Kaur, Ravinder Jeet

Abstract Background: Adrenal tumors are reported in 5% of adults, with malignancy rates in 1–12%, and rates of overt hormonal excess in 1–15 %. However, most estimates originate from convenience samples. Our objective was to determine the incidence, prevalence and clinical presentation of adrenal tumors in a population-based setting. Methods: We used a centralized epidemiologic database to identify patients diagnosed with adrenal tumors in a local community 1995 to 2017. The database is a unique medical records linkage system that allows access to hospital and community medical records for local residents (population 137,000). We calculated incidence rates (IR) as the number of new patients diagnosed while living in the study area, and prevalence as the number of patients living in the study area on Dec 31 2017. IR and prevalence were sex- and age-adjusted to the 2010 US Census population. Results: Of 1,287 patients diagnosed with adrenal tumor, the median age of diagnosis was 62 years (IQR 52–72), 713 (55%) were women, and 13 (1%) were younger than 18 years at diagnosis. IR was highest in patients >65 YO, followed by patients 40–64 YO, 18–39 YO and <18 YO (142 vs 66 vs 9 vs 2 per 100,000 persons years). IR per 100,000 increased from 4.4 (CI95% 0.3–8.6) in 1995 to 47.8 (CI95% 36.9–58.7) in 2017. Overall prevalence in the population was 0.53% in 2017, ranging from 0.01% among 0–17 YO to 1.9% among +65 YO. Malignant adrenal mass was diagnosed in 8.7% patients (4 patients with adrenal cortical carcinoma (0.3%) and 108 (8.4%) patients with other malignant mass). Pheochromocytoma was diagnosed in 11 (1.1%) patients and benign adrenal mass was diagnosed in 1,175 (90.2%) patients (1,076 (83.6%) with adrenal adenoma and 85 (6.6%) with other benign mass). Median tumor size was 15 mm (range 5–255), and 184 (14%) of patients had bilateral tumors. Only 255 (20%) patients had dexamethasone suppression test, 93 (36%) with cortisol>1.8 mcg/dl. Of 1,076 adrenal adenomas, 53 (4.9%) had overt hormone excess, 140 (13%) had nonfunctioning adrenal adenomas, and 88 (8.2%) had mild autonomous cortisol secretion. Hormonal work up for was incomplete in 795 (73.9%) adenomas. Patients discovered incidentally (1,050, 81.6%) had a lower rate of malignancy and hormone excess (5.3% vs 52% of patients with non-incidental discovery, p <0.001). Rate of malignancy was highest in children (67% vs 8% >18YO, p<0.001), bilateral tumors (16% vs 8% unilateral, p<0.001), tumors ≥4 cm (33% vs 7% in < 4 cm, p<0.001). Conclusion: IR of adrenal tumors increased 10-fold since 1995, and was highest in patients >65 YO. 8.7% of tumors were malignant, with a majority represented by malignant adrenal tumors other than adrenal cortical carcinoma. The risk of malignancy was highest in non-incidental discovery, children, and tumors > 4 cm. Overt hormone excess was diagnosed in 4.5% of patients. The majority of patients with adrenal adenomas had a suboptimal work up for hormone excess.

Abstract Introduction: Patients and their families and medical providers have assumed that psychologic stress impacts glucose control in T1D (Type 1 Diabetes) though studies providing confirmatory evidence in real world settings are, to our knowledge, lacking. We hypothesized that self-reported psychologic stress worsens glucose control in T1D. Method: We studied 20 adults with T1D on continuous glucose monitor (CGM), sensor augmented insulin pump (SAP) prospectively at 2 clinical research centers. Patients reported psychological stress through stress diaries for 5 weeks on a severity scale of 1-7 using hard copy logs including time of onset and offset of stress and severity. For analytic purpose, grades 1-4 are classified as mild and grades 5-7 as severe. Results: Baseline characteristics were age 44.9±15.0 years, F/M 12/8, HbA1c 6.8 ± 0.7%, and diabetes duration of 22.9±15.9 years. We analyzed glucose variability during days of stress versus days without stress. During a 24 hour period, patients experienced less hypoglycemia during days with stress versus days without stress (p value 0.03). During the 5 week period, patients reported 23 ± 19.5 events. We analyzed the impact of self-reported stress on CGM data streams after excluding stress events associated with missing CGM data, nocturnal events (from 12 MN to 6 AM, too few events) and events for which subjects did not provide duration of stress. Thus, we analyzed 19.5 ± 17 events per patient from 6AM to 12MN. From 6 AM to 12 MN, the episodes lasted 179 ± 255 minutes with 83 % episodes being mild/moderate and 17% moderate/ severe. Number of CGM readings during daytime stress episodes were 717± 1120 compared to 8768± 1238 during non-stress periods. Impact of stress from 6 AM to 12 MN (Mid-Night) on CGM glucose was analyzed using matched paired t test. Mean glucose (160.6±41.9 vs 148.3± 28.6) and SD (53.2 ±17.7 vs 56.1±14.6) did not show a difference; however % of time spent below 70 mg/dl was less (4 ± 5) in patients during stressful periods compared to times without stress (6.3± 5.5, P value 0.02). Conclusions: To our knowledge, this is the first study attempting to analyze the impact of self-reported stress using daily stress diaries on CGM data streams in T1D patients on SAP. The study revealed significant challenges experienced by patients in reporting adequate data. Self-reported stress was not associated with hyperglycemia. However, days of self-reported stress and periods during patients reported stress were characterized by less hypoglycemia on CGM data streams.

Abstract Background: Adrenal adenoma is reported in around 5% of adults undergoing cross-sectional imaging. Although most adenomas are considered non-functioning (NFAT), up to 48% present with mild autonomous cortisol secretion (MACS). Several studies reported increased prevalence and incidence of vertebral fractures in MACS; however conclusions are limited by small sample size, selection bias, inadequate reference population and length of follow up. Objective: To determine the prevalence and incidence of site-specific fragility fractures in a population-based cohort of patients with adrenal adenomas. Methods: Residents of local community with a radiographic diagnosis of adrenal adenoma between 1995 and 2017 were identified using a centralized epidemiologic database and matched with reference subjects for sex and age. All subjects were followed through 2017, until death or migration from the community. MACS was diagnosed based on cortisol level ≥1.8 mcg/dl after overnight 1mg dexamethasone suppression, NFAT based on cortisol level <1.8 mcg/dl, and patients not tested with dexamethasone were considered as adenoma with unknown cortisol secretion (AUCS). Results: Of 1003 patients with adrenal adenomas (581 women (58%), median age of diagnosis 63 years (20–96)), 136 (14%) were diagnosed with NFAT, 86 (9%) with MACS, and 781(78%) with AUCS. At the time of diagnosis, patients had higher BMI (median 30 vs 28 kg/m2, p<0.001), and higher prevalence of tobacco use (70% vs 54%, p<0.001) than reference subjects. Of 154 patients and 113 reference subjects with BMD available at baseline, patients had a higher median BMD at the total hips (0.93 vs 0.89, p=0.02) but similar median BMD at lumbar spine (1.05 vs 1.03, p=0.49) when compared to reference subjects. However, patients had a higher prevalence of fractures than reference subjects (any fracture: 50% vs 42%, p<0.001, vertebral fracture: 6.5% vs 3.7%, P=0.004). When adjusted for age, sex, and prior history of fracture, patients with adenoma had HR of 1.24 (CI 95% 1.04–1.48) for developing a new fracture and HR of 1.18 (CI 95% 0.97–1.44) when also adjusted for BMI and smoking. Subgroup analysis demonstrated that the prevalence of fractures at the time of diagnosis was higher in all 3 subgroups at any fragility fracture site when compared to reference subjects (NFAT: 44% vs 37%, MACS: 48% vs 43%, AUCS: 51% vs 43%); patients with MACS had the highest incidence of new fracture after 5 years of follow up when compared to AUCS and NFAT (cumulative incidence: MACS 25% vs NFAT 19% vs AUCS 16%), though the differences were not significant. Conclusions: Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis. During follow up, patients with adenoma have a higher incidence of fractures even when adjusted for sex, age, and prior history of fracture, possibly due to underlying undiagnosed abnormal cortisol secretion.

Abstract INTRODUCTION: Type 1 Diabetes (T1D) patients have an increased risk for major adverse cardiovascular events (MACE). Pancreas Transplantation Alone (PTA) in patients with T1D achieves near normal glucose control for a prolonged period but limited data are available to date regarding MACE during a 10 year follow up period after the procedure. OBJECTIVE: We studied incidence of MACE after PTA in T1D patients over a 10 year follow-up period. METHODS: Retrospectively, we studied 113 T1D recipients of PTA at Mayo Clinic, Rochester with the procedure performed between January 1998 and August 2018 and follow up of at least 1 year. Data were collected before transplantation and up to 10 year follow up after the first PTA. MACE data were gathered until primary non function, re-transplantation, or complete loss of c-peptide (<0.01ng/ml). We report vascular risk factors including hypertension, hyperlipidemia, smoking and BMI along with MACE (defined as cardiac events as unstable angina, Myocardial Infarction (MI), need for re-vascularization, cardiac death, cerebral events as Transient ischemic attack (TIA), stroke, need for re-vascularization and peripheral arterial disease as need for re-vascularization, gangrene and amputation). RESULTS: Eighteen subjects had pre-transplant MACE. A total of 14 subjects had graft failure within 24 to 36 hours due to thrombosis, with 3 in pre-transplant MACE cohort and 11 in no MACE cohort. Thus, we followed 99 subjects for the development of post-transplant MACE for a period of 6.3 ± 3.6 years. T1D subjects with MACE (n=15) had baseline characteristics: Age 48± 7.8 years, gender F/M 9/6,, duration of diabetes 33 ± 12 years, BMI 26± 3.1(Kg/m2), HbA1c 9.3 ± 1.5% and C-peptide 0.09 ng/ml. 84 T1D patients without MACE were age 42 ± 10.6 years, gender F/M 55/29, duration of diabetes 26.5 ± 10.7 years, BMI 26 ± 5.2(Kg/m2), HbA1c 6.7 ± 2.5 and C-peptide 0.09 ng/ml. There are a total of 584 person-years of follow up to first MACE event and 632 person-years of graft failure, death or last follow-up. Nine patients developed 11 MACE events post-PTA. Therefore, the event rate is 1.5 MACE events per 100 person-years for first MACE event and the total event rate is 1.7 MACE events per 100 person-years of follow-up. Age, smoking (yes), gender, duration of diabetes, HTN and Hyperlipidemia presence did not show any significant impact on post-transplant MACE outcome based on univariate Cox regression but the pre-transplant BMI (HR = 1.14; CI = (1.04, 1.26); p = 0.008) and pre-transplant HbA1c (HR = 1.26; CI = (1.06, 1.51); p = 0.01) showed statistically significant impact. CONCLUSIONS: At our center, MACE is low in PTA recipients. There is no impact of presence of pre-transplant MACE on development of post-transplant MACE but pre-transplant BMI and HbA1c account for risk of MACE.

Abstract OBJECTIVE: Low dose dexamethasone suppression testing (DST) is standard of care in patients with adrenal incidentalomas or suspected endogenous hypercortisolism. False positive total serum cortisol (TC) results occur due to poor absorption, rapid metabolism or estrogen use. Free serum cortisol (FC) measurement is an alternative, but optimal cut-offs are unknown. We aimed to establish the optimal serum dexamethasone concentrations (DEXA) to interpret TC and FC results and identify reasons for discrepancies between TC and FC values in healthy male and female (with and without oral contraceptive therapy, OCT) subjects. METHODS: Single center prospective study of healthy subjects >17 years old undergoing assessment with DST between 2016 and 2019. Measurement of FC and DEXA was performed by tandem mass spectrometry and TC by immune-enzymatic assay at 8 AM following overnight administration of 1 mg dexamethasone at 11pm. Subjects were excluded if they had a known adrenal adenoma, any form of endogenous cortisol excess, or exogenous steroid use. RESULTS: DST was performed in 165 healthy volunteers, median age of 29.5 (18-74) years; 53 men (32%) and 112 (67%) women, median BMI 25 (18-42) kg/m2, 47 (42%) of which were taking OCT (median daily ethinyl-estradiol dose of 30 (20-35) mcg). The median DEXA was 0.34 (0.09-1.12) mcg/dl, median TC was 0.8 (0.25-15.7) mcg/dl and median FC was 24 (4-714) ng/ml. TC and FC measurements were highly correlated (r2=0.89, p<0.0001). The median FC/TC was 3% (0.3-6.7), lowest in women on OCT (median 2.5% vs 3.3% in women not on OCT and men, p<0.0001). TC>1.8 mcg/dl was demonstrated in 18 (11%) healthy subjects (men: 3/53, 5.7% vs women not on OCT: 3/65, 4.6% and women on OCT: 12/47, 25.5%, p=0.0007). Excluding women on OCT, the proportion of subjects with TC>1.8 was higher when DEXA was <0.2mcg/dl (4/15, 27%) vs when DEXA was >0.2mcg/dl (2/101, 2%),(p<0.0001). After excluding 24 (14%) healthy subjects with DEXA <0.2 mcg/dl, in the remaining 142 subjects (51 (35%) men, 54 (38%) women not on OCT and 39 (27%) women on OCT), median TC was 0.75 (0.25-4.6) mcg/dl and median FC was 23 (4-103) ng/ml). Significant differences were noted in both TC and FC following DST within subgroups: men vs women not on OCT vs women on OCT, TC: 0.6 vs 0.7 vs 1.3 mcg/dl, (p<0.0001) and FC: median 20 vs 22 vs 31 ng/ml, (p<0.0001). All men and all women not on OCT demonstrated post-DST FC <50 ng/ml (97.5% cutoff of 47 and 37), while women on OCT demonstrated post-DST FC <50 in 80% and FC<75 in 95%. CONCLUSION: Post-DST TC>1.8 mcg/dl was demonstrated in 11% of all healthy subjects, of which 1 in 4 were women on OCT and 1 in 4 had DEXA<0.2 mcg/dl. Simultaneous measurement of serum DEXA during DST may be valuable when false positive results are suspected. Despite a lower FC/TC ratio in women on OCT, post-DST FC cutoffs were higher in women on OCT. Measurement of FC after DST may be helpful in some but not all women on OCT.

AbstractBackgroundCurrent therapy for Type 1 diabetes (T1D) is characterized by significant glucose variability (GV). Pancreas transplantation (PT) is performed in certain T1D patients with and without end‐stage renal disease. To date, GV has been examined to a limited extent after PT.MethodsWe investigated GV using continuous glucose monitoring (CGM) 3‐6 weeks after PT.ResultsEleven patients had simultaneous kidney pancreas transplantation (SPK), nine pancreas after kidney (PAK), and six pancreas transplantation alone (PTA). Mean CGM showed no difference between SPK, 126.5 ± 13.9, PAK 119.9 ± 12.8, and PTA 131.1 ± 29 mg/dL (P value .6). Percentage of time in range (TIR, 70‐180 mg/dL) was 92% for SPK, 93.4% in PAK, and 88.5% in PTA with only 0.3%, 1.5%, and 0.3% of time <70 mg/dL. Percentage >180 mg/dL was 7.9% for SPK, 4.9% PAK, and 11% in PTA. Other measures of GV were similar in the three cohorts. In six patients, CGM was performed before and after PT and improved significantly. GV was also better compared with a matched cohort of T1D patients.ConclusionsAll 3 types of PT resulted in excellent glucose control 3‐6 weeks post‐procedure. CGM outcomes represent an important objective outcome after PT.