McKenzie, Travis J.

Objective Increased visceral fat and sarcopenia are cardiovascular risk factors that may explain increased cardiovascular morbidity and frailty in patients with adrenal adenomas. Our objective was to compare body composition measurement of patients with adrenal adenomas to referent subjects without adrenal disease. Design Cross-sectional study, 2014–2018. Methods Participants were adults with nonfunctioning adrenal tumor (NFAT), mild autonomous cortisol secretion (MACS), and Cushing syndrome (CS) and age, sex, and BMI 1:1 matched referent subjects without adrenal disorders. Main outcome measures were body composition measurements calculated from abdominal CT imaging. Intra-abdominal adipose tissue and muscle mass measurements were performed at the third lumbar spine level. Results Of 227 patients with adrenal adenomas, 20 were diagnosed with CS, 76 with MACS, and 131 with NFAT. Median age was 56 years (range: 18–89), and 67% were women. When compared to referent subjects, patients with CS, MACS, and NFAT demonstrated a higher visceral fat (odds ratio (OR): 2.2 (95% CI: 0.9–6.5), 2.0 (1.3–3.2), and 1.8 (1.2–2.7) and a lower skeletal muscle area (OR: 0.01 (95% CI: 0–0.09), 0.31 (0.18–0.49), and 0.3 (1.2–2.7)) respectively. For every 1 µg/dL cortisol increase after overnight dexamethasone, visceral fat/muscle area ratio increased by 2.3 ( P = 0.02) and mean total skeletal muscle area decreased by 2.2 cm 2 ( P = 0.03). Conclusion Patients with adrenal adenomas demonstrate a lower muscle mass and a higher proportion of visceral fat when compared to referent subjects, including patients with NFAT. Even a subtle abnormality in cortisol secretion may impact health of patients with adenomas.

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with an annual incidence of ~1 case per million population. Differentiating between ACC and benign adrenocortical tumors can be challenging in patients who present with an incidentally discovered adrenal mass, due to the limited specificity of standard diagnostic imaging. Recently, urine steroid metabolite profiling has been prospectively validated as a novel diagnostic tool for the detection of malignancy with improved accuracy over current modalities. Surgery represents the only curative treatment for ACC, although local recurrence and metastases are common, even after a margin-negative resection is performed. Unlike other intra-abdominal cancers, the role of minimally invasive surgery and lymphadenectomy in ACC is controversial. Adjuvant therapy with the adrenolytic drug mitotane is used to reduce the risk of recurrence after surgery, although evidence supporting its efficacy is limited; it is also currently unclear whether all patients or a subset with the highest risk of recurrence should receive this treatment. Large-scale pan-genomic studies have yielded insights into the pathogenesis of ACC and have defined distinct molecular signatures associated with clinical outcomes that may be used to improve prognostication. For patients with advanced ACC, palliative combination chemotherapy with mitotane is the current standard of care; however, this is associated with poor response rates (RR). Knowledge from molecular profiling studies has been used to guide the development of novel targeted therapies; however, these have shown limited efficacy in early phase trials. As a result, there is an urgent unmet need for more effective therapies for patients with this devastating disease.

Autonomous cortisol secretion (ACS) affects up to 50% of patients with adrenal adenomas. Despite the limited evidence, clinical guidelines recommend measurement of serum concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and corticotropin (ACTH) to aid in the diagnosis of ACS. Our objective was to determine the accuracy of serum concentrations of DHEA-S and ACTH in diagnosing ACS. We conducted a retrospective single center study of adults with adrenal adenoma evaluated between 2000−2020. Main outcome measure was diagnostic accuracy of DHEA-S and ACTH. ACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. Of 468 patients, ACS was diagnosed in 256 (55%) patients with a median post-DST cortisol of 3.45 mcg/dL (range, 1.9–32.7). Patients with ACS demonstrated lower serum concentrations of DHEA-S (35 vs. 87.3 mcg/dL, p < 0.0001) and ACTH (8.3 vs. 16 pg/mL, p < 0.0001) compared to patients with non-functioning adrenal tumors (NFAT). Serum DHEA-S concentration <40 mcg/dL diagnosed ACS with 84% specificity and 81% PPV, while serum ACTH concentration <10 pg/mL diagnosed ACS with 75% specificity and 78% PPV. The combination of serum concentrations of DHEA-S <40 mcg/dL and ACTH <10 pg/mL diagnosed ACS with the highest accuracy with 92% specificity and 87% PPV. Serum concentrations of DHEA-S and ACTH provide additional value in diagnosing ACS.

Mesenchymal stem/stromal cells (MSCs) facilitate repair in experimental diabetic kidney disease (DKD). However, the hyperglycemic and uremic milieu may diminish regenerative capacity of patient-derived therapy. We hypothesized that DKD reduces human MSC paracrine function. Adipose-derived MSC from 38 participants with DKD and 16 control subjects were assessed for cell surface markers, trilineage differentiation, RNA sequencing (RNA-seq), in vitro function (coculture or conditioned medium experiments with T cells and human kidney cells [HK-2]), secretome profile, and cellular senescence abundance. The direction of association between MSC function and patient characteristics were also tested. RNA-seq analysis identified 353 differentially expressed genes and downregulation of several immunomodulatory genes/pathways in DKD-MSC versus Control-MSC. DKD-MSC phenotype, differentiation, and tube formation capacity were preserved, but migration was reduced. DKD-MSC with and without interferon-γ priming inhibited T-cell proliferation greater than Control-MSC. DKD-MSC medium contained higher levels of anti-inflammatory cytokines (indoleamine 2,3-deoxygenase 1 and prostaglandin-E2) and prorepair factors (hepatocyte growth factor and stromal cell–derived factor 1) but lower IL-6 versus control-MSC medium. DKD-MSC medium protected high glucose plus transforming growth factor-β–exposed HK-2 cells by reducing apoptotic, fibrotic, and inflammatory marker expression. Few DKD-MSC functions were affected by patient characteristics, including age, sex, BMI, hemoglobin A1c, kidney function, and urine albumin excretion. However, senescence-associated β-galactosidase activity was lower in DKD-MSC from participants on metformin therapy. Therefore, while DKD altered the transcriptome and migratory function of culture-expanded MSCs, DKD-MSC functionality, trophic factor secretion, and immunomodulatory activities contributing to repair remained intact. These observations support testing of patient-derived MSC therapy and may inform preconditioning regimens in DKD clinical trials.

AbstractBackgroundTertiary 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 methodsWe 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.ResultsWe 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).ConclusionIn 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.

AbstractObjectiveTo describe the presentation and outcomes of patients with adrenal ganglioneuromas (AGNs).DesignSingle‐centre retrospective cohort study (1 January 1995 to 31 December 2019) and systematic review of literature (1 January 1980 to 19 November 2019).PatientsDiagnosed with histologically confirmed AGN.MeasurementsBaseline 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).ResultsThe 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.ConclusionsAGNs 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.

Background In Jan 2018, we began routinely obtaining neck ultrasound (US) with 123I/99Tc-sestamibi (MIBI) for parathyroid gland localization and to identify thyroid pathology in the setting of primary hyperparathyroidism (1HPT). The aim of this study is to assess if routine neck US is a useful adjunct to 123I/99Tc-MIBI in 1HPT. Methods Patients undergoing surgery for 1HPT with both 123I/99Tc-MIBI and US at our institution after implementation of routine US were reviewed. Biopsy and surgical management of thyroid pathology was evaluated. 123I/99Tc-MIBI and US results were compared to intraoperative findings to determine sensitivity and positive predictive value (PPV) for parathyroid localization. Results From January 2018 to September 2019, there were 423 patients (mean, 61 years) that met inclusion criteria (80% women). Thyroid nodules were found on US in 57%, mean size 1.3 + 0.8 cm. Fine needle aspiration (FNA) was performed in 87 patients with nodules (36%). 35 patients (8.5%) required total or partial thyroidectomy for diagnoses/treatment. Papillary thyroid cancer (PTC) was found in 3.5% of the cohort with micro-PTC 53% and PTC 1-2 cm 40%. A successful parathyroid operation for 1HPT was achieved in 98.6% of patients. Positive predictive value for localization of abnormal parathyroid glands was 97% when US and 123I/99Tc-MIBI had concordant findings. Discussion Routine use of US in 1HPT commonly identifies nodules that are benign or low-risk PTC. Ultrasound is less sensitive for parathyroid localization but when used with 123I/99Tc-MIBI, concordant imaging has a high PPV.

AbstractBackgroundThe 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.MethodsThe 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.ResultsA 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.ConclusionLymphadenectomy 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.

We performed a retrospective study of our large patient cohort aiming to examine the ability to predict postthyroidectomy hypocalcemia. A retrospective review of patients who underwent total or near-total thyroidectomy at our institution between 2008 and 2018 was performed. Postoperative hypocalcemia was defined as Ca level <8.0 mg/dL (reference range: 8.9–10.1 mg/dL) within 30 days of operation. Logistic regression was used to develop models for prediction of the occurrence of postoperative hypocalcemia. Inclusion criteria were met by 1463 patients. Hypocalcemia was documented in 223 patients (15%). Models based on parathyroid hormone (PTH) levels alone had an associated receiver operator characteristic with an areas under the curve (AUC) of 0.79. There was an inverse relationship between time of measurement and PTH levels within the first two hours after thyroidectomy ( P < 0.01). When measured two to six hours after closure, the predictive ability of PTH compared favorably (AUC = 0.82) with either earlier (within the first two hours after closure, AUC = 0.79) or later measurement (6–24 hours after closure, AUC = 0.77). When measured between two and six hours postoperatively, PTH < 19 pg/mL had a sensitivity of 90 per cent and negative predictive value of 96 per cent for postoperative hypocalcemia. The model that included the PTH level, concurrently measured total blood calcium level, and time of measurement had an improved predictive ability with an AUC of 0.87. PTH level of 19 pg/mL measured two to six hours after thyroidectomy had a sensitivity of 90 per cent and a negative predictive value of 96 per cent in our cohort. The model including postoperative PTH level, calcium level, and time of measurement may further improve the ability to predict postthyroidectomy hypocalcemia.