Dual radiotracer analysis of cholinergic neuronal changes in prediabetic mouse pancreas.

BACKGROUND: Pancreatic neuronal changes associated with beta cell loss in type 1 diabetes mellitus are complex, involving, in part, parasympathetic mechanisms to compensate for preclinical hyperglycemia. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor has been shown to be a useful marker of cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[(18)F]fluorobenzyltrozamicol ([(18)F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. The compound 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), available in a tritiated form, binds to M3 muscarinic receptors on beta cells and is a potential target for assessing pancreatic beta cell mass. In this study, we investigate the feasibility of dual radiotracer analysis in identifying neurofunctional changes that may signify type 1 diabetes mellitus in its early preclinical state. METHODS: Ex vivo determinations of pancreatic uptake were performed in prediabetic nonobese diabetic mice and controls after intravenous injection of [(18)F]FBT or 4-[(3)H]DAMP. Beta cell loss in prediabetic mice was confirmed using immunohistochemical methods. RESULTS: [(18)F]FBT uptake was significantly higher in prediabetic pancreata than controls: 3.22 +/- 0.81 and 2.51 +/- 1.04, respectively (P < 0.03). 4-[(3)H]DAMP uptake was significantly lower in prediabetic pancreata than controls: 0.612 +/- 0.161 and 0.968 +/- 0.364, respectively (P = 0.01). CONCLUSIONS: These data suggest that a combination of radiotracer imaging agents that bind to neuronal elements intimately involved in insulin production may be an effective method of evaluating changes associated with early beta cell loss using PET.

Enhanced cholinergic response in pancreata of nonhuman primates with impaired glucose tolerance shown on [18F]fluorobenzyltrozamicol positron emission tomography.

BACKGROUND: Islet cell adaptation to insulin resistance in type 2 diabetes mellitus may be due in part to increased stimulation of beta cells by the autonomic nervous system. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor correlates with cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[18F]fluorobenzyltrozamicol ([18F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. In this study, we utilize [18F]FBT PET to demonstrate pancreatic cholinergic activity before and after dextrose infusion in nonhuman primates with normal (NGT) and impaired (IGT) glucose tolerance. METHODS: Seven adult female vervet (Chlorocebus aethiops) monkeys were maintained on an atherogenic Western diet. They were divided into two groups: four with NGT and three with IGT. Each subject underwent [18F]FBT PET twice: first, a baseline PET under fasting conditions; and second, PET under fasting conditions but after intravenous infusion of dextrose solution. Quantitative analysis of pancreatic uptake at 60 min post-injection was performed. RESULTS: There was no difference in pancreatic uptake of [18F]FBT on baseline scans between the two groups. Pancreatic uptake of [18F]FBT increased in every subject after dextrose infusion (P = 0.03). On post-dextrose PET scans, pancreatic uptake of [18F]FBT was significantly higher in IGT subjects compared with NGT subjects (P = 0.03). The post-dextrose to pre-dextrose uptake ratios were higher in IGT subjects (P = 0.08). CONCLUSIONS: Acute increases in pancreatic cholinergic activity in vivo were detected in the pancreata of nonhuman primates with NGT and IGT after intravenous dextrose infusion on [18F]FBT PET. In subjects with IGT, this activity was significantly higher, suggesting increased autonomic nervous system stimulation of the pancreatic islets in insulin-resistant subjects.

Left ventricular infarct size assessed with 0.1 mmol/kg of gadobenate dimeglumine correlates with that assessed with 0.2 mmol/kg of gadopentetate dimeglumine.

OBJECTIVE: To determine myocardial infarct (MI) size during cardiovascular magnetic resonance at 1.5 Tesla using 0.1 mmol/kg body weight of gadobenate dimeglumine (Gd-BOPTA) and 0.2 mmol/kg body weight of gadopentetate dimeglumine (Gd-DTPA). METHODS: Twenty participants (16 men, 4 women), aged 58 +/- 12 years, with a prior chronic MI were imaged in a crossover design. Participants received 0.2 mmol/kg body weight of Gd-DTPA and 0.1 mmol/kg body weight of Gd-BOPTA on 2 occasions separated by 3 to 7 days. RESULTS: The correlations were high between Gd-DTPA and Gd-BOPTA measures of infarct volume (r = 0.93) and the percentage of infarct relative to left ventricular myocardial volume (r = 0.85). The size and location of the infarcts were similar (P = 0.9) for the 2 contrast agents. Interobserver correlation of infarct volume (r = 0.91) was high. CONCLUSIONS: In chronic MI, late gadolinium enhancement identified with a single 0.1 mmol/kg body weight dose of Gd-BOPTA is associated in volume and location to a double (0.2 mmol/kg body weight) dose of Gd-DTPA. Lower doses of higher relaxivity contrast agents should be considered for determining left ventricular myocardial infarct size.

Brain abnormalities detected on whole-body 18F-FDG PET in cancer patients: spectrum of findings.

OBJECTIVE: The purpose of this article is to discuss and show examples of the PET appearance of common brain abnormalities that radiologists encounter when interpreting whole-body 18F-FDG PET examinations of cancer patients. CONCLUSION: Knowledge of the PET appearance of various brain abnormalities can yield diagnostically relevant information in cancer patients. Detection of brain abnormalities on whole-body PET often requires adjusting window settings to reduce the intensity of normal brain FDG activity. Often, close correlation of PET/CT and MRI with clinical history offers the most complete radiologic diagnosis.

Futility of fluorodeoxyglucose F 18 positron emission tomography in initial evaluation of patients with T2 to T4 melanoma.

BACKGROUND: Evaluation of newly diagnosed patients with melanoma for metastasis is requisite to treatment planning. The reported diagnostic yield of whole-body conventional radiological imaging in initial staging of patients with melanoma is low. However, the diagnostic yield of positron emission tomography (PET) for distant metastases is unclear. HYPOTHESIS: There is no utility of PET as part of a routine metastatic survey in patients with T2 to T4 melanoma. DESIGN: Retrospective review of a cohort study between December 1998 and July 2004. SETTING: University hospital tertiary care center. PATIENTS AND METHODS: There were 64 patients with T2 to T4 melanomas who underwent PET for detection of occult metastases at our institution. All patients underwent surgical excision of the primary lesion and sentinel lymph node dissection. Data included were pathologic findings of the primary lesion and sentinel lymph nodes, laboratory data, and radiological reports. None of the patients had clinically suspected regional or distant metastases prior to PET. The diagnostic yield of PET was evaluated through retrospective analysis. Positive scans were then correlated for accuracy with follow-up imaging, biopsy, and clinical information when available. RESULTS: Positron emission tomography did not reveal occult distant metastases in any of the patients. Positron emission tomographic scans showed no abnormalities in 94% of these patients. In 2 patients (3%), false-positive findings were reported on PET (muscular activity and intranodal melanocytic nevocellular inclusion). Further, PET was not useful in predicting regional lymph node metastases. Nineteen of 64 patients had positive sentinel lymph nodes, and only 2 (11%) were identified on PET. Overall, PET did not change clinical management in any of the patients. CONCLUSIONS: This study suggests no utility for PET in the detection of occult metastases in patients at initial diagnosis of melanoma. Omission of PET imaging from preoperative evaluations for patients with melanoma is recommended.

Reversal of hypermetabolic brown adipose tissue in F-18 FDG PET imaging.

OBJECTIVES: With the increasing application of F-18-fluorodeoxyglucose (FDG) positron emission imaging, there has been an evolving appreciation for the range of normal variants and the realization that false-positives can lead to serious consequences. RESULTS: One of the most common causes of a false-positive study is the uptake of FDG in areas of hypermetabolic brown adipose tissue (HBAT). Areas of involvement are often spatially closely related to important lymph node groups in the neck, axilla, and upper mediastinum, making critical differentiation difficult, even with PET-CT. CONCLUSIONS: FDG uptake in HBAT has been noted to occur more frequently in cold months and benzodiazepines have been proposed for its prevention. The use of these drugs is, in our experience, of limited value and may complicate patient care in both inpatient and outpatient populations. In this report, we describe considerable success by completely reversing HBAT in 9 of 10 sequential patients with simple core warming maneuvers, which obviate the use of benzodiazepines.

A prospective evaluation of the impact of 18-F-fluoro-deoxy-D-glucose positron emission tomography staging on survival for patients with locally advanced esophageal cancer.

PURPOSE: To determine the impact of 18-F-fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the staging and prognosis of patients with locally advanced esophageal cancer (LAEC). METHODS AND MATERIALS: Between January 2000 and October 2004, all patients with LAEC evaluated in the Department of Radiation Oncology were considered for enrollment into a Phase II trial of preoperative chemoradiation. Entry required a staging whole-body FDG-PET scan. RESULTS: One hundred ten consecutive patients were evaluated; 38 were ineligible for reasons including treatment elsewhere, prior malignancy, or refusal of treatment. After conventional staging (clinical examination, endoscopic ultrasound, and chest/abdominal computerized tomography), 33 patients were ineligible because of metastatic disease or poor performance status. Of the remaining 39 patients, 23 were confirmed to have LAEC after FDG-PET staging and were treated in the Phase II trial (Cohort I). Sixteen patients, however, had FDG-PET findings consistent with occult metastatic disease and were deemed ineligible for the trial but were treated with curative intent (Cohort II). The 2-year survival rate for the 23 patients in Cohort I was 64%, compared with 17% (p=0.003) for patients in Cohort II (FDG-PET positive). CONCLUSIONS: More than one-third of patients determined to have LAEC with conventional staging were upstaged with the use of FDG-PET. Despite comparable therapy, upstaging with FDG-PET predicts poor 2-year survival.

Is parathyroid carcinoma indeed a lethal disease?

BACKGROUND: Parathyroid carcinoma is a rare malignancy with a wide range of aggressiveness. There is no current staging system. Our primary aim was to review the presentation, diagnosis, surgical treatment, and outcomes of patients, with the goal of assessing the incidence of death related to parathyroid carcinoma. METHODS: The authors present a retrospective chart review on patients with parathyroid carcinoma from 1975 to 2004, identified by the tumor registry of a single tertiary-care center. Diagnoses were confirmed histologically, clinical and radiographical data were recorded, and statistical analyses were performed. RESULTS: Twenty-three cases were identified. The mean patient age was 54 years. The female:male ratio was 1.5:1. Follow-up ranged from 1 month to 23 years (median, 134 months). Mean preoperative calcium was 12.9 mg/dL. Median parathyroid hormone was 290 pg/mL. Two patients (9%) had an asymptomatic presentation, and five (22%) presented with a palpable neck mass. Only nine (39%) underwent initial comprehensive en-bloc resection. Median survival was 22 years. Five- and 10-year survival was 85.9% and 69.4%, respectively. Five- and 10-year survival with en-bloc resection was 90% and 67.5%, respectively. Local resection resulted in survival rates of 82.5% and 70.7%. Three of ten deaths were attributed to parathyroid carcinoma. In recurrent disease, computed tomography and scintigraphy had localization rates of 53% and 67%, respectively, with a concordance of 22%. CONCLUSIONS: Long-term survival is possible with parathyroid carcinoma. Death associated with parathyroid carcinoma was uncommon. A staging may be warranted despite the rarity of this disease.

The scintigraphic appearance of subcapsular parathyroid adenomas.

PURPOSE: Approximately 5 to 10% of parathyroid adenomas are located within the thin, fibrous capsule of the thyroid gland. These subcapsular adenomas can complicate minimally invasive parathyroidectomy. The small incision used in this procedure limits the view of the surgical bed. Palpation is less sensitive when the adenoma is covered by the thyroid capsule. If a subcapsular parathyroid adenoma can be identified on preoperative parathyroid scintigraphy, nuclear medicine physicians can recommend exploration of the thyroid capsule early, leading to an easier, more efficient operation. The objective of this observational study was to identify the scintigraphic appearance of subcapsular parathyroid adenomas. MATERIALS AND METHODS: A total of 109 patients with primary hyperparathyroidism underwent preoperative dual-phase Tc-99m sestamibi parathyroid scintigraphy at our tertiary care center from October 2002 to March 2004. Tc-99m pertechnetate was used as a supplemental technique when deemed necessary for optimal interpretation. Retrospective chart review identified 16 surgically proved subcapsular parathyroid adenomas. Parathyroid scintigraphy was reviewed. RESULTS: Subcapsular parathyroid adenomas tend to conform to the expected shape of the thyroid gland. In this small series, subcapsular parathyroid adenomas followed 1 of 3 patterns on lateral images: (1) focal convex distortion of the posterior wall of the thyroid, (2) polar lentiform configuration, and (3) compression of the posterior thyroid parenchyma. CONCLUSION: Subcapsular parathyroid adenomas often have a distinct appearance on scintigraphy. Preoperative identification of this type of parathyroid adenoma can direct a subcapsular surgical approach, optimizing the efficiency of the minimally invasive parathyroidectomy.

Enhanced scintigraphic protocol required for optimal preoperative localization before targeted minimally invasive parathyroidectomy.

At our tertiary care institution, a targeted minimally invasive parathyroidectomy (MIP) is the preferred surgical procedure for primary hyperparathyroidism. Similar to unilateral neck exploration (UNE), preoperative scintigraphic localization of the adenoma in relation to the midline is required. However, in contrast to the abbreviated standard incision for UNE, 2 distinct incision sites, 1 medial and 1 lateral, are available on each side with MIP. The incision site is ultimately chosen based on scintigraphic determination of the adenoma's vascular origin to facilitate ligation and removal. Unfortunately, the scintigraphic location of a parathyroid adenoma does not necessarily reflect the site of its vascular origin. We reviewed our database to identify factors that accurately predict the site of vascular origin of parathyroid adenomas. A retrospective chart review was performed on 125 patients who underwent Tc-99m sestamibi scintigraphy and parathyroidectomy. Scintigraphic localization, surgical findings, and histopathology were recorded. Preoperative image interpretations that were discordant with operative findings were independently reviewed. Scintigraphy identified the presence of an adenoma in 105 of 118 patients (89%) with primary hyperparathyroidism. In 17 of the 105 cases (16%), the scintigraphic interpretation did not accurately reflect the site of superior or inferior vascular origin seen at surgery. In many discordant cases, anterior images were insufficient for determining the vascular origin. The posterior displacement of an adenoma in relation to the thyroid on early lateral images was often critical in determining the superior or inferior vascular origin. Scintigraphic determination of the superior or inferior vascular origin of a parathyroid adenoma directs incision placement for MIP. Imaging protocols should include early lateral images when localizing parathyroid adenomas before minimally invasive parathyroidectomy.

Experienced scintigraphers contribute to success of minimally invasive parathyroidectomy by skilled endocrine surgeons.

Minimally invasive parathyroidectomy (MIP) has become the preferred surgical treatment for selected patients diagnosed with primary hyperparathyroidism (PHPT) at our tertiary-care center. Preoperative scintigraphy establishes the position of a parathyroid adenoma, dictates the incision site, and can minimize incision size and consequent tissue dissection. We reviewed our database and sought to identify factors that led to discordant preoperative imaging and operative findings and to assess the effect of experience on these findings. A retrospective review was performed on all patients with biochemically proven PHPT who underwent Tc-99m sestamibi scintigraphy and surgical intervention. Patient demographics, date of surgical intervention, scintigraphic localization, surgical findings, pre- and postoperative biochemical markers, histopathology, coexisting thyroid pathology, and 6-month follow up were recorded. Preoperative images that were discordant with operative findings were independently reviewed. Parathyroid scintigraphy was performed on 125 consecutive patients for PHPT between November 1999 and January 2002. Seventy-six patients had MIPs, 35 had standard cervical explorations, 11 had MIPs that were converted to standard cervical explorations, and three had surgery directed to an ectopic location. At 6-month follow-up 98.4 per cent were cured. Preoperative imaging and surgical findings were ipsilateral and concordant in 105 of 118 (89%) patients with parathyroid adenoma. The anatomic origin of an adenoma was predicted in only 83 of 118 (68%) patients. Most of the inaccurate scintigraphy readings occurred during the first 13 of the 26 months that MIPs were performed at our institution. Only two discordant cases occurred during the last 9 months of this period. Biochemical markers, prior neck operation, and concomitant thyroid pathology had no correlation with imaging sensitivity. Scintigraphic interpretation of smaller adenomas was less reliable; discordant cases were more common in small adenomas. Communication between endocrine surgeons and nuclear medicine physicians about the MIP technique and anatomic orientation of adenomas led to better scintigraphic localization as experience increased. Now that MIP by skilled endocrine surgeons is becoming the favored treatment for PHPT experienced nuclear medicine physicians may be the most important factor to achieve maximum success.