Faculty Bibliography

BACKGROUND: There is no effective therapy for patients (pts) with IDH-mutant gliomas that progress after RT and chemotherapy. At time of progression, these tumors have often transformed to glioblastoma (GBM) and have increased numbers of somatic mutations, i.e. have a ?hypermutator phenotype?. We hypothesized that there is synergistic efficacy of Avelumab (anti-PD-L1) combined with HFRT in pts with secondarily trans- formed IDH-mutant GBMs. Safety-lead-in results will be presented.
METHOD(S): This is a phase II, open-label, single-arm, multicenter study of Avelumab with HFRT in adults with transformed IDH-mutant GBM who previously received RT and TMZ and/or PCV. All pts received Avelumab 10 mg/kg IV followed at Day 8 by HFRT (25 Gy in 5 daily 5-Gy fractions) and then Avelumab 10 mg/kg IV every 2 weeks. A 3 + 3 design was used for a 6-patient safety-lead-in cohort. Adverse events were recorded according to CTCAE.
RESULT(S): Six pts (F=4, M=2) with a median age= 45.5 yrs (range 31.5-54.4 yrs) were enrolled in the safety-lead-in cohort. No DLT was observed. Grade >= 3 AEs included increased cerebral edema (3 pts), hyponatremia (1 pt) and worsening hemiparesis (3 pts). Grade <= 2 AEs included nausea, hypothyroidism, lymphopenia, thrombocytopenia, transaminase elevation, and fever/chills. Median follow-up time was 8.9 mo. Best treatment response was SD in 1 patient. At time of last follow-up all pts have discontinued treatment for PD. Median PFS was 4.2 mo (range 1.4-5.7). Median OS was 10.1 (range 6.8-21+) mo. 4 pts (67%) died, 2 pts remain alive in follow-up at 6.9 and 21.6 months after treatment initiation. The study was closed after the safety lead-in completed enrollment due to slow accrual.
CONCLUSION(S): Avelumab combined with HFRT was tolerable without dose-limiting toxicity in this safety-lead-in cohort of adult patients with transformed IDH-mutant GBM. Further studies are necessary to determine efficacy of this treatment regimen

Melanoma in the head and neck is known to metastasize to cranial nerves. Prompt treatment is critical for preventing progression and reducing neuropathy. We report a patient who presented with cranial neuropathy related to a malignant skull base lesion that originated as lentigo maligna. The diagnosis was challenging, requiring two surgeries to obtain tissue and neither biopsy leading to a definitive diagnosis. Pathological analyses demonstrated positive immunoreactivity for SOX10 and S100, preservation of H3K27me3, and PTEN and STK11 mutations. The patient was managed with Gamma Knife Radiosurgery and combination immunotherapy. Imaging at 9 months post-SRS showed resolution of the mass lesion. Clinically, the patient has occasional left-sided facial pain requiring no medication and denies facial numbness. We favor a diagnosis of desmoplastic neurotropic melanoma due to the neurotropic spread and response to melanoma-targeted immunotherapy.

BACKGROUND:Chromosomal instability is associated with earlier progression in isocitrate dehydrogenase (IDH)-mutated astrocytomas. Here we evaluated the prognostic significance of polysomy in gliomas tested for 1p19q status. METHODS:We analyzed 412 histologic oligodendroglial tumors with use of 1p19q testing at 8 institutions from 1996 to 2013; fluorescence in situ hybridization (FISH) for 1p19q was performed. Polysomy was defined as >2 1q and 19p signals in cells. Tumors were divided into groups on the basis of their 1p19q status and polysomy and were compared for progression-free survival (PFS) and overall survival (OS). RESULTS:In our cohort, 333 tumors (81%) had 1p19q loss; of these, 195 (59%) had concurrent polysomy and 138 (41%) lacked polysomy, 79 (19%) had 1p19q maintenance; of these, 30 (38%) had concurrent polysomy and 49 (62%) lacked polysomy. In agreement with prior studies, the group with 1p19q loss had significantly better PFS and OS than did the group with 1p19q maintenance (p < 0.0001 each). Patients with 1p19q loss and polysomy showed significantly shorter PFS survival than patients with 1p19q co-deletion only (p-<0.0001), but longer PFS and OS than patients with 1p19q maintenance (p < 0.01 and p<0.0001). There was no difference in survival between tumors with >30% polysomic cells and those with <30% of polysomic cells. Polysomy had no prognostic significance on progression-free or overall survival in patients with 1p19q maintenance. CONCLUSIONS:The presence of polysomy in oligodendroglial tumors with co-deletion of 1p19q predicts early recurrence and short survival in patients with 1p19q co-deleted tumors.

PURPOSE/OBJECTIVE:There is variability in survival within IDH mutant gliomas determined by chromosomal events. Copy number variation (CNV) abundance associated with survival in low-grade and IDH mutant astrocytoma has been reported. Our purpose was to correlate the extent of genome-wide CNV abundance in IDH mutant astrocytomas with MRI features. METHODS:Presurgical MRI and CNV plots derived from Illumina 850k EPIC DNA methylation arrays of 18 cases of WHO grade II-IV IDH mutant astrocytomas were reviewed. IDH mutant astrocytomas were divided into CNV stable group (CNV-S) with ≤ 3 chromosomal gains or losses and lack of focal gene amplifications and CNV unstable group (CNV-U) with > 3 large chromosomal gains/losses and/or focal amplifications. The associations between MR features, relative cerebral blood volume (rCBV), CNV abundance, and time to progression were assessed. Tumor rCBV estimates were obtained using DSC T2* perfusion analysis. RESULTS:There were nine (50%) CNV-S and nine (50%) CNV-U IDH mutant astrocytomas. CNV-U tumors showed larger mean tumor size (P = 0.004) and maximum diameter on FLAIR (P = 0.004) and also demonstrated significantly higher median rCBV than CNV-S tumors (2.62 vs 0.78, P = 0.019). CNV-U tumors tended to have shorter time to progression although without statistical significance (P = 0.393). CONCLUSIONS:Larger size/diameter and higher rCBVs were seen associated CNV-U astrocytomas, suggesting a correlation of aggressive imaging phenotype with unstable and aggressive genotype in IDH mutant astrocytomas.

BACKGROUND:Intraosseous petrous apex schwannomas are an exceedingly rare entity; little is known about their epidemiology, natural history, and post-operative outcomes. CASE DESCRIPTION/METHODS:Here, we present the fourth known case of a primary intraosseous schwannoma of the petrous apex: a 68-year-old woman presenting with diplopia, facial numbness, progressive intermittent vertigo, tinnitus, diminished hearing, and ataxia. She underwent a transtemporal approach for subtotal resection of the tumor with subsequent stereotactic radiosurgery. CONCLUSIONS:Our two-year follow-up demonstrates slow growth and success of multimodal management in the treatment of these tumors. We review the three prior reports of petrous apex schwannomas, and identify unifying radiographic and clinical characteristics in order to aid in future diagnostic considerations of lesions of the petrous apex.

PURPOSE/OBJECTIVE:Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct glioma molecular subtype for which no effective molecularly-directed therapy exists. Low-grade gliomas, which are 80-90% IDH mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by immunohistochemistry in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in IDH mutant glioma. EXPERIMENTAL DESIGN/METHODS:We evaluated DLL3 expression by RNA using TCGA data and by immunohistochemistry in a discovery set of 63 gliomas and 20 non-tumor brain tissues and a validation set of 62 known IDH wildtype and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous IDH mutant glioma tumorspheres was determined by cell viability assay. RESULTS:Compared to IDH wildtype glioblastoma, IDH mutant gliomas have significantly higher DLL3 RNA (P<1x10-15) and protein by immunohistochemistry (P=0.0014 and P<4.3x10-6 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in IDH mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 non-tumor brains. Patient-derived IDH mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner. CONCLUSIONS:DLL3 is selectively and homogeneously expressed in IDH mutant gliomas and can be targeted with Rova-T in patient-derived IDH mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.

Objectives  AlloDerm is an acellular dermal matrix often used for reconstruction throughout the body. AlloDerm has been shown to undergo revascularization when used to reconstruct soft tissue such as in abdominal wall reconstruction. In this study, the authors review the literature on revascularization of AlloDerm and demonstrate the histologic findings of AlloDerm after implantation during skull base reconstruction. Study Design  Literature review and case reports. Setting  Tertiary Care Institution Participants  Patients from a tertiary care institution Main Outcome Measures  Histologic slides are evaluated and compared with nonimplanted AlloDerm. Methods  The authors review a case of explanted AlloDerm that had been used for skull base reconstruction after endoscopic skull base surgery. Results  Upon reviewing the histologic slides of explanted AlloDerm to nonimplanted AlloDerm, we demonstrate revascularization of AlloDerm when used in skull base reconstruction. Representative slides will be included. Conclusions  AlloDerm undergoes revascularization when used for skull base reconstruction.

Introduction: Dimethyl sulfoxide (DMSO), propylene glycol (PG) and miglyol (MG) are common organic solvents often used to dissolve neuro-pharmacological agents for in vivo assays in animal models of various pediatric brain disorders. Nonetheless, these compounds were reported to exhibit pharmacological and pathological effects on the central nervous system of their own. Here we report chronic effects of these solvents on behavior, motoric functions and brain morphology in young rats (P35-37), following neonatal exposure to one of the compounds (P6).
Method(s): Compounds were administered intraperitoneally (DMSO, 2 or 4 ml/kg; MG, 2 ml/kg) or per os (PG, 2.5 ml/kg) at concentrations considered safe and non-interfering with neuroscience research. Age/sex matched controls received phosphate-buffered saline (PBS). Animals were sacrificed following behavioral and locomotor assays (P40) and their brains were subjected to pathological analyses.
Result(s): Rats exposed to DMSO (n = 10; 4 ml/kg only), spent significantly more time in the open field center and traveled shorter distance (p < 0.05) vs. controls (n = 10). Rats exposed to DMSO and MG exhibited shorter social interactions vs. controls (p < 0.05). CatWalk gait analysis showed various disturbances (p < 0.05) in rats exposed to any of the three compounds (DMSO, 4 ml/kg only). Brain pathological analyses revealed increased expression of microglia (Iba-1+) and reactive astrocytes (GFAP+) in rats exposed to DMSO (p < 0.05).
Conclusion(s): Observed chronic behavioral, motoric and morphologic sequelae of neonatal exposure to DMSO, PG or MG at concentrations that are generally considered safe raise concerns about under-appreciated neuro-toxicity of these common organic solvents, which warrants further exploration in larger translational studies