Rina Dvir

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

PURPOSE Recurrent 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. PATIENTS AND METHODS We 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. RESULTS All 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. CONCLUSION This 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.

Role of 18F-FDG PET/CT in staging and follow-up of lymphoma in pediatric and young adult patients

Objective: To assess the role of 18F-Fluorodeoxyglucose (18F-FDG) PET/CT in pediatric patients with Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). Materials and Methods: 31 patients, mean age 12.9 ± 5.1, HD (n = 24), and NHL (n = 7) underwent 18F-FDG PET/CT at diagnosis (n = 31 studies) and later in the course of the disease (n = 75 studies). The findings of PET/CT were correlated with diagnostic CT and clinical follow-up. Results: PET/CT findings resulted in a change of disease staging in 10 patients (32.3%), upstaging in 7 (22.6%) and downstaging in 3 (9.6%). On a lesion analysis, 164 disease sites were detected by PET/CT of which 38 were overlooked by DCT. At mid-treatment, PET was negative in 28 out of 31 patients (90%) with negative predictive value of 96% as all latter patients except for 1, were disease free (mean 15.4 ± 8.8 months). The positive predictive value of persistent increased 18F-FDG uptake was 100% as 3 patients with latter findings had active disease. On the CT part, 76 residual masses were identified in 22 patients. Increased 18F-FDG uptake was detected in 11 masses in 4 patients who had active disease. Remaining 65 PET negative masses were false positive findings. The positive predictive value of residual CT mass was 14%. Conclusions: PET/CT is associated with change in staging in approximately 1 out of 3 pediatric patients with HD and NHL. When used for monitoring response to treatment, a negative study is associated with disease-free period, even when residual mass is detected. A positive PET study indicates residual malignant disease.

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.

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.

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.

Molecular Characterization of Choroid Plexus Tumors Reveals Novel Clinically Relevant Subgroups

Purpose: To investigate molecular alterations in choroid plexus tumors (CPT) using a genome-wide high-throughput approach to identify diagnostic and prognostic signatures that will refine tumor stratification and guide therapeutic options. Experimental Design: One hundred CPTs were obtained from a multi-institutional tissue and clinical database. Copy-number (CN), DNA methylation, and gene expression signatures were assessed for 74, 36, and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes. Results: Unique molecular signatures distinguished choroid plexus carcinomas (CPC) from choroid plexus papillomas (CPP) and atypical choroid plexus papillomas (aCPP); however, no significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis of CPCs revealed two novel subgroups according to DNA content: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy events. Somatic mutations in TP53 were observed in 60% of CPCs. Investigating the number of mutated copies of p53 per sample revealed a high-risk group of patients with CPC carrying two copies of mutant p53, who exhibited poor 5-year event-free (EFS) and overall survival (OS) compared with patients with CPC carrying one copy of mutant p53 (OS: 14.3%, 95% confidence interval, 0.71%–46.5% vs. 66.7%, 28.2%–87.8%, respectively, P = 0.04; EFS: 0% vs. 44.4%, 13.6%–71.9%, respectively, P = 0.03). CPPs and aCPPs exhibited favorable survival. Discussion: Our data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity. A greater number of copies of mutated TP53 were significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs. Clin Cancer Res; 21(1); 184–92. ©2014 AACR.

Gastrointestinal Findings in the Largest Series of Patients With Hereditary Biallelic Mismatch Repair Deficiency Syndrome: Report from the International Consortium

Objectives:Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data.Methods:The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates.Results:Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8–25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9–25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11–33). Two CRC and two SBC were detected during surveillance within 6–11 months and 9–16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed.Conclusions:The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3–5 and 8 years, respectively.

MRI internal segmentation of optic pathway gliomas: clinical implementation of a novel algorithm

PurposeOptic pathway gliomas (OPGs) are diagnosed based on typical MR features and require careful monitoring with serial MRI. Reliable, serial radiological comparison of OPGs is a difficult task, where accuracy becomes very important for clinical decisions on treatment initiation and results. Current radiological methodology usually includes linear measurements that are limited in terms of precision and reproducibility.MethodWe present a method that enables semiautomated segmentation and internal classification of OPGs using a novel algorithm. Our method begins with co-registration of the different sequences of an MR study so that T1 and T2 slices are realigned. The follow-up studies are then re-sliced according to the baseline study. The baseline tumor is segmented, with internal components classified into solid non-enhancing, solid-enhancing, and cystic components, and the volume is calculated. Tumor demarcation is then transferred onto the next study and the process repeated. Numerical values are correlated with clinical data such as treatment and visual ability.ResultsWe have retrospectively implemented our method on 24 MR studies of three OPG patients. Clinical case reviews are presented here. The volumetric results have been correlated with clinical data and their implications are also discussed.ConclusionsThe heterogeneity of OPGs, the long course, and the young age of the patients are all driving the demand for more efficient and accurate means of tumor follow-up. This method may allow better understanding of the natural history of the tumor and provide a more advanced means of treatment evaluation.

Burkitt lymphoma in children: the Israeli experience.

Background We analyzed the results of the French-American-British-LMB 96 protocol performed in 9 centers in Israel on 88 patients with B-cell non-Hodgkin lymphoma treated from 2000 to 2005. Procedure The majority of the patients was male (63/88, 72%), with a median age of 8.9 years (range, 2.5 to 20 y). Ethnic origin was Jewish in 73% (64/88), and Arabic in 27%. Fifty (57%) patients were classified as Burkitt lymphoma, 5 (5.7%) as Burkitt-like lymphoma, 22 (25%) as diffuse large B cell (DLBC), and 9 (10.2%) as Burkitt leukemia with over 25% of their bone marrow (BM) involved. Initial disease sites included the abdomen in 43%, head and neck in 45%, and mediastinum in 7%. Stage I: 9.1%; stage II: 28.4%; stage III: 45.5%, stage IV: 17%. Two patients had BM involvement alone, 5 patients had central nervous system (CNS) involvement alone, and 4 had both CNS and BM. The children were divided into 3 groups according to risk factors, with 5 in group A, 69 in group B, and 14 in group C. Results With a median follow-up of 3 years (12 mo to 7.6 y), the Kaplan-Meier for event-free survival (EFS) and overall survival (OS) according to whole group treatment was 88.6% and 90.9%, group A was 100% and 100%; group B was 89.9% and 92.8%; and group C was 78.6% and 78.6%. There were no untoward events or deaths in group A, whereas 6 patients relapsed in group B, 4 of whom died (all relapsed during the first year), with tumor lysis syndrome in 3 patients and death of toxicity in 1 patient who had multiorgan failure 2 days after initiation of COP. Three patients in group C relapsed and died (all patients relapsed during the first 6 months), with tumor lysis syndrome in 4 patients but no deaths from toxicity. EFS for LDH less than twice was 96.4%, EFS for LDH more than twice was 73.3% (P=0.002). OS according to primary site: bone and ovary: 100%; head and neck: 95%; abdomen: 92%; mediastinum: 50%. The difference between the mediastinal primary site to all other primary sites was statistically significant with P=0.003. All the mediastinal tumors were of DLBC origin but no significant differences in outcome were found when DLBC was compared with other histologies (DLBC: 81.8%, other B line: 90.9%). OS for patients of Arabic ethnic origin was 79.2%, for Jewish patients was 95.3%, P=0.02. We could not determine any prognostic factors that were different between the groups, which raises the question of a genetic influence. Conclusions In nonresected mature B-cell lymphoma of childhood and adolescence with no BM or CNS involvement, a 93% cure rate can be achieved, similar to the French-American-British/LMB 96 trial. Patients with primary DLBC mediastinal mass had a significantly reduced OS, indicating the need for a different therapeutic approach.