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The convergence of the HIV and SARS-CoV-2 pandemics is an emerging field of interest. In this review, we outline the central nervous system (CNS) effects of COVID-19 in the general population and how these effects may manifest in people with HIV (PWH). We discuss the hypothetical mechanisms through which SARS-CoV-2 could impact the CNS during both the acute and recovery phases of infection and the potential selective vulnerability of PWH to these effects as a result of epidemiologic, clinical, and biologic factors. Finally, we define key research questions and considerations for the investigation of CNS sequelae of COVID-19 in PWH.

Objective To compare racial differences in male fertility history and treatment. Design Retrospective review of prospectively collected data. Setting North American reproductive urology centers. Patient(s) Males undergoing urologist fertility evaluation. Intervention(s) None. Main Outcome Measure(s) Demographic and reproductive Andrology Research Consortium data. Result(s) The racial breakdown of 6,462 men was: 51% White, 20% Asian/Indo-Canadian/Indo-American, 6% Black, 1% Indian/Native, Conclusion(s) Racial differences exist for males undergoing fertility evaluation by a reproductive urologist. Better understanding of these differences in history in conjunction with societal and biologic factors can guide personalized care, as well as help to better understand and address disparities in access to fertility evaluation and treatment.

Vascular access planning is critical in the management of patients with advanced kidney disease who elect for hemodialysis for RRT. Policies put in place more than two decades ago attempted to standardize vascular access care around the model of optimal, namely arteriovenous fistula, and least preferred, namely central venous catheter, type of access. This homogenized approach to vascular access care emerged ineffective in the increasingly heterogeneous and complex dialysis population. The most recent vascular access guidelines acknowledge the limitations of standardized care and encourage tailoring vascular access care on the basis of patient and disease characteristics. In this article, we discuss available literature in support of patient-tailored access care on the basis of differences in vascular access outcomes by biologic and social factors—age, sex, and race. Further, we draw attention to the overlooked dimension of patient-reported preferences and shared decision making in the practice of vascular access planning. We discuss milestones to overcome as requisite steps to implement effective shared decision making in vascular access care. Finally, we take into consideration local practice cofactors as major players in vascular access fate. We conclude that a personalized approach to hemodialysis vascular access will require dynamic care specifically relevant to the individual on the basis of biologic factors, fluctuating clinical needs, values, and preferences.

For cancer prediction, the prognostic stage is the main factor that helps medical experts to decide the optimal treatment for a patient. Specialists study prognostic stage information from medical reports, often in an unstructured form, and take a larger review time. The main objective of this study is to suggest a generic clinical decision-unifying staging method to extract the most reliable prognostic stage information of breast cancer from medical records of various health institutions. Additional prognostic elements should be extracted from medical reports to identify the cancer stage for getting an exact measure of cancer and improving care quality. This study has collected 465 pathological and clinical reports of breast cancer sufferers from India's reputed medical institutions. The unstructured records were found distinct from each institute. Anatomic and biologic factors are extracted from medical records using the natural language processing, machine learning and rule-based method for prognostic stage detection. This study has extracted anatomic stage, grade, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) from medical reports with high accuracy and predicted prognostic stage for both regions. The prognostic stage prediction's average accuracy is found 92% and 82% in rural and urban areas, respectively. It was essential to combine biological and anatomical elements under a single prognostic staging method. A generic clinical decision-unifying staging method for prognostic stage detection with great accuracy in various institutions of different regional areas suggests that the proposed research improves the prognosis of breast cancer.

Biologic factors that predict risk for and mediate the development of common outcomes of trauma exposure such as chronic posttraumatic pain (CPTP) are poorly understood. In the current study, we examined whether peritraumatic circulating 17β-estradiol (E2) levels influence CPTP trajectories. 17β-estradiol levels were measured in plasma samples (n = 254) collected in the immediate aftermath of trauma exposure from 3 multiethnic longitudinal cohorts of men and women trauma survivors. Chronic posttraumatic pain severity was evaluated 6 weeks, 6 months, and 1 year after traumatic stress exposure. Repeated measures mixed models were used to test the relationship between peritraumatic E2 levels and prospective CPTP. Secondary analyses in a nested cohort assessed the influence of participant body mass index on the E2-CPTP relationship. In women, a statistically significant inverse relationship between peritraumatic E2 and CPTP was observed (β = -0.280, P = 0.043) such that higher E2 levels predicted lower CPTP severity over time. Secondary analyses identified an E2 * body mass index interaction in men from the motor vehicle collision cohort such that obese men with higher E2 levels were at greater risk of developing CPTP. In nonobese men from the motor vehicle collision cohort and in men from the major thermal burn injury cohort, no statistically significant relationship was identified. In conclusion, peritraumatic circulating E2 levels predict CPTP vulnerability in women trauma survivors. In addition, these data suggest that peritraumatic administration of E2 might improve CPTP outcomes for women; further research is needed to test this possibility.

Immediately after the removal of orthodontic appliances, the teeth might start to drift away from their corrected position in an attempt to reach a new equilibrium. Medications and biologic factors could potentially modulate these processes. The objective of the present systematic review is to systematically investigate and appraise the quality of the evidence regarding the effect of various medications and biologic factors on the rate of relapse following active tooth movement. Search without restrictions in eight databases and hand searching until April 2020 were conducted. Studies performed on animal models investigating the effects of medication and biologic factors on the rate of relapse following orthodontic tooth movement were considered. Following study retrieval and selection, relevant data were extracted and the risk of bias was assessed. Seventeen studies were finally identified, mostly at either high or unclear risk of bias. Ketorolac did not show any significant effects on relapse, while the administration of tetracycline, atorvastatin, psoralen and raloxifene decreased it. Overall, the same result was observed with bisphosphonates with the exception of low dosage of risedronate, which did not have an effect. Osteoprotegerin and strontium resulted in reduced relapse, but not in the immediate post-administration period. Inconsistent or conflicting effects were noted after the use of simvastatin and relaxin. The quality of the available evidence was considered at best as low. It can be concluded that specific medications and biologic factors may have an effect on the rate of relapse following tooth movement. The orthodontist should be knowledgeable about the substances potentially affecting retention.

Background: Isolated bulbar amyotrophic lateral sclerosis (IBALS) is a regional variant of amyotrophic lateral sclerosis (ALS) with weakness restricted to the bulbar muscles for at least 2 years, and slower progression than generalized ALS. Bulbar-onset generalized ALS, by contrast, typically has a more rapid progression than limb-onset ALS.Objective: To characterize patients with IBALS and compare them to patients with isolated bulbar disease at presentation who progress to generalized ALS.Methods: We performed a retrospective chart review of patients seen in our ALS specialty clinic at the University of Kansas Medical Center between 2001-2011. Results: Of 543 patients seen in the ALS clinic, 150 presented with bulbar symptoms at disease onset: 28 (18.7%) had bulbar signs and no evidence of extremity involvement on exam or electrodiagnostic testing at their initial visit; and 14 (9.3%) had weakness restricted to the bulbar muscles after 2 years of follow up (IBALS). IBALS patients were 57.1% male, with a mean age of symptom onset of 60.8 years (range 39-77 years). The mean disease duration was 3.1 years (range of 2-8 years), with 50% mortality at a mean follow up of 3.5 years. Minimal denervation changes were seen in at least one limb in 6 subjects (42.9%). Other clinical features included: 4 subjects (28.6%) had cognitive impairment, 4 (28.6%) had pseudo-bulbar affect, and 5 subjects (35.7%) had impaired eye movements on smooth pursuit.Conclusion: Isolatred bulbar ALS IBALS is an identifiable restricted regional ALS pattern if there is no clinical limb weakness 2 years after symptom onset. It may have a slower progression from typical ALS. The biologic factors that account for the IBALS restricted pattern are unknown.

The American Joint Committee on Cancer (AJCC) breast cancer pathological prognostic stage, which incorporates biologic factors, was developed using data from patients undergoing upfront surgery, and its application in patients receiving neoadjuvant chemotherapy (NAC) is unknown. We previously developed the Neo-Bioscore, incorporating clinical and pathological TNM categories with biologic factors, to improve the prognostic stratification of NAC patients. This study was undertaken to evaluate the use of available staging models incorporating biologic factors in NAC patients. Patients treated with NAC between 2005 and 2012 at MD Anderson (n = 2363) were staged using the Neo-Bioscore and the AJCC 8th edition: (1) clinical anatomic stage; (2) pathological anatomic stage; (3) clinical prognostic stage; and (4) pathological prognostic stage. Five-year disease-specific survival (DSS) and overall survival (OS) rates, along with Harrell’s concordance index (C-index), were estimated. A National Cancer Database (NCDB) cohort (n = 12,887) treated with NAC between 2010 and 2013 was used for validation. In the MD Anderson cohort, staging systems incorporating biologic factors better predicted DSS (bias-corrected C-index: pathological prognostic stage = 0.8026; Neo-Bioscore = 0.7483) and OS (bias-corrected C-index: pathological prognostic stage = 0.7780; Neo-Bioscore = 0.7260) than those using anatomic factors only. Similar results were seen in the NCDB cohort. In pairwise comparisons, the pathological prognostic stage was significantly better (p

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. Appropriate treatment of this aggressive and heterogeneous cancer requires accurate staging and prognostic stratification, as does patient selection for clinical trials. Over the past two decades, several staging systems and prognostic models for ICC have been developed. Most include independent prognostic factors such as tumor extent, clinical parameters and histopathological features and are inaccurate. Accumulating findings offer new insights into the genetic and molecular basis of ICC progression. Hence, staging systems and prognostic models that incorporate in clinicalpathological factors, molecular and genomic information, and tumor biomarkers, and hence more accurately estimate prognosis, will become a reality. This review summarizes the current staging systems and prognostic models for ICC and highlights the need to establish more precise and personalized systems and models that incorporate tumor biologic factors.

The authors analyzed pathogenetic, clinical and epidemiologic features of occupational kidney disorders due to physical and biologic factors, and problems of diagnosis and prevention. The review presented covers national and foreign literature data on occupational diseases of kidneys and urinary tract due to contact with various occupational factors.

Introduction The objective of this study was to observe the patterns of usage, efficacy, and safety of tocilizumab (TCZ) in clinical practice in patients with rheumatoid arthritis. Methods Data on the real-world usage, efficacy, and safety of TCZ were collected from patients during routine follow-up visits conducted over a 6-month period. Patients were grouped by previous exposure to biologic therapies (biologic exposed vs. biologic naive). Results Of 1912 patients enrolled from 16 countries, 639 (33.4%) received TCZ monotherapy and 1273 (66.6%) received TCZ combination therapy. At baseline, 1073 patients (56.1%) were biologic naive and 839 (43.9%) were biologic exposed. At 6 months, 1504 patients (78.7%) continued to receive TCZ treatment, with no descriptive differences in retention rates between biologic-exposed and biologic-naive patients and between patients receiving TCZ monotherapy or combination therapy. Dose and use of methotrexate and prednisone were reduced at 6 months. Efficacy at 6 months, including patient-reported outcomes, was demonstrated in both biologic-naive and biologic-exposed groups. Adverse events (AEs) occurred in 817 patients [42.7%; incidence rate: 179 events per 100 patient-years (PY)], and serious AEs (SAEs) occurred in 118 patients (6.2%; 17 events per 100 PY), with comparable rates of AEs and SAEs between subgroups. Conclusion In routine clinical practice, TCZ discontinuation rates were low and unaffected by prior use of biologics. Effectiveness was similar between groups, and no new safety signals were identified. Funding F. Hoffmann-La Roche. Electronic supplementary material The online version of this article (10.1007/s40744-019-0150-x) contains supplementary material, which is available to authorized users.

Introduction: Cancer staging has historically been based solely on the anatomic extent of the tumor (T), spread to lymph nodes (N), and the presence of distant metastases (M). More recently biologic factors have been added to modify TNM stage groups to provide more accurate prognosis for patients.Areas covered: The American Joint Committee on Cancer (AJCC) updated breast cancer staging in 2016 to include T, N, M, tumor grade and expression of estrogen and progesterone receptors and HER2. Addition of these factors changed the stage group for a large fraction of cases compared to prior TNM stage groupings. This updated ‘prognostic stage’ provides more robust and precise prognosis information.Expert opinion: Inclusion of biological information in staging changes the meaning and the use of stage in clinical practice. This paper reviews the evidence supporting these changes, limitations affecting staging, and discusses the implications for clinical practice and the future of breast cancer staging.

Background: The American Joint Committee for Cancer (AJCC) 8th edition cancer staging system for breast cancer incorporated biologic factors in addition to the 7th edition anatomic stage. We analyzed how the new AJCC 8th edition prognostic stage refined its stratification compared with the anatomic stage. Methods: We reviewed the data of 4,134 patients with stage I to III breast cancer who underwent surgery at Tokyo Metropolitan Komagome Hospital between 2000 and 2016. The anatomic stage and prognostic stage were re-staged according to the AJCC 8th edition staging manual. Patients who received neoadjuvant chemotherapy or had bilateral breast cancer and those with unknown clinicopathologic factors were excluded. The 21-gene Oncotype DX breast recurrence score was not used for staging in this study. Results: A total of 2,469 patients with a median follow-up of 4.7 years (range 0.1-15.5 years) were identified. According to the anatomic stage, there were 1,259 patients of stage IA, 132 of IB, 591 of IIA, 206 of IIB, 130 of IIIA, 14 of IIIB and 73 of IIIC. According to the prognostic stage, there were 1,610 patients of stage IA, 331 of IB, 236 of IIA, 73 of IIB, 85 of IIIA, 43 of IIIB and 27 of IIIC. Sixty-four patients (2.6%) could not be assigned using the new staging system for the presence of micrometastases in lymph nodes with tumors larger than 2 cm. The 5-year disease-free survival (DFS) rates according to the anatomic stage were 97.4% for stage IA, 97.1% for IB, 95.8% for IIA, 86.5% for IIB, 77.9% for IIIA, 49.2% for IIIB and 54.9% for IIIC. According to the prognostic stage, the 5-year DFS rates were 97.9% for stage IA, 92.9% for IB, 91.2% for IIA, 79.8% for IIB, 67.4% for IIIA, 53.3% for IIIB and 38.7% for IIIC. Compared with the AJCC anatomic stage, the prognostic stage was increased in 148 patients (6.2%) and decreased in 808 patients (32.8%). For those in whom the stage changed, the change was by one stage up or down in 463 (19.3%), by 2 stages up or down in 401 (16.7%) and by 3 stages up or down in 92 (3.8%). Of the 1,842 patients with hormone receptor (HR)-positive and human epidermal growth factor 2 (HER2)-negative (HR+/HER2-) disease, 40.5% (745/1842) of cases were downstaged, and 0.7% (1/1842) were upstaged. Discussion: The AJCC 8th edition prognostic staging system provided more refined stratification than the anatomic stage. In the Japanese cohort, the proportion of the downstaging rate was higher than the upstaging rate, and the prognostic evaluation of HR+ patients in particular was improved. Citation Format: Miyamoto H, Saita C, Onishi M, Goto R, Iwamoto N, Honda Y, Aruga T. Validation of the AJCC eighth edition prognostic stage compared with the anatomic stage for breast cancer with a Japanese single-institutional cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-16.

Instrumented fixation and fusion of the thoracic spine present distinct challenges and complications including pseudarthrosis and junctional kyphosis. When complications arise, morbidity to the patient can be significant, involving neurologic injury, failure of instrumentation constructs, as well as iatrogenic spinal deformity. Causes of fusion failure are multifactorial, and incompletely understood. Most likely, a diverse set of biomechanical and biologic factors are at the heart of failures. Revision surgery for thoracic fusion failures is complex and often requires revision or extension of instrumentation, and frequently necessitates complex soft tissue manipulation to manage index level injury or to augment the changes of fusion.

Donor race should not be used in models to predict allograft and patient survival. Removing donor race from the Kidney Donor Risk Index may reduce kidney discard by reclassifying approximately 50% of high kidney donor profile index kidneys. Future prediction models should focus on using relevant biologic factors rather than social constructs when trying to predict outcomes.

The hallmark of precision medicine involves tailoring the treatment to the patient and/or tumor-specific biomarkers. Candidate biomarkers in bladder cancer are abundant, but few have been validated in clinical practice. Significant obstacles to precision medicine in bladder cancer include the limited predictive value of candidate biomarkers, lack of standardization in biomarker assessment, heterogeneity in biomarker expression and function, and limited insight into the biologic factors that influence biomarker expression and predictive capacity. This review summarizes key biomarkers explored in bladder cancer and outlines innovative trial designs to approach these obstacles.

Women continue to be underrepresented in cardiovascular studies, while heart disease remains a major cause of mortality and morbidity in women as in men. In this review, we explore the differences in presentation, characteristics, and treatment of women presenting for coronary intervention for stable coronary disease or acute coronary syndromes. Recent, large meta-analyses of clinical trials have shown that the sex differences in outcomes after non-ST-elevation acute coronary syndrome are attenuated after thorough adjustment for baseline comorbidities, but worse outcomes and more complications are still seen in women after percutaneous coronary intervention. Young women presenting for coronary angiogram are particularly at risk. Biologic factors, differences in presentation, and care disparities all contribute to worse outcomes after MI and PCI in women compared to men; both health behaviors and healthcare system behaviors should and can be modified to improve morbidity and survival in women with heart disease.

Contains fulltext : 235822.pdf (Publisher’s version ) (Open Access) Auto-aggressive behaviour, especially treatment refractory suicidality in adolescents with psychiatric disorders, may be challenging to clinicians. In search of therapeutic possibilities, we have integrated current opinions regarding causality and interdependency of suicidality and auto-aggressive behaviour across disorders within the HiTOP framework. We propose a developmental model regarding these unsettling behaviours in youths that may help to guide future directions for research and interventions. We argue that the interdependent development of biologic factors, attachment, moral reasoning and emotion regulation in an overprotective environment may lead to social anxiety and later during development to emotion dysregulation and severe internalizing behaviour disorders. To optimize treatment efficacy for both internalizing and externalizing behaviour, we emphasize the importance transdiagnostic interventions, such as addressing non-compliance, restoration of trust between parents and their child, and limitation of avoidance behaviour. These may be seen as higher order interventions within the HiTOP framework.

The date of acute lymphoblastic leukemia (ALL) diagnosis has been studied regarding potential etiologic roles with contrasting results and the issue remains controversial. The principal aim of this study was to analyze monthly variation of ALL diagnosis in a large homogenous Hispanic Latin American cohort over 15 years; its association with survival rates was also assessed.Clinical files and electronic records of 501 consecutive patients of all ages with ALL in northeastern Mexico over the years of 2004-2018 were scrutinized. Patients were divided into children ≤18 and adults18 years. The Chi-square heterogeneity analysis was used to test for non-uniform variation. The Poisson regression analysis was used to fit sinusoidal (harmonic) models to the data, using the month of diagnosis as a covariate in a separate model.During the study period 363 children (72.5%) and 138 adults (27.5%) (p 0.001) were diagnosed with ALL. Heterogeneity across the months of diagnosis was confirmed (p = 0.019) and the Poisson regression analysis confirmed a significant monthly variation (p 0.001) (95% CI, 3.024-3.745), a higher annual peak being observed in the month of March (p = 0.002), followed by a second peak in October (p = 0.026). The five-year OS for children was 68.2% (95% CI, 67.64-68.74) and for adults, 43.7% (95% CI, 42.67-44.71) (p 0.001). No significant association between the month of diagnosis and OS was found (p = 0.789).The monthly variation of ALL diagnosis was documented; these results confirm the heterogeneous behavior of the disease and appear to be consistent with an interplay of environmental and biologic factors. Further studies are needed to examine putative candidate agents.

Drug- and toxin-induced pulmonary arterial hypertension (PAH) is an increasingly important sub-group of group 1 pulmonary hypertension (PH). In the last 60 years, we have seen the rise and fall of numerous prescription and illicit agents that have caused severe and deadly outbreaks of PAH. Currently, drugs and toxins are classified into “possible” and “definite” risk factors for PAH. While the exact mechanisms and pathogenesis of drug- and toxin-induced PAH are currently unknown, novel clinical and basic science studies are beginning to unravel the biologic factors and genetic underpinnings responsible for disease development. The clinical management of affected patients can be challenging as it is often difficult to identify patients early and demonstrate causality between drugs and PAH. Given the recent trends in drug utilization and development, it is highly likely that we will continue to identify new agents capable of causing pulmonary vascular disease. We must keep a high index of suspicion in order to identify patients and new compounds deemed definite or likely risk factors for PAH. Practicing pharmacovigilance, raising awareness, and working in tandem with PH patient associations and drug regulatory agencies may ultimately be our most effective strategy in preventing the next deadly outbreak of drug- and toxin-induced PAH.

Importance The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease. Observations The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or of neural tissue to support a diagnosis of definite neurosarcoidosis. Conclusions and Relevance Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue examination. The diagnostic criteria we propose are designed to focus investigations on NS as accurately as possible, recognizing that multiple pathophysiologic pathways may lead to the clinical manifestations we currently term NS. Research recognizing the clinical heterogeneity of this diagnosis may open the door to identifying meaningful biologic factors that may ultimately contribute to better treatments.

The American Joint Committee on Cancer staging system has evolved in response to improved imaging, refined surgical techniques, enhanced pathologic evaluation, and greater understanding of tumor biology. The 8th edition has introduced clinical and pathologic prognostic stages for breast cancer that incorporate biologic variables (grade, estrogen/progesterone receptor status, HER2 status, multigene panels) with TNM categories that define the anatomic stage. The prognostic staging system facilitates more refined stratification than the anatomic stage with respect to survival and is an important advance that maintains the clinical relevance of the staging system by taking into account tumor biology and current treatment algorithms.

Histologic subtype, receptor status, and other biologic factors greatly affect the avidity of breast malignancy on fluorodeoxyglucose (FDG) PET. FDG PET/computed tomography (CT) has demonstrated excellent value in the evaluation of extra-axillary nodal and distant metastases. Patients with early-stage breast cancers do not benefit from FDG PET/CT; however, unsuspected distant metastases may be revealed by systemic staging of locally advanced breast cancers by FDG PET/CT, and this has substantial impact on patient management. FDG PET/CT has demonstrated value in the evaluation of treatment response and in detection of disease recurrence.

Hematopoietic cell transplantation is an important treatment option for malignant and non-malignant hematologic diseases. Despite increasing the potential donor pool for hematopoietic cell transplantation there are many patients who are unable to access this treatment. There are several biologic and non-biologic factors that may explain lower utilization of transplantation. Biologic factors associated with lower utilization include older age, multiple comorbidities, persons of African American descent and high-risk disease that may not respond optimally to hematopoietic cell transplantation. Non-biologic factors associated with lower utilization include lower educational (without a high school diploma) or social status, uninsured, Medicaid or Medicare insurance and in persons aged ≥60 years, when the distance between their residence and hospital was greater than 37 miles. The decision to proceed to hematopoietic cell transplantation is a dialogue between the patient and the treating physician. While some patients may be considered poor candidates for continued treatment including hematopoietic cell transplantation others may be offered novel pharmacologic and cellular therapies with a capacity to deliver specific immunologic antitumor responses. Pharmacologic and cellular therapies are relatively recent, and it is not known whether the biologic and non-biologic factors that limit access to transplantation will limit access to these newer treatments.

Mesenchymal stem cells (MSCs) are self-renewing multipotent cells that have the capacity to secrete multiple biologic factors that can restore and repair injured tissues. Preclinical and clinical evidence have substantiated the therapeutic benefit of MSCs in various medical conditions. Currently, MSCs are the most commonly used cell-based therapy in clinical trials because of their regenerative effects, ease of isolation and low immunogenicity. Experimental and clinical studies have provided promising results using MSCs to treat diabetes. This review will summarize the role of MSCs on tissue repair, provide emerging strategies to improve MSC function and describe how these processes translate to clinical treatments for diabetes.

Neoadjuvant chemoradiation has been a standard of care for locally advanced rectal cancers. Recent reports suggest that a pathologic complete response to neoadjuvant treatment correlates to improved overall survival. In addition, some series suggest that patients who have a complete response to neoadjuvant therapy may safely defer surgery in favor of a “watch and wait” approach, therefore avoiding the potential complications and adverse bowel function associated with surgery. It is therefore important to understand the clinical and biologic factors which affect the response of rectal cancers to chemoradiation. This review highlights the current literature examining the biomarkers of tumor response to chemoradiation.

Background: The current breast cancer staging system, based on anatomy, does not always reflect the variable clinical course outcomes seen in the clinic. Other important and known determinants of prognosis and survival in breast cancer are age, grade, and receptor subtypes. In this analysis, we sought to demonstrate that these additional factors were important determinants of breast cancer specific and overall survival with an intention to propose a new staging classification. Methods: Through a prospectively maintained electronic database at the University of Texas MD Anderson Cancer Center, we identified patients with newly diagnosed invasive breast cancer, stage I-IV, who received surgery as an initial treatment from 1997 to 2014. Data points for the earliest invasive breast cancer event were recorded: age, pathologic stage (7th edition AJCC), grade, ER status, PR status, HER2-neu status, adjuvant treatment history, and outcomes (breast cancer-specific survival [BCSS] and overall survival [OS]). Cox proportional hazards model was used for the statistical analysis. Results: Of 22,131 patients, 99% were women in the following age groups (median age at surgery, 53 years [range, 16-98 years]): age < 40 (13%), 40-69 (76%), >70 (11%). Pathologic stages were: I: 50%, II: 39%, III: 9% and IV: 2%; 768 (3.5%) patients had bilateral breast cancer. Biological subtypes were as follows: Triple-negative (TN): 6%, Hormone receptor-positive/HER2-negative (HR+/HER2-): 70%, HER2-positive (HER2+): 24% (HR+, 9%; HR- 15%). Median follow-up was 7.9 years (95% CI, 7.8-8.0). In multivariate Cox regression modeling, age, grade, and clinical biomarker-based subtypes were significantly associated with breast cancer specific survival (BCSS). Table 1. Breast cancer specific-survival: Multivariate modelCovariateLevelHR95% CI (p value)Overall p valueAge at DiagnosisLess than 401.521.37-1.68 ( Conclusion: More individualized prediction of outcomes for breast cancer is possible by considering clinical and biologic characteristics in addition to anatomic stage. We intend to integrate pathologic stage, age, and biologic factors into a novel prognostic model to propose a new staging classification for breast cancer. Citation Format: Murthy RK, Song J, Raghavendra AS, Li Y, Hsu L, Barcenas CH, Tripathy D, Berry D, Hortobagyi GN. Proposal for a new breast cancer staging classification: Incorporating clinical and biologic factors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-35.

There are many biologic factors that may influence the adverse effect of a drug, chemical, or substance in mammalian organisms. This chapter describes the basic concepts of protein receptors and chemical interactions and the possible adverse biological consequences of these interactions. Chemical absorption, translocation, and elimination, and extracellular, cellular, and subcellular compartmentalization of substances is explained and illustrated. Basic concepts of chemical bioaccumulation and storage are presented, in addition to the phenomenon of chemical/drug tolerance and organ functional reserve capacity following tissue injury in mammalian organisms.

402 Background:: Men have higher rates of bladder cancer and are more likely to undergo cystectomy than women, yet women seem to have worse oncologic outcomes. This is attributed to biologic factors including adverse histologic variants and social factors including delay in diagnosis. There is early evidence that women also have worse surgical outcomes. We further examined the role of gender in 30-day perioperative outcomes following radical cystectomies in a national cohort. Methods: We examined the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) from 2012 to 2016. The database was searched for CPT codes reflecting radical cystectomy and a diagnosis of “cancer of the bladder.” Frailty was estimated by the modified frailty index (functional status, diabetes, chronic obstructive pulmonary disorder, history of chronic heart failure, and hypertension requiring medication.) To compare demographic and perioperative characteristics between genders, Chi-Square analyses were performed for categorical variables, student’s t test to compare averages, and the Wilcoxon rank sum test for operative time and length of stay (LOS). Results: 4,681 radical cystectomies were identified including 842 (18.0%) females. Of the female cohort, average age was 68.6 (+/-11.2 years), 77.3% was Caucasian and 278 (33%) had a BMI of at least 30. There were no differences appreciated between genders with regards to age, average ASA score, frailty, or minimally-invasive approach (all p=NS). Compared to males, female gender was associated with longer operative time (350 vs. 336 min, p

The retromolar-oropharynx junction cancer is a rare malignancy situated at the border between the oral cavity and the oropharynx. There is an important number of factors involved in the ethiology, pathogenesis and evolution of patients with this kind of lesions. We performed a prospective study involving 50 patients with this type of cancer, hospitalized between 20132015 in the Otorhinolaryngology and Maxillofacial Departments of the Sf. Spiridon Emergency Hospital, Iasi, Romania, to identify the environmental and biologic factors that may be involved in the damaged tissues. The purpose of our study is to appraise and validate the significance of the risk factors involved in the occurrence of deglutition and swallowing troubles, to achieve a treatment protocol for this kind of patients.

Dentistry, like various branches in the healthcare profession, is susceptible to overtreatment, especially in the management of dental caries, due to the adoption of an aggressive restorative approach. This philosophy provides no actual benefits to the patient in terms of arresting the disease process, which initially led to the carious lesions. Yet practitioners routinely continue to initiate restorative treatment procedures without attempting to understand and alter the biologic factors contributing to the caries process. This paper examines the available scientific literature in this regard and makes recommendations to the clinicians of today based on the available evidence. CPD/Clinical Relevance: The paper provides clinicians an approach to avoiding overtreatment by adhering to established clinical guidelines and accepted operative strategies.

Purpose The prognosis of young colorectal cancer (CRC) patients has not fully been addressed. The prognostic significance of systemic inflammatory markers was examined in those patients. Methods A total of 965 patients with resectable CRC were divided into young (≤ 50 years, n = 101) and old groups (> 51 years, n = 864). Neutrophil-to-lymphocyte ratio (NLR) > 5, derived NLR (dNLR) > 3, lymphocyte-to-monocyte ratio (LMR) < 2, platelet-to-lymphocyte ratio (PLR) > 150, and prognostic nutritional index (PNI) < 45 were analyzed for prognosis. Overall survival (OS) and progression-free survival (PFS) were compared using the log-rank test. A multivariate analysis was performed using a Cox proportional hazards regression model. Results In the young group, NLR > 5, LMR < 2, and PNI < 45 were significantly associated with OS with univariate analyses. dNLR > 3 and those markers showed significance for PFS. LMR < 2 was a significant marker for poor PFS (hazard ratio [HR], 5.81; P = 0.020) in the multivariate analysis. In the old group, all inflammatory markers were significantly associated with OS and PFS with univariate analyses. LMR < 2 (HR, 2.66; P = 0.016) and PNI < 45 (HR, 2.14; P = 0.016) were independently associated with OS in multivariate analyses. PLR > 150 (HR, 1.45; P = 0.036) and PNI < 45 (HR, 1.73; P = 0.002) were significant markers for PFS. Conclusion Systemic inflammation might be one of biologic factors that influence on prognosis of young CRC.

Noninvasive circulating tumor DNA (ctDNA) assays have the potential to revolutionize clinical trial design; however, challenges still remain in using ctDNA for the molecular profiling of cancer with next-generation sequencing (NGS). Our previous work has defined some of the technical and biologic factors that contribute to these challenges, in particular for variants below 1% allele frequency (AF). To continue to examine these factors, we have designed a study to investigate tumor-plasma discordant variants reported from commercial vendors with an orthogonal ultrasensitive NGS assay focusing primarily on false positive variant calls. The study used 24 commercially purchased matched FFPE tumor-plasma samples from breast, prostate, lung, and ovarian cancer. The FFPE tumor-normal pairs were sent to Foundation Medicine (FMI) for sequencing, while replicate sets of plasma were shipped to three commercial vendors for ctDNA sequencing using the currently available panel at the time of shipment. An additional set of samples, which included tumor, normal, and plasma samples, was sent to a fourth vendor for ultrasensitive NGS assay design and sequencing. The returned variants from three commercial vendors were compared to the tissue variants to define truth. True positive variants were defined as an alteration in the plasma that matches either the tissue or another vendors plasma result, while a false positive is a reported variant identified by only one vendor. The comparative analysis identified that Vendor A had the highest sensitivity at 87%, while Vendor B had the highest PPV at 91%. It should be noted that Vendor B had the smallest targeted panel. Vendors A and C contributed the majority of reported false positive variants with Vendor B only having two false positive variants. A total of 54 false positive variant calls were identified, collated along with several driver mutations and germline SNPs, and sent to Vendor D in a blinded fashion for assay design and sequencing. The orthogonal NGS data returned from Vendor D found that two false positive variants had read support to be tissue false negatives. The tissue AF of both variants was found to be just below the standard cutoff for FMI of 5% AF. Both variants were from Vendor A, which improved the sensitivity of Vendor A to 88%. The additional false positive calls from Vendor A were found in the plasma only, with no supporting evidence in the tissue. Vendor B’s false positive calls had no support from the orthogonal assay in either plasma or tissue. Vendor C had variants that had no support in either the tissue or plasma and variants that have support in the plasma. Overall, the false positive variants tested with the ultrasensitive NGS assay could be grouped into three general categories: variant was not found in either the tissue or plasma, variant was found in only the plasma, and variant had support in both the tissue and plasma. The false positive variants found in plasma or in both tissue and plasma may represent true positive variants and need to be investigated further. Citation Format: Daniel Stetson, Ambar Ahmed, Barrett Nuttall, Tristan Lubinski, J. Carl Barrett, Brian Dougherty. Examination of ctDNA false positive variants reported from commercial vendors by ultrasensitive orthogonal testing [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A63.

e12576 Background: Breast cancer is classified into three prognostic groups based on the following biologic factors: estrogen-receptor (ER) status, progesterone-receptor (PR) status, and nuclear grade (NG). According to this classification, we determined the biological behavior in order to understand if a small breast cancer is biologically more favorable than a large one (T1-2 breast cancers). Methods: The inclusion criteria for this study were (1) presence of T1-2 breast cancer measurable by magnetic resonance imaging (MRI) or ultrasound(US), and (2) availability for determination of ER, PR, and NG histological status. Inflammatory breast cancer, male breast cancer, tumors of unknown size on MRI or US, and complications due to other cancers were excluded from this study. From April 2007 to December 2019, 1173 patients with surgically proven breast cancer presented at National Hospital Organization Nagasaki Medical Center, and 1080 patients were retrospectively analyzed. The favorable (F), intermediate (I), and unfavorable (UF) groups were defined as follows. F: NG1 (ER+PR+, ER+PR-, ER-PR+), UF: NG2 (ER-PR-) or NG3 (ER-PR-, ER+PR-, ER-PR+). IF: all other types of F and UF. Overall survival (OS) was calculated using the Kaplan-Meier method. All statistical analyses were performed using JMP 9.0.2, and probability values of

Rotator cuff tears are common problems among middle age and older adults that can result in significant morbidity. While many patients do well after rotator cuff repair, there is still a high percentage of patients with recurrent tearing of their rotator cuff. There is great interest in the use of biologic augmentation of rotator cuff repairs to improve tendon healing and encourage a more native-like tendon-to-bone attachment after repair. In vitro studies have shown promise, with results demonstrating significant improvement in strength and collagen orientation with the use of platelet-rich plasma (PRP) and stem cells, as well as matrix metalloproteinases (MMP) modulating antibiotics. However, in vivo studies still struggle to show significant benefits in the biomechanical properties, patient functionality, or clinical outcomes. More research is needed to better understand these biologic factors to optimize healing results.

Background Physiological bone formation and bone regeneration occurring during bone repair can be considered distinct but similar processes. Mesenchymal stem cells (MSC) and associated biologic factors are crucial to both bone formation and bone regeneration. Aim To perform a narrative review of the current literature regarding the role of MSC and biologic factors in bone formation with the aim of discussing the clinical relevance of in vitro and in vivo animal studies. Methods The literature was searched for studies on MSC and biologic factors associated with the formation of bone in the mandible and maxilla. The search specifically targeted studies on key aspects of how stem cells and biologic factors are important in bone formation and how this might be relevant to bone regeneration. The results are summarized in a narrative review format. Results Different types of MSC and many biologic factors are associated with bone formation in the maxilla and mandible. Conclusion Bone formation and regeneration involve very complex and highly regulated cellular and molecular processes. By studying these processes, new clinical opportunities will arise for therapeutic bone regenerative treatments.

Objective: Biologic factors and adjunctive therapies are known to affect the degree of orthodontically induced inflammatory root resorption (OIIRR). However, a systematic overall assessment of their impact on OIIRR has not previously been reported. We, therefore, aimed to systematically assess effects on OIIRR of biologic factors and adjunctive therapies in human and animal subjects. Methods: A comprehensive search strategy was performed for all major electronic databases. Two reviewers independently selected studies, undertook data extraction and assessed the risk of bias for all included studies according to a pre-specified protocol inspired by Cochrane and the PRISMA guidelines. Eligible studies compared the effect of intervention(s) in an experimental and a control group. Results: A total of 9 human and 36 animal trials met the inclusion criteria. Where appropriate, random-effect meta-analyses were carried out to determine the outcome measure OIIRR. The randomeffect meta-analysis demonstrated that OIIRR was inhibited by fluoride (ES = -2.08 [-3.02, -1.14]), thyroxine (ES = -1.91 [-3.20, -0.61]), and steroids (ES = -2.79 [-4.26, -1.33]). In contrast, corticotomy (ES = 0.38 [0.05, 0.71]) significantly enhanced OIIRR. Conclusion: In animals, administration of fluoride, thyroxine and steroids decreased OIIRR, whereas corticotomy increased OIIRR. In general, the effect on OIIRR increased with higher dosage and/or exposure time. Despite methodological limitations of the included studies, this systematic review provides an important overview of the effect of biologic factors and adjunctive therapies on OIIRR.

Background: Visceral pleural invasion (VPI) in early-stage non-small cell lung cancer (NSCLC) is traditionally believed as the result of too much close distance between cancerous lesion and the visceral pleura, but whether there are any other biologic factors correlated to VPI beyond our instinctive thoughts remains unclear. Therefore, we conducted this study to investigate potential factors correlated to VPI comprehensively. Methods: Both clinical and pathological characteristics of patients undergoing surgery for NSCLC with a size of ≤3 cm were retrospectively analysed. Results: A total of 403 patients were included for analysis. Patients with VPI had older age than those without (61.1 vs . 56.1 years; P vs . 1.6 cm; P vs . 1.3 cm; P vs . 45.6%; P vs . 34.7%; P vs . 92.7%; P=0.097), and was more likely to be poorly differentiated (38.0% vs . 15.3%; P vs . 0.7%; P=0.001) and lymph node metastasis (29.5% vs . 10.2%; P Conclusions: Besides shorter distance to visceral pleura and pleural indentation, elderly, adenocarcinoma, and poor tumor differentiation were novel biologic factors correlated to VPI in early-stage NSCLC, which may explain why VPI was an unfavorable prognostic factor for early-stage NSCLC.

Bone is a biologically and structurally sophisticated multifunctional tissue. It dynamically responds to biochemical, mechanical and electrical clues by remodelling itself and accordingly the maximum strength and toughness are along the lines of the greatest applied stress. The challenge is to develop an orthopaedic biomaterial that imitates the micro- and nano-structural elements and compositions of bone to locally match the properties of the host tissue resulting in a biologically fixed implant. Looking for the ideal implant, the convergence of life and materials sciences occurs. Researchers in many different fields apply their expertise to improve implantable devices and regenerative medicine. Materials of all kinds, but especially hierarchical nano-materials, are being exploited. The application of nano-materials with hierarchical design to calcified tissue reconstructive medicine involve intricate systems including scaffolds with multifaceted shapes that provides temporary mechanical function; materials with nano-topography modifications that guarantee their integration to tissues and that possesses functionalized surfaces to transport biologic factors to stimulate tissue growth in a controlled, safe, and rapid manner. Furthermore materials that should degrade on a timeline coordinated to the time that takes the tissues regrow, are prepared. These implantable devices are multifunctional and for its construction they involve the use of precise strategically techniques together with specific material manufacturing processes that can be integrated to achieve in the design, the required multifunctionality. For such reasons, even though the idea of displacement from synthetic implants and tissue grafts to regenerative-medicine-based tissue reconstruction has been guaranteed for well over a decade, the reality has yet to emerge. In this paper, we examine the recent approaches to create enhanced bioactive materials. Their design and manufacturing procedures as well as the experiments to integrate them into engineer hierarchical inorganic materials for their practical application in calcified tissue reparation are evaluated.

Aspirin is the key treatment in the secondary prevention of atherothrombosis. Interindividual variability of response has been linked to a higher risk for ischemic events. The aim of this study was to identify clinical and biologic factors predicting high on-aspirin platelet reactivity (HPR) in a high-risk, "real-world" population of vascular patients. All platelet testing performed from 2011 to 2013 in consecutive patients receiving long-term treatment with aspirin for coronary or cerebrovascular disease was retrospectively analyzed. Indications for platelet testing were recurrent ischemic events or high-risk angioplasty. HPR was defined as aggregation intensity≥20% using light-transmission aggregometry with arachidonic acid 0.5 mg/ml. Collagen-epinephrine platelet function analysis was also performed (threshold165 seconds). Cardiovascular risk factors, usual biologic parameters, and antiplatelet treatment were recorded. A total of 1,508 patients were included (mean age 63 years, 71% men, 23% with diabetes). Antiplatelet treatment was aspirin alone in 333 patients and dual-antiplatelet therapy in 1,175 patients. HPR was found in 11.1% of patients. In multivariate analysis, independent predictive factors of HPR on light-transmission aggregometry with arachidonic acid were diabetes mellitus (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.39 to 3.16), age (OR 1.25, 95% CI 1.06 to 1.47), fibrinogen level (OR 1.20, 95% CI 1.02 to 1.42), and von Willebrand factor level (OR 1.06, 95% CI 1.03 to 1.09). On light-transmission aggregometry with arachidonic acid and collagen-epinephrine platelet function analysis, fibrinogen remained the main factor associated with HPR (OR 1.33, 95% CI 1.19 to 1.61). Similar results were found in patients treated with aspirin alone or dual-antiplatelet therapy. A fibrinogen level4.0 g/L was associated with a 3.9-fold increased risk for HPR in patients aged75 years. In conclusion, fibrinogen level was the major predictor of HPR on aspirin in this large population of high-risk vascular patients.

In this chapter, we consider how falls result from interactions between humans and their environment, and the implications of these interactions on the prevention of falls and fall-related injuries. We take a lifespan approach, and examine the human behaviors that create risk for falls and injuries in various environments, and the social and biologic factors that shape those behaviors. While not always stated explicitly, we draw on our experience in collecting and analyzing video footage of hundreds of falls. We consider that most falls do not result in significant injury, and issues of self-autonomy for pursuing a lifestyle that may create risk for falls. To help guide falls management, we propose a mechanism for classifying falls as “acceptable” versus “unacceptable.” We also provide an ecology of falls checklist to guide stakeholders in identifying ecologic aspects of falls that may be useful targets for intervention.

The formation of hydroxyapatite crystals in biologic tissues is regulated by physicochemical and biologic factors. This chapter reviews these factors in terms of the indirect and direct effects of vitamin D on the regulation of mineral deposition in bones and teeth. Changes in mineral chemical composition, mineral crystal size, and tissue mechanical properties in animal models of vitamin D deficiency and excess, provide insight into the mechanisms of vitamin D action.

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Multiple and diverse factors are involved in its cause although biologic factors are prominent. The present study reviews the evidence about the role that gamma-aminobutyric acid plays in the complex pathogenesis of depression, particularly in women. The implication of gamma-aminobutyric acid (GABA) is based mainly from animal models whereas clinical studies in depressed patients show alterations of GABA levels in plasma and cerebrospinal fluid. Neuroimaging studies using spectroscopy indicate also decreased GABA levels in different brain areas which in turn may normalize after antidepressant therapy, and these findings translate into clinical response. It has been observed that depression has a higher prevalence among women which suggests a link between depression and hormonal changes. Similarly, gonadal hormones have a regulatory effect on the hypothalamic–pituitary–adrenal axis through GABA receptors making women more vulnerable to suffer stress and depression. Therefore, the implication of GABA in the neurobiology of depression should be explored in order to search for new therapeutic strategies.

The prevalence of androgenic alopecia (AGA) increases with age and it affects both men and women. Patients diagnosed with AGA may experience decreased quality of life, depression, and feel self-conscious. There are a variety of therapeutic options ranging from prescription drugs to non-prescription medications. Currently, AGA involves an annual global market revenue of US$4 billion and a growth rate of 1.8%, indicating a growing consumer market. Although natural and synthetic ingredients can promote hair growth and, therefore, be useful to treat AGA, some of them have important adverse effects and unknown mechanisms of action that limit their use and benefits. Biologic factors that include signaling from stem cells, dermal papilla cells, and platelet-rich plasma are some of the current therapeutic agents being studied for hair restoration with milder side effects. However, most of the mechanisms exerted by these factors in hair restoration are still being researched. In this review, we analyze the therapeutic agents that have been used for AGA and emphasize the potential of new therapies based on advances in stem cell technologies and regenerative medicine., Video abstract

Background and Objectives Racial and ethnic variations have been described in the different malignancies, but no such data exists for ampullary cancer. The aim of this study was to present an updated report on the epidemiology, treatment patterns, and survival of a national cohort of ampullary cancer patients. Methods Patients diagnosed with ampullary cancer between 2004 and 2014 were identified in the National Cancer Database. Overall survival was estimated and compared between racial/ethnic groups using the log-rank test. Results A total of 14 879 patients were identified; 78% of the patients were White, 9% Hispanic, 8% Black, and 5% Asian. We noted significant differences in disease presentation, socioeconomic status, and outcomes. Blacks had the lowest median overall survival at 18.9 months followed by Whites at 23.9 months, Hispanics at 32.7 months, and Asians at 37.4 months. On a multivariate Cox proportional-hazards model, being Black was associated with worse survival compared to being White while being Asian and Hispanic were associated with better survival. Conclusions Overall survival of ampullary cancer patients was independently associated with race and ethnicity. Further studies are needed to clarify whether these disparities are primarily due to socioeconomic status or biologic factors.

The diagnosis of skin diseases relies on several clinical signs, among which color is of paramount importance. In this review, we consider certain clinical presentations of both eczematous and noneczematous contact dermatitis in which color plays a peculiar role orientating toward the right diagnosis. The conditions that will be discussed include specific clinical-morphologic subtypes of eczematous contact dermatitis, primary melanocytic, and nonmelanocytic contact hyperchromia, black dermographism, contact chemical leukoderma, and others. Based on the physical, chemical, and biologic factors underlying a healthy skin color, the various skin shades drawing a disease picture are thoroughly debated, stressing their etiopathogenic origins and histopathologic aspects.

The progression of acute to chronic pain, also known as pain chronification, remains incompletely understood. Biologic factors involved in this transition include central sensitization, neuroplastic changes, altered pain modulation, and changes to the "neuromatrix." Chronic pain may involve irreversible pathophysiologic changes, so interrupting the cascade of events that allows acute pain to advance to chronic pain is of crucial importance. This involves recognition and prompt treatment of acute pain, better awareness and application of evidence-based guidelines on pain management by all clinicians (not just pain specialists), and patient education. By interrupting nociceptive input in acute pain conditions, it might be possible to prevent transition to chronic pain syndromes.

Background ENB is a rare skull base tumor arising from the olfactory neuroepithelium with variable prognosis and no consensus guidelines for treatment. Previous genomic studies (Classe 2018, Capper 2018) have reported scant genomic alterations (GA) in advanced and metastatic ENB (mENB), including mutation of IDH2. Here, we explore the cytogenetic landscape of in 94 cases of mENB as assessed by NGS-based comprehensive genomic profiling (CGP). Methods Tumour specimens from 94 patients with mENB were assayed using hybrid capture-based CGP to delineate all classes of GA as point mutations, insertions deletions (indels), rearrangements and focal ( Results mENB cases had 1 or fewer GA detected in 80% (75/94) of cases with a corresponding median tumor mutational burden of 1.5 mut/mb. TP53 was the most frequently altered gene in the cohort, while IDH2 mutations were found in only 2 cases (2.1%). Focal and homozygous deletions were identified in 11.7% (11/94) and 14.9% (14/94) of cases respectively. We then assessed chr arm gain and LOH1/X and identified a median of 11 events per case. Based on chr arm level changes, we identified 3 distinct subtypes of mENB: type IA (n = 53), defined by wide spread LOHx, type IB (n = 22), defined by wide spread LOH1, and type II (n = 19) generally lacking arm CNA. Type IB lacked chr5 or chr20 gain, which were both seen in 36% of type IA (p = 0.001). Patients with IA/B types were older than type II (mean 54.9 v 46.5 years, p = 0.015) and both IDH2 mutated cases segregated into type II. Conclusions Given the pauci-mutational genomic landscape of mENB, clustering by chr arm level changes identifies distinct classes of mENB, which were associated with biologic factors including age and IDH2 mutation. Further studies to correlate clinico-pathologic characteristics with the cytogenetic characteristics of these newly defined subtypes of mENB are needed. Legal entity responsible for the study Foundation Medicine Inc. Funding Foundation Medicine Inc. Disclosure R. Madison: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. D.C. Pavlick: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. S. Khan: Honoraria (self): Ariad; Honoraria (self): Genentech; Honoraria (self): Foundation Medicine; Honoraria (self): EMD Serono; Honoraria (self): Genzyme; Honoraria (self): Guardant; Honoraria (self): Takeda; Honoraria (self): Oak Ridge Universities; Honoraria (self): Onyx Pharmaceuticals. J. Lee: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. J.S. Ross: Leadership role, Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Officer / Board of Directors: Celcius Therapeutics. V.A. Miller: Leadership role, Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Scientific Advisory Board: Revolution Medicines. B.M. Alexander: Full / Part-time employment, Officer / Board of Directors: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Personal Fees: AbbVie; Advisory / Consultancy, Personal Fees: Schlesinger Associates; Advisory / Consultancy, Personal Fees: Bristol-Myers Squibb; Advisory / Consultancy, Personal Fees: Precision Health Economics; Research grant / Funding (self), grants outside submitted work: Puma Biotechnology; Research grant / Funding (self), grants outside submitted work: Celgene; Research grant / Funding (self), grants outside submitted work: Eli Lily. J. Chung: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. All other authors have declared no conflicts of interest. A.B. Schrock: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. S.M. Ali: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche.