Outcome after first relapse in children with acute lymphoblastic leukemia: a report based on the Dutch Childhood Oncology Group (DCOG) relapse all 98 protocol

Background

We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late relapse, without donor; (3) Postponement of cerebro‐spinal irradiation in late isolated CNS relapse; and (4) Treatment in very late bone marrow relapse with chemotherapy only.

Methods

From January 1999 until July 2006 all 158 Dutch pediatric patients with ALL in first relapse were recorded. Ninety‐nine patients were eligible; 54 patients with early and 45 with late relapse. Eighteen patients had an isolated extra‐medullary relapse; 69 patients had bone marrow involvement only.

Results

Five‐years EFS rates for early and late relapses were 12% and 35%, respectively. For early relapses 5 years EFSs were 25% for patients transplanted; 0% for non‐transplanted patients. For late relapses 5 years EFS was 64% for patients treated with chemotherapy only, and 16% for transplanted patients. For very late relapses EFS was 58%.

Conclusions

Our data suggest the superiority of SCT for early relapse patients. For late relapses a better outcome is achieved with chemotherapy only using the rotational chemotherapy scheme. The most important factor for survival was interval between first CR and occurrence of the first relapse. Pediatr Blood Cancer 2011; 57: 210–216. © 2011 Wiley‐Liss, Inc.

     

Treatment efficiency, outcome and surgical treatment problems in patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma: a report from the Cooperative Soft Tissue Sarcoma trial CWS-96

Background

To analyze the clinical course, treatment modalities, complications and outcome of patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma (BPRMS) treated on the CWS‐96 trial.

Procedure

There were 85 patients with BPRMS enrolled and 63 patients with embryonal non‐metastatic BPRMS were analyzed. Fifty‐six patients received neoadjuvant chemotherapy and response was assessed radiographically after 9 weeks. Local therapy with radiation and or surgery was performed based on age, tumor size, and response. Patients were treated with adjuvant chemotherapy following local control.

Results

Patient's age ranged from 0 to 16 years with a median follow up of 5.3 years. Eighty nine percent of the patients had IRS group III disease. The 5‐year overall survival (OS) for the whole group was 76.3 ± 5.6% and the 5‐year event‐free survival (EFS) 69.8 ± 6.2%. Seventeen patients underwent preoperative radiochemotherapy followed by tumor resection (5‐year‐OS: 87.8 ± 8.1%). Eight patients were treated with solely radiochemotherapy (87.5 ± 11.7%). Twenty‐five patients received chemotherapy and tumor resection (OS: 83.6 ± 7.5%). Thirteen patients underwent incomplete tumor resection and were treated with radiochemotherapy postoperatively (OS: 39.9 ± 14.8%, P < 0.05 vs. other groups).

Conclusions

Local therapy is an important factor for prognosis of localized embryonal BPRMS. Inadequate primary or secondary surgery compromises the outcome and should be avoided. Radiotherapy alone, complete surgical tumor resection or combined preoperative radiotherapy with surgical resection lead to similar good local control rates and prognosis. Pediatr Blood Cancer 2011;56:718–724. © 2010 Wiley‐Liss, Inc.

     

Influence of fitness on health status among survivors of acute lymphoblastic leukemia

Introduction

We aimed to determine the prevalence of self‐reported adverse health status among childhood acute lymphoblastic leukemia (ALL) survivors and to identify associations between components of physical fitness and health status.

Methods

Participants included 365 ALL survivors (mean age at evaluation of 28.6 ± 5.9 years) and 365 age‐, sex‐, and race‐matched community controls. Self‐report of poor general health, poor mental health, functional impairments, and activity limitations were used to describe adverse health status. Fitness was evaluated by assessing flexibility, muscular strength and endurance, peak oxygen uptake, and balance. Generalized linear models were used to examine associations between fitness metrics and health status.

Results

Survivors were more likely than controls to report poor general health (20.6% vs. 10.4%, risk ratio [RR] = 2.0, 95% confidence intervals [CI] = 1.4–2.9), poor mental health (28.0% vs. 14.5%, RR = 1.9, 95% CI = 1.4–2.6), functional impairments (10.5% vs. 4.1%, RR = 2.5, 95% CI = 1.4–4.6), and activity limitations (29.0% vs. 14.4%, RR = 2.0, 95% CI = 1.5–2.7). Survivors whose balance scores were more than 1.5 standard deviations below the mean of the control population were more likely to report poor general health (RR = 1.7, 95% CI = 1.1–2.8), poor mental health (RR = 1.9, 95% CI = 1.3–2.8), and functional limitations (RR = 2.5, 95% CI = 1.2–56). Survivors with low strength were more likely to report poor general health (RR = 1.8, 95% CI = 1.1–3.1), functional impairments (RR = 4.2, 95% CI = 1.7–10.4), and activity limitations (RR = 1.8, 95% CI = 1.2–2.8).

Conclusions

ALL survivors, particularly those with poor balance and reduced muscular strength, are at increased risk for adverse health status.

     

Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: A report from the Children's Oncology Group

Background

Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children's Oncology Group trial.

Procedure

Following surgery, patients received craniospinal radiotherapy with concurrent carboplatin followed by six months of maintenance chemotherapy with cyclophosphamide and vincristine.

Results

Five‐year overall survival (OS) and progression‐free survival (PFS) for all patients was 58 ± 7% and 48 ± 7%. For patients with pineoblastoma (n = 23), five‐year OS and PFS was 81 ± 9% and 62 ± 11%. Extent of resection but not M‐stage was prognostic. Five‐year OS and PFS for 37 patients with non‐pineal tumors (NPsPNET) was 44 ± 8% and 39 ± 8%, significantly worse than for PB (P = 0.055 and 0.009 respectively). Extent of resection and major radiotherapy deviations were prognostic. Five year OS was 59 +/? 11.4% for those undergoing complete resection versus 10.4 +/? 7% for those who did not (P = 0.017). Central pathologic review called 14 (38%) “classic” sPNET, 8 (22%) “undifferentiated” and 13 (35%) “malignant gliomas.” There was no significant difference between the subgroups, although survival distributions approached significance when the combined “classic” and “undifferentiated” group was compared to the “malignant gliomas.”

Conclusions

Carboplatin during RT followed by 6 months of non‐intensive chemotherapy is a feasible treatment strategy for patients with sPNET. Aggressive surgical resection should be attempted if feasible. The classification of supratentorial small cell malignancies can be difficult. Pediatr Blood Cancer 2015;62:776–783. © 2015 Wiley Periodicals, Inc.

     

Incidence of bacteremias and invasive mycoses in children with acute non‐lymphoblastic leukemia: Results from a multi‐center Italian study

Background

Data on the epidemiology of bacteremias and invasive fungal diseases (IFD) in children with acute myeloid leukemia (AML) are scarce.

Design and Methods

In a multi‐center, retrospective study, we analyzed proportion, rate per 1,000 person‐days at risk, and cumulative risk of bacteremias and IFD in children with AML.

Results

Between January 1998 and December 2005, 240 children were treated for AML at 8 Italian Centers, for a total of 521 treatment courses and 63,232 person‐days at risk. Bacteremia was observed in 32% of treatment courses and IFD was seen in 10% (P < 0.0001), with rates of 2.62 and 0.84, respectively (P < 0.001). There was a significantly higher frequency of IFD during relapse treatment: proportion 15% versus 9% (P = 0.05), rate 2.10 versus 0.64 (P = 0.008) and cumulative risk 32% versus 12% (P = 0.007), while there were no differences in the proportion, rate and cumulative risk of bacteremia during front‐line or relapse treatment. The epidemiology of bacteremias and IFD was different during front‐line therapy for M3 as compared to other types of AML, but the differences were not statistically significant.

Conclusions

Severe infectious complications are frequent during the treatment of pediatric AML, especially during relapse treatment, and bacteremias are more frequent than IFD. Pediatr Blood Cancer. 2010;55:1103–1107. © 2010 Wiley‐Liss, Inc.

     

Infliximab regulates monocytes and regulatory T cells in Kawasaki disease

Background

The effect of infliximab (IFX ) on immune cells has not been fully reported in Kawasaki disease (KD ). To investigate the mechanism of IFX in KD , we examined changes in the abundance of CD 14⁺CD 16⁺ activated monocytes, regulatory T cells (T_reg) cells, and T‐helper type 17 (Th17) cells following treatment with IFX .

Methods

We collected peripheral blood from patients with i.v. immunoglobulin (IVIG )‐resistant KD and analyzed absolute CD 14⁺CD 16⁺ monocyte, T_reg (CD 4⁺CD 25⁺FOXP 3⁺) and Th17 cell (CD 4⁺IL ‐17A⁺) counts on flow cytometry. We also measured changes in serum soluble interleukin (IL )‐2 receptor (IL ‐2R), IL ‐6, and tumor necrosis factor (TNF )‐α on enzyme‐linked immunosorbent assay.

Results

T_reg cells and Th17 cells significantly increased after IFX treatment compared with baseline (126 ± 85 cells/μL vs 62 ± 53 cells/μL, P < 0.01; 100 ± 111 cells/μL vs 28 ± 27 cells/μL, P < 0.05, respectively). In contrast, in a subgroup of patients with CD 14⁺CD 16⁺ monocytes above the normal range before IFX , the CD 14⁺CD 16⁺ monocytes significantly decreased following IFX treatment (72 ± 51 cells/μL vs 242 ± 156 cells/μL, P < 0.05).. Serum TNF ‐α did not change, but soluble IL ‐2R and IL ‐6 decreased after IFX treatment.

Conclusion

IFX could downregulate activated monocytes and upregulate T_reg cells towards the normal range. IFX treatment thus contributes to the process of attenuating inflammation in KD .

     

Bone marrow minimal disseminated disease (MDD) and minimal residual disease (MRD) in childhood T‐cell lymphoblastic lymphoma stage III,detected by flow cytometry (FC) and real‐time quantitative polymerase chain reaction (RQ‐PCR)

Background

Despite overlapping features of T‐cell lymphoblastic lymphoma (T‐LLy) and T‐cell acute lymphoblastic leukemia (T‐ALL), which respond favorably to T‐ALL treatment, clinical and biological differences exist. We retrospectively assessed the prevalence of submicroscopic bone marrow (BM) minimal disseminated disease (MDD) at diagnosis and the early response to treatment (minimal residual disease—MRD) and their prognostic significance in 17 children with stage III T‐LLy treated according to Berlin‐Frankfurt‐Munster (BFM) non‐Hodgkin lymphoma protocols.

Procedure

Four‐color flow cytometry (FC) was used for lymphoma associated immunophenotype and real‐time quantitative polymerase chain reaction (RQ‐PCR) for T‐cell receptor (TCR β/δ/γ) gene rearrangements with at least 0.01% sensitivity.

Results

Two markers per patient were identified in all cases using FC and in 80% using RQ‐PCR. BM MDD at diagnosis of ≥0.01% was detected by FC and RQ‐PCR in 88% and 80% of patients, respectively, and by at least one of the methods in all patients. A significant correlation was achieved between the methods by Pearson correlation analysis (P = 0.004). MRD levels significantly decreased to very low levels on day 33 in 9 out of 10 patients studied. The only patient that remained positive relapsed.

Conclusions

MDD was prevalent in stage III T‐LLy, for which we could not prove a prognostic significance in the context of ALL‐like treatment. This study shows that both FC and RQ‐PCR methods are efficient for MDD and MRD analyses in T‐LLy. Pediatr Blood Cancer 2009;52:20–25. © 2008 Wiley‐Liss, Inc.     

Five-year single-center study of asparaginase therapy within the ALL-BFM 2000 trial

Background

Therapeutic drug monitoring (TDM) of asparaginase (ASNase), a fundamental element of acute lymphoblastic leukemia treatment, was integrated in the ALL‐BFM 2000 protocol on a voluntary basis.

Methods

Over a 5‐year period, 127 patients (1,355 samples) were monitored for asparaginase activity in a single‐center setting. We report monitoring data from throughout the ASNase containing treatment elements. Additional information obtained on risk stratification, minimal residual disease (MRD), steroid randomization and relapse is discussed in relation to ASNase activity.

Results

At completion of the induction phase 93% (115/124) of patients showed sufficient ASNase activity (5,000 U/m² Escherichia coli ASNase), 77 of 86 (90%) monitored patients finished the first re‐intensification element without requiring Erwinia ASNase. MRD, risk stratification and steroid randomization were not associated with significant differences in ASNase activity. Of patients who relapsed, only 25% (3/12) were able to maintain sufficient ASNase activity after E. coli ASNase.

Conclusion

This single‐center data set gives a true and unbiased insight into clinical reality of ASNase therapy. It shows no significant relationship between MRD positivity or risk stratification and ASNase treatment intensity. Overall, within the ALL‐BFM 2000 trial, 90% of patients completed first re‐intensification without requiring third‐line Erwinia ASNase. Pediatr Blood Cancer 2011; 57: 378–384. © 2011 Wiley‐Liss, Inc.     

Observation study showed that the continuity of skin‐to‐skin contact with low‐birthweight infants in Uganda was suboptimal

Aim

Kangaroo mother care (KMC) is a safe and effective method of reducing neonatal mortality in resource‐limited settings, but there has been a lack of data on the duration of skin‐to‐skin contact (SSC) in busy, low‐resource newborn units. Previous studies of intermittent KMC suggest the duration of SSC ranged from 10 minutes to 17 hours per day.

Methods

This was an observational study of newborn infants born weighing less than 2000 g, which collected quantitative data on SSC over the first week after birth. The study took place in July 2016 in the newborn unit of a low‐resource facility in Uganda.

Results

The mean daily duration of SSC over the first week after birth was three hours. This differed significantly from the World Health Organization recommendation of at least 20 hours of SSC per day. SSC was provided by mothers most of the time (73.5%), but other family members also took part, especially on the day of birth.

Conclusion

Our study found a disappointingly low daily duration of SSC in this Ugandan newborn unit. However, advocacy and community education of SSC may help to decrease the stigma of KMC, improve overall acceptance and reduce the age at SSC initiation.

     

Quality of life in children with retinoblastoma after enucleation in China

Objective

To study the quality of life of Chinese pediatric patients with retinoblastoma (RB) after enucleation and the influencing factors.

Methods

A questionnaire survey was performed on 71 cases of pediatric patients with RB after enucleation and 80 cases of healthy children, using the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL? 4.0).

Results

The social dimension scores, school dimension scores, and total scores for the PedsQL? 4.0 among the pediatric patients with RB were statistically significantly lower than those of healthy children. The influencing factors were unilateral/bilateral affected eyes, diagnosis age, and ocular prosthesis satisfaction.

Conclusion

Early discovery, timely treatment, increased eye salvage rate, and cosmetic effects of ocular prosthesis were key factors for increasing the quality of life of pediatric patients with RB. Attention should be paid to the health, social, and school development of pediatric patients with RB.

     

Stress From Uncertainty and Resilience Among Depressed and Burned Out Residents: A Cross-Sectional Study

Background

Depression and burnout are highly prevalent among residents, but little is known about modifiable personality variables, such as resilience and stress from uncertainty, that may predispose to these conditions. Residents are routinely faced with uncertainty when making medical decisions.

Treatment of Langerhans cell histiocytosis with a modified risk‐adapted protocol—experience from a tertiary cancer institute in India

Background

Involvement of risk‐organs (RO+) in Langerhans cell histiocytosis (LCH) and inadequate early response identifies patients at high risk for relapse and mortality requiring intensive salvage therapy including stem cell transplant, adding cost and toxicity. To mitigate this, we used a standard induction, augmented with metronomic etoposide, and prolonged maintenance—similarly augmented for RO+, and retrospectively analyzed its impact.

Procedure

LCH patients from 2009 through 2014 were included. Patients received standard vinblastine and prednisolone therapy weekly till week 25 for RO+. Single site (SS) and multisystem (MS) without risk organ involvement (RO?) received 3‐weekly pulses from week 13 till week 25. Maintenance was 3‐weekly vinblastine and 5‐day prednisolone pulses, daily 6‐mercaptopurine (60 mg/m²) and weekly methotrexate (15 mg/m²) for 18 and 9 months for RO+ and MSRO?, respectively. RO+ also received oral etoposide (50 mg/m²) for 21 of every 28‐day cycle for the first year.

Results

Fifty consecutive patients were analyzed. Median age was 36 months (4–189 months). SS, MSRO?, and RO+ were 29 (58%), 12 (24%), and nine (18%), respectively. Four were lost to follow‐up and excluded from further evaluation. On response evaluation at week 6, 24 (52%) had no active disease (NAD), 17 (37%) had AD‐better (where AD is active disease), and one (2%) had AD‐worse. In RO+, eight (66.6%) had AD‐better and three (25%) had NAD. Forty‐five patients had NAD by week 12. Three patients relapsed. With median follow‐up of 39 months (8–84), 5‐year event free survival was 85.6% (RO? and SS), and 100% for RO+. One patient's death in remission from unrelated causes resulted in overall survival of 97%.

Conclusions

RO+LCH receiving oral etoposide augmented induction and maintenance had early and durable responses. Prolonging maintenance lowered reactivation rates in RO+ and RO?LCH, resulting in excellent survival.

     

Prospective evaluation for respiratory pathogens in children with sickle cell disease and acute respiratory illness

Background

Human rhinovirus (HRV), human coronavirus (hCoV), human bocavirus (hBoV), and human metapneumovirus (hMPV) infections in children with sickle cell disease have not been well studied.

Procedure

Nasopharyngeal wash specimens were prospectively collected from 60 children with sickle cell disease and acute respiratory illness, over a 1‐year period. Samples were tested with multiplexed‐PCR, using an automated system for nine respiratory viruses, Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Bordetella pertussis. Clinical characteristics and distribution of respiratory viruses in patients with and without acute chest syndrome (ACS) were evaluated.

Results

A respiratory virus was detected in 47 (78%) patients. Nine (15%) patients had ACS; a respiratory virus was detected in all of them. The demographic characteristics of patients with and without ACS were similar. HRV was the most common virus, detected in 29 of 47 (62%) patients. Logistic regression showed no association between ACS and detection of HRV, hCoV, hBoV, hMPV, and other respiratory pathogens. Co‐infection with at least one additional respiratory virus was seen in 14 (30%) infected patients, and was not significantly higher in patients with ACS (P = 0.10). Co‐infections with more than two respiratory viruses were seen in seven patients, all in patients without ACS. Bacterial pathogens were not detected.

Conclusion

HRV was the most common virus detected in children with sickle cell disease and acute respiratory illness, and was not associated with increased morbidity. Larger prospective studies with asymptomatic controls are needed to study the association of these emerging respiratory viruses with ACS in children with sickle cell disease. Pediatr Blood Cancer 2014;61:507–511. © 2013 Wiley Periodicals, Inc.

     

Nutritional therapy complications in children with ultra‐short bowel syndrome include growth deficiency but not cholestasis

Aim

Children with ultra‐short bowel syndrome (USBS) have not been extensively studied to date because the condition is rare. The aim of the study was to assess the nutritional status of children with USBS receiving home parenteral nutrition, using citrulline serum concentration and cholestasis.

Methods

We studied 17 patients with USBS, with a median age of 6.6 years and median duration of parenteral nutrition of 6.6 years. The study was carried out at The Children's Memorial Health Institute, Warsaw, from January 2014 to January 2015.

Results

The median standard deviation score (SDS) was ?1.2 for body mass according to chronological age, ?1.72 according to height and ?0.59 according to height for age. Patients requiring seven days per week parenteral nutrition had a citrulline concentration below 10 μmol/L. Decreased bone‐mineral density was observed in 87% of the patients. Low values of 25‐hydroxyvitamin D were found in 53% of the children. None of the patients had elevated conjugated bilirubin levels above 34.2 μmol/L.

Conclusion

Children with USBS were growth deficient according to their chronological age, with frequent abnormal bone mineralisation and vitamin D deficiency. Children requiring parenteral nutrition seven days a week had citrulline concentrations below 10 μmol/L. Cholestasis was not seen.

     

Virus detection in critically ill children with acute respiratory disease: a new profile in view of new technology

Aim

To describe the epidemiology of critically ill children admitted to a paediatric intensive care unit (PICU) with acute respiratory disease. The association with intubation was analysed for the three most prevalent viruses and in those with and without viral co‐infection.

Methods

Patients admitted to the PICU (2004–2014) with acute respiratory disease were included. Analyses were performed utilising each respiratory viral infection or multiple viral infections as an exposure.

Results

There were 1766 admissions with acute respiratory disease of which 1372 had respiratory virus testing and 748 had one or more viruses detected. The risk of intubation before or during the PICU stay was higher if parainfluenza virus was detected compared to respiratory syncytial virus (RSV) (OR: 2.20; 95% CI: 1.06–4.56). Sixty‐three admissions had two or more viruses detected, and the combination of RSV and Rhinovirus/enterovirus was the most common. No significant difference was observed in the risk of intubation between patients with multiple and single viral infections.

Conclusion

Higher risk of intubation was found in patients with parainfluenza as compared to RSV. The risk of intubation comparing parainfluenza virus to other viruses and for patients with multiple versus single virus needs to be further studied.

     

Gender disparities in preterm neonatal outcomes

Aim

From birth to old age, males generally have poorer disease outcomes compared to females. Preterm infants display a marked gender disparity in disease outcomes, and the underlying mechanisms are not well delineated. Our aim was to review the literature on clinical outcomes between preterm infants of different genders and discuss the potential mechanisms underlying the differences observed.

Methods

A literature review was undertaken for experimental and clinical research related to gender differences in preterm outcomes.

Results

Preterm male infants appear to have consistently worse outcomes compared to females, and the aetiology of these differences, while mostly undetermined, is likely multifactorial.

Conclusion

The male disadvantage in preterm outcomes is likely multifactorial with hormonal, genetic and immunological differences likely playing key roles. Gender is an important variable in preterm outcome and should be considered when designing clinical and experimental research.

     

Perspectives on periviability counselling and decision‐making differed between neonatologists in the United States and the Netherlands

Aim

American guidelines suggest that neonatal resuscitation be considered at 23 weeks of gestation, one week earlier than in the Netherlands, but how counselling practices differ at the threshold of viability is unknown. This pilot study compared prenatal periviability counselling in the two countries.

Methods

In 2013, a cross‐sectional survey was sent to 121 Dutch neonatologists as part of a nationwide evaluation of prenatal counselling. In this pilot study, the same survey was sent to a convenience sample of 31 American neonatologists in 2014. The results were used to compare the organisation, content and decision‐making processes in prenatal counselling at 24 weeks of gestation between the two countries.

Results

The survey was completed by 17 (55%) American and 77 (64%) Dutch neonatologists. American neonatologists preferred to meet with parents more frequently, for longer periods of time, and to discuss more intensive care topics, including long‐term complications, than Dutch neonatologists. Neonatologists from both countries preferred shared decision‐making when deciding whether to initiate intensive care.

Conclusion

Neonatologists in the United States and the Netherlands differed in their approach to prenatal counselling at 24 weeks of gestation. Cross‐cultural differences may play a role.