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Objectives The diagnosis and management of oral cavity cancers are often complicated by the uncertainty of which patients will undergo malignant transformation, obligating close surveillance over time. However, serial biopsies are undesirable, highly invasive, and subject to inherent issues with poor inter-pathologist agreement and unpredictability as a surrogate for malignant transformation and clinical outcomes. The goal of this study was to develop and evaluate a Multivariate Analytical Risk Index for Oral Cancer (MARIO) with potential to provide non-invasive, sensitive, and quantitative risk assessments for monitoring lesion progression. Materials and methods A series of predictive models were developed and validated using previously recorded single-cell data from oral cytology samples resulting in a “continuous risk score”. Model development consisted of: (1) training base classification models for each diagnostic class pair, (2) pairwise coupling to obtain diagnostic class probabilities, and (3) a weighted aggregation resulting in a continuous MARIO. Results and conclusions Diagnostic accuracy based on optimized cut-points for the test dataset ranged from 76.0% for Benign, to 82.4% for Dysplastic, 89.6% for Malignant, and 97.6% for Normal controls for an overall MARIO accuracy of 72.8%. Furthermore, a strong positive relationship with diagnostic severity was demonstrated (Pearson’s coefficient = 0.805 for test dataset) as well as the ability of the MARIO to respond to subtle changes in cell composition. The development of a continuous MARIO for PMOL is presented, resulting in a sensitive, accurate, and non-invasive method with potential for enabling monitoring disease progression, recurrence, and the need for therapeutic intervention of these lesions.

Samples of uranium diboride were sintered in inert, reducing and vacuum conditions with and without the addition of powdered carbon to green pellets. Carbon has been shown to improve the sintering of diboride materials via the formation of gaseous phases at lower temperatures than those at which grain coarsening occurs. The addition of 0.5 wt% carbon was seen to improve sample density in both vacuum and reducing conditions, while an increase in carbon content to 1 wt% carbon decreased the density achieved in reducing atmosphere and had a negligible effect in vacuum.Keywords: Nuclear, Fuel, Uranium, High Density Fuels

Fanconi anemia (FA) is a hereditary genomic instability disorder with a predisposition to leukemia and oral squamous cell carcinomas (OSCCs). Hematopoietic stem cell transplantation (HSCT) facilitates cure of bone marrow failure and leukemia and thus extends life expectancy in FA patients; however, survival of hematologic malignancies increases the risk of OSCC in these patients. We developed a "cytology-on-a-chip" (COC)-based brush biopsy assay for monitoring patients with oral potentially malignant disorders (OPMDs). Using this COC assay, we measured and correlated the cellular morphometry and Minichromosome Maintenance Complex Component 2 (MCM2) expression levels in brush biopsy samples of FA patients' OPMD with clinical risk indicators such as loss of autofluorescence (LOF), HSCT status, and mutational profiles identified by next-generation sequencing. Statistically significant differences were found in several cytology measurements based on high-risk indicators such as LOF-positive and HSCT-positive status, including greater variation in cell area and chromatin distribution, higher MCM2 expression levels, and greater numbers of white blood cells and cells with enlarged nuclei. Higher OPMD risk scores were associated with differences in the frequency of nuclear aberrations and differed based on LOF and HSCT statuses. We identified mutation of FAT1 gene in five and NOTCH-2 and TP53 genes in two cases of FA patients' OPMD. The high-risk OPMD of a non-FA patient harbored FAT1, CASP8, and TP63 mutations. Use of COC assay in combination with visualization of LOF holds promise for the early diagnosis of high-risk OPMD. These minimally invasive diagnostic tools are valuable for long-term surveillance of OSCC in FA patients and avoidance of unwarranted scalpel biopsies.

The lack of standard tools and methodologies and the absence of a streamlined multimarker approval process have hindered the translation rate of new biomarkers into clinical practice for a variety of diseases afflicting humankind. Advanced novel technologies with superior analytical performance and reduced reagent costs, like the programmable bio-nano-chip system featured in this article, have potential to change the delivery of healthcare. This universal platform system has the capacity to digitize biology, resulting in a sensor modality with a capacity to learn. With well-planned device design, development, and distribution plans, there is an opportunity to translate benchtop discoveries in the genomics, proteomics, metabolomics, and glycomics fields by transforming the information content of key biomarkers into actionable signatures that can empower physicians and patients for a better management of healthcare. While the process is complicated and will take some time, showcased here are three application areas for this flexible platform that combines biomarker content with minimally invasive or non-invasive sampling, such as brush biopsy for oral cancer risk assessment; serum, plasma, and small volumes of blood for the assessment of cardiac risk and wellness; and oral fluid sampling for drugs of abuse testing at the point of need.

Despite significant advances in surgical procedures and treatment, long-term prognosis for patients with oral cancer remains poor, with survival rates among the lowest of major cancers. Better methods are desperately needed to identify potential malignancies early when treatments are more effective. Objective To develop robust classification models from cytology-on-a-chip measurements that mirror diagnostic performance of gold standard approach involving tissue biopsy. Materials and methods Measurements were recorded from 714 prospectively recruited patients with suspicious lesions across 6 diagnostic categories (each confirmed by tissue biopsy -histopathology) using a powerful new ‘cytology-on-a-chip’ approach capable of executing high content analysis at a single cell level. Over 200 cellular features related to biomarker expression, nuclear parameters and cellular morphology were recorded per cell. By cataloging an average of 2000 cells per patient, these efforts resulted in nearly 13 million indexed objects. Results Binary “low-risk”/“high-risk” models yielded AUC values of 0.88 and 0.84 for training and validation models, respectively, with an accompanying difference in sensitivity + specificity of 6.2%. In terms of accuracy, this model accurately predicted the correct diagnosis approximately 70% of the time, compared to the 69% initial agreement rate of the pool of expert pathologists. Key parameters identified in these models included cell circularity, Ki67 and EGFR expression, nuclear-cytoplasmic ratio, nuclear area, and cell area. Conclusions This chip-based approach yields objective data that can be leveraged for diagnosis and management of patients with PMOL as well as uncovering new molecular-level insights behind cytological differences across the OED spectrum.

Fanconi anemia (FA) is caused by mutations of DNA repair genes. The risk of oral squamous cell carcinoma (OSCC) among FA patients is 800-folds higher than in the general population. Early detection of OSCC, preferably at it precursor stage is critical in FA patients to improve their survival. In an ongoing clinical trial, we are evaluating the effectiveness of the programmable bio-nano-chip (p-BNC)-based oral cytology test in diagnosing oral potentially malignant disorders (OPMD) in non-FA patients. We used this test to compare the cytomorphometric and molecular biomarkers in OSCC cell lines derived from FA patients and non-FA patients and brush biopsy samples of a FA patient’s OPMD and normal mucosa of healthy volunteers. Our data showed that expression patterns of molecular biomarkers were not notably different between sporadic and FA OSCC cell lines. The p-BNC assay revealed significant differences in cytometric parameters and biomarker MCM2 expression between cytobrush samples of the FA patient and cytobrush samples of normal oral mucosa obtained from healthy volunteers. Microscopic examination of the FA patient’s OPMD confirmed the presence of dysplasia. Our pilot data suggests that p-BNC brush biopsy test recognizes dysplastic oral epithelial cells in a brush biopsy sample of a FA patient.

Fanconi Anemia (FA) is an autosomal recessive disorder caused by mutations of DNA repair genes. The risk of oral cancer (OC) among FA patients is 800-times higher than in the general population, occurring at younger ages. Hematopoietic stem cell transplantation (HSCT), which greatly extends the life-expectancy in FA patients further increases the risk of OC in these patients. Patients with FA cannot tolerate chemo-and radiation therapy; hence, early detection of OC is critical to improve survival. Objective: To investigate the role of a numerical index for monitoring OC progression applied to FA patients in combination with a microfluidic “cytology-on-chip” assay and autofluorescence visualization (AFV) using VELscope (Visually Enhanced Lesion scope). Methods: Patients attending the Meeting for Adults with FA, held in Baltimore, Maryland in March 2014 underwent a conventional oral examination followed by AFV. Transepithelial brush samples of mucosal lesions suspected of being oral potentially malignant disorders (OPMD) were obtained using Orcellex® brush (Rovers Medical Devices, Oss, The Netherlands) and transported in ThinPrep® CytoLyt® for cytology-on-chip assays. A numerical OC risk index (0-100) developed and validated on 506 prospectively recruited non-FA patients with OPMD was applied to site-matched brush biopsy samples of FA patients. Results: A total of 28 FA patients (Age range: 18-61 yrs., M = 9, F = 19) participated in this study, of whom 13 have had HSCT. The majority of these lesions (89%) revealed loss of fluorescence (LOF+ve) with AFV. Compared to a cohort of prospectively recruited non-FA patients with OPMD (mean = 36.71, SD = 33.60), the mean OC risk index score for FA patients was 50.66 (SD = 32.83). Additionally, HSCT-recipient FA patients exhibited higher risk index scores (mean = 58.69, SD = 32.16) compared to non -HSCT-recipient FA patients (mean = 40.34, SD = 33.08). The frequency of nuclear aberrations such as micronuclei, bi- and poly-nucleated cells was significantly higher in FA patient cells than healthy controls and significantly higher in LOF+ve compared to LOV-negative OPMD. Two samples exhibited significantly higher WBC (white blood cell) counts, an indicator of inflammation; both were from LOF+ve OPMD found in HSCT-recipient FA patients. Conclusion: FA patients who are HSCT recipients have significantly higher OC risk index scores as well as increased prevalence of LOF+ve OPMD that demonstrate higher incidence of nuclear aberrations and inflammation. These findings are consistent with recent reports that HSCT in FA patients increases their risk for oral cancer. Therefore, use of the OC numerical index and cytology-on-chip assay in combination with AFV may improve the efficacy of conventional oral examination for long-term surveillance of OC in this high-risk patient population, while minimizing unwarranted scalpel biopsies. Citation Format: Timothy J. Abram, Pierre N. Floriano, Rameez Raja, Nancy Bass, Anne Gillenwater, Nadarajah Vigneswaran, John T. McDevitt. Minimally-invasive “cytology-on-chip” assay combined with continuous risk index for screening and surveillance of oral cancer in patients with Fanconi anemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-248.

A Next Generation Nuclear Plant (NGNP) fuel acquisition strategy was first established in 2007. In that report, a detailed technical assessment of potential fuel vendors for the first core of NGNP was conducted by an independent group of international experts based on input from the three major reactor vendor teams. Part of the assessment included an evaluation of the credibility of each option, along with a cost and schedule to implement each strategy compared with the schedule and throughput needs of the NGNP project. While credible options were identified based on the conditions in place at the time, many changes in the assumptions underlying the strategy and in externalities that have occurred in the interim requiring that the options be re-evaluated. This document presents an update to that strategy based on current capabilities for fuel fabrication as well as fuel performance and qualification testing worldwide. In light of the recent Pebble Bed Modular Reactor (PBMR) project closure, the Advanced Gas Reactor (AGR) fuel development and qualification program needs to support both pebble and prismatic options under the NGNP project. A number of assumptions were established that formed a context for the evaluation. Of these, the most important are: • Basedmore » on logistics associated with the on-going engineering design activities, vendor teams would start preliminary design in October 2012 and complete in May 2014. A decision on reactor type will be made following preliminary design, with the decision process assumed to be completed in January 2015. Thus, no fuel decision (pebble or prismatic) will be made in the near term. • Activities necessary for both pebble and prismatic fuel qualification will be conducted in parallel until a fuel form selection is made. As such, process development, fuel fabrication, irradiation, and testing for pebble and prismatic options should not negatively influence each other during the period prior to a decision on reactor type. • Additional funding will be made available beginning in fiscal year (FY) 2012 to support pebble bed fuel fabrication process development and fuel testing while maintaining the prismatic fuel schedule. Options for fuel fabrication for prismatic and pebble bed were evaluated based on the credibility of each option, along with a cost and schedule to implement each strategy. The sole prismatic option is Babcock and Wilcox (B&W) producing uranium oxycarbide (UCO) tristructural-isotropic (TRISO) fuel particles in compacts. This option finishes in the middle of 2022 . Options for the pebble bed are Nuclear Fuel Industries (NFI) in Japan producing uranium dioxide (UO2) TRISO fuel particles, and/or B&W producing UCO or UO2 TRISO fuel particles. All pebble options finish in mid to late 2022.« less

Objective Interobserver agreement in the context of oral epithelial dysplasia (OED) grading has been notoriously unreliable and can impose barriers for developing new molecular markers and diagnostic technologies. This paper aimed to report the details of a 3-stage histopathology review and adjudication process with the goal of achieving a consensus histopathologic diagnosis of each biopsy. Study Design Two adjacent serial histologic sections of oral lesions from 846 patients were independently scored by 2 different pathologists from a pool of 4. In instances where the original 2 pathologists disagreed, a third, independent adjudicating pathologist conducted a review of both sections. If a majority agreement was not achieved, the third stage involved a face-to-face consensus review. Results Individual pathologist pair κ values ranged from 0.251 to 0.706 (fair-good) before the 3-stage review process. During the initial review phase, the 2 pathologists agreed on a diagnosis for 69.9% of the cases. After the adjudication review by a third pathologist, an additional 22.8% of cases were given a consensus diagnosis (agreement of 2 out of 3 pathologists). After the face-to-face review, the remaining 7.3% of cases had a consensus diagnosis. Conclusions The use of the defined protocol resulted in a substantial increase (30%) in diagnostic agreement and has the potential to improve the level of agreement for establishing gold standards for studies based on histopathologic diagnosis.