Shlomi Constantini

Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient

Background Neural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells. Methods and Findings A boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patients peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors. Conclusions This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.

Endoscopic Third Ventriculostomy in the Treatment of Childhood Hydrocephalus

OBJECTIVE To develop a model to predict the probability of endoscopic third ventriculostomy (ETV) success in the treatment for hydrocephalus on the basis of a childs individual characteristics. STUDY DESIGN We analyzed 618 ETVs performed consecutively on children at 12 international institutions to identify predictors of ETV success at 6 months. A multivariable logistic regression model was developed on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). RESULTS In the training set, 305/455 ETVs (67.0%) were successful. The regression model (containing patient age, cause of hydrocephalus, and previous cerebrospinal fluid shunt) demonstrated good fit (Hosmer-Lemeshow, P = .78) and discrimination (C statistic = 0.70). In the validation set, 105/163 ETVs (64.4%) were successful and the model maintained good fit (Hosmer-Lemeshow, P = .45), discrimination (C statistic = 0.68), and calibration (calibration slope = 0.88). A simplified ETV Success Score was devised that closely approximates the predicted probability of ETV success. CONCLUSIONS Children most likely to succeed with ETV can now be accurately identified and spared the long-term complications of CSF shunting.

Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium

BACKGROUND Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. METHODS We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. RESULTS Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. DISCUSSION CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.

Endoscopic Third Ventriculostomy Vs Cerebrospinal Fluid Shunt in the Treatment of Hydrocephalus in Children: A Propensity Score-Adjusted Analysis

BACKGROUNDEndoscopic third ventriculostomy (ETV) has preferentially been offered to patients with more favorable prognostic features compared with shunt. OBJECTIVETo use advanced statistical methods to adjust for treatment selection bias to determine whether ETV survival is superior to shunt survival once the bias of patient-related prognostic factors is removed. METHODSAn international cohort of children (≤ 19 years of age) with newly diagnosed hydrocephalus treated with ETV (n = 489) or shunt (n = 720) was analyzed. We used propensity score adjustment techniques to account for 2 important patient prognostic factors: age and cause of hydrocephalus. Cox regression survival analysis was performed to compare time-to-treatment failure in an unadjusted model and 3 propensity score—adjusted models, each of which would adjust for the imbalance in prognostic factors. RESULTSIn the unadjusted Cox model, the ETV failure rate was lower than the shunt failure rate from the immediate postoperative phase and became even more favorable with longer duration from surgery. Once patient prognostic factors were corrected for in the 3 adjusted models, however, the early failure rate for ETV was higher than that for shunt. It was only after about 3 months after surgery did the ETV failure rate become lower than the shunt failure rate. CONCLUSIONSThe relative risk of ETV failure is initially higher than that for shunt, but after about 3 months, the relative risk becomes progressively lower for ETV. Therefore, after the early high-risk period of ETV failure, a patient could experience a long-term treatment survival advantage compared with shunt. It might take several years, however, to realize this benefit.

Automatic segmentation, internal classification, and follow-up of optic pathway gliomas in MRI

This paper presents an automatic method for the segmentation, internal classification and follow-up of optic pathway gliomas (OPGs) from multi-sequence MRI datasets. Our method starts with the automatic localization of the OPG and its core with an anatomical atlas followed by a binary voxel classification with a probabilistic tissue model whose parameters are estimated from the MR images. The method effectively incorporates prior location, tissue characteristics, and intensity information for the delineation of the OPG boundaries in a consistent and repeatable manner. Internal classification of the segmented OPG volume is then obtained with a robust method that overcomes grey-level differences between learning and testing datasets. Experimental results on 25 datasets yield a mean surface distance error of 0.73 mm as compared to manual segmentation by experienced radiologists. Our method exhibits reliable performance in OPG growth follow-up MR studies, which are crucial for monitoring disease progression. To the best of our knowledge, this is the first method that addresses automatic segmentation, internal classification, and follow-up of OPG.

Practical Decisions in the Treatment of Pediatric Brain Stem Tumors

The treatment of brain stem gliomas has evolved over the last few decades, reflecting advances in imaging (MR), microsurgical techniques and biological understanding. The aim of this chapter is to provide a preoperative classification for intrinsic brain stem lesions that will predict histopathology and biological behavior from the clinical syndrome and the MR appearance. Such a classification system may help in selecting children with brain stem tumors that can benefit from surgery. Technical considerations, potential surgical complications, and the ways to avoid them are discussed.

Risk of venous thromboembolism in pediatric patients with brain tumors

Venous thromboembolism (VTE) is a common event in adults with malignant brain tumors approaching 24% throughout the course of the disease. The high morbidity and mortality of this complication yielded several protocols for prevention of the disease in adults undergoing neurosurgery for brain tumors and possible primary prevention afterwards. We investigated the incidence and complications of VTE in pediatric neuro‐oncology patients.

The occurrence of obstructive vs absorptive hydrocephalus in newborns and infants: relevance to treatment choices

Background and objectiveThe classification of hydrocephalus in newborns and in infants is different from the classification in adulthood. This difference exists due to disparity in the source pathologies that produce the hydrocephalus, and the practical distinctions in prognosis and treatment choices. The objective of this paper is to present the spectrum of obstructive-communicating hydrocephalus, which is more complex in the pediatric group, and to propose the relevance of this particular classification to treatment options.Materials and methodsThe authors categorized infants with active hydrocephalus at time of presentation into the following four groups along the spectrum of communicating vs obstructive HCP. Group 1: patients with a purely absorptive (communicating) HCP. In these patients, tetraventricular dilatation is usually observed with occasional extraaxial fluid accumulation. An extracranial CSF diversion (shunt) is the treatment of choice. Group 2: patients with an obstructive component together with a persistent absorptive component. In these patients, a technically successful endoscopic procedure will not prevent progression of clinical symptoms of HCP. An extracranial CSF diversion (shunt) should be the treatment of choice even though some of these patients are currently treated by endoscopy. Group 3: patients with an obstructive component together with a temporary absorptive component. In these patients, a technically successful ETV should be followed by temporary CSF drainage [via LP, continuous spinal drainage (CLD), or ventriculostomy] with or without supplemental medical treatment (i.e., Diamox) for several days. Such temporary drainage may decrease failure rate in this subgroup. Group 4: patients with a purely obstructive HCP. In these patients, an endoscopic procedure (ETV) is the treatment of choice. According to this spectrum classification, the authors classify different entities with representative cases and discuss relevancy to treatment options and prognosis.ResultsThe data suggest that obstructive hydrocephalus in the very young population may be rather a combination of obstructive and absorptive problem. The outcome of the patient depends mainly not only on the basic pathology causing the hydrocephalus but also on the treatment that is chosen and its complications. While bleeding and infection represent the major causes for communicating hydrocephalus, patients with complex pathologies of congenital type and intra- or interventricular obstructions may reflect obstructive hydrocephalus. Treatment of these patients may be successful by shuntless procedures if the absorptive problem is not the major component. In transient absorptive hydrocephalus, temporary measures were effective in many cases leading to successful procedures of ETV and/or posterior-fossa decompression in selected cases.ConclusionsShuntless procedures are the dream of a pediatric neurosurgeon provided it solves the problem and does not imply unacceptable risk. However, the benefit has to be evaluated years after the procedure is performed, as only prospective multicenter studies will truly show which procedure may have the best overall results in the developing child. Until such studies are available, understanding the basic pathology or the combination of pathologies leading to hydrocephalus in a given child may open the window of opportunities for other than shunt surgery in many hydrocephalic children with major obstructive component.

A feasibility and efficacy study of rapamycin and erlotinib for recurrent pediatric low‐grade glioma (LGG)

To determine the toxicity and efficacy of rapamycin and erlotinib for the treatment of recurrent pediatric low‐grade gliomas (LGGs).

Visual outcome following chemotherapy for progressive optic pathway gliomas

Optic pathway gliomas (OPG) are relatively indolent tumors that may occur sporadically or in association with neurofibromatosis 1. Treatment is initiated only when a clear clinical or radiological deterioration is documented. Chemotherapy is the standard first line of treatment. Due to the indolent nature of this tumor, the most important challenge in OPG treatment is vision preservation.