CNS Embryonal Tumors Research Articles

Atypical Teratoid Rhabdoid Tumor (AT/RT): Improved Long-Term Survival with an Intensive Multimodal Therapy and Delayed Radiotherapy. The Medical University of Vienna Experience 1992–2012

Atypical teratoid rhabdoid tumors (AT/RTs) are recently defined highly aggressive embryonal CNS tumors with a poor prognosis and no definitive guidelines for treatment. We report on the importance of an initial correct diagnosis and disease specific therapy on outcome in 22 consecutive patients and propose a new treatment strategy.

A prognostic analysis of pediatrics central nervous system small cell tumors: evaluation of EGFR family gene amplification and overexpression.

BackgroundCentral nervous system (CNS) tumors are the most common solid tumors that occur in children, however there were few big-data follow-up analysis published in China. Overexpression of epidermal growth factor receptor (EGFR) family members was reported on glioblastoma (GBM) and medulloblastoma (MB) before. However, the correlation between EGFR family members expression with prognosis of MB, supratentorial primitive neuroectodermal tumor (PNET) and small cell GBM is unclear in Chinese children.MethodsA retrospective and survival analysis was performed on children (age ≤ 16 years) diagnosed as CNS primary small cell tumors in the Affiliated Provincial Hospital, Shandong University from 2000 to 2012, including MB (n = 44), PNET (n = 8) and small cell GBM (n = 19). The expression of EGFR, ERBB-2, ERBB-3 and ERBB-4 were detected by immunohistochemistry (IHC). The fluorescence in situ hybridization (FISH) was used to observe the amplification of EGFR and ERBB-2 gene.ResultsMedian survival times of MBs, small GBMs and PNETs were 23 ± 6.7 months, 8 ± 4.7 months and 10 ± 1.4 months. Expression and amplification of ERBB-2, ERBB-3 and ERBB-4 were not observed in all tumor samples. The multiply Cox regression suggested the overexpression and amplification of EGFR were negative prognostic factors for MB. Radiotherapy had the positive function for all pediatric patients.ConclusionOverexpression of EGFR predicts poor outcomes of MBs, small cell GBMs and PNETs, suggesting those three CNS tumor subtypes can be considered as one group for the potential common mechanism. The current individual treatment and big data analysis of pediatric CNS embryonal tumors and GBM continues to be very challenging in China.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7649640001237474

Ependymoblastoma of the brainstem: MRI findings and differential diagnosis

Ependymoblastoma (EBL) is a rare malignant CNS tumor of early childhood, listed as a subgroup of primitive neuroectodermal tumors (PNET) in the 2007 WHO Classification of Tumours of the Central Nervous System. Histologically, EBL can be defined by multilayered, mitotically active "ependymoblastic" rosettes with central lumen as a histological hallmark. The prognosis seems to be far inferior to other embryonal CNS tumors, and known clinical and MRI characteristics of EBL are based on scattered case reports. We present and discuss two uncommon cases of histopathologically confirmed ependymoblastoma that both seem to originate from the brainstem.

Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity

Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.

LIN28A immunoreactivity is a potent diagnostic marker of embryonal tumor with multilayered rosettes (ETMR)

Embryonal tumor with multilayered rosettes (ETMR, previously known as ETANTR) is a highly aggressive embryonal CNS tumor, which almost exclusively affects infants and is associated with a dismal prognosis. Accurate diagnosis is of critical clinical importance because of its poor response to current treatment protocols and its distinct biology. Amplification of the miRNA cluster at 19q13.42 has been identified previously as a genetic hallmark for ETMR, but an immunohistochemistry-based assay for clinical routine diagnostics [such as INI-1 for atypical teratoid rhabdoid tumor (AT/RT)] is still lacking. In this study, we screened for an ETMR-specific marker using a gene-expression profiling dataset of more than 1,400 brain tumors and identified LIN28A as a highly specific marker for ETMR. The encoded protein binds small RNA and has been implicated in stem cell pluripotency, metabolism and tumorigenesis. Using an LIN28A specific antibody, we carried out immunohistochemical analysis of LIN28A in more than 800 childhood brain-tumor samples and confirmed its high specificity for ETMR. Strong LIN28A immunoexpression was found in all 37 ETMR samples tested, whereas focal reactivity was only present in a small (6/50) proportion of AT/RT samples. All other pediatric brain tumors were completely LIN28A-negative. In summary, we established LIN28A immunohistochemistry as a highly sensitive and specific, rapid, inexpensive diagnostic tool for routine pathological verification of ETMR.

Pilot study of systemic and intrathecal mafosfamide followed by conformal radiation for infants with intracranial central nervous system tumors: a pediatric brain tumor consortium study (PBTC-001)

A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children <3 years with newly diagnosed embryonal CNS tumors was performed. Ninety-three newly diagnosed infants and children (<3 years) with embryonal CNS tumors were enrolled. Twenty weeks of systemic multi-agent chemotherapy commenced within 35 days of surgery. Patients without CSF flow obstruction (n = 71) received IT mafosfamide (14 mg) with chemotherapy. Localized (M(0)) patients with SD or better subsequently received RT followed by 20 additional weeks of chemotherapy. Second look surgery was encouraged prior to RT if there was an incomplete surgical resection at diagnosis. 71 evaluable patients with normal CSF flow received IT Mafosfamide with systemic chemotherapy; patients with M + disease were removed from protocol therapy at 20 weeks and those with PD at the time of progression. One and 5-year progression free survival (PFS) and overall survival (OS) for the cohort of 71 evaluable patients were 52 ± 6.5 % and 33 ± 13 %, and 67 ± 6.2 % and 51 ± 11 %, respectively. The 1-year Progression Free Survival (PFS) for M0 patients with medulloblastoma (MB, n = 20), supratentorial primitive neuroectodermal tumor (PNET, n = 9), and atypical teratoid rhabdoid tumor (ATRT, n = 12) was 80 ± 7 %, 67 ± 15 % and 27 ± 13 % and 5-year PFS was 65 ± 19 %, 37 ± 29 %, and 0 ± 0 %, respectively. The addition of IT mafosfamide to systemic chemotherapy in infants with embryonal CNS tumors was feasible. The PFS for M0 patients appears comparable to or better than most prior historical comparisons and was excellent for those receiving conformal radiotherapy.

Targeting Aurora Kinase A enhances radiation sensitivity of atypical teratoid rhabdoid tumor cells

Atypical teratoid/rhabdoid tumors (ATRT) are rare, highly malignant, embryonal CNS tumors with a poor prognosis. Therapy relies on highly toxic chemotherapy and radiotherapy. To improve outcomes and decrease morbidity, more targeted therapy is required. Gene expression analysis revealed elevated expression of multiple kinases in ATRT tissues. Aurora Kinase A was one of the candidate kinases. The objective of this study was to evaluate the impact of Aurora Kinase A inhibition in ATRT cell lines. Our analysis revealed that inhibition of Aurora Kinase A induces cell death in ATRT cells and the small molecule inhibitor MLN 8237 sensitizes these cells to radiation. Furthermore, inhibition of Aurora Kinase A resulted in decreased activity of pro-proliferative signaling pathways. These data indicate that inhibition of Aurora Kinase A is a promising small molecule target for ATRT therapy.

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) with loss of morphological but retained genetic key features during progression

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a recently recognized, rare embryonal CNS tumor, which predominantly occurs in young children and is associated with a highly aggressive disease course [1–3, 5–8, 13, 14, 18, 19, 23]. The histopathological diagnosis of ETANTR is based on the presence of primitive neuroectodermal tumor cells forming distinct multilayered ‘ependymoblastic’ rosettes and characteristic neuropil islands. Recently, genome-wide analyses have revealed a novel amplification at 19q13.42 [16, 19], which is meanwhile considered the genetic hallmark of ETANTR [13, 16]. The characteristic clinical, morphological, and genetic features support the concept of a distinct CNS PNET variant and suggest its introduction to the WHO classification of Tumors of the Central Nervous System [17]. As the amplification at 19q13.42 has also been found in the vast majority of ependymoblastomas analyzed to date [13, 16], the common genetic background suggests the fusion of these two tumor types to a single entity. Herein, we report for the first time the evolution of morphological features and genetic aberrations during the disease course in a patient with ETANTR. A 33-monthold girl presented with a 6-month history of episodic headaches, increased head circumference and mild gait disturbance. Magnetic resonance (MR) imaging showed a 9.6 9 8.6 9 11.7 cm left parieto-occipital, space-occupying, partly cystic lesion displaying T1-weighted hypoto isointense signals (Fig. 1a) with cerebrospinal fluid-intense cysts on FLAIR sequence (Fig. 1b), and marked choline/ creatine increase as a sign of cell proliferation on single voxel spectroscopy (Fig. 1c). Near-total surgical resection was performed. Histopathology revealed a primitive neuroectodermal tumor with highly cellular areas. Furthermore, hypocellular neuropil islands and multilayered rosettes were

Novel amplifications in pediatric medulloblastoma identified by genome-wide copy number profiling

Medulloblastoma (MB) is a WHO grade IV, invasive embryonal CNS tumor that mainly affects children. The aggressiveness and response to therapy can vary considerably between cases, and despite treatment, ~30% of patients die within 2 years from diagnosis. Furthermore, the majority of survivors suffer long-term side-effects due to severe management modalities. Several distinct morphological features have been associated with differences in biological behavior, but improved molecular-based criteria that better reflect the underlying tumor biology are in great demand. In this study, we profiled a series of 25 MB with a 32K BAC array covering 99% of the current assembly of the human genome for the identification of genetic copy number alterations possibly important in MB. Previously known aberrations as well as several novel focally amplified loci could be identified. As expected, the most frequently observed alteration was the combination of 17p loss and 17q gain, which was detected in both high- and standard-risk patients. We also defined minimal overlapping regions of aberrations, including 16 regions of gain and 18 regions of loss in various chromosomes. A few noteworthy narrow amplified loci were identified on autosomes 1 (38.89-41.97 and 84.89-90.76 Mb), 3 (27.64-28.20 and 35.80-43.50 Mb), and 8 (119.66-139.79 Mb), aberrations that were verified with an alternative platform (Illumina 610Q chips). Gene expression levels were also established for these samples using Affymetrix U133Plus2.0 arrays. Several interesting genes encompassed within the amplified regions and presenting with transcript upregulation were identified. These data contribute to the characterization of this malignant childhood brain tumor and confirm its genetic heterogeneity.

Extracellular Matrix Metalloproteinase Inducer is a Negative Prognostic Factor of Pediatric Medulloblastoma

Medulloblastoma (MB) is the most common embryonal CNS tumor of childhood. Its survival rates have significantly improved over the years due to developments in diagnostic techniques and therapeutic strategies. However, it is still an important cause of cancer-related deaths in children. Extracellular matrix metalloproteinase inducer (EMMPRIN) is a member of the immunoglobulin family and a glycoprotein enriched on the surface of many types of tumor cells. Therefore, the aim of this study was to investigate whether the expression patterns of EMMPRIN may predict the clinical prognosis in MB. EMMPRIN expression in a series of 56MB with various grades and pathological types was analyzed by immunohistochemical staining on paraffin-embedded sections. Then, the correlation of EMMPRIN expression patterns with clinical-pathological features of patients and its prognostic relevance were determined. Immunohistochemistry revealed that the positive expression rate of EMMPRIN in MB (75.0%, 42/56) was significantly higher than that in normal cerebellums (6.7%, 2/30, p < 0.001). In addition, EMMPRIN expression in MB was up-regulated in higher metastatic stage (p < 0.01), aggressive histopathological type (p < 0.005), necrosis (p < 0.01), as well as with undifferentiated tumor (p < 0.01). Furthermore, over-expression of EMMPRIN correlated significantly with poor prognosis (0.01 < p < 0.05) and represented an independent prognostic marker of overall survival on multivariate analysis (p = 0.01). Our study suggests that EMMPRIN expression was associated with the progression of MB and its over-activation may be an important predictor of poor survival in this patient cohort. Therefore, EMMPRIN may be regarded both as a prognostic factor and a therapeutic target for MB.

Necrosis after Craniospinal Irradiation: Results from a Prospective Series of Children with CNS Embryonal Tumors

Brain necrosis is a known complication of radiation therapy in children with medulloblastoma and similarly treated CNS embryonal tumors including supratentorial primitive neuroectodermal and atypical teratoid rhabdoid tumor. We reviewed the incidence of brain necrosis from our institutional series to determine factors associated with this potentially devastating complication.

Histological and immunohistochemical characterization of AT/RT: A report of 15 cases from India

Atypical teratoid rhabdoid tumor (AT/RT) is a highly malignant embryonal CNS tumor, generally unresponsive to any form of therapy, uniformly fatal within 1 year. We report 15 cases of AT/RT diagnosed at our center over a period of 5 years (2003-08). Tumors were located in different sites of the neuraxis, posterior fossa being the most common (n = 10) followed by cerebral lobes (n = 3). There was one each at the supra sellar and cervical spinal regions, respectively. Radiologically most of the tumors were heterodense and enhancing heterogeneously. The tumors exhibited diverse histological profile that included rhabdoid and PNET areas in all cases, mesenchymal and epithelial areas in 73.3% and 53.3% cases, respectively. Necrosis was evident in all cases and one showed calcification. Tumor cells displayed a polyphenotypic immunoprofile. All cases were consistently positive for vimentin and epithelial membrane antigen and were negative for desmin. Variable positivity was seen for other markers. The number of cases positive for these were: CK (53%), SMA (60%), synaptophysin (66%), NFP (33.3%) and GFAP (85%). CK staining was prominent in epithelial areas, while PNET cells labeled prominently with synaptophysin. There was lack of INI1 expression in all cases. Follow-up was available in 46.6% of cases which revealed a uniform poor prognosis.

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.

POSTERIOR FOSSA TUMOR IN A 2 YEAR‐OLD GIRL

We report a case of a 2 year-old girl who presented with three weeks' history of deterioration of walking, then became unable to walk and later she developed projectile vomiting. Neurological examination revealed bilateral papilledema, nystagmus, and truncal ataxia with intention tremor. Radiological studies showed an enhancing mass in the posterior fossa extending from the cerebellum to the roof of the fourth ventricle. The tumor was diagnosed as an embryonal tumor with abundant neuropil and true rosettes (ETANTR). The tumor cells in the neuroblastic component were diffusely positive for synaptophysin and CD56, with scattered positive cells for glial fibrillary acidic protein. The true rosettes were only positive for vimentin. Ki67 showed high index (over 90%) in the true rosettes, while the neuroblastic areas were up to 15%. Our patient developed recurrent disease 6 months after resection and chemotherapy. ETANTR is a very rare aggressive embryonal CNS tumor that combines features of neuroblastoma and ependymoblastoma. We review the thirteen cases reported in the literatures. This case represents the second report of an ETANTR arising in the cerebellum.

Non‐pineal supratentorial primitive neuro‐ectodermal tumors (sPNET) in teenagers and young adults: Time to reconsider cisplatin based chemotherapy after cranio‐spinal irradiation?

Supratentorial PNET (sPNET) are rare CNS tumors of embryonal origin arising in children and adults. The treatment of sPNET for all age groups at our cancer center has been based on the management of medulloblastoma (MB), involving neurosurgical debulking followed by cranio-spinal irradiation (CSI) and systemic chemotherapy. Medical records were reviewed to gather demographic and clinical data about all embryonal CNS tumors in children and adults from 2001 to 2007. Tumor pathology, clinical management and survival data were also assessed, particularly as regards those patients who received the Packer chemotherapy regimen for either sPNET or MB. Eleven patients (five children and six adults) were identified with non-pineal sPNET, three children with pineal sPNET, and 19 patients (18 children and 1 adult) with MB. There was no difference in overall survival (OS) rates between pediatric and adult sPNET. When all sPNET were compared to all MB, 5-year OS was 14% versus 73%, respectively, but was only 9% for non-pineal sPNET. When only considering those patients treated with the Packer chemotherapy regimen, the 5-year OS was 12% for sPNET versus 79% for MB. This retrospective study demonstrates that non-pineal sPNET are clinically distinct from MB and are resistant to the Packer chemotherapy regimen. We suggest that it is time to reconsider the use of this regimen in teenage and young adult non-pineal sPNET and to investigate the utility of alternative approaches.

Endocrine Outcomes for Children With Embryonal Brain Tumors After Risk-Adapted Craniospinal and Conformal Primary-Site Irradiation and High-Dose Chemotherapy With Stem-Cell Rescue on the SJMB-96 Trial

To estimate the cumulative incidence of specific hormone deficiencies and the influence of hypothalamic-pituitary (HP) axis radiation dose in a cohort of children with embryonal brain tumors treated with risk-adapted craniospinal irradiation (CSI), conformal primary site irradiation, and high-dose chemotherapy. Clinical data and HP axis radiation dosimetry data were obtained from 88 eligible children. All patients received regular endocrine follow-up that included screening tests of thyroid function and stimulation testing for growth hormone deficiency (GHD), and adrenocorticotropin hormone deficiency. The cumulative incidence of GHD, thyroid-stimulating hormone (TSH) deficiency, adrenocorticotropic hormone deficiency, and primary hypothyroidism at 4 years from diagnosis was 93% +/- 4%, 23% +/- 8%, 38% +/- 6%, and 65% +/- 7%, respectively. Radiation dosimetry to the HP axis was associated only with the development of TSH deficiency; the 4-year cumulative incidence was 44% +/- 19% and 11% +/- 8% (P = .014) for those receiving more or less than the median dose to the hypothalamus (>or= 42 v < 42 Gy), respectively. The median dose of CSI for the average-risk (AR) patients was 23.4 and 39.6 Gy (36 to 40.5 Gy) for the high-risk patients. The estimated mean decline in height Z-score after radiation therapy was greater in high-risk patients (-0.65 units/yr) when compared with AR patients (-0.54 units/yr; P = .039). Pediatric patients with CNS embryonal tumors are at high risk for treatment-related hormone deficiencies. GHD and primary hypothyroidism were diagnosed in a majority of subjects relatively soon after the completion of therapy. Radiation dose to the hypothalamus in excess of 42 Gy was associated with an increase in the risk of developing TSH deficiency.

Folate pathway genetic polymorphisms and susceptibility of central nervous system tumors in Thai children

Background: Folate is an important micronutrient molecule participating in DNA synthesis, methylation and repair mechanisms. Genetic polymorphisms in folate pathway related enzymes including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, thymidylate synthase (TS) 28-bp tandem repeat, and reduced folate carrier (RFC) G80A have been shown to be associated with increased susceptibility for several cancers. The aim of the present study was to evaluate whether single nucleotide polymorphisms in the genes encoding enzymes of the folate pathway predispose to any CNS tumors in Thai children. Methods: In the present case–control study, we investigated these polymorphisms in genomic DNA from peripheral blood mononuclear cells in 73 Thai children with various types of central nervous system tumors and in 205 age and sex matched controls. Results: Thirty-one out of 73 patients were diagnosed with glial tumors (astrocytoma, oigodendroglioma and ependymoma), 28 with embryonal CNS tumors (medulloblastoma, pinealoblastoma and primitive neuroectodermal tumor), 13 with germ cell tumors and 1 with meningioma. We found that the homozygous CC allele of MTHFR A1298C conferred an increased risk of embryonal CNS tumors (OR: 3.9; 95% CI: 1.3–11.4, p = 0.02). Conclusion: Our findings thus suggest that folate metabolism may play a role in the pathogenesis of certain specific subtypes of pediatric brain tumor in Thai children, especially embryonal CNS tumors.

A case of congenital supratentorial tumor: Atypical teratoid/rhabdoid tumor or primitive neuroectodermal tumor?

Two embryonal CNS tumors, atypical teratoid/rabdoid tumor (AT/RT) and primitive neuroectodermal tumor (PNET), may be confused with each other and misdiagnosed. Here we report an infant with a congenital supratentorial tumor, which was detected by fetal MRI at 37 weeks gestation. On routine histological examination, the tumor was composed mainly of small undifferentiated cells, among which many rhabdoid cells and occasional sickle-shaped embracing cells were observed. No mesenchymal or epithelial areas were evident. Our impression was that the tumor was an atypical example of AT/RT. Immunohistochemically, almost all the tumor cells were strongly positive for vimentin. However, epithelial membrane antigen was notably negative, and most of the tumor cell nuclei were clearly positive for INI1. In addition, many tumor cells were positive for neurofilament protein. There were also occasional small areas containing many tumor cells positive for glial fibrillary acidic protein. Finally, a diagnosis of PNET, with a rhabdoid phenotype and expression of neuronal and glial markers, was made. In the present case, application of INI1 immunostaining was very helpful for distinguishing PNET from AT/RT.

Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors

An open-label Phase II study of oxaliplatin was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB), supratentorial primitive neuroectodermal tumors (SPNET), and atypical teratoid rhabdoid tumor (ATRT). Patients were stratified as follows: stratum IA, first recurrence MB with measurable disease; IB, recurrent MB with only cerebral spinal fluid (CSF) positivity or linear leptomeningeal disease (LLD); IC, MB > or =second recurrence; stratum II, recurrent SPNET; stratum III, recurrent ATRT. Patients received oxaliplatin, 130 mg/m(2) intravenously over 2 hours every 3 weeks. The primary objective was to estimate the sustained response rate in stratum 1A. Plasma ultrafiltrate platinum pharmacokinetics were evaluated. A total of 43 patients with a median age of 8.5 years (range, 0.6-18.9 years) were enrolled. In stratum 1A, 2 of 15 had partial responses (PRs, 1 sustained PR). No responses were observed in other strata. The most frequent Grade 3 and 4 toxicities included thrombocytopenia (25.6%), neutropenia (16.3%), leukopenia (12%), increase in serum alanine transaminase (ALT) (7%), vomiting (4.7%), and sensory neuropathy (4.7%). No severe ototoxicity or nephrotoxicity was reported. Plasma ultrafiltrate platinum pharmacokinetic parameters were similar to adults, with a median clearance of 12.2 L/hr (range, 4.4-30 L/hr) and median area under the curve (AUC(0-infinity)) of 9.4 microg/mL/hr (range, 6.2-13.9 microg/mL/hr). Oxaliplatin was well tolerated in children but has limited activity in children with recurrent CNS embryonal tumors previously treated with platinum compounds.

Modeling Radiation Dosimetry to Predict Cognitive Outcomes in Pediatric Patients with CNS Embryonal Tumors

Materials/Methods: Pediatric patients (n 39) with CNS embryonal tumors were prospectively evaluated with serial cognitive testing before and after post-operative risk-adapted craniospinal (CSI) and conformal primary site irradiation followed by chemotherapy. Patients were characterized according to age (median 7.3 years); median follow-up (42.7 months); male:female ratio 25:14; diagnosis (MB, n 34; sPNET, n 1; ATRT, n 4); tumor location (infratent 35; supratent 4); and risk-classification (average 14; high 25). Average-risk included residual tumor 1.5cm and no evidence of metastases regardless of tumor location. Risk-adapted CSI (23.4 Gy-average risk; 36–39.6 Gy-high risk), conformal posterior fossa irradiation (36.0 Gy-average risk only) and conformal primary site irradiation (CTV 2cm) to 55.8 Gy was delivered at 1.8 Gy/day. Differential DVHs were calculated from composite dosimetry for the total brain, supratentorial brain, infratentorial brain, and left and right temporal lobe volumes and integrated in 5 Gy increments for correlation with IQ evaluations conducted after surgery and 1, 2, and 5 years from completion of therapy using standard instruments; all patients had 3 or more evaluations. A linear mixed model with random coefficients was used to estimate the impact of the specific dose intervals and their fractional volumes on the slope of longitudinal IQ and included age and other covariates. Integrated dosimetry was partitioned into two (low and high) or three (low, intermediate and high) dose intervals with corresponding divisions determined by experimenting over the range of dose in increments of 5 Gy. Model were checked by examining the estimating equation for direction of slope, magnitude of the dose-volume coefficients and their p-value. The divisions which resulted in coefficients with the highest level of statistical significance were chosen.