Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients.

BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Radiomics-Based Machine Learning for Outcome Prediction in a Multicenter Phase II Study of Programmed Death-Ligand 1 Inhibition Immunotherapy for Glioblastoma.

BACKGROUND AND PURPOSE: Imaging assessment of an immunotherapy response in glioblastoma is challenging due to overlap in the appearance of treatment-related changes with tumor progression. Our purpose was to determine whether MR imaging radiomics-based machine learning can predict progression-free survival and overall survival in patients with glioblastoma on programmed death-ligand 1 inhibition immunotherapy. MATERIALS AND METHODS: Post hoc analysis was performed of a multicenter trial on the efficacy of durvalumab in glioblastoma (n = 113). Radiomics tumor features on pretreatment and first on-treatment time point MR imaging were extracted. The random survival forest algorithm was applied to clinical and radiomics features from pretreatment and first on-treatment MR imaging from a subset of trial sites (n = 60-74) to train a model to predict long overall survival and progression-free survival and was tested externally on data from the remaining sites (n = 29-43). Model performance was assessed using the concordance index and dynamic area under the curve from different time points. RESULTS: The mean age was 55.2 (SD, 11.5) years, and 69% of patients were male. Pretreatment MR imaging features had a poor predictive value for overall survival and progression-free survival (concordance index = 0.472-0.524). First on-treatment MR imaging features had high predictive value for overall survival (concordance index = 0.692-0.750) and progression-free survival (concordance index = 0.680-0.715). CONCLUSIONS: A radiomics-based machine learning model from first on-treatment MR imaging predicts survival in patients with glioblastoma on programmed death-ligand 1 inhibition immunotherapy.

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study.

BACKGROUND: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). RESULTS: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. CONCLUSIONS: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study.

BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma.

BACKGROUND: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). METHODS: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). RESULTS: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). CONCLUSIONS: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.

Extensive genomic abnormalities in childhood medulloblastoma by comparative genomic hybridization.

We analyzed 27 samples of primary medulloblastoma, using comparative genomic hybridization and a novel statistical approach to evaluate chromosomal regions for significant gain or loss of genomic DNA. An array of nonrandom changes was found in most samples. Two discrete regions of high-level DNA amplification of chromosome bands 5p15.3 and 11q22.3 were observed in 3 of 27 tumors. Nonrandom genomic losses were most frequent in regions on chromosomes 10q (41% of samples), 11 (41%), 16q (37%), 17p (37%), and 8p (33%). Regions of DNA gain most often involved chromosomes 17q (48%) and 7 (44%). These findings suggest a greater degree of genomic imbalance in medulloblastoma than has been recognized previously and highlight chromosomal loci likely to contain oncogenes or tumor suppressor genes that may contribute to the molecular pathogenesis of this tumor.

Comparison of lumbar and shunt cerebrospinal fluid specimens for cytologic detection of leptomeningeal disease in pediatric patients with brain tumors.

PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with primary CNS tumors. Cytologic examination of lumbar CSF is routinely used to detect LMD. To determine whether examination of CSF obtained from ventricular shunt taps is a more sensitive method of detecting LMD in these patients, we designed a prospective study to compare the findings of cytologic examinations of CSF obtained from concurrent lumbar and ventriculoperitoneal (VP) shunt taps. PATIENTS AND METHODS: As a part of diagnostic staging, follow-up testing, or both, 52 consecutive patients underwent concurrent lumbar and shunt taps on 90 separate occasions, ranging from the time of diagnosis to treatment follow-up. CSF from both sites was examined cytologically for malignant cells. RESULTS: The median age of the 28 males and 24 females was 7.5 years (range, 0.6 to 21.4 years). The primary CNS tumors included medulloblastoma (n = 29), astrocytoma (n = 10), ependymoma (n = 5), germinoma (n = 3), atypical teratoid rhabdoid tumor (n = 2), choroid plexus carcinoma (n = 2), and pineoblastoma (n = 1). Each site yielded a median CSF volume of 1.0 mL. Fourteen of 90 paired CSF test results were discordant: in 12, the cytologic findings from shunt CSF were negative for malignant cells, but those from lumbar CSF were positive; in two, the reverse was true. Malignant cells were detected at a higher rate in lumbar CSF than in shunt CSF (P =.0018). When repeat analyses were excluded, examination of lumbar CSF remained significantly more sensitive in detecting malignant cells (P =.011). Analysis of the subset of patients with embryonal tumors showed similar results (P =.0008). CONCLUSION: Cytologic examination of lumbar CSF is clearly superior to cytologic examination of VP shunt CSF for detecting leptomeningeal metastases in pediatric patients with primary CNS tumors.

Pediatric choroid plexus neoplasms.

PURPOSE: Choroid plexus tumors (CPT) are rare childhood neoplasms. The relatively small number of reported cases and the controversies surrounding the clinical and pathological classification of these tumors have made it difficult to define a standard of care for these patients. Our intention is to contribute to the body of knowledge of these tumors and further define the role of adjuvant therapy. METHODS AND MATERIALS: We performed a retrospective review of 14 children with choroid plexus neoplasms referred to St. Jude Children's Research Hospital between October 1985 and December 1987. Ten patients had choroid plexus carcinoma (CPC) based on pathologic criteria and evidence of brain invasion at surgery or leptomeningeal disease (M+); 4 patients had choroid plexus papilloma (CPP). Patients with CPP were initially treated with surgery alone whereas patients with CPC were generally treated with postoperative therapy that included chemotherapy (CT) and/or craniospinal irradiation (CSI) with a focal boost to the primary site. For most patients CT consisted of combinations of cyclophosphamide, etoposide, vincristine, and a platinum agent. The median CSI dose was 35.2 Gy (range 24-46.2 Gy). The median primary site dose was 55.2 Gy (range 49.6-64 Gy). RESULTS: Seven of the 10 CPC cases presented with leptomeningeal dissemination; two of these patients have succumbed to disease. Of the 3 patients with M0 status, all are alive with no evidence of disease (NED). The medial time to relapse from the time of surgery was 5.3 mo (range 3-25 mo). Seven CPC patients were treated with gross total resection (GTR). Three of these patients (2 M0, 1 M+) received CT without CSI and are currently NED (27, 69, and 60 mo respectively). One M+ patient progressed on CT and has stable disease after CSI (6 mo), one (M0) received CT and CSI and is NED (120 mo), one (M+) is currently on CT with objective response (3 mo) and one (M+) died of progressive disease (24.5 mo) despite CT and CSI. Three patients with CPC had subtotal resection (STR). One of these patients (M+) received CT and CSI and is NED (23 mo), one (M0) had an elective second resection GTR alone and is currently NED (153 mo), and one (M+) developed progressive disease (13.5 mo) while on CT and died despite CSI. Among the 4 CPP patients, GTR was performed in two; both were NED at 54 and 81 mo. Two patients with CPP (one with focal atypia) were treated with STR initially; both transformed to CPC at 7 and 27 mo, respectively. Both were currently NED following salvage with (1) GTR and CSI alone (98 mo) or (2) STR, CT, and CSI (62 mo). Six of the 12 survivors in this series had significant neuropsychological sequelae. CONCLUSION: The prognosis of CPP is good for patients treated with GTR. Malignant transformation occurred in 2 CPP patients with less than GTR. Patients with localized CPC who undergo GTR have had a favorable outcome with the addition of chemotherapy or irradiation. CSI may not be routinely indicated in M0 children following GTR. There is evidence that salvage with radiation therapy may be successful following progression on chemotherapy. For patients treated with STR, the use of CT and CSI appears to be necessary.

Prognostic significance of parameters derived from co-registered 18F-fluorodeoxyglucose PET and contrast-enhanced MRI in patients with high-grade glioma.

OBJECTIVE: The aim of this study was to determine the prognostic significance of the volume and intensity of abnormal (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) accumulation within areas of contrast enhancement on post-therapeutic volumetric MRI. METHODS: A total of 10 patients with Grade III or IV glioma were treated with resection followed by intracavitary radiation therapy with (131)I-labelled antitenascin monoclonal antibody. Patients underwent serial FDG-PET and 1.5 T MR imaging. For each patient, MR and FDG-PET image volumes at each time point were aligned using a rigid-body normalised mutual information algorithm. Contrast-enhancing regions of interest (ROIs) were defined using a semi-automated k-means clustering technique. Activity within the ROI on the co-registered PET scan was calculated as a ratio (mean activity ratio; MAR) to activity in contralateral normal-appearing white matter (NAWM). The PET lesion was defined as the portion of the ROI associated with activity greater than two standard deviations above the mean in NAWM. Survival was assessed using the logrank test. RESULTS: Larger contrast-enhancing ROIs were strongly associated with an increased MAR (r = 0.51; p<0.002). Enhancing lesions with an MAR >1.2 were associated with decreased survival (p<0.016). In nine patients who died, the MAR on PET correlated inversely with survival duration (r = -0.43; p<0.01), whereas PET lesion volume did not. CONCLUSION: Following intracavitary radiation therapy, the development of contrast-enhancing lesions that are associated with high mean FDG-PET accumulation suggests poor prognosis.

Lineage switch in Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: An 8-year-old boy, initially diagnosed with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) (French-American-British [FAB]-L1), relapsed with Ph+ acute myelogenous leukemia (AML) (FAB-M2) 21 months after successful ALL treatment with standard therapy. METHODS: The initial ALL presentation and subsequent AML relapse were analyzed by conventional morphologic, cytochemical, immunophenotypic, and cytogenetic studies. RESULTS: Molecular analysis based on the polymerase chain reaction identified the presence of a bcr-I-abl fusion transcript at initial ALL presentation, the completion of ALL therapy, and AML relapse. CONCLUSIONS: The cytogenetic and molecular results support a common clonal origin for this process. This is a case of lineage switch in a Ph+ acute leukemia. This case thus illustrates a manifestation of heterogeneous lineage differentiation among Ph+ acute leukemias.

Detection of circulating donor white blood cells in patients receiving multiple transfusions.

Significant morbidities are associated with the routine administration of blood products. Although the exact etiology of these complications may be unknown, many are thought to arise from the incidental cotransfusion of "donor" lymphocytes. We have developed an assay to detect small numbers of male white blood cells (WBCs) circulating in female patients who have received multiple blood transfusions using the polymerase chain reaction (PCR). Twenty female patients undergoing major surgical procedures were studied and received an average of 9.3 U of packed red blood cells (4.8 U from male donors) and 11.7 U of platelets (6.1 U from male donors). DNA was extracted from whole blood or peripheral blood buffy coats posttransfusion and PCR performed using oligonucleotides designed to amplify a segment within the repetitive Y-chromosome DYZ1 locus. Posttransfusion, 15 of 20 women showed evidence of circulating male WBCs for an average of 2.0 days (range, 1 to 6). We conclude that (1) DYZ1 PCR analysis is a useful approach for the detection of small numbers of circulating transfused male WBCs in female patients; and (2) circulating donor WBCs persist for a mean of 2.0 days in the majority of women receiving multiple transfusions. Future application of this technique may detect persisting or proliferating WBCs and lead to an improved understanding of common transfusion-related morbidities.

Virus-associated hemophagocytic syndrome following bone marrow transplantation.

Multiple-organ infiltration by mature, benign erythrophagocytic histiocytes is the pathologic hallmark of the virus-associated hemophagocytic syndrome (VAHS). Although VAHS has been described in a number of clinical settings, it has been reported following bone marrow transplantation (BMT) only once previously. Our report identifies the clinical and laboratory features associated with VAHS and compares the immune defects described in VAHS with those known to occur following BMT.

Multiple genomic alterations including N-myc amplification in a primary large cell medulloblastoma.

The large cell (LC) subtype is a recently described histologic variant of medulloblastoma (Mb) associated with a rapid and aggressive clinical course. We describe the genomic profile of a LC-Mb tumor obtained from a patient who developed recurrent and fulminant disease despite 'good-risk' features at diagnosis and state- of-the-art multidisciplinary therapy. The tumor sample was analyzed using comparative genomic hybridization (CGH) and complementary molecular approaches. CGH revealed amplicons at chromosome bands 2p24-25, 2q12-22, and 17p11; losses of chromosomes 11q and 18; and low-level gains of 3q, 11p, 13q and 14q. Southern blot analysis confirmed N-myc amplification. No evidence of p53 mutation was detected. The genomic profile of this LC-Mb tumor sample revealed a distinctive pattern of genetic alterations including amplification of N-myc and anonymous oncogenes at chromosome bands 2q12-22 and 17p11. These genomic abnormalities are uncommon in other subtypes of Mb.

High-grade pediatric spinal cord tumors.

Our institutional experience with high-grade pediatric spinal cord tumors includes 11 children treated during the period of 1981-1997. All patients underwent a biopsy or an attempt at resection and received postoperative radiation therapy. Three patients had a gross-total resection of their primary tumor, 6 patients had a subtotal resection and the remaining 2 were biopsied. Histologically, these tumors were characterized as anaplastic astrocytoma (n = 6), glioblastoma multiforme (n = 3) or anaplastic oligodendroglioma (n = 2). Three patients were treated with craniospinal irradiation (38-48 Gy) in addition to a boost to the residual tumor. The median dose to the primary site for all patients was 48.6 Gy (range 38-55 Gy). The median overall survival was 13 months (range 8-149 months). Only 2 patients were alive at 138 and 149 months following radiation therapy. The median progression-free survival following radiation therapy was 10 months (range 2-80 months). There was no difference in progression-free or overall survival for those diagnosed with glioblastoma multiforme when compared to patients diagnosed with anaplastic astrocytoma or anaplastic oligodendroglioma. The pattern of failure was either diffuse or local. For the patients who failed diffusely (n = 6), the median progression-free survival was 2 months compared to 23 months for those whose failure was entirely local (p < 0.01). The median overall survival was significantly shorter for those who failed diffusely compared to those who failed locally (10 vs. 37 months, p < 0.01). High-grade spinal cord tumors in children have a poor prognosis based on this report. It is important to document the extent of disease accurately prior to the initiation of radiation therapy, since a subset of these patients progress rapidly outside of the field of irradiation.

Tamoxifen and carboplatin for children with low-grade gliomas: a pilot study at St. Jude Children's Research Hospital.

PURPOSE: The authors conducted a single-arm, prospective study using tamoxifen and carboplatin for the treatment of children with progressive or symptomatic low-grade gliomas. PATIENTS AND METHODS: Fourteen children with consecutively diagnosed cases of low-grade glioma were enrolled in this Study; all patients were younger than 14 years. One patient was excluded after induction chemotherapy because of the diagnosis of a nonmalignant condition. Patients were treated with daily tamoxifen (20 mg/m2 administered twice per day) in addition to targeted, monthly intravenous carboplatin at an area under the curve (AUC) exposure of 6.5 mg/mL x minute for 1 year or until they had clinical or radiologic evidence of disease progression. RESULTS: The median age at diagnosis was 5.3 years, the median age at initiation of chemotherapy was 8.3 years. Eight patients had tumors of the hypothalamus/optic pathway, two patients had thalamic tumors, and one patient each had tumors in the temporal lobe, tectum, and brain stem. Tumor histologic findings included fibrillary astrocytoma (n = 2), juvenile pilocytic astrocytoma (n = 6), and oligodendroglioma (n = 1). The best response to therapy was a partial response in two patients, stable disease in nine patients, and progressive disease in two patients. The overall survival at 3 years is 69%. The 3-year progression-free survival is 47%. Tamoxifen and carboplatin chemotherapy did not result in a significant number of objective responses in children with low-grade gliomas. The progression-free survival is similar to that of other published series. Nonmyelosuppressive agents such as tamoxifen deserve additional evaluation in the treatment of children with low-grade gliomas.

Chromosome arm 6q loss is the most common recurrent autosomal alteration detected in primary pediatric ependymoma.

We analyzed 23 samples of primary pediatric ependymoma for significant gains or losses of genomic DNA, using comparative genomic hybridization (CGH) and a rigorous statistical approach. Nine of the tumors in this series (39%) appeared normal by CGH. The remainder had a limited number of regions of genomic imbalance, most often involving losses of chromosome arms 6q and 22q and the X chromosome, or gains of either 1q or 9. Recurrent and exclusive losses of 6q or 22q suggest that these regions harbor tumor suppressor genes that may contribute independently to the pathogenesis of childhood ependymoma.

Bithalamic involvement predicts poor outcome among children with thalamic glial tumors.

Clinical features and treatment of 36 consecutive pediatric patients with thalamic glial tumors confirmed by histology and characterized by neuroimaging were reviewed to identify prognostic factors. The median age at diagnosis was 10 years (range 1-18 years). Twenty-four patients had low-grade tumors (juvenile pilocytic astrocytoma n = 9, fibrillary astrocytoma n = 6, astrocytomas not otherwise specified n = 6, ganglioglioma n = 2 and oligodendroglioma n = 1) and 12 patients had high-grade tumors (glioblastoma multiforme n = 7, anaplastic astrocytoma n = 4 and unclassified malignant tumor n = 1). With a median follow-up of 4.3 years among survivors, estimates of 4-year progression-free survival (PFS) and overall survival (OS) for the entire group are 28+/-10 and 37 +/- 10%, respectively. Low-grade tumors were associated with a significantly better 4-year PFS (36 +/- 12 vs. 0% for the high-grade group; p = 0.03) and OS (52 +/- 12 vs. 0%; p < 0.001). This review identified that bithalamic involvement, characterized by neuroimaging, exerted an independent and significant negative impact on PFS and OS for patients with low-grade tumors. Estimates of 4-year PFS and OS among patients with tow-grade bithalamic versus monothalamic tumors were 58 +/- 15 vs. 0% and 85 +/- 11 vs. 0% (p < 0.00001), respectively. The presence of bithalamic involvement did not affect outcome among patients with high-grade tumors. Additionally, age at diagnosis, enhancement with neuroimaging contrast, extension beyond the thalamus and extent of surgical resection did not correlate with overall outcome. Because treatment approaches varied during the study period, the impact of radiation therapy or chemotherapy could not be assessed. This contemporary, single-institution series of pediatric thalamic glial tumors demonstrates, for the First time, the statistical significance of bithalamic involvement as a marker of poor prognosis among patients with low-grade glial lesions.

Malignant evolution of choroid plexus papilloma.

Choroid plexus tumors are rare CNS neoplasms. The distinction between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC) is made on the basis of clinical and histological criteria. Malignant evolution of CPP may occur, and the presence of mitotic figures in CPP may predict the likelihood of recurrence or malignant evolution. Close surveillance is mandated for these patients. We report on two such cases of CPP that transformed to CPC at the time of recurrence.