Faculty Bibliography

PROBLEM IDENTIFICATION/UNASSIGNED:The impact of mental health disorders (MHDs) and substance use disorders (SUDs) on healthcare utilization (HCU) in patients with cancer is an understudied phenomenon. LITERATURE SEARCH/METHODS:A literature search of studies published prior to January 2018 that examined HCU in patients with preexisting MHDs or SUDs diagnosed with cancer was conducted. DATA EVALUATION/UNASSIGNED:The research team evaluated 22 studies for scientific rigor and examined significant trends in HCU, as well as types of the MHD, SUD, and cancer studied. SYNTHESIS/RESULTS:The heterogeneity of HCU outcome measures, MHD, SUD, sample sizes, and study settings contributed to inconsistent study findings. However, study trends indicated higher rates of HCU by patients with depression and lower rates of HCU by patients with schizophrenia. In addition, the concept of HCU measures is evolving, addressing not only volume of health services, but also quality and efficacy. IMPLICATIONS FOR RESEARCH/CONCLUSIONS:Oncology nurses are essential to improving HCU in patients with MHDs and SUDs because of their close connections with patients throughout the stages of cancer care. Additional prospective studies are needed to examine specific MHDs and different types of SUDs beyond alcohol use, improving cancer care and the effectiveness of HCU in this vulnerable population.

OBJECTIVES/OBJECTIVE:To develop and validate an algorithm to predict occult nodal metastasis in clinically node negative oral cavity squamous cell carcinoma (OCSCC) using machine learning. To compare algorithm performance to a model based on tumor depth of invasion (DOI). MATERIALS AND METHODS/METHODS:Patients who underwent primary tumor extirpation and elective neck dissection from 2007 to 2013 for clinical T1-2N0 OCSCC were identified from the National Cancer Database (NCDB). Multiple machine learning algorithms were developed to predict pathologic nodal metastasis using clinicopathologic data from 782 patients.The algorithm was internally validated using test data from 654 patients in NCDB and was then externally validated using data from 71 patients treated at a single academic institution. Performance was measured using area under the receiver operating characteristic (ROC) curve (AUC). Machine learning and DOI model performance were compared using Delong's test for two correlated ROC curves. RESULTS:The best classification performance was achieved with a decision forest algorithm (AUC = 0.840). When applied to the single-institution data, the predictive performance of machine learning exceeded that of the DOI model (AUC = 0.657, p = 0.007). Compared to the DOI model, machine learning reduced the number of neck dissections recommended while simultaneously improving sensitivity and specificity. CONCLUSION/CONCLUSIONS:Machine learning improves prediction of pathologic nodal metastasis in patients with clinical T1-2N0 OCSCC compared to methods based on DOI. Improved predictive algorithms are needed to ensure that patients with occult nodal disease are adequately treated while avoiding the cost and morbidity of neck dissection in patients without pathologic nodal disease.

BACKGROUND:The impact of middle turbinate resection (MTR) on olfaction remains a point of debate in the current literature. Few studies have objectively evaluated olfactory cleft airflow following MTR; thus, the mechanism by which MTR may impact olfaction is poorly understood. It is not known whether the postsurgical changes in airway volume, flow, and resistance increase odorant transport or disrupt the patterns of normal airflow. Computational fluid dynamics can be used to study the nasal airway and predict responses to surgical intervention. OBJECTIVE:To evaluate the functional impact of MTR on nasal airflow, resistance, and olfaction. METHODS:Five maxillofacial computed tomography scans of patients without signs of significant sinusitis or nasal polyposis were used. Control models for each patient were compared to their corresponding model after virtual total MTR. For each model, nasal airway volume, nasal resistance, and air flow rate were determined. Odorant transport of 3 different odorants in the nasal cavity was simulated based on the computed steady airflow field. RESULTS:Total airflow significantly increased following bilateral MTR in all patient models ( P < .05). Consistent with our airflow results, we found a decrease in nasal resistance following MTR. MTR significantly increased area averaged flux to the olfactory cleft when compared to controls for phenylethyl alcohol (high-sorptive odorant). Results for carvone (medium sorptive) were similarly elevated. MTR impact on limonene, a low flux odorant, was equivocal. CONCLUSION/CONCLUSIONS:MTR increases nasal airflow while decreasing the nasal resistance. Overall, olfactory flux increased for high sorptive (phenylethyl alcohol) and medium sorpitve (l-carvone) odorants. However, the significant variation observed in one of our models suggests that the effects of MTR on the nasal airflow and the resultant olfaction can vary between individuals based on individual anatomic differences.

The Mongolian gerbil (Meriones unguiculatus) is a member of the rodent family that displays several features not found in mice or rats, including sensory specializations and social patterns more similar to those in humans. These features have made gerbils a valuable animal for research studies of auditory and visual processing, brain development, learning and memory, and neurological disorders. Here, we report the whole gerbil annotated genome sequence, and identify important similarities and differences to the human and mouse genomes. We further analyze the chromosomal structure of eight genes with high relevance for controlling neural signaling and demonstrate a high degree of homology between these genes in mouse and gerbil. This homology increases the likelihood that individual genes can be rapidly identified in gerbil and used for genetic manipulations. The availability of the gerbil genome provides a foundation for advancing our knowledge towards understanding evolution, behavior and neural function in mammals.

OBJECTIVES/OBJECTIVE: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/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/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.

Understanding the cellular interactions during oral carcinogenesis has the potential to identify novel prognostic and therapeutic targets. This study aimed at investigating the cancer stem cell (CSC)-fibroblast niche interactions using in-vitro dysplastic cell line models developed from different stages of 4NQO-induced oral carcinogenic mice model. The spontaneously transformed epithelial cells (DysMSCTR6, 14 and 16) were developed from three time points (mild/moderate/severe), while two fibroblast cell lines (FibroMSCTR12, 16) were developed from moderate and severe dysplastic tissue. The epithelial (Epcam+/Ck+) and the fibroblast cell lines (Vimentin+/α-SMA+/Ck-) were authenticated and assessment of cells representing progressive grades of dysplastic severity indicated a significant increase in dysplastic marker profile (P < 0.05). Evaluation of the CSC characteristics showed that an increase in expression of Cd133, Cd44, Aldh1a1, Notch1, and Sox2 was accompanied by an increase in migratory (P > 0.05) and colony formation capacity (P > 0.005). Targeting Notch1 (GSI inhibitor PZ0187; 30 μM), showed a significant reduction in cell proliferation capacity (P < 0.05) and in the dysplastic marker profile. Further, Notch1 inhibition resulted in down regulation of Cd133 and Aldh1a 1 (P < 0.05) and a complete abrogation of colony formation ability (P < 0.0001). The effect of niche interactions evaluated using FibroMSCTR12-conditioned media studies, revealed an enrichment of ALDH1A1+ cells (P < 0.05), induction of spheroid formation ability (P < 0.0001) and increased proliferation capacity (3.7 fold; P < 0.005). Although PZ0187 reduced cell viability by ∼40%, was unable to abrogate the conditioned-media induced increase in proliferation capacity completely. This study reports a Notch-1 dependent enrichment of CSC properties during dysplastic progression and a Notch-1 independent dysplastic cell-fibroblast interaction during oral carcinogenesis.

PURPOSE/OBJECTIVE:Preoperative localization of a parathyroid adenoma is usually obtained by the combination of ultrasound and scintigraphy with technetium-99m methoxyisobutylisonitrile. We evaluated the role of F18-fluorocholine in neck positron emission tomography/magnetic resonance imaging as a novel tool for localizing parathyroid adenomas. METHODS:Patients with primary hyperparathyroidism were recruited from February 2016 to August 2017 and F18-fluorocholine positron emission tomography/magnetic resonance imaging was performed to localize the parathyroid adenoma prior to surgery. We compared sensitivity and accuracy of this modality with ultrasound and technetium-99m methoxyisobutylisonitrile scintigraphy using the verified location of the diseased parathyroid as found in surgery. RESULTS:Nineteen patients were included in our study (15 women and 4 men, mean age 60.5 ± 9.8 years). Positron emission tomography/magnetic resonance imaging precisely localized the pathologic parathyroid gland in 16/19 cases (84.2%) and predicted the diseased side in 19/19 cases (100%). Ultrasound and technetium 99 m methoxyisobutylisonitrile sestamibi scintigraphy predicted the location of the parathyroid adenoma in 16/19 (84.2%) and 14/19 (74%), respectively. In 3/19 patients, positron emission tomography/magnetic resonance imaging localized the parathyroid adenoma where as other modalities failed. Positron emission tomography/magnetic resonance imaging was more accurate when compared to each modality separately (p < 0.001, p = 0.017), however, when comparing the three modalities all together no differences were found (p = 0.506). CONCLUSIONS:Localizing parathyroid adenomas with F18-fluorocholine positron emission tomography/magnetic resonance imaging may be a promising secondary imaging modality.

PURPOSE/OBJECTIVE:Medical error in the United States carries substantial economic and safety costs, which manifest in a large number of malpractice suits filed each year. The aim of this study was to characterize the various sociologic and medical factors that influence malpractice suits occurring from cases of facial trauma. MATERIALS AND METHODS/METHODS:test, and Fisher t test were performed using SPSS. RESULTS:Of the 69 defendants (76.8% men and 23.2% women; age range, 17 to 57 yr), which resulted from 53 claims, 12 (17.4%) involved plastic surgeons and 10 (14.5%) involved emergency physicians. Most complaints consisted of inadequate care that deviated from treatment standards (32 [46.4%]) and delayed diagnosis (24 [34.8%]). Of delayed diagnosis cases, 14 patients had radiographic imaging performed. Geographic location of the claim was statistically significant-the Midwest upheld 40% of complaints (P = .007) and the South dismissed 91.4% (P = .027). CONCLUSIONS:The impact of sociologic factors, including geographic region, informed consent, and cosmesis, and medical factors, such as delayed diagnosis and deviation from standard of care, in facial trauma litigation were found to be incongruent with previous studies describing the medicolegal influences in facial plastic procedures. This analysis provides greater insight to surgical practitioners across subspecialty disciplines regarding the potential legal implications of malpractice.

G protein-coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. Within the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication amongst cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of over one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have revealed that GPCRs are not static binary switches that operate from the plasma membrane to control a defined set of intracellular signals. Rather, GPCRs are dynamic signaling proteins that adopt distinct conformations and subcellular distributions when associated with different ligands and intracellular effectors. An understanding of the dynamic nature of GPCRs has provided insights into the mechanism of activation and signaling of GPCRs, and has revealed opportunities for drug discovery. We review the allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases. We highlight the implications of these concepts for the development of selective and effective drugs to treat diseases of the gastrointestinal tract.

Infertility is known to decrease quality of life among adults. In some cases, infertility is caused by medical conditions and/or treatments prescribed in childhood, and using methods to protect or preserve fertility may expand future reproductive possibilities. Structured programs to offer counseling about infertility risk and fertility preservation options are essential in the care of pediatric patients facing fertility-threatening conditions or treatments, yet multiple barriers to program development exist. This report was developed from the institutional experiences of members of the Pediatric Initiative Network of the Oncofertility Consortium, with the intent of providing guidance for health care providers aiming to establish programs at institutions lacking pediatric fertility preservation services. The mechanics of building a fertility preservation program are discussed, including essential team members, target populations, fertility preservation options (both established and experimental), survivorship issues, research opportunities, and ethical considerations. Common barriers to program development and utilization, including low referral rates and financial concerns, are also discussed, and recommendations made for overcoming such barriers.