Hypoxia-Inducible Factor 1α Stabilization Restores Epigenetic Control of Nitric Oxide Synthase 1 Expression and Reverses Gastroparesis in Female Diabetic Mice.

BACKGROUND & AIMS: Although depletion of neuronal nitric oxide synthase (NOS1)-expressing neurons contributes to gastroparesis, stimulating nitrergic signaling is not an effective therapy. We investigated whether hypoxia-inducible factor 1α (HIF1A), which is activated by high O2 consumption in central neurons, is a Nos1 transcription factor in enteric neurons and whether stabilizing HIF1A reverses gastroparesis. METHODS: Mice with streptozotocin-induced diabetes, human and mouse tissues, NOS1+ mouse neuroblastoma cells, and isolated nitrergic neurons were studied. Gastric emptying of solids and volumes were determined by breath test and single-photon emission computed tomography, respectively. Gene expression was analyzed by RNA-sequencing, microarrays, immunoblotting, and immunofluorescence. Epigenetic assays included chromatin immunoprecipitation sequencing (13 targets), chromosome conformation capture sequencing, and reporter assays. Mechanistic studies used Cre-mediated recombination, RNA interference, and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)-mediated epigenome editing. RESULTS: HIF1A signaling from physiological intracellular hypoxia was active in mouse and human NOS1+ myenteric neurons but reduced in diabetes. Deleting Hif1a in Nos1-expressing neurons reduced NOS1 protein by 50% to 92% and delayed gastric emptying of solids in female but not male mice. Stabilizing HIF1A with roxadustat (FG-4592), which is approved for human use, restored NOS1 and reversed gastroparesis in female diabetic mice. In nitrergic neurons, HIF1A up-regulated Nos1 transcription by binding and activating proximal and distal cis-regulatory elements, including newly discovered super-enhancers, facilitating RNA polymerase loading and pause-release, and by recruiting cohesin to loop anchors to alter chromosome topology. CONCLUSIONS: Pharmacologic HIF1A stabilization is a novel, translatable approach to restoring nitrergic signaling and treating diabetic gastroparesis. The newly recognized effects of HIF1A on chromosome topology may provide insights into physioxia- and ischemia-related organ function.

Clinical, imaging and biochemical presentation of cystic pheochromocytomas.

OBJECTIVE: Cystic adrenal mass is a rare imaging presentation of pheochromocytoma. We aimed to describe the clinical, biochemical and imaging characteristics of patients with cystic pheochromocytoma. DESIGN: Single-centre, retrospective study, 2000-2020. PATIENTS: Consecutive patients with cystic pheochromocytoma were identified from our institutional pathology and adrenal tumour database. RESULTS: Of the 638 patients with pheochromocytomas, 21 (3.2%) had cystic pheochromocytomas (median age: 57 years, 57% women). Most pheochromocytomas were discovered incidentally (57%) or due to symptoms of catecholamine excess (24%). The median tumour size was 6.4 cm. On imaging, cystic pheochromocytomas were round or oval (90%), heterogeneous lesions (86%) with a thick solid rim (median rim thickness 13.9 mm, unenhanced computed tomography (CT) attenuation 40 Hounsfield units (HU), venous-phase CT attenuation 83 HU), and a median cystic component of 40% (unenhanced CT attenuation 17.6 HU, venous-phase CT attenuation 20.4 HU), and rarely with calcifications (15%). All 20 patients with biochemical testing had functioning tumours (adrenergic in 80%, noradrenergic in 20%). Total urinary metanephrine excretion correlated with the volume of the solid component (R2 = .75, p < .0001) but not the cystic component (R2 = .04, p = .4386). All patients underwent adrenalectomy (48% laparoscopic, 52% open), and the median duration of hospital stay was 4 days. CONCLUSIONS: Cystic pheochromocytomas are rare, large tumours with a phenotypic appearance that can masquerade as other adrenal cystic lesions. The degree of biochemical abnormality in cystic pheochromocytomas is associated with the volume of the solid component. All patients with adrenal cysts that have a solid component or an unenhanced attenuation >10 HU should undergo biochemical testing for pheochromocytoma.

Adrenal venous sampling for lateralization of cortisol hypersecretion in patients with bilateral adrenal masses.

OBJECTIVE: The objective of this study was to evaluate the role of adrenal venous sampling (AVS) in guiding the management of patients with corticotropin (ACTH)-independent glucocorticoid secretory autonomy and bilateral adrenal masses. DESIGN AND PATIENTS: A cohort with 25 patients underwent AVS and surgical management. MEASUREMENTS: Cortisol was measured from the adrenal veins (AVs) and inferior vena cava (IVC). AV/IVC cortisol ratio and cortisol lateralization ratio (CLR) (dominant AV cortisol concentration divided by the nondominant AV cortisol concentration) were calculated. Posthoc receiver-operating characteristic curves were generated to determine the specificity of revised AV/IVC cortisol ratio and CLR in differentiating unilateral from bilateral disease. RESULTS: Patients underwent unilateral (n = 21) or bilateral (n = 4) adrenalectomy. The mean AV/IVC cortisol ratio for unilateral adrenalectomy was 12.1 ± 9.6 (dominant) and 4.7 ± 3.8 (contralateral) with a mean CLR of 3.6 ± 3.5. The mean AV/IVC cortisol ratio for bilateral adrenalectomy was 7.5 ± 2.1, with a mean CLR of 1.1 ± 0.6. At a mean follow-up of 22 months, one patient who underwent unilateral adrenalectomy for the predicted bilateral disease developed recurrent mild autonomous cortisol secretion. Posthoc analyses demonstrated a specificity of 95%-100% for unilateral disease with AV/IVC cortisol ratio >9 for one side, <2.0 for the opposite side and a CLR > 2.3. The specificity was 80%-90% for bilateral disease with AV/IVC cortisol ratio >5.1 bilaterally and a CLR < 1.1. CONCLUSIONS: Among patients with bilateral adrenal masses and ACTH-independent autonomous cortisol secretion, AVS can distinguish between unilateral and bilateral disease with high specificity and may guide surgical management.

Disparities in Parathyroidectomy: Who Receives Appropriate Treatment for Primary Hyperparathyroidism?

INTRODUCTION: Parathyroidectomy is underperformed despite clear benefits in primary hyperparathyroidism (PHPT). We evaluated disparities in receipt of parathyroidectomy following PHPT diagnosis to explore barriers to care. METHODS: Adults diagnosed with PHPT 2013-2018 at a health system were identified. Recommended indications for parathyroidectomy include age ≤50 y, calcium >11 mg/dL, or the presence of nephrolithiasis, hypercalciuria, nephrocalcinosis, decreased glomerular filtration rate, osteopenia, osteoporosis, or pathological fracture 1 y prior to diagnosis. Kaplan-Meier analysis assessed rates of parathyroidectomy within 12 mo following diagnosis as well as median time to parathyroidectomy, and multivariable Cox proportional hazards analyses assessed factors associated with undergoing parathyroidectomy. RESULTS: Of 2409 patients, 75% were females, 12% aged ≤50 y, and 92% non-Hispanic White, while 52% had Medicaid/Medicare, 36% were commercial/self-pay or uninsured, and 12% unknown. Parathyroidectomy was performed within 1 y in 50% of patients. Within the 68% that met recommendations, parathyroidectomy was performed within 1 y in 54%; median time from diagnosis to surgery was shorter for males, patients aged ≤50 y, commercial/self-pay/no insurance patients (versus Medicaid/Medicare), and those with fewer comorbidities, P < 0.05. Multivariable analysis demonstrated non-Hispanic White patients and those with commercial/self-pay/uninsured were more likely to undergo parathyroidectomy after adjusting for comorbidity, age, and facility site. Among those strongly indicated, patients not on Medicare/Medicaid and aged ≤50 y were more likely to undergo parathyroidectomy after adjusting for race, comorbidity, and facility site. CONCLUSIONS: Disparities in parathyroidectomy for PHPT were observed. Insurance type was associated with undergoing parathyroidectomy; patients on governmental insurance were less likely to undergo surgery and waited longer for surgery despite strong indications. Barriers to referral and access to surgery should be investigated and addressed to optimize all patients' access to care.

Unilateral Adrenalectomy for Primary Aldosteronism Due to Bilateral Adrenal Disease Can Result in Resolution of Hypokalemia and Amelioration of Hypertension.

BACKGROUND: Bilateral idiopathic hyperaldosteronism (IHA) is responsible for 60% of primary aldosteronism (PA) cases. Medical management is standard of care for IHA. Unilateral adrenalectomy (UA) with the intent of debulking total aldosterone production as a palliative measure remains controversial. METHODS: Single-center retrospective review (2010-2020) of patients undergoing UA with a diagnosis of PA due to IHA (lateralization index [LI] on adrenal venous sampling [AVS] < 4). Demographic, pre-operative, intra-operative, and post-operative variables were assessed. Hypertensive regimens were converted to the WHO Defined Daily Dose (DDD). RESULTS: Twenty-four patients were identified, 14, 58% male and mean age 52 ± 10 years. Preoperative hypokalemia was present in 22, 92% of patients. Median number of antihypertensives taken was 3 (interquartile range [IQR], 2-4) and median DDD was 4 (IQR, 3-5.3). Median lateralization index on AVS was 3.52 (range, 1.19-3.88). All operations were performed in minimally invasive fashion. There were no conversions to open procedure, ICU admissions, or post-operative complications. Median follow-up was 10.5 months (range, 1-145 months). Hypokalemia resolved in 17, 76% of patients at last follow-up. Post-operative median number of antihypertensives taken was 1 (IQR, 1-3) and median DDD was 2 (IQR, 0.5-2.75) from 4, P = 0.003. Three (%) patients required continuation of mineralocorticoid receptor antagonists post-operatively. Blood pressure control improved in 65% of patients. CONCLUSION: Unilateral adrenalectomy in the setting of bilateral hyperaldosteronism can improve blood pressure control and stabilize potassium levels in selected patients. Further prospective studies in larger cohorts will be necessary to further define the role of unilateral adrenalectomy in the setting of PA due to bilateral adrenal disease.

The Role of Three-Dimensional Magnetic Resonance Elastography in the Diagnosis of Nonalcoholic Steatohepatitis in Obese Patients Undergoing Bariatric Surgery.

The lack of reliable, noninvasive methods to diagnose early nonalcoholic steatohepatitis (NASH) is a major unmet need. We aimed to determine the diagnostic accuracy of three-dimensional magnetic resonance elastography (3D-MRE), with shear stiffness measured at 60 Hz, damping ratio at 40 Hz, and magnetic resonance imaging proton density fat fraction (MRI-PDFF) in the detection of NASH in individuals undergoing bariatric surgery. Obese adults at risk for NASH were enrolled between 2015 and 2017 (prospective cohort, n = 88) and 2010 and 2013 (retrospective cohort, n = 87). The imaging protocol consisted of multifrequency 3D-MRE (mf3D-MRE) with shear waves delivered at different frequencies to explore parameters that best correlated with histologic NASH, and MRI-PDFF to estimate steatosis. The prospective cohort was used to establish the optimal mf3D-MRE technical parameters for NASH detection. The two cohorts were then combined to derive predictive models of NASH and disease activity by nonalcoholic fatty liver disease activity score (NAS) using the three imaging parameters that correlated with NASH. A total of 175 patients (median age 45, 81% women, and 81 [46%] with histologic NASH) were used for model derivation. From the complex shear modulus output generated by mf3D-MRE, the damping ratio at 40 Hz and shear stiffness at 60 Hz best correlated with NASH. The fat fraction obtained from MRI-PDFF correlated with steatosis (P < 0.05 for all). These three parameters were fit into a logistic regression model that predicted NASH with cross-validated area under the receiver operating characteristic curve (AUROC) = 0.73, sensitivity = 0.67, specificity = 0.80, positive predictive value = 0.73 and negative predictive value = 0.74, and disease activity by NAS with cross-validated AUROC = 0.82. Conclusion: The mf3D-MRE allows identification of imaging parameters that predict early NASH and disease activity. This imaging biomarker represents a promising alternative to liver biopsy for NASH diagnosis and monitoring. The results provide motivation for further studies in nonbariatric cohorts.

Endoscopic management of refractory leaks and fistulas after bariatric surgery with long-term follow-up.

BACKGROUND: In selected cases of post-bariatric leaks and fistulas, endoscopy is an initial treatment modality. Management can be complex and require multiple endoscopic sessions with varying degrees of success. Our aim was to describe our tertiary care experience on endoscopy management of refractory post-bariatric leaks and fistulas. METHODS: Patients with post-bariatric leaks and/or fistulas who failed an initial endoscopic intervention were included. Endoscopic treatments were classified into four strategies: (1) closure management, (2) active drainage, (3) passive drainage, and (4) plugging. Clinical success and adverse events were assessed. RESULTS: A total of 25 patients (mean age = 45.3 ± 11.8 years and 56% female) were included. Clinical success was achieved in 20 patients (80%) with a mean of 3.0 ± 1.5 procedures and a median time to healing of 114.5 (53-210.3) days. Closure and plugging were the main successful strategies used for early and acute leaks/fistulas, while drainage was for late and chronic leaks/fistulas. Adverse events were observed in 13 patients (52%) with one serious adverse event. Patients with fistulas had a lower success rate (72.2% vs. 100%, P = 0.052). Of those with clinical failure (n = 5), four underwent reconstructive surgery, eventually led to success in 3 patients. The other one died of septic shock related to a complicated fistula. CONCLUSIONS: Complex multi-modality endoscopic management ultimately achieved clinical success in most cases of refractory leaks/fistulas post-bariatric with an acceptable safety profile. However, a close follow-up to detect the development of long-term failure is warranted. These patients should be referred to a specialized bariatric center with expertise in bariatric endoscopy and surgery.

Positive Lymph Nodes in Adrenocortical Carcinoma: What Does It Mean?

BACKGROUND: The role of lymphadenectomy in adrenocortical carcinoma resection is controversial. Therefore, we conducted a population-based study to assess the association between positive lymph nodes (LN) and survival. METHODS: The Surveillance, Epidemiology, and End Results set of cancer registries were utilized. The associations between positive lymph nodes and tumor size, grade and laterality were assessed. Cancer specific survival (CSS) trends and factors affecting survival were analyzed. RESULTS: A total of 2170 adult patients were identified; 60% underwent resection. Among those resected, LN were examined in 23% and were positive in 25% of patients with LN examined. Patients with positive LN tended to have smaller tumors compared to those with negative LN (12 ± 5 vs 15 ± 11 cm, p = 0.02). The rate of positive LN was higher in right ACC, p = 0.03. Median overall CSS was 21 months, with significant differences between resection (42 months) and no resection (4 months), p < 0.01. Median CSS did not change over time when comparing ACC patients who underwent surgery before 2000, 2000-2009, and 2010-2016. On multivariable analysis including resection group, advanced age, grades III and IV, regional and distant stage, in addition to positive LN were associated with worse survival, p < 0.05. CONCLUSION: Lymphadenectomy is infrequently performed during ACC resection, and when performed, regional LN involvement tends to be associated with worse survival. Neoplasm size and grade were not associated with LN involvement and therefore, do not inform lymphadenectomy need. Further studies are needed to assess the indications for, and value of lymphadenectomy in ACC.

Bilateral Adrenalectomy: Differences between Cushing Disease and Ectopic ACTH-Producing Tumors.

BACKGROUND: Bilateral adrenalectomy (BA) is a curative treatment for hypercortisolism in patients with corticotropin (ACTH)-dependent Cushing syndrome. Indications include refractory Cushing's disease (CD) following failed pituitary surgery, and occult or unresectable ectopic ACTH-producing neoplasms (EA). METHODS: This was a single-center, retrospective review (1995-2017) of patients undergoing BA for CD or EA. Demographics, laboratory findings, and intraoperative and postoperative variables were analyzed. RESULTS: Of 137 patients, 83 (61%) had CD and 54 (39%) had EA; 87% of CD patients were female versus 46% of EA patients (p < 0.0001). Mean age at diagnosis was 40 ± 15 years for CD and 49 ± 18 years for EA (p = 0.004). Preoperative serum cortisol concentrations were higher in the EA cohort (63 ± 40 µg/dL) versus the CD cohort (33 ± 19 µg/dL) [p < 0.001], with no significant differences in serum ACTH. Time from diagnosis until adrenalectomy was 54 ± 69 months for CD versus 4 ± 13 for EA (p = 0.002). Most patients underwent minimally invasive surgery (MIS; 86% CD vs. 75% EA; p = 0.19). There was no difference between the rates of conversion to an open approach, intraoperative blood loss, or operative time between groups, and no difference between complications in CD versus EA (p = 1.0). Five-year survival was significantly shorter among the EA cohort (30% for EA vs. 80% for CD; p < 0.001). CONCLUSION: Patients with EA presented with higher serum cortisol levels compared with patients with CD. EA patients were more likely to require intraoperative transfusion and postoperative intensive care. BA in patients with CD and EA can be performed safely in an MIS fashion, with similar morbidity; however, survival at 5 years was significantly less in the EA cohort.

Clinical course of adrenal myelolipoma: A long-term longitudinal follow-up study.

OBJECTIVE: We aimed to describe clinical course of myelolipoma and to identify predictors of tumour growth and need for surgery. DESIGN: A retrospective study. PATIENTS: Consecutive patients with myelolipoma. RESULTS: A total of 321 myelolipomas (median size, 2.3 cm) were diagnosed in 305 patients at median age of 63 years (range, 25-87). Median follow-up was 54 months. Most myelolipomas were incidentally detected (86%), whereas 9% were discovered during cancer staging and 5% during workup of mass effect symptoms. Thirty-seven (12%) patients underwent adrenalectomy. Compared to myelolipomas <6 cm, tumours ≥6 cm were more likely to be bilateral (21% vs 3%, P < .0001), cause mass effect symptoms (32% vs 0%, P < .0001), have haemorrhagic changes (14% vs 1%, P < .0001) and undergo adrenalectomy (52% vs 5%, P < .0001). Among patients with ≥6 months of imaging follow-up, median size change was 0 mm (-10, 115) and median growth rate was 0 mm/y (-6, 14). Compared to <1 cm growth, ≥1 cm growth correlated with larger initial size (3.6 vs 2.3 cm, P = .02), haemorrhagic changes (12% vs 2%, P = .007) and adrenalectomy (35% vs 8%, P < .0001). CONCLUSIONS: Most myelolipomas are incidentally discovered on cross-sectional imaging. Myelolipomas ≥6 are more likely to cause mass effect symptoms, have haemorrhagic changes and undergo resection. Tumour growth ≥1 cm is associated with larger myelolipoma and haemorrhagic changes. Adrenalectomy should be considered in symptomatic patients with large tumours and when there is evidence of haemorrhage or tumour growth.

Optimizing Opioid-Prescribing Practices After Parathyroidectomy.

BACKGROUND: To help control opioid overprescription, we conducted a large institutional, 3-site initiative to provide discharge prescribing guidelines for different procedures. Our aim is to refine institutional guidelines for parathyroidectomy. METHODS: Patients undergoing parathyroidectomy completed a 28-question survey about opioid consumption. Discharge opioid prescription amounts were converted into morphine milligram equivalents (MMEs) and reported as median and interquartile range (IQR). Consumption was dichotomized into top quartile MME users (Q4) versus standard users (Q1, Q3). Univariate analysis compared opioid consumption. RESULTS: A total of 91 patients were included; 90% were opioid-naive. While the median prescribed was 75 (IQR 75, 150) MME, the median consumed was 0 (IQR 0, 20). Top users reported higher pain scores [median (IQR): 2 (2, 4)] compared to standard users [1 (0, 3), P = 0.01]. However, there was no difference in opioid consumption between unilateral neck exploration, bilateral exploration, or thyroidectomy and parathyroidectomy, P = 0.11. There was no difference in opioid consumption by age, sex, or BMI (all P > 0.05). Of those receiving a prescription, 94.6% had left-over opioids at the time of survey, resulting in 82% of prescribed opioids being unused. CONCLUSIONS: Over half of patients undergoing parathyroidectomy did not consume any opioid, and very few needed more than 2 d of opioid. Moreover, most patients did not dispose the unused opioids, which put these pills at risk of diversion and misuse. Surgical approach did not change consumption, illustrating that these guidelines are applicable to thyroidectomy given the similarity between techniques. We recommend prescribing nonopioid analgesics for patients undergoing parathyroidectomy.

Malignant Insulinoma: A Rare Form of Neuroendocrine Tumor.

INTRODUCTION: Due to the rarity of malignant insulinoma, a lack of the literature describing factors affecting outcomes exists. Our aim was to review malignant insulinoma incidence, characteristics and survival trends. METHODS: We identified all patients with malignant insulinoma in the SEER registries from 1973 to 2015. Incidence, neoplasm characteristics and factors affecting cancer-specific survival (CSS) were described. RESULTS: A total of 121 patients were identified. The crude annual overall incidence was low (range 0.0-0.27 cases per million person years). The largest proportion had localized disease (40%), while 16% had regional disease, 39% distant metastatic disease, and stage was unreported in 5%. Most neoplasms were in the body/tail of the pancreas, followed by the head of the pancreas. Grade was reported in 40% of patients; only a single patient reported as having grade IV with the remainder all grades I/II. Surgical resection was performed in 64% of patients. Within surgical patients, the median primary neoplasm size was 1.8 cm. Regional lymph nodes were examined in 57.1% of surgical patients, while 34% of examined nodes were positive. The median CSS was 183 months. On multivariable analysis, surgical resection, male sex and absence of metastatic disease were associated with superior survival. CONCLUSION: While the greatest proportion of patients with malignant insulinoma present with localized disease, regional lymph node involvement was found in 34% of whose nodes were tested. Further studies are needed to assess the role of lymph node dissection in improving survival and preventing recurrence given the observed frequency of lymph node involvement.

Adrenalectomy for non-neuroblastic pathology in children.

BACKGROUND: Adrenalectomy for non-neuroblastic pathologies in children is rare with limited data on outcomes. We reviewed our experience of adrenalectomy in this unique population. METHODS: Retrospective study of children (age ≤ 18) who underwent adrenalectomy with non-neuroblastic pathology from 1988 to 2018. Clinical and operative details of patients were abstracted. Outcomes included length of stay and 30-day postoperative morbidity. RESULTS: Forty children underwent 50 adrenalectomies (12 right-sided, 18 left-sided, 10 bilateral). Six patients (15%) presented with an incidental adrenal mass while 4 (10%) had masses found on screening for genetic mutations or prior malignancy. The remaining 30 (75%) presented with symptoms of hormonal excess. Nineteen patients (48%) underwent genetic evaluation and 15 (38%) had genetic predispositions. Diagnoses included 9 patients (23%) with pheochromocytoma, 8 (20%) with adrenocortical adenoma, 8 (20%) with adrenocortical carcinoma, 7 (18%) with adrenal hyperplasia, 2 (5%) with metastasis, and 6 (14%) with additional benign pathologies. Of 50 adrenalectomies, twenty-five (50%) were laparoscopic. Median hospital length of stay was 3 days (range 0-11). Post-operative morbidity rate was 17% with the most severe complication being Clavien-Dindo grade II. CONCLUSION: Adrenalectomy for non-neuroblastic pathology can be done with low morbidity. Its frequent association with genetic mutations and syndromes requires surgeons to have knowledge of appropriate pre-operative testing and post-operative surveillance.

Proteomics in gastroparesis: unique and overlapping protein signatures in diabetic and idiopathic gastroparesis.

Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full-thickness gastric biopsies from gastroparesis patients. We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying, and symptoms. Full-thickness gastric antrum biopsies were obtained from nine DG patients, seven IG patients, and five nondiabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1,305 human proteins was used. Protein fold changes were computed, and differential expressions were calculated using Limma. Ingenuity pathway analysis and correlations were carried out. Multiple-testing corrected P < 0.05 was considered statistically significant. Seventy-three proteins were differentially expressed in DG, 132 proteins were differentially expressed in IG, and 40 proteins were common to DG and IG. In both DG and IG, "Role of Macrophages, Fibroblasts and Endothelial Cells" was the most statistically significant altered pathway [DG false discovery rate (FDR) = 7.9 × 10-9; IG FDR = 6.3 × 10-12]. In DG, properdin expression correlated with GCSI bloating (r = -0.99, FDR = 0.02) and expressions of prostaglandin G/H synthase 2, protein kinase C-ζ type, and complement C2 correlated with 4 h gastric retention (r = -0.97, FDR = 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Protein expression changes suggest a central role of macrophage-driven immune dysregulation in gastroparesis, specifically, complement activation in diabetic gastroparesis.NEW & NOTEWORTHY This study uses SOMAscan, a novel proteomics assay for determination of altered proteins and associated molecular pathways in human gastroparesis. Seventy-three proteins were changed in diabetic gastroparesis, 132 in idiopathic gastroparesis compared with controls. Forty proteins were common in both. Macrophage-based immune dysregulation pathway was most significantly affected in both diabetic and idiopathic gastroparesis. Proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis.

Comprehensive Lateral Neck Dissection in Papillary Thyroid Carcinoma may Reduce Lateral Neck Recurrence Rates.

OBJECTIVE: To Identify predictors of recurrent disease following lateral neck dissection (LND) for papillary thyroid carcinoma (PTC). METHODS: A retrospective review of patients who underwent first-time LND for PTC at our institution (2000-2015) was performed. Medical records were examined for biopsy or pathologically proven lateral neck recurrence. Differences between the groups with and without recurrence were compared. All LNDs were then classified in to two groups: "comprehensive" (CND), involving levels IIa-Vb at minimum, or "selective", labelling less extensive dissection (SND). RESULTS: Four hundred nine patients underwent 467 LNDs. Surveillance data were available for 317 patients who underwent 362 LNDs (mean age 45 ± 16; range 18-88). The median follow-up was 64 ± 48 months (range 3-197). Recurrence was detected in 71 lateral necks (20%). The total number of lymph nodes was greater in the group without recurrence compared to those with recurrence (23 vs. 19, p = 0.02). Among patient demographics, radioactive iodine treatment, primary tumor characteristics and characteristics of nodal metastases, only an older patient age (mean 50 vs. 43 years) was associated with lateral neck recurrence (p < .01). CND was performed in 102 lateral necks and SND in 143 necks. There were 12 recurrences recorded in the CND group (12%) vs. 31 in the SND group (22%, p = .04). The majority of recurrences (70%) involved levels included in the original dissection. CONCLUSIONS: Younger patients, more extensive dissection and a higher total number of lymph nodes removed are associated with a lower incidence of lateral neck recurrence after LND for papillary thyroid carcinoma.

Evaluation of Parathyroid Glands with Indocyanine Green Fluorescence Angiography After Thyroidectomy.

BACKGROUND: Indocyanine green fluorescence angiography (ICGA) is a new adjunct that has been used in surgical procedures to assess blood flow. This study evaluated the utility of ICGA compared to visual inspection to predict parathyroid function, guide autotransplantation and potentially decrease permanent hypoparathyroidism. METHODS: This was a retrospective study of patients who underwent total or near-total thyroidectomy (T-NT) between January 2015 and March 2018. Patients with preoperative hyperparathyroidism and those undergoing reoperation were excluded. Patients who had ICGA were compared to T-NT patients without ICGA. Data were analyzed to assess the frequency of autotransplantation and incidence of hypoparathyroidism between groups. RESULTS: In total, 210 patients underwent T-NT: 86 with ICGA and 124 without. Autotransplantation was more common in the ICGA group at 36% compared to 12% in the control (p = 0.0001). There was no correlation with at least one normal parathyroid gland on ICGA and postoperative PTH levels (p = 0.75). There was a difference in having normal postoperative PTH when there were at least two normal parathyroid glands (n = 50) compared to patients with less than two normal ICGA glands (n = 36, p = 0.044). Visual assessment and ICGA assessment of vascularity were in agreement, 245/281 (87%). There were 19 glands (6.8%) that would have undergone autotransplant based on visual inspection that had adequate blood supply on ICGA. Transient hypoparathyroidism was present in 45 out of 124 controls (36%) and 32 out of 86 (37%) in the ICG group. CONCLUSIONS: ICGA is a novel technique that may improve the assessment of parathyroid gland blood supply compared to visual inspection. ICGA can guide more appropriate autotransplantation without compromising postoperative parathyroid function. At least two vascularized glands on ICGA may predict postoperative parathyroid gland function.

Primary Aldosteronism: Does Underlying Pathology Impact Clinical Presentation and Outcomes Following Unilateral Adrenalectomy?

INTRODUCTION: Patients undergoing unilateral adrenalectomy for primary aldosteronism (PA) may have a solitary adenoma, unilateral hyperplasia, or multiple adenomas on final pathology. This study investigated whether the underlying pathological diagnosis was associated with differences in clinical presentation and postoperative outcomes. METHODS: A retrospective cohort study of patients undergoing unilateral adrenalectomy for PA from 2004 to 2015 at our institution was performed. Baseline clinical and laboratory parameters, as well as postoperative biochemical and hypertension cure rates, were compared across the three aforementioned pathological groups. RESULTS: Of 206 patients who met criteria for inclusion, 152 (73.8%) had a single adenoma, 33 (16%) had unilateral hyperplasia, and 21 (10.2%) had multiple unilateral adenomas. Patients with unilateral hyperplasia were more likely to be male (81.2% vs 57.9%, P = .03), undergo left-sided adrenalectomy (78.8% vs 47.4%, P < .01), and had a lower median adrenal venous sampling lateralization index (9.8 vs 19.8, P = .04) compared to those with solitary, but not multiple unilateral adenomas. No differences were seen in age, duration of hypertension, preoperative plasma aldosterone levels, plasma renin activities, 24-h urinary aldosterone excretion, serum potassium concentrations, and the number of preoperative antihypertensive medications across all three pathological groups. All patients achieved biochemical cure following adrenalectomy, and no significant differences in the rates of hypertension cure or improvement were observed in comparisons across pathological subtype. CONCLUSIONS: Clinical presentation and postoperative outcomes are similar regardless of underlying pathology in patients with PA. Because one in four patients may harbor unilateral hyperplasia or multiple adenomas, total unilateral adrenalectomy should be performed as the operation of choice over adrenal-sparing approaches.

Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas.

CONTEXT: Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality. OBJECTIVE: To assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy. DESIGN: Retrospective cohort study. PATIENTS: Twenty-five patients with overt Cushing's syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE) and 32 patients with a nonfunctioning adrenal tumour (NFAT) were included. METHODS: Medical records were reviewed, and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT). RESULTS: In patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P < .001) and by 0.3 (P < .001); however, these measurements were decreased by 0.04 (P = .007) and 0.2 (P = .01), respectively, in patients with MACE. Total muscle mass was decreased by -10 cm2 (P = .02) in patients with overt CS compared to patients with NFAT. Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28 nmol/L cortisol increase there was a 0.008 increase in V/T (P < .001), 0.02 increase in the V/S fat ratio (P < .001) and a 1.2 cm2 decrease in mean total muscle mass (P = .002). CONCLUSIONS: The severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT-based markers may allow for a more reliable and objective assessment of glucocorticoid-related disease severity in patients with adrenal adenomas.

Transoral outlet reduction with full thickness endoscopic suturing for weight regain after gastric bypass: a large multicenter international experience and meta-analysis.

BACKGROUND AND AIMS: Many patients who undergo bariatric surgery will experience weight regain and effective strategies are needed to help these patients. A dilated gastrojejunal anastomosis (GJA) has been associated with weight recidivism after Roux-en-Y gastric bypass surgery (RYGB). Endoscopic transoral outlet reduction (TORe) with a full thickness endoscopic suturing device (Overstitch, Apollo Endosurgery, Austin, TX) is a minimally invasive therapeutic option. The primary aim of this project was to examine the safety and long-term efficacy data from three bariatric surgery centers and to conduct a systematic review and meta-analysis of the existing literature. METHODS: Patients who underwent TORe with the Overstitch device from Jan 2013 to Nov 2016 at 3 participating bariatric surgery centers were included in the multicenter analysis. For the systematic review and meta-analysis, a comprehensive search of multiple English databases was conducted. Random effects model was used. RESULTS: 130 consecutive patients across three centers underwent TORe with an endolumenal suturing device. These patients (mean age 47; mean BMI 36.8) had experienced 24.6% weight regain from nadir weight after RYGB. Average weight lost at 6, 12, and 18 months after TORe was 9.31 ± 6.7 kg (N = 84), 7.75 ± 8.4  kg (N = 70), 8 ± 8.8 kg (N = 46) (p < 0.01 for all three time points), respectively. The meta-analysis included 330 patients. The pooled weight lost at 12 months was 8.4 kg (95% CI 6.5-10.3) with no significant heterogeneity across included studies (p = 0.07). Overall, 14% of patients experienced nausea, 18% had pain and 8% required a repeat EGD. No serious adverse events reported. CONCLUSION: When implemented as part of a multidisciplinary intervention, TORe using endolumenal suturing is safe, reproducible, and effective approach to manage weight recidivism after RYGB and should be utilized early in the management algorithm of these patients.

Surgery for Primary Hyperparathyroidism with Normal Non-suppressed Parathyroid Hormone can be Both Challenging and Successful.

BACKGROUND: Criteria for diagnosing primary hyperparathyroidism (PHPT) include hypercalcemia in the presence of parathyroid hormone (PTH) levels that are either elevated (classic PHPT) or normal but non-suppressed. However, there is no standard definition of what constitutes normal non-suppressed levels, and data are lacking regarding the potential for surgical cure in these patients. METHODS: A retrospective review of patients undergoing parathyroidectomy for sporadic PHPT between 2012 and 2014 was performed. Patients with normal PTH were compared to classic PHPT patients to assess demographics, imaging, operative findings, and outcomes. RESULTS: In total, 332 patients met study criteria, and 60 (18%) had normal PTH levels. Negative sestamibi scans were seen more often with normal PTH levels (18.3 vs. 4.8%, p < 0.001). Patients with normal PTH were more likely to have ≥2 glands removed (26.7 vs. 14.3%, p = 0.02), and the specimens were more likely to be classified as only mildly hypercellular or normocellular (20 vs. 2.9%, p < 0.001). Average follow-up was 24 months (range 6-55). Cure rate was 88% in the normal PTH group, compared to 96% in classic PHPT (p = 0.02). Among patients with normal PTH, those with PTH ≤ 55 pg/mL had an 83% cure rate, whereas those with PTH 56-65 had a 96% cure rate (p = 0.12). CONCLUSIONS: Parathyroidectomy can have a high cure rate in the context of normal PTH levels despite an increased likelihood of negative imaging and multigland resection. Operative success is equivalent to classic PHPT when PTH levels are > 55 pg/mL.