Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Hypofractionated Gamma Knife radiosurgery (hfGKRS) is increasingly considered for treating large or near-critical structure meningiomas because of potential safety advantages. However, data on optimal fractionation and long-term outcomes remain limited. This study evaluated the longer-term tumor control and toxicity after hfGKRS for intracranial meningiomas at 2 large centers, supplemented by a systematic review and meta-analysis of existing literature. METHODS:The analysis included 34 patients (site 1 = 25, site 2 = 9, median age 62.6 years) with 40 tumors (median volume 11.2 cm3). 62% was low-grade (World Health Organization grade 0-1) and 38% was high-grade (World Health Organization grade 2-3). The most common fractionation schemes were 20 Gy in 5 fractions for low-grade and 21 Gy in 3 fractions for high-grade tumors. The mean follow-up was 28.8 months. RESULTS:Only 6 of 34 patients did not have any previous treatment including surgery and/or radiotherapy. 82% of patient patients had neurological deficits before stereotactic radiosurgery. The estimated rate of 5-year tumor progression for low-grade and high-grade tumors was 7.7% (95% CI 0.41%-30%) and 36% (95% CI 12%-62%). Symptoms improved in 12 patients (35%) and worsened in 6 patients (16%), with 1 case attributed to tumor progression and no significant visual deterioration in 16 tumors within 3 mm of the optic apparatus. There was no statistically significant association between fractionation (3 vs 5) scheme and tumor control (P = .07) or survival (P = .12). Karnofsky Performance Status performance was a significant predictor of death (HR 0.89, P = .012) and tumor progression (HR 0.93, P = .048). The combined meta-analysis revealed a 5-year tumor control rate of 91.6% for low-grade and 37.9% for high-grade meningiomas. CONCLUSION/CONCLUSIONS:hfGKRS demonstrates durable control and acceptable safety for low-grade intracranial meningiomas. High-grade tumors showed less favorable outcomes comparable with single-session Gamma Knife radiosurgery historical data. Further prospective data are needed to confirm these findings and optimize fractionation strategies.

Oxytocin is a small, nine amino acid peptide synthesized and released mostly in the brain. It was discovered first as a hormone that facilitates labor and lactation but has since attracted interest for having important roles in social bonding. Although sometimes informally called a 'love hormone', this is erroneous and does not accurately reflect the biological action of oxytocin across different contexts. Here we provide an overview of the organization of the oxytocin system, which subserves different biological functions that ultimately coordinate physiological and behavioral states supporting reproductive success (Figure 1).

We conducted an umbrella review to synthesize the evidence on the diagnostic performance of liquid biopsy tests for detection of head and neck squamous cell carcinoma (HNSCC). Systematic reviews (SRs) were searched in Medline, Embase, and Google Scholar through December 6, 2023. The Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews was used to assess methodological quality. Two independent reviewers extracted data. We examined the pooled sensitivity and specificity of biomarker classes. We also statistically pooled sensitivity and specificity of individual biomarkers for oral SCC in cases where meta-analysis was not yet published, since most HNSCC occurs in the oral cavity. Performance was also assessed by specimen type (saliva, serum, plasma, and whole blood). Thirty-one SRs met inclusion criteria and 21 included meta-analyses on transcriptomic, proteomic, genomic, or metabolomic biomarkers. Overall methodologic quality was moderate to high. Primary study overlap was ≥ 15 % in 9.3 % of SR pairwise comparisons. MicroRNA (miRNA) was the biomarker class represented in the most SRs (n = 19) and individual studies (n = 106). Among these, the highest sensitivity was 77 % (95 % CI, 68-84 %), observed in miRNA-21. Hypermethylated DNA was the biomarker class with the highest pooled sensitivity (86 %; 95 % CI, 60-96 %) and specificity (92 %; 95 % CI, 80-97 %) overall, and with superior performance when used in panels compared to individual markers. In studies focused on OSCC detection, no other biomarker class or fluid type demonstrated superior performance over others. In future clinical studies, panels including hypermethylated DNA merit more rigorous evaluation to establish high specificity in addition to sufficient sensitivity.

OBJECTIVE/UNASSIGNED:We sought to consolidate the anatomical findings from radiologic research and prior surgical literature to develop a stepwise surgical approach utilizing cadaveric specimens which can serve to improve the accuracy and scalability of surgical apical cochleostomies in the future. METHODS/UNASSIGNED:Cadaveric temporal bone dissections, with subsequent image documentation and distance measurements to confirm surgical accuracy. RESULTS/UNASSIGNED:All four temporal bones (100%) that were drilled utilizing the newly developed surgical approach had an accurately placed apical cochleostomy. No inadvertent entry into the middle turn of the cochlea occurred. There was no violation of the labyrinthine facial nerve, or carotid artery. CONCLUSIONS/UNASSIGNED:Preliminary findings are promising for the described steps to achieve a substantial improvement in apical cochleostomy accuracy, with reduced trauma compared to historically taught techniques.

Although many internalized G protein-coupled receptors (GPCRs) continue to signal, the mechanisms and outcomes of intracellular GPCR signaling are uncertain due to the challenges of measuring organelle-specific signals and of selectively antagonizing receptors in intracellular compartments. Herein, genetically encoded biosensors targeted to the plasma membrane and early endosomes were used to analyze compartmentalized signaling of protease-activated receptor 2 (PAR₂); the propensity of nanoparticles (NPs) to accumulate in endosomes was leveraged to preferentially antagonize intracellular PAR₂ signaling of pain. PAR₂ agonists evoked sustained activation of PAR₂, Gαq, and β-arrestin-1 in early endosomes and activated extracellular signal regulated kinase (ERK) in the cytosol and nucleus, measured with targeted biosensors. Fluorescent dendrimer and core-shell polymeric NPs accumulated in endosomes of HEK293T cells, colonic epithelial cells, and nociceptors, detected by confocal microscopy. NPs efficiently encapsulated and slowly released AZ3451, a negative allosteric PAR₂ modulator. NP-encapsulated AZ3451, but not unencapsulated AZ3451, rapidly and completely reversed PAR₂, Gαq, and β-arrestin-1 activation in early endosomes and ERK activation in the cytosol and nucleus. When administered into the mouse colon lumen, fluorescent dendrimer NPs accumulated in endosomes of colonocytes and polymeric NPs accumulated in neurons, sites of PAR₂ expression. Both NP formulations of AZ3451, but not unencapsulated AZ3451, caused long-lasting analgesia and normalized aberrant behavior in preclinical models of inflammatory bowel disease. These results provide evidence that PAR₂ endosomal signaling mediates pain and that nanomedicines that antagonize PAR₂ in endosomes effectively relieve pain. NP-mediated delivery may improve the efficacy of other GPCR antagonists for treatment of diverse diseases.

BACKGROUND:Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories. METHODS:In this study, we analyzed clinical, immunohistochemical and DNA methylation data of 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs and identify epigenetic classes. RESULTS:CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the three lineages when the calibrated score is ≥0.3. Unsupervised DNA methylation analysis separated PitNETs into two major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation. CONCLUSION/CONCLUSIONS:Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.

PURPOSE/OBJECTIVE:This prospective, non-randomized phase II single-arm pilot trial aimed to explore favorable mid-treatment nodal response (FMNR) through CT imaging to guide de-escalated chemoradiation therapy (CRT) in patients with favorable risk, node-positive HPV-associated oropharyngeal cancer (OPC). MATERIALS AND METHODS/METHODS:. At week 4, CT imaging evaluated nodal response: ≥40% reduction warranted de-escalation to 60 Gy, while <40% reduction continued standard CRT. Primary endpoint was 2-year PFS from initiation of dose de-escalated CRT. Tissue tumor modified viral (TTMV) HPV DNA samples and DW-MRI were collected at baseline and week 4. MDADI questionnaires were collected at baseline, 1, 3, 6, 12, and 24 months. RESULTS:Of 39 patients, 26 had FMNR and underwent de-escalated treatment. 13 pts had slow mid-treatment nodal shrinkage and received standard dose. At a median follow-up of 47.4 months, the 2-year PFS was 92.1% (95% CI: 0.72-0.98) for the deescalated dose group and 92.3% for the standard dose patients (95% CI: 0.57-0.99), p=0.96. With a median survival follow up of 48.9 months (range: 16.7-77.8 months), there were no deaths or distant failures. FMNR was associated with rapid TTMV HPV DNA clearance, reduced TTMV HPV DNA flare, lower baseline and week 4 MRI diffusivity, and higher baseline and week 4 MRI diffusional kurtosis. No differences in acute or late maximum grade 3-4 toxicity by patient were noted. MDADI composite scores showed minimal clinical important difference (MCID) in the de-escalated group at 1-month post-treatment while the standard group had MCID up to 1-year post-treatment. No patients required feeding tube placement. CONCLUSIONS:De-escalated CRT using CT-based mid-treatment nodal response in favorable risk, node-positive HPV-associated OPC achieved excellent 2-year PFS and OS rates and represents a potential approach in better selecting patients for treatment de-escalation.

IMPORTANCE/UNASSIGNED:Stage I squamous cell carcinoma (SCC) of the glottic larynx carries a favorable prognosis after treatment with endoscopic surgery or radiation therapy (RT). In addition to tumor control, goals of therapy include preservation of voice quality, swallow function, and breathing. Multidisciplinary consensus guidelines are needed to assist clinicians in treatment selection and the appropriate use of both surgical and radiation-based techniques. OBSERVATIONS/UNASSIGNED:Treatment of clinical T1N0 glottic SCC has evolved over time, with advances in both transoral laser microsurgery and RT designed to become more targeted and reduce the overall treatment burden for patients. When selecting a treatment option, consideration should be given to patient-specific factors, including tumor position/extent, age, and medical and psychosocial factors. This 16-member multidisciplinary American Radium Society (ARS) Head and Neck Cancer Appropriate Use Criteria (AUC) expert panel performed a review of the English-language medical literature from 2000 to 2022 to inform consensus guidelines. Clinical case variants were developed to represent commonly encountered clinical scenarios, and the RAND/UCLA appropriateness method was used to rate the appropriate use of various treatments. The modified Delphi method was used to reach consensus recommendations, which were approved by the ARS Executive Committee and subject to public comment per established ARS procedures. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Given the range of treatment options available, early glottic SCC management should be done in a multidisciplinary fashion including otolaryngologists and radiation oncologists. The ARS Head and Neck AUC expert panel created an appropriate-use consensus document by performing a literature review of the current treatment strategies for stage I glottic SCC, providing recommendations regarding the appropriateness of surgery or RT for various clinical scenarios and highlighting areas of controversy and uncertainty.

By improving the delivery and tumor retention of chemotherapeutics, nanomedicines hold potential for cancer treatment. The usefulness of nanoparticle (NP)-encapsulated analgesics for the cancer pain treatment is comparatively unexplored. We investigated whether NPs encapsulating olcegepant (OCP), an antagonist of the calcitonin receptor-like receptor (CLR) for the calcitonin gene-related peptide (CGRP), effectively relieved oral cancer pain in mice. Because persistent endosomal CLR signaling in Schwann cells mediates craniofacial pain, we reasoned that the predisposition of NPs to accumulate in endosomes could be leveraged to effectively relieve oral cancer pain. By expressing biosensors for activated CLR, Gα proteins and β-arrestins in HEK293T and Schwann cells, we found that CGRP activates CLR signaling first at the plasma membrane and then in early, late and recycling endosomes and the cis- and trans-Golgi apparatus. We synthesized biocompatible NPs encapsulating OCP and fluorophores by integrating hydrophobic ion pairing nanoformulation with Flash NanoPrecipitation. NPs slowly released OCP and accumulated in early endosomes, leading to sustained inhibition of endosomal CLR signaling in HEK293T and Schwann cells. Oral cancers were established in mice, which led to heightened pain-like responses. After intra-tumoral injection, NPs were retained in tumors for at least one week. OCP-loaded NPs almost completely reversed allodynia and hyperalgesia for a prolonged period, whereas unencapsulated OCP had small and transient effects. The NP accumulation in endosomal sites of pain signaling, the sustained release of antagonist, and the retention of NPs in tumors explain their beneficial actions. Thus, NP-encapsulation holds promise for the relief of painful cancers that are inadequately treated by opioids.