The REASON score: an epigenetic and clinicopathologic score to predict risk of poor survival in patients with early stage oral squamous cell carcinoma

Background Oral squamous cell carcinoma (OSCC) is a capricious cancer with poor survival rates, even for early-stage patients. There is a pressing need to develop more precise risk assessment methods to appropriately tailor clinical treatment. Genome-wide association studies have not produced a viable biomarker. However, these studies are limited by using heterogeneous cohorts, not focusing on methylation although OSCC is a heavily epigenetically-regulated cancer, and not combining molecular data with clinicopathologic data for risk prediction. In this study we focused on early-stage (I/II) OSCC and created a risk score called the REASON score, which combines clinicopathologic characteristics with a 12-gene methylation signature, to predict the risk of 5-year mortality. Methods We combined data from an internal cohort (n = 515) and The Cancer Genome Atlas (TCGA) cohort (n = 58). We collected clinicopathologic data from both cohorts to derive the non-molecular portion of the REASON score. We then analyzed the TCGA cohort DNA methylation data to derive the molecular portion of the risk score. Results 5-year disease specific survival was 63% for the internal cohort and 86% for the TCGA cohort. The clinicopathologic features with the highest predictive ability among the two the cohorts were age, race, sex, tobacco use, alcohol use, histologic grade, stage, perineural invasion (PNI), lymphovascular invasion (LVI), and margin status. This panel of 10 non-molecular features predicted 5-year mortality risk with a concordance (c)-index = 0.67. Our molecular panel consisted of a 12-gene methylation signature (i.e., HORMAD2, MYLK, GPR133, SOX8, TRPA1, ABCA2, HGFAC, MCPH1, WDR86, CACNA1H, RNF216, CCNJL), which had the most significant differential methylation between patients who survived vs. died by 5 years. All 12 genes have already been linked to survival in other cancers. Of the genes, only SOX8 was previously associated with OSCC; our study was the first to link the remaining 11 genes to OSCC survival. The combined molecular and non-molecular panel formed the REASON score, which predicted risk of death with a c-index = 0.915. Conclusions The REASON score is a promising biomarker to predict risk of mortality in early-stage OSCC patients. Validation of the REASON score in a larger independent cohort is warranted

Preparation of the Neck for Advanced Flap Reconstruction.

Microvascular free tissue transfer has revolutionized the reconstruction of complex maxillofacial defects. These cases often necessitate a 2-teamed approach, with an ablative surgeon at the head and a reconstructive surgeon at a distant site for flap harvest. Careful attention to recipient vessel identification and preservation establishes the foundation for successful reconstruction. This article describes the surgical landmarks of the frequently utilized arteries and veins, vessel handling techniques, and general principles for the preparation of free tissue transfer recipient sites in head and neck reconstruction

Regeneration of a Tooth in a Tissue-Engineered Mandible After Resection of a Central Giant Cell Tumor. Demonstrating Evidence of Functional Matrix Theory and Ectodermal Origin of Teeth in a Human Model-A Case Report

Central giant cell tumors (CGCTs) are uncommon lesions occurring in the jaw. They are benign but locally destructive osteolytic lesions. They usually occur in pediatric patients 5 to 15 years of age. Multiple noninvasive modalities of treatment (intralesional steroids, interferon, calcitonin, and denosumab) have been described for those lesions, but for those that are refractory to treatment, enucleation and curettage or resection is a curative surgery. This case report describes a pediatric patient who was diagnosed with an aggressive CGCT of the left mandible encompassing the right angle to the condyle. The lesion became refractory to noninvasive treatments and immediate resection and reconstruction was performed using principles of tissue engineering. After 5 years of close observation, the patient showed normal morphology and growth of his mandible, but surprisingly developed a left mandibular third molar (tooth 17) in the site of the mandibular resection and reconstruction. This is the first case report in the literature to show the spontaneous development of teeth in a human reconstructed mandible, contributing evidence toward the functional matrix theory of mandibular growth and ectodermal origin of teeth

Custom Plate in a Day-Accurate Predictive Hole Fabrication Using Point-of-Care 3-Dimensional Printing.

PURPOSE: In computer surgical planned (CSP) fibular reconstructions of the mandible, custom plates facilitate accurate and efficient transfer of the digital plan intraoperatively by a way of predrilled fixation holes. Stock plates are more easily accessible and are more economical but typically preclude the utilization of these predictive holes. The purpose of this article is to describe an accurate and economical alternative to custom plates, while still having the ability to create predictive holes for plate alignment and execution of a digital surgical plan. METHODS: An in vitro accuracy study was performed on a point-of-care resin-printed predictive hole guide termed prebent plate analog (PPA). Twenty stock 2.0 reconstruction plates prebent against a 3-dimensional printed mandibular model reconstructed with a 2-piece fibula were used to fabricate 20 PPAs. The proximal and distal 4 holes of each prebent plate and corresponding PPA were assessed using a heat map overlay, measuring difference in millimeters between matching points of the predictive hole segments. The median distance from the points of reference in the PPA versus the prebent plate was calculated for each predictive hole position in addition to the average error of the PPA to the stock plate. RESULTS: Eighteen PPAs were used for statistical analysis; 2 were damaged in transport. The mean error between the body (-0.265) and condylar segments (-0.116 mm) and mean difference in error between the proximal predictive holes (-0.124 mm) and distal predictive holes (-0.215 mm) on the PPA were not statistically different (P = .061, P = .314 general estimating equation regression, respectively). The mean error across the PPA predictive holes and corresponding holes of the prebent plates was -0.194 mm (P \u3c .001, general estimating equation regression). CONCLUSIONS: The PPA is a precise and accurate analog that faithfully replicates the position of proximal and distal components of a prebent stock plate, thereby allowing for predictive hole placement in lieu of a custom plate in fibula mandibular reconstruction cases

Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance.

BACKGROUND: The risk of delayed autoimmunity occurring months or years after discontinuation of immunotherapy is frequently asserted in the literature. However, specific cases were rarely described until 2018, when a wave of reports surfaced. With expanding I-O indications in the adjuvant/neoadjuvant curative setting, growing numbers of patients will receive limited courses of immunotherapy before entering routine surveillance. In this context, under-recognition of DIRE could pose a growing clinical hazard. METHODS: The aim of this study was to characterize DIRE through identification of existing reports of delayed post-treatment irAE in cancer patients treated with immunotherapy. We performed a PubMed literature review from 2008 through 2018 to determine the median data safety reporting window from existing I-O clinical trials, which we then applied to define the DIRE cutoff, and collated all qualifying reports over the same time span. DIRE was defined as new immune-related adverse events (irAE) manifesting ≥90 days after discontinuation of immunotherapy. RESULTS: Median duration of I-O clinical trials data safety reporting was 90 days (82% ≤ 90 days). DIRE cutoff was thus set as ≥90 days post-immunotherapy. We identified 23 qualifying cases; 21 by literature review and 2 from our institution. Median off-treatment interval to DIRE was 6 months (range: 3 to 28). Median cumulative immunotherapy exposure was 4 doses (range: 3 to 42). Involvement included endocrine, neurologic, GI, pulmonary, cardiac, rheumatologic and dermatologic irAE. CONCLUSIONS: As immunotherapy indications expand into the curative setting, often with brief exposure and potentially sequenced with multimodality treatments, it will be necessary to recognize an emerging diagnostic complex, which we have termed delayed immune-related events (DIRE). Clinical vigilance has the potential to reduce morbidity from diagnostic delay, as irAE are generally manageable with prompt initiation of treatment - or from misdiagnosis - as misattribution can lead to unnecessary or harmful interventions as we describe. DIRE should therefore figure prominently in the differential diagnosis of patients presenting with illnesses of unclear etiology, irrespective of intervening treatments or interval post-immunotherapy, both of which can confound diagnosis. Increased recognition will rest on delineation of DIRE as a clinical diagnostic entity

Immune-related adverse events are associated with improved response, progression-free survival, and overall survival for patients with head and neck cancer receiving immune checkpoint inhibitors.

BACKGROUND: The authors hypothesized that patients developing immune-related adverse events (irAEs) while receiving immune checkpoint inhibition (ICI) for recurrent/metastatic head and neck cancer (HNC) would have improved oncologic outcomes. METHODS: Patients with recurrent/metastatic HNC received ICI at 2 centers. Univariate and multivariate logistic regression, Kaplan-Meier methods, and Cox proportional hazards regression were used to associate the irAE status with the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in cohort 1 (n = 108). These outcomes were also analyzed in an independent cohort of patients receiving ICI (cohort 2; 47 evaluable for irAEs). RESULTS: The median follow-up was 8.4 months for patients treated in cohort 1. Sixty irAEs occurred in 49 of 108 patients with 5 grade 3 or higher irAEs (10.2%). ORR was higher for irAE+ patients (30.6%) in comparison with irAE- patients (12.3%; P = .02). The median PFS was 6.9 months for irAE+ patients and 2.1 months for irAE- patients (P = .0004), and the median OS was 12.5 and 6.8 months, respectively (P = .007). Experiencing 1 or more irAEs remained associated with ORR (P = .03), PFS (P = .003), and OS (P = .004) in multivariate analyses. The association between development of irAEs and prolonged OS persisted in a 22-week landmark analysis (P = .049). The association between development of irAEs and favorable outcomes was verified in cohort 2. CONCLUSIONS: The development of irAEs was strongly associated with an ICI benefit, including overall response, PFS, and OS, in 2 separate cohorts of patients with recurrent/metastatic HNC

Cohort Expansion Study of Neoadjvuant Immunoradiotherapy in Locoregionally Advanced HPV+ and HPV- Head and Neck Squamous Cell Carcinoma

Purpose/Objective(s): We recently reported the results of a phase Ib clinical trial in which 10 patients with previously untreated stage I-III (AJCC 8th Ed) p16+ head and neck squamous cell carcinoma (HNSCC) underwent neoadjuvant immunoradiotherapy (NIRT) with nivolumab 240mg IV q2 weeks x3 prior to surgery (NCT03247712). Stereotactic body radiation (SBRT) to gross tumor volume was delivered between doses 1 & 2 of nivolumab in one of two dose finding cohorts: Cohort A (40Gy, 8Gy X5, M-F); and Cohort B (24Gy, 8Gy X3, M-W-F). The pathologic complete response rate (pCR) was 90% and all patients were successfully down-staged prior to surgery. Here we aim to test the hypothesis that nivolumab contributed to the exceptional local response to radiation by modulating the tumor microenvironment via blockade of upregulated PD-L1. Materials/Methods: Following assessment of dose limiting toxicity in the safety portion of the trial, we opened two expansion cohorts that evaluated NIRT at the lower radiation dose (24Gy, 8Gy X3) with and without immunotherapy: Cohort C consisted of patients with stage I-III HPV+ HNSCC who were treated with SBRT alone; Patients in Cohort D had stage III-IV HPV-negative HNSCC and were treated with nivolumab and SBRT as in Cohort B. Surgery in all cohorts was performed five weeks post-SBRT, followed by adjuvant nivolumab 480mg IV q 4 weeks X3 starting four weeks after surgery. The primary endpoints were pathological response by irPRC and rate of pathologic and radiographic down-staging after neoadjuvant therapy. A Simon two-stage optimal design was applied, assuming that a decrement in T or N stage by week 6 in \u3e 10% of cases would be clinically significant (alpha Z.05 level of significance with a power of 90% to detect a difference when the true rate of down-staging _ 33%). Results: Between April 8, 2019 and December 17, 2019, 11 patients with previously untreated, loco-regionally advanced HNSCC involving the oral cavity (NZ2), oropharynx (NZ7), and larynx (NZ2) were enrolled into Cohort C (NZ6) or D (NZ5). Neoadjuvant treatment was well tolerated and there were no grade 3 or 4 adverse events. To date, 8/11 patients completed surgery and had evaluable pathologic reports. Of these, all patients were successfully down-staged and one patient with HPV-negative cancer required adjuvant radiation per protocol. Although the pCR rate was higher in Cohorts A and B than in the expansion cohorts evaluated to date, resection specimens were characterized by major pathologic responses (\u3c10% viable tumor cells) in the majority of patients, as well as robust inflammatory infiltrates into the regression bed, plasma cells and cholesterol clefts. Conclusion: NIRT prior to surgery for loco-regionally advanced HNSCC results in significant rates of major pathologic response and pathologic downstaging regardless of HPV status

Internet for mathematics

Internet for mathematics is a tutorial from the Virtual Training Suite. The Virtual Training Suite tutorials aim to help university and college students to develop Internet research skills to assist with their coursework and assignments. The tutorials were written by a national team of UK university or college lecturers and librarians. They recommend key websites in their subject and help students to make discerning use of the Internet to help find information for coursework, literature reviews or personal research. This is an archived version of the tutorial. As of the 1st of August 2011 any further development of the tutorials is being undertaken by TutorPro at http://www.vtstutorials.co.u