Pancreas System Research Articles

Abstract 2739: Defining and evaluating drug additivity in clinical trials of combination cancer therapy

Abstract BACKGROUND The benefits of combination therapy are often attributed to synergy, that is, drug interactions resulting in an anti-cancer effect that is more than the sum of its parts. Accordingly, the rationale for designing new drug combinations is often based on synergy measured in preclinical models. However, preclinical metrics of drug interaction are not applicable to clinical trial data, and there has been no established quantitative method to assess synergy versus additivity in clinical settings. We recently showed that because of extensive patient-to-patient heterogeneity in single drug responsiveness, increasing the chance of a good response to at least one drug was a quantitatively sufficient explanation for the clinical efficacy of many approved combination therapies. Some combinations surpass this ‘highest single-agent’ model, which could be due to either drug additivity or synergy. Here we propose and test a model of drug additivity for Progression-Free Survival (PFS) data from clinical trials, to identify if any approved combinations are clinically synergistic, as compared to additive. METHODS We used PFS from trials as the clinical measure of drug efficacy. We defined ‘clinical drug additivity’ as the sum of PFS times observed from each drug in a combination. Inter-patient heterogeneity in drug responses was simulated by sampling from the joint distribution of drugs’ PFS distributions. For each combination, the clinically observed PFS distribution was compared to the additivity model, or the highest single-agent model (Palmer & Sorger, 2017). Synergy is exhibited if an observed PFS distribution is significantly superior to PFS expected from additivity (by Cox Proportional Hazards). To search for drug synergy in clinical data, we analyzed approved combination therapies where synergy was most likely to explain efficacy, which are combinations where part of the regimen is not approved as monotherapy in the same disease. We analyzed 11 approved combination therapies for advanced cancers in the breast, ovary, pancreas, colon, cervix, and lymphatic system. RESULTS None of the 11 approved combinations analyzed were significantly superior to the model of clinical additivity. For five combinations, the additivity model made the most accurate predictions of clinical efficacy (mean R2=0.97 for additivity, versus R2=0.83 for highest single-agent), and the other six combinations were most accurately described by the highest single-agent model (mean R2=0.97 for highest single-agent, versus R2=0.91 for additivity). CONCLUSIONS Approved combination therapies are rarely ‘more than the sum of their parts’ in quantitative terms. A straightforward definition of clinical drug additivity accurately matched trial results for combination therapies where synergy was expected. This suggests that single-agent efficacy by each drug is usually required for the clinical success of combination therapy. Citation Format: Haeun Hwangbo, Adam C. Palmer. Defining and evaluating drug additivity in clinical trials of combination cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2739.

Geraniol ameliorated serum lipid profile and improved antioxidant defense system in pancreas, liver and heart tissues of alloxan-induced diabetic rats

Geraniol ameliorated serum lipid profile and improved antioxidant defense system in pancreas, liver and heart tissues of alloxan-induced diabetic rats

BANDHA (Inner Lock)-MUDRA (Hand Gesture): Essences of Optimizing Health

Background: Bandha and Mudras are found in ancient Indian literature to stimulate internal energy. The simplest know a few things approximately our subtle body, our soul. The act of bandhas stimulates the prana and chakras. Madra is a technique to stimulate the nervous system and glands to minimize the dysfunction of the mind and the mysterious powers of man; kundalini (the inner core energy) can rise to carry our consciousness to the cosmic sense. Purpose of the Study: To know our internal environment and the possible ways to control the internal vital energy. Through bandhas and practicing mudras one can able to get disease-free optimal health. The present article critically discussed the various aspects of bandhas and mudras and their benefit on human health and disease. Findings: Yogic practices help to better the functioning of the thyroid, pancreas, and comparable different important glandular systems to your body. Jalandhara bandha, for example, balances the thyroid gland and thereby benefitting digestion, increase, and weight management issues. Focusing and mental integration allows many hidden and unused cycles of the brain to reach our consciousness. Various psychological problems as for example, unconscious neurosis and complex repetitive actions lose their ability to affect our lives. Madras is a practical and simultaneous way to change your life. Conclusion: Traditionally, bandhas are classified as a part of the mudras, and are given orally from guru to student. Hatha Yoga Pradipika works with bandhas and mudras together. Bandha is heavily embedded in the mudra techniques and pranayama.

Study on the effect of polyethylene glycol emodin in the treatment of severe acute pancreatitis in rats

Severe acute pancreatitis (SAP) is a common gastrointestinal disorder requiring hospitalization. Pancreatic edema, hemorrhage, and pancreatic necrosis are potentially fatal complications. Therefore, the development of new drugs for the treatment of SAP is essential. We developed a nanocomposite drug (polyethylene glycol [PEG]-loaded emodin [EMD] liposomes [PEG-EMD Lip]) for the treatment of SAP that was constructed based on the excellent biocompatibility, non-toxicity, moisture retention, and favorable dispersive properties of PEG. In vitro experiments revealed that the effect of PEG-EMD Lip (15 μg/mL) modified by PEG on the activity of mononuclear macrophages (RAW264.7) remained above 93.3%, which was 1.12 times higher than that of EMD Lip alone. This suggests that PEG-modified EMD can effectively reduce the side effects observed with the parental drug. In addition, PEG–EMD Lip significantly decreased the levels of serum inflammatory factors, oxidative stress induced by SAP, and the degree of damage to the pancreas and lung organized system.

The Role of Immune Checkpoint Inhibitors in the Treatment of Extensive-Stage Extrapulmonary Small Cell Carcinoma.

Small cell carcinoma is a type of highly aggressive poorly differentiated neuroendocrine tumor that can arise from multiple organs, including but not limited to bronchial tissue, pancreas, gastrointestinal tract, and genitourinary system. The most commonly studied type is small cell lung cancer (SCLC) which carries the worst prognosis among lung cancers. After multiple promising clinical trials, the National Comprehensive Cancer Network has recently added atezolizumab and durvalumab in combination with platinum-based chemotherapy/etoposide to the first-line treatment regimen for extensive-stage SCLC (ES-SCLC). Meanwhile, the recommended treatment for extrapulmonary small cell carcinoma (EPSCC) remains unchanged. In this review, we try to explore the role of immunotherapy in the treatment of EPSCC.

1007-P: Clinical Evaluation of Multivariable Automated Insulin Delivery

Background: Multivariable artificial pancreas (mAP) systems are developed to supplement the continuous glucose monitoring (CGM) data with physiological measurements from wearable devices and automatically incorporate physical activity information in proactive insulin dose decisions. The wearable devices incorporated into mAP systems collect data in real-time to determine the type and intensity of the physical activity without requiring manual entries. As the first mAP, our multivariable Automated Insulin Delivery (mAID) system does not require user input for meals or exercise. In silico studies and clinical experiments have shown improvement in glycemic control with mAID during unannounced physical activity compared to the glucose-only AP systems. Methods: mAID is evaluated in three clinical experiments, with one experiment conducted in a crossover fashion where the glucose-only AP is compared with the mAID. The experiments involved two subjects (1 male and 1 female) with T1DM, age 35 - 45 years, bodyweight 70 - 110 kg, total daily insulin of 35 - 80 U, and insulin-to-carb ratio 6.5 - 7 g/U. The experiments included meals and medium-intensity exercises (treadmill run and stationary bike) without any announcements to the system. The target glycemic range was [70, 180] mg/dL. Results: The mAID system regulated glycemia more effectively, than the glucose-only AP, which had 13.33% of time spend below 70 mg/dL and 86.67% of time spent in the target range, with a significant 55 g of rescue carbs given to avert impending low glucose. The mAID system resulted in all time spent in the target range for the same subject. Across the closed-loop experiments, subjects spent a total of 87.69% of time in the target range. Conclusions: The mAID system supplements the CGM data with real-time physiological data to automatically handle physical activity and maintain tight glycemic control. Disclosure M. Rashid: None. M. Sevil: None. N. Hobbs: None. I. Hajizadeh: None. M. Askari: None. R. Brandt: None. M. Park: None. L.T. Quinn: None. A. Cinar: Research Support; Self; Dexcom, Inc., JDRF. Stock/Shareholder; Self; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S, Tandem Diabetes Care. Funding National Institutes of Health (1DP3DK101075-01, 1DP3DK101077-01); JDRF (A18-0036-001)

998-P: Alerts from an Ideal Artificial Pancreas (AP) System: Preferences of Young Persons with Type 1 Diabetes (T1D) and Parents

Aim: Current automated insulin delivery systems utilize insulin pumps and CGMs, both of which impose multiple alerts/alarms upon users. Patients and parents must respond to such notifications in order to effectively manage glucose levels. We interviewed children, teens, and young adults with T1D and parents of youth with T1D to explore preferences for alerting features of an ideal AP system. Methods: Semi-structured interviews were conducted with 39 youth, ages 10-25 years with T1D duration ≥1 year, and 28 parents at 2 diabetes centers. Interview transcripts were coded and underwent content analysis. Youth (72% female, 82% white) were (M±SD) age 17.0±4.7 years, with T1D duration 9.4±4.9 years, and A1c 8.4±1.1%; 79% used an insulin pump and 82% used a CGM. Of parents, 96% parents were mothers and 89% were white. Results: Youth and parents both endorsed a desire for the following 5 alerting features: 1) personalized sounds and volumes for different treatment situations (e.g., low vs. high glucose levels, insulin delivery issues), 2) custom schedules and glucose thresholds to account for different activities or times of day/night, 3) pleasant sounds to avoid negative emotional reactions, 4) flexible share settings (e.g., which alerts followers receive), and 5) consistent and personalized overnight alerts. Some youth wanted the option to turn off alerts completely. Parents wanted certainty that they would receive share alerts and suggested adding more share options (e.g., confirmation of insulin coverage for food or correction dose for high glucose), stating that such notifications may lessen their emotional distress and worry for their child’s safety. Conclusions: Youth and parents emphasized need for customizable alerts and control over alert settings to reduce physical and emotional burdens of diabetes care. AP designs that provide comprehensive, customizable alert options are essential to reduce care burden for youth with T1D and their parents. Disclosure L. Roethke: None. P.V. Commissariat: None. J.L. Finnegan: None. L.K. Volkening: None. D.A. Butler: None. E. Dassau: Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., DreaMed Diabetes, Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; Roche Diabetes Care. Other Relationship; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care. S.A. Weinzimer: Consultant; Spouse/Partner; Tandem Diabetes Care. Consultant; Self; Zealand Pharma A/S. Speaker’s Bureau; Self; Insulet Corporation. L.M. Laffel: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Insulogic LLC, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi US. Funding National Institutes of Health (P30DK036836, DP3DK113511, DP3DK104057, K12DK094721, T32DK007260)

1298-P: “I Would Rather Bolus”: Youth and Parents Prefer Manual Bolusing to Carbohydrate Limitations in a Fully Automated Artificial Pancreas (AP) System

Aim: Although hybrid closed loop insulin delivery systems simplify self-care with automated insulin delivery, it remains necessary for patients to enter planned carbohydrate intake for meals and snacks. We interviewed children, teens, and young adults with T1D and parents of youth with T1D about their willingness to trade off limiting carb intake to 50g if this would remove need to manually bolus for each meal/snack. Methods: Semi-structured interviews were conducted with 39 youth, ages 10-25 years, and 44 parents of youth at 2 U.S. diabetes centers. Interviews were audio-recorded, transcribed, and coded using thematic analysis. Youth (72% female, 82% white) were (M±SD) age 17.0±4.7 years, with T1D duration 9.4±4.9 years and A1c 8.4±1.1%; 79% were pump users and 82% were CGM users. Of parents, 86% were white and 91% were mothers. Results: Most youth and parents strongly preferred to manually bolus for meals/snacks rather than use a fully automated system that requires limiting carb intake at each meal/snack; many stated they did not want to feel restricted. However, both youth and parents said they would like automatic coverage for meals/snacks of <50g if they also had the option to bolus for higher carb intake. The majority believed 50g was too little for meals and some suggested a higher allowable carb intake would be acceptable to them. The few participants who were willing to limit carb intake tended to eat <50g of carbs at meals already. Youth reported that any automation without carb limitation would make self-care easier; parents reported that automation without carb limitation would reduce overall mental burden. Conclusions: Youth and parents agreed that a fully automated system that did not require manual bolusing would reduce physical and mental burdens of care, but not if it limited carb intake in order for the system to work effectively. AP designers should address patient and parent aversions to dietary restrictions in future AP devices. Disclosure P.V. Commissariat: None. L. Roethke: None. J.L. Finnegan: None. L.K. Volkening: None. D.E. McGill: None. E. Dassau: Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., DreaMed Diabetes, Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; Roche Diabetes Care. Other Relationship; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care. S.A. Weinzimer: Consultant; Spouse/Partner; Tandem Diabetes Care. Consultant; Self; Zealand Pharma A/S. Speaker’s Bureau; Self; Insulet Corporation. L.M. Laffel: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Insulogic LLC, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi US. Funding National Institutes of Health (P30DK036836, DP3DK113511, DP3DK104057, K12DK094721, T32DK007260)

Еxtraintestinal manifestations of inflammatory bowel disease

Inflammatory bowel diseases, that include Crohn's disease and ulcerative colitis, are considered systemic processes since their symptoms and manifestations are not limited to the gastrointestinal tract. Extraintestinal manifestations are characteristic of inflammatory bowel disease and can be observed in almost every system of the patient’s body. Extraintestinal symptoms are present in approximately 42 % of patients with inflammatory bowel disease during the manifestation of the pathological process. They can also precede the onset of gastrointestinal symptoms. Nowadays, the pathogenesis of extraintestinal manifestations of inflammatory bowel disease is not completely obvious. It is currently believed that the mucous membrane of the patient's gastrointestinal tract can provoke an immune response in the extraintestinal areas due to the presence of common epitopes in individuals with a genetic predisposition. Extraintestinal symptoms are most often observed in the joints (peripheral and axial arthropathy), skin (nodular erythema, gangrenous pyoderma, aphthous stomatitis), visual organ (episcleritis, uveitis) and hepatobiliary system (primary sclerosing cholangitis). Other organs and systems of the body, such as the lungs, kidneys, pancreas and venous system, are also affected; however, their damages are much less common. Some extraintestinal manifestations, for instance arthritis of several joints, erythema nodosum, episcleritis, and aphthous ulcers of the oral cavity, are associated with inflammatory activity in the intestine. Other extraintestinal symptoms, such as uveitis and ankylosing spondylitis, are not associated with inflammatory bowel disease activity. Manifestations like primary sclerosing cholangitis and gangrenous pyoderma may or may not be associated with inflammatory bowel activity. Extraintestinal manifestations of inflammatory bowel disease exacerbate the negative impact of the pathological process on the patient's quality of life, and some of them, such as venous thromboembolism, can be life-threatening.

2156-P: Development of the Immune System in the Normal Rat Pancreas

The role of resident immune cells in organogenesis has not been extensively studied in pancreas. We hypothesized that during the critical stage of ß-cell remodeling during the newborn period, immune cell populations would also change. Using flow cytometry and immunohistochemistry, we identified immune cell populations in the endocrine (islets) and exocrine portion of the pancreas at postnatal day 1, 7 and 14. When corrected for the expected increase in pancreatic weight, immune cell populations increase in the exocrine pancreas in males and females from P1 to P7 but not further at P14. Interestingly, in islets the number of immune cells further increases in males from P7 to P14. Macrophages, T cells, B cells, granulocytes and NK cells are present in islets and exocrine pancreas. Macrophages are the dominant population in islets (M: 47%, F: 47%) and exocrine (M:30%, F: 34%) pancreas. In islets, M2 macrophages are favored at P1. M1 macrophages dramatically decrease with age. In exocrine pancreas, M1 macrophages are initially favored, but with age the M2 population increases. T cells are also present in islets (M:6%, F:6%) and exocrine (M:8%, F: 6%) pancreas. Cd3+ Cd4- Cd8- is the dominant T cell population at P1 but decreases with age replaced by Cd3+ Cd4+ Cd8- cells. In islets from male, but not females, the number of T cells, specifically Cd4+ T cells, increases with age. B cells (Cd45Ra+) are present in islets (M:20%, F:19%) and exocrine (M:20%, F:25%) pancreas and numbers do not change with age. Neutrophils (HIS48hi Cd68) are also present in islets (M:6%, F:6%) and exocrine (M:13%, F: 10%) pancreas. NK cells are a minor cell population present at about 1% of total immune cells in male and female pancreas at P1. Interestingly, NK cells increase with age in females in islets and exocrine pancreas. These data demonstrate significant sex specific changes in the pancreas during the critical period of postnatal pancreas development suggesting a role for immune cells in normal postnatal development and function in the endocrine and exocrine pancreas. Disclosure T. Golden: None. G. Worthen: None. R.A. Simmons: None. Funding National Institutes of Health

728-P: Accuracy of Energy Expenditure Measurements by Activity Monitors in Type 1 Diabetes and Control Subjects

Physical activity monitors have become increasingly popular in recent years and researchers have started integrating these devices into artificial pancreas (AP) systems to improve the management of T1D. The accuracy of these devices at measuring energy expenditure (EE) may be important for the function of AP systems. Most research to date has determined the accuracy of activity monitors during steady state aerobic exercise in healthy individuals. In this study, the accuracy of the Fitbit Ionic and Garmin vívosmart 3 at measuring EE was assessed against indirect calorimetry (Cosmed K5) during 5 forms of non-steady state activities in individuals with and without T1D. Fourteen adults (Age: 25.8 ± 8.1 year; BMI: 24.1 ± 3.4 kg/m2; 8 T1D) performed a VO2 peak test, resistance exercise, activities of daily living, and high-intensity interval training on treadmill and cycle ergometer, while wearing a Fitbit and Garmin watch. A significant difference in accuracy was displayed by Garmin between individuals with T1D and healthy controls (T1D: 22.6 ± 35.4%; Control: -15.6 ± 24.0%, P<0.0001), but no such difference was exhibited by Fitbit (T1D: 13.5 ± 35.8%; Control: 19.5 ± 37.0%) (Figure). In summary, the Garmin vívosmart 3 overestimates EE during physical activity in individuals with T1D as compared to healthy controls. This difference may need to be addressed before integrating these devices into AP systems. Disclosure R. Pooni: None. S. McGaugh: None. R. Patel: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; Medtronic MiniMed, Inc., OmniPod. Stock/Shareholder; Self; Zucara Therapeutics Inc.

Retroperitoneal Mass-Lesion with Calcificaction; Cystic Lymphangioma; Case Report

Lymphangioma in retroperitoneum is a rare mass-like lesion which presented histopatholigically with single or multi-cystic type and/or cavernous type; and clinically is often asymptomatic. Imaging studies was not enough to conclude exact diagnosis due to wide distribution of differential diagnosis resulted from different organ origination of tumor including of pancreas, liver, gastrointestinal and urologic system. This report described a 36 years old women complaining of 8 months vague abdominal pain underwent surgery in order to trans-abdominal total resection of a cystic mass-like tumor just located between abdominal aorta and inferior vena cava. Pathologic studies revealed benign multi-cystic lymphangioma with calcified foci. Symptoms completely removed after surgery and in follow-up period.

Abstract B50: YAP induces development of mesenchymal subtype of high-grade serous ovarian cancer from granulosa cells

Abstract The Hippo pathway plays critical roles in both organ development and tumorigenesis. Our previous studies demonstrated that Yes-Associated Protein 1 (YAP), a transcription coactivator and the major effector of the Hippo pathway, plays a critical role in ovarian cancer development. The present study investigates the role of the Hippo/YAP signaling pathway in the tumorigenesis of ovarian granulosa cells. Fluorescent and chromogenic immunohistochemistry were used to examine YAP expression in human and mouse ovaries. Western blot and qRT-PCR were used to determine protein and mRNA expression. Retrovirus-based YAP expressing constructs and YAP siRNAs were utilized to manipulate YAP levels in primary or immortalized human granulosa cells. A new three-dimensional hanging-drop culture system was used to mimic the growth of granulosa cells in vivo. The soft agar assay and xenograft mouse models were employed to investigate the role of YAP in transformation and tumorigenesis of granulosa cells. Immunohistochemical analyses showed that the active form of YAP (nuclear YAP) was expressed in proliferative granulosa cells in human and mouse ovaries, whereas the inactive form of YAP (cytoplasmic YAP) was detected predominantly in terminally differentiated luteal cells, indicating that YAP activity may be involved in the regulation of granulosa cell proliferation and differentiation. Overexpression of wild-type or constitutively active YAP compromised the expression of genes required for steroidogenesis and induced de-differentiation of differentiated granulosa cells. Ectopic expression of the constitutively active form of YAP in less-differentiated human granulosa cells derived from growing follicles induced tumors in a xenograft mouse model. Intriguingly, we found that these tumors resembled human high-grade serous ovarian cancer (HGSOC) morphologically, histologically, and genetically. The tumors were accompanied by accumulation of large amount of ascites in the peritoneal cavity. Highly proliferative and aggressive tumor cells invaded into omentum, visceral fat tissue, diaphragm, pancreas, liver, and gastrointestinal system. Deletion of the BRCA1 gene in these tumor cells promoted tumor progression and significantly reduced survival rate. Interestingly, these tumors have high expression of N-cadherin but very low expression of CA125 and E-cadherin, which are molecular characteristics of a recently identified mesenchymal subtype of HGSOC. Studies from The Cancer Genome Atlas and the Australian Ovarian Cancer Study Group indicate that the mesenchymal subtype of HGSOC has the poorest prognosis among all subtypes of ovarian cancers. In conclusion, results from this study indicate that YAP plays a critical role in regulating granulosa cell proliferation and differentiation. Overactivation of YAP can result in de-differentiation and reprogramming of ovarian granulosa cells, leading to development of mesenchymal subtype of HGSOC. Our results identify early-stage granulosa cells as a cell of origin of newly identified mesenchymal type of HGSOC. Citation Format: Xiangmin Lv, Chunbo He, Cong Huang, Guohua Hua, Bowen Ma, Xingcheng Chen, Jin Zhou, Zhengfeng Wang, Jixin Dong, Bo R. Rueda, John S. Davis, Cheng Wang. YAP induces development of mesenchymal subtype of high-grade serous ovarian cancer from granulosa cells. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B50.

Adaptive Modeling of Glucose Measurements with Unannounced Meals and Exercise

Reliable artificial pancreas (AP) systems require accurate models of the glucose-insulin dynamics in people with type 1 diabetes mellitus (T1DM). The realization of a fully automated AP system, however, is not possible with manual user entries for meals and exercise. To promote the development of automated AP systems without any user inputs, an adaptive and personalized data-driven model is developed that characterizes the evolving glycemic dynamics of individuals while explicitly considering the estimated effects of unknown disturbances such as meals and exercise. To achieve this adaptive and personalized modeling approach that best describes the glucose dynamics at any given instant without manual user input, we first quantify the effects of the unknown meals through adaptive estimates of time-varying parameters in dynamic physiological model. The evaluated meal effects are incorporated with plasma insulin concentration estimates and readily measured physiological data from noninvasive sensors, such as heart rate and energy expenditure, to determine the overall state of the individuals. The proposed modeling approach integrates first-principles physiological models and data-driven empirical techniques to determine an accurate and comprehensive perspective of the individual at any given time. Simulation case studies involving in silico subjects from the U.S. Food and Drug Administration approved University of Virginia/Padova metabolic simulator demonstrate the improvement in prediction ability of the proposed approach. The root-mean-square error and mean absolute error for 30-, 45-, and 60-min-ahead predictions are 15.61 and 8.98 mg/dL, 21.82 and 13.49 mg/dL, and 25.96 and 17.00 mg/dL, respectively. The accurate predictions of future glucose concentration measurements without requiring manual user inputs will enable fully-automated AP systems that perform efficiently by maintaining euglycemia and mitigating glucose excursions. Disclosure I. Hajizadeh: None. M. Rashid: None. A. Cinar: None.

A Novel Ceruloplasmin Mutation Causing Aceruloplasminemia with Diabetes in China

Background: Hereditary aceruloplasminemia is a rare adult-onset autosomal recessive disease characterized by a ceruloplasmin(CP) gene mutation and defective or absent ceruloplasmin function. The absence of ceruloplasmin leads to pathological iron overload in the liver, pancreas, retina, and central nervous system. It is clinically characterized by diabetes mellitus, anaemia, retinal degeneration and neurological abnormalities. Material and Methods: A 34-year-old Chinese woman who had had diabetes mellitus characterized by fast plasma glucose increasing for more than 3 years. She had tried all kinds of hypoglycemic medicines,the postprandial blood glucose could be well controlled, but still had a fast hyperglycemia. Here, we reported the identification, clinical characterization, and analysis of a novel mutation in the ceruloplasmin gene of this patient and her family members. Results: Laboratory findings revealed a complete undetectable serum Cp. Increased serum ferritin levels, elevated iron saturation, as well as results of iron quantification in the liver and CT scan also suggested iron overload in the liver. Imaging examination showed a pronounced hyperintensity in the bilateral putamina, caudate, thalamus and dentate nuclei suggesting the presence of iron overload. By sequencing the ceruloplasmin gene, A novel homozygous ceruloplasmin gene mutation, c.146+1G>T, was identified as the cause of aceruloplasminemia in this patient. Another healthy family members were heterozygous as well. Conclusion: So far, less than 60 families cases of aceruloplasminemia have been reported world-wide and mainly missense and nonsense mutations in the ceruloplasmin gene were detected. There was only one case about aceruloplasminemia has been reported in China before. We report herein a case of aceruloplasminemia accompanied by diabetes with a novel mucutation of CP gene, which suggests that increased awareness should be paid to this disorder as diabetes is an important typical symptoms of it. Disclosure Y. Xiao: None.

PROSPECTIVE RESEARCH OF HEMOSTASIS DISORDERS IN THE I PHASE OF SERIOUS ACUTE PANCREATITIS

Background: Acute pancreatitis is one of the most common surgical abdominal diseases. The development of trypsin autoaggression which provokes hemostasis disorders play significant role for pathogenesis of severe acute pancreatitis. The study of biochemical hemostasis-related markers and general homocysteine as a marker of endothelium damage at acute pancreatitis and their influence on development of heavy complications of the I phase of a disease is actual and relevant task. These complications are the reason for about 40% of lethal outcomes.Aims: To study hemostasis disorders and homocysteine as marker of damage of endothelial cells in patients with acute pancreatitis during the initial period of a disease depending on disease severity, the volume of injury of a pancreas, and development of complications.Materials and methods: 127 patients who were divided into two groups: with severe AP and not severe AP. We investigated variables and indicators of hemostasis system: activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), international normalized ratio (INR) fibrinogen, and homocysteine.Results: The most expressed hemostasis disorders and level of the general homocysteine were registered on 3rd day from the disease onset. On the 7th day, the tendency to decrease in indexes of a coagulative link of a hemostasis and decrease in level of the general homocysteine was registered in patients with severe acute pancreatitis. There were correlative communications of high and average degree between the volume of a pancreatonecrosis and violation of a hemostasis on 3rd day from the disease onset, and the level of the general homocysteine rS=0.94 (p1=0.001). In patients with severe pancreatitis, systemic complications of different degree of expressiveness were observed in 69.57% of cases. There were average and high correlations between violation of system of a hemostasis on the 3rd day and systemic complications development, as well as high direct correlation between increase in level of the general homocysteine and systemic complications development rS=0.77, p1=0.001.Conclusions: Hemostasis disorders and the level of general homocysteine correlated with volume of pancreas and retroperitoneal cellular tissue affection and system complications development at the 1-th phase of severe acute pancreatitis.

Abstract 14: The Influence of Provider Specialty on Anticoagulation Prescription Fills and Stroke Risk in Atrial Fibrillation Patients With History of Cancer

Background: Early cardiology involvement within 90 days of atrial fibrillation (AF) diagnosis is associated with greater likelihood of oral anticoagulant use and a reduced risk of stroke. Due to variation in cardiovascular care for patients with cancer, it is possible that a similar association does not exist for AF patients with cancer. Methods: We examined the association of early cardiology involvement with oral anticoagulation use among non-valvular AF patients with history of cancer (past or active), using data from 388,045 patients (mean age=68±15 years; 59% male) from the MarketScan database (2009-2014). ICD-9 codes in any position were used to identify cancer diagnosis prior to AF diagnosis. Provider specialty and filled anticoagulant prescriptions 3 months prior to and 6 months after AF diagnosis were obtained. Poisson regression models were used to compute the probability of an oral anticoagulant prescription fill and Cox regression was used to estimate the risk of stroke and major bleeding. Results: A total of 64,016 (17%) AF patients had a prior history of cancer. Cardiology involvement was less likely to occur among patients with history of cancer than those without (relative risk=0.92, 95% confidence interval (0.91, 0.93)). Similar differences were observed for cancers of the colon (0.90 (0.88, 0.92)), lung (0.76 (0.74, 0.78)), pancreas (0.74 (0.69, 0.80)), and hematologic system (0.88 (0.87, 0.90)), while no differences were observed for breast or prostate cancers. Patients with cancer were less likely to fill prescriptions for anticoagulants (0.89 (0.88, 0.90)) than those without cancer, and similar results were observed for cancers of the colon, lung, prostate, pancreas, and hematologic system. However, patients with cancer were more likely to fill prescriptions for anticoagulants (1.48 (1.45, 1.52)) if seen by a cardiology provider, regardless of cancer type. A reduced risk of stroke (hazard ratio=0.89 (0.81, 0.99)) was observed among all cancer patients who were seen by a cardiology provider than among those who were not, without an increased risk of bleeding (1.04 (0.95, 1.13)). Conclusion: AF patients with cancer were less likely to see a cardiologist, and less likely to fill an anticoagulant prescription than AF patients without cancer. However, cardiology involvement was associated with increased anticoagulant prescription fills and reduced risk of stroke, suggesting a beneficial role for cardiology providers to improve outcomes in AF patients with history of cancer.

Parental Decision-Making Processes in Pediatric Trial Enrollment: Recommendations for Informed Consent in Juvenile Type 1 Diabetes Research

Background: Clinical trials for novel interventions, including cell therapies and devices, for Type 1 diabetes are beginning to recruit pediatric participants. It is, therefore timely to consider how to communicate risks and potential benefits of trial participation with parents who make clinical decisions on behalf of their child. Parents have high expectations for new treatment options, which may encourage them to pursue clinical trial opportunities or join risky movements. For example, the Do It Yourself Pancreas System uses open access coding communities to share unproven automated insulin delivery via smartphones.

Keeping Up with the Diabetes Technology: 2016 Endocrine Society Guidelines of Insulin Pump Therapy and Continuous Glucose Monitor Management of Diabetes.

Decades after the invention of insulin pump, diabetes management has encountered a technology revolution with the introduction of continuous glucose monitoring, sensor-augmented insulin pump therapy and closed-loop/artificial pancreas systems. In this review, we discuss the significance of the 2016 Endocrine Society Guidelines for insulin pump therapy and continuous glucose monitoring and summarize findings from relevant diabetes technology studies that were conducted after the publication of the 2016 Endocrine Society Guidelines. The 2016 Endocrine Society Guidelines have been a great resource for clinicians managing diabetes in this new era of diabetes technology. There is good body of evidence indicating that using diabetes technology systems safely tightens glycemic control while managing both type 1 and type 2 diabetes. The first-generation diabetes technology systems will evolve as we gain more experience and collaboratively work to improve them with an ultimate goal of keeping people with diabetes complication and burden-free until the cure for diabetes becomes a reality.

Abstract 1293: ABO blood type and cancer risk: preliminary findings from a phenome analysis

Abstract Introduction: ABO blood type has long been implicated in disease susceptibility, including cancer. However, evidence for associations with many malignancies is mixed. We applied a novel phenome approach to test to cancer codes from electronic medical records (EMR) in relation to ABO blood type in a large predominantly Caucasian study population. Approach: Among adults aged 18-100, cancer case and control status were assigned using 58 general neoplasm related phenome codes to de-identified EMR at the Vanderbilt University Medical Center. Blood type from serologic assays was ascertained from EMR-linked laboratory reports. Associations between blood type and cancer phenomes were quantified with Odds Ratios (OR) and corresponding 95% Confidence Intervals (CI) from logistic regression in models adjusted for sex and stratified by race/ethnicity. Only analyses with at least 100 cases per strata were conducted. Results: Among 221,015 Non-Hispanic Caucasians, 37,841 Blacks, 7,714 Hispanic Caucasians, and 3,616 Asian subjects with ABO blood type available in linked EMR, we evaluated 56, 37, 4, and 3 general cancer phenome codes, respectively. After employing Bonferroni corrections, ABO blood type was significantly associated with cancers of the pancreas, ovary, cervix, skin, and hematopoietic system. Caucasians with blood type O were less likely to have ovarian cancer (OR: 0.82, 95% CI 0.73-0.91) and pancreatic cancer (OR: 0.83, 95% CI: 0.74-0.92), and more likely to have squamous cell or other skin cancer (OR: 1.08, 95% CI: 1.04-1.13) and myeloid leukemia (OR: 1.15, 95% CI: 1.06-1.25) than those with other blood types (A, B, or AB). Hispanic Caucasians with blood type O were less likely to have cervical cancer (OR: 0.56, 95% CI: 0.38-0.82) than those with other blood types. No associations surpassed correction for multiple comparisons among Blacks or Asians. Conclusions: Our phenome approach confirmed known associations between blood type and risk of pancreatic and ovarian cancer, and adds to accumulating evidence supporting associations with skin cancer and leukemia. Our novel cervical cancer association among Hispanic Caucasians and other nominally significant findings, especially in understudied non-Caucasians, should be further evaluated in large and diverse populations. In addition, research to determine how ABO blood type may influence cancer development and progression, and if such associations can be exploited for risk prediction or cancer prevention is warranted. Citation Format: Alicia Beeghly-Fadiel, Ayush Giri, Lisa Bastarache, Jill Pulley, Jeremy Warner, Josh Denny. ABO blood type and cancer risk: preliminary findings from a phenome analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1293. doi:10.1158/1538-7445.AM2017-1293