Faculty Bibliography

PURPOSE:ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A "window-of-opportunity" study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC. PATIENTS AND METHODS:Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-week interval prior to tumor resection. The primary study objective was to achieve ≥50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed. RESULTS:= 0.04; 95% confidence interval, 27.7%-84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment-related toxicity was grade 1-2 and included diarrhea, fatigue, and acneiform dermatitis. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus-negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment. CONCLUSIONS:This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC.

Oral cancer is a growing health issue in low- and middle-income countries due to betel quid, tobacco, and alcohol use and in younger populations of middle- and high-income communities due to the prevalence of human papillomavirus. The described point-of-care, smartphone-based intraoral probe enables autofluorescence imaging and polarized white light imaging in a compact geometry through the use of a USB-connected camera module. The small size and flexible imaging head improves on previous intraoral probe designs and allows imaging the cheek pockets, tonsils, and base of tongue, the areas of greatest risk for both causes of oral cancer. Cloud-based remote specialist and convolutional neural network clinical diagnosis allow for both remote community and home use. The device is characterized and preliminary field-testing data are shared.

BACKGROUND:H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS:Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence. FINDINGS/RESULTS:Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms. INTERPRETATION/CONCLUSIONS:The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

BACKGROUND:The anterior skull base (ASB) remains one of the greatest challenges for reconstructive surgeons. The current armamentarium includes endoscopic placement of free grafts, endonasal vascularized pedicled flaps, regional flaps, and microvascular free flaps. As the defect size increases, reconstruction complexity increases along with potential complications. Here, we report an endoscopic-assisted paramedian forehead flap, a novel adaptation of an age-old technique, for ASB reconstruction. CASE DESCRIPTION/METHODS:A 66-year-old male underwent a dual bifrontal and transnasal endoscopic approach for the resection of a T4N0M0 sinonasal squamous cell carcinoma. The resulting ASB defect was repaired using simultaneous pericranial and nasoseptal flaps. Adjuvant radiation therapy resulted in delayed radiation necrosis in the right frontal lobe 3 years later requiring debridement via a supraorbital approach. Recovery from this operation was complicated by an ASB defect and cerebrospinal fluid (CSF) leak. The defect remained despite multiple attempts at endoscopic repairs. Due to multiple medical comorbidities, the patient was not a candidate for microvascular reconstruction. Prior surgeries had disrupted the traditional regional flaps (i.e., pericranial, nasoseptal, and temporoparietal fascia flaps) bilaterally. Therefore the novel endoscopic-assisted paramedian forehead flap was used to successfully repair the ASB defect. Postoperatively, the patient has done well with no recurrences in the CSF leak. CONCLUSIONS:The endoscopic-assisted paramedian forehead flap is a robust regional flap whose advantages include the utilization of muscle, low donor morbidity, and endoscopic placement with avoidance of craniotomies. Therefore it should be considered an important option for ASB reconstruction of recalcitrant CSF leaks when all other options are unavailable.

BACKGROUND:Research on the patterns of use of medical cannabis among cancer patients is lacking. OBJECTIVE:To describe patterns of medical cannabis use by patients with cancer, and how patterns differ from patients without cancer. DESIGN/MEASUREMENTS/METHODS:We performed secondary data analysis using data from a medical cannabis licensee in New York State, analyzing demographic information, qualifying conditions, and symptoms, and the medical cannabis product used, including tetrahydrocannabinol (THC) to cannabidiol (CBD) ratios. SETTING/SUBJECTS/METHODS:Adults age ≥18 who used New York State medical cannabis licensee products between January 2016 and December 2017. RESULTS:There were a total of 11,590 individuals with 1990 (17.2%) having cancer who used at least one cannabis product. Patients with cancer using cannabis were older and more likely to be female. The most common qualifying symptom for both cancer and noncancer patients was severe or chronic pain. Cancer patients were more likely to use the sublingual tincture form of cannabis (n = 1098, 55.2%), while noncancer patients were more likely to use the vaporization form (n = 4222, 44.0%). Over time, across all patients, there was an increase in the THC daily dose by a factor of 0.20 mg/week, yielding a corresponding increase in the THC:CBD daily ratio. Compared with noncancer patients, these trends were not different in the cancer group for THC daily dose, but there were less pronounced increases in the THC:CBD daily ratio over time among cancer patients. CONCLUSIONS:Our study found some key differences in demographics and medical cannabis product use between patients with cancer and without cancer.

BACKGROUND:Alveolar soft part sarcoma (ASPS) is an uncommon malignancy which may present in a manner similar to benign vascular tumors. METHODS:A six-year-old male with autism spectrum disorder was referred to the Johns Hopkins All Children's Hospital vascular anomalies clinic for the evaluation of a tongue mass. RESULTS:Prior to the presentation, at five years of age a neck computed tomography (CT) scan was performed. This study showed a well circumscribed, enhancing mass at the anterior aspect of the tongue. The radiologic impression concluded that this lesion was most likely a hemangioma. Two years later, the patient was evaluated in the vascular anomalies clinic. The examination demonstrated a 2-3 cm swelling on the dorsal aspect of the tongue. The mass was fleshy and firm with discrete borders. A handheld Doppler examination demonstrated a high flow lesion. The patient underwent an excisional biopsy. The lesion was identified as an alveolar soft part sarcoma based on pathologic characteristics. CONCLUSION/CONCLUSIONS:Familiarity with common vascular tumors and malformations allow providers to diagnose the majority of these lesions with the combination of clinical history and physical examination. Atypical and combined lesions do benefit from imaging studies to help characterize and aid in the differential diagnosis. Biopsy represent the definitive means of obtaining a diagnosis but are necessary in the minority of cases. When in doubt, referral to a specialized, multidisciplinary vascular anomalies clinic will ensure these patients receive management for this challenging collection of conditions. This article is protected by copyright. All rights reserved.

BACKGROUND:YouTube has rapidly become one of the most widely accessed educational platforms of our time. Over 1 billion hours of YouTube content are viewed every day, including neurosurgical videos. To date, there has never been a qualitative analysis of neurosurgical content on YouTube. METHODS:By evaluating the search interest of neurosurgical terms via Google Trends, we selected 8 search terms to assess on YouTube. For each term, we selected the top 20 videos, 10 when sorting by view count and 10 when sorting by relevance. Using the DISCERN criteria, we evaluated 131 unique YouTube videos to assess bias and overall educational quality. In addition, we categorized each video based on its intended utility and the credentials of the video's commentator. The number of views, average DISCERN scores, and bias scores were compared between search terms and between video categories. RESULTS:There were 131 unique and 29 duplicate videos. The videos received 143,538,363 combined views (1,104,141 average). The average video age was 4.6 years (range, 66 days to 12.5 years). The term "brain surgery" received the most total views (62,339,885), with an average DISCERN score of 1.65 overall and 2 for bias. The average DISCERN score was 2.02 overall and 2.39 for bias. There were 45 advertisements for either hospitals, physicians, or companies, totaling 18,052,873 views and averaging a DISCERN score of 2.04. CONCLUSIONS:YouTube is a frequently viewed but biased source for neurosurgical information. Advertisements are frequently disguised as educational material, and few videos provide references or sources for their information.

Recurrent somatic missense mutations in histone H3 genes have been identified in subsets of pediatric cancers. H3K36 histone mutations have recently been recognized as oncogenic drivers in rare subsets of malignant soft tissue sarcomas but have not been reported in histiocytic neoplasms. Currently, the histological and molecular spectrum, as well as the clinical behavior of H3K36-mutant soft tissue malignancies, is largely unknown. We describe a pediatric patient with a HIST1H3B K36I-mutant histiocytic tumor arising in the skull. After the failure of upfront therapy for histiocytosis and development of widely disseminated metastatic disease, the patient had an exceptional response to empiric chemotherapy and remains in complete disease remission for more than 5 years. Our report expands the histological spectrum of H3K36M/I-mutant soft tissue malignancies to histiocytic neoplasms and indicates that multiagent sarcoma-like chemotherapy can be highly effective even in the setting of widely disseminated metastatic disease.

The incidence of thyroid cancer in Graves'Disease (GD) patients is estimated to be low. However, it is unclear what impact the recent rise in the incidence of thyroid cancers has had in this population. Furthermore, it is not clear if these cancers behave more aggressively than cancers in the general population. We investigated the incidence of malignancy and its features in a contemporary cohort of GD patients treated by surgery. All patients who underwent thyroidectomy for GD in our center were reviewed from 2013-2018. Demographics, clinicopathologic features, rate of incidental cancer and outcomes were reviewed. We identified 130 patients with GD who underwent thyroidectomy. Median age was 40.5 (16-80). Majority were female (112, 86%). All but five (4%) were radioactive iodine naive. Thirtyfour (26%) were found to harbor malignancy. While the majority (18, 53%) were papillary microcarcinoma; 12 (34%) had multifocal disease; 10 (29%) had tall cell features, 3 (9%) had positive lymph nodes, and 2 (6%) had extrathyroidal extension. One patient (3%) was diagnosed with follicular carcinoma. No permanent hyperparathyroidism or recurrent laryngeal nerve injury was encountered. With a median follow up of 23 months no recurrences were identified. The risk of incidental malignancy in GD patients was high in our cohort. While the majority were low risk microcarcinomas, a number of patients harbored higher risk tall cell features. Our data suggest that for GD patients who are medically managed, careful surveillance and biopsy of suspicious nodules might be warranted. The outcome of surgical treatment was excellent for controlling both hyperthyroidism and cancer