occur during the intensely arid Sudanese dry season and during years of drought. The malaria situation in the study site, the village of Daraweesh, was analysed during 3 consecutive malaria seasons in 1993-95 during which the 457 inhabitants suffered at total of 436 episodes of falciparum malaria. Using an Andersen-Gill proportional hazard model for recurrent events stratified by family, we have calculated the relative hazard for clinical malaria episodes by age, sex, haemoglobin genotype, blood type and infection in the previous season. The malaria risk was significantly lower in individuals aged 20-88 years than in the 5-19 years age-group. The relative protection due to adulthood varied between seasons (relative risk, RR, 0x34 to 0x67). Serological data were not consistent with the hypothesis that the age difference in incidence was due to differences in exposure. During the 1993 season the malaria incidence in males was lower than in females (RR = 0x75), during the 1994 season the incidences were comparable, whereas males had an increased risk of malaria in 1995 (RR = 1x87). The relative risk in individuals carrying the haemoglobin AS genotype compared to homozygous AA individuals was 0x57.

Role of parvovirus B19 infection in childhood idiopathic thrombocytopenic purpura.

Although parvovirus B19 exhibits a strong tissue-tropism for erythroid progenitor cells leading to anaemia, several case reports indicate that parvovirus B19 infection may also cause the development of thrombocytopenia. Despite recent studies, the frequency and clinical relevance of this association have remained questionable. Consequently, and in view of the paucity of evidence regarding a viral aetiology for idiopathic thrombocytopenic purpura (ITP), we examined the role of parvovirus B19 in 47 children with newly diagnosed ITP. Specific viral DNA indicating a current or recent parvovirus B19 infection was demonstrated in 6 of 47 patients (13%) employing the polymerase chain reaction technique. Our study suggests that children with ITP and associated parvovirus B19 infection are characterized by acute onset of profound thrombocytopenia. Among the parvovirus B19 positive children, duration of disease was brief in three children treated with immunoglobulin but chronic in the remaining three patients given high-dose steroids. Prospective studies are needed to confirm these initial observations. This virus should be considered as a possible aetiologic agent in some children with ITP.