Human biodistribution of [111In]diethylenetriaminepentaacetic acid-(DTPA)-D-[Phe1]-octreotide and peroperative detection of endocrine tumors.

Requisites for preoperative and intraoperative tumor localization with [111In]diethylenetriaminepentaacetic acid-D-[Phe1]-octreotide scanning were explored in 23 patients with endocrine tumors (15 carcinoids, 4 insulinomas, and single cases of gastrinoma, medullary thyroid carcinoma, aldosteronoma, and paraganglioma). The patients were subjected to Octreoscan single photon emission computed tomographic examination prior to surgery and well counter investigation of nuclide uptake in tumors and normal tissues sampled at surgery. Somatostatin receptor-positive tumors demonstrated efficient nuclide accumulation with mean tumor:blood radioactivity ratios of 180-370 (for carcinoids and insulinoma), compared with tissue:blood ratios of 302 for spleen, 42 for liver, and < 10-15 in other normal tissues (pancreas, small intestine, and mesenteric fat). Inefficient preoperative visualization of lesions was related to inconspicuous size, as for primary intestinal carcinoids, tiny liver metastases, and a single small insulinoma. High background activity, pronounced tumor fibrosis, and meager accumulation of tracer also interfered with visualization. Tumor deposits in organs with low background activity (such as carcinoid mesenteric metastases and endocrine pancreatic tumors) were generally most readily detected. Intraoperative investigations with hand-held gamma detector probes were disturbed by obvious high background activity. These investigations revealed two preoperatively unrecognized primary intestinal carcinoids, which, however, were both palpable during surgery. These studies, therefore, had little impact on the surgical strategy.

Nuclear localization of 111In after intravenous injection of [111In-DTPA-D-Phe1]-octreotide in patients with neuroendocrine tumors.

UNLABELLED: Treatment with tumor-targeting substances is currently being evaluated in clinical trials. For patients with neuroendocrine tumors expressing somatostatin receptors, the 111In-labeled somatostatin analog [diethylenetriaminepentaacetic acid (DTPA)-DPhe1]-octreotide has been used with promising results. To further investigate the clinical effect of the injected conjugate, we analyzed the cellular distribution of 111In by ultrastructural autoradiography. METHODS: Seven patients with somatostatin receptor-expressing midgut carcinoid tumors scheduled for abdominal surgery were investigated by somatostatin receptor scintigraphy. During operation, tumor tissue samples and samples of normal intestine were collected, fixed, and processed for electron microscopy. A thin layer of film emulsion was applied on sections and after the exposure film was developed. The cellular distribution of silver precipitations indicating the presence of isotope was evaluated. RESULTS: Cell surface receptor binding and internalization of [111In-DTPA-D-Phe1]-octreotide in the tumor cells was easily revealed by silver precipitations in the film. Multiple silver grains were seen at the plasma membrane, in the cytoplasmic area among secretory granules and vesicular compartments, and in the perinuclear area. Silver grains were also regularly located in the nucleus. For all patients, the silver precipitation patterns from 111In decay were identical in all examined cells from removed tumors, and in most cells 111In could be seen in the nucleus. The specificity of the silver reaction products is supported by the observation that enterocytes in intestinal tissue specimens from near the tumor did not show any silver grains and no background labeling was seen in the plastic. CONCLUSION: After internalization through the somatostatin receptor system, 111In is translocated to the perinuclear area and into the nucleus. Whether the nuclide is still conjugated to the intact somatostatin analog or to part of it cannot be evaluated in this study. Despite the short irradiation range of 111In, the nuclear localization can explain its clinical effectiveness. The results from this study suggest that [111In-DTPA-D-Phe1]-octreotide may act as a powerful tumor cell-targeting substance.

Scintigraphy and biodistribution of monoclonal adrenocortical antibody in mice grafted with human adrenocortical carcinoma.

BACKGROUND: A murine monoclonal antibody recognizing normal and neoplastic human adrenocortical cells has been evaluated for scintigraphic localization and biodistribution in 53 nude mice grafted subcutaneously with human adrenocortical cell lines SW-13 and T-CAR 1. METHODS: The immunoglobulin G1 antibody and its Fab'2 fragment were purified and labeled with 125I. The tumor grafts exhibited diameters of 5 to 15 mm at 4 to 6 weeks after transplantation, when mice received a single subcutaneous or intraperitoneal injection of 50 micrograms iodinated intact or fragmented antibody, respectively. RESULTS: Examination up to 8 days after immunoglobulin G administration showed mean radioactivity ratios less than 1.0 for tumor to blood and corresponding ratios in tumor to lung, liver, spleen, and kidney from 0.6 to 5.3 at the time of peak tumor to blood ratio. A high background activity was noted on scintigraphic tumor visualization with the iodinated immunoglobulin G. In contrast, the radiolabeled Fab'2 fragment displayed gradually rising tumor to blood ratios, which, 4 days after injection, averaged 10.5 for T-CAR1 and 5.3 for SW-13. Tumor transplants were scintigraphically visualized without substantial background activity 3 days after Fab'2 injection, when the ratio of radioactivity in the tumor to the investigated murine organs was 0.5 to 7.3. CONCLUSIONS: The findings substantiate that immunoscintigraphy with the Fab'2 fragment of the antiadrenocortical Ac5 antibody may become a tool to localize human adrenocortical carcinoma.

Incidence, structure, and function of enlarged parathyroid glands discovered accidentally during thyroid surgery.

BACKGROUND: Operation on rare patients with mainly a severe renal stone disease and considerably elevated urinary calcium excretion has substantiated the association of parathyroid gland abnormalities with normocalcemia. This study examines incidence, structure, and functional characteristics of enlarged parathyroid glands of patients with normocalcemia scheduled for thyroid surgery. METHODS: Eleven enlarged parathyroid glands weighing 110 to 1000 mg were discovered in 9 (1.5%) of 594 patients with normocalcemia undergoing thyroid operation. The preoperative total serum calcium concentration was 2.30 to 2.52 mmol/L and less than 2.38 mmol/L in four of the nine patients. Intact serum parathyroid hormone and alkaline phosphatase levels were elevated in only one individual, and all patients showed normal serum creatinine values. RESULTS: All but three of the 11 enlarged parathyroid glands exhibited microscopic abnormality on routine histopathologic examination, including staining for cytoplasmic fat with oil red 0. Immunohistochemical staining with a monoclonal antibody recognizing the functionally important calcium receptor of the parathyroid cell surface and analysis of the calcium-regulated cytoplasmic Ca2+ concentration of dispersed parathyroid cells substantiated that only a single gland of 130 mg had no discernible functional abnormality. CONCLUSIONS: The findings underline the diagnostic difficulties of parathyroid histopathology and support the presence of disturbed parathyroid hormone secretion even in normocalcemic patients with enlarged parathyroid glands. The functional derangement of these glands substantiates the indication for their surgical excision even in patients exhibiting midnormal serum calcium concentrations, although their possible contribution to the development of a clinically overt hyperparathyroidism can only be speculated.

The ambulance helicopter is a prerequisite for centralised emergency care.

During the summer seasons of 1978-1983 (56 weeks), trial activity with a physician-manned ambulance helicopter was carried out in the County of Stockholm (population 1.5 million). The area includes an extensive archipelago. Within the region there are 11 large general hospitals, three of which are supplied with a helicopter pad. During the trial period 1 246 helicopter missions were undertaken, of which 943 resulted in emergency transportation of the patient (83% by helicopter, 17% by ambulance). The number of missions per day varied from 0-11, with a mean number of 3.2. The turn-out time from receipt of the call to arrival at the scene of the accident or illness was less than 30 minutes in 75% of the cases. Of the emergency calls, 57% involved cases of illness and 43% accidents. Therapeutic intervention by doctors at the scene was considered to have been of vital importance in 22% of the cases, desirable in 28% and unnecessary in 50%. This intervention was regarded as life-saving in 18 cases (2%). By special training of emergency call operators, the number of unnecessary helicopter missions could be minimised (9% of all missions). To continuing specialisation and centralisation of emergency care with extended catchment areas, demands an advanced transport system. This trial has shown that through the use of a physician-manned ambulance helicopter the emergency care within the region can be centralised with retention of adequate turn-out times.

Method for dissection of mesenteric metastases in mid-gut carcinoid tumors.

With adequate medical management the midgut carcinoid tumor generally is an indolent malignancy associated with substantial life expectancy and appreciable life quality, even in the presence of liver metastases and significant tumor burden. Abdominal complications may occur in this entity of carcinoids owing to entrapment of intestines and encasement of mesenteric vessels by mesenteric metastases and associated marked mesenteric fibrosis. This may be the cause of abdominal pain, disabling diarrhea, weight loss to the extent of malnutrition, and eventually the risk of death with acute or chronic intestinal obstruction or intestinal gangrene. Operative removal of the mesentericointestinal lesion is often indicated to prevent or treat these complications but may be technically difficult when mesenteric metastases extend in the vicinity of major vessels in the mesenteric root. At laparotomy 56 patients with advanced midgut carcinoids underwent removal of the mesenteric tumor with a method for preserving the mesenteric vessels. This was feasible by mobilizing and releasing the right colon and mesenteric root from posterior adhesions, identifying the mesenteric artery below the pancreas, and free-dissecting this artery on the tumor capsule in the mobilized mesentery. Dissection was successful even with tumors initially judged inoperable unless tumor growth completely surrounded the mesenteric vessels or extended retroperitoneally. One patient was subjected to distal intestinal artery bypass. Symptom relief was been substantial and often of long duration after mesenteric tumor removal in patients who prior to surgery often had threatening intestinal ischemia. Patients with advanced midgut carcinoids may benefit markedly from dissectional removal of mesenteric tumors, which (conceivably better than conventional wedge resection) preserves the length of the remaining intestine.

Surgery for sporadic primary hyperparathyroidism in the elderly.

Retrospective analysis has been performed on 108 consecutive patients operated for primary hyperparathyroidism (HPT) at 75 to 85 years of age (mean 79 years). The preoperative serum calcium value averaged 2.99 mM, and six patients had hypercalcemic crisis. Psychic disturbances were seen in 60 patients (56%), 40% of whom demonstrated dementia. Skeletal and muscular complaints were registered in 29% and 19%, respectively, and only 6% were overtly asymptomatic. Cardiovascular diseases were presented by 69% of the patients, 13% had diabetes mellitus, and 26% were institutionalized prior to surgery. Bilateral neck exploration disclosed a single adenoma in 69%, which was of the oxyphil cell type in 13%, and water-clear (n = 3) or chief cell hyperplasia in 27%. The total glandular weight averaged 1085 mg. Altogether 72 patients operated on after 1980 demonstrated a perioperative (30-day) mortality of 1.4%; the corresponding morbidity of 8.7% mainly included infections as well as a vocal cord paralysis in one patient and two incisional hematomas. Analysis for mean 3.1 years postoperatively displayed reversal of hypercalcemia in 95% of the patients; 2.8% of those operated after 1980 had persistent disease. Symptoms seemed to be alleviated in 62%, with a similar rate attained in patients with dementia. Altogether 60 patients died from mainly cardiovascular diseases mean 4.2 years after the operation. Those succumbing the first postoperative year (n = 21) showed overrepresentation of cardiac diseases and diabetes mellitus. The results demonstrate prevalent psychic disturbances, oxyphil adenomas, and multiglandular parathyroid disease in elderly patients with primary HPT and favor rather liberal application of parathyroid surgery among these individuals.

In vivo cellular distribution and endocytosis of the somatostatin receptor-ligand complex.

Radioactive tumor targeting agents are highly interesting and for treatment of neuroendocrine tumors expressing somatostatin receptors, radiolabeled somatostatin analogues (including [(111)In-DTPA-D-Phe1]-octreotide) has been tried in a small number of patients with encouraging results. To increase our knowledge about the in vivo processing of administered [(111)In-DTPA-D-Phe1]-octreotide we have examined tumor and normal tissue material from a patient with a midgut carcinoid tumor. By ultrastructural autoradiography, silver grains indicating the presence of [(111)In-DTPA-D-Phe1]-octreotide could be identified within tumor cells, both in the primary tumor and in the mesenteric metastases. Silver grains were also found in leukocytes and in blood vessels. However, normal enterocytes did not show any specific radioligand uptake. This study indicates that the binding and endocytosis of [(111)In-DTPA-D-Phe1]-octreotide is a specific process that takes place in cells expressing somatostatin receptors. However, the importance of the number of somatostatin receptors and subtypes expressed will have to be further studied.

Intraoperative gamma detection reveals abdominal endocrine tumors more efficiently than somatostatin receptor scintigraphy.

BACKGROUND: [(111)In]-diethylenetriamine pentaacetic acid (DTPA)-D-[Phe1]-octreotide (OctreoScan, Mallinckrodt Medical, Petten, The Netherlands), combined with single photon emission computed tomography (SPECT), has limited possibilities to detect small abdominal endocrine tumors. This study explores the efficacy of OctreoScan and a newly developed handheld gamma detector probe (H-probe2) for the localization of neuroendocrine abdominal tumors. METHODS: Twenty-one patients with endocrine pancreatic or midgut carcinoid tumors were given 100-200 megabecquerels (MBq) [(111)In]-DTPA-D-[Phe1]-octreotide and underwent preoperative SPECT examination, after which time surgery was undertaken within 24-48 hours. Intraoperatively the radioactivity of tumors and normal tissues was measured with the H-probe2 connected to a portable personal computer. Resected intestinal specimens of ten patients with carcinoid tumors were examined by gamma camera ex vivo. Biopsies of all tumors subsequently were investigated in a wellcounter and by routine histopathology. RESULTS: Disregarding liver metastases, a total of 34 of 60 abdominal tumors were detected by SPECT; however, SPECT failed to visualize any tumor < 9 mm. The shielding of the manual probe allowed intraoperative examination despite the substantial radiation energy of (111)In. The H-probe2 detected 91% of the tumors investigated, and these included all those > 5 mm. In the wellcounter the H-probe2-detected tumors exhibited 4.7-157.7 times higher radionuclide uptake than the surrounding normal tissues. The gamma camera analysis detected 68% of tumors in the resected specimens. CONCLUSIONS: The intraoperative H-probe2 examination provided substantial improvement in the detection of small endocrine lesions accumulating [(111)In]-DTPA-D-[Phe1]-octreotide and all lesions with a size > 5 mm in greatest dimension could be identified.

A gamma detector probe with ex vivo detection of carcinoid tumors superior to intraoperative palpation.

BACKGROUND: Despite the generally successful scintigraphic detection of endocrine tumors with [(111)In]-DTPA-D-[Phe1]-octreotide (OctreoScan, Mallinckrodt Medical, Petten, The Netherlands), its intraoperative application awaits the development of suitable gamma detectors. This study describes a novel probe (H-probe2) and its ex vivo efficacy for the detection of midgut carcinoid tumors. METHODS: The probe measures 180 mm x 24 mm, and contains a bismuth germinate crystal connected to a photomultiplicator tube, a lead shield, and a tantalum collimator with an angled, 3-mm wide opening. It was characterized in a test bench utilizing solublilized (111)In and 99mTc, and 8 fresh operative specimens containing 26 histologically verified midgut carcinoid tumors (2-40 mm) from patients exposed to OctreoScan. Measurements were made at 2.5-mm intervals over the entire specimens and presented three dimensionally. RESULTS: The test bench analysis supported efficient shielding, and a total collimation of 27 degrees for (111)In and 20 degrees for 99mTc. In addition to 18 palpable tumors, 4 of 6 surgically occult tumors (2-3 mm in dimension) could be discovered with H-probe2. Small tumors in close apposition to a large tumor could not be separated. Wellcounter examination showed that tumors detected with the H-probe2 exhibited 1.7-84.1 times higher radionuclide uptake than the surrounding normal tissue. CONCLUSION: Ex vivo analysis of H-probe2 supported detection of tumors inaccessible to surgical palpation, but its clinical efficiency awaits intraoperative evaluation.

Treatment with high dose [(111)In-DTPA-D-PHE1]-octreotide in patients with neuroendocrine tumors--evaluation of therapeutic and toxic effects.

Carcinoid tumors and endocrine pancreatic tumors often express somatostatin receptors (sst). Tumor spread may be visualized by sst scintigraphy using [(111)In-DTPA-D-Phe1]-octreotide. In this study, tumor targeting therapy with [(111)In-DTPA-D-Phe1]-octreotide at high doses (6 GBq every third week) was used to treat patients with sst-expressing tumors. Five patients entered the protocol and three were evaluable for response, while all could be evaluated for toxicity. Two patient responded with a significant reduction in tumor markers (> 50%). The third patient showed increasing levels of tumor markers. Side effects were expressed as depression of bone-marrow function. In one patient a grade 4 reduction in platelet count was observed requiring several thrombocyte transfusions. In another two patients platelet counts decreased significantly. We conclude that treatment with [(111)In-DTPA-D-Phe1]-octreotide can be used in patients with neuroendocrine tumors but blood parameters have to be carefully monitored to avoid severe side effects.