Michael Capra

Prognostic stratification for children with hepatoblastoma: The SIOPEL experience

PURPOSE To identify factors relevant to long-term outcome in newly diagnosed hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient. PATIENTS AND METHODS Between 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for hepatoblastoma patients. Patients were stratified into high-risk (AFP < 100 ng/mL and/or PRETEXT IV and/or vascular invasion and/or extra-hepatic intra-abdominal disease (V+/P+/E+) and/or metastases) and standard-risk (all others). The hierarchy of these factors plus multifocality, PRETEXT III, AFP > 1,200,000 ng/mL, patient age, platelet count and histology were further explored. The outcome measure was event-free survival (EFS). RESULTS In 541 patients, reduced EFS correlated significantly with AFP < 100 ng/ml (hazard ratio [HR] 4.09, 95% confidence interval 2.16-7.75), AFP ≥ 1.2 × 10(6)ng/mL (2.48, 1.47-4.17), metastatic disease (3.02, 2.05-4.44), PRETEXT IV (2.15, 1.19-3.87), multifocality (1.59, 1.01-2.50), age > 5 years (2.76, 1.68-4.53); borderline with small cell undifferentiated (SCU) histology (2.29, 95% confidence interval 0.91-5.77); but not with PRETEXT III, age 30-60 months, platelet count or V+/P+/E+. By using the significant factors and SCU to stratify the population, we have identified three distinct prognostic groups: PRETEXT I/II/III, and no other factors, have 3 year EFS of 90%, PRETEXT IV and/or multifocal tumour and/or age> 5 years and/or AFP > 1.2 × 10(6) have 3 year EFS of 71% and SCU and/or AFP < 100 ng/mL and/or metastatic have a 3year EFS of 49%. CONCLUSION Prognostic stratification for clinical research on newly diagnosed hepatoblastoma should take into consideration PRETEXT, metastatic disease, AFP, multifocality, age and SCU histology.

Pilomyxoid astrocytoma in a patient with neurofibromatosis

Pilomyxoid astrocytoma (PMA), a recently described variant of low‐grade astrocytoma is associated with a high rate of recurrence and a propensity for CSF seeding. While cases of PMA have been reported in infants and young children, there has been no report of PMA in patients with neurofibromatosis. The first reportable case of PMA occurring in a child with neurofibromatosis type 1 (NF1) is described. Following presentation with obstructive hydrocephalus, the patient underwent a partial resection of a third ventricular tumor. Histology confirmed the typical features of PMA. The patient demonstrated a partial response to chemotherapy. The authors review the literature on PMA and discuss the specific issues associated with this diagnosis in the context of a child with neurofibromatosis.

Salvage chemotherapy for metastatic and recurrent ependymoma of childhood

IntroductionChemotherapy has limited role in the up-front management of ependymoma. At the time of recurrence, the role of chemotherapy is also ill defined and the choice of chemotherapeutic agents is often arbitrary, based on anecdotal data and personal experience.MethodsThe purpose of this review is to describe and critically analyze the published literature on chemotherapy in patients with recurrent and metastatic ependymoma.DiscussionThe disappointing response rate with single agents (12.9%) and combinations (17.4%) emphasizes the need to re-evaluate the current chemotherapeutic approach of intracranial ependymoma, and biological studies are needed to identify targets that may be considered for clinical trials.

Childhood cancer survival in Ireland: Temporal, regional and deprivation-related patterns

Survival after childhood cancer varies across Europe, but national or regional studies have so far shown no survival differences related to socio-economic disparity. The relationship of childhood cancer survival to disparity has not been studied in Ireland. We assessed observed survival for Irish children (ages 0-14 years) diagnosed with cancer during the period 1994-2005, overall (for all cancers included in the 3rd edition of the International Classification of Childhood Cancer) and for three main diagnostic groups - leukaemias, lymphomas, and central nervous system tumours. Comparisons were made between two diagnosis periods (1994-1999 and 2000-2005), between four regions of residence, and between five area-based deprivation categories. Regional patterns of treatment were examined to help assess the impact of centralisation of services. There was only limited evidence of improvements in survival over time. No clear evidence was found of deprivation-related influences on childhood cancer survival in Ireland, overall or for the three main diagnostic groups examined, although a weak trend was apparent for lymphoid leukaemias. Regional variation in survival was likewise not clear-cut, with the possible exception of CNS tumours (significantly higher survival amongst patients resident in the Western region). The absence of clear trends or patterns for regional or deprivation-related variation in survival may reflect a high degree of coordination and uniformity of treatment (and perhaps diagnostic) services, and application of standard treatment protocols nationally.

Survival and long-term outcomes in children with hepatoblastoma treated with continuous infusion of cisplatin and doxorubicin.

Despite high survival rates, many survivors of hepatoblastoma develop late effects including ototoxicity and cardiomyopathy. With the goal of minimizing long-term toxicities, our institution treated hepatoblastoma with continuous infusion of doxorubicin and cisplatinum (PLADO), rather than short infusion or bolus dosing as used in other treatment protocols. This retrospective cohort study includes consecutive patients diagnosed between 1985 and 2007. Patients were scheduled for treatment with 6 cycles of continuous infusion of PLADO with resection after the third or fourth cycle. Audiograms and echocardiograms were obtained at baseline, after every 2 chemotherapy cycles and yearly after the completion of therapy. Fifty-five patients were treated (34 localized; 21 metastatic). Fifty-one patients received at least 1 cycle of PLADO. Median follow-up was 7.0 years (range, 0.11 to 17.8 y). Event-free and overall survival for these 51 patients were 72.2% (standard error 6.3%) and 75.6% (standard error 6.2%) respectively. Of the 38 survivors treated with cisplatin who had an audiogram during follow-up, 4 (11%) demonstrated severe (Brock grade 3/4) and 13 (34%) mild (Brock grade 1/2) hearing loss. At a median of 10.0 years (range, 5.0 to 13.0 y) after therapy, 2 of 41 (5%) patients who were still alive had evidence of cardiac dysfunction. Overall, continuous infusion of PLADO therapy resulted in survival rates consistent with those observed in intergroup studies, but rates of chronic cardiac and ototoxicity did not differ sufficiently from those observed after shorter infusion of PLADO therapy to warrant the use of continuous infusions.

Ectomesenchymoma with t(1;12)(p32;p13) evolving from embryonal rhabdomyosarcoma shows no rearrangement of ETV6 ☆

Ectomesenchymoma is a rare mesenchymal malignancy occurring mainly in the pediatric population. The hallmark diagnostic features are a combination of sarcoma, usually rhabdomyosarcoma (RMS) with admixed ganglion cells. The lesion arises either in soft tissues or the cranial cavity, and outcomes vary considerably. Current knowledge about the genetics and biology of ectomesenchymoma is extremely limited with only 4 published karyotypes, showing overlaps only in trisomies 2, 8, and 11. Here, we describe a case with genetic findings that, in conjunction with preexisting observations, offer some additional insights into the genetic aberrations of ectomesenchymoma.

Congenital Fibrosarcoma of the Ileum: Case Report with Molecular Confirmation and Literature Review

Congenital fibrosarcoma is a rare, soft tissue malignancy of infancy, most commonly involving the distal extremities. We report a case of congenital fibrosarcoma of the ileum in a 5-day-old boy who presented with an acute abdomen due to ileal perforation. Partial ileal resection was carried out with successful anastomosis. Grossly, the resected small bowel showed focal luminal stenosis with a thickened, indurated wall. Histology showed a transmural primitive spindle cell proliferation with a morphology consistent with congenital fibrosarcoma. The associated hallmark chromosomal translocation t(12;15)(q13;q25) was demonstrated by reverse transcriptase polymerase chain reaction.

Supratentorial Primitive Neuroectodermal Tumors in Young Children

TO THE EDITOR: In the April issue of the Journal of Clinical Oncology, Timmermann et al suggest that radiotherapy plays a major role in the treatment of young children with supratentorial primitive neuroectodermal tumors (stPNET) and conclude that a delay in irradiation may compromise survival. Although stPNET are undoubtedly aggressive brain tumors and results of treatments are still disappointing, the conclusions of Timmermann et al should be considered with caution. Twenty-nine children younger than 37 months were diagnosed with stPNET and were registered in these consecutive multiinstitutional protocols. The protocols used two different chemotherapy regimens, and recommendations regarding radiation were fundamentally different between HIT-SKK87 (all patients received systematic radiation at the age of 3 years, or earlier with progression) and HIT-SKK92 (radiation for patients 18 months old with recurrence/progression). The 3-year overall survival and progression-free survival of 17.2% and 14.9% of patients, respectively, are in agreement with previous reports from cooperative groups. Five children were disease-free survivors (including four who received craniospinal irradiation [CSI]), and radiation therapy was a statistically significant factor for survival. Based on their experience, the authors recommend whole CNS irradiation (54 Gy to the tumor bed, 35 Gy CSI) and also advise limiting the delay of radiation to a maximum of 6 months. The arguments of Timmermann et al are based on solid evidence that stPNET in infants has an aggressive behavior. However, their conclusions regarding the role of prophylactic radiation may be flawed, as they analyzed the impact of radiation after the fact. Almost every child whose parents, or treating physicians, refused irradiation for their children had early disease progression (14 of 15 patients). Conversely, the median time to progression was longer in the group that underwent radiation. Prophylactic radiation was offered for 10 children in remission at completion of chemotherapy. This certainly represents a subgroup of patients whose tumors behaved unusually, and one may wonder whether some of these patients who received radiation may have been overtreated. Only intent-to-treat statistics may help to refine the conclusions of this study. In addition, detailed information on the five survivors is lacking, in particular their neurocognitive assessments. The morbidity related to CSI in very young children is well documented. Walter et al reported a median IQ of 62 (44 to 86) at 5 years in a cohort of 19 young children with medulloblastoma who received CSI at a median age of 3.3 years. As stPNET are located supratentorially, concerns regarding long-term effects of radiation are even more important, as the size of these tumors is often considerable and the morbidity of a boost greater than 50 Gy is a major issue. In the absence of measurable data on neurointellectual outcome, the conclusions and recommendations of Timmermann et al should be considered with extreme caution, since the decision to avoid or delay standard-dose CSI in infants is primarily based on the unacceptable long-term morbidity of this treatment modality in this specific population. Long-term survival without radiation therapy has been reported using intensive or high-dose chemotherapy with stem cell rescue. Although the success observed with chemotherapy only is still low, new strategies are currently under investigation to improve these results. The recommended use of standard-dose CSI may represent a step back after 20 years of experience using and developing “baby brain” strategies.

Rhabdomyosarcoma-Associated Renal Cell Carcinoma: A Link with Constitutional TP53 Mutation:

The 2004 World Health Organization classification includes the new entity “neuroblastoma-associated renal cell carcinoma.” The pathogenetic link between these entities is unknown as yet. The patient reported herein developed renal cell carcinoma after anaplastic embryonal rhabdomyosarcoma, a previously unknown association. The 2nd malignancy developed very soon after the 1st one, prompting concern for inherent cancer predisposition rather than a therapy-induced 2nd malignancy. A variety of features raised suspicion for Tp53 mutation, and indeed a pathogenic germline Tp53 mutation was identified in this child, despite a negative family history for Li-Fraumeni syndrome. Consideration of underlying predisposition is advocated in the context of rapid evolution of 2nd childhood malignancy.

Spermatogenesis in a Prepubertal Boy

Michael J O’Grady MRCPI Niamh McGrath MRCPI Fergal M Quinn MD FRCSI Michael L Capra FRCPCH Michael B McDermott Nuala P Murphy Department of Endocrinology & Diabetes, Childrens University Hospital, Temple St. Dublin 1 Department of Surgery, Our Lady’s Childrens Hospital, Crumlin, Dublin 12 Department of Oncology, Our Lady’s Childrens Hospital, Crumlin, Dublin 12 Department of Histopathology, Our Lady’s Childrens Hospital, Crumlin, Dublin 12