DNA methylation signature is prognostic of choroid plexus tumor aggressiveness.

BACKGROUND: Histological grading of choroid plexus tumors (CPTs) remains the best prognostic tool to distinguish between aggressive choroid plexus carcinoma (CPC) and the more benign choroid plexus papilloma (CPP) or atypical choroid plexus papilloma (aCPP); however, these distinctions can be challenging. Standard treatment of CPC is very aggressive and often leads to severe damage to the young child's brain. Therefore, it is crucial to distinguish between CPC and less aggressive entities (CPP or aCPP) to avoid unnecessary exposure of the young patient to neurotoxic therapy. To better stratify CPTs, we utilized DNA methylation (DNAm) to identify prognostic epigenetic biomarkers for CPCs. METHODS: We obtained DNA methylation profiles of 34 CPTs using the HumanMethylation450 BeadChip from Illumina, and the data was analyzed using the Illumina Genome Studio analysis software. Validation of differentially methylated CpG sites chosen as biomarkers was performed using pyrosequencing analysis on additional 22 CPTs. Sensitivity testing of the CPC DNAm signature was performed on a replication cohort of 61 CPT tumors obtained from Neuropathology, University Hospital Münster, Germany. RESULTS: Generated genome-wide DNAm profiles of CPTs showed significant differences in DNAm between CPCs and the CPPs or aCPPs. The prediction of clinical outcome could be improved by combining the DNAm profile with the mutational status of TP53. CPCs with homozygous TP53 mutations clustered as a group separate from those carrying a heterozygous TP53 mutation or CPCs with wild type TP53 (TP53-wt) and showed the worst survival outcome. Specific DNAm signatures for CPCs revealed AK1, PER2, and PLSCR4 as potential biomarkers for CPC that can be used to improve molecular stratification for diagnosis and treatment. CONCLUSIONS: We demonstrate that combining specific DNAm signature for CPCs with histological approaches better differentiate aggressive tumors from those that are not life threatening. These findings have important implications for future prognostic risk prediction in clinical disease management.

Perinatal (fetal and neonatal) choroid plexus tumors: a review.

INTRODUCTION: The object of this review is to describe the choroid plexus tumors (CPTs) occurring in the fetus and neonate with regard to clinical presentation, location, pathology, treatment, and outcome. MATERIALS AND METHODS: Case histories and clinical outcomes were reviewed from 93 cases of fetal and neonatal tumors obtained from the literature and our own institutional experience from 1980 to 2016. RESULTS: Choroid plexus papilloma (CPP) is the most common tumor followed by choroid plexus carcinoma (CPC) and atypical choroid plexus papilloma (ACPP). Hydrocephalus and macrocephaly are the presenting features for all three tumors. The lateral ventricles are the main site of tumor origin followed by the third and fourth ventricles, respectively. CPTs of the fetus are detected most often near the end of the third trimester of pregnancy by fetal ultrasound. The extent of surgical resection plays an important role in the treatment and outcome. In spite of excellent survival, which is especially true in the case of CPP, surgical resection may carry significant risks in an immature baby. Given the neonatal low blood volume and increased vascularity of the tumors, there is potential risk for hemorrhage. Although advances in neurosurgical techniques have led to a greater degree of complete surgical resections, survival for the perinatal CPC group remains low even with multimodality therapies. CONCLUSION: Perinatal CPTs have variable overall survivals depending on degree of surgical resection and tumor biology. An increased understanding of the molecular features of these tumors may lead to improved therapies and ultimately survival.

Choroid plexus tumors in adult and pediatric populations: the Cleveland Clinic and University Hospitals experience.

Choroid plexus tumors (CPT) are rare neoplasms accounting for 1-4% of all pediatric brain tumors. They are divided into choroid plexus papilloma (CPP), atypical choroid plexus papilloma (APP) and choroid plexus carcinoma (CPC). CPTs are known to primarily affect children less than 2 years of age. Gross total resection is the most important predictor of survival especially in CPC. Although small case series have been published, limited clinical data are available to describe treatment and outcome of CPTs. More clinical data would be necessary to complete the picture, particularly in populations that are not age limited. Here we share data from the two major hospitals in Cleveland to describe treatment and outcome of adult and pediatric patients. We performed a retrospective analysis of patients with CPT seen in Cleveland Clinic from 1990 to 2015 and at University Hospitals from 1994 to 2015. Results were compared to previously published historical controls. We identified 30 cases with CPT, including 22 pediatric and eight adult cases; 11 females and 19 males. The mean age at presentation was 12.4 years with a median age of 4.5 years (range 2 months-51 years). Gross total surgical resection was achieved in 22, subtotal resection in four, partial resection in two and unknown in two. The histology was CPP in 23 patients, two of whom developed recurrence requiring repeat resection and adjuvant therapy. Median event free survival (EFS) for CPP patients was 7.6 years. The histology was CPC in seven patients. All CPC patients were treated with adjuvant therapy. Median EFS of CPC patients was 4.4 years. Overall survival of all CPT patients was 100% with a median follow up of 7 years. A systematic literature review identified 1012 CPT patients treated from 1989 to 2013. The mean and median age of CPT patients was 13 and 3 years respectively. The median survival of 541 CPP patients was undefined vs. 2.7 years for the 452 CPC patients. The difference between the two populations was highly significant (p < 0.001). Kaplan-Meier survival curves comparing CPTs at Cleveland Clinic and University Hospitals versus a systematic literature review showed a statistically significant advancement in overall survival among the patients treated at Cleveland Clinic and University Hospitals. Our data are consistent with the literature review regarding epidemiology, clinical presentation, and treatment modalities but differed in regards to survival. Differences in survival may be related to different methods of data collection or details in patient care.

Primary tumors of the lateral ventricles of the brain.

BACKGROUND: The lateral ventricles are located in the center of the brain. Each ventricle lies in contact with five critical neural structures: the caudate nucleus, the thalamus, the fornix, the corpus callosum, and the genu of internal capsule.The authors report their experience in primary tumors of the lateral ventricles of the brain by analysing the symptomatology,the surgical treatment, the complications and the postoperative results. OBJECTIVE: To determine the importance of the surgical technique on the morbidity and the recurrence of lateral ventricles tumors. Total surgical resection followed by radiotherapy and or chemotherapy had been the main objective in the cases of anaplastic tumors. METHODS: This retrospective study makes reference to 202 primary tumors of the lateral ventricles operated by Leon Danaila between 1982 and 2012. The respective analysis is based on the operative approaches and on the extent of resection. The surgical access routes were the interhemispheric transcallosal approach and the transcortical approach. RESULTS: A number of 177 (87%) of the primary tumors of the lateral ventricles were benign (low grade lesions), while 25(12.37%) of them were anaplastic. The most frequent tumors were ependymomas, astrocytomas, subependymomas, choroid plexus papillomas and meningiomas. Out of the total of 202 tumor cases, 164 (81.18%) were discharged with very good and good results, 35 (17.32%) were left with neurological deficits,and 3 (1.48%) died. A significant proportion of the patients undergoing surgery develop cerebrospinal fluid outflow obstruction, and this fact made the postoperative mounting of a number of ventricular shunts necessary. CONCLUSION: The majority of these tumors were benign, with are latively slow growth rate. Owing to this fact, the preoperative dimensions of the tumors were of several centimeters. The average age of the patients was lower than that of those with similar lesions located intraparenchymatously. The symptoms were determined by the ventricular outflow obstruction and by the affectation of the periventricular structures. Interhemispheric transcallosal and transcortical approaches were the best surgical access routes.

The relative patient benefit of gross total resection in adult choroid plexus papillomas.

Choroid plexus papillomas are rare neuroepithelial tumors found mainly in children. Although well studied in the pediatric population, there is a paucity of literature focusing specifically on adults. We sought to assess the relative advantage of gross total resection (GTR) and further characterize the natural history of this disease in adults. A comprehensive PubMed search was performed to identify adults who underwent surgical resection for choroid plexus papillomas with clearly reported age, tumor location, and extent of resection. Kaplan-Meier analysis was used to assess progression-free survival (PFS) and overall survival (OS). Multivariate analysis was performed using Cox proportional hazards models. A total of 193 patients were identified with a mean age of 39.9 ± 1.1 years. GTR was achieved in 72% of patients with subtotal resection (STR) in 28%. GTR was associated with a significant increase in both PFS (p = 0.015) and OS (p = 0.004) compared to STR. In a multivariate Cox proportional hazards model we found that only GTR was associated with recurrence (hazard ratio [HR] = 0.47, 95% confidence interval [CI] 0.25-0.90), while both age (HR = 1.03, 95% CI 1.00-1.05) and GTR (HR = 0.36, 95% CI 0.17-0.78) were associated with OS. Interestingly, our observed recurrence and death rates were higher than those in previously published studies. These findings demonstrate the benefit of GTR for the treatment of choroid plexus papillomas in adults. Our analysis suggests that these lesions are not as indolent as previously thought and while GTR is preferred, it is not always curative.

Surgical outcomes in choroid plexus papillomas: an institutional experience.

Choroid plexus papillomas (CPPs) are rare, indolent lesions that comprise less than 0.5 % of intracranial tumors. We sought to assess the long-term outcomes and associated surgical complications at our institution. A review of the University of California, San Francisco (UCSF) Brain Tumor Research Center (BTRC) database was performed to identify a cohort of patients treated for CPP from 1997 to 2011. Patients were grouped based on tumor location and extent of resection. Outcomes including progression-free survival and surgical complications were assessed. We identified 24 patients (16 female, 8 male) ranging in age from 6 months to 55 years (median 29 years) treated at our institution. Tumors were found in the following locations: 16 (67 %) fourth ventricle/cerebellopontine angle; 7 (29 %) lateral ventricle; 1 (4 %) third ventricle. Gross total resection (GTR) was achieved in 20 patients (83 %) with subtotal resection (STR) in 4 (17 %). Median follow-up time was 2.8 years with 3 recurrences identified at 1.6, 3.3, and 8.5 years. Extent of resection and tumor location were not associated with recurrence. There was one new permanent neurologic deficit detected after surgery. All patients were alive at most recent follow-up. Attempted gross total resection is the standard treatment for CPPs and generally associated with excellent outcomes. Since recurrences are rare, even among patients who undergo STR, radiation may be reserved for cases of tumor progression. This modern experience at a tertiary care center performed exclusively during the MRI-era demonstrates that CPPs can be safely removed with minimal morbidity and good tumor control.

Choroid plexus tumors in children: a population-based study.

BACKGROUND: Choroid plexus tumors are rare neoplasms that primarily occur in children. The use of the SEER (Surveillance, Epidemiology and End Results) database allows for the analysis of the relationship between prognostic factors and survival. METHODS: We analyzed the SEER database to select pediatric patients (<18 years old) with histologically confirmed diagnoses of choroid plexus papillomas (CPP; WHO Grade 0), atypical CPP (WHO Grade I) and choroid plexus carcinomas (CPC; WHO grade III). In univariate and multivariate analysis, we analyzed the relationship between demographic (age, gender, race, date of diagnosis) and treatment factors (extent of surgical resection, use of adjuvant radiation) on survival. RESULTS: Overall, 168 pediatric subjects with choroid plexus tumors were identified as follows: 75 cases of CPP, 12 cases of atypical CPP and 81 cases of CPC. The median follow-up time was 3.5 years for CPP and 7.7 years for CPC. The median age at diagnosis was 4 years for CPP (10-90th percentile 0-16 years) and 1 year for CPC (10-90th percentile 0-10 years). In univariate regression analysis, CPC histology (ß = -3.2, 95% confidence interval, CI -4.8 to -1.5, p < 0.001) was significantly associated with younger age at diagnosis in comparison to CPP. The mean tumor size was 3.7 cm for CPP and 6.0 cm for CPC (p < 0.001). A higher-grade tumor was associated with significantly increased mortality (hazard ratio, HR = 28.90, 95% CI 3.94-211.83, p = 0.001). Overall survival at 5 years was 98.7% for CPP and 58.5% for CPC (p < 0.001). Among those patients with CPC, gross total resection (GTR) was associated with a significantly lower mortality (HR = 0.21, 95% CI 0.07-0.66, p = 0.007). Overall survival at 5 years was 70.9% after GTR, significantly better than 35.9% after subtotal resection (p = 0.012) and 30% after no surgery (p = 0.003). Radiation treatment was not found to confer a survival benefit in CPC. No demographic characteristics (age, sex, race, date of diagnosis) were significantly associated with mortality. CONCLUSIONS: Analysis of a pediatric cohort of choroid plexus tumors in children in the SEER database shows that tumor grade is predictive of survival. In cases of CPC, the extent of surgical resection, especially GTR, is significantly associated with increased survival. Radiation did not confer survival benefit.

Infantile intracranial neoplasms: characteristics and surgical outcomes of a contemporary series of 21 cases in an Egyptian referral center.

OBJECTIVE: To investigate the demographic, clinical, radiological, pathological and surgical features and outcomes of infantile intracranial neoplasms, the second most common neoplasm in infants. PATIENTS AND METHODS: We conducted a retrospective study in the Department of Pediatric Neurosurgery at the Abo El-Reish Children's Hospital from 2005 to 2008. RESULTS: Out of 451 patients with primary intracranial neoplasms (age 0-14 years), 21 infants (<1 year) underwent surgery, representing 4.7% of total cases. The most common tumor was choroid plexus papilloma (23.8%), followed by teratoma (19%) then astrocytoma and ependymoma (14.3% each). Of the 21 surgical cases, 90% were intra-axial, 80% were in the supratentorial region, and 57% were intraventricular. There was only 1 case of intraoperative mortality (4.8%). Gross total excision was achieved in 65%, debulking in 30%, and biopsy in 5%. Three patients received chemotherapy, but none received radiotherapy. The statistically significant predictors of prognosis were the extent of resection and tumor grade. CONCLUSION: Although the prognosis for infantile intracranial neoplasms is worse than for older children, an overall promising outcome with low operative morbidity and mortality was achieved using gross total excision and appropriate adjuvant chemotherapy as part of a multidisciplinary approach.

TP53 alterations determine clinical subgroups and survival of patients with choroid plexus tumors.

PURPOSE Choroid plexus carcinomas are pediatric tumors with poor survival rates and a strong, but poorly understood, association with Li-Fraumeni syndrome (LFS). Currently, with lack of biologic predictors, most children are treated with aggressive chemoradiation protocols. PATIENTS AND METHODS We established a multi-institutional tissue and clinical database, which enabled the analysis of specific alterations of the TP53 tumor suppressor and its modifiers in choroid plexus tumors (CPTs). We conducted high-resolution copy-number analysis to correlate these genetic parameters with family history and outcome. Results We studied 64 patients with CPTs. All individuals with germline TP53 mutations fulfilled LFS criteria, whereas all patients not meeting these criteria harbored wild-type TP53 (P < .001). TP53 mutations were found in 50% of choroid plexus carcinomas (CPCs). Additionally, two sequence variants known to confer TP53 dysfunction, TP53 codon72 and MDM2 SNP309, coexisted in the majority of TP53 wild-type CPCs (92%) and not in TP53 mutated CPC (P = .04), which suggests a complementary mechanism of TP53 dysfunction in the absence of a TP53 mutation. High-resolution single nucleotide polymorphism (SNP) array analysis revealed extremely high total structural variation (TSV) in TP53-mutated CPC tumor genomes compared with TP53 wild-type tumors and choroid plexus papillomas (CPPs; P = .006 and .004, respectively). Moreover, high TSV was associated with significant risk of progression (P < .001). Five-year survival rates for patients with TP53-immunopositive and -immunonegative CPCs were 0% and 82 (+/- 9%), respectively (P < .001). Furthermore, 14 of 16 patients with TP53 wild-type CPCs are alive without having received radiation therapy. CONCLUSION Patients with CPC who have low tumor TSV and absence of TP53 dysfunction have a favorable prognosis and can be successfully treated without radiation therapy.

Clinicopathologic and immunohistochemical study of choroid plexus tumors: single-institution experience in Mexican population.

In recent years, few studies have specifically focused on only histological features in choroid plexus tumors. We retrospectively reviewed the clinicopathologic and histological features in 37 patients with choroid plexus tumors and correlated these with glial fibrillary acidic protein (GFAP) expression and proliferation cell nuclear antigen (PCNA), p53, p21, and Rb labeling indexes, with special attention to tumor recurrence/regrowth. The study included 24 choroid plexus papillomas (CPPs), 4 atypical choroid plexus papillomas (ACPPs), and 9 choroid plexus carcinomas (CPCs). Patient age ranged from 15 to 70 years (mean 44 years). Most of the choroid plexus tumors were located in the IV ventricle. Recurrence was observed in 21 (52%) cases, 14 of which were CPP and 7 of which were CPC (P = 0.032). Histologic findings included major necrosis, fibrosis and psammoma bodies, amyloid deposits, inflammation, and thick vessels in recurrent tumors. The PCNA labeling index was 52.04 + or - 13.92 in CPPs, 76.50 + or - 17 in ACPPs, and 95.22 + or - 21.34 in CPCs (P = 0.009), and 67.43 + or - 28 in recurrent tumors. Similar values were found for p53, p21, and Rb. Furthermore, we observed that these presented more histological changes, adding, than nonrecurrent tumors, as well as a higher proliferation index of cell-cycle markers, and these were dependent predictor factors of survival. Recurrent tumors showed a different biological behavior than nonrecurrent tumors, but histological observations showed no mitotic features in order to consider them as grade II.

Congenital tumors of the central nervous system: the MCH experience.

INTRODUCTION: Congenital brain tumors in the younger pediatric population are rare lesions that are histologically distinct from those in the older pediatric population. Malignant histology is common, with persistently poor outcomes despite accessible neuroimaging and evolving adjuvant therapy. There remains scant literature about the natural history of these patients because of rarity and varied institutional experiences. METHODS: A retrospective review was performed of congenital brain tumor patients surgically treated at the Montreal Children's Hospital (MCH) over a 22-year period. Patients presenting in the first year of life were evaluated for demographic information, presenting symptoms, lesion location, and management. Analysis was by median rank test and chi(2) statistics. RESULTS: 13 cases of congenital brain tumors were identified: 5 supratentorial and 8 infratentorial. Median age (p = 0.93) and gender (p = 0.57) did not differ by location, and predominant histologies were choroid plexus papilloma and primitive neuroectodermal tumor. Seizure activity was exclusive to supratentorial lesions (40%, p = 0.03), with hypotonia observed only among infratentorial lesions (50%, p = 0.02). There was equal incidence of hydrocephalus (69%, p = 0.57) and increasing head circumference (38%, p = 0.27) by lesion location. Supratentorial lesions were treated by total resection (n = 3), subtotal resection (n = 1), and biopsy (n = 1). Infratentorial lesions were treated by total resection (n = 1), subtotal resection (n = 2), biopsy (n = 1), no operation (n = 2), and decompressive laminectomy for two spinal lesions. CONCLUSIONS: Congenital brain tumor patients represent fewer than 2% of patients treated at MCH. An evolving understanding of management objectives for these lesions requires understanding institutional experiences. Patients with supratentorial lesions frequently present with seizures, hydrocephalus, and macrocrania, and more frequently underwent total resection at surgery.

Atypical choroid plexus papilloma: clinical experience in the CPT-SIOP-2000 study.

Atypical choroid plexus papilloma (APP) represents a novel intermediate-grade subtype of choroid plexus tumor (CPT), the clinical outcome of which has not been described yet. We present the first analysis of a group of APP patients enrolled in the ongoing CPT-SIOP-2000 study of CPTs. A worldwide registration and a randomized trial for those patients who require chemotherapy started in 2000. For APP, maximal surgical resection was recommended. After surgery, patients who had undergone complete resection were observed, whereas patients with incompletely resected or metastasized APP were treated with six chemotherapy courses (etoposide and vincristine, combined with either carboplatin or cyclophosphamide). Risk-adapted radiotherapy was given only to patients older than 3 years of age. Of the 106 patients with a centrally confirmed CPT histology, 30 had APP, 42 CPP and 34 CPC. APP patients were significantly younger (median = 0.7 years) than patients with CPP or CPC (both medians = 2.3 years). Complete resection was achieved in 68 (64%) patients (79% in CPP, 63% in APP, and 47% in CPC). Metastases were present at diagnosis in 17% of APP patients, 5% of CPP patients, and 21% of CPC patients. All nine APP patients who received postoperative chemotherapy showed an early response after two cycles: two had complete remission, four had partial response, and three had stable disease. In the observation group of 15 patients, one event was seen, and all patients were alive. In the treatment group, one patient with a metastasized tumor and incompletely resected APP died. While APP was defined histologically, median percentages of both the Ki-67/MIB-1 proliferation marker and the p53 tumor suppressor protein increased across the three histological subtypes (from CPP to APP and then CPC), suggesting that the subtypes comprise an ordinal categorization of increasingly severe CPT tumors. This ordering was reiterated by clinical outcome in the 92 patients treated per the study protocol, with 5-year EFS rates of 92% in 39 CPP patients, 83% in 24 APP patients, and 28% in 29 CPC patients. A similar ordering was seen when all 106 patients were evaluated for EFS. APP responded favorably to chemotherapy. The intermediate position of APP between CPP and CPC was supported by the clinical data.

Enhancing antitumor immunity: combining IL-12 with TGFbeta1 antagonism.

With respect to CD8 effector T cells, interleukin-12 (IL-12) and transforming growth factor beta (TGFbeta) are 2 cytokines that exert opposing effects. IL-12 promotes antitumor immune responses by augmenting activated CD8 T-cell proliferation and interferon-gamma secretion. Conversely, TGFbeta generates a permissive environment for cancer growth, in part by antagonizing the effects of immunomodulatory cytokines, including IL-12. We demonstrate that TGFbeta-resistant T cells are capable of sustaining IL-12-induced mitogenesis and interferon-gamma secretion in a TGFbeta-rich milieu. Furthermore, in 2 murine tumor models associated with high TGFbeta1 levels in the local microenvironment, treatment with IL-12 and adoptively transferred TGFbeta-resistant T cells provided improved survival times. These results suggest that combining IL-12 with TGFbeta neutralization strategies may be effective in enhancing antitumor immune responses.

Childhood choroid plexus papillomas: operative complications.

METHODS: Eight children (below 12 years of age) operated on for intraventricular choroid plexus papilloma (CPP) were retrospectively reviewed to identify the factors responsible for their high postoperative morbidity and mortality. Seven of these patients were aged between 2 months and 2 years and 1 was aged 12 years. Six CPP lesions were in the lateral ventricles and the remaining 2 were in the anterior third ventricle. All children presented with features of raised intracranial pressure. Due to gross hydrocephalus with severe manifestations at admission two patients required CSF diversion before definitive surgery. RESULTS: Microsurgical excision of CPPs was achieved in 7 and near total removal of the tumor in an 8th child. Brain shift was noted during operation and was attributed to acute CSF drainage and/or tumor excision in all cases. External ventricular drainage was postoperatively placed in 2 patients, who ultimately required shunt installation. One child died during definitive surgery. Due to neurological deterioration 6 of the remaining 7 patients had a postoperative CT scan within a week of surgery. One had an uneventful recovery, and pneumocephalus and subdural effusion were found in all 6 scanned children. Pneumocephalus was significant enough in 4 of them to warrant a surgical evacuation. CONCLUSION: Acute CSF drainage leading to significant intraoperative brain shift, postoperative external ventricular drainage, pneumocephalus, subdural effusion, and persistent postoperative hydrocephalus were identified as chief factors for higher morbidity in these children.

Evaluation of proliferative index and cell cycle protein expression in choroid plexus tumors in children.

Choroid plexus tumors are papillary neoplasms originating from the epithelium of the choroid plexus within the cerebral ventricles. They may be highly proliferative tumors, but detailed studies confirming their proliferative potential are lacking. Accordingly, we performed a clinicopathological correlation study of neoplasms arising from the choroid plexus in children using immunohistochemistry to characterize both their proliferative potential and their degree of cell cycle dysregulation when compared to non-neoplastic choroid epithelium. Twelve children with choroid plexus papillomas (CPPs) and 11 with choroid plexus carcinomas (CPCs) were identified from the time period 1982-1997. The outcome and survival of these children following treatment was determined from the medical record. Immunohistochemical studies were performed on CPPs and CPCs in this patient population and on non-neoplastic choroid epithelium using antibodies to MIB-1, p53, cyclin E, retinoblastoma protein (pRB), p107, and E2F-1. In 5 children with CPCs, tumor tissue was available for immunohistochemistry at a second surgery after cycles of chemotherapy had been given. The mean survival for patients with CPPs was 8.5 years, and with CPCs 5.2 years with a minimum follow-up of 4 years for the group. The expression of cell cycle markers and MIB-1 was greater in CPCs than in CPPs or normal choroid plexus. The expression of MIB-1, p53, pRB, and E2F-1 was significantly lower in patients with CPCs after chemotherapy than before. The MIB-1 labeling index for CPC patients who are alive and well after treatments was 15.19+/-3.2 compared to 22.63+/-3.04 for patients who have died from their disease (P<0.05). We conclude that CPCs in children are characterized by a higher MIB-1 labeling index and greater cell cycle dysregulation than are CPPs. Chemotherapy may work in part on CPCs to decrease their proliferative potential and expression of cell cycle regulatory proteins.