Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

Clinical Outcomes and Complications of Pituitary Blastoma.

CONTEXT: Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome. OBJECTIVE: This work aims to describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases. DESIGN AND SETTING: A multi-institutional case series is presented from tertiary pediatric oncology centers. PATIENTS: Patients included children with pituitary blastoma. INTERVENTIONS: Genetic testing, surgery, oncologic therapy, endocrine support are reported. OUTCOME MEASURES: Outcome measures included survival, long-term morbidities, and germline and tumor DICER1 genotypes. RESULTS: Seventeen pituitary blastoma cases were studied (10 girls and 7 boys); median age at diagnosis was 11 months (range, 2-24 months). Cushing syndrome was the most frequent presentation (n = 10). Cushingoid stigmata were absent in 7 children (2 with increased adrenocorticotropin [ACTH]; 5 with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n = 7), subtotal resection (n = 9), and biopsy (n = 1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, 9 patients were alive; 8 patients died of the following causes: early medical/surgical complications (n = 3), sepsis (n = 1), catheter-related complication (n = 1), aneurysmal bleeding (n = 1), second brain tumor (n = 1), and progression (n = 1). Surgery was the only intervention for 5 of 9 survivors. Extent of resection, but neither Ki67 labeling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n = 8), visual (n = 4), and neurodevelopmental (n = 3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities. CONCLUSIONS: Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.

Excellent outcome of young children with nodular desmoplastic medulloblastoma treated on "Head Start" III: a multi-institutional, prospective clinical trial.

BACKGROUND: "Head Start" III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma. METHODS: Following surgery, patients received 5 cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction. RESULTS: Between 2003 and 2009, 92 children <10 years old with medulloblastoma were enrolled. Five-year event-free survival (EFS) and overall survival (OS) rates (±SE) were 46 ±â€…5% and 62 ±â€…5% for all patients, 61 ±â€…8% and 77 ±â€…7% for localized medulloblastoma, and 35 ±â€…7% and 52 ±â€…7% for disseminated patients. Nodular/desmoplastic (ND) medulloblastoma patients had 5-year EFS and OS (±SE) rates of 89 ±â€…6% and 89 ±â€…6% compared with 26 ±â€…6% and 53 ±â€…7% for classic and 38 ±â€…13% and 46 ±â€…14% for large-cell/anaplastic (LCA) medulloblastoma, respectively. In multivariate Cox regression analysis, histology was the only significant independent predictor of EFS after adjusting for stage, extent of resection, regimen, age, and sex (P <0.0001). Five-year irradiation-free EFS was 78 ±â€…8% for ND and 21 ±â€…5% for classic/LCA medulloblastoma patients. Myelosuppression was the most common toxicity, with 2 toxic deaths. Twenty-four survivors completed neurocognitive evaluation at a mean of 4.9 years post-diagnosis. IQ and memory scores were within average range overall, whereas processing speed and adaptive functioning were low-average. CONCLUSION: We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy, with most patients surviving without irradiation.

Bone marrow transplant and pediatric multiple myeloma.

Multiple myeloma is a malignant plasma cell disorder that is rare in the pediatric population, with only approximately 0.3% of cases diagnosed before the age of 30. In this report, we present two patients diagnosed with multiple myeloma between the ages of 12 and 16. Their respective treatment regimens are discussed, including the use of both autologous and allogeneic stem cell transplant.

Hypothalamic Glioma in a Patient With Sturge-Weber Syndrome.

Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations involving brain, skin, and occasionally eyes. There is no recognized tumor predisposition in patients with SWS as there is with some other phakomatoses. We present a patient with SWS who developed a low-grade glioma (LGG). We hypothesize that there could be an association between SWS and LGG formation, noting that GNAQ mutations have been implicated in the underlying biology of both SWS and a subset of pediatric LGG. It is suggested that SWS may be a cancer predisposition syndrome.

Topical amphotericin B in combination with standard therapy for severe necrotizing skin and soft-tissue mucormycosis in an infant with bilineal leukemia: case report and review.

During chemotherapy for bilineal leukemia, a 6-month-old infant presented with a necrotizing skin and soft-tissue infection of the chest wall due to Rhizopus sp. Successful outcome was achieved by systemically administered liposomal amphotericin B and local wound control with the novel administration of topical deoxycholate amphotericin B and surgical resection.

Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis.

BACKGROUND: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. METHODS: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. RESULTS: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). INTERPRETATION: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases.

Constitutional mismatch repair deficiency presenting in childhood as three simultaneous malignancies.

A 13-year-old child presented with three simultaneous malignancies: glioblastoma multiforme, Burkitt lymphoma, and colonic adenocarcinoma. She was treated for her diseases without success and died 8 months after presentation. Genetic analysis revealed a homozygous mutation in the PMS2 gene, consistent with constitutional mismatch repair deficiency. Her siblings and parents were screened: three of four siblings and both parents were heterozygous for this mutation; the fourth sibling did not have the mutation.

Rituximab as potential therapy for paraneoplastic cerebellar degeneration in pediatric Hodgkin disease.

Paraneoplastic cerebellar degeneration (PCD) is a rare neurological syndrome associated with lung cancer, breast adenocarcinoma,ovarian adenocarcinoma, and Hodgkin disease. It is rarely seen in pediatrics. We report a case of a 10-year-old boy with a 2-year prodrome that led to a diagnosis of PCD in association with stage IV Hodgkin disease. He received radiation and chemotherapy for his Hodgkin disease with resolution of his lymphoma. Based on promising data in adults on the efficacy of rituximab over other immuno suppressive agents in paraneoplastic disorders, he was treated with rituximab with marked improvement of the cerebellar syndrome.

Infantile choriocarcinoma in a neonate with massive liver involvement cured with chemotherapy and liver transplant.

A 6-week-old boy presented with fever, pallor, and hepatomegaly. Ultrasound showed a huge midline abdominal mass. ß-human chorionic gonadotropin was markedly elevated, suggesting a diagnosis of infantile choriocarcinoma of the liver. A biopsy confirmed the diagnosis. The patient received 6 cycles of bleomycin, cisplatin, and etoposide with significant decrease in tumor size. However, the tumor remained unresectable. A donor liver became available, and the infant underwent successful liver transplantation. He received 2 posttransplant cycles of moderate dose of methotrexate. This case shows the use of liver transplantation in cases of infantile choriocarcinoma of the liver where the tumor remains unresectable despite chemotherapy.

Ehrlichia-induced hemophagocytic lymphohistiocytosis in two children.

Two children presented with a history of fever and rash. Lab values revealed pancytopenia, elevated ferritin, coagulopathy, and elevated triglycerides. Both children quickly developed respiratory distress and hypotension requiring admission to the ICU. Bone marrow biopsies revealed hemophagocytosis. Studies for Ehrlichia returned positive. The patients were started on doxycycline and treated for hemophagocytic lymphohistiocytosis (HLH). Each made a full recovery. In both patients, testing for MUNC and perforin genes were found to have no mutation. These two cases demonstrate the importance of considering Ehrlichiosis as a possible trigger of HLH.

Pancytopenia in hospitalized children: a five-year review.

BACKGROUND: Pancytopenia in hospitalized children is not a common occurrence. The causes may vary in different patients and in diverse areas of the world. There are no reports in the literature describing these etiologies in a developed country. Our review focused on children presenting with pancytopenia at a children's hospital in the United States with the purpose to allow us to better evaluate and care for children. PROCEDURE: Charts of children aged 2 months to 18 years who were admitted to our hospital over a 5-year period were retrospectively reviewed to identify the diagnosis of pancytopenia. The diagnosis of pancytopenia was confirmed by laboratory values showing neutropenia, anemia, and thrombocytopenia. These etiologies and patient characteristics were reported in our review. RESULTS: A total of 64 children were identified with the diagnosis of pancytopenia. The most common diagnoses were infectious in origin (64%), followed by hematologic (28%), and miscellaneous (8%) etiologies. CONCLUSIONS: The most common etiology of pancytopenia in hospitalized children without cancer was infections. This differs from earlier reports in other countries, where megaloblastic anemia was found most often. Our review should provide guidance to the diagnoses which should be considered when evaluating a child with pancytopenia.

Granulocyte colony stimulating factor in neonatal alloimmune neutropenia: a possible association with induced thrombocytopenia.

Neonatal alloimmune neutropenia (NAIN) is a rare cause of congenital neutropenia seen in <1% of births. Significant morbidity, usually infections, may result from this disease. The pathophysiology of NAIN, mediated by maternal antibodies crossing the placenta to destroy fetal cells expressing paternal antigens, is similar to that of neonatal alloimmune thrombocytopenia, as well as Rh/ABO hemolytic disease of the newborn. The use of high-dose granulocyte colony stimulating factor in patients with NAIN may cause a reversible thrombocytopenia in some patients.

Natural progression of an unresected supratentorial ependymoma.

Ependymomas are rare gliomas that have been associated with a poor outcome despite aggressive therapy including surgery, chemotherapy and radiation therapy. We present a case report of a 16-year-old male with an untreated supratentorial ependymoma that lay dormant for 15 years without significant morbidity. Supratentorial ependymomas are thought to have a better outcome than infratentorial ependymomas, primarily because of the increased likelihood of achieving a gross total resection in the supratentorial space. Our case report suggests that the improved outcome may be due in part to the biologically benign nature of some supratentorial ependymomas. This highly unusual case illustrates the unpredictable heterogeneity of pediatric ependymomas.