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.

Persistence and Recurrence of Hypercalcemia After Parathyroidectomy Over 5 Decades (1965-2010) in a Community-based Cohort.

BACKGROUND: There is limited long-term follow-up of patients undergoing parathyroidectomy. Recurrence is described as 4% to 10%. This study evaluated persistence and recurrence of hypercalcemia in primary hyperparathyroidism after parathyroidectomy. METHODS: Single-institution retrospective (1965-2010) population-based cohort from Olmsted County (MN) of patients undergoing surgery for primary hyperparathyroidism. Patients' demographic data, preoperative and postoperative laboratory values, clinical characteristics, surgical treatment, and follow-up were noted. RESULTS: A total of 345 patients were identified, 75.7% female, and median age 58.4 years [interquartile range (IQR): 17.6]. In all, 68% of patients were asymptomatic and the most common symptoms were musculoskeletal complaints (28.4%) and nephrolithiasis (25.6%). Preoperative median serum calcium was 11 mg/dL (IQR: 10.8-11.4 mg/dL), and median parathyroid hormone was 90 pg/mL (IQR: 61-169 pg/dL). Bilateral cervical exploration was performed in 38% and single gland resection in 79% of cases. Median postoperative serum calcium was 9.2 mg/dL (IQR: 5.5-11.3). Nine percent of patients presented persistence of hypercalcemia, and recurrence was found in 14% of patients. Highest postoperative median serum calcium was 10 mg/dL (IQR: 6-12.4), and median number of postoperative calcium measurements was 10 (IQR: 0-102). Postoperative hypercalcemia was identified in 37% of patient. Fifty-three percent were attributed to secondary causes, most commonly medications, 22%. Three percent of patients required treatment for postoperative hypercalcemia. Median time to recurrence and death were 12.2 and 16.7 years, respectively. CONCLUSION: Recurrent hypercalcemia after successful parathyroidectomy is higher than previously reported. Most cases are transient and often associated to other factors with only the minority requiring treatment. Long-term follow-up of serum calcium should be considered in patients after successful parathyroidectomy.

Adrenal and juxta-adrenal schwannomas: A single-centre study.

OBJECTIVE: Adrenal schwannomas and juxta-adrenal schwannomas are rare tumours. We aimed to summarise their clinical, biochemical and imaging characteristics. DESIGN: Single-centre retrospective study of eligible patients between 1995 and 2022. PATIENTS AND MEASUREMENTS: Patients with a histopathologic diagnosis of adrenal or juxta-adrenal schwannoma. RESULTS: Twenty-four patients were diagnosed with either primary adrenal schwannoma (8, 33%) or juxta-adrenal schwannoma (16, 67%). Most tumours (21, 88%) were discovered incidentally on imaging. All tumours were unilateral, with 15 (62%) on the left and 9 (38%) on the right. At diagnosis, the median tumour size was 4 cm (range, 2-13 cm). Adrenal schwannomas were smaller when compared to juxta-adrenal schwannomas (median of 3.1 cm [range, 2-9 cm] vs. 4.6 cm [range, 2.3-13.3 cm], p = .037). On imaging, the tumours were round or oval in shape in 16 (70%), lobulated in 7 (30%), solid in 15 (68%), solid-cystic in 7 (32%), heterogeneous in 14 (61%) and homogeneous in 9 (39%). The median unenhanced computed tomography attenuation was 30 Hounsfield units (HU) (range, 12-38 HU). Of the 20 patients who underwent complete hormonal testing, all had nonfunctioning tumours. There was no recurrence or new tumour development in our cohort. CONCLUSIONS: Adrenal and juxta-adrenal schwannomas are nonfunctioning benign tumours that present with indeterminate radiographic features, including large tumour size and increased unenhanced CT attenuation. We did not find an imaging phenotype that was diagnostic of schwannoma. The diagnosis of this rare tumour is based on biopsy or resection.

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.

Effect of operative times in bariatric surgery on outcomes: a matched analysis of the MBSAQIP database.

BACKGROUND: The implications of operative time (OT) have been studied in different surgical specialties, showing a correlation with higher incidence rates of postoperative complications. However, the impact of OT on bariatric surgery complications is not well elucidated. METHODS: A retrospective review of the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database between 2015 and 2019 was performed. A total of 358,382 SG patients and 123,357 RYGB patients were included. The median OT was 68 min (10-720) and 113 min (10-640) for the sleeve gastrectomy (SG) group and the Roux-en-Y gastric bypass group, respectively. The groups were subdivided into two subgroups based on OT in comparison to the median time of each group. The subgroups were compared for surgical complications and outcomes. To reduce selection bias and risk of confounders, we performed a propensity score matching (PSM) for 22 variables. RESULTS: In the PSM-matched cohort, 18,915 SG and 6,495 RYGB patients were included in each subgroup. The SG cohort showed higher rates of Clavien-Dindo Class 1, 2, 3a, 4, and 5 complications as well as higher rates of readmission, reoperation, and reintervention in the longer OT group before matching. After PSM, the subgroup with longer times continued to have higher rates of Clavien-Dindo Class 2 complications and higher rates of readmission and reoperation. Similarly, there were higher rates of all Clavien-Dindo class complications as well as readmission, reoperation, and reintervention in the RYGB group with higher OT. After PSM, there were still higher rates of Clavien-Dindo Class 3a complications as well as readmission and reintervention in the RYGB subgroup with prolonged OT. CONCLUSION: In both SG and RYGB, longer OT was associated with increased rates of complications as well as readmission, reoperation, and reintervention. Surgeons should be cognizant of the increased rates of complications when operative times are longer.

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.

Ten year comparative analysis of sleeve gastrectomy, Roux-en-Y gastric bypass, and biliopancreatic diversion with duodenal switch in patients with BMI ≥ 50 kg/m2.

INTRODUCTION: Bariatric surgery is the most effective modality to stably reduce weight and related comorbidities in patients suffering from class II and III obesity. Data comparing long-term safety and efficacy of the three most effective bariatric operations are limited in patients with BMI ≥ 50 kg/m2, which complicate shared surgeon-patient decision making regarding optimal procedure selection. METHODS: A retrospective analysis was performed on all patients with BMI ≥ 50 kg/m2 who underwent biliopancreatic diversion with duodenal switch (BPD/DS), Roux-en-Y gastric bypass (RYGB), or sleeve gastrectomy (SG) at our institution between 2009 and 2019. Data collected from patients' electronic medical records included operative details as well as BMI and presence and resolution of obesity-related comorbidities at 0, 6, 12, 24, 48, and 60 months post-operatively. RESULTS: Among 537 patients with BMI ≥ 50 kg/m2 who had a primary bariatric procedure, 93 patients underwent BPD/DS (17.3%), 341 patients underwent RYGB (63.5%), and 103 patients underwent SG (19.2%). BMI decreased by 23.7 kg/m2 in BPD/DS, 14.7 kg/m2 in RYGB, and 13.6 kg/m2 in SG cohorts at 60 months post-operatively (p < 0.0001). The greatest %TWL occurred in BPD/DS cohort (38.4%) followed by the RYGB (26.3%) and SG (23.6%) cohorts (p < 0.0001). The thirty-day complication rate was 12.9% for BPD/DS, 4.7% for RYGB, and 8.7% for SG (p = 0.015). CONCLUSIONS: Our study demonstrated that the BPD/DS is the most effective operation at long-term reduction of BMI and achieved highest %TWL while SG and RYGB had similar results at 60 months post-op. BPD/DS is associated with increased early and late surgical complications compared to RYGB and SG.

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.

Presentation and outcomes of adrenal ganglioneuromas: A cohort study and a systematic review of literature.

OBJECTIVE: To describe the presentation and outcomes of patients with adrenal ganglioneuromas (AGNs). DESIGN: Single-centre retrospective cohort study (1 January 1995 to 31 December 2019) and systematic review of literature (1 January 1980 to 19 November 2019). PATIENTS: Diagnosed with histologically confirmed AGN. MEASUREMENTS: Baseline clinical, imaging and biochemical characteristics, recurrence rates and mortality. Subgroup analysis was performed on tumours with histologic elements of ganglioneuroma and pheochromocytoma (ie composite tumours). RESULTS: The cohort study included 45 patients with AGN, 20 (44%) of which had composite tumours. Compared to pure AGN, patients with composite tumour were older (median age, 62.5 vs. 35 years, p < .001), had smaller tumours (median size, 3.9 vs. 5.7 cm, p = .016) and were discovered incidentally less frequently (65% vs. 84%, p = .009). No recurrences or ganglioneuroma-specific mortality occurred during follow-up (range, 0-266 months). The systematic review included 14 additional studies and 421 patients. The mean age of diagnosis was 39 years, and 47% were women. AGNs were discovered incidentally in 72% of patients, were predominantly unilateral (99%) and had a mean diameter of 5.8 cm and an unenhanced computed tomography (CT) attenuation of -118 to 49 Hounsfield units (HU). On imaging, 69% of AGNs were homogenous, 41% demonstrated calcifications, and 40% were lobulated. CONCLUSIONS: AGNs are rare benign tumours that present with variable imaging features including large size, unenhanced CT attenuation >20 HU, calcifications and lobulated shape. Imaging characteristics can assist in establishing a diagnosis and avoiding an unnecessary adrenalectomy. The association of pheochromocytomas with AGNs is frequent. Diagnosis should include biochemical testing.

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.

Preoperative Imaging in Renal Transplant Patients with Tertiary Hyperparathyroidism.

BACKGROUND: Tertiary hyperparathyroidism following kidney transplantation is most commonly characterized by 4-gland hyperplasia, but single and double adenomatous disease has been demonstrated in this population as well. It is unknown whether preoperative imaging can assist in identifying patients who may qualify for focused surgery for adenomatous disease. MATERIALS AND METHODS: We performed a retrospective review of our patient database from 1998-2018 for patients with tertiary hyperparathyroidism following renal transplant. Patient charts were reviewed for patient demographics, laboratory values, preoperative imaging, operative findings, pathology, and complications. RESULTS: We identified 113 patients with tertiary hyperparathyroidism following renal transplant who underwent parathyroidectomy. There were 51 females and 62 males with a mean age of 53.4 ± 13.4 years. Median preoperative calcium and PTH were 10.9 mg/dl (IQR 10.3-11.2) and 228 pg/ml (IQR 118-305). Preoperative ultrasound was performed in 60 patients. Of these, 11 (18%) were negative, 38 (63%) showed 1-2 adenomas, and 11 (18%) showed ≥ 3 adenomas. 99mTc-sestamibi parathyroid scintigraphy was performed in 101/113 patients. Of these, 11 (11%) were negative, 62 (61%) showed 1-2 areas of discordant sestamibi uptake, and 28 (28%) showed ≥ 3 areas of discordant uptake. Ultimately, 19 (17%) patients had a single adenoma removed, 16 (14%) had 2 adenomas removed, and (69%) had multi-gland disease. There were 26 ectopic glands found in 21 patients, 42.3% of which were identified on preoperative imaging. 94.1% of patients were eucalcemic at last follow-up, mean (± SD) 5.8 ± 3.6 years. Adenomas that were visualized on ultrasound were larger on pathology than those non-visualized (997 ± 120 mg (mean ± SE) vs. 388 ± 109 mg, p = 0.0003). This was also true for parathyroid scintigraphy (647 ± 41 mg vs. 355 ± 51 mg, p = 0.0001). CONCLUSION: In patients with tertiary hyperparathyroidism, preoperative imaging can aid in predicting which patients will have 1-2 gland disease. In patients with 1-2 gland disease on congruent ultrasound and nuclear medicine imaging studies, the accuracy increases to 59%. Preoperative imaging can help identify ectopic glands. Larger adenomas are more likely to be identified on both imaging modalities.

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.