Apparent failed and discordant adrenal vein sampling: A potential confounding role of cortisol cosecretion?

OBJECTIVE: Adrenal vein sampling (AVS) and computed tomography (CT) often show confusingly discordant lateralisation results in primary aldosteronism (PA). We tested a biochemical algorithm using AVS data to detect cortisol cosecretion as a potential explanation for discordant cases. DESIGN: Retrospective analysis from a large PA + AVS database. PATIENTS: All patients with PA and AVS, 2005-2020. MEASUREMENTS: An algorithm using biochemical data from paired AVS + CT images was devised from physiological first principles and informed by data from unilateral, AVS-CT concordant patients. The algorithm involved calculations based upon the expectation that low cortisol levels exist in adrenal vein effluent opposite an aldosterone-and-cortisol-producing adrenal mass and may reverse lateralisation due to inflated aldosterone/cortisol ratios. MAIN OUTCOMES: The algorithm was applied to cases with discordant CT-AVS lateralisation to determine whether this might be a common or explanatory finding. Clinical and biochemical characteristics of identified cases were collected via chart review and compared to CT-AVS concordant cases to detect evidence of biological plausibility for cortisol cosecretion. RESULTS: From a total of 588 AVS cases, 141 AVS + CT pairs were clear unilateral PA cases, used to develop the three-step algorithm for AVS interpretation. Applied to 88 AVS + CT discordant pairs, the algorithm suggested possible cortisol cosecretion in 40%. Case review showed that the proposed cortisol cosecretors, as identified by the algorithm, had low/suppressed adrenocorticotropic hormone levels, larger average nodule size and lower plasma aldosterone. CONCLUSIONS: Pending external validation and outcome verification by surgery and tissue immunohistochemistry, cortisol cosecretion from aldosteronomas may be a common explanation for discordant CT-AVS results in PA.

Intraoperative parathormone monitoring to predict operative success in patients with normohormonal hyperparathyroidism.

BACKGROUND: It is unclear whether parathyroidectomy guided by intraoperative parathormone (PTH) monitoring is predictive of operative success in patients with normohormonal hyperparathyroidism (nhHPT), a variant of primary hyperparathyroidism (pHPT) in which patients develop clinical manifestations similar to those of pHPT. This study examined intraoperative PTH monitoring in patients undergoing parathyroidectomy for nhHPT. METHODS: We performed a retrospective review of prospectively collected data from adult (age > 18 yr) patients who underwent parathyroidectomy for pHPT at 1 of 2 North American medical centres (in Calgary, Alberta, Canada, or Miami, Florida, United States) between 2007 and 2015. In patients with nhHPT, we used the criterion of an intraoperative decrease of more than 50% in PTH after abnormal gland excision. We defined operative success as continuous eucalcemia more than 6 months after parathyroidectomy. RESULTS: Of 333 patients, 38 (11.4%) had nhHPT, with mean preoperative calcium and PTH levels of 2.7 mmol/L and 53 pg/dL, respectively. An intraoperative decrease of more than 50% in PTH level was seen in 27 patients (71.0%) with nhHPT and 265 patients (89.8%) with classic pHPT at 5 minutes (p < 0.001); the corresponding values at 20 minutes were 35 (92.1%) and 286 (96.9%). Although 5 patients (13.2%) with nhHPT did not reach this criterion until 20 minutes, the rate of operative success was still 97.0% at long-term follow-up (mean 13 mo, range 6-67 mo). Of the 38 patients, 3 (7.9%) did not have an intraoperative decrease of more than 50% in PTH level by 20 minutes. Two of the 3 achieved operative success and remained normocalemic, and 1 developed recurrent disease at 12 months. CONCLUSION: Parathyroidectomy guided by intraoperative PTH monitoring accurately predicted operative success in patients with nhHPT. Intraoperative PTH monitoring may also help identify multiglandular disease in patients with nhHPT, using criteria similar to those in classic pHPT, with comparable operative success.

Multifocal Small Bowel Neuroendocrine Tumours.

In contemporary surgical series, the incidence of multifocal tumours (MFT) in small bowel neuroendrocrine tumours (SBNET) is as high as 50%. Familial forms of SBNET appear to have an even higher rate of MFTs in the range of 80%. Multifocal disease poses several challenges and questions for the operating surgeon, including the cause of the disease whether it is local metastases or a genetic field defect, the extent of the resection, and the prognosis. The etiology of these multiple tumours appears to be multifactorial and may represent localized metastases in some, a genetic mutation resulting in the rare familial form of this disease in others, or the integration of genetic and epigenetic events within the bowel. Contrary to historical series, recent data suggest that MFT are not associated with a poorer prognosis. The challenge remains on the long-term surveillance of these unique tumours.

A Multi-institutional Comparison of Adrenal Venous Sampling in Patients with Primary Aldosteronism: Caution Advised if Successful Bilateral Adrenal Vein Sampling is Not Achieved.

INTRODUCTION: In patients with primary aldosteronism (PA), adrenal venous sampling (AVS) is recommended to differentiate between unilateral (UNI) or bilateral (BIL) adrenal disease. A recent study suggested that lateralization could be predicted, based on the ratio of aldosterone/cortisol levels (A/C) between the left adrenal vein (LAV) and inferior vena cava (IVC), with a 100% positive predictive value (PPV). This study aimed to validate those findings utilizing a larger, multi-institutional cohort. METHODS: A retrospective review was performed of patients with PA who underwent AVS from 2 tertiary-care institutions. Laterality was predicted by an A/C ratio of >3:1 between the dominant and non-dominant adrenal. AVS results were compared to LAV/IVC ratios utilizing the published criteria (Lt ≥ 5.5; Rt ≤ 0.5). RESULTS: Of 222 patients, 124 (57%) had UNI and 98 (43%) had BIL disease based on AVS. AVS and LAV/IVC findings were concordant for laterality in 141 (64%) patients (69 UNI, 72 BIL). Using only the LAV/IVC ratio, 54 (24%) patients with UNI disease on AVS who underwent successful surgery would have been assumed to have BAH unless AVS was repeated, and 24 (11%) patients with BIL disease on AVS may have been incorrectly offered surgery (PPV 70%). Based on median LAV/IVC ratios (left 5.26; right 0.31; BIL 2.84), no LAV/IVC ratio accurately predicted laterality. DISCUSSION: This multi-institutional study of patients with both UNI and BIL PA failed to validate the previously reported PPV of LAV/IVC ratio for lateralization. Caution should be used in interpreting incomplete AVS data to differentiate between UNI versus BIL disease and strong consideration given to repeat AVS prior to adrenalectomy.

Hemodynamic Stability During Pheochromocytoma Resection: Lessons Learned Over the Last Two Decades.

BACKGROUND: Ideal perioperative management of pheochromocytomas/paragangliomas (pheo) is a subject of debate and can be highly variable. The purpose of this study was to identify potential predictive factors of hemodynamic instability during pheo resection. METHODS: A retrospective review of pheo resections from 1992 to 2013 was undertaken. Intraoperative hemodynamics, patient demographics, tumor characteristics, and perioperative management were examined. Postoperative intensive-care admission, myocardial infarction, stroke, and 30-day mortality were reviewed. Linear regression was used to analyze factors influencing intraoperative hemodynamics. RESULTS: During the 20-year study period, 100 patients underwent pheo resection. Postoperative morbidity and mortality was significantly reduced (p = 0.003) in the last 10 years of practice, and there was a trend towards greater morbidity and mortality with intraoperative hemodynamic instability (p = 0.06). The preoperative dose of phenoxybenzamine and the number of laparoscopic procedures has increased in the last decade [59 mg (95 % CI 32-108) to 106 mg (95 % CI 91-124), p = 0.008, and 27 vs. 54 %, p = 0.05, respectively]. Increased preoperative phenoxybenzamine dose was a significant predictor of improved intraoperative hemodynamic stability (p = 0.01). Lack of intraoperative magnesium use resulted in greater hemodynamic instability as preoperative systolic blood pressure increased (p = 0.002). CONCLUSIONS: Postoperative outcomes following pheo resection have improved over the last two decades. Preoperative α-blockade plays a significant role in improving intraoperative hemodynamics and post-op outcomes. Increased doses of phenoxybenzamine and utilization of laparoscopic approaches have likely contributed to improved outcomes in the last decade. Intraoperative magnesium use may provide protection against hemodynamic instability and warrants further study.

Consensus Recommendations for the Diagnosis and Management of Pancreatic Neuroendocrine Tumors: Guidelines from a Canadian National Expert Group.

Pancreatic neuroendocrine tumors (pNETs) are rare heterogeneous tumors that have been steadily increasing in both incidence and prevalence during the past few decades. Pancreatic NETs are categorized as functional (F) or nonfunctional (NF) based on their ability to secrete hormones that elicit clinically relevant symptoms. Specialized diagnostic tests are required for diagnosis. Treatment options are diverse and include surgical resection, intraarterial hepatic therapy, and peptide receptor radionuclide therapy (PRRT). Systemic therapy options include targeted agents as well as chemotherapy when indicated. Diagnosis and management should occur through a collaborative team of health care practitioners well-experienced in managing pNETs. Recent advances in pNET treatment options have led to the development of the Canadian consensus document described in this report. The discussion includes the epidemiology, classification, pathology, clinical presentation and prognosis, imaging and laboratory testing, medical and surgical management, and recommended treatment algorithms for pancreatic neuroendocrine cancers.

Cognitive impairment associated with carcinoid syndrome.

OBJECTIVES: To evaluate the cognitive performance of patients with carcinoid syndrome (CS) compared with population norms and cancer patients with non-neuroendocrine (non-NET) liver metastases. BACKGROUND: The release of serotonin into the systemic circulation from metastatic small bowel neuroendocrine tumors (SB NET) causes CS. Many patients with CS followed in a multidisciplinary NET clinic seemed to exhibit a unique cognitive impairment. Because serotonin is known to influence a range of cognitive function, the question arouse as to whether cognitive impairment is another manifestation of CS. METHODS: Patients were recruited from the multidisciplinary NET and the hepatobilary cancer clinics at the cancer center. The CS group consisted of patients with proven SB NETs metastatic to liver; the cancer comparison group consisted of patients with liver metastases from non-NET cancer. All completed a self-reported cognitive questionnaire and a battery of 6 standardized neurocognitive tests. Both groups were compared to age/sex/educational-matched norms. RESULTS: Thirty-six patients with CS and 20 with non-NET metastases were enrolled. Patients with CS reported greater cognitive dysfunction in all cognitive domains than both norms and the comparison cancer group. On cognitive testing, patients with CS demonstrated weakness in initiation, processing speed, visual memory, cognitive efficiency, and delayed verbal recall compared with norms. Although the patients with non-NET cancer also demonstrated some cognitive dysfunction compared with norms, the patients with CS did significantly worse on delayed recall (P = 0.03) and marginally slower on speeded mental flexibility (P = 0.097) compared with patients with non-NET cancer. CONCLUSION: This study confirmed our clinical observation that patients with CS suffer from cognitive impairment that is different from the non-NET cancer group and population norms.

A clinical prediction score for diagnosing unilateral primary aldosteronism may not be generalizable.

BACKGROUND: A published clinical prediction score indicated that a unilateral adrenal adenoma and either hypokalemia or an estimated glomerular filtration rate of 100 ml/min/1.73 m2 was 100% specific for unilateral primary aldosteronism. This study aimed to validate this score in a separate cohort of patients with primary aldosteronism. METHODS: A review of patients with primary aldosteronism from June 2005 to July 2013 at a single center's hypertension clinic. One hundred twelve patients with primary aldosteronism underwent successful adrenal vein sampling and the 110 patients with full data available were included in the final analysis. Adrenal vein sampling was performed all patients desiring surgery by the simultaneous collection of sample prior to and 15 minutes after a cosyntropin infusion with a 3:1 aldosterone/cortisol ratio diagnosing unilateral primary aldosteronism. The derived score was applied to the cohort. Sensitivity and specificity were calculated for clinical prediction score of ≥5 points. RESULTS: There were 64 patients found to have unilateral primary aldosteronism and 48 had bilateral disease. A score ≥5 points had 64% sensitivity (95% confidence interval, 51-76) and 85% specificity (95% confidence interval, 71-94) for unilateral disease. Four patients had lateralization of primary aldosteronism to the side contralateral to the adenoma. CONCLUSIONS: The 100% specificity of the score for the unilateral origin of primary aldosteronism was not validated in this cohort with a score of ≥5 points. At best, a high score in this prediction rule may be an additional tool for helping to confirm a decision to offer patients adrenal vein sampling.

Cushing syndrome from an ACTH-producing pheochromocytoma or paraganglioma: structured review of 94 cases.

Adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas are rare neuroendocrine tumors that co-secrete excess catecholamines and adrenocorticotropic hormone, resulting in Cushing syndrome (CS). This review aims to summarize important patient characteristics, investigations, and outcomes in all cases reported in the English literature. A literature search was conducted to identify all English-language case reports and case series describing adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas. Relevant characteristics were systematically recorded. Cases that did not provide definitive evidence of an adrenocorticotropin (ACTH)-producing pheochromocytoma/paraganglioma were excluded. Our search strategy identified 93 published cases that met the inclusion criteria. We additionally reported one patient for a total of 94 cases. Details related to patient characteristics, laboratory data, and outcomes were commonly underreported. The median age was 47 years, and females accounted for 72% of cases. A cushingoid appearance was reported in 82% of patients, and hypertension in 86%. Infections were reported in 23% of patients. Urinary metanephrines were elevated at least three-fold above normal in 74% of cases. ACTH levels were high in 88% of patients and inappropriately normal in 12%. The median 24-hour urinary cortisol was 21-fold the upper limit of normal. Adrenalectomy was performed in nearly all patients, with 88% achieving a cure for both catecholamine and glucocorticoid excess. A total of 11 patients died. Metastases were uncommon (6%). Adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas are associated with considerable morbidity and mortality. It should be considered in the diagnostic workup of all patients with ectopic CS. Surgical cure is achieved in most patients, and infections are the leading cause of peri-operative mortality.

Radiation Exposure from GEP NET Surveillance.

BACKGROUND: Neuroendocrine tumors (NET) are neoplasms that secrete peptides and neuroamines. For gastroenteropancreatic (GEP) NET, surgical resection represents the only curative option. Ten-year imaging surveillance programs are recommended due to long time-to-recurrence following resection. We performed retrospective chart review evaluating radiation exposure and practice patterns from surveillance of completely resected GEP NET. METHODS: We performed a retrospective cohort study of cases with well-differentiated GEP NET from January 2005 to July 2020. Location of primary, modality of imaging, and duration of follow-up were collected. Dosimetry data was collected to calculate effective dose. RESULTS: 62 cases were included with 422 surveillance scans performed. Cross-sectional imaging was used in 82% and functional imaging was used in 18% of scans. Mean number of scans per year was 1.25 (0.42-3). Mean total effective dose was 56.05 mSv (SD 45.56; 0 to 198 mSv) while mean total effective dose per year was 10.62 mSv (SD 9.35; 0 to 45 mSv). Over the recommended ten years of surveillance the estimated total effective dose was 106 mSv. CONCLUSIONS: Surveillance of completely resected GEP NET results in cumulative radiation doses in the range associated with secondary malignancy development. Strategies to minimize radiation exposure in surveillance should be considered in future guideline development.

Use of perioperative telotristat in a patient with carcinoid heart disease.

Summary: Carcinoid heart disease is a rare complication of carcinoid syndrome, resulting in right-sided valvular heart disease and subsequent heart failure due to long-term exposure to vasoactive substances. The management of this condition is complex, often requiring surgical intervention. Current perioperative regimens entail the use of prophylactic somatostatin analogs to prevent carcinoid crisis; however, regimens vary widely among practitioners and evidence supporting their efficacy in this clinical setting is mixed. This case report describes the perioperative management of a 65-year-old man with carcinoid heart disease requiring tricuspid and pulmonary valve replacement surgery. As an adjunct to somatostatin analog therapy, the novel tyrosine hydroxylase inhibitor, telotristat, was initiated preoperatively. This combination resulted in normalization of preoperative urinary 5-HIAA levels. The patient successfully underwent tricuspid and pulmonic valve replacement without evidence of carcinoid crisis. This clinical case is the first published documenting the use of telotristat in the perioperative period in a patient with carcinoid syndrome and carcinoid heart disease and was associated with a good long-term outcome despite the high-risk nature of the case. Learning points: Carcinoid crisis is a life-threatening complication of carcinoid syndrome, resulting in hemodynamic instability, bronchospasm, and arrhythmia. Cardiac surgical patients with carcinoid syndrome present a unique challenge as they are subject to physiologic conditions and medications which can potentiate intraoperative carcinoid crisis. Perioperative management of patients with carcinoid syndrome currently entails the use of prophylactic somatostatin analogs; however, these agents do not prevent carcinoid crisis in all cases. Telotristat, a tryptophan hydroxylase inhibitor, shows promise as an adjunctive therapy to somatostatin analogs to reduce the risk of intraoperative carcinoid crisis.

Time to Benefit of Surgery vs Targeted Medical Therapy for Patients With Primary Aldosteronism: A Meta-analysis.

CONTEXT: Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, but the comparative outcomes of targeted treatment remain unclear. OBJECTIVE: To compare the clinical outcomes in patients treated for primary aldosteronism over time. METHODS: Medline and EMBASE were searched. Original studies reporting the incidence of mortality, major adverse cardiovascular outcomes (MACE), progression to chronic kidney disease, or diabetes following adrenalectomy vs medical therapy were selected. Two reviewers independently abstracted data and assessed study quality. Standard meta-analyses were conducted using random-effects models to estimate relative differences. Time to benefit meta-analyses were conducted by fitting Weibull survival curves to estimate absolute risk differences and pooled using random-effects models. RESULTS: 15 541 patients (16 studies) with PA were included. Surgery was consistently associated with an overall lower risk of death (hazard ratio [HR] 0.34, 95% CI 0.22-0.54) and MACE (HR 0.55, 95% CI 0.36-0.84) compared with medical therapy. Surgery was associated with a significantly lower risk of hospitalization for heart failure (HR 0.48 95% CI 0.34-0.70) and progression to chronic kidney disease (HR 0.62 95% CI 0.39-0.98), and nonsignificant reductions in myocardial infarction and stroke. In absolute terms, 200 patients would need to be treated with surgery instead of medical therapy to prevent 1 death after 12.3 (95% CI 3.1-48.7) months. CONCLUSION: Surgery is associated with lower all-cause mortality and MACE than medical therapy for PA. For most patients, the long-term surgical benefits outweigh the short-term perioperative risks.

Biomarkers to Inform Prognosis and Treatment for Unresectable or Metastatic GEP-NENs.

Importance: Evidence-based treatment decisions for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) require individualized patient-centered decision-making that accounts for patient and cancer characteristics. Objective: To create an accessible guidance document to educate clinicians and patients on biomarkers informing prognosis and treatment in unresectable or metastatic GEP-NENs. Methods: A multidisciplinary panel in-person workshop was convened to define methods. English language articles published from January 2016 to January 2023 in PubMed (MEDLINE) and relevant conference abstracts were reviewed to investigate prognostic and treatment-informing features in unresectable or metastatic GEP-NENs. Data from included studies were used to form evidence-based recommendations. Quality of evidence and strength of recommendations were determined using the Grading of Recommendations, Assessment, Development and Evaluations framework. Consensus was reached via electronic survey following a modified Delphi method. Findings: A total of 131 publications were identified, including 8 systematic reviews and meta-analyses, 6 randomized clinical trials, 29 prospective studies, and 88 retrospective cohort studies. After 2 rounds of surveys, 24 recommendations and 5 good clinical practice statements were developed, with full consensus among panelists. Recommendations focused on tumor and functional imaging characteristics, blood-based biomarkers, and carcinoid heart disease. A single strong recommendation was made for symptomatic carcinoid syndrome informing treatment in midgut neuroendocrine tumors. Conditional recommendations were made to use grade, morphology, primary site, and urinary 5-hydroxyindoleacetic levels to inform treatment. The guidance document was endorsed by the Commonwealth Neuroendocrine Tumour Collaboration and the North American Neuroendocrine Tumor Society. Conclusions and Relevance: The study results suggest that select factors have sufficient evidence to inform care in GEP-NENs, but the evidence for most biomarkers is weak. This article may help guide management and identify gaps for future research to advance personalized medicine and improve outcomes for patients with GEP-NENs.

The effect of wait times on oncological outcomes from periampullary adenocarcinomas.

BACKGROUND: Overall few patients presenting with periampullary adenocarcinomas have resectable lesions. We postulated that rapid diagnosis and treatment would enhance the likelihood of successful resection, improving survival. METHODS: A retrospective analysis of patients undergoing surgery for resection of a pancreatic or periampullary lesion was conducted. Resection rate, disease stage and survival were evaluated as a function of wait times. RESULTS: Pancreatic resections were booked in 355 patients. Of 193 patients with periampullary adenocarcinomas, 119 patients (61.7%) had resectable disease. There was no difference in median time from initial physician consultation to surgery in patients with resectable and unresectable disease (61 days vs. 64 days, respectively). The likelihood of successful resection was virtually identical in patients with wait times ≤ 30 and > 30 days (from surgical consultation to procedure). There was a trend toward a higher T-stage in patients who waited >30 days for surgery (P = 0.055). However, there was no difference in survival as a function of wait time. CONCLUSIONS: This series does not demonstrate an advantage for rapid diagnosis and surgery, in terms of resection rate and survival. However, further study is required in a larger cohort of patients, to confirm these findings.

Perception versus reality: A case-matched study assessing the intraoperative hemodynamics of minimally invasive retroperitoneal versus transperitoneal approach to pheochromocytomas.

BACKGROUND: Pheochromocytomas produce excess catecholamines that can result in intraoperative hemodynamic instability. Centers have reported variations in intraoperative hemodynamics with the retroperitoneoscopic versus the laparoscopic transperitoneal approach to adrenalectomies. When the retroperitoneoscopic approach was initiated for pheochromocytomas at our institution, the perception was of improved intraoperative hemodynamics, hypothesizing that increased retroperitoneoscopic insufflation pressures caused decreased venous return and less fluctuation in circulating catecholamines. The purpose of this study was to examine if a difference in intraoperative hemodynamics exists between a size-matched cohort of laparoscopic transperitoneal and retroperitoneoscopic pheochromocytoma patients. METHODS: Unilateral adrenalectomies for pheochromocytoma performed via laparoscopic transperitoneal or retroperitoneoscopic approaches from 2015 to 2021 were identified from a surgical database. As larger tumors often underwent a laparoscopic transperitoneal approach, cases were matched 1:1 by tumor size. All patients received phenoxybenzamine. Groups were compared by patient characteristics, preoperative blockade, intraoperative hemodynamics and management, and early postoperative outcomes. RESULTS: There were 13 laparoscopic transperitoneal adrenalectomy cases matched to 13 retroperitoneoscopic cases according to tumor size. Both groups (laparoscopic transperitoneal and retroperitoneoscopic) were similar for age (53 years), body mass index (28.5 vs 29.7), sex (69% female), and side (8 vs 7 right). There was no difference in preoperative 24-hour urine metanephrines/normetanephrines (9.9/8.0 vs 2.4/5.7 µmol/day). The phenoxybenzamine dose was similar in both groups (112 vs 114 mg/24 hours), as were baseline heart rate, blood pressure, and mean arterial pressure. There was no difference in any intraoperative hemodynamic parameters or vasoactive interventions. Operative time, length of stay, and 30-day emergency visits were similar between groups. CONCLUSION: This matched cohort study did not find a difference in intraoperative hemodynamics between laparoscopic transperitoneal and retroperitoneoscopic adrenalectomy approaches for pheochromocytoma in appropriately selected and blocked patients.

Practical considerations when providing palliative care to patients with neuroendocrine tumors in the context of routine disease management or hospice care.

This serves as a white paper by the North American Neuroendocrine Tumor Society (NANETS) on the practical considerations when providing palliative care to patients with neuroendocrine tumors in the context of routine disease management or hospice care. The authors involved in the development of this manuscript represent a multidisciplinary team of patient advocacy, palliative care, and hospice care practitioners, endocrinologist, and oncologists who performed a literature review and provided expert opinion on a series of questions often asked by our patients and patient caregivers affected by this disease. We hope this document serves as a starting point for oncologists, palliative care teams, hospice medical teams, insurers, drug manufacturers, caregivers, and patients to have a frank, well-informed discussion of what a patient needs to maximize the quality of life during a routine, disease-directed care as well as at the end-of-life.