Transoral Robotic Surgery and Radiation Volume Deintensification in Unknown Primary Squamous Cell Carcinoma of the Neck: The Phase 2 FIND Nonrandomized Controlled Trial.

Importance: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects. Objective: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control. Design, Setting, and Participants: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022. Intervention: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0. Main Outcomes and Measures: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings. Results: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, -20.4; 95% CI, -34.1 to -6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%). Conclusions and Relevance: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03281499.

The Quantification of Radiation Fibrosis Using Clinically Indicated Magnetic Resonance Imaging for Head and Neck Cancer Patients.

Currently, no objective method exists to measure the extent of fibrosis in swallowing musculature in head and neck cancer (HNC) patients. We developed and psychometrically tested a method of quantifying fibrosis volume using magnetic resonance imaging (MRI). The overall aim of this study was to determine if clinical MRI is a reliable tool to measure fibrosis of the pharyngeal musculature in patients with HNC managed with RT and to assess its potential to capture changes in fibrosis over time. Eligible participants were adults with HNC treated with radiation therapy (RT) who received minimally two MRIs and videofluoroscopic swallow (VFS) studies from baseline (pre-RT) up to 1-year post-RT. Two neuroradiologists independently contoured fibrosis volume in batches from MRIs using Vitrea™. Sufficient inter-rater reliability was set at Intraclass Correlation Coefficient (ICC) > 0.75. Two speech-language pathologists independently rated VFSs for swallowing impairment using standardized scales, with discrepancies resolved by consensus. MRI and VFS scores were correlated using Spearman's rank coefficient. Participants included 42 adults (male = 33); mean age 59 (SD = 8.8). ICC (95% Confidence Interval) for fibrosis volume was 0.34 (0, 0.76) for batch one and 0.43 (0, 0.82) for batch two. Consensus meetings were held after each batch. Sufficient reliability was reached by batch three (ICC = 0.95 (0.79, 0.99)). Fibrosis volume increased significantly from 3 to 12 months (mean change = 1.28 mL (SD = 5.21), p = 0.006), as did pharyngeal impairment from baseline to 12 months (mean score change = 3.05 (SD = 3.02), p = 0.003). Fibrosis volume moderately correlated with pharyngeal impairment at 3 and 12 months (0.49, p = 0.004 and 0.59, p = 0.005, respectively). We demonstrated a reliable measure of fibrosis volume in swallowing musculature from existing clinical MRIs and identified that larger fibrosis volume was associated with worse swallowing function. The reliable capture of fibrosis volume offers a pragmatic method for early detection of fibrosis and concomitant dysphagia.

Tumor volumes in T3 supraglottic cancers treated with radiotherapy in the modern era: A study of the Canadian Head & Neck Collaborative Research Initiative.

PURPOSE: To evaluate the association of primary tumor volume (TV) with overall survival (OS) and disease-free survival (DFS) in T3 N0-3M0 supraglottic cancers treated with intensity-modulated radiotherapy (IMRT). METHODS: This was a retrospective cohort study involving 239 patients diagnosed with T3 N0-3M0 supraglottic cancers between 2002 and 2018 from seven regional cancer centers in Canada. Clinical data were obtained from the patient records. Supraglottic TV was measured by neuroradiologists on diagnostic imaging. Kaplan-Meier method was used for survival probabilities, and a restricted cubic spline Cox proportional hazards regression analysis was used to analyze TV associations with OS and DFS. RESULTS: Mean (SD) of participants was 65.2 (9.4) years; 176 (73.6%) participants were male. 90 (38%) were N0, and 151 (64%) received concurrent systemic therapy. Mean TV (SD) was 11.37 (12.11) cm3 . With mean follow up (SD) of 3.28 (2.60) years, 2-year OS was 72.7% (95% CI 66.9%-78.9%) and DFS was 53.6% (47.4%-60.6%). Increasing TV was associated (per cm3 increase) with worse OS (HR, 1.01, 95% CI 1.00-1.02, p < 0.01) and DFS (HR, 1.01, 95% CI 1.00-1.02, p = 0.02). CONCLUSIONS: Increasing primary tumor volume is associated with worse OS and DFS in T3 supraglottic cancers treated with IMRT, with no clear threshold. The findings suggest that patients with larger tumors and poor baseline laryngeal function may benefit from upfront laryngectomy with adjuvant radiotherapy.

Association of Primary Tumor Volume With Survival in Patients With T3 Glottic Cancer Treated With Radiotherapy: A Study of the Canadian Head & Neck Collaborative Research Initiative.

Importance: The association of primary tumor volume with outcomes in T3 glottic cancers treated with radiotherapy with concurrent chemotherapy remains unclear, with some evidence suggesting worse locoregional control in larger tumors. Objective: To evaluate the association of primary tumor volume with oncologic outcomes in patients with T3 N0-N3 M0 glottic cancer treated with primary (chemo)radiotherapy in a large multi-institutional study. Design, Setting, and Participants: This multi-institutional retrospective cohort study involved 7 Canadian cancer centers from 2002 to 2018. Tumor volume was measured by expert neuroradiologists on diagnostic imaging. Clinical and outcome data were extracted from electronic medical records. Overall survival (OS) and disease-free survival (DFS) outcomes were assessed with marginal Cox regression. Laryngectomy-free survival (LFS) was modeled as a secondary analysis. Patients diagnosed with cT3 N0-N3 M0 glottic cancers from 2002 to 2018 and treated with curative intent intensity-modulated radiotherapy (IMRT) with or without chemotherapy. Overall, 319 patients met study inclusion criteria. Exposures: Tumor volume as measured on diagnostic imaging by expert neuroradiologists. Main Outcomes and Measures: Primary outcomes were OS and DFS; LFS was assessed as a secondary analysis, and late toxic effects as an exploratory analysis determined before start of the study. Results: The mean (SD) age of participants was 66 (12) years and 279 (88%) were men. Overall, 268 patients (84%) had N0 disease, and 150 (47%) received concurrent systemic therapy. The mean (SD) tumor volume was 4.04 (3.92) cm3. With a mean (SD) follow-up of 3.85 (3.04) years, there were 91 (29%) local, 35 (11%) regional, and 38 (12%) distant failures. Increasing tumor volume (per 1-cm3 increase) was associated with significantly worse adjusted OS (hazard ratio [HR], 1.07; 95% CI, 1.03-1.11) and DFS (HR, 1.04; 95% CI, 1.01-1.07). A total of 62 patients (19%) underwent laryngectomies with 54 (87%) of these within 800 days after treatment. Concurrent systemic therapy was associated with improved LFS (subdistribution HR, 0.63; 95% CI, 0.53-0.76). Conclusions and Relevance: Increasing tumor volumes in cT3 glottic cancers was associated with worse OS and DFS, and systemic therapy was associated with improved LFS. In absence of randomized clinical trial evidence, patients with poor pretreatment laryngeal function or those ineligible for systemic therapy may be considered for primary surgical resection with postoperative radiotherapy.

Near-real-time MODIS-derived vegetation index data products and online services for CONUS based on NASA LANCE.

This paper describes a set of Near-Real-Time (NRT) Vegetation Index (VI) data products for the Conterminous United States (CONUS) based on Moderate Resolution Imaging Spectroradiometer (MODIS) data from Land, Atmosphere Near-real-time Capability for EOS (LANCE), an openly accessible NASA NRT Earth observation data repository. The data set offers a variety of commonly used VIs, including Normalized Difference Vegetation Index (NDVI), Vegetation Condition Index (VCI), Mean-referenced Vegetation Condition Index (MVCI), Ratio to Median Vegetation Condition Index (RMVCI), and Ratio to previous-year Vegetation Condition Index (RVCI). LANCE enables the NRT monitoring of U.S. cropland vegetation conditions within 24 hours of observation. With more than 20 years of observations, this continuous data set enables geospatial time series analysis and change detection in many research fields such as agricultural monitoring, natural resource conservation, environmental modeling, and Earth system science. The complete set of VI data products described in the paper is openly distributed via Web Map Service (WMS) and Web Coverage Service (WCS) as well as the VegScape web application ( https://nassgeodata.gmu.edu/VegScape/ ).

Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease.

Down syndrome (DS) is caused by human chromosome 21 (HSA21) trisomy. It is characterized by a poorly understood intellectual disability (ID). We studied two mouse models of DS, one with an extra copy of the <i>Dyrk1A</i> gene (189N3) and the other with an extra copy of the mouse Chr16 syntenic region (Dp(16)1Yey). RNA-seq analysis of the transcripts deregulated in the embryonic hippocampus revealed an enrichment in genes associated with chromatin for the 189N3 model, and synapses for the Dp(16)1Yey model. A large-scale yeast two-hybrid screen (82 different screens, including 72 HSA21 baits and 10 rebounds) of a human brain library containing at least 10⁷ independent fragments identified 1,949 novel protein-protein interactions. The direct interactors of HSA21 baits and rebounds were significantly enriched in ID-related genes (<i>P</i>-value &lt; 2.29 × 10^-8). Proximity ligation assays showed that some of the proteins encoded by HSA21 were located at the dendritic spine postsynaptic density, in a protein network at the dendritic spine postsynapse. We located HSA21 DYRK1A and DSCAM, mutations of which increase the risk of autism spectrum disorder (ASD) 20-fold, in this postsynaptic network. We found that an intracellular domain of DSCAM bound either DLGs, which are multimeric scaffolds comprising receptors, ion channels and associated signaling proteins, or DYRK1A. The DYRK1A-DSCAM interaction domain is conserved in <i>Drosophila</i> and humans. The postsynaptic network was found to be enriched in proteins associated with ARC-related synaptic plasticity, ASD, and late-onset Alzheimer's disease. These results highlight links between DS and brain diseases with a complex genetic basis.

Genetic Mapping of APP and Amyloid-ß Biology Modulation by Trisomy 21.

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the buildup of aggregated amyloid-ß (Aß) and tau proteins in the brain. Aß is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have DS have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of AD in these individuals. Here we use a combination of next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of Aß accumulation (AppNL-F ) to determine how chromosome 21 genes, other than APP, modulate APP/Aß in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate Aß accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene(s) causing this decrease in Aß accumulation and investigate the role of two lead candidate genes, Dyrk1a and Bace2 Thus, an additional copy of chromosome 21 genes, other than APP, can modulate APP/Aß in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD in DS, compared with those who have familial AD caused by triplication of APP SIGNIFICANCE STATEMENT Trisomy of chromosome 21 is a commonly occurring genetic risk factor for early-onset Alzheimer's disease (AD), which has been previously attributed to people with Down syndrome having three copies of the amyloid precursor protein (APP) gene, which is encoded on chromosome 21. However, we have shown that an extra copy of other chromosome 21 genes modifies AD-like phenotypes independently of APP copy number (Wiseman et al., 2018; Tosh et al., 2021). Here, we use a mapping approach to narrow down the genetic cause of the modulation of pathology, demonstrating that gene(s) on chromosome 21 decrease Aß accumulation in the brain, independently of alterations to full-length APP or C-terminal fragment abundance and that just 38 genes are sufficient to cause this.

Nasopharyngeal Carcinoma Radiomic Evaluation with Serial PET/CT: Exploring Features Predictive of Survival in Patients with Long-Term Follow-Up.

PURPOSE: We aim determine the value of PET and CT radiomic parameters on survival with serial follow-up PET/CT in patients with nasopharyngeal carcinoma (NPC) for which curative intent therapy is undertaken. METHODS: Patients with NPC and available pre-treatment as well as follow up PET/CT were included from 2005 to 2006 and were followed to 2021. Baseline demographic, radiological and outcome data were collected. Univariable Cox proportional hazard models were used to evaluate features from baseline and follow-up time points, and landmark analyses were performed for each time point. RESULTS: Sixty patients were enrolled, and two-hundred and seventy-eight (278) PET/CT were at baseline and during follow-up. Thirty-eight percent (38%) were female, and sixty-two patients were male. All patients underwent curative radiation or chemoradiation therapy. The median follow-up was 11.72 years (1.26-14.86). Five-year and ten-year overall survivals (OSs) were 80.0% and 66.2%, and progression-free survival (PFS) was 90.0% and 74.4%. Time-dependent modelling suggested that, among others, PET gray-level zone length matrix (GLZLM) gray-level non-uniformity (GLNU) (HR 2.74 95% CI 1.06, 7.05) was significantly associated with OS. Landmark analyses suggested that CT parameters were most predictive at 15 month, whereas PET parameters were most predictive at time points 3, 6, 9 and 15 month. CONCLUSIONS: This study with long-term follow up data on NPC suggests that mainly PET-derived radiomic features are predictive for OS but not PFS in a time-dependent evaluation. Furthermore, CT radiomic measures may predict OS and PFS best at initial and long-term follow-up time points and PET measures may be more predictive in the interval. These modalities are commonly used in NPC surveillance, and prospective validation should be considered.

Augmenting inter-rater concordance of radiologic extranodal extension in HPV-positive oropharyngeal carcinoma: A multicenter study.

OBJECTIVES: To assess intra- and inter-institutional concordance and identify methods to increase precision in radiologic extranodal extension (rENE) ascertainment in HPV+ oropharyngeal carcinoma. METHODS: Six radiologists, blinded to clinical outcomes, from three centers assessed rENE in two phases: Phase-I (20 cases) utilized each individual's a priori appreciation of the literature. Phase-II (30 additional cases) was performed after deliberating experience and consolidating operating definitions. Intra- and inter-institutional Kappa were calculated at >50% and >75% certainty levels, respectively. RESULTS: The Phase-I intra-institutional kappa was 0.76, 0.32, and 0.44 at >50% certainty and improved to 0.89, 0.61, and 0.66 at >75% certainty. Inter-institutional Fleiss' kappa also improved with higher certainty (from 0.40 to 0.57, p = 0.039).  The Phase-II inter-rater kappa was significantly higher than Phase-I at the same certainty level (both p < 0.001). CONCLUSION: A learning curve exists for rENE assessment. Strategies to augment reliability include high certainty for declaration, consolidated operating definitions, and sharing experience among radiologists.

Clinical presentation and outcome of human papillomavirus-positive nasopharyngeal carcinoma in a North American cohort.

BACKGROUND: The objective of this study was to describe the clinical presentation and outcomes of human papillomavirus (HPV)-positive nasopharyngeal cancer (NPC) versus Epstein-Barr virus (EBV)-positive NPC and HPV-positive oropharyngeal cancer (OPC). METHODS: Clinical characteristics and presenting signs/symptoms were compared between patients who had viral-related NPC versus viral-related OPC treated with intensity-modulated radiotherapy from 2005 to 2020 and who were matched 1:1 (by tumor and lymph node categories, smoking, age, sex, histology, and year of diagnosis). Locoregional control (LRC), distant control (DC), and overall survival (OS) were compared using the 2005-2018 cohort to maintain 2 years of minimum follow-up. Multivariable analysis was used to evaluate the cohort effect. RESULTS: Similar to HPV-positive OPC (n = 1531), HPV-positive NPC (n = 29) occurred mostly in White patients compared with EBV-positive NPC (n = 422; 86% vs. 15%; p < .001). Primary tumor volumes were larger in HPV-positive NPC versus EBV-positive NPC (median volume, 51 vs. 23 cm3 ; p = .002), with marginally more Level IB nodal involvement. More patients with HPV-positive NPC complained of local pain (38% vs. 3%; p = .002). The median follow-up for the 2005-2018 cohort was 5.3 years. Patients who had HPV-positive NPC (n = 20) had rates of 3-year LRC (95% vs. 90%; p = .360), DC (75% vs. 87%; p = .188), and OS (84% vs. 89%; p = .311) similar to the rates in those who had EBV-positive NPC (n = 374). Patients who had HPV-positive NPC also had rates of LRC (95% vs. 94%; p = .709) and OS (84% vs. 87%; p = .440) similar to the rates in those who had HPV-positive OPC (n = 1287). The DC rate was lower in patients who had HPV-positive disease (75% vs. 90%; p = .046), but the difference became nonsignificant (p = .220) when the analysis was adjusted for tumor and lymph node categories, smoking, and chemotherapy. CONCLUSIONS: HPV-positive NPC and EBV-positive NPC seem to be mutually exclusive diseases. Patients who have HPV-positive NPC have greater local symptom burden and larger primary tumors but have similar outcomes compared with patients who have EBV-positive NPC or HPV-positive OPC.

Radiologic-pathologic correlation of major versus minor extranodal extension in oral cavity cancer.

BACKGROUND: To evaluate the diagnostic performance of radiologic extranodal extension (rENE) in predicting major (>2 mm) and minor (≤2 mm) pathologic ENE (pENE). METHODS: All oral cavity squamous cell carcinoma patients who underwent neck dissection with pathological nodal disease (pN+) between 2010 and 2015 were reviewed. Preoperative computed tomography and/or magnetic resonance imaging were reviewed by two head and neck neuroradiologists. RESULTS: Three hundred and thirty-four patients were included. The sensitivity and specificity of rENE were 37% [95% CI 29-44] and 98% [95% CI 96-100], respectively. Sensitivity for pENE improved in the subset of patients with major ENE (48% [95% CI 38-57]). The presence of rENE was associated with inferior 3-year overall survival: 26% [95% CI 17-41] versus 60% [95% CI 54-67]. CONCLUSIONS: This large cohort study demonstrates high specificity, but low sensitivity for preoperative imaging in the detection of pENE in OCSCC. Patients with rENE demonstrated poor OS. pENE in the absence of rENE is still an adverse risk factor.

Inter-rater concordance and operating definitions of radiologic nodal feature assessment in human papillomavirus-positive oropharyngeal carcinoma.

BACKGROUND AND PURPOSE: This study aims to evaluate the reliability of radiologic nodal feature assessment in clinical node-positive human papillomavirus-positive oropharyngeal carcinoma. MATERIALS AND METHODS: Baseline CTs or MRIs of clinical node-positive human papillomavirus-positive oropharyngeal carcinoma diagnosed between 2012 and 2015 were reviewed independently by two neuroradiologists for seven nodal features: radiologic nodal involvement, cystic change, presence of necrosis, clustering, conglomeration, coalescence, and extranodal extension. Consensus operating definitions were derived after discussion. The features were re-reviewed in a randomly selected cohort. Levels of certainty (probability of presence: <25%, ∼50%, ∼75%, and >90%) were recorded. Interrater concordance was calculated using Cohen's kappa coefficient. RESULTS: A total of 413 patients (826 necks) were eligible. At initial review, the inter-rater kappa values for: radiologic nodal involvement, cystic change, necrosis, clustering, conglomeration, coalescence, and extranodal extension were 0.92, 0.64, 0.48, 0.32, 0.32, 0.62, and 0.56, respectively. A re-review of 94 randomly selected cases (188 necks) after consolidation of operating definitions for nodal features showed that the inter-rater kappa values of these features were 0.83, 0.62, 0.58, 0.32, 0.18, 0.68, and 0.74 when considering ≥50% certainty as positive, and improved to 0.94, 0.66, 0.59, 0.33, 0.19, 0.76, and 0.86 when considering ≥75% certainty as positive. CONCLUSION: Clearly defined nomenclature results in improved interrater reliability when assessing radiologic nodal features, especially for coalescent adenopathy and extranodal extension. Higher levels of certainty are associated with higher inter-rater agreement. Radiology reporting should include clear definitions of clinically relevant nodal features as well as levels of certainty to serve various needs in clinical care and research.

Evaluation of Sarcopenia in Older Patients Undergoing Head and Neck Cancer Surgery.

OBJECTIVES/HYPOTHESIS: Sarcopenia is a hallmark of aging and its identification may help predict adverse postoperative events in patients undergoing head and neck surgery. The study objective was to assess the relationship between sarcopenia and postoperative complications and length of stay in patients undergoing major head and neck cancer surgery. STUDY DESIGN: Prospective cohort study. METHODS: A prospective cohort study was performed of patients 50 years and older undergoing major head and neck surgery. Sarcopenia was defined as low muscle mass (determined by neck muscle cross-sectional imaging) with either low muscle strength (grip strength) or low muscle performance (timed walk test). Logistic regression was applied on binary outcomes, and linear regression was used for log-transformed length of hospital stay (LOS). Univariate and multivariate analyses were performed. RESULTS: Of the 251 patients enrolled, pre-sarcopenia was present in 34.9% (n = 87) and sarcopenia in 15.6% (n = 39) of patients. Patients with sarcopenia were more likely to be older (P = .001), female (P = .001), have a lower body mass index (P = .001), and lower preoperative hemoglobin (P < .001). On univariate analysis, the presence and severity of sarcopenia was associated with the development of medical complications (P = .029), higher grade of complications (P = .032), LOS (P = .015), and overall survival (P = .001). On multivariate analysis, sarcopenia was associated with a longer LOS (ß = 0.32 [95% CI: 0.19-0.45], P < .001) and worse overall survival (HR = 2.21 [95% CI: 1.01-4.23], P = .017). CONCLUSIONS: Sarcopenia may aid in the prediction of prolonged hospital stay and death in patients who are candidates for major head and neck surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:356-363, 2022.

Regional Recurrences and Hyams Grade in Esthesioneuroblastoma.

Objective The aim of this study is to determine if Hyams grade may help predict which patients with esthesioneuroblastoma (ENB) tumors are likely to develop regional recurrences, and to determine the impact of tumor extent on regional failure in ENB patients without evidence of nodal disease at presentation. Design The study was designed as a retrospective review for ENB patients. Settings The study was prepared at tertiary care academic center for ENB patients. Participants Patients with ENB were included in the study. Main Outcome Measures Oncologic outcomes (5-year regional and locoregional control (LRC) and overall survival) in patients with Hyams low grade versus high grade. Oncologic outcomes based on radiographic disease extent. Results A total of 43 patients were included. Total 25 patients (58%) had Hyams low-grade tumor, and 18 (42%) had high-grade tumor. Of the 34 patients without regional disease at presentation, 8 (24%) were treated with elective nodal radiation. There were no statistically significant differences in 5-year regional control in the Hyams low-grade versus high-grade groups (78 vs. 89%; p = 0.4). The 5-year LRC rates in patients with low grade versus high grade were 73 versus 89% ( p = 0.6). The 5-year overall survival rates in patients with low-grade versus high-grade tumors were 86 versus 63% ( p = 0.1). Radiographic extension of disease into the olfactory groove, olfactory nerve, dura, and periorbita were statistically associated with decreased 5-year overall survival (5-year OS 49 vs. 91% [ p = 0.04], 49 vs. 91% [ p = 0.04], 44 vs. 92% [ p = 0.02], and 44 vs. 80% [ p = 0.04], respectively). Conclusion ENBs are associated with a risk of regional failure. The current analysis suggests that Hyams low-grade and high-grade malignancies have comparable rates of early and delayed regional recurrences, although small sample size may limit our conclusions.

Defect Engineering of Graphene to Modulate pH Response of Graphene Devices.

Graphene-based pH sensors are a robust, durable, sensitive, and scalable approach for the sensitive detection of pH in various environments. However, the mechanisms through which graphene responds to pH variations are not well-understood yet. This study provides a new look into the surface science of graphene-based pH sensors to address the existing gaps and inconsistencies among the literature concerning sensing response, the role of defects, and surface/solution interactions. Herein, we demonstrate the dependence of the sensing response on the defect density level of graphene, measured by Raman spectroscopy. At the crossover point (ID/IG = 0.35), two countervailing mechanisms balance each other out, separating two regions where either a surface defect induced (negative slope) or a double layer induced (positive slope) response dominates. For ratios above 0.35, the pH-dependent induction of charges at surface functional groups (both pH-sensitive and nonsensitive groups) dominates the device response. Below a ratio of 0.35, the response is dominated by the modulation of charge carriers in the graphene due to the electric double layer formed from the interaction between the graphene surface and the electrolyte solution. Selective functionalization of the surface was utilized to uncover the dominant acid-base interactions of carboxyl and amine groups at low pH while hydroxyl groups control the high pH range sensitivity. The overall pH-sensing characteristics of the graphene will be determined by the balance of these two mechanisms.

Prognostic importance of radiologic extranodal extension in nasopharyngeal carcinoma treated in a Canadian cohort.

PURPOSE: To confirm the prognostic value of radiologic extranodal extension (rENE) and its role in clinical-N classification in nasopharyngeal carcinoma (NPC) treated in a western institution. METHODS AND MATERIALS: NPC treated between 2010 and 2017 were included. Pre-treatment MRI were reviewed for unequivocal rENE and its grade: grade-1: tumour invading through any nodal capsule but confined to perinodal fat; grade-2: ≥2 adjacent nodes forming a coalescent nodal mass; grade-3: tumour extending beyond perinodal fat to invade/encase adjacent structures. Overall survival (OS) and disease-free survival (DFS) were compared between rENE-positive (rENE+) and rENE-negative (rENE-) patients. Multivariable analysis (MVA) confirmed the prognostic importance of rENE and its grade. Staging schemas including rENE in N-classification were proposed and their performance evaluated. RESULTS: A total of 274 patients were eligible (43 cN0; 231 cN-positive). rENE was identified in 83/231 (36%) cN-positive, including grade 1/2/3 rENE in 14/58/11 cases. Compared to rENE-, rENE+ patients had a lower OS (68% vs 89%, p < 0.001) and DFS (58% vs 80%, p < 0.001). MVA confirmed the prognostic importance of grade-2 [HR: OS: 2.85 (p = 0.005); DFS: 2.89 (p < 0.001)] and grade-3 rENE [HR: OS 5.28 (p = 0.004); DFS 3.86 (p = 0.005)], with a trend for grade-1 vs rENE- [HR: OS 2.63 (p = 0.13); DFS 1.49 (p = 0.520)]. We evaluated classifying any rENE as cN3 (Proposal-I) or any grade-2/grade-3 rENE as cN3 (Proposal-II). The stage schema with Proposal-I cN-classification ranked the highest in the performance evaluation. CONCLUSIONS: rENE is an important prognostic factor in this western NPC cohort. We propose classifying any unequivocal rENE as cN3.

Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome.

Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Loss-of-function mutations in the DYRK1A gene, located on human chromosome 21 (Hsa21,) lead to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles. Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg(Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16Lipi-Zbtb21)1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in postnatal glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key post-synaptic proteins implicated in mechanism leading to long-term enhanced synaptic plasticity. Altogether, our work gives important information to understand the action of DYRK1A inhibitors and have a better therapeutic approach.

Site-Specific Variation in Radiomic Features of Head and Neck Squamous Cell Carcinoma and Its Impact on Machine Learning Models.

Current radiomic studies of head and neck squamous cell carcinomas (HNSCC) are typically based on datasets combining tumors from different locations, assuming that the radiomic features are similar based on histopathologic characteristics. However, molecular pathogenesis and treatment in HNSCC substantially vary across different tumor sites. It is not known if a statistical difference exists between radiomic features from different tumor sites and how they affect machine learning model performance in endpoint prediction. To answer these questions, we extracted radiomic features from contrast-enhanced neck computed tomography scans (CTs) of 605 patients with HNSCC originating from the oral cavity, oropharynx, and hypopharynx/larynx. The difference in radiomic features of tumors from these sites was assessed using statistical analyses and Random Forest classifiers on the radiomic features with 10-fold cross-validation to predict tumor sites, nodal metastasis, and HPV status. We found statistically significant differences (p-value ≤ 0.05) between the radiomic features of HNSCC depending on tumor location. We also observed that differences in quantitative features among HNSCC from different locations impact the performance of machine learning models. This suggests that radiomic features may reveal biologic heterogeneity complementary to current gold standard histopathologic evaluation. We recommend considering tumor site in radiomic studies of HNSCC.