EGFR is a prototypical receptor tyrosine kinase that is overexpressed in multiple cancers including head and neck squamous cell carcinoma (HNSCC). The standard of care for HNSCC remains largely unchanged despite decades of research. While EGFR blockade is an attractive target in HNSCC patients and anti-EGFR strategies including monoclonal antibodies and kinase inhibitors have shown some clinical benefit, efficacy is often due to the eventual development of resistance. In this review, we discuss how the acquisition of mutations in various domains of the EGFR gene not only alter drug binding dynamics giving rise to resistance, but also how mutations can impact radiation response and overall survival in HNSCC patients. A better understanding of the EGFR mutational landscape and its dynamic effects on treatment resistance hold the potential to better stratify patients for targeted therapies in order to maximize therapeutic benefits.

It is known that cetuximab (an epidermal growth factor receptor [EGFr] inhibitor) is a radiosensitizer. Also, cetuximab is known to only partially inhibit the signal transducer and activator of transcription – 3 (STAT-3); a mediator of protection from apoptosis. Studies were performed to determine if the radiosensitizing effects of cetuximab could be enhanced with the addition of an inhibitor of STAT-3. The interaction of JAK-STAT-3 inhibition ([JAK1i]; Calbiochem, LaJolla, CA) and EGFr inhibition (cetuximab) was assessed with and without radiation. Four human head and neck cell lines were studied: UM-SCC-1 and UM-SCC-5, and two modified UM-SCC-5 lines; a STAT-3 knockdown line (STAT-3-2.4) and control (NEG-4.17). Exposure to either 0.5 μg/ml of cetuximab or 1 μM JAK1i for 8 or 24 h resulted in reduced activated STAT-3 (immunoblot), and the combination treatment showed greater reduction in activated STAT-3 compared to the individual treatments. The use of either post-radiation JAK1i (1 μM for 72 h) or post-radiation cetuximab (0.5 μg/ml) enhanced radiation-induced anti-proliferative and apoptotic effects but the greatest enhancement was seen when cells were exposed to both JAK1i and cetuximab post-radiation. Similar results were seen for radiosensitization as assessed by colony formation. Finally, the combination treatment of JAK1i (1 μM) and cetuximab (0.5 μg/ml), following radiation, resulted in an increase of unrepaired radiation-induced DNA double strand breaks at 6 and 24 h after radiation compared to the use of post-radiation JAK1i or cetuximab alone as delineated by neutral comet assay. These findings suggest that dual inhibition of EGFr (cetuximab) and JAK-STAT-3 (JAK1i) leads to greater radiosensitization than with either cetuximab or JAK1i alone and suggests that this combination treatment may be clinically relevant even for tumors with a marked range of STAT-3 activity.

BACKGROUND AND PURPOSE: Given the increased use of stereotactic radiosurgical thalamotomy and other ablative therapies for tremor, new biomarkers are needed to improve outcomes. Using resting-state fMRI and MR tractography, we hypothesized that a “connectome fingerprint” can predict tremor outcomes and potentially serve as a targeting biomarker for stereotactic radiosurgical thalamotomy. MATERIALS AND METHODS: We evaluated 27 patients who underwent unilateral stereotactic radiosurgical thalamotomy for essential tremor or tremor-predominant Parkinson disease. Percentage postoperative improvement in the contralateral limb Fahn‐Tolosa‐Marin Clinical Tremor Rating Scale (TRS) was the primary end point. Connectome-style resting-state fMRI and MR tractography were performed before stereotactic radiosurgery. Using the final lesion volume as a seed, “connectivity fingerprints” representing ideal connectivity maps were generated as whole-brain R-maps using a voxelwise nonparametric Spearman correlation. A leave-one-out cross-validation was performed using the generated R-maps. RESULTS: The mean improvement in the contralateral tremor score was 55.1% (SD, 38.9%) at a mean follow-up of 10.0 (SD, 5.0) months. Structural connectivity correlated with contralateral TRS improvement (r = 0.52; P  = .006) and explained 27.0% of the variance in outcome. Functional connectivity correlated with contralateral TRS improvement (r = 0.50; P  = .008) and explained 25.0% of the variance in outcome. Nodes most correlated with tremor improvement corresponded to areas of known network dysfunction in tremor, including the cerebello-thalamo-cortical pathway and the primary and extrastriate visual cortices. CONCLUSIONS: Stereotactic radiosurgical targets with a distinct connectivity profile predict improvement in tremor after treatment. Such connectomic fingerprints show promise for developing patient-specific biomarkers to guide therapy with stereotactic radiosurgical thalamotomy.

Background: There are a limited data examining the effects of prior hemorrhage on outcomes after stereotactic radiosurgery (SRS). The goal of this study was to identify risk factors for arteriovenous malformation (AVM) rupture and compare outcomes, including post-SRS hemorrhage, between patients presenting with ruptured and unruptured AVMs. Methods: A retrospective review of consecutive patients undergoing SRS for intracranial AVMs between 2009 and 2019 at our institution was conducted. Chi-square and multivariable logistic regression analyses were utilized to identify patient and AVM factors associated with AVM rupture at presentation and outcomes after SRS including the development of recurrent hemorrhage in both ruptured and unruptured groups. Results: Of 210 consecutive patients with intracranial AVMs treated with SRS, 73 patients (34.8%) presented with AVM rupture. Factors associated with AVM rupture included smaller AVM diameter, deep venous drainage, cerebellar location, and the presence of intranidal aneurysms (P < 0.05). In 188 patients with adequate follow-up time (mean 42.7 months), the overall post-SRS hemorrhage rate was 8.5% and was not significantly different between ruptured and unruptured groups (10.3 vs. 7.5%, P = 0.51). There were no significant differences in obliteration rate, time to obliteration, or adverse effects requiring surgery or steroids between unruptured and ruptured groups. Conclusion: Smaller AVM size, deep venous drainage, and associated intranidal aneurysms were associated with rupture at presentation. AVM rupture at presentation was not associated with an increased risk of recurrent hemorrhage or other complication after SRS when compared to unruptured AVM presentation. Obliteration rates were similar between ruptured and unruptured groups.

9522 Background: Gliomas are among the most lethal of human tumors. A hallmark genomic feature of gliomas is the presence of complex chromosomal aberrations that result in altered gene copy numbers. For some of these aberrations, certain genes have been linked to gliomagenesis, whereas for others, the presumed relevant targets remain to be identified. High-resolution, genome-wide mapping of exact boundaries of chromosomal alterations should facilitate the localization and identification of genes involved in gliomagenesis and may characterize genetic subgroups of glial brain tumors. Methods: We have performed such mapping using cDNA microarray-based comparative genomic hybridization technology to profile copy number alterations across 42,000 mapped human cDNA clones, in a series of 54 gliomas of varying histogenesis and tumor grade. Results: This gene-by-gene analysis demonstrated the power of the created maps to precisely localize and size target regions and new recurrent regions of gene copy number alteration in these tumors. Our study has also identified novel, common, minimally altered regions in a subset of gliomas. The focal and informative nature of these recurrent regions can be best appreciated by consideration of the peak amplitude of recurrence of individual gene alterations within a region. We have discovered five minimally deleted regions, harboring deletions in putative tumor suppressor genes, not previously reported in gliomas. Finally, our study has revealed recurrent patterns of occurrence of distinct chromosomal aberrations as well as their interrelationships, and shows that gliomas can be clustered into distinct genetic subgroups. A subset of alterations was demonstrated to be associated with either the astrocytic or oligodendrocytic tumor phenotypes. Conclusions: High-resolution genetic profiling in human gliomas has permitted the precise characterization of target regions and new regions of gene copy number change, has revealed recurrent patterns of occurrence of distinct chromosomal aberrations as well as their interrelationships, and has identified five common minimally deleted regions involving putative tumor suppressor genes that could have a role in gliomagenesis. No significant financial relationships to disclose.