Congenital Heart Disease Long‐term Improvement in Functional hEalth (CHD LIFE): A partnership programme to improve the long‐term functional health of children with congenital heart disease in Queensland

Children who undergo open‐heart surgery in the first year of life for congenital heart disease (CHD) are at high‐risk for impaired development across multiple domains. International recommendations include systematic periodic developmental surveillance into adolescence and the establishment of long‐term follow‐up programmes. This article describes the establishment and evolution of the Queensland Paediatric Cardiac Service neurodevelopmental follow‐up programme – CHD LIFE (Long‐term Improvement in Functional hEalth). Contextualising best practice recommendations to ensure a family‐centred and sustainable approach to understand and support the long‐term functional health needs of high‐risk children with CHD as standard care was needed. We describe the transition from a centralised pilot Programme to the implementation of an integrated statewide approach aimed at delivering consistent high‐level standards of care and a platform to evaluate therapeutic interventions.     

Safety and efficacy of inhaled nitric oxide treatment for premature infants with respiratory distress syndrome: follow-up evaluation at early school age

Aims: The aims of the study were to assess the long‐term safety and compare neurodevelopmental outcomes in school‐age children born prematurely who received inhaled nitric oxide or placebo during the first week of life in a randomized, double‐blinded study. Children treated with inhaled nitric oxide had previously been shown to have decreased intraventricular haemorrhage and periventricular leukomalacia as newborns and decreased cognitive impairment at 2 years (L.W. Doyle and P.J. Anderson. (2005) Arch Dis Child Fetal Neonatal Ed, 90, F484–F8). Methods: It is follow‐up study of medical outcomes, neurodevelopmental assessment and school readiness in 135 of 167 (81%) surviving premature infants seen at 5.7 ± 1.0 years. Results: Compared to placebo‐treated children (n = 65), iNO‐treated children (n = 70) demonstrated no difference in growth parameters, school readiness or need for subsequent hospitalization. However, iNO‐treated children were less likely to have multiple chronic morbidities or technology dependence (p = 0.05). They also had less functional disability (p = 0.05). Conclusion: These results demonstrate the long‐term safety of iNO in premature infants. Furthermore, iNO treatment may improve health status by decreasing the incidence of severe ongoing morbidities and technology dependence and may also decrease the incidence of educational and community functional disability of premature infants at early school age.     

Surveillance imaging for high‐grade childhood brain tumors: What to do 10 years after completion of treatment?

Brain tumors are the second most common childhood cancer. Treatment protocols for high‐grade pediatric brain tumors recommend regular follow‐up imaging for up to 10 years. We review maximal time to recurrence and minimal time to radiologically detectable long‐term sequelae such as secondary malignancies, vascular complications, and white matter disease. No tumors recurred after the 10‐year point, but radiological long‐term sequelae grew more common as the treatment completion date receded. We do not recommend regular imaging more than 10 years after treatment has ended, unless there are clinical symptoms.     

Peritoneal sarcomatosis in pediatric malignancies

Peritoneal sarcomatosis (PSC) is defined as peritoneal involvement of multiple sarcomatous tumors. Desmoplastic small round cell tumors (DSRCT) and rhabdomyosarcomas are the most common pediatric PSC cases. PSC has been treated with chemotherapy and mainly palliative surgery, but long‐term outcome has been poor. New imaging technologies have improved the evaluation of disease extent and patterns of peritoneal dissemination, and cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is being evaluated as a treatment option to prolong remission in pediatric patients. We will review the clinical characteristics, potential biologic mechanisms, radiographic characteristics, and potential therapies for pediatric PSC patients. Pediatr Blood Cancer 2013; 60: 12–17. © 2012 Wiley Periodicals, Inc.     

Recognizing Endocrinopathies Associated With Tyrosine Kinase Inhibitor Therapy in Children With Chronic Myelogenous Leukemia

Side effects of tyrosine kinase inhibitor (TKI) treatment vary in children and adults with chronic myelogenous leukemia (CML). As children have a much longer life expectancy than adults, TKI therapy may continue for decades and with long‐term consequences that differ from adults. Children may develop endocrinopathies related to “off‐target” effects of TKIs, such as delayed growth, changes in bone metabolism, thyroid abnormalities, and effects on puberty and fertility. These endocrinopathies present additional challenges for pediatric patients with CML. This review critically evaluates the literature on long‐term endocrine side effects of TKIs in the pediatric CML population and provides suggested recommendations.     

Thyroid cancer after radiotherapy for childhood cancer*

The thyroid gland in children is among the most sensitive organs to the carcinogenic effects of ionizing radiation, and very young children are at especially high risk. Risk associated with exposure to external X‐ or γ‐radiation increases linearly with increasing dose to the thyroid gland at low‐to‐moderate doses, but the dose–response relationship appears to flatten at the very high doses characteristic of cancer radiotherapy. Because of the extreme sensitivity of the thyroid gland in children, there is a risk of radiation‐induced thyroid cancer even when the thyroid gland is outside of the irradiated field. Increased incidence of thyroid cancer has been noted following radiotherapy for childhood Hodgkin disease, non‐Hodgkin lymphoma, neuroblastoma, Wilms tumor, acute lymphocytic leukemia and tumors of the central nervous system. Radiation‐induced tumors begin to appear 5–10 years after irradiation and excess risk persists for decades, perhaps for the remainder of life. The background incidence of thyroid cancer is two‐ to threefold higher among females than males, and the absolute increase in risk due to irradiation is higher in females as well. Most of the thyroid cancers that occur in association with irradiation are of the papillary type, for which the cure rate is high if tumors are detected early. This highlights the importance of long‐term surveillance of persons irradiated during childhood. Important areas for research include the possibility that children with certain types of first cancer are especially susceptible, the basis of the greater female susceptibility, the joint effects of radiation and other factors, and genetic mechanisms in radiation‐induced and spontaneously occurring thyroid cancer. Med. Pediatr. Oncol. 36:568–573, 2001. © 2001 Wiley‐Liss, Inc.     

Stroke in Swedish children II: long‐term outcome

Aim: To evaluate the long‐term outcome of childhood stroke in a population‐based cohort of Swedish children. Methods: We followed up children with stroke over 7 years from 2000 to 2006 in a health care region covering one‐fifth of the Swedish population. Children aged between 28 days and 18 years, who had arterial ischaemic stroke, cerebral sinus venous stroke or nontraumatic haemorrhagic stroke, were included. The long‐term outcome study 1.6–8.6 years later included a clinical investigation, evaluation of school performance, everyday activities and participation and health‐related quality of life questionnaires (International Classification of Functioning, Disability and Health, Child Health Questionnaire and Short‐Form General Health Survey). Results: Of 51 children, 4 (8%) had died and 85% of the long‐term survivors had some acquired impairment: 65% of the children had neurological impairment, and 59% had deficits affecting school activity and participation. The parents experienced the negative effect of the stroke on their child’s general health, daily life activities and participation and also on their own family life. Conclusion: Childhood stroke results in serious long‐term functional deficits in 85% of survivors affecting their everyday life, the child’s performances and the life of the family as a whole.     

The association of breastfeeding with insulin resistance at 17 years: Prospective observations from Hong Kong's “Children of 1997” birth cohort

Breastfeeding has many benefits for mother and infant. Whether breastfeeding also protects against type 2 diabetes is unclear. To clarify the role of breastfeeding in type 2 diabetes, we assessed the association of breastfeeding with insulin resistance in late adolescence in a birth cohort from a non‐Western setting where breastfeeding was not associated with higher socio‐economic position. We used multivariable linear regression, with multiple imputation and inverse probability weighting, to examine the adjusted associations of contemporaneously reported feeding in the first 3 months of life (exclusively breastfed, mixed feeding, or always formula‐fed) with fasting glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA‐IR) at 17 years in a subset (n = 710, 8.6% of entire cohort) of the Hong Kong Chinese birth cohort “Children of 1997.” We found a graded association of breastfeeding exclusivity in the first 3 months of life with lower fasting insulin and HOMA‐IR (p‐for‐trend < .05), but not fasting glucose, at 17 years. Exclusively breastfed adolescents (7%) had nonsignificantly lowest fasting insulin and HOMA‐IR, adjusted for sex, birth weight, parity, length of gestation, pregnancy characteristics, parents' education, and mother's place of birth. Exclusively breastfeeding for 3 months may be causally associated with lower insulin resistance in late adolescence. Further follow‐up studies into adulthood are required to clarify the long‐term protection of breastfeeding from type 2 diabetes.     

Sirolimus for the treatment of complicated vascular anomalies in children

Background

Vascular anomalies comprise a diverse group of diagnoses. While infantile hemangiomas are common, the majority of these conditions are quite rare and have not been widely studied. Some of these lesions, though benign, can impair vital structures, be deforming, or even become life‐threatening. Vascular tumors such as kaposiform hemangioendotheliomas (KHE) and complicated vascular malformations have proven particularly difficult to treat.

Procedure

Here we retrospectively evaluate a series of six patients with complicated, life‐threatening vascular anomalies who were treated with the mTOR inhibitor sirolimus for compassionate use at two centers after failing multiple other therapies.

Results

These patients showed significant improvement in clinical status with tolerable side effects.

Conclusions

Sirolimus appears to be effective and safe in patients with life‐threatening vascular anomalies and represents an important tool in treating these diseases. These findings are currently being further evaluated in a Phase II safety and efficacy trial. Pediatr Blood Cancer 2011; 57: 1018–1024. © 2011 Wiley‐Liss, Inc.     

Multivisceral transplantation for abdominal tumors in children: A single center experience and review of the literature

Standard management of intra‐abdominal pediatric solid tumors requires complete resection. However, tumors with multiple organ and vascular involvement present a unique surgical challenge. We conducted a retrospective chart review of four patients, aged 2‐14 years, undergoing MVT for intra‐abdominal tumors with significant involvement of the visceral arteries and/or portomesenteric venous system at our institution. Indications for MVT included hepatocellular carcinoma, inflammatory myofibroblastic tumor, and two cases of hepatoblastoma. Grafts included liver, stomach, small bowel, and pancreas in all patients, with two patients also receiving spleens, and one, a partial esophageal transplant. Median hospital stay was 80 days. Postoperative complications included reoperation for abdominal hematoma and bowel obstruction, steroid responsive intestinal rejection, wound dehiscence, fungemia, seizures, and chyle leak with pleural effusion. One patient developed Epstein‐Barr virus‐associated complications which responded well to treatment. On follow‐up (range 2.8‐7.8 years), all patients have satisfactory graft function and no evidence of recurrent disease. MVT is an effective means of achieving complete gross resection of intra‐abdominal malignancies in patients with multiple organ and vascular involvement.     

Secondary neuroendocrine tumor after allogeneic bone marrow transplantation

Here we report a case of aggressive neuroendocrine tumor (NET), which is an extremely rare secondary solid tumor that occurs after allogeneic hematopoietic cell transplantation (allo‐HSCT). A patient with chronic active Epstein–Barr virus infection received allo‐HSCT from an HLA‐DR two allele‐mismatched unrelated donor. Four years later, he developed NET with multiple metastases. He received thoraco‐abdominal irradiation as a conditioning regimen, and developed repeated episodes of intestinal graft‐versus‐host disease, for which he received long‐term immunosuppressive therapy. Although these factors may be potential contributing factors to the development of secondary NET, the exact pathogenesis remains unclear.     

Acute megakaryocytic leukemia (AMKL,FAB;M7) with Beckwith–wiedemann syndrome

Beckwith–Wiedemann syndrome (BWS) is characterized by an accumulation of multiple congenital anomalies. Although patients with BWS are known to have a higher incidence of embryonal tumors, there has been no reports associated with acute leukemia. This report describes the case of a patient with BWS who developed Acute Megakaryocytic Leukemia (AMKL,FAB;M7). Because most patients with BWS present gigantism, the therapy‐related toxicity of chemotherapy can be a very serious problem. This patient exhibited no therapy‐related toxicity after chemotherapy, suggesting that acute leukemia with BWS may not require a reduction in dosage. Pediatr Blood Cancer. 2010;55:733–735. © 2010 Wiley‐Liss, Inc.     

Functional validation of the oncogenic cooperativity and targeting potential of tuberous sclerosis mutation in medulloblastoma using a MYC‐amplified model cell line

Medulloblastoma is the most common malignant brain tumor of childhood. To identify targetable vulnerabilities, we employed inhibitor screening that revealed mTOR inhibitor hypersensitivity in the MYC‐overexpressing medulloblastoma cell line, D341. Concomitant exome sequencing unveiled an uncharacterized missense mutation, TSC2^A415V, in these cells. We biochemically demonstrate that the TSC2^A415V mutation is functionally deleterious, leading to shortened half‐life and proteasome‐mediated protein degradation. These data suggest that MYC cooperates with activated kinase pathways, enabling pharmacologic intervention in these treatment refractory tumors. We propose that identification of activated kinase pathways may allow for tailoring targeted therapy to improve survival and treatment‐related morbidity in medulloblastoma.     

Liver transplantation for pediatric inherited metabolic disorders: Considerations for indications,complications, and perioperative management

LT is an effective therapeutic option for a variety of IEM. This approach can significantly improve the quality of life of patients who suffer from severe disease manifestations and/or life‐threatening metabolic decompensations despite medical/dietary management. Due to the significant risks for systemic complications from surgical stressors, careful perioperative management is vital. Even after LT, some disorders require long‐term dietary restriction, medical management, and monitoring of metabolites. Successful liver transplant for these complex disorders can be achieved with disease‐ and patient‐specific strategies using a multidisciplinary approach. In this article, we review indications, complications, perioperative management, and long‐term follow‐up recommendations for IEM that are treatable with LT.     

New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney–liver complications

Improved neonatal medical care and renal replacement technology have improved the long‐term survival of patients with ARPKD. Ten‐yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life. In addition to renal pathology, patients with ARPKD develop ductal plate malformations with cystic dilation of intra‐ and extrahepatic bile ducts resulting in CHF and Caroli syndrome. Many patients with CHF will develop portal hypertension with resulting esophageal varices, splenomegaly, hypersplenism, protein losing enteropathy, and gastrointestinal bleeding. Management of portal hypertension may require EBL of esophageal varices or porto‐systemic shunting. Complications of hepatic involvement can include ascending cholangitis, cholestasis with malabsorption of fat‐soluble vitamins, and rarely benign or malignant liver tumors. Patients with ARPKD who eventually reach ESRD, and ultimately require kidney transplantation, present a unique set of complications related to their underlying hepato‐biliary disease. In this review, we focus on new approaches to these challenging patients, including the indications for liver transplantation in ARPKD patients with severe chronic kidney disease awaiting kidney transplant. While survival in patients with ARPKD and isolated kidney transplant is comparable to that of age‐matched pediatric patients who have received kidney transplants due to other primary renal diseases, 64–80% of the mortality occurring in ARPKD kidney transplant patients is attributed to cholangitis/sepsis, which is related to their hepato‐biliary disease. Recent data demonstrate that surgical mortality among pediatric liver transplant recipients is decreased to <10% at one yr. The immunosuppressive regimen used for kidney transplant recipients is adequate for most liver transplant recipients. We therefore suggest that in a select group of ARPKD patients with recurrent cholangitis or complications of portal hypertension, combined liver–kidney transplant is a viable option. Although further study is necessary to confirm our approach, we believe that combined liver–kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with ESRD and clinically significant CHF.     

Molecular alterations in pediatric brainstem gliomas

1 Background

Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27‐mutated diffuse midline gliomas, and whether rare long‐term survivors also belong to this group.

2 Methods

We studied tumor samples obtained at diagnosis or upon autopsy from 23 children, including two long‐term survivors. Based on clinical, radiological, and histological findings, all tumors were previously diagnosed as DIPGs. All samples were analyzed for genetic alterations by next‐generation sequencing (NGS) and for protein expression by immunohistochemistry (IHC).

3 Results

H3 K27 was mutated in NGS or IHC in 20 patients, excluding both long‐term survivors. One of these long‐term survivors harbored a mutation in IDH1, formerly considered to be an alteration absent in pediatric diffuse brainstem gliomas. Other altered genes in NGS included TP53 (10 patients), MET and PDGFRA (3 patients each), VEGFR and SMARCA4 (2 patients each), and PPARγ, PTEN and EGFR in 1 patient, respectively. IHC revealed cMYC expression in 15 of 24 (63%) of all samples, exclusively in the biopsies.

4 Conclusions

Eighty‐seven percent of the tumors formerly diagnosed as DIPGs could be reclassified as H3 K27‐mutated diffuse midline gliomas. Both long‐term survivors lacked this alteration. Contrary to former conceptions, IDH1 mutations may occur also in pediatric brainstem gliomas.     

The challenges of high‐dose chemotherapy in CNS tumors

High‐dose, myeloablative chemotherapy with hematopoietic stem cell rescue is used in children and young adults with brain tumors for which conventional therapy is either excessively toxic (e.g., radiotherapy in infants) or ineffective. Thus, the aims of such strategies are to improve both quantity and quality of life. Whether high‐dose chemotherapy is less neurotoxic and more effective than other therapeutic approaches is still controversial. We will consider the difficulties in analyzing published data and the challenges of designing effective clinical trials that test high‐dose chemotherapy in patients with brain tumors. Pediatr Blood Cancer 2010;54:652–653. © 2010 Wiley‐Liss, Inc.     

Two‐step transplantation for primary hyperoxaluria: A winning strategy to prevent progression of systemic oxalosis in early onset renal insufficiency cases

Several transplant strategies for PH1 have been proposed, and LT is performed to correct the metabolic defects. The patients with PH1 often suffer from ESRD and require simultaneous LKT, which leads to a long wait due to the shortage of suitable organ donors. Five patients with PH1 underwent LDLT at our institute. Three of the five patients were under dialysis before LDLT, while the other two patients were categorized as CKD stage 3. An isolated LDLT was successfully performed in all but our first case, who had complicated postoperative courses and consequently died due to sepsis after retransplantation. The renal function of the patients with CKD stage 3 was preserved after LDLT. On the other hand, our second case with ESRD underwent successful LDKT six months after LDLT, and our infant case is waiting for the subsequent KT without any post‐LDLT complications after the early establishment of PD. In conclusion, a two‐step transplant strategy may be needed as a life‐saving option for patients with PH1 and may be possible even in small infants with systemic oxalosis. While waiting for a subsequent KT, an early resumption of PD should be considered from the perspective of the long‐term requirement of RRT.     

Long‐term outcome for kaposiform hemangioendothelioma: A report of two cases

Kaposiform hemangioendothelioma (KHE) is a rare aggressive vascular tumor of skin and deep soft tissues that typically presents in infancy and may be associated with a potentially life‐threatening coagulopathy known as Kasabach–Merrit phenomenon (KMP). Recent advances in medical therapy have successfully treated many patients. However, our knowledge regarding the natural history of these lesions and optimum surveillance strategies remains rudimentary. We report two young women who had KHE with KMP treated in infancy and presented in adolescence with comorbidities related to their KHE tumor. This presentation supports the need for long‐term surveillance in these patients.     

Management of Growth Failure in the Treatment of Malignant Disease

Growth failure due to endocrine dysfunction as a result of treatment for malignant disease is becoming increasingly common. It may occur after cranial or craniospinal irradiation given in the treatment of acute lymphoblastic leukemia and brain tumors, and is often coupled with early or precocious puberty. It also occurs after neck and gonadal radiation and is particularly severe after total body irradiation where multiple endocrine deficiencies frequently occur. Failure to appreciate its occurrence or failure to institute therapy early enough may lead to short stature in adult life. Accurate and regular monitoring of standing and sitting height, bone age, and endocrine data should be undertaken by the oncologist in close collaboration with an endocrinologist, to ensure appropriate management of the patient.