Pavel Nockel

Localization of Insulinoma Using 68Ga-DOTATATE PET/CT Scan

Context Reliable localization of insulinoma is critical for successful treatment. Objective This study compared the accuracy of 68Gallium DOTA-(Tyr3)-octreotate (Ga-DOTATATE) positron emission tomography (PET)/computed tomography (CT) to anatomic imaging modalities, selective arterial secretagogue injection (SASI), and intraoperative ultrasound (IO ultrasound) and palpation for localizing insulinoma in patients who were biochemically cured. Design, Setting, and Patients We conducted a retrospective analysis of 31 patients who had an insulinoma. The results of CT, magnetic resonance imaging (MRI), ultrasound, IO ultrasound, 68Ga-DOTATATE PET/CT, SASI, and operative findings were analyzed. Intervention, Main Outcome Measures, and Results The insulinomas were correctly localized in 17 out of 31 (55%) patients by CT, in 17 out of 28 (61%) by MRI, in 6 out of 28 (21%) by ultrasound, and in 9 out of 10 (90%) by 68Ga-DOTATATE. In 29 of 31 patients (93.5%) who had IO ultrasound, an insulinoma was successfully localized. Thirty patients underwent SASI, and the insulinoma was regionalized in 28 out of 30 patients (93%). In 19 out of 23 patients (83%), manual palpation identified insulinoma. In patients who had all 4 noninvasive imaging studies, CT was concordant with 68Ga-DOTATATE in 6 out of 9 patients (67%), MRI in 8 out of 9 (78%), ultrasound in 0 out of 9; the lesion was only seen by 68Ga-DOTATATE in 1 out of 9 (11%). Conclusions 68Ga-DOTATATE PET/CT identifies most insulinomas and may be considered as an adjunct imaging study when all imaging studies are negative and when a minimally invasive surgical approach is planned.

Association between neuroendocrine tumors biomarkers and primary tumor site and disease type based on total 68Ga-DOTATATE-Avid tumor volume measurements

OBJECTIVE To determine the association between neuroendocrine tumor (NET) biomarker levels and the extent of disease as assessed by 68Ga DOTATATE PET/CT imaging. DESIGN A retrospective analysis of a prospective database of patients with NETs. METHODS Fasting plasma chromogranin A (CgA), neuron-specific enolase (NSE), gastrin, glucagon, vasoactive intestinal peptide (VIP) and pancreatic polypeptide (PP), and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) levels were measured. Correlation between biomarkers and total 68Ga-DOTATATE-avid tumor volume (TV) was analyzed. RESULTS The analysis included 232 patients. In patients with pancreatic NETs (n = 112), 68Ga-DOTATATE TV correlated with CgA (r = 0.6, P = 0.001, Spearman). In patients with multiple endocrine neoplasia type 1 (n = 39), 68Ga-DOTATATE TV correlated with glucagon (r = 0.5, P = 0.01) and PP levels (r = 0.5, P = 0.049). In patients with von Hippel-Lindau (n = 24), plasma VIP (r = 0.5, P = 0.02) and PP levels (r = 0.7, P < 0.001) correlated with 68Ga-DOTATATE TV. In patients with small intestine NET (SINET, n = 74), 68Ga-DOTATATE TV correlated with CgA (r = 0.5, P = 0.02) and 5-HIAA levels (r = 0.7, P < 0.001), with 5-HIAA ≥8.1 mg/24 h associated with metastatic disease with high positive (81.8%) and negative (85.7%) predictive values (P = 0.001). 68Ga-DOTATATE TV in patients with NET of unknown primary (n = 16) and those with NET of other primary location (n = 30) correlated with 5-HIAA levels (r = 0.8, P = 0.002 and r = 0.7, P = 0.02 respectively). CONCLUSIONS Our data supports the use of specific NET biomarkers based on the site of the primary NET and the presence of hereditary syndrome-associated NET. High urinary 5-HIAA levels indicate the presence of metastatic disease in patients with SINET.

Preoperative genetic testing in pheochromocytomas and paragangliomas influences the surgical approach and the extent of adrenal surgery

Background. Our knowledge of the susceptibility genes for pheochromocytomas/paragangliomas has increased; however, data on its impact on surgical decision‐making has not been described. The aim of this study was to determine the effect of routine preoperative genetic testing on the operative intervention in patients with pheochromocytomas/paragangliomas. Methods. One‐hundred‐eight patients diagnosed with pheochromocytomas/paragangliomas who underwent 118 operations had preoperative genetic testing for 9 known pheochromocytoma/paraganglioma susceptibility genes. A retrospective analysis of a prospective database was performed to evaluate clinical factors associated with the surgical approach selected and the outcome of the surgical intervention. Results. In 51 patients (47%), a germline mutation was detected and one‐third had no family history of pheochromocytoma/paraganglioma. In 77 operations (65%), it was the first operative intervention for the disease site (60 laparoscopic, 17 open), and 41 (35%) were reoperative interventions (36 open, 5 laparoscopic). For initial operations, variables associated with whether an open or laparoscopic approach was used were tumor size (P = .009) and presence of germline mutation (P = .042). Sixty‐eight adrenal operations were performed (54 total, 14 cortical‐sparing). Variables significantly associated with a cortical‐sparing adrenalectomy being performed were the presence of germline mutation (P = .006) and tumor size (P = .013). Conclusion. Preoperative knowledge of the germline mutation status affects the surgical approach and extent of adrenalectomy.

Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is more aggressive and has a lesser rate of biochemical cure

Background. Hereditary primary hyperparathyroidism may be syndromic or nonsyndromic (familial isolated hyperparathyroidism). Recently, germline activating mutations in the GCM2 gene were identified in a subset of familial isolated hyperparathyroidism. This study examined the clinical and biochemical characteristics and the treatment outcomes of GCM2 mutation‐positive familial isolated hyperparathyroidism as compared to sporadic primary hyperparathyroidism. Methods. We performed a retrospective analysis of clinical features, parathyroid pathology, and operative outcomes in 18 patients with GCM2 germline mutations and 457 patients with sporadic primary hyperparathyroidism. Results. Age at diagnosis, sex distribution, race/ethnicity, and preoperative serum calcium concentrations were similar between the 2 groups. The preoperative serum levels of intact parathyroid hormone was greater in patients with GCM2‐associated primary hyperparathyroidism (239 ± 394 vs 136 ± 113, P = .005) as were rates of multigland disease and parathyroid carcinoma in the GCM2 group (78% vs 14.3%, P < .001 and 5% vs 0%, P = .04, respectively), but the biochemical cure rate was less in the GCM2 group (86% vs 99%, P < .001). Conclusion. GCM2‐associated primary hyperparathyroidism patients have greater preoperative parathyroid hormone levels, a greater rate of multigland disease, a lesser rate of biochemical cure, and a substantial risk of parathyroid carcinoma. Knowledge of these clinical characteristics could optimize the surgical management of GCM2‐associated familial isolated hyperparathyroidism.

In silico VHL Gene Mutation Analysis and Prognosis of Pancreatic Neuroendocrine Tumors in von Hippel–Lindau Disease

Context Patients with von Hippel-Lindau (vHL) disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types. Objective To define pancreatic neuroendocrine tumor (PNET) aggressiveness according to VHL genotype. Design A prospective natural history study. Setting The National Institutes of Health clinical center. Patients Patients with vHL disease, pancreatic manifestations, and germline missense VHL gene mutations. Intervention In-silico prediction of VHL mutation via five computational prediction models. Patients with >80% prediction for disease-causing mutations in all models [high predicted risk (HPR)] were compared with others [low predicted risk (LPR)]. Main Outcome Measure Rates of metastases, surgical intervention, and disease progression. Results Sixty-nine patients were included: 2 developed metastases, 12 needed surgery, and 31 had disease progression during a median follow-up of 60 months (range 13 to 84 months). Thirteen patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), the HPR group (n = 13) had a higher rate of disease progression than the LPR group (n = 43) in multivariable analysis (hazard ratio 3.6; 95% confidence interval, 1.1 to 11.9; P = 0.037). The HPR group also had a higher risk of developing metastases (P = 0.015). Among patients with codon 167 hotspot mutations (n = 26), those in the HPR group had a higher risk for disease progression (P = 0.03) than other patients. Conclusions Computational models for predicting the impact of missense VHL gene mutations may be used as a prognostic factor in patients with PNETs in the context of vHL disease.

Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment

Background: There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer. Methods: We compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database. Results: A total of 78 patients with familial nonmedullary thyroid cancer from 31 kindreds presented at a younger age (P = .04) and had a greater rate of T1 disease (P = .019), lymph node metastasis (P = .002), and the classic variant of papillary thyroid cancer on histology (P < .001) compared with the Surveillance, Epidemiology, and End Results cohort. Patients with ≥3 affected family members presented at a younger age (P = .04), had a lesser female‐to‐male ratio (P = .04), and had a greater rate of lymph node metastasis (P = .009). Compared with the Surveillance, Epidemiology, and End Results cohort, we found a higher prevalence of lymph node metastasis in familial nonmedullary thyroid cancer index cases (P = .003) but not in those diagnosed by screening ultrasonography (P = .58). Conclusion: Patients with familial nonmedullary thyroid cancer present at a younger age and have a greater rate of lymph node metastasis. The treatment for familial nonmedullary thyroid cancer should be more aggressive in patients who present clinically and in those who have ≥3 first‐degree relatives affected.

Radioguided Surgery With Gallium 68 Dotatate for Patients With Neuroendocrine Tumors

Importance Neuroendocrine tumors (NETs) express somatostatin receptors, which can be targeted with radiolabeled peptides. In a variety of solid tumors, radioguided surgery (RGS) has been used to guide surgical resection. Gallium 68 (68Ga) dota peptides have been shown to be more accurate than other radioisotopes for detecting NETs. A pilot study previously demonstrated the feasibility and safety of 68Ga-dotatate RGS for patients with NETs. Objective To evaluate what intraoperative techniques and thresholds define positive lesions that warrant resection during 68Ga-dotatate RGS. Design, Setting, and Participants This prospective cohort study, conducted between October 23, 2013, and February 14, 2018, included 44 patients with NETs who underwent 68Ga-dotatate RGS. Intervention Gallium 68–dotatate RGS. Main Outcomes and Measures The in vivo and ex vivo tumor to background ratio (TBR) was assessed for resected lesions and correlated with the histopathologic findings. Results Forty-four patients (22 women and 22 men; mean [SD] age, 51.0 [13.7] years) had 133 lesions detected on preoperative imaging scans, with a diagnosis of a pancreatic NET (19 of 44 [43%]), gastrointestinal NET (22 of 44 [50%]), and pheochromocytoma or paraganglioma (3 of 44 [7%]). The TBR was obtained by normalizing to the omentum (106 of 133 [79.7%]) or other solid organs (27 of 133 [20.3%]). The omentum had a significantly lower mean (SD) count than other solid organs for background count activity 3 hours after injection (22.1 [17.0] vs 34.5 [39.0]; P < .001). The lesions containing NETs had a higher TBR than those that did not contain NETs (18.9 vs 4.4; P < .001). On a receiver operating characteristic curve analysis, a TBR of 2.5 had a sensitivity of 90% and a specificity of 25%, and a TBR of 16 had a sensitivity of 54% and a specificity of 81%. Conclusions and Relevance A TBR of 2.5 or greater is a highly sensitive threshold for indicating a lesion to be consistent with a NET on histologic findings and thus warranting surgical resection. The omentum should be used as the background count activity for 68Ga-dotatate RGS for patients with abdominal NETs.

Incidence and management of postoperative hyperglycemia in patients undergoing insulinoma resection

PurposeIt has been proposed that rebound hyperglycemia after resection of insulinoma indicates a biochemical cure. However, there is scant objective data in the literature on the rate and need for intervention in hyperglycemia in patients undergoing resection of insulinoma. The goal of our study was to evaluate the rate of postoperative hyperglycemia, any predisposing factors, and the need for intervention in a prospective cohort study of all patients undergoing routine glucose monitoring.MethodsA retrospective analysis of 33 patients who had an insulinoma resected and who underwent routine postoperative monitoring of blood glucose (every hour for the first six hours then every four hours for the first 24 h) was performed. Hyperglycemia was defined as glucose greater than 180 mg/dL (10 mmol/l).ResultsTwelve patients (36%) developed hyperglycemia within 24 h (range 1–16 h). In patients with hyperglycemia, the mean maximum plasma glucose level was 221.5 mg/dL (range 97–325 mg/dL) (12.3 mmol/l), and four (33%) patients were treated with insulin. There was no significant difference in age, gender, body mass index (BMI), tumor size, biochemical profile, or surgical approach and extent of pancreatectomy between patients who developed hyperglycemia and those who did not. Pre-excision and post-excision intraoperative insulin levels were evaluated in 14 of 33 patients. The percentage decrease of the intraoperative insulin levels was not significantly different between patients who developed hyperglycemia and those who did not. All patients with postoperative hyperglycemia had normalization of their glucose levels, and none were discharged on anti-hyperglycemic agents.ConclusionsHyperglycemia is common after insulinoma resection, and a subset of patients require transient treatment with insulin.

Epidemiology of Adrenal Neoplasms

Adrenal neoplasms are common and are most commonly detected incidentally. The prevalence of adrenal neoplasms/incidentaloma ranges from 1 % to up to 8.7 % depending on patient age and the use of anatomic imaging studies. The estimated incidence is 2–8 cases per 100,000 individuals per year. Although the vast majority of adrenal neoplasms discovered incidentally are benign and nonfunctioning, work up to exclude functioning tumors and malignant disease is necessary. Long-term follow up is also important in patients with benign and nonfunctioning tumors as their natural history is not always innocuous. The main risk factor for developing adrenal neoplasms is a family history due to inherited mutations in susceptibility genes. We review the epidemiology of adrenal neoplasms to underscore the important elements that need to be considered when making management decisions regarding patients who have adrenal neoplasms identified on clinical presentation and those that are discovered incidentally.