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Background and Aims Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. Approach and Results Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5‐year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary‐to‐secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary‐to‐secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine‐learning model, PSC‐BA profile score (concordance statistic [C‐statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C‐statistic, 0.86). Conclusions Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.

Abstract Context Mild autonomous cortisol secretion (MACS) affects up to 50% of patients with adrenal adenomas. Frailty is a syndrome characterized by the loss of physiological reserves and an increase in vulnerability, and it serves as a marker of declining health. Objective To compare frailty in patients with MACS versus patients with nonfunctioning adrenal tumors (NFAT). Design Retrospective study, 2003-2018 Setting Referral center Patients Patients >20 years of age with adrenal adenoma and MACS (1 mg overnight dexamethasone suppression (DST) of 1.9-5 µg/dL) and NFAT (DST <1.9 µg/dL). Main outcome measure Frailty index (range 0-1), calculated using a 47-variable deficit model. Results Patients with MACS (n = 168) demonstrated a higher age-, sex-, and body mass index–adjusted prevalence of hypertension (71% vs 60%), cardiac arrhythmias (50% vs 40%), and chronic kidney disease (25% vs 17%), but a lower prevalence of asthma (5% vs 14%) than patients with NFAT (n = 275). Patients with MACS reported more symptoms of weakness (21% vs 11%), falls (7% vs 2%), and sleep difficulty (26% vs 15%) as compared with NFAT. Age-, sex- and BMI-adjusted frailty index was higher in patients with MACS vs patients with NFAT (0.17 vs 0.15; P = 0.009). Using a frailty index cutoff of 0.25, 24% of patients with MACS were frail, versus 18% of patients with NFAT (P = 0.028). Conclusion Patients with MACS exhibit a greater burden of comorbid conditions, adverse symptoms, and frailty than patients with NFAT. Future prospective studies are needed to further characterize frailty, examine its responsiveness to adrenalectomy, and assess its influence on health outcomes in patients with MACS.

OBJECTIVEThe sitting or semisitting position in neurosurgery allows for several technical advantages, including improved visualization of the surgical field. However, it has also been associated with an increased risk of venous air embolisms and positioning-related complications that limit its commonplace adoption. The authors report a large, single-center series of cervical spine procedures performed with patients in the sitting or prone position in order to assess the perceived risk of intraoperative and postoperative complications associated with the sitting position.METHODSNoninstrumented, single-level posterior cervical spine procedures performed with patients in the sitting/semisitting or prone position from 2000 to 2016 at a single institution were reviewed. Institutional abstraction tools (DataMart and Chart Plus) were used to collect data from the medical records. The two positions were compared with regard to preoperative factors, intraoperative variables, and postoperative outcomes. Multivariable logistic regression models were fitted for 30-day readmission, 30-day return to the operating room, and complication rates.RESULTSA total of 750 patients (sitting, n = 480; prone, n = 270) were analyzed. The median age was 53 years for those who underwent surgery in the prone position and 50 years for those who underwent surgery in the sitting position (IQRs 45–62 years and 43–60 years, respectively), and 35% of the patients were female. Sitting cases were associated with significantly longer anesthetic times (221 minutes [range 199–252 minutes] vs 205 minutes [range 179–254 minutes]) and operative times (126 minutes [range 101–163 minutes] vs 149 minutes [120–181 minutes]). Cardiorespiratory events in the postanesthesia care unit (PACU) were comparable between the two groups, with the exception of episodes of apnea (2.6% vs 0.6%, p = 0.041) and hypoventilation (4.4% vs 0.8%, p < 0.003), which were more frequent in the prone-position cohort. On multivariable analysis, the effect of the sitting versus the prone position was not significant for 30-day readmission (OR 0.77, 95% CI 0.34–1.71, p = 0.52) or reoperation (OR 0.71, 95% CI 0.31–1.60, p = 0.40). The sitting position was associated with lower odds of developing any complication (OR 0.31, 95% CI 0.16–0.62, p < 0.001).CONCLUSIONSBased on the intraoperative and postoperative complications chosen in this study, the sitting position confers a similar safety profile to the prone position. This can be explained by a more anatomic positioning accounting for reduced temporary neurological deficits and reduced PACU-associated hypoventilation noted in this series. Nevertheless, the findings may also reflect institutional familiarity, experience, and mastery of this position type, and outcomes may not reflect practices in general.

Abstract Context Reduced bone material strength index (BMSi) and increased cortical porosity (CtPo) have emerged as potentially contributing to fracture risk in type 2 diabetes mellitus (T2DM) patients. Objective To determine whether BMSi or CtPo are related to other diabetic complications. Design Cross-sectional observational study. Setting Subjects recruited from a random sample of southeast Minnesota residents. Participants A total of 171 T2DM patients (mean age, 68.8 years) and 108 age-matched nondiabetic controls (mean age, 67.3 years). Main Measures Bone material strength index was measured using microindentation, skin advanced glycation end-products (AGEs) measured using autofluorescence, high-resolution peripheral quantitative computed tomography at the distal radius and tibia, assessment of diabetic microvascular complications including urine microalbuminuria, retinopathy, neuropathy, and vascular disease (ankle brachial index and transcutaneous oxygen tension [TcPO2]). All analyses were adjusted for age, sex, and body mass index. Results Skin AGEs were negatively correlated with the BMSi in both T2DM (r = -0.30, P &lt; 0.001) and control (r = -0.23, P = 0.020) subjects. In relating diabetic complications to CtPo, we found that T2DM patients with clinically significant peripheral vascular disease (TcPO2 ≤ 40 mm Hg) had higher (+21.0%, P = 0.031) CtPo at the distal tibia as compared to controls; in these subjects, CtPo was negatively correlated with TcPO2 at both the distal tibia (r = -0.39, P = 0.041) and radius (r = -0.41, P = 0.029). Conclusions Our findings demonstrate that bone material properties are related to AGE accumulation regardless of diabetes status, while CtPo in T2DM patients is linked to TcPO2, a measure of microvascular blood flow.

Produced by senescent cells, the senescence-associated secretory phenotype (SASP) is a potential driver of age-related dysfunction. We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20–90 years (retrospective cross-sectional) was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60–90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis (prospective longitudinal) or ovarian cancer (prospective case-control) were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes. We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), TNF receptor superfamily member 6 (FAS), osteopontin (OPN), TNF receptor 1 (TNFR1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.

7018 Background: Standard reporting of symptomatic adverse events (AEs) in oncology relies on clinicians to rate patient (pt) experience using CTCAE; each symptom is represented by a single graded item. To capture direct pt experience, NCI developed PRO-CTCAE to supplement CTCAE. In PRO-CTCAE, the pt answers up to 3 questions per AE about a symptom’s frequency, severity and interference with daily activities. To align PRO-CTCAE with CTCAE, we developed an algorithm for mapping sets of questions for an AE to a single composite numerical grade. Methods: We used a 5-step process. (1) All 187 possible PRO-CTCAE score permutations were presented to clinical investigators to subjectively map permutations to single numerical grades (range 0-3). (2) Permutations with < 75% agreement were presented to investigator committees at a National Clinical Trials Network meeting to gain majority consensus via anonymous voting. (3) The resulting algorithm was refined via graphical and tabular approaches to assure directional consistency. (4) Validity, reliability and sensitivity were assessed in a national study dataset. (5) Accuracy for delineating AEs between study arms was measured in 2 phase III clinical trials (Alliance for Clinical Trials in Oncology A091105 and Exelixis COMET-2). Results: (1) 12/187 score permutations had < 75% initial agreement. (2) Majority consensus was reached for all permutations. (3) 5 mappings were adjusted to assure directional consistency. (4) Composite grades for 46/59 (78%) AEs were higher in pts with ECOG performance status 2-4 vs 0-1 (median effect size 0.23 [range -0.49-0.73]; 32/59 effect size ≥0.2; 25/59 p< 0.05), similar to when conducting analysis on individual unmapped items. The test-retest reliability for 24 selected composite grades ranged from 0.57-0.96 (median intraclass correlation coefficient [ICC] 0.77) with 18/24 (75%) grades having ICC ≥0.7. Median (range) standardized response means in pts reporting worsening, no change, and improvement were 0.20 (0.03-0.34), -0.06 (-0.20-0.03) and -0.12 (-0.32-0.06). (5) Pattern, directionality and statistical significance of between-arm differences in both trials were preserved with composite grades as compared to individual unmapped items. Conclusions: A composite grading algorithm for PRO-CTCAE was rigorously developed and validated. PRO-CTCAE composite grades may be useful in analyses to provide a single metric for each pt-reported AE for trial and real-world reporting. Support: UG1CA189823; U01CA233046; HHSN261200800043C; Bayer (A091105); https://acknowledgments.alliancefound.org .

Abstract Background: Mild autonomous cortisol secretion (MACS) affects up to 50% of patients with adrenal adenomas. Frailty is a syndrome characterized by diminished strength and endurance and serves as a marker of declining health and dependency. We hypothesized that patients with MACS are more frail when compared to patients with nonfunctioning adrenal tumors (NFAT). Methods: This is a retrospective study of adult patients with adrenal adenoma evaluated at a tertiary center from 2004 to 2018. MACS and NFAT were defined as cortisol after 1 mg overnight dexamethasone suppression (DST) between 1.8-5 mcg/dl and &lt;1.8 mcg/dl, respectively. Frailty index (FI, range 0-1) was calculated using a 47 variables -deficit model (20 comorbidities, 14 activities of daily living, and 13 symptoms). Patients were excluded if treated with exogenous glucocorticoids, if diagnosed with overt adrenal hormone excess, another adrenal disorder, or if missing variables of interest. Results: MACS was diagnosed in 168 patients (67% women) at a median age 65 (30-91) years and NFAT in 275 patients (61% women) at a median age of 59 (21-84) years. Patients with MACS demonstrated higher prevalence of hypertension (73% vs 62%), cardiac arrhythmias (50% vs 40%), and chronic kidney disease (25% vs 17%), but lower prevalence of asthma (5% vs 14%), when compared to patients with NFAT, p&lt;0.05 for all. Patients with MACS reported more symptoms of weakness (21% vs 11%), falls (7% vs 2%), and sleep difficulty (26% vs 15%) as compared to patients with NFAT, p&lt;0.05 for all. Age, sex and BMI-adjusted FI was higher in patients with MACS vs patients with NFAT (0.17 vs 0.15, p=0.009). Using cut-off FI of 0.2, 42% of patients with MACS were frail, versus 30% of patients with NFAT (p=0.01). Conclusion: Higher frailty in patients with MACS supports a more aggressive management, such as adrenalectomy over conservative follow up. Future prospective studies are needed to characterize frailty in greater detail in patients with MACS, as well as to examine frailty reversal by adrenalectomy.

Abstract Background: Benign adrenal tumors are frequently diagnosed on imaging and may pose health risks to patients regardless of functional status. Both non-functioning adrenal tumors (NFAT) and tumors with mild autonomous cortisol secretion (MACS) have been associated with increased cardiovascular events and risk factors. However, limited data exist on the association of adrenal adenomas with cardiometabolic outcomes in the population-based setting. Aim: 1) To determine the prevalence of cardiovascular co-morbidities and events and 2) to assess mortality in a population-based cohort of patients with adrenal adenomas. Methods: We identified adult patients living in the community diagnosed with an adrenal tumor from 1995-2017 using a medical records linkage system. Adrenal tumors were classified as MACS if cortisol was ≥1.8mcg/dL after 1 mg dexamethasone suppression test, NFAT if cortisol was &lt;1.8 mcg/dL, and adenoma with unknown cortisol secretion (AUCS) if dexamethasone suppression test was not performed. Cardiovascular co-morbidities and events were assessed at baseline. Patients were then followed until death, migration out of the community, or through December 31, 2018. Results were compared to age and sex matched reference subjects without adrenal tumors and adjusted for tobacco use and BMI. Results: A total of 1,003 patients had adrenal adenomas with 136 (14%) NFAT, 86 (9%) MACS, and 781 (78%) AUCS. The median age of diagnosis was 63 years (range, 20-96) and 581 (58%) were women. At baseline, patients with adrenal adenomas were more likely to have hypertension (92% vs 81%, p&lt;0.001), overweight/obesity (89% vs 82%, p&lt;0.001), pre-diabetes/diabetes (82% vs 70%, p&lt;0.001), dyslipidemia (89% vs 82%, p&lt;0.001), and chronic kidney disease (11% vs 7%, p=0.004) than age and sex matched reference subjects. Myocardial infarctions (13% vs 8%, p &lt;0.001), coronary intervention (9% vs 6%, p= 0.007), heart failure (12% vs 6%, p&lt;0.001), peripheral vascular disease (26% vs 15%, p&lt;0.001), and thromboembolic disease (7% vs 3%, p&lt;0.001) were more prevalent in patients with adrenal adenomas, whereas overall survival was lower compared to reference subjects (60% vs 65%, p value = 0.013). Subgroup analysis (adjusted for age, sex, BMI, and smoking) demonstrated prevalence of cardiovascular events including peripheral vascular disease was highest in those with MACS (44.7%), followed by AUCS (40.1%), and then NFAT (36.6%), although differences between groups were not significant. Overall survival was lower in patients with MACS (62%) and AUCS (59%) compared to NFAT (71%), p&lt;0.001. Conclusions: Adrenal adenomas are associated with significantly higher prevalence of cardiovascular risk factors and morbidity at the time of diagnosis and with increased morality during follow-up. Results are potentially related to abnormal cortisol secretion but are limited by suboptimal evaluation for hormone excess.

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 &gt;65 YO, followed by patients 40–64 YO, 18–39 YO and &lt;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&gt;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 &lt;0.001). Rate of malignancy was highest in children (67% vs 8% &gt;18YO, p&lt;0.001), bilateral tumors (16% vs 8% unilateral, p&lt;0.001), tumors ≥4 cm (33% vs 7% in &lt; 4 cm, p&lt;0.001). Conclusion: IR of adrenal tumors increased 10-fold since 1995, and was highest in patients &gt;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 &gt; 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 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 &lt;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&lt;0.001), and higher prevalence of tobacco use (70% vs 54%, p&lt;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&lt;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.