Shlomi Constantini

Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency

PURPOSEnRecurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition.nnnPATIENTS AND METHODSnWe performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab.nnnRESULTSnAll malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P < .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P < .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti-programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response.nnnCONCLUSIONnThis report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.

Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers

DNA replication−associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10−13). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

Repeat endoscopic third ventriculostomy: is it worth trying?

Abstract. Object: The goal of this study was to evaluate the safety, efficacy, and indications for repeat endoscopic third ventriculostomies (ETV). Methods and results: We reviewed the records of 20 patients who had undergone repeat ETV from 1987 to 1999. Their ages ranged from 8xa0months to 53xa0years (mean 17xa0years). The primary etiologies of hydrocephalus were: primary aqueductal stenosis (9 cases), tumor (5), Chiari malformation (2), prior infection (2), prior intraventricular hemorrhage (1), and blocked foramen of Monro (1 patient). The interval between the first and second ETVs ranged from 8xa0days to almost 6xa0years (mean 12.8xa0months). The intraoperative findings at repeat surgery were: occlusion of the primary orifice by scar (10 cases), virginal floor of the third ventricle (5 cases), pinhole ventriculostomy (3 cases), incompletely penetrated membrane (1 case), and blood clot occluding the orifice (1 case). The follow-up period ranged from 3 to 47xa0months (median 20xa0months). Repeat ETV was successful in 13 patients (65%). These patients did not require further shunting or other procedures during follow-up. Seven patients (35%) required placement of a shunt after repeat ETV. Several complications were observed in 1 patient (5%), including seizures, elevated ICP, bilateral pulmonary edema, and cardiac arrhythmia. This patient ultimately recovered fully; the ETV was successful, and the patient did not require a shunt. Conclusions: Based on the experience of this group of patients, repeat ETV is as effective and as safe as a primary ETV procedure, and should be attempted in selected patients.

Ventricular catheter placement in children with hydrocephalus and small ventricles: the use of a frameless neuronavigation system

Abstract.Object: Accurate placement of ventricular catheters in children with small ventricles can be difficult. Too often, shunt catheters are misplaced with regard to optimal postion and trajectory. The objective of this study was to determine whether neuronavigation-guided free-hand placement of ventricular catheters is an effective adjunct for children with hydrocephalus and small ventricles. Methods: Nine children with hydrocephalus (ages 1–12xa0years) participated in this study. Four children were diagnosed as suffering from slit ventricle syndrome and 5 children had small to mildly dilated ventricles. Of the 9 shunted children, 6 underwent previous shunt placements, and 1 child previously underwent an endoscopic third ventriculostomy. In 8 children the primary procedure was insertion of ventricular catheters using a frameless neuronavigation system. In 1 child, the neuronavigation system was used after failure to insert the ventricular catheter using a standard technique. All children showed significant improvement of their symptoms and signs following the procedure and none of them required shunt revision during the follow up period (mean 8±5xa0months). Conclusion: The usage of a neuronavigation system is safe and may be beneficial for optimal postioning and trajectory of ventricular catheters in children with small ventricles or an abnormal ventricular anatomy.

Risk factors for progressive spinal deformity following resection of intramedullary spinal cord tumors in children: an analysis of 161 consecutive cases.

OBJECTnGross-total resection of pediatric intramedullary spinal cord tumors (IMSCTs) can be achieved in the majority of cases, with preservation of long-term neurological function. However, progressive spinal deformity requiring subsequent fusion occurs in many cases. It remains unknown which subgroups of patients have the greatest risk for progressive spinal deformity.nnnMETHODSnData for 161 patients undergoing resection of IMSCTs at a single institution were retrospectively collected and analyzed with regard to the development of progressive spinal deformity requiring fusion and patient functional status (based on the modified McCormick Scale [mMS] and Karnofsky Performance Scale [KPS]) by conducting telephone interviews corroborated by medical records. The independent association of all clinical, radiographic, and operative variables to subsequent progressive spinal deformity was assessed using multivariate logistic regression analysis.nnnRESULTSnPatients were a mean of 8.6 +/- 5.7 years old at the time of surgery. The tumor spanned a mean of six +/- three spinal levels. Preoperative scoliotic deformity was present in 56 cases (35%). Seventy-six patients (47%) had undergone a previous biopsy procedure, and 28 (17%) a prior resection. Gross-total resection (> 95%) was achieved in 122 cases (76%). A median of 9 years (range 1-21) after surgery, progressive spinal deformity requiring fusion developed in 43 patients (27%). The median functional scores at the last follow-up were worse in patients who required fusion compared with those who did not (mMS: 3 compared with 2, p = 0.006; KPS: 80 compared with 90, p = 0.04) despite similar mMS scores between the groups at 3 months postoperatively. An age less than 13 years, preoperative scoliotic deformity (Cobb angle > 10 degrees), involvement of the thoracolumbar junction, and tumor-associated syrinx independently increased the odds of a postoperative progressive deformity requiring fusion 4.4-, 3.2-, 2.6-, and 3.4-fold, respectively (p < 0.05). Each subsequent resection increased the odds of a progressive deformity 1.8-fold (p < 0.05). Symptoms lasting less than 1 month before resection decreased the odds of spinal deformity requiring fusion ninefold (p < 0.05).nnnCONCLUSIONSnProgressive spinal deformity requiring fusion occurred in 27% of children undergoing resection of an IMSCT and was associated with a decreased functional status. Preoperative scoliotic deformity, an increasing number of resections, an age less than 13 years, tumor-associated syrinx, and surgery spanning the thoracolumbar junction increased the risk for progressive spinal deformity. Patients possessing one or more of these characteristics should be monitored closely for progressive spinal deformity following surgery.

Low-Risk Lumbar Skin Stigmata in Infants: The Role of Ultrasound Screening

OBJECTIVEnTo reassess the utility and validity of ultrasound (US) screening in infants with lumbar midline skin stigmata (MSS) that may be associated with tethering of the spinal cord.nnnSTUDY DESIGNnWe conducted a prospective observational study of 254 infants under age 6 months with suspicious dorsal MSS between 2005 and 2007. All infants were examined by US and neurosurgical clinical evaluation, and 50 infants also underwent magnetic resonance imaging (MRI). The US and MRI findings were analyzed for correlation. Associations between the imaging findings and the presence of the low-risk skin lesions simple dimple (113 cases) and deviated gluteal fold (DGF; 44 cases) also were evaluated.nnnRESULTSnAnalysis of US and MRI results for the cohort of 50 neonates in whom both examinations were performed showed high concordance. The low-risk group of infants with simple dimple and DGF constituted 157 US procedures, 96% of which were of high quality, providing clear visualization of spinal components. None demonstrated any clinically significant pathological findings.nnnCONCLUSIONSnOur data reaffirm the reliability of US as a screening tool for tethered cord syndrome. Infants with low-risk lesions, such as simple dimple and DGF, may be absolved from US screening, because these findings alone do not indicate underlying pathological lesions. We propose a simplified diagnostic classification system for MSS.

Optic Nerve Sheath Diameter on MR Imaging: Establishment of Norms and Comparison of Pediatric Patients with Idiopathic Intracranial Hypertension with Healthy Controls

BACKGROUND AND PURPOSE: IIH is a disorder associated with increased intracranial pressure with no clinical, laboratory, or radiologic evidence of an intracranial space-occupying lesion. The aim of this study was to establish ONSD standards of healthy pediatric subjects and compare the normal measurements with those of patients with IIH. MATERIALS AND METHODS: One hundred fifteen MR imaging studies of children 4 months to 17 years of age were blinded and reviewed by a pediatric neuroradiologist. A total of 230 optic nerves were measured. Eighty-six MR imaging examinations were performed in apparently healthy subjects. This control group included subjects who underwent MR imaging for various reasons, and their MR imaging findings were interpreted as normal. Twenty-nine MR imaging examinations were performed in patients with documented IIH. The ONSD was measured 1 cm anterior to the optic foramina on an axial T2 sequence. For statistical analysis, both patients and controls were stratified into 4 age groups (I, 0–3 years; II, 3–6 years; III, 6–12 years; IV, 12–18 years). RESULTS: The mean ONSD of the control group in all age groups (I, 3.1 mm; II, 3.41 mm; III, 3.55 mm; IV, 3.56 mm) was significantly smaller than the mean ONSD of patients (I, 4.35 mm; II, 4.37 mm; III, 4.25 mm; IV, 4.69 mm). A positive correlation between age and ONSD (r = 0.414, P < .01) was found in the control group. CONCLUSIONS: According to our study, in pediatric patients with IIH, the ONSD is significantly larger than that in healthy controls regardless of age group and sex. This measurement might prove to be an auxiliary tool in the diagnosis of increased intracranial pressure in pediatric patients.

Cyst Wall Enhancement in Pilocytic Astrocytoma: Neoplastic or Reactive Phenomena

Cystic pilocytic astrocytomas (CPA) consist of a mural nodule and an accompanying cyst, which may prominently enhance on MRI after contrast administration. This raises the question whether an enhanced wall represents a tumor and thus should be resected together with the solid nodule, as radical tumor surgery is associated with better prognosis. Until now, no systematic histopathological examinations of cyst walls have been reported in correlation with MRI, intraoperative appearance and postoperative clinical and MRI follow-up. We present 3 patients with CPAs and brightly enhanced cyst walls on MRI. Because of the benign, transparent appearance of the cyst wall intraoperatively, it was biopsied but not resected, and only radical removal of the nodule and its immediate surroundings was performed. Separate specimens taken from the cyst wall showed no tumor. MRI performed annually, up to 48–56 months after surgery showed no recurrence of the cyst or the tumor. In such cases of CPA, we suggest that enhancement of cyst walls may represent reactive rather than tumoral tissue, and may be left intact without risking worse prognosis. Mechanisms leading to cyst wall enhancement and the optimal surgical treatment are discussed.

Intraoperative Portable 0.12-Tesla MRI in Pediatric Neurosurgery

Objectives: Intraoperative MRI (iMRI) is used mainly in the adult neurosurgical population. The main indications for iMRI usage are resection control and updated intraoperative navigation capabilities. In this paper we present our experience using this technique in children. Specific advantages of iMRI for this age group are discussed. Methods and Results: We retrospectively reviewed 31 pediatric neurosurgical procedures in which a portable iMRI system was used. The indications for iMRI usage were preoperative navigation, resection control during tumor removal, shunt placements, and needle biopsy. In 7 children the use of the iMRI changed the course of the surgical procedure. Operative morbidity and mortality were not increased with use of the iMRI. Conclusions: iMRI systems have advantages for the pediatric neurosurgical population, including both real-time basic navigation and improved resection control.

Surgical Treatment of Hypothalamic Hamartoma and Refractory Seizures

Refractory gelastic seizures are often associated with hypothalamic hamartoma (HH). Presurgical evaluation in such children often points to a distinct cortical region as the source of the seizures. A case of a child with HH and refractory seizures is presented. Video-EEG monitoring revealed a well-defined epileptic focus in the left frontal region. In accordance with the current understanding of the nature of hamartoma-related seizures, the hamartoma was resected. Follow-up evaluations revealed a marked improvement in seizure frequency and global functioning.