Differential responsiveness among "high risk" pediatric brain tumors in a pilot study of dose-intensive induction chemotherapy

BACKGROUND: These factors have been predictive for progressive disease on therapy (PDOT) among pediatric brain tumors: >1.5 cm(2) unresectable tumor, glioblastoma, supratentorial primitive neuroectodermal tumor, and metastatic medulloblastoma (MBL). This pilot study sought to correlate cytoreductive response with progression free survival. PROCEDURES: Four courses of cisplatinum, cyclophosphamide, etoposide, and vincristine preceded hyperfractionated radiotherapy (RT). Maintenance chemotherapy consisted of eight cycles of carboplatin, etoposide, and vincristine. Biopsy specimens were immunohistochemically studied for labeling index, hypoxia, and multidrug resistance proteins. RESULTS: Twenty newly diagnosed patients [nine primitive neuroectodermal tumors/MBL, one choroid plexus carcinoma, eight malignant gliomas, and two anaplastic ependymomas] were treated. Ten patients, who required neuraxis irradiation, constituted the "PNET" group. These demonstrated five complete and one partial response (PR), with an estimated median progression free survival of 44 months and median survival in excess of 53 months. Patients treated with involved field irradiation were designated the "Glioma" group. Induction chemotherapy produced partial and minor responses (MRs) among 5/10. Their estimated median progression free survival was 6.9 months (P = 0.035 relative to the PNET) with a median survival of 10.7 months (P = 0.04). Age, labeling index, the presence of hypoxia, and Pgp/MDR1 expression failed to discriminate between the two groups. CONCLUSIONS: This induction regimen produced a cytoreductive response in 6/10 and achieved a significant improvement in progression free survival among 7/10 in the PNET group. Unfortunately, responses among Glioma patients did not translate into durable control. Expression of the biologic factors was similar between both groups and did not correlate with diagnosis or response.     

Phase II study of ifosfamide in childhood brain tumors: A report by the French society of pediatric oncology (SFOP)

Forty-two evaluable pediatric patients with a variety of recurrent primary brain tumors participated in a phase II ifosfamide trial. Their mean age was 10 years. All patients were treated with ifosfamide, 3 g/m²/day for 2 days every 2 weeks. Response was assessed on clinical and radiological criteria after at least 2 courses of therapy. The overall response rate was 12% (5/42). One complete and 2 partial responses were documented in 21 patients with medulloblastoma. A partial response was demonstrated in 1 patient with primitive neurectodermal tumor (PNET) and in 1 patient with ependymoma. No activity was observed in astrocytic tumors. Toxicity was primarily neurologic (16 out of 54 patients, 30%). Hematological toxicity, without severe morbidity, was encountered in 9% of courses (16/179). Ifosfamide, administered at this dose regimen has modest efficacy in the treatment of recurrent childhood medulloblastoma and ependymoma and appears inactive for gliomas. Further trials with other dose schedules are necessary to assess the activity of this drug. However, according to the neurotoxicity observed in our trial, we would not recommend building a protocol using ifosfamide for highly progressive brain tumors. © 1993 Wiley-Liss, Inc.     

Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas

Seventeen patients less than or equal to 20 years of age with newly diagnosed (n = 10) or recurrent (n = 7) malignant gliomas (anaplastic astrocytoma and glioblastoma multiforme) were treated with cyclophosphamide in association with hematopoietic cytokines (GM-CSF or G-CSF). Cyclophosphamide was given at a dose of 2 g/m² daily for 2 days at 4-week intervals. Toxicity consisted of grade IV neutropenia and thrombocytopenia in 95% and 48% of cycles, respectively. There were no cyclophosphamide-related cardiac, pulmonary, or urothelial toxicities observed. Four of 10 patients with newly diagnosed disease demonstrated responses (three complete and one partial responses; one CR was only of 2 months duration). None of the seven patients with recurrent tumors demonstrated a response. We conclude that high-dose cyclophosphamide warrants further evaluation in children with newly diagnosed malignant glioma. Med. Pediatr. Oncol. 30:75–80, 1998. © 1998 Wiley-Liss, Inc.     

Congenital Cns Primitive Neuroectodermal Tumor: Case Report and Review of the Literature

A 30-week gestational age male fetus was found to have a congenital neoplasm involving the posterior cranial fossa, identified by fetal ultrasound examination in utero. Histological and immunohistochemical examination confirmed a diagnosis of primitive neuroectodermal tumor (PNET) of the posterior fossa, also referred to as medulloblastoma. Although PNETs have been well documented, there are relatively few reports of these occurring as congenital neoplasms. We present a case of an in utero, congenital PNET with a review of the literature and discussion of the criteria defining congenital tumors.     

Fanconi anemia and biallelic BRCA2 mutation diagnosed in a young child with an embryonal CNS tumor

Medulloblastoma, the most common pediatric malignant brain tumor often arises sporadically; however, in a subgroup of patients, there exist familial conditions such as Fanconi anemia with biallelic BRCA2 mutation that predispose patients to developing medulloblastoma. Biallelic inactivation of BRCA2 in Fanconi anemia has been previously described in only 11 patients with medulloblastoma in the literature to date. Here we report two siblings diagnosed with central nervous system embryonal tumors at an early age in association with biallelic BRCA2 inactivation, including the first reported case of a spinal cord primitive neuroectodermal tumor (PNET) in a BRCA2/FANCD1 kindred. Pediatr Blood Cancer 2009;53:1140–1142. © 2009 Wiley‐Liss, Inc.     

COEXISTENCE OF CEREBELLAR PRIMITIVE NEUROECTODERMAL TUMOR AND CEREBELLAR DYSPLASIA: Case Report

It has been speculated that the cerebellar primitive neuroectodermal tumor (PNET) in part recapitulates stages in the maturation of normal human neuroblasts. One theory suggests that these tumors may arise from "primitive cells" or "remnants" of the external granular layer of the cerebellum, which forms a subpial, proliferative zone that gives rise to neurons of the internal granular layer and stellate and basket cells. In the present report, the coexistence of marked cerebellar cortical disorganization and cerebellar PNET is described in a 1-year-old boy. The abnormal dysplastic cortex was in close proximity as well as contiguous to the tumor. Although minor degrees of cerebellar dysplasia may be found incidentally, the coexistence of a severe malformative process contiguous to cerebellar PNET merits the consideration of a possible pathogenetic association between aberrant neuronal migration or maturation and the development of PNET in this patient.     

Brainstem primitive neuroectodermal tumors (bstPNET): results of treatment with intensive induction chemotherapy followed by consolidative chemotherapy with autologous hematopoietic cell rescue

We have evaluated the response rate and survival utilizing intensified chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and adjuvant radiation therapy in six young children with newly diagnosed brainstem primitive neuroectodermal tumors (bstPNET). Following maximum surgical resection of the tumor, patients received high dose induction chemotherapy including vincristine, cisplatin, cyclophosphamide, and etoposide. Eligible patients received a single cycle of myeloablative chemotherapy followed by AuHCR. Two patients survive at least 32 months with stable disease. This approach provides an alternative for young patients with bstPNET who in prior reports have had a uniformly fatal prognosis.     

Primitive Neuroectodermal Tumor of the Brain Associated with Malignant Rhabdoid Tumor of the Liver: A Histologic, Immunohistochemical, and Electron Microscopic Study

A 14-day-old white male, born with a large primitive neuroectodermal tumor of the left cerebral hemisphere, was found to have a solitary rhabdoid tumor in the liver incidentally at autopsy. Cells resembling the liver rhabdoid cells were also found by histology, immunohistochemistry, and electron microscopy in the brain tumor. The concurrence of rhabdoid cells in the tumors of the brain and liver suggests a common histogenesis and further supports the previous suggestion that the rhabdoid tumor is of neuroectodermal origin. The rhabdoid tumor in the liver in this case is likely to be a metastatic tumor from the brain rather than a second primary tumor.     

High-dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high-risk or relapsed medulloblastoma or supratentorial primitive neuroectodermal tumor

BACKGROUND: Single or tandem double high-dose chemotherapy (HDCT) was used to treat children with newly diagnosed high-risk or relapsed medulloblastoma and supratentorial primitive neuroectodermal tumor (MB/sPNET) in order to defer or avoid radiotherapy in young children. PROCEDURE: Thirty-seven HDCTs were given to 25 children with newly diagnosed high-risk or relapsed MB/sPNET. Tandem double HDCT was used for 12 of 15 patients initially intended to receive double HDCT. RESULTS: Three-year EFS (+/-SE) in 6 newly diagnosed high-risk (>3 years old), 8 newly diagnosed (<3 years old), and 11 relapsed MB/sPNET was 83.3 +/- 15.2%, 62.5 +/- 20.5%, and 29.1 +/- 15.7%, respectively. Three-year EFS for patients in CR or PR and in less than PR at first HDCT was 67.4 +/- 11.0% and 16.7 +/- 15.2%, respectively (P = 0.001). Three-year EFS in patients initially intended to receive double HDCT and single HDCT was 66.0 +/- 12.4% and 40.0 +/- 15.5%, respectively. For 19 patients in CR or PR at first HDCT, 3-year EFS was 88.9 +/- 10.5% in tandem double HDCT group, and 44.4 +/- 16.6% in single HDCT group, respectively (P = 0.037). Although four treatment-related mortalities (TRMs) occurred during 25 first HDCTs, no TRM occurred during 12 second HDCTs. In four of eight young children, craniospinal radiotherapy was successfully withheld without subsequent relapse. CONCLUSIONS: High-dose chemotherapy may improve the survival of children with newly diagnosed high-risk MB/sPNET, and, to some extent, the survival of those with relapsed MB/sPNET. Further study is necessary to elucidate the efficacy of tandem double HDCT.     

Molecular and Cytogenetic Analysis of a Cerebellar Primitive Neuroectodermal Tumor with Prominent Neuronal Differentiation: Detection of MYCN Amplification by Differential Polymerase Chain Reaction and Southern Blot Analysis

Oncogene amplification is uncommon in cerebellar primitive neuroectodermal tumor (medullo-blastoma) and its frequency and diversity are greater in medulloblastoma cell lines. We describe a medulloblastoma in a 10-year-old-girl with striking neuronal differentiation evident in the islands of ganglion cells intermixed with more primitive undifferentiated cells. The islands of ganglion cells showed prominent synaptophysin positivity. Karyotypic analysis revealed hypo -and hyperdiploidy with multiple random rearrangements and double minute chromosomes. Differential polymerase chain reaction and Southern blot analysis revealed up to 25-fold MYCN amplification.     

CCG7942/POG9354方案治疗儿童外周型原始神经外胚层肿瘤的临床研究

目的 研究儿童外周型原始神经外胚层肿瘤(pPNET)的临床表现、诊断、治疗及生存情况.方法 回顾性分析2008 年10 月至2013 年10 月收治的10 例pPNET 患儿完整的临床资料,其中3 例存在转移,7 例无转移.7 例无转移患儿采用美国儿童癌症协作组CCG7942 治疗方案,3 例有转移患儿采用美国儿童肿瘤协作组POG9354 治疗方案.治疗后采用WHO 实体瘤疗效评定标准和通用不良反应术语标准对相关毒副反应进行评价.结果 采用CCG7942 方案治疗的7 例患儿中,完全缓解4 例,稳定1 例,进展2 例,复发2 例;采用POG9354 方案治疗的3 例患儿中,完全缓解1 例,进展2 例,复发2 例,死亡2 例.目前7 例无转移患儿的生存期为5~60 个月,无事件生存率为71%;3 例有转移患儿的生存期为13~25 个月,无事件生存率为33%.所有患儿除均有4 级骨髓抑制的毒性损害外,其他毒性反应如消化道、肝肾功能多为1~2 级损害.结论 CCG7942方案对治疗没有转移的pPNET 患儿有效、安全;存在转移的pPNET 患儿即使采用POG9354 方案疗效仍然欠佳,需要研究新的治疗方案以提高疗效.     

Malignant peripheral neuroectodermal tumor in an infant with neurofibromatosis type 1

A case of multifocal malignant peripheral neuroectodermal tumor (PNET) arising from a plexiform neurofibroma in a 4-month-old Chinese boy with neurofibromatosis type 1 (NF-1) is described. Cytogenetic culture demonstrated hypotriploid karyotype with an abnormal clone characterized by 59–60, XY, +2, +3, +6, +8, +8, +12, +i(13)(q10), +der(14)t(1;14)(q21;q32), +16, +19, +20, +mar[cp3] with no apparent abnormality of chromosome 17. The child was treated with combination chemotherapy comprising ifosphamide, vincristine and doxorubicin. Despite initial partial response the child finally died of tumor progression and pulmonary metastases 8 months after diagnosis. We believe this is the first reported case of PNET in a child with NF-1 and may support an association between these two disorders of neural crest origin. © 1996 Wiley-Liss, Inc.     

Phase II study of daily oral etoposide in children with recurrent brain tumors and other solid tumors

Pre-clinical data and adult experience suggests that topoisomerase targeted anti-cancer agents may be highly schedule dependent, and efficacy may improve with prolonged exposure. To investigate this hypothesis, 28 children with recurrent brain and solid tumors were enrolled in a phase II study of oral etoposide (ETP). Patients were prescribed ETP at 50 mg/m²/ day for 21 consecutive days. Courses were repeated every 28 days pendinng bone marrow recovery. Evaluation of response was initially performed after 8 weeks and then every 12 weeks either by CT or MRI. Three of 4 patients with PNET (primitive neuroectodermal tumor)/medulloblastora achieved a partial response (PR). Two of 5 with ependymoma responded, one with a complete response and one with a PR. Toxicity was manageable with only 1 admission for fever and neutropenia in 120 cycles of therapy. Five patients had grade 3 or 4 neutropenia. One had grade 4 thrombocytopenia and one grade 2 mucositis and withdrew as a result. One patient had grade 2 diarrhea. Two patients who achieved a PR had received ETP as part of prior combination chemotherapy regimens. Daily oral etoposide is active in recurrent PNET/medulloblastoma and ependymoma. Toxicity is manageable and rarely requires intervention. Daily oral etoposide in combination with crosslinking agents should be considered in future phase III trials. Determination of activity in glioma and solid tumors is not complete. Med. Pediatr. Oncol. 29:28–32, 1997. © 1997 Wiley-Liss, Inc.     

Peripheral primitive neuroectodermal tumor presenting with diffuse cutaneous involvement and 7;22 translocation

We report an unusual case of peripheral primitive neuroectodermal tumor (pPNET) in an infant presenting with congenital cutaneous nodules and a t(7;22)(p21;q11.2). The biologic behavior of the tumor diverged over time from a slowly growing tumor with multiple cutane-ous nodules to a more aggressive neoplasm characterized by pulmonary metastases and a soft tissue mass showing additional cytogenetic alterations. Med. Pediatr. Oncol. 30:357–363, 1998. © 1998 Wiley-Liss, Inc.     

Malignant peripheral primitive neuroectodermal tumor (PNET) of the kidney

We describe a 61-year-old patient with primitive neuroectodermal tumor (PNET) arising from the kidney. Despite intensive treatment including surgery, combination chemotherapy and radiotherapy, rapid progression of the tumor was encountered and the patient died within six months with widespread disease. This appears to be the first recorded case of PNET of the kidney. © 1994 Wiley-Liss, Inc.