Impact of diagnostic and end-of-induction Curie scores with tandem high-dose chemotherapy and autologous transplants for metastatic high-risk neuroblastoma: A report from the Children's Oncology Group

Background

Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end-of-induction (EOI) Curie scores (CS) was previously described in patients undergoing a single course of high-dose chemotherapy (HDC) and autologous hematopoietic cell transplant (AHCT) as consolidation therapy.

Objective

We now examine the prognostic significance of CS in patients randomized to tandem HDC and AHCT on the Children's Oncology Group (COG) trial ANBL0532.

Study design

A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 was performed. Evaluable patients had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received either single or tandem HDC (n = 80). Optimal CS cut points maximized the outcome difference (≤CS vs. >CS cut-off) according to the Youden index.

Results

For recipients of tandem HDC, the optimal cut point at diagnosis was CS = 12, with superior event-free survival (EFS) from study enrollment for patients with CS ≤ 12 (3-year EFS 74.2% ± 7.9%) versus CS > 12 (59.2% ± 7.1%) (p = .002). At EOI, the optimal cut point was CS = 0, with superior EOI EFS for patients with CS = 0 (72.9% ± 6.4%) versus CS > 0 (46.5% ± 9.1%) (p = .002).

Conclusion

In the setting of tandem transplantation for children with high-risk neuroblastoma, CS at diagnosis and EOI may identify a more favorable patient group. Patients treated with tandem HDC who exhibited a CS ≤ 12 at diagnosis or CS = 0 at EOI had superior EFS compared to those with CS above these cut points.     

A randomised cross‐over study showed no difference in diaphragm activity during weaning from respiratory support

Aim

We measured electrical activity of the diaphragm (Edi) to compare the breathing effort in preterm infants during weaning from respiratory support with high‐flow nasal cannulae (HFNC) or nasal continuous positive airway pressure (nCPAP).

Methods

This randomised cross‐over study was carried out at St Olav's University Hospital, Trondheim, Norway, from December 2013 to June 2015. We gave 21 preterm infants weighing at least 1000 g HFNC 6 L/minute for four hours and nCPAP 3 cmH₂O for four hours with a one‐hour wash‐out period. Measurements included diaphragmatic load, Edi, vital signs and a modified Silverman‐Andersen Retraction Score.

Results

We found no differences in HFNC and nCPAP in the median Edi peak (8.0 μV versus 7.8 μV, p = 0.095), median Edi min (1.1 μV versus 1.2 μV in, p = 0.958) or mean heart rate (157 versus 159, p = 0.300) in the 21 infants who took part. The mean respiratory rate was significantly lower during HFNC than nCPAP (47 versus 52, p = 0.012). The modified Silverman‐Andersen Retraction Score showed no significant differences.

Conclusion

This study of preterm infants found no difference in the breathing effort measured by Edi between HFNC 6 L/minute and nCPAP 3 cmH₂O. HFNC could replace nCPAP when preterm infants are ready for weaning.     

The management of pain during pediatric hematopoietic stem cell transplantation: A qualitative study of contextual factors that influenced pain management practices

Background

Children hospitalized following hematopoietic stem cell transplantation (HSCT) experience complex and prolonged pain in response to the intensity of this treatment.

Objectives

To describe how pain was managed for children during HSCT therapy and how contextual factors related to the clinical environment influenced healthcare providers' and parents' pain management practices.

Methods

A qualitative case study was conducted and involved semi-structured interviews at two time points following transplantation (30 and 90 days) with parents (n = 10) and naturalistic observations of pain-related care provided to children (n = 29) during HSCT therapy by their healthcare providers (n = 10). Semi-structured interviews were also conducted with healthcare providers (n = 14).

Results

The effectiveness of pain management interventions was hindered by the multifactorial nature of pain children experienced, a gap in the provision of psychosocial interventions for pain and a lack of evidence-based guidelines for the sustained, and often long-term, administration of opioids and adjuvant medications. Misconceptions were demonstrated by healthcare providers about escalating pain management according to pain severity and differentiating between opioid tolerance and addiction. Parents were active in the management of pain for children, especially the provision of nonpharmacological interventions. Collaboration with external pain services and the impact of caring for children in protective isolation delayed timely management of pain.

Conclusions

There is a pressing need to create evidence-based supportive care guidelines for managing pain post transplantation to optimize children's relief from pain. If parents and children are to be involved in managing pain, greater efforts must be directed toward building their capacity to make informed decisions.     

Poor family functioning mediates the link between childhood adversity and adolescent nonsuicidal self‐injury

Background

Non‐suicidal self‐injury (NSSI) is a common harmful behavior during adolescence. Exposure to childhood family adversity (CFA) is associated with subsequent emergence of NSSI during adolescence. However, the pathways through which this early environmental risk may operate are not clear.

Aims

We tested four alternative hypotheses to explain the association between CFA and adolescent‐onset NSSI.

Methods

A community sample of n = 933 fourteen year olds with no history of NSSI were followed up for 3 years.

Results

Poor family functioning at age 14 mediated the association between CFA before age 5 and subsequent onset of NSSI between 14 and 17 years.

Conclusions

The findings support the cumulative suboptimal environmental hazards ( proximal family relationships as a mediator) hypothesis. Improving the family environment at age 14 may mitigate the effects of CFA on adolescent onset of NSSI.     

B‐type natriuretic peptide for assessment of haemodynamically significant patent ductus arteriosus in premature infants

Aim

Haemodynamically significant patent ductus arteriosus (hsPDA) is frequently observed in premature infants. This study was conducted to explore whether the blood BNP can be a valuable biomarker to assess the necessity of treatment for hsPDA in premature infants.

Methods

Serial measurements of the blood BNP were performed during the first 5 days of life in premature infants with hsPDA (Group I) and those without hsPDA (Group N). The definition of the hsPDA was the PDA requiring treatment, such as indomethacin administration and/or surgical ligation.

Results

Forty‐six subjects were enrolled. Compared with Group N, Group I showed significantly higher level of blood BNP at postnatal 24–96 h and demonstrated the peak value at postnatal 24–48 h. With the ROC curve using the data at postnatal 24–48 h in Group I, we deduced the predictive value of 250 pg/mL of blood BNP for indomethacin treatment. Similarly, with the ROC curve using the maximal value of blood BNP within the first 5 days of life, the predictive value of 2000 pg/mL for surgical ligation was deduced.

Conclusions

Blood BNP during early postnatal period can be a useful biomarker to assess the necessity of treatment for hsPDA in premature infants.     

Impact of ovarian transposition before pelvic irradiation on ovarian function among long‐term survivors of childhood Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort Study

1 Background

We reviewed the effect of ovarian transposition (OT) on ovarian function among long‐term survivors of childhood Hodgkin lymphoma (HL) treated with pelvic radiotherapy.

2 Procedure

Female participants (age 18+ years) with HL in the St. Jude Lifetime Cohort Study (SJLIFE) were clinically evaluated for premature ovarian insufficiency (POI) 10 or more years after pelvic radiotherapy. Reproductive history including age at menopause and pregnancy/live births was available on all patients.

3 Results

Of 127 eligible females with HL, 90 (80%) participated in SJLIFE, including 49 who underwent OT before pelvic radiotherapy. Median age at STLIFE evaluation was 38 years (range 25–60). In a multiple regression adjusted for age at diagnosis, pelvic radiotherapy doses > 1,500 cGy (hazard ratio [HR] = 25.2, 95% confidence interval [CI] = 3.1–207.3; P = 0.0027) and cumulative cyclophosphamide equivalent doses of alkylating agents > 12,000 mg/m² (HR = 11.2, 95% CI = 3.4–36.8; P < 0.0001) were significantly associated with POI. There was no significant association between OT and occurrence of POI (HR = 0.6, 95% CI = 0.2–1.9; P = 0.41).

4 Conclusions

OT did not appear to modify risk of POI in this historic cohort of long‐term survivors of HL treated with gonadotoxic therapy. Modern fertility preservation modalities, such as mature oocyte cryopreservation, should be offered to at‐risk patients whenever feasible.     

Comparative study of preterm infants fed new and existing human milk fortifiers showed favourable markers of gastrointestinal status

Aim

This study examined the influence of different human milk fortifiers on biomarkers of gastrointestinal immaturity and inflammation in preterm infants.

Methods

We report secondary outcomes from a controlled, double-blind, randomised, parallel group study conducted from 2011 to 2014 in neonatal intensive care units at 11 metropolitan hospitals in France, Belgium, Germany, Switzerland and Italy. Preterm infants born at up to 32 weeks or weighing up to 1500 g were randomised to a new powdered human milk fortifier (n = 77) or a control fortifier (n = 76) for a minimum of 21 days. We analysed faecal markers of gut inflammation, namely alpha-1 antitrypsin and calprotectin, and maturity, namely elastase-1.

Results

Faecal alpha-1 antitrypsin was slightly lower in the new than control fortifier group after 21 days of full enteral feeding, with a geometric mean and standard deviation of 1.52 ± 1.32 vs 1.82 ± 1.44 mg/g stools (P = .01). There was no significant difference in faecal calprotectin (median [Q1-Q3] of 296 [136-565] μg/g stools in both groups combined at study day 21). Faecal elastase-1 was lower in the new fortifier than control fortifier group (202.5 ± 1.6 vs 257.7 ± 1.5 μg/g stools, P = .016).

Conclusion

Mean values for each parameter were within the ranges in healthy term infants, indicating favourable markers of gastrointestinal status in both groups. In addition, for faecal calprotectin, the relatively high concentration observed in preterm infants fed fortified human milk suggests that the threshold level for detecting necrotising enterocolitis should be revised.

     

Evaluation of cardiac iron load by cardiac magnetic resonance in thalassemia

Objective  

To quantify myocardial iron stores by Cardiac Magnetic Resonance (CMR).     

Determining the prevalence of vestibular screening failures in pediatric cancer patients whose therapies include radiation to the head/neck and platin‐based therapies: A pilot study

1 Background

Sensorineural hearing loss due to ototoxic cancer therapy is well established; effects on the vestibular system are unknown. We examined the feasibility of implementing vestibular screens for pediatric cancer survivors exposed to ototoxic agents. The prevalence of screening failures is reported.

2 Methods

Cancer survivors who were 6–17 years, at least 1‐month posttreatment, and received ototoxic therapy (radiation to the head/neck, cisplatin, carboplatin) were eligible. Screening measures included (1) Pediatric Vestibular Symptom Questionnaire, (2) Modified Clinical Test of Sensory Interaction on Balance, and (3) Dynamic Visual Acuity.

3 Results

Vestibular screening failures were observed in 30 participants (60%). Patients with a brain tumor diagnosis were at increased risk for failures compared to nonbrain tumor patients (74.2% vs. 36.8%, P = 0.009). Patients who underwent brain surgery were at increased risk for failures compared to patients without brain surgery (71% vs. 42%, P = 0.043). Patients with a longer duration between end of treatment and vestibular screening had a reduced risk of failures, with an almost 20% decrease for each year between the time points (odds ratio = 0.812; 95% confidence interval: 0.683–0.964, P = 0.018). Receiving carboplatin correlated with a decreased risk of failure (P = 0.016), due to a negative correlation with other clinical risk factors (diagnosis of a brain tumor, major brain surgery) that are associated with vestibular screening failure.

4 Conclusion

Vestibular screening failures are highly prevalent in childhood cancer survivors who received ototoxic therapy. Broad screening of this population and further characterization of these patients are warranted.     

Outcome of patients with undifferentiated embryonal sarcoma of the liver treated according to European soft tissue sarcoma protocols

Background

To assess the outcomes of pediatric patients with undifferentiated embryonal sarcoma of the liver (UESL) and treatment including at least surgery and systemic chemotherapy.

Methods

This study included patients aged up to 21 years with a pathological diagnosis of UESL prospectively enrolled from 1995 to 2016 in three European trials focusing on the effects of surgical margins, preoperative chemotherapy, use of radiotherapy (RT), and chemotherapy.

Results

Out of 65 patients with a median age at diagnosis of 8.7 years (0.6–20.8), 15 had T2 tumors, and one had lymph node spread, 14 were Intergroup Rhabdomyosarcoma Study (IRS) I, nine IRS II, 38 IRS III, and four IRS IV. Twenty-eight upfront surgeries resulted in five operative spillages and 11 infiltrated surgical margins, whereas 37 delayed surgeries resulted in no spillages (p = .0119) and three infiltrated margins (p = .0238). All patients received chemotherapy, including anthracyclines in 47. RT was administered in 15 patients. With a median follow-up of 78.6 months, 5-year overall and event-free survivals (EFS) were 90.1% (95% confidence interval [CI]: 79.2–95.5) and 89.1% (95% CI: 78.4–94.6), respectively. Two out four local relapses had previous infiltrated margins and two out of three patients with metastatic relapses received reduced doses of alkylating agents. Infiltrated margins (p = .1607), T2 stage (p = .3870), use of RT (p = .8731), and anthracycline-based chemotherapy (p = .1181) were not correlated with EFS.

Conclusions

Multimodal therapy improved the outcome of UESL. Neoadjuvant chemotherapy for pediatric patients increases the probability of complete surgical resection. The role of anthracyclines and RT for localized disease remains unclear.     

Eight-year-old very and extremely preterm children showed more difficulties in performance intelligence than verbal intelligence

Aim

This study determined possible discrepancies between verbal IQ and performance IQ in 8-year-old very preterm (VPT) and extremely preterm (EPT) children, and examined associations between verbal IQ and performance IQ, and sociodemographic factors, perinatal factors, early cognitive outcomes and also with school achievement scores.

Methods

This prospective cohort study included 120 eight-year-old VPT/EPT children. Cognitive development was assessed at the ages of 2, 5 and 8 years. Eight years’ school achievement results in arithmetic, reading and spelling were collected. Multiple regression analyses were performed to determine predictors of verbal IQ and performance IQ at the age of 8 years and to determine associations with school achievement scores.

Results

Mean performance IQ (89.8) was significantly lower than mean verbal IQ (99.4; Cohen's d = 0.59) at the age of 8 years. Gestational age (GA), small for GA status, and cognitive scores at the ages of 2 and 5 years significantly predicted verbal IQ and performance IQ at the age of 8 years. Performance IQ at age 8 years was an important predictor for arithmetic scores (β = 0.42).

Conclusion

Performance IQ was more strongly affected than verbal IQ in 8-year-old VPT/EPT children and was strongly related to mathematical difficulties.

     

Epidemiology of Childhood Injuries in Rural Puducherry,South India

Objective  

To study the epidemiology of injuries among children (<14 years) in a rural population.     

Hippocampal sclerosis in children younger than 2 years

Background  

Hippocampal sclerosis (HS) is rarely considered as a diagnosis in children younger than 2 years.     

Abnormal corpus callosum in neonates after hypoxic-ischemic injury

Background  

Literature regarding callosal injury after hypoxic-ischemic injury (HII) is scant.     

Intralaparoscopic endoscopy: its value during laparoscopic repair of choledochal cyst

Aim  

We report our experience of laparoscopic repair of choledochal cyst (CC).     

Facial deformation following treatment for pediatric head and neck rhabdomyosarcoma; the difference between treatment modalities. Results of a trans-Atlantic,multicenter cross-sectional cohort study

Background

The four different local therapy strategies used for head and neck rhabdomyosarcoma (HNRMS) include proton therapy (PT), photon therapy (RT), surgery with radiotherapy (Paris-method), and surgery with brachytherapy (AMORE). Local control and survival is comparable; however, the impact of these different treatments on facial deformation is still poorly understood. This study aims to quantify facial deformation and investigates the differences in facial deformation between treatment modalities.

Methods

Across four European and North American institutions, HNRMS survivors treated between 1990 and 2017, more than 2 years post treatment, had a 3D photograph taken. Using dense surface modeling, we computed facial signatures for each survivor to show facial deformation relative to 35 age–sex–ethnicity-matched controls. Additionally, we computed individual facial asymmetry.

Findings

A total of 173 HNRMS survivors were included, survivors showed significantly reduced facial growth (p < .001) compared to healthy controls. Partitioned by tumor site, there was reduced facial growth in survivors with nonparameningeal primaries (p = .002), and parameningeal primaries (p ≤.001), but not for orbital primaries (p = .080) All patients were significantly more asymmetric than healthy controls, independent of treatment modality (p ≤ .001). There was significantly more facial deformation in orbital patients when comparing RT to AMORE (p = .046). In survivors with a parameningeal tumor, there was significantly less facial deformation in PT when compared to RT (p = .009) and Paris-method (p = .007).

Interpretation

When selecting optimal treatment, musculoskeletal facial outcomes are an expected difference between treatment options. These anticipated differences are currently based on clinicians’ bias, expertise, and experience. These data supplement clinician judgment with an objective analysis highlighting the impact of patient age and tumor site between existing treatment options.     

A comparison of clinical protocols for assessing postoperative fecal continence in anorectal malformation

Background  

We compared four protocols for assessing fecal continence (FC) in anorectal malformation (ARM).     

The effect of montelukast on early‐life wheezing: A randomized,double‐blinded placebo‐controlled study

Background

Cysteinyl‐leukotrienes are increased in the airways of infants with virus‐associated wheezing. We aimed to determine the effects of a cysteinyl‐leukotriene‐1 receptor antagonist on symptoms during an early‐life wheezing illness and to investigate the factors that affect the response to this drug.

Method

This placebo‐controlled double‐blinded randomized controlled trial recruited children aged 3‐36 months with wheezing illness and randomized to active drug or placebo for 56 days. A symptom score diary (SSD) was kept by the children's caregivers.

Results

One‐hundred patients completed the study, and 62 (30 montelukast and 32 placebo) were analyzed. There were no significant differences in the percent of symptom‐free days, symptom scores, and the need for rescue salbutamol between the two groups. However, the percent of symptom‐free days within the first week was significantly higher for the montelukast than for the placebo group (13.8 ± 4.1% vs. 5.4 ± 3.4%; P = 0.028); wheezing score at 7th day was significantly lower for the montelukast than for the placebo group (0.5 ± 0.1 vs. 1.4 ± 0.2; P = 0.002). In addition, the number of inhaled ß₂‐agonist rescue episodes per day during the first week was significantly lower for the montelukast compared with the placebo group (12.7 ± 1.8 vs. 19.2 ± 1.6; P = 0.013).

Conclusions

Our results indicate that montelukast may be effective for reducing caregiver‐observed wheezing and the need for salbutamol during the first week of treatment for early‐life wheezing. The impact for caregivers and the optimal duration of treatment will need to be explored in studies of larger size.     

Study on Clinical Characteristics and Follow-up Visit of Acquired Aplastic Anemia Associated with Parvovirus B19 Infection

Objective  

To investigate clinical characteristics of parvovirus (B19) related aplastic anemia (AA).