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Indoleamine 2,3 dioxygenase (IDO), first discovered in the 1960s, is an enzyme that has become a highly investigated metabolic target in cancer research. IDO is the rate-limiting step in tryptophan metabolism catabolism into its byproducts - kynurenines. Both IDO and kynurenines have been implicated in altering the tumor microenvironment, allowing for a tolerogenesis by affecting T-cell maturation and proliferation, and more specifically by inducing differentiation into T regulatory cells. Two mechanisms have been suspected in creating this environment: tryptophan starvation and metabolite toxicity. IDO has been shown to be expressed not only in cancer cells but also in antigen-presenting cells. The exact mechanisms underlying the two different sites of expression have not been fully elucidated. To date, most literature has focused on the role of IDO in solid tumors; we provide a review of IDO and its impact on hematological malignancies - more specifically, acute myeloid leukemia. The pathophysiology of IDO will be discussed, including a summarization of the literature to date on how IDO expression effects prognosis and disease progression in acute myeloid leukemia, along with current IDO-specific therapeutics with future considerations.

Background: Severe infections caused by the novel coronavirus 2 display similarities to secondary hemophagocytic lymphohistiocytosis (HLH). However, HLH is a rare disease and has not been well described in critically ill patients. Methods: We used the Nationwide Inpatient Sample (NIS), the largest all-payer inpatient care database publicly available in the United States to identify all adult discharges with Hemophagocytic syndrome (ICD-9 CM code 288.4) between 2007 and 2015. Critical illness was considered present if patient had either ICD-9 CM code indicating the requirement of invasive mechanical ventilation or the presence of shock. We used ICD-9-CM codes to identify various infections (inf-HLH), malignancies (mal-HLH) and autoimmune diseases associated with HLH (MAS-HLH) and classified them in their respective groups. Primary outcome was in-hospital mortality in critically ill patients. We developed multivariable regression model to examine variables associated with mortality in critically ill HLH patients. P value was kept at < 0.05. Results: Of the 7420 (95% CI 6959-7881) estimated discharges with HLH, 2313 (31%) were critically ill. Of the critically ill patients, 442 (34%) were mal-HLH, 422 (43.3%) were inf-HLH, 403 (30.7%) were MAS-HLH and 1046 (27.3%) were unable to be classified. In hospital mortality rates were 6.4% in non-critically ill and 48.4% in critically ill patients. Among the subtypes of HLH, in-hospital mortality was 53% in mal-HLH, 49.4% in inf-HLH, 26% in MAS-HLH and 54.6% in unclassified group. On multivariable regression analysis, development of acute renal failure requiring hemodialysis (OR 2.06, 95% CI 1.29-3.3, P=0.002) and acute hepatic failure (OR 2.21, 95% CI 1.38-3.52, P=0.001) were significantly associated with higher mortality. Conclusion: Inpatient mortality of critically ill patients is remarkably high. Patients with MAS-HLH had better outcomes when compared to other groups of HLH.

UNSTRUCTURED As access to the internet has grown over the years, social media has become an important resource in the health care sector. Third-party physician-rating websites in particular have gained popularity. However, there are ethical implications of such websites. These websites provide a platform for patients to evaluate and review physicians and likewise increase visibility and advertisement of physicians, but they also violate the rights to privacy that these doctors should have. This paper aims to study and assess the ethical implications of these websites on the visibility and privacy of physicians. After presenting the ethical dilemma associated with such websites, it provides guidelines that can be incorporated by both physicians and third-party sites to help maintain physician privacy while providing public service in the form of advertisement and visibility.

Background: Geriatric patients and minority patients are often under-represented in cancer clinical trials. The presence of multiple comorbidities makes geriatric patients ineligible for most clinical trials. Racial diversity may vary by geographical location and socio-economically backward areas may have a very different racial mix. The increase in cancer incidence in geriatric patients’ raises the question of applicability of the results is such clinical trials. This study also explores the representation of different races in phase 3 clinical trials conducted in the past 10 years. Methods: Data about Phase III trials was extracted from the clinical trials.gov for 3 common solid organs and 3 hematological malignancies [breast, colon, lung, diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)]. The time period studied was for the past 10 years and included only adult patients (≥18 years). The age and race distribution of the patient population in these trials were extracted and analyzed. Results: Geriatric patients and minorities are under-represented in all phase III cancer clinical trials. The range of the proportion of geriatric patients varied from 10% to 40%. African American and Asian patients are under-represented in all phase III cancer clinical trials. Conclusions: The results of phase III clinical trials that are currently conducted on non-geriatric and Caucasian patient population may not meaningfully be applicable to geriatric patients and minorities. This study highlights the disparity of age and race for patients enrolled in clinical trials as against the patients seen in the real world.

Background: Essential thrombocythemia (ET) is a subtype of myeloproliferative neoplasm associated with an increased risk of thrombohemorrhagic complications such as stroke. However, studies of prevalence and outcomes of stroke in hospitalized patients with ET have been limited to case series. Methods: Data from the National Inpatient Sample was utilized to identify outcomes in hospitalized patient with ET who were admitted for stroke. Utilizing the current procedural terminology code (CPT) for ET, outcomes of patients with ET who were hospitalized with stroke were studied for the years 2006 to 2014. Patient demographics of age, gender and race were collected and hospital characteristics of location and size were correlated to outcomes. Chi square test was used to determine odds ratios and multiple logistic regression was used to determine independent predictors of mortality. Results: Between the years of 2006 to 2014, a total of 552422 hospitalizations involved patients with a diagnosis of ET, 20650 of which were due to stroke. The percentage of stroke in these hospitalizations varied between 3.64 to 4.29 over 9 years and mortality in these patients did not significantly change during this time period. The prevalence of stroke was highest amongst Asians and Caucasians (4.7% and 3.86%) with a statistically significant difference (P=0.0000). A majority of ET patients with stroke were discharged to skilled nursing facilities. Multiple regression showed that female gender, atrial fibrillation, stroke, higher Charlson’s comorbidity score and 80+ age were independent predictors of mortality (OR: 0.75, 1.35, 1.8, 2 to 5.7, 13.9 respectively). Conclusions: This study demonstrated that Female gender, atrial fibrillation, stroke, higher Charlson’s comorbidity score and 80+ age group were found to be statistically significant independent predictors of mortality (OR: 0.75, 1.35, 1.8, 2 to 5.7, 13.9 respectively) in patients with ET and stroke. Inclusion of these factors in the risk stratification of patients with ET may decrease the morbidity and mortality associated with the disease.

Background: There have been significant advances in the management of acute myeloid leukemia (AML) in the past decade. However, management of AML in the pregnant patient has been challenging as most interventions are contraindicated in pregnancy. Medical termination of pregnancy is advocated over chemotherapy in the first trimester as delaying chemotherapy could often be fatal. Chemotherapy during second and third trimesters may be provided with close surveillance of fetal abnormalities. The outcomes in these patients have not been systematically studied and have been limited to case reports and case series in medical literature. Methods: Patients hospitalized with a diagnosis of AML were identified using the International Classification of Disease (ICD-9) codes in the National Inpatient Sample database. This database is maintained by the Agency of Healthcare Research Quality under the United States Department of Health and Human Services. It represents 20% of all hospitalizations occurring in the United States every year. Amongst these AML patients, all patients who were pregnant were identified and their demographic information was extracted. Other details related to their hospitalization, hospital size, location, region and teaching status were also determined. The association of outcomes with common medical comorbidities was studied. Pregnancy related outcomes, mode of delivery and mortality rates were calculated for the 15 year time period. Results: During the time period of 2000 to 2014, 678942 hospitalizations involved AML patients of which 5076 were noted to be from pregnant women. The hospitalization trend gradually increased over these years and was noted to be the highest in the age group of 18-34 years. The highest hospitalization rates were noted in African American and Native American patient populations. Hypertension, hyperlipidemia, chronic kidney disease and smoking were noted to be more prevalent in pregnant women with AML. A majority of these patients had a Charlson’s comorbidity index of 1-3. 3.5% of patients underwent medical termination of pregnancy, 16.25% suffered from pregnancy related complications, 0.6% suffered from puerperal infection, 4% of patients had normal vaginal delivery, 2.8% of patients had caesarian section and 5.7% of patient died. The rate of mortality was the highest in Native Americans followed by Caucasians. Multiple regression showed that odds of mortality have decreased from 2000 to 2015 and that a higher Charlson’s comorbidity score was an independent predictor of mortality. Conclusions: This is the first nationwide study to document the outcomes of pregnancy in hospitalized AML patients. AML in pregnancy is rare and this study shows that the mortality has been improving over the past 15 years. Notably, vaginal delivery has been more common than caesarian section in pregnant AML patients. Native Americans have high prevalence and high mortality rates, a likely result of healthcare disparity. Pregnant AML patients with high Charlson’s comorbidity score may benefit from aggressive management of their comorbidities. Further studies are required to better characterize outcomes in pregnant women with AML.

Background: Sickle cell patient population in the U.S. continues to increase due a combination of birth of sickle cell disease infants, extension of lifespan of existing patients and also possibly, a contributing immigration component. These factors and most importantly the latter, might be altering national estimates by both underestimating the number of affected individuals as well as underestimating the impact of public health strategies given the estimates for which there were conceived. Methods: National sickle cell disease estimates as per Centers for Disease Control (CDC) and immigrant population trends obtained from the U.S. Census Bureau from years 2010-2017 were examined. Immigrant groups from geographical regions highly prevalent for sickle cell disease were evaluated throughout this period of time. Results: From years 2010 to 2017 Western Africa (Nigeria, Ghana, Cape Verde, Liberia, Sierra Leona), showed a population increase of 45.2%, 44.15%, 24%, 19.0% and 16.3% respectively. Eastern Africa (Ethiopia, Kenya and Eritrea) had a population increase of 55.7%, 46.8% and 65% respectively. Caribbean island (Dominican Republic, Haiti and Jamaica) showed an increase of 31.8%, 18.6% and 46.8% respectively. Extrapolation of the prevalence in these populations shows that the sickle cell disease prevalence is likely higher than what is reported in US. Conclusions: The complexities of reaching an estimated number may be more challenging in an ever-changing and growing population. More so considering the different situations behind the immigration of each group and the migratory status which might be inducing an underestimation of the sickle cell population in the U.S. This study attempts to shed light on factors that may be skewing previous statistical estimates. Examining the migratory aspects inducing possible statistical bias may contribute to further address this disease encompassing this population’s growth rate into prospective public health strategies to a more comprehensive approach to the disease.

Background: Sickle cell disease affects a significant portion of US patients with African descent. It continues to be one of the leading causes of frequent hospitalizations and high in-hospital morality risk. Until the approval of disease-modifying therapies in last two years, medical therapy has relied mostly on management of pain episodes and the use of hydroxyurea. We discuss the nationwide analysis of trends in in-hospital mortality in patients with Sickle Cell Disease from 2000 to 2014. Methods: Trends of in-hospital mortality in sickle cell patients were analyzed from a database provided by the Agency of Healthcare Research and Quality. From the data hospitalization rates and in-hospital mortality in categories by region in the US, hospital size, health insurance status, comorbidities and gender were examined. Patterns of in-hospital mortality were analyzed by logistic regression. Results: Ratio for hospitalization and mortality among the four regions described Northeast, Midwest, South, West with respective values of 0.63%, 0.65%, 0.76% and 0.89% with P = 0.008 and OR = 1.07. Odds ratio for sickle cell patients that died during hospitalization and health insurance status was OR = 0.08. Comorbidities considered in sickle cell patients; diabetes mellitus (DM), hypertension (HTN), hyperlipidemia (HLD), chronic kidney disease (CKD), smoking status. The odds ratio for comorbidities show A-fib with a value of OR = 4.47, followed by hypertension OR = 1.92, diabetes mellitus OR = 1.44 and chronic kidney disease OR = 1.29, smoking status OR = 0.60. Mortality-hospitalization ratio by gender was: males 0.77% and females 0.69% with OR = 0.87. Conclusions: In-hospital mortality by US regions, as well as health insurance status are important measurable elements that show the impact of the disease from a public health perspective. Further and more specific data of regions by states, comorbidities by states and sex, as well as health insurance status by states will provide further insight in local mortality trends.

Background: Immune Thrombocytopenic Purpura (ITP) is an autoimmune disorder characterized by low platelet counts and mucocutaneous bleeding. The outcomes of hospitalized patients with ITP and myocardial infarction (MI) have not been extensively studied and may help identify risk factors associated with adverse outcomes in this unique patient population. Methods: Patients with ITP who were admitted with MI using the National Inpatient Database for the years 2000 to 2014. Patient demographics, hospital characteristics and medical comorbidities were studied. Chi square test was used to determine associations with statistical significance and logistic regression was used to determine independent predictors of mortality. Results: A total of 753732 hospitalized patients with ITP were identified over the time period of 2000 to 2014, of which 37695 patients had both ITP and acute MI. There were more females with ITP in general (60% females vs. 40 males), but more males with ITP and acute MI (55.8% males vs. 44.2% females; P=0.0000). Caucasians were affected the most (5.5%) amongst all races and the age group of 65-79 years had the highest percentage of patients with ITP and MI (7.3%). The classical risk factors of hypertension, hyperlipidemia, and diabetes were also noted to be highly prevalent in patients with ITP and MI. 10.05% of patients with ITP and acute MI died during hospitalization, while 4% of all patients with ITP died during hospitalization (P

Purpose of Study Over 240,000 individuals are diagnosed with breast cancer each year in the USA. Outcomes depend on DNA deregulations in tumors. Carriers of deleterious BRCA1 and BRCA2 mutations are predisposed to 30 fold higher lifetime risks of breast and ovarian cancer. Aims: 1. To check for differences in SNPs of genomic DNA obtained in BRCA+/− with and without BrCa. 2. Analyze correlates of molecular mechanisms occurring in BRCA mutant patients. Methods Used We analyzed 94 subjects (41 BRCA positive) with or without BrCa to detect SNPs whose expression is significantly differentially expressed between breast cancer and controls. DNA samples were extracted from PBMCs. Samples were measured for DNA concentration using an Invitrogen QuBit Fluorometer, and diluted to 50 ng/µL. All samples were collected between 2010 and 2014 and survival data was known in all cancer patients. Processed samples were sequenced using an Illumina MiSeq Sequencer with a 300 cycle kit to detect SNPs. Variant Call Files were analyzed in Microsoft Excel using Fisher9s Exact Test. Summary of Results ALK SNPs were commonly found in cancer relative to control. Significant associations of ALK SNPs were seen in BRCA mutation subjects. ALK protein was overexpressed in 47% of BRCA mutations cases, which was significantly higher than in non-BRCA cases. Our results show that the ALK signaling pathway possibly is more common in early onset of breast cancer as seen with BRCA mutations. Coremine analysis showed SNPs identified in cancer were most commonly associated with deregulation of Transforming Growth Factor-Beta Superfamily protein synthesis and binding function. Conclusions Differences in the associations of the modifying polymorphisms with BrCarisk for BRCA1 and BRCA2 mutation carriers are likely to reflect differences in the biology of tumor development in these two groups of women at high risk of breast cancer. The identification of modifying polymorphisms could therefore lead to a better understanding of the etiology of tumors in mutation carriers and also to the development of effective and more specific therapies for BrCa in mutation carriers.

Purpose of Study More than 100,000 pelvic surgeries to remove ovarian masses (BOM) are performed yearly in the USA only 8% of those remove ovarian cancer. Circulating microRNA are biomarkers for disease detection. Purpose of study: 1. To analyze patterns of microRNAs in women with BOM vs. OvCa 2. Discover pathway involved malignant transformation. Methods Used Plasma from 32 women OvCa, 24 controls 32 (BOM) was analyzed using ABI Taqman OpenArray MicroRNA pools A and B to measure the expression of 754 known miRNAs .Real-time PCR was performed on the Taqman Open Array MicroRNA arrays using the Applied Biosystem Open Array Real-Time PCR system. Data were processed using the OpenArray Real-Time qPCR Analysis software and exported for analysis using the Applied Biosystems DataAssist Software Data analysis was done with the R programming language. A cutoff for Ct values at 30 was used. MiRNAs with Ct values higher than 30 were considered not detected. Data was normalized using a mean-centering restricted (MCR), a modification of the traditional delta Ct method and uses miRNAs which are expressed in all samples for data normalization. Statistical analysis was performed via custom scripts based on the R/Bioconductor package LIMMA (Linear Models for Microarray). Summary of Results BOM had higher expression (2–14 fold higher) of miRs −195, −126, −139-5p, −27b, −127, −152, −28, −106b, −17, −363, −181a, −192 relative to OvCa (p Conclusions BOM patients have immune recognition and pro-apoptotic protective circulating microRNAs. It is unknown whether miRs originate in ovary or another tissue. Recent work shows that BH3 mimetics are very effective in inducing cancer cell death.

Current modalities of cancer therapy utilize different agents to block key steps involved in cell division. Newer agents also block specific parts of molecular pathways that are vital for survival of the cancer cells but cells may develop resistance to all these agents and their use may also be limited by toxic effects on healthy normal cells. There is increasing evidence that the seat of cancer may be located in cancer stem cells which seldom divide. This property protects them from most of the chemotherapeutic agents which act on dividing cells. Identification of markers for cancer stem cells has been difficult and targeted therapy towards them has been elusive. The hypothesis proposed here utilizes the phenomenon of enucleation that is commonly observed in maturing red blood cells. Specifically, by utilizing protein fragment complementation it proposes that cancer cells may be induced to undergo enucleation. The specific advantage of this system is that the cells lose their nucleus and hence the emergence of resistance is very unlikely. The system also utilizes the binding of cytoplasmic cancer specific proteins to render it specific to cancer cells. It has the advantage of potentially being effective in cancer stem cells which may be resistant to conventional modes of therapy.

This study investigated the effects on cardiomyocyte differentiation of embryonic stem cells by the overexpression of the transcription factor, Pitx2c, and examined the effects of transplantation of these differentiated cells on cardiac function in a mouse model of myocardial infarction. Pitx2c overexpressing embryonic stem cells were characterized for cardiac differentiation by immunocytochemistry, RNA analysis, and electrophysiology. Differentiated cells were transplanted by directed injection into the infarcted murine myocardium and functional measurements of blood pressure, contractility, and relaxation were performed. Histochemistry and FISH analysis performed on these mice confirmed the engraftment and cardiac nature of the transplanted cells. Pitx2c overexpressing embryonic stem cells robustly differentiated into spontaneously contracting cells which acquired cardiac protein markers and exhibited action potentials resembling that of cardiomyocytes. These cells could also be synchronized to an external pacemaker. Significant improvements (P < 0.01) in blood pressure (56%), contractility (57%), and relaxation (59%) were observed in infarcted mice with transplants of these differentiated cells but not in mice which were transplanted with control cells. The Pitx2c overexpressing cells secrete paracrine factors which when adsorbed onto a heparinated gel and injected into the infarcted myocardium produce a comparable and significant (P < 0.01) functional recovery. Pitx2c overexpression is a valuable method for producing cardiomyocytes from embryonic stem cells, and transplantation of these cardiomyocytes into infracted myocardium restores cardiac function through multiple mechanisms.