Effects of preoperative parathyroid localisation studies on the cost of operations for persistent hyperparathyroidism.

OBJECTIVE: To find out whether preoperative parathyroid localisation studies are cost-effective in patients with persistent hyperparathyroidism (HPT). DESIGN: Retrospective study. SETTING: University hospital, Sweden. PATIENTS: 29 consecutive patients with persistent HPT who were reoperated on with or without localisation studies. 15 other patients had initial operations for HPT without localisation studies. INTERVENTIONS: Initial or repeat operation for HPT, localisation studies with 99mTc sestamibi scintigraphy, and catheterisation of large cervical and mediastinal veins with measurements of serum concentrations of parathyroid hormone. MAIN OUTCOME MEASURES: Operative time. Cost of operations, frozen section biopsy and localisation studies. RESULTS: The mean durations of reoperation with localisation studies and for the initial operation without them, were 124 and 135 minutes, respectively, while it was 269 minutes for reoperation without studies. For patients who had localisation studies the mean total cost of the investigations, operating time, and frozen section biopsy was 28% less than for patients who were reoperated on without such studies. CONCLUSION: Preoperative localisation studies before repeat operations for HPT were cost-effective. Even if it has not been shown in this series, the reduction in operating time and the extent of dissection by localisation studies has the potential to decrease morbidity.

Scintigraphic assessment of interdigestive duodenogastric reflux in humans: distinguishing between duodenal and biliary reflux material.

BACKGROUND: Late duodenal phase III is characterized by retroperistalsis. The physiologic function of this phenomenon is unknown. Our aim was to study the relationship between duodenal motility and the transport of duodenal contents from the biliary tract and the duodenum by using a double-isotope technique. METHODS: Manometric analysis of the direction of interdigestive duodenal pressure waves was performed in 12 volunteers. Duodenal marker was infused directly into the proximal duodenum, and bile marker was infused intravenously for 2 h. Radionuclide activity was examined for regions corresponding to the stomach, gallbladder, and duodenum. RESULTS: In phase II, antegrade pressure waves dominated with propulsion of both markers to the jejunum. Retroperistalsis occurred in 90% of the activity fronts and was always (100%) followed by retropulsion of duodenal marker to the stomach. A clear-cut reflux of bile marker was seen in only 17% of the activity fronts. The incidence rate of duodenogastric reflux was highest in phase III (P=0.008) compared with phase II with an infrequent (P=0.002) admixture of bile. Bile marker contents increased abruptly in the gallbladder during phase III. CONCLUSIONS: Late phase III acts as a retroperistaltic pump, retropelling duodenal contents to the stomach. In this physiologic duodenogastric reflux. bile is avoided by deviation to the gallbladder, probably by a phase lll-associated occlusion of the sphincter Oddi.

Isolated hepatic perfusion with extracorporeal oxygenation using hyperthermia, tumour necrosis factor alpha and melphalan.

AIMS: To determine the toxicity and efficacy of isolated hepatic perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan (Alkeran) under mild hyperthermic conditions. METHODS: A phase I trial was performed. Eleven patients with unresectable metastatic malignancies in the liver were pre-treated with 3 x 10(6) U leukocyte IFN daily 2 days before the perfusion. The liver was isolated and inflow catheters inserted in the hepatic artery and the portal vein. The hepatic veins were drained via a catheter in the retrohepatic caval vein. The venous blood flow from the lower extremities and the splanchnic circulation was bypassed to the axillar vein. The liver circuit was perfused with oxygenated blood and 30-200 microg TNF-alpha was added. At 39 degrees C in the liver circuit 0.5 mg/kg melphalan was added and the perfusion was continued for 1 h. RESULTS: Six patients underwent re-operation due to post-operative bleeding. Two patients died of coagulopathy or multiple organ failure within the first post-operative month. Three of six patients with liver metastases from malignant melanoma or leiomyosarcoma showed a partial response while no patients with liver metastases from colorectal cancer showed any response. The mean survival time was 20 months, which is within the same range as seen in previous isolated hepatic perfusion (IHP) studies. CONCLUSIONS: IHP with this drug regimen is a method with a considerable toxicity, though it is hard to distinguish between toxicity from TNF-alpha and that from the perfusion procedure itself. The method was not effective in patients with colorectal liver metastasis, but the results in melanoma and leiomyosarcoma patients warrant further studies.

Assessment of gastric emptying: comparison of solid scintigraphic emptying and emptying of radiopaque markers in patients and healthy subjects.

The gold standard for measuring gastric emptying is scintigraphy, either with digestible solids or liquids. Unfortunately, this method is expensive and of limited availability. An alternative could be to use radiopaque markers (ROMs). Our aim was to compare these two tests in healthy volunteers and in patients to see whether emptying of ROMs can substitute for scintigraphic solid emptying. We also intended to see if patients with small intestinal bacterial overgrowth (SIBO) had delayed gastric emptying. Twenty healthy subjects and 21 patients, 11 with SIBO and 10 with insulin-dependent diabetes mellitus (IDDM), were included. A standard meal with a [99mTc]MAA-labeled omelet and 20 ROMs was given. Scintigraphic emptying and ROM emptying were followed simultaneously. Reference values for gastric emptying of ROMs were determined in 50 healthy subjects. The scintigraphic method and the radiologic method correlated significantly in healthy subjects (P < 0.05), and in patients (P < 0.001), when comparing half-emptying time for both methods. Scintigraphic half-emptying time correlated significantly with emptying of ROMs after 6 hr. Six of 11 patients with SIBO (P < 0.02) and 7/10 patients with IDDM (P < 0.02) had delayed scintigraphic emptying of solids using the 95th percentile in the controls as the upper reference value. Gastric emptying of ROMs was, similar to solid scintigraphic gastric emptying, slower in women than in men. In conclusion, scintigraphic emptying of solids and emptying of ROMs are closely correlated. The radiologic method can be used as a simpler and more readily available method. Women have slower gastric emptying of ROMs than men, which necessitates separate reference values. A high proportion of patients with symptomatic IDDM and with SIBO have delayed gastric emptying.

Expression of somatostatin receptors in oncocytic (Hürthle cell) neoplasia of the thyroid.

Ten consecutive patients with Hürthle cell lesions of the thyroid (nodule/adenoma/carcinoma) were studied by (111)In-DTPA-D-Phe1-octreotide scintigraphy. Octreotide scintigraphy localized the primary Hürthle cell tumour in eight patients as distinct areas of increased uptake of radionuclide. Two patients with Hürthle cell carcinoma, previously thyroidectomized, had their metastases visualized by octreotide scintigraphy. Northern analyses showed expression of multiple somatostain receptor subtypes. Visualization of the Hürthle cell tumour may be due to a higher expression of somatostatin receptors in the lesions than in surrounding normal thyroid tissue. The tissue/blood (111)In concentration ratios for tumour samples from five patients showed clearly higher values than observed for normal connective tissue, muscle or lymph nodes. A relatively high uptake of (111)In was also observed in goiter tissue, which may lead to misinterpretations. The main indication for octreotide scintigraphy in patients with Hürthle cell carcinoma is suspicion of metastatic disease.

Bile acid malabsorption after continent urinary diversion with an ileal reservoir.

PURPOSE: We determine the effect of urinary diversion with a Kock ileal reservoir on bile acid absorption and bowel habits. MATERIALS AND METHODS: We asked 96 patients with a Kock ileal urinary reservoir to record bowel habits and abdominal symptoms for 1 week. Data on 75 patients were further analyzed. Bile acid absorption was determined in 29 healthy control subjects, in 17 before and 6 months after continent urinary diversion, and in 21, 2 to 14 years postoperatively. Bile acid absorption was considered pathological when retention of less than 10% of an oral capsule containing selenium-75 labeled tauroselcholic acid (SeHCAT) was noted after 1 week. RESULTS: Mean number of defecations plus or minus standard deviation was 9.4 +/- 6.1 (75 cases). Of the patients 13% had 15 or more stools per week and 15% complained of always having loose stools. Mean value for the SeHCAT test was 32 +/- 19% preoperatively and 17 +/- 16% 6 months postoperatively (p = 0.0023). The corresponding value for healthy controls was 39 +/- 18%. Significant relationships were found between the results of the SeHCAT test postoperatively, and the number of stools per week and consistency of the feces. All patients with more than 10 defecations per week had a pathological SeHCAT test. CONCLUSIONS: Most patients with an ileal urinary reservoir have fairly normal bowel habits. Bile acid absorption is significantly reduced postoperatively and approximately a third of the patients have a pathological SeHCAT test. Preoperative investigation of bowel habits is recommended and a SeHCAT test should be performed in patients with frequent, loose defecations. Other types of diversion should be offered when preoperative retention is below 10 to 20% especially in patients with impaired anal control.

Somatostatin receptor subtypes, octreotide scintigraphy, and clinical response to octreotide treatment in patients with neuroendocrine tumors.

Several types of neuroendocrine tumor express high numbers of somatostatin receptors (sstr). We have compared the expression of sstr subtypes with the outcome of octreotide scintigraphy in patients with carcinoids and medullary thyroid carcinoma (MTC) in comparison with Hürthle cell tumors. The effect of sstr activation (octreotide treatment) on tumor markers was also studied in patients with disseminated carcinoid tumors. Six patients with carcinoid tumors (four midgut and two foregut), and three patients with thyroid tumors (one MTC, one Hürthle cell carcinoma, and one Hürthle cell adenoma) were studied. Octreotide scintigraphy visualized tumor sites in all nine patients. Macroscopic tumor was verified at these sites at subsequent surgical exploration. Using Northern blotting and subtype-specific riboprobes, sstr could be detected in all tumors examined. All five sstr subtypes were detected in most of the carcinoid tumors. All six carcinoids expressed sstr2. This was in contrast to the findings for the thyroid tumors analyzed, which also expressed several sstr subtypes but in some cases lacked expression of sstr2. This was also the case for normal thyroid tissue. Clinically, octreotide treatment of the patients with midgut carcinoid tumors resulted in palliation of hormonal symptoms accompanied by a significant reduction of urinary 5-HIAA levels (28-71%). These results indicate that carcinoid tumors frequently express all five sstr subtypes. The thyroid tumors also expressed multiple sstr but could lack expression of sstr2. Nevertheless, these tumors were visualized by octreotide scintigraphy, indicating that sstr2 expression is not a prerequisite for tumor imaging.

Comparative studies on the expression of somatostatin receptor subtypes, outcome of octreotide scintigraphy and response to octreotide treatment in patients with carcinoid tumours.

We have compared the expression of somatostatin receptor (sstr) subtypes with the outcome of somatostatin receptor scintigraphy and the effect of somatostatin receptor activation in patients with disseminated carcinoid tumours. Tumour tissues from nine patients with midgut carcinoids (ileal) and three patients with foregut carcinoids (gastric, thymic) were analysed using Northern blotting. Expression of somatostatin receptors was demonstrated in all tumours (12 out of 12), with all five receptor subtypes present in 9 out of 12 tumours. Somatostatin receptor scintigraphy using [111In]DTPA-D-Phe1-octreotide visualized tumours in all patients (12 out of 12). The 111In activity concentrations in tumour tissue (T) and blood (B) were determined in three tumours 1-7 days after injection of the radionuclide. The T/B 111In activity concentration ratios ranged between 32 and 651. Clinically, treatment with the long-acting somatostatin analogue octreotide resulted in marked symptom relief accompanied by a significant reduction in tumour markers, for example urinary-5-HIAA levels (28-71% reduction). Incubation of midgut carcinoid tumours in primary culture with octreotide (10 microM) resulted in a reduction in spontaneously secreted serotonin (45-71% reduction) and 5-HIAA (41-94% reduction). The results demonstrate that carcinoid tumours possess multiple somatostatin receptor subtypes and that somatostatin analogues such as octreotide, which preferentially bind to somatostatin receptor subtype 2 and 5, can be used in the diagnosis and medical treatment of these tumours. In the future, novel somatostatin analogues with subtype specific receptor profiles may prove to be of value for individualizing the treatment of disseminated carcinoid tumour disease.

Somatostatin receptor scintigraphy in medullary thyroid carcinoma.

BACKGROUND: 111In-radiolabelled (DTPA-D-Phe1)-octreotide scintigraphy can be used to localize neuroendocrine tumours expressing somatostatin receptors (SSTRs). The aim of this paper was to analyse the importance of tumour volume and growth for the visualization by SSTR scintigraphy of metastases from medullary thyroid carcinoma (MTC). METHODS: Serum calcitonin concentrations were used to estimate volume and growth rate of MTC. Twenty-two patients who had persistent hypercalcitoninaemia after total thyroidectomy for MTC, indicating the presence of metastases, were studied. RESULTS: SSTR scintigraphy visualized 15 tumours in 11 patients. Patients with scintigraphically visualized tumours had higher serum calcitonin and carcinoembryonic antigen concentrations and larger tumours, and the serum calcitonin concentration increased more rapidly with time. Tumour-associated symptoms and death from MTC occurred only in patients with scintigraphically visualized tumours. CONCLUSION: Scintigraphically visualized tumours grow more rapidly and are more aggressive than nonvisualized lesions. SSTR scintigraphy can be helpful in the planning of palliative surgery for MTC and for diagnosing distant metastases, but cannot localize microscopic metastases.

[Somatostatin receptors. A new way to diagnosis and therapy of neuroendocrine tumors]. / Somatostatinreceptorer. Ny väg till diagnos och terapi av neuroendokrina tumörer.

Verification of the presence of somatostatin receptors on neuroendocrine tumour cells opened up unique diagnostic and therapeutic possibilities. Long-acting somatostatin analogues are currently used to alleviate symptoms of excessive hormone synthesis in patients with such tumours. Radiolabelled somatostatin analogues can be used both for high specificity and high sensitivity scintigraphic localisation of such tumours and for intraoperative scintillation detection. Detailed studies in patients and in tumour cells in vitro have shown 111In-octreotide uptake to be high and retention times long in tumour tissue, and have yielded evidence of intracellular localisation of the radionuclide. These findings thus showed somatostatin receptor-mediated radiotherapy to be a possible treatment alternative after close characterisation of the individual tumour. In the future, it may be possible to use other peptide receptors (e g, growth factor receptors) according to the same principles as applied in the case of somatostatin receptors.

Somatostatin Receptors in the Diagnosis and Therapy of Neuroendocrine Tumor.

The expression of somatostatin receptors in neuroendocrine tumors has facilitated the diagnosis and surgical treatment of patients with these tumors. After injection of a radiolabeled long-acting somatostatin analog, (111)In-octreotide, scintigraphic tumor imaging can ben performed as well as intraoperative tumor localization. During localization studies very high (111)In concentration values were found in tumor tissues versus normal tissues, especially in carcinoid tumors and endocrine pancreatic tumors. Studies on such tumors in cell culture further indicated internalization of (111)In into tumor cells, which is a prerequisite for a radiobiological effect from short range Auger and conversion electrons. Attempts to systemic radionuclide therapy via somatostatin receptors in patients with neuroendocrine tumors have been initiated.

The relevance of somatostatin receptors in thyroid neoplasia.

111In-octreotide scintigraphy in patients with persistent medullary thyroid carcinoma (MTC) visualized tumors in about half of the surgically explored sites. Tumor visualization correlated with rapid tumor growth and large tumor volume as judged from calcitonin levels. The 111In concentration ratio between tumor (T) and blood (B) in surgically excised lymph node metastases of MTC showed a large variation, with low values for microscopic and high values for macroscopic metastases in individual patients. Three cases of MTC, Hürthle cell adenoma and papillary thyroid cancer are reported with preoperative scintigraphy, T/B ratios and Northern analyses of the surgical biopsies. Visualization of tumors was possible in the absence of sstr2 (the high affinity receptor for octreotide) with the exception of microscopic tumor growth. T/B values in the patient with Hürthle cell adenoma were similar to those found in the contralateral thyroid lobe with goitre. The relatively high uptake of 111In in benign thyroid conditions probably limits the use of octreotide scintigraphy in the diagnosis of primary tumors. The technique has certain advantages over radioiodine scintigraphy after the surgical treatment of thyroid tumors: no need for withdrawal of thyroxin substitution; a possibility to diagnose metastases of tumors that do not concentrate radioiodine (MTC, Hürthle cell cancer); and complementary information about metastatic sites of non-medullary thyroid cancer (papillary and follicular tumors).

Internalization of indium-111 into human neuroendocrine tumor cells after incubation with indium-111-DTPA-D-Phe1-octreotide.

UNLABELLED: Neuroendocrine tumor cells frequently overexpress somatostatin receptors at their cell surfaces. To evaluate the possibility of using the somatostatin analog 111In-DTPA-D-Phe1-octreotide for radiation therapy, we studied the binding and subsequent internalization of 111In into three types of cultured human neuroendocrine tumor cells. METHODS: Primary cultures of gastric carcinoid, midgut carcinoid and glucagonoma cells were incubated with 111In-DTPA-D-Phe1-octreotide and cell-surface bound, internalized and released 111In activity was measured. Electron microscopic autoradiography was also performed. RESULTS: All three cell types specifically (80%-95%) bound 111In-DTPA-D-Phe1-octreotide and internalized 111In. After 1 hr pulse incubation with 111In-DTPA-D-Phe1-octreotide, there was an initial decrease in intracellular 111In to about 50% during the subsequent 6-hr incubation. Almost no further release was observed during the remaining 18-42 hr studied. Autoradiography showed that the internalized 111In was found in the cytoplasm and nucleus in the midgut carcinoid cells. CONCLUSION: Indium-111 DTPA-D-Phe1-octreotide might be useful for radiation therapy of patients with surgically incurable tumors having high somatostatin receptor densities.

Improved survival of patients with papillary thyroid cancer after surgical microdissection.

A total of 195 patients had surgery for papillary thyroid cancer. The mean age at operation was 50 years. A microdissection technique was used for total thyroidectomy and lymph node clearance. Postoperative radioiodine tests showed no uptake or an uptake close to the background activity in 77% of the examined patients. By counting the lymph nodes removed at surgery we were able to check on the quality of the lymph node dissection. Men had a higher incidence (70%) of lymph node metastases than women (45%). Only 4% of the patients had radioiodine ablation of the thyroid remnant. The median follow-up time was 13 years. None of the patients below 45 years of age at surgery died of thyroid cancer. In the older age group eight patients died of thyroid cancer at a mean age of 75 years. Five of those who died of a thyroid carcinoma had distant metastases at diagnosis. Among patients with resectable disease, three (1.6%) died of thyroid cancer, all of whom had lived for more than 17 years after surgery. Hence longer follow-up is needed before we know the final mortality in our series. The results suggest that surgical technique and strategy can positively influence the survival of patients with papillary thyroid cancer.

Systemic radionuclide therapy using indium-111-DTPA-D-Phe1-octreotide in midgut carcinoid syndrome.

A 55-yr-old woman with a midgut carcinoid syndrome due to metastatic spread of an ileal tumor to the liver, paraortic and mediastinal lymph nodes and to the skeleton was given systemic radionuclide therapy with 111In-DTPA-D-Phe1-octreotide. Before therapy, dosimetric calculations were performed on whole-body scintigraphs and 111In retention was shown to be long-lasting. Excretion was mainly seen during the first 24 hr after injection; thereafter whole-body retention remained stationary at 30%. Indium-111 activity in tumor biopsies and blood was measured using a gamma counter. Very high tumor-to-blood ratios were obtained: 150 for the primary tumor and 400-650 for liver metastases, which further justified radiation therapy. Indium-111-DTPA-D-Phe1-octreotide treatment was given on three separate occasions (3.0, 3.5 and 3.1 GBq) 8 and 4 wk apart. After each therapy, the patient experienced facial flush and pain over the skeletal lesions followed by symptomatic relief, even though no objective tumor regression was found radiologically after 5 mo. After initiation of octreotide treatment, there was a 14% reduction of the main tumor marker, urinary 5-HIAA. After three subsequent radionuclide therapies, there was a further 31% reduction of 5-HIAA levels. No adverse reactions, other than a slight decrease in leukocyte counts, were seen. The mean absorbed radiation dose after the three treatments was estimated to be about 10-12 Gy in liver metastases and 3-6 Gy in other tumors, depending on the size and location of the metastases. Assuming internalization of 111In into tumor cells and a radiobiological effect from short range Auger and conversion electrons, there might be a therapeutic effect on the tumor.

[Glucagonoma. A tumor disease with multiple clinical manifestations]. / Glukagonom. Tumörsjukdom med mångfasetterad klinisk bild.

Glucagon-producing neoplasms are rare pancreatic tumours that may give rise to a characteristic syndrome including, diabetes and typical skin manifestations (necrolytic migrating erythema). Dermatological problems are often the first signs of the disease and the diagnosis is easily overlooked. In most series reported to date, glucagonomas had already metastasized at diagnosis, which means that curative surgery was possible to perform in less than half of the patients. To increase awareness of glucagonoma symptomatology a review of the syndrome is presented together with the clinical histories of three patients, recently treated. These cases illustrate aspects of modern diagnosis and treatment.

Assessment of spleen size using gamma camera scintigraphy in newly diagnosed patients with essential thrombocythaemia and polycythaemia vera.

By using gamma camera imaging the spleen size was assessed in 18 consecutive patients with essential thrombocythaemia (ET) and in 18 consecutive patients with polycythaemia vera (PV). All ET and PV patients were newly diagnosed and had not received any myelosuppressive therapy prior to study. The spleen areas in both posterior and left lateral projections were determined. Eighteen consecutive patients with idiopathic thrombocytopenic purpura (ITP) served as a control group since by definition they do not present with splenic enlargement; in these latter subjects the mean posterior and left lateral splenic areas were almost identical (48 +/- 15 and 47 +/- 17 cm2, respectively). In comparison with this control group patients with ET and PC had significantly larger spleens. In both ET and in PV patients the left lateral spleen scan area exceeded the posterior one. Patients with PV had larger splenic areas in both projections than did patients with ET, but the differences were not statistically significant. Compared to the ITP patients it was found that at least 50% of the ET patients and at least 61% of the PV patients at diagnosis presented with splenomegaly.

Intraoperative detection of somatostatin-receptor-positive neuroendocrine tumours using indium-111-labelled DTPA-D-Phe1-octreotide.

After injection of 111In-labelled DTPA-D-Phe1-octreotide, intraoperative tumour localisation was performed using a scintillation detector in 23 patients with neuroendocrine tumours. Count rates from suspect tumour lesions and adjacent normal tissue were expressed as a ratio before (Rin situ) and after (Rex vivo) excision. 111In activity concentration ratios of tumour tissue to blood (T/B) were determined in a gamma counter. In patients with midgut carcinoids, (all scintigraphy positive), false Rin situ recordings were found in 4/29 macroscopically identified tumours. T/B ratios were all high (27-650). In patients with medullary thyroid carcinomas (eight out of ten scintigraphy positive), misleading Rin situ results were found in 4/37 macroscopically identified tumours. T/B ratios were lower (3-39) than those seen in midgut carcinoids. Two out of four patients with endocrine pancreatic tumours had positive scintigraphy, reliable intraoperative measurements and very high T/B ratios (910-1500). One patient with a gastric carcinoid had correct measurements in situ and ex vivo with high T/B ratios (71-210). In situ measurements added little information to preoperative scintigraphy and surgical findings using the present detection system. Rex vivo measurements were more reliable. The very high T/B ratios seen in midgut carcinoids and some endocrine pancreatic tumours would be favourable for future radiation therapy via somatostatin receptors.

Liver uptake function measured by IODIDA clearance rate in liver transplant patients and healthy volunteers.

Hepatobiliary scintigraphy with 99Tc(m)-diethyl-iodo-HIDA (IODIDA), an iminodiacetic acid derivative, is used to assess hepatocyte function and to visualize the hepatobiliary system. The aim of this study was to evaluate whether it is possible to describe liver function by calculating the clearance rate of IODIDA from the blood. Clearance rate was evaluated in 18 liver transplant patients (28 studies) and 11 healthy volunteers (11 studies). Two different clearance rates were calculated: the clearance of IODIDA from the blood due to liver uptake and the total clearance of IODIDA from the blood due to all possible routes of elimination. Both for the healthy controls and the liver transplant patients, there was an excellent correlation between these two methods (r = 0.92 and r = 0.93, respectively), indicating that the liver is the only essential pathway for elimination of IODIDA from the blood. The difference in clearance rate between healthy controls and liver transplant patients was highly significant (P < 0.01), corresponding to the clinical condition of the two groups. We conclude that the clearance rate of IODIDA, based on a simple measurement from the time-activity curve derived from a blood pool region of interest, is a reliable test of liver function.