The efficacy of oral anticholinergics for sympathetic overactivity in a thoracic surgery clinic.

OBJECTIVE: Little is known of the success rates of oral anticholinergics for the treatment of primary hyperhidrosis and facial blushing as alternatives to surgical intervention. We examine predictors of success with these medications. METHODS: A retrospective review was performed at a single institution, including all patients presenting with symptoms of primary hyperhidrosis, facial blushing, or both from 2004 to 2015. All patients were offered a trial of oral anticholinergics. If oral anticholinergic therapy was not successful, patients were offered surgery. Statistical analyses were performed to compare patients who declined surgery given the trial of oral anticholinergics with those who proceeded with surgery. RESULTS: A total of 381 patients presented with symptoms of primary hyperhidrosis (86.6%), facial blushing (2.4%), or both (11.0%). A total of 230 patients (60.4%) declined surgery after using oral anticholinergics, and 151 patients (39.6%) chose surgery. Patients who declined surgery were more likely to have symptoms of primary hyperhidrosis without facial blushing (89.6% vs 82.1%; P = .02) or have primary symptoms involving the axilla, torso, scalp, or groin. Patients who proceeded with surgery had higher rates of palmar symptoms as a primary site (77.6% vs 61.1%; P = .01) and were more likely to have facial blushing alone or in combination with primary hyperhidrosis. Presentation with palmar symptoms and greater number of prior therapy attempts were independent predictors of proceeding with surgery after controlling for concomitant symptom type and location (P = .01 and P < .0001, respectively). CONCLUSIONS: The majority of patients presenting with sympathetic overactivity decline surgery when a trial of oral anticholinergics is included in the treatment algorithm. Facial blushing and palmar symptoms were each associated with choosing surgery.

Assessment of tumor growth in pancreatic neuroendocrine tumors in von Hippel Lindau syndrome.

BACKGROUND: The incidence of pancreatic neuroendocrine tumors (PNETs) is increasing, but only a subset of these heterogeneous tumors will progress to malignant disease, which is associated with a poor prognosis. Currently, there are limited data on the natural history of these tumors and it is difficult to determine which patients require surgical intervention because the risk of metastatic disease cannot be accurately determined. STUDY DESIGN: We conducted a prospective study of 87 patients with von Hippel Lindau syndrome-associated solid pancreatic lesions to determine the natural history of these tumors with biochemical testing, follow-up anatomic and functional imaging, and advanced imaging analysis, with a median follow-up of 4 years. RESULTS: Approximately 20% of consecutive tumor measurements during follow-up were decreased in size and 20% showed no change. This included 2 of 4 surgically proven malignant tumors, which had a net decrease in tumor size over time. Tumor volume, as derived from greatest diameter and volumetric measurements, showed good correlation to pathology tumor measurement of surgically resected tumors (Spearman rank correlation ρ = 0.72, p = 0.0011, and ρ = 0.83, p < 0.0001, respectively). Tumor density measurement had an inverse relationship with tumor size (Spearman rank correlation -0.22, p = 0.0047). A tumor density cutoff of 200 was 75% specific for malignant tumors. CONCLUSIONS: Pancreatic neuroendocrine tumors demonstrate a nonlinear growth pattern, which includes periods of no growth and apparent decrease in size by imaging. These growth patterns are variable and are not associated with tumor grade and malignancy. Tumor density, as measured in this cohort, may offer a specific diagnostic tool for malignant disease.

MiR-34a and miR-483-5p are candidate serum biomarkers for adrenocortical tumors.

BACKGROUND: Nonfunctioning adrenal incidentalomas are common and many patients undergo adrenalectomy to exclude adrenocortical carcinoma (ACC). Recent studies have shown dysregulated microRNA (miRNA) expression in ACC. The objective of this study was to determine the feasibility and diagnostic accuracy of measuring serum miRNAs in patients with benign and malignant adrenocortical neoplasms. METHOD: Five miRNAs were selected from miRNA profiling studies in ACC (miR-let-7d, -34a, -195, -214, and 483-5p). Total miRNA was extracted from serum samples in patients with malignant and benign adrenal neoplasms. miRNAs levels were measured by quantitative reverse transcript polymerase chain reaction and normalized to miR-16. To determine if miRNAs were secreted from ACC cells, we measured miRNA levels in culture. RESULTS: Serum samples from 22 patients with cortical adenomas and 17 patients with ACC were analyzed, and all 5 miRNAs were detected. We found greater levels of miR-34a (P = .001) and miR-483-5p (P = .011) in patients with ACC. The area under the receiver operating characteristic curve was 0.81 for miR-34a and 0.74 for miR-438-5p. MiR-34a and miR-483-5p levels in ACC cells were greater in the supernatant at 48 hours compared with intracellular levels. CONCLUSION: We show that dysregulated miRNAs in ACC are detectable in human serum samples. MiR-34a and miR-483-5p are candidate serum biomarkers for distinguishing between benign and malignant adrenocortical tumors.

Prospective screening in familial nonmedullary thyroid cancer.

BACKGROUND: Approximately 8% of nonmedullary thyroid cancers are familial. The optimal age for screening in familial nonmedullary thyroid cancer (FNMTC) is unknown. METHODS: Kindreds with FNMTC (2 or more first-degree relatives affected) were screened prospectively with thyroid ultrasonography. RESULTS: Fifteen kindreds showed an overall prevalence of thyroid nodule(s) ≥5 mm of 44% at screening; 19% in the second generation, and 90% in the generation anterior to the index case. The youngest age of detection was 10 years for thyroid nodules and 18 years for thyroid cancer. Microcalcification of thyroid nodules at screening was associated with a greater risk of cancer (P < .05). Family members diagnosed with thyroid cancer by ultrasonographic screening were diagnosed at a younger age and had a lower rate of extra thyroidal invasion (P < .05). CONCLUSION: In FNMTC, first-degree relatives 10 years or older, including the generation anterior to the index case, should have thyroid screening by ultrasonography, which may result in earlier diagnosis.

Telomere length is shorter in affected members of families with familial nonmedullary thyroid cancer.

BACKGROUND: The theory that short telomere length and genetic defects in maintaining telomere length are associated with familial nonmedullary thyroid cancer (FNMTC) is controversial. Thus, the aim of this study was to determine whether telomere length and genes involved in maintaining telomere length are altered in FNMTC. METHODS: Blood samples were collected from 44 members (13 affected and 31 unaffected) of six families with FNMTC and from 60 controls. Quantitative polymerase chain reaction (Q-PCR) and reverse transcription PCR were performed to analyze relative telomere length (RTL), gene copy number, and mRNA expression of telomerase reverse transcriptase (hTERT), telomere repeat binding factor 1 (TRF1), telomere repeat binding factor 2 (TRF2), repressor activator protein 1 (RAP1), TRF1 interacting nuclear factor 2 (TIN2), tripeptidyl peptidase 1 (TPP1), and protection of telomere 1 (POT1). RESULTS: Affected members had shorter RTL, as compared with unaffected members (0.98 vs. 1.23, p<0.01). There was no significant difference in hTERT, TRF1, TRF2, RAP1, TIN2, TPP1, and POT1 gene copy number or mRNA expression between affected and unaffected members. CONCLUSIONS: RTL is shorter in affected members with FNMTC but is not associated with altered copy number or expression in hTERT, TRF1, TRF2, RAP1, TIN2, TPP1, and POT1. The small differences in RTL preclude the utility of RTL as a marker for FNMTC in at-risk individuals.

von Hippel-Lindau disease-associated solid microcystic serous adenomas masquerading as pancreatic neuroendocrine neoplasms.

BACKGROUND: Patients with von Hippel-Lindau disease (VHL) commonly develop pancreatic cysts and neuroendocrine neoplasms (PNENs or PNETs). Solid microcystic serous adenoma (SMSA), a rare neoplasm described in VHL patients, can be mistaken for PNEN on imaging. METHODS: Clinical, pathologic, and radiologic data were reviewed on VHL patients who underwent surgery for a preoperative diagnosis of PNEN since 1994 at 1 institution. Blinded to the pathologic diagnoses, radiologists reassessed available imaging. RESULTS: For 55 patients, 79 pancreatectomies were performed for presumed PNENs. Ten (18%) patients underwent 12 (15%) resections for neoplasms diagnosed as SMSA on final pathology. The average size of a SMSA leading to operation was 3.6 ± 0.4 cm. Four out of 11 SMSAs were still mistaken for PNENs when imaging was reassessed. The mean FDG-positron emission tomography (PET) standardized uptake value was greater for 17 PNENs (12.1 ± 1.2) compared with 6 SMSAs (4.2 ± 0.5; P = .002). The mean doubling time of SMSAs and PNENs was similar. Seven (15%) patients with pathologically proven PNENs had malignant disease. CONCLUSION: SMSAs can mimic PNENs on nonfunctional imaging; FDG-PET may help to differentiate them. A high index of suspicion is needed to minimize operations performed for SMSA and to counsel VHL patients of their risks of undergoing operation for a lesion with no known malignant potential.

Clinical utility of functional imaging with ¹8F-FDOPA in Von Hippel-Lindau syndrome.

CONTEXT: Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome in which patients are at risk of developing multiple tumors in different organs. 6-L-¹8F-fluorodihydroxyphenylalanine (¹8F-FDOPA) positron emission tomography (PET) is a relatively new metabolic imaging tracer proposed for the use of localizing sites of neuroendocrine tumors. There are limited data on the clinical utility of using ¹8F-FDOPA PET for identifying neuroendocrine tumors in a high-risk population such as VHL. OBJECTIVE: The aim of this prospective study was to evaluate the clinical utility of ¹8F-FDOPA PET in patients with VHL-related tumors. DESIGN: Radiological findings were prospectively collected from four imaging modalities: computed tomography, magnetic resonance imaging (MRI), ¹8F-fluorodeoxyglucose PET, and ¹8F-FDOPA PET. ¹8F-FDOPA PET findings were compared with those from other imaging modalities, as well as with clinical and laboratory data, and pathology findings if patients underwent an operation. RESULTS: In 52 patients with VHL, 390 lesions were identified by computed tomography (n = 139), MRI (n = 117), ¹8F-fluorodeoxyglucose PET (n = 94), and ¹8F-FDOPA PET (n = 40). ¹8F-FDOPA PET identified 20 pancreatic and 20 extrapancreatic tumors, including lesions in the adrenal gland (n = 11), kidney (n = 3), liver (n = 4), lung (n = 1), and cervical paraganglioma (n = 1). These tumor sites were not seen by conventional imaging studies in 9.6% of patients and 4.4% of lesions. Seven of eight patients who had an ¹8F-FDOPA PET-positive lesion underwent resection, and pathology showed a neuroendocrine tumor. Four of 10 patients with positive adrenal uptake had elevated catecholamine levels, and six of 10 patients had a discrete mass on axial imaging. CONCLUSIONS: ¹8F-FDOPA PET is a useful complementary imaging study to detect neuroendocrine tumors in patients with VHL undergoing surveillance, especially in those suspected to have adrenal pheochromocytoma or unusual ectopic locations.

Comparison of 6-18F-fluoro-L-DOPA, 18F-2-deoxy-D-glucose, CT, and MRI in patients with pancreatic neuroendocrine neoplasms with von Hippel-Lindau disease.

INTRODUCTION: There are limited data on the utility of 6-(18)F-fluoro-l-3,4-dihydroxyphenylalanine ((18)F-DOPA) and (18)F-2-deoxy-d-glucose ((18)F-FDG) in the workup of patients with pancreatic neuroendocrine tumors (PNETs). The aim of our study was to determine the accuracy of (18)F-DOPA and (18)F-FDG to detect PNETs in patients with von Hippel-Lindau disease (vHL). METHODS: We studied prospectively 69 patients with a diagnosis of vHL and pancreatic lesion(s) using computed tomography (CT), magnetic resonance imaging (MRI), (18)F-FDG, and (18)F-DOPA. Clinical, genetic, and laboratory characteristics were analyzed to determine association with imaging study results. RESULTS: In sum, 40 patients underwent evaluation by all 4 modalities; 98 PNETs and 55 PNETs were identified on CT and MRI, respectively. Only 11 of the 98 lesions (11%) were positive on (18)F-DOPA and 45 of the 98 (46%) lesions were positive on (18)F-FDG. There were 13 (18)F-DOPA and 26 (18)F-FDG avid extrapancreatic lesions. One patient underwent resection of an (18)F-DOPA avid extrapancreatic lesion in the lung, with pathology demonstrating a NET. There was no association between (18)F-DOPA and (18)F-FDG avidity and tumor size, age, gender, vHL mutation, or serum chromogranin A level. CONCLUSION: (18)F-FDG and MRI may be adjuncts to CT in identifying PNETs and metastatic disease. (18)F-DOPA has limited value in identifying PNETs in patients with vHL, but may be useful for identifying extrapancreatic NET lesions.