Faculty Bibliography
Searched for:
person:karajm01
Total Results:
180
Preliminary report of a multicenter, phase 2 study of bevacizumab in children and adults with neurofibromatosis 2 and progressive vestibular schwannomas: An NF clinical trials consortium study [Meeting Abstract]
Profound hearing loss is common in patients with neurofibromatosis 2 (NF2) and vestibular schwannomas (VS). Bevacizumab treatment at 7.5 mg/kg every 3 weeks has been associated with hearing improvement and tumor shrinkage in 36% and 43% of patients, respectively. However, the optimal treatment dose and schedule are unknown. This multicenter, phase II, openlabel study evaluated subjects (>=6 years old) with NF2 and progressive VS. Subjects received bevacizumab 10 mg/kg every 2 weeks during induction therapy (6 months), and 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing response was defined as a significant increase in word recognition score above baseline. Radiographic response was defined as >=20% decrease in tumor volume from baseline. The primary endpoint was hearing response rate in the target ear at 6 months. We enrolled 22 subjects (median age=23 years). The overall hearing and radiographic response rates were 41% (9/22) and 23% (5/22), respectively. In an unplanned post-hoc analysis, the hearing and radiographic response rates were 14% (1/7) and 0% in pediatric subjects <=21 years, as compared with 53% (8/15) and 33% (5/15) in adult subjects. Bevacizumab was well tolerated. Adverse events included hypertension, proteinuria, arthralgias, AST/bilirubin elevation, delayed wound healing, fatigue, and irregular menstruation. 11/13 women with elevated FSH underwent evaluation for premature ovarian insufficiency. All continued treatment with bevacizumab. Bevacizumab treatment at 10 mg/kg every 2 weeks is associated with hearing and radiographic response rates comparable to previous studies using lower doses. Pediatric subjects appear to benefit less than adults during bevacizumab treatment
EMBASE:623098401
ISSN: 1523-5866
CID: 3211342
PDL-1 expression on circulating CD68 (-) monocyte-like cells in NF2 meningioma as a biomarker for tumor progression [Meeting Abstract]
Program cell death ligand-1 (PD-L1) membranous expression on >5% tumor cells (PD-L1 positive tumors) is an unfavorable prognostic marker in many solid tumors. We previously showed that approximately 40% of neurofibromatosis type 2 (NF2) meningiomas are PD-L1 positive tumors. However, due to the invasive nature of biopsies, collection of tumor tissue is not always feasible. Thus, a non-invasive alternative is needed to evaluate the status of tumor growth and confirm PD-L1 positive tumors before the consideration of immunotherapy. It has recently been revealed that expression of PD-L1 on tumor associated macrophages is also a strong prognostic indicator. We retrieved formalin-fixed paraffin-embedded (FFPE) tissue from 10 NF2 meningioma cases to identify PD-L1 expression on macrophages and/or monocytes. We found that 3 out of 4 PD-L1 positive tumors were associated with expression of PDL-1 on CD68 (-) monocyte-like cells located in the peri-and intravascular lumens. These cells were only observed in 1 out of 6 PD-L1 negative tumors. Compared to others, tumors with PD-L1 expression on monocyte-like cells presented a higher Ki-67 proliferative index that was above 10%. Our results suggest that PD-L1 positive circulating CD68 (-) monocyte-like cells are correlated with tumor cell PD-L1 expression and progression in NF2 meningiomas
EMBASE:623098590
ISSN: 1523-5866
CID: 3211292
Patterns of relapse for children with localized intracranial ependymoma
We examined patterns of relapse and prognostic factors in children with intracranial ependymoma. Records of 82 children diagnosed with localized intracranial ependymoma were reviewed. 52% first presented to our institution after relapse. Median age at initial diagnosis was 4 years (range 0-18 years). Gender was 55% male. Initial tumor location was infratentorial in 71% and supratentorial in 29%. Histology was WHO Grade II in 32% and Grade III in 68%. As part of definitive management, 99% had surgery, 70% received RT (26% 2D/3D-conformal RT[CRT], 22% intensity-modulated RT [IMRT], 22% proton), and 37% received chemotherapy. Median follow-up was 4.6 years (range 0.2-32.9). Overall, 74% of patients relapsed (50% local, 17% distant, 7% local + distant) at a median 1.5 (range 0.1-17.5) years. Five-year OS and FFS for patients presenting prior to relapse are 70% (95% confidence interval [CI], 50-83%) and 48% (95% CI 30-64%), respectively. On log-rank, superior overall survival (OS) was demonstrated for gross total resection (p = 0.03). Superior failure-free survival (FFS) was demonstrated for age < 5 years (p = 0.04). No difference in OS or FFS was found between 2D/3D-CRT versus IMRT/proton (p > 0.05). On multivariate analysis, age ≤ 5 was independently associated with a lower risk of death and failure versus older patients (p < 0.05). Contrary to previous reports, young age may not be a poor prognostic factor in patients who can tolerate intensive treatment. Future studies examining patients stratified by clinical and molecular attributes are warranted.
PMID: 29511977
ISSN: 1573-7373
CID: 2992072
Pediatric meningiomas are molecularly distinct from adult counterparts [Meeting Abstract]
In contrast to adulthood, meningiomas are rare among children and adolescents. Although recent papers have characterized the genomics of adult meningiomas, the molecular profiles of childhood meningiomas have not been elucidated in detail. We analyzed 41 tumor samples from 37 pediatric meningioma patients (female: 17, male: 20; age range: 1-21 years). Atypical meningioma WHO grade II was the most frequent histological subtype (N=14, 38%). Most tumors were located at the convexity (N=18) or the skull base (N=15). Lack of SMO, AKT, KLF4/TRAF7 mutations by Sanger sequencing (n=22) prompted whole genome sequencing of a subset (n=7). All seven cases exhibited bi-allelic inactivation of NF2 (combined large deletion and germline (5/7) or somatic (2/7) base exchanges/frameshifts). Subsequently, tumor samples from all 37 patients were subjected to 450K DNA methylation profiling and targeted DNA sequencing using brain tumor specific gene panel. Loss of chromosome 22 was frequent (N=28, 76%), followed by loss of chromosome 1 (N=12, 32%) and chromosome 18 (N=7, 19%). Moreover, separation into three groups was evident: One encompassing all clear-cell meningiomas with enrichment for SMARCE1 mutations, a second dominated by atypical meningiomas, and a third group composed of benign meningiomas, as well as rare subtypes such as rhabdoid meningiomas. When analyzed with 105 adult tumors, most of pediatric meningiomas (28/37) clustered into a separate methylation group both by unsupervised hierarchical clustering and t-stochastic nearest neighbor embedding (t-SNE). Four recurrences were similar to the primary tumor. These data suggest that pediatric meningiomas are genetically distinct from adult counterparts
EMBASE:623098441
ISSN: 1523-5866
CID: 3211322
Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP containing the ancestral DUF1220 domain in pineoblastoma [Meeting Abstract]
BACKGROUND: Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. METHODS: We analyzed pediatric and adult pineoblastoma samples (n=23) using integrated genomic studies, including genome-wide DNA methylation profiling, whole-exome or whole-genome sequencing, and whole-transcriptome analysis. RESULTS: Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower grade pineal tumors and normal pineal gland. Recurrent somatic mutations were found in genes involved in PKA-and NF-kappaB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expression of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain. Whole-transcriptome analysis showed that homozygous loss of DROSHA led to distinct changes in RNA expression profile. Disruption of the DROSHA locus in human neural stem cells using the CRISPR/Cas9 system, led to decrease of the DROSHA protein, and massive loss of miRNAs. CONCLUSION: We identified recurrent homozygous deletions of DROSHA in pineoblastoma, suggesting that different mechanisms disrupting miRNA processing are involved in the pathogenesis of familial versus sporadic pineoblastoma. Furthermore, a novel microduplication of PDE4DIP leading to upregulation of DUF1220 protein suggests DUF1220 as a novel oncogenic driver in pineoblastoma
EMBASE:623098707
ISSN: 1523-5866
CID: 3211282
Remarkable objective response and favorable survival for BRAF-V600E childhood low-grade gliomas to BRAF inhibitors compared conventional chemotherapy [Meeting Abstract]
Activation of the MAPK pathway represents a hallmark of pediatric low-grade glioma (pLGG) and is frequently caused by BRAF alterations. BRAF-V600E represent an aggressive type of pLGG with less than optimal response to conventional chemo-radiation approaches. While clinical trials using BRAF-V600E inhibitors are ongoing, these data are not yet available. We have assembled an international cohort of BRAF-V600E glioma patients treated off-label with BRAF inhibitors as a monotherapy. Complete molecular, clinical and imaging data is being collected and compared to previous chemo-radiation therapies. Ongoing data form the taskforce on 40 BRAF-V600E gliomas from 25 international institutions is summarized below. The most prevalent histologies were ganglioglioma, pilocytic astrocytoma and pleomorphic xanthoastrocytoma, located mainly in the chiasm, brainstem and temporal lobes. Strikingly, 66% of BRAF V600E pLGG patients achieved partial response (PR) to targeted inhibitors versus only 6.6% response to conventional chemotherapy (p<0.001). Five patients progressed during treatment 0.5 to 2.1 years after the start of BRAF inhibitor therapy. Additionally, 3 pLGG progressed after discontinuation of therapy. Two-year progression-free survival was 84.2% (95%CI,69.3-100) versus 50% (95%CI,32.2-77.5) with targeted agents and chemotherapy, respectively (p=0.021). Interestingly, 6 patients with BRAF V600E positive high-grade glioma did not exhibit objective responses to BRAF inhibitor therapy and the majority suffered from early progression. Our data suggest BRAF inhibitors to be potent therapeutic agents in BRAF-V600E pLGG but not HGG. Future studies aimed at mechanism of resistance and differential response to targeted agents are required
EMBASE:623098828
ISSN: 1523-5866
CID: 3211252
2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis
Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.
PMCID:5918269
PMID: 29681099
ISSN: 1552-4833
CID: 3236812
Programmed death ligand 1 expression and tumor infiltrating lymphocytes in neurofibromatosis type 1 and 2 associated tumors
Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) have been shown to be effective in treating patients with a variety of cancers. Biomarker studies have found positive associations between clinical response rates and PD-L1 expression on tumor cells, as well as the presence of tumor infiltrating lymphocytes (TILs). It is currently unknown whether tumors associated with neurofibromatosis types 1 and 2 (NF1 and NF2) express PD-L1. We performed immunohistochemistry for PD-L1 (clones SP142 and E1L3N), CD3, CD20, CD8, and CD68 in NF1-related tumors (ten dermal and six plexiform neurofibromas) and NF2-related tumors (ten meningiomas and ten schwannomas) using archival formalin-fixed paraffin-embedded tissues. Expression of PD-L1 was considered positive in cases with > 5% membranous staining of tumor cells, in accordance with previously published biomarker studies. PD-L1 expression in tumor cells (using the SP142 and E1L3N clones, respectively) was assessed as positive in plexiform neurofibromas (6/6 and 5/6) dermal neurofibromas (8/10 and 6/10), schwannomas (7/10 and 10/10), and meningiomas (4/10 and 2/10). Sparse to moderate presence of CD68, CD3, or CD8 positive TILs was found in 36 (100%) of tumor specimens. Our findings indicate that adaptive resistance to cell-mediated immunity may play a major role in the tumor immune microenvironment of NF1 and NF2-associated tumors. Expression of PD-L1 on tumor cells and the presence of TILs suggest that these tumors might be responsive to immunotherapy with immune checkpoint inhibitors, which should be explored in clinical trials for NF patients.
PMCID:5930071
PMID: 29427150
ISSN: 1573-7373
CID: 2969022
Multicenter, phase 2 study of bevacizumab in children and adults with neurofibromatosis 2 and progressive vestibular schwannomas: an NF Clinical Trials Consortium study [Meeting Abstract]
ISI:000453090805278
ISSN: 0028-3878
CID: 3561652
DNA methylation-based classification of central nervous system tumours
Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
PMCID:6093218
PMID: 29539639
ISSN: 1476-4687
CID: 2992882
