A rare case of a large spinal meningioma with mediastinal extension and malignant behavior classified histologically as benign.

AIM: To report a rare case of a spinal WHO grade I meningioma extending through intervertebral foramina C7 to D4 with an extensive mediastinal mass and infiltration of the vertebrae, and to discuss the malignant behavior of a tumor classified as benign. METHODS: (Clinical Presentation, Histology, and Imaging): A 54-year-old man suffered from increasing lower back pain with gait difficulties, weakness and numbness of the lower extremities, as well as urge incontinence. CT scan of the thorax and MRI scan of the spine revealed a large prevertebral tumor, which extended to the spinal canal and caused compression of the spinal cord at the levels of C7 to D4 leading to myelopathy with hyperintense signal alteration on T2-weighted MRI images. The signal constellation (T1 with and without contrast, T2, TIR) was highly suspicious for infiltration of vertebrae C7 to D5. Somatostatin receptor SPECT/CT with (111)In-DTPA-D: -Phe-1-octreotide detected a somatostatin receptor-positive mediastinal tumor with infiltration of multiple vertebrae, dura, and intervertebral foramina C7-D4, partially with Krenning score >2. Percutaneous biopsies of the mediastinal mass led to histopathological findings of WHO grade I meningioma of meningothelial subtype. RESULTS: (Therapy): C7 to D4 laminoplasty was performed, and the intraspinal, extradural part of the tumor was microsurgically removed. Postoperative stereotactic radiation therapy was done using the volumetric modulated arc therapy (VMAT) technique (RapidArc). No PRRNT with (90)Y-DOTA-TOC was done. CONCLUSIONS: Due to the rare incidence and complex presentation of this disease not amenable to complete surgical resection, an individualized treatment approach should be worked out interdisciplinarily. The treatment approach should be based not only on histology but also on clinical and imaging findings. Close clinical and radiological follow-up may be mandatory even for benign tumors.

Glucagon-like peptide-1 (GLP-1) receptors are not overexpressed in pancreatic islets from patients with severe hyperinsulinaemic hypoglycaemia following gastric bypass.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) receptors are highly overexpressed in benign insulinomas, permitting in vivo tumour visualisation with GLP-1 receptor scanning. The present study sought to evaluate the GLP-1 receptor status in vitro in other pancreatic disorders leading to hyperinsulinaemic hypoglycaemia, specifically after gastric bypass surgery. METHODS: Fresh frozen pancreatic tissue samples (n=7) from six gastric bypass surgery patients suffering from hyperinsulinaemic hypoglycaemia were evaluated for GLP-1 receptor content using in vitro receptor autoradiography, and compared with normal pancreas and with pancreatic insulinoma tissues. RESULTS: GLP-1 receptor analysis of the pancreatic tissues, which histopathologically were compatible with nesidioblastosis and originated from post-bypass hypoglycaemic patients, revealed a mean density value of GLP-1 receptors in the islets of 1,483 ± 183 dpm/mg tissue. Pharmacological characterisation indicated the presence of specific GLP-1 receptors. The density of islet GLP-1 receptor in post-gastric bypass patients did not differ from that of normal pancreas (1,563 ± 104 dpm/mg tissue, n = 10). Receptor density in pancreatic acini was low in post-bypass and control conditions. In contrast, benign insulinomas showed a high density of GLP-1 receptors, with a mean value of 8,302 ± 1,073 dpm/mg tissue (n = 6). CONCLUSIONS/INTERPRETATION: In contrast to insulinoma, hyperinsulinaemic hypoglycaemia after gastric bypass surgery is not accompanied by overexpression of GLP-1 receptor in individual islets. Thus, patients with post-gastric bypass hyperinsulinaemic hypoglycaemia are not candidates for GLP-1 receptor imaging in vivo using radiolabelled exendin. These GLP-1 receptor data support the notion that the islet pathobiology of post-gastric bypass hypoglycaemia is distinctly different from that of benign insulinomas.

Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8,Met(O2)11]-substance P: a pilot trial.

PURPOSE: Functionally critically located gliomas represent a challenging subgroup of intrinsic brain neoplasms. Standard therapeutic recommendations often cannot be applied, because radical treatment and preservation of neurological function are contrary goals. The successful targeting of gliomas with locally injected beta radiation-emitting (90)Y-DOTAGA-substance P has been shown previously. However, in critically located tumours, the mean tissue range of 5 mm of (90)Y may seriously damage adjacent brain areas. In contrast, the alpha radiation-emitting radionuclide (213)Bi with a mean tissue range of 81 microm may have a more favourable toxicity profile. Therefore, we evaluated locally injected (213)Bi-DOTA-substance P in patients with critically located gliomas as the primary therapeutic modality. METHODS: In a pilot study, we included five patients with critically located gliomas (WHO grades II-IV). After diagnosis by biopsy, (213)Bi-DOTA-substance P was locally injected, followed by serial SPECT/CT and MR imaging and blood sampling. Besides feasibility and toxicity, the functional outcome was evaluated. RESULTS: Targeted radiopeptide therapy using (213)Bi-DOTA-substance P was feasible and tolerated without additional neurological deficit. No local or systemic toxicity was observed. (213)Bi-DOTA-substance P showed high retention at the target site. MR imaging was suggestive of radiation-induced necrosis and demarcation of the tumours, which was validated by subsequent resection. CONCLUSION: This study provides proof of concept that targeted local radiotherapy using (213)Bi-DOTA-substance P is feasible and may represent an innovative and effective treatment for critically located gliomas. Primarily non-operable gliomas may become resectable with this treatment, thereby possibly improving the prognosis.

Cholecystokinin-B/gastrin receptors enhance wound healing in the rat gastric mucosa.

Although physiological functions of the CCK-B/gastrin receptor are well explored, little is known about its role during healing. Here, we evaluated the role of this receptor in the rat oxyntic mucosa following the introduction of a cryoulcer. In this model, we located and quantified CCK-B/gastrin receptors by reverse transcriptase PCR and receptor autoradiography. Rats with cryoulcers were treated with placebo, omeprazole, the CCK-B/gastrin receptor antagonist YF-476, omeprazole plus YF-476, gastrin-17, and gastrin 17 plus YF-476. During wound healing, CCK-B/gastrin receptors were specifically expressed and localized to the regenerative mucosal ulcer margin. This high expression was limited in time, and the pattern of expression of CCK-B/gastrin receptors correlated closely with the proliferative activity of the regenerative mucosa. Functionally, omeprazole and gastrin-17 caused profound hypergastrinemia, increased cell proliferation in the mucosal ulcer margin and accelerated the late ulcer healing phase. These effects were completely reversed by cotherapy with YF-476. These in vivo and vitro data suggest that CCK-B/gastrin receptors in regenerative rat gastric oxyntic mucosa enhance trophic effects during wound healing.

Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation.

Bombesin-like peptides such as gastrin-releasing peptide (GRP) have been shown to play a role in cancer as autocrine growth factors that stimulate tumor growth through specific receptors. To search for potential clinical indications for GRP analogues, it is important to identify human tumor types expressing sufficient amounts of the respective receptors. In the present study, we have evaluated the expression of GRP receptors in human nonneoplastic and neoplastic prostate tissues using in vitro receptor autoradiography on tissue sections with 125I-Tyr4-bombesin as radio-ligand. GRP receptors were detected, often in high density, in 30 of 30 invasive prostatic carcinomas and also in 26 of 26 cases of prostatic intraepithelial proliferative lesions, corresponding mostly to prostatic intraepithelial neoplasias. Well-differentiated carcinomas had a higher receptor density than poorly differentiated ones. Bone metastases of androgen-independent prostate cancers were GRP receptor-positive in 4 of 7 cases. Conversely, GRP receptors were identified in only a few hyperplastic prostates and were localized in very low density in glandular tissue and, focally, in some stromal tissue. In all of the cases, the receptors corresponded to the GRP receptor subtype of bombesin receptors, having high affinity for GRP and bombesin and lower affinity for neuromedin B. These data demonstrate a massive GRP receptor overexpression in prostate tissues that are neoplastically transformed or, like prostatic intraepithelial neoplasias, are in the process of malignant transformation. GRP receptors may be markers for early molecular events in prostate carcinogenesis and useful in differentiating prostate hyperplasia from prostate neoplasia Such data may not only be of biological significance but may also provide a molecular basis for potential clinical applications such as GRP-receptor scintigraphy for early tumor diagnosis, radiotherapy with radiolabeled bombesin-like peptide analogues, and chemotherapy with cytotoxic bombesin analogues.

Somatostatin receptors in human renal cell carcinomas.

The presence of somatostatin receptors was evaluated in samples of 39 surgically removed human renal cell carcinomas with receptor autoradiography on tumor sections by using iodinated [Tyr3]octreotide as the radioligand. All types, grades and stages of tumors were represented. Twenty-eight of 39 renal cell carcinomas (72%) were shown to be somatostatin receptor positive. The receptors were saturable, of high affinity (KD = 0.8 nM), and were specific for somatostatin and bioactive somatostatin analogues. No evident correlations were found between the status of somatostatin receptors in the tumor and the age or sex of the patients, the histopathological type or grade of the tumor, or the tumor-node-metastasis stage of the disease. However, numerous cases considered to be of poor prognosis were somatostatin receptor positive. No functional correlates for these receptors have been established, although the presence of somatostatin receptors in human kidneys and somatostatin effects on renal tubular functions in normal human volunteers have been reported. In a patient scanned in vivo for islet cell carcinoma with an 123I-labeled somatostatin analogue, bilateral renal cell carcinomas were also visualized; multiple bilateral renal cell carcinomas were identified on the 1- and 4-h images taken after injection of 123I-labeled somatostatin analogue. In conclusion, the high incidence of somatostatin receptors in renal cell carcinomas may have diagnostic value when performing in vivo imaging of somatostatin receptors and it may have potential therapeutic implications.

Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors.

Cholecystokinin (CCK)-A and CCK-B/gastrin receptors were evaluated with in vitro receptor autoradiography in 406 human tumors of various origins using a sulfated 125I-labeled CCK decapeptide analogue 125I-(D-Tyr-Gly, Nle28,3l)-CCK 26-33 and 125I-labeled Leu15-gastrin as radioligands. CCK-B/gastrin receptors were found frequently in medullary thyroid carcinomas (92%), in small cell lung cancers (57%), in astrocytomas (65%), and in stromal ovarian cancers (100%). They were found occasionally in gastroenteropancreatic tumors, breast, endometrial, and ovarian adenocarcinomas. They were either not expressed or rarely expressed in colorectal cancers, differentiated thyroid cancers, non-small cell lung cancers, meningiomas, neuroblastomas, schwannomas, glioblastomas, lymphomas, renal cell cancers, prostate carcinomas, and the remaining neuroendocrine tumors (i.e., pituitary adenomas, pheochromocytomas, paragangliomas, and parathyroid adenomas). CCK-A receptors were expressed rarely in tumors except in gastroenteropancreatic tumors (38%), meningiomas (30%), and some neuroblastomas (19%). The identified CCK-A and CCK-B receptors were specific and of high affinity in the subnanomolar range. The rank order of potency of various CCK analogues was: sulfated CCK-8 = L-364,718 >> nonsulfated CCK-8 = L-365,260 > or = gastrin for CCK-A receptors and sulfated CCK-8 > gastrin = nonsulfated CCK-8 > L-365,260 > L-364,718 for CCK-B receptors. CCK-B receptors could also be selectively and specifically labeled with a newly designed nonsulfated 125I-(D-Tyr-Gly, Nle28,31)-CCK 26-33. Gastrin mRNA measured by in situ hybridization was present in most CCK-B receptor-positive small cell lung cancers, breast tumors, and ovarian tumors, representing the molecular basis of a possible autocrine growth regulation of these tumors. Gastrin and CCK mRNAs were lacking in medullary thyroid cancers. Thus, these results may have pathogenic, diagnostic, differential diagnostic, and therapeutic implications.

Expression and localization of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger RNAs in primary human tumors using in situ hybridization.

Somatostatin receptor gene expression of SSTR1, SSTR2, and SSTR3 subtypes was evaluated by in situ hybridization in 55 human primary tumors shown to contain a high density of somatostatin receptors in binding assays. All 55 tumors expressed at least one SSTR subtype. Of 55 somatostatin receptor-positive tumors, 46 had SSTR2 mRNA; all 46 were characterized as having receptors with a high affinity for the synthetic analogue octreotide. Of 55 tumors, 12 expressed SSTR1, and 14 expressed SSTR3 mRNA. The subtype SSTR1 was expressed alone in 4 cases, SSTR2 was expressed alone in 33 cases, and SSTR3 was expressed alone in one case. In 4 cases, all 3 SSTR were expressed simultaneously. The cases having SSTR1 mRNA were identified in binding experiments with 125I-labeled somatostatin-14 and -28 analogues rather than with 125I-[Tyr3]-octreotide. Whereas meningiomas, neuroblastomas, pituitary adenomas, small cell lung carcinomas, lymphomas, and breast tumors expressed primarily a high abundance of SSTR2, carcinoids, islet cell carcinomas, medullary thyroid carcinomas, and ovarian tumors had a mixed distribution of the somatostatin receptor subtypes. This is the first demonstration of the presence of SSTR1, SSTR2, and SSTR3 in primary human tumors using in situ hybridization. Since these somatostatin receptor subtypes probably mediate distinct somatostatin actions, it may be worthwhile to search for subtype-specific analogues to use for the treatment and diagnosis of these tumors.

Somatostatin and vasoactive intestinal peptide receptors in human mesenchymal tumors: in vitro identification.

Somatostatin and vasoactive intestinal peptide (VIP) have been shown to be of diagnostic and therapeutic interest in several types of human epithelial tumors expressing the respective receptor. The present study evaluates the presence of somatostatin and VIP receptors in 64 primary or metastatic human mesenchymal tumors. In vitro receptor autoradiography on cryostat sections was performed using 125I-labeled [Tyr3]-octreotide as well as 125I-labeled [Leu8,D-Trp22,Try25]-somatostatin-28 as radioligands for somatostatin receptors and 125I-labeled VIP as radioligand for VIP receptors. Somatostatin receptors were identified in bone and vascular/perivascular tumors (3 of 3 osteosarcomas, 1 of 1 giant cell tumor, 2 of 2 angiosarcomas, and 4 of 4 hemangiopericytomas), in 2 of 2 synovial sarcomas, in 2 of 5 histiocytomas, and in several muscle cell tumors (1 of 2 leiomyomas, 2 of 4 leiomyosarcomas, and 3 of 5 rhabdomyosarcomas) but were absent in 4 liposarcomas, 3 mesotheliomas, 3 chondrosarcomas, 10 Ewing sarcomas, 11 schwannomas, and 5 Wilms' tumors. VIP receptors were identified in 3 of 3 differentiated liposarcomas, 2 of 2 angiosarcomas, 4 of 4 hemangiopericytomas, 2 of 2 synovial sarcomas, 3 of 3 mesotheliomas, 5 of 5 Wilms tumors, as well as in 2 of 5 histiocytomas, 1 of 2 leiomyomas, 2 of 4 leiomyosarcomas, 3 of 3 intermediately differentiated rhabdomyosarcomas, and 1 of 3 osteosarcomas but not in chondrosarcomas, Ewing sarcomas, schwannomas, or undifferentiated rhabdomyosarcomas. The receptors were located on neoplastic cells. The somatostatin receptors were of high affinity and of high specificity for biologically active somatostatin analogues with high affinity for somatostatin-14 and somatostatin-28 as well as for octreotide, thus representing the sst2 subtype; in a few cases of tumors having somatostatin receptors with low affinity for octreotide, in situ hybridization techniques identified preferentially sst1 mRNA. These data suggest that human mesenchymal tumors may be targets for somatostatin and/or VIP receptor in vivo imaging; they may also be potential targets for somatostatin or VIP analogue therapy.

Y(1)-mediated effect of neuropeptide Y in cancer: breast carcinomas as targets.

Overexpression of selected peptide receptors in human tumors has been shown to represent clinically relevant targets for cancer diagnosis and therapy. Neuropeptide Y (NPY) is a peptide neurotransmitter mediating feeding behavior and vasoconstriction. It has never been shown to be involved in human cancer. We show here, using in vitro receptor autoradiography, a NPY receptor incidence of 85% in primary human breast carcinomas (n = 95) and of 100% in lymph node metastases of receptor-positive primaries (n = 27), predominantly as Y(1) subtype, whereas non-neoplastic human breast expressed Y(2) preferentially. Y(1) mRNA was detected in Y(1)-expressing tumors by in situ hybridization, whereas Y(2) mRNA was found in normal breast tissue. The strong predominance of Y(1) in breast carcinomas compared with Y(2) in normal breast suggests that neoplastic transformation can switch the NPY receptor expression from Y(2) to Y(1) subtype. Moreover, in Y(1)-expressing human SK-N-MC tumor cells, an NPY-induced, dose-dependent inhibition of tumor cell growth of >40% was observed, suggesting a functional role of NPY in cancer, mediated by Y(1). NPY should therefore be added to the list of small regulatory peptides related to cancer. The high incidence of Y(1) in in situ, invasive, and metastatic breast cancers allows for the possibility to target them for diagnosis and therapy with NPY analogues.

Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin.

The evaluation of peptide receptors in man is needed not only to discover the physiological target tissues of a given peptide but also to identify diseases with a sufficient receptor overexpression for diagnostic or therapeutic interventions. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors have been evaluated in human tumors and in their tissues of origin using in vitro receptor autoradiography with 125I-VIP or 125I-acetyl-PACAP-27 in tissue sections. The VIP/PACAP receptor subtypes VPAC1, VPAC2, and PAC1 were evaluated in these tissues by determining the rank order of potencies of VIP and PACAP as well as VPAC1- and VPAC2-selective analogues. The VIP/PACAP receptors expressed in the great majority of the most frequently occurring human tumors, including breast (100% receptor incidence), prostate (100%), pancreas (65%), lung (58%), colon (96%), stomach (54%), liver (49%), and urinary bladder (100%) carcinomas as well as lymphomas (58%) and meningiomas (100%), are predominantly of the VPAC1 type. Their cells or tissues of origin, i.e., hepatocytes, breast lobules and ducts, urothelium, prostate glands, pancreatic ducts, lung acini, gastrointestinal mucosa, and lymphocytes, also predominantly express VPAC1. Leiomyomas predominantly express VPAC2 receptors, whereas paragangliomas, pheochromocytomas, and endometrial carcinomas preferentially express PAC1 receptors. Conversely, VPAC2 receptors are found mainly in smooth muscle (i.e., stomach), in vessels, and in stroma (e.g., of the prostate), whereas PAC1 receptors are present in the adrenal medulla and in some uterine glands. Whereas the very wide distribution of VIP/PACAP receptors in the normal human body is indicative of a key role of these peptides in human physiology, the high VIP/PACAP receptor expression in tumors may represent the molecular basis for clinical applications of VIP/PACAP such as in vivo scintigraphy and radiotherapy of tumors as well as VIP/PACAP analogue treatment for tumor growth inhibition.

Somatostatin receptors in human endocrine tumors.

A selection of 90 mainly endocrine but nonpituitary tumors have been tested for their content of specific somatostatin receptors using receptor autoradiography. Somatostatin receptors were detected in the following tumors: in all 5 meningiomas tested; in 3 of 39 malignant breast tumors; and in 3 growth hormone releasing factor-producing tumors, i.e., one mediastinal carcinoid, one intestinal carcinoma, and its liver metastasis. Receptor density varied greatly among individual tumors. Some of the positive tumors were biochemically characterized using in vitro binding assay and were shown to have saturable and high affinity receptors with pharmacological specificity for somatostatin. The following tumors did not contain somatostatin receptors: prostate carcinomas (n = 17); prostate hyperplasia (n = 2); ovarian carcinomas (n = 6); endometrial carcinomas (n = 4); primary liver cell carcinomas (n = 3); pheochromocytomas (n = 3); aldosteronomas (n = 2); medullary thyroid carcinomas (n = 2); one adrenocorticotropic hormone-secreting pulmonary carcinoid; one astrocytoma; one neurofibroma; one lung tumor; and one bladder tumor. Somatostatin receptors can be found in benign or malignant tumors, originating in part from tissue not primarily known as a somatostatin target. The biological function of such receptors is, therefore, partly unknown. If they can mediate antiproliferative properties, as has been suggested to be the case for somatostatin receptors in selected endocrine tumors in rats and humans, the present data could be of potential therapeutic interest.

Distribution and biochemical characterization of somatostatin receptors in tumors of the human central nervous system.

Fifty-two brain tumors, consisting of 17 astrocytomas, 4 oligodendrogliomas, 20 glioblastomas, 3 neurinomas, 2 ependymomas, 1 neurofibroma, 1 ganglioneuroblastoma, 1 medulloblastoma, 1 plexus papilloma, 1 teratoma, and 1 germinoma, were tested for their content of specific somatostatin receptors using autoradiographic techniques or in vitro binding assays with membrane homogenates. Somatostatin receptors were found in most of the differentiated glia-derived tumors such as astrocytomas and oligodendrogliomas whereas the poorly differentiated glioblastomas were usually free of receptors. Tumors originating from neuroblasts, i.e., ganglioneuroblastoma and medulloblastoma, contained a high density of somatostatin receptors, whereas neurinomas and neurofibromas as well as the ependymomas, one teratoma, and one plexus papilloma were lacking such receptors. In one germinoma, low amounts of somatostatin receptors were observed over the lymphocytic elements. Receptor-positive tumors had saturable and high affinity receptors with pharmacological specificity for somatostatin and somatostatin analogues resembling that of normal human central nervous system tissue. In most instances, they could be labeled with two different iodinated radioligands, a somatostatin octapeptide derivative (204-090) or a somatostatin-28 analogue. This is the first time that somatostatin receptors have been shown to exist not only on neuronal structures of the central nervous system but also on glial elements. The precise function of such somatostatin receptors on glial cells, which may be different from neurotransmission, remains to be determined.

Breast cancer growth is inhibited by vasoactive intestinal peptide (VIP) hybrid, a synthetic VIP receptor antagonist.

Breast cancer vasoactive intestinal peptide (VIP) receptors were characterized. Using in vitro autoradiographic techniques, 125I-labeled VIP bound with high affinity to breast biopsy sections. 125I-labeled VIP bound specifically to give breast cancer cell lines examined using receptor-binding techniques. Specific 125I-labeled VIP binding to MDA-MB-231 cells was inhibited with high affinity by VIP and pituitary adenylate cyclase-activating polypeptide (IC50, = 2 nM) and with moderate affinity by the VIP hybrid (IC50 = 0.5 microM). VIP elevated the cAMP in a dose-dependent manner, and VIP hybrid (10 microM) inhibited the increase in cAMP caused by VIP. Using Northern blot analysis, VIP (10 nM) stimulated c-fos and c-myc mRNA, and the increase caused by VIP was reversed by the VIP hybrid. The VIP hybrid inhibited breast cancer growth in vitro and in vivo using nude mice bearing breast cancer xenografts. These data suggest that the VIP hybrid is a breast cancer VIP receptor antagonist.

Metastatic hormone-refractory prostatic adenocarcinoma expresses somatostatin receptors and is visualized in vivo by [111In]-labeled DTPA-D-[Phe1]-octreotide scintigraphy.

Thirty-one patients with metastatic hormone-refractory prostatic adenocarcinoma were investigated scintigraphically with the 111In-labeled somatostatin analogue [DTPA-D-Phe1]-octreotide (OctreoScan) and with 99mTc-labeled HDP. In vitro somatostatin receptor autoradiography was performed on biopsies obtained from eight patients with hormone-refractory prostatic adenocarcinoma. In 30 of 31 patients (94%), at least one metastasis was positive at OctreoScan scintigraphy. Of the 346 lesions detected with 99mTc-labeled HDP bone scintigraphy, 128 were visualized with the OctreoScan technique, thus accounting for a 37% detection rate. Two uptakes on OctreoScan could not be identified on bone scintigraphy and were, thus, assessed as false positive. The biopsies of the eight patients disclosed a low density of receptors, localized on the tumor cells, as demonstrated with receptor autoradiography. Two patients with untreated metastatic prostatic adenocarcinoma were investigated in vivo before the start of endocrine therapy. However, none of the lesions detected by bone scintigraphy in these patients could be visualized with the OctreoScan technique. Positron emission tomography using [11C] methionine showed a decreased uptake in a metastatic index lesion in a patient treated with octreotide. It is concluded that hormone-refractory prostatic adenocarcinoma expresses somatostain receptors both in vitro and in vivo. The results obtained form the basis for the development of a new tool for in vivo characterization and of a new treatment strategy in patients with hormone-refractory prostatic adenocarcinoma.

Prognostic value of receptors for insulin-like growth factor 1, somatostatin, and epidermal growth factor in human breast cancer.

The prognostic significance, as well as the relationship with known prognostic factors in breast cancer, of insulin-like growth factor 1 receptor (IGF-1-R), epidermal growth factor receptor (EGF-R), and somatostatin receptor (SS-R) was evaluated. IGF-1-R was positively correlated with estrogen receptor and age, but not significantly with progesterone receptor, lymph node status, and tumor size. EGF-R was negatively correlated to estrogen receptor and progesterone receptor, whereas no association was found with age, lymph node status, and tumor size. The levels of the tumor contents of IGF-1-R and EGF-R were not significantly related to tumor recurrence in 214 patients (test for trend, P = 0.20 and P = 0.08, respectively). However, patients with tumors containing intermediate levels of EGF-R (0.5 to 2.0 fmol/mg of membrane protein) experienced a longer disease-free survival than did patients with tumors possessing lower or higher levels of EGF-R. This effect was most pronounced in the subgroup of patients with positive axillary lymph nodes: 66% disease-free after 5 yr compared with 38% and 46% for the groups with lower and higher EGF-R levels, respectively. The relapse-free survival for patients with tumors containing SS-R (15%) was significantly longer than for patients with SS-R-negative tumors (82% versus 46% disease free after 5 yr, P = 0.04). Assessment by multivariate analysis showed that lymph node status, tumor size, and differentiation grade were independent prognostic factors for relapse. In the Cox model, estrogen receptor and progesterone receptor were both negatively correlated with tumor recurrence, whereas overall EGF-R and IGF-1-R did not show such a relation.

Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas.

Somatostatin (SS) receptor status was investigated in the tumor tissues from 62 patients with carcinoid tumors and 15 patients with islet cell carcinomas using receptor autoradiography techniques with two different iodinated somatostatin analogues as radioligands, a [Leu8, DTrp22, Tyr25]somatostatin-28 and a somatostatin octapeptide, Tyr3-octreotide. The carcinoid tumors were either primaries (n = 32) or metastases (n = 43), sampled as surgical specimens or as small needle liver biopsies. Fifty-four of 62 carcinoid patients had SS receptor-positive tumors (87%). All 15 islet cell carcinoma patients had positive tumors (4 primaries, 11 metastases), i.e., 3 vipomas, 3 insulinomas, 2 glucagonomas, 1 gastrinoma, 2 polyfunctional tumors, and 4 nonfunctioning tumors. Saturation and competition experiments on tissue sections revealed saturable, high affinity binding sites pharmacologically specific for bioactive SS analogues. In a majority of the tumors, the receptors were densely distributed and were always homogeneously found in the whole tumor. All except two tumors were labeled with both radioligands. Multiple liver metastases (n = 16) from three different patients were all shown to contain a comparable amount of receptors. SS receptors could be demonstrated even in very small tissue samples of liver metastases obtained by percutaneous liver biopsies (mean weight, 6.8 mg). The majority of the eight SS receptor-negative carcinoids were mainly bronchial carcinoids (n = 5), usually poorly differentiated. On the contrary, SS receptor-positive cases were never found to be anaplastic. All tumors except one from patients pretreated with octreotide (3 days to 3.8 years) were SS receptor positive. In the majority of carcinoids or islet cell carcinomas, the SS receptor status correlated with the in vivo biochemical response (hormone inhibition) to octreotide. These data demonstrate (a) the high prevalence of SS receptors in the primary tumors of both carcinoids and islet cell carcinomas, (b) their presence in metastases as well, (c) their continuous expression even during long term octreotide therapy, (d) the possibility of measuring SS receptors in percutaneous needle liver biopsies, and (e) the evidence of their functionality. This study therefore suggests that tumoral SS receptors may be the likely molecular basis for octreotide action and may be an important parameter for predicting the therapeutic efficacy of SS analogues in carcinoids and islet cell carcinomas.

Multiple actions of somatostatin in neoplastic disease.

The role played by the neuropeptide somatostatin, also known as somatotropin release inhibitory factor (SRIF), in human cancer is not well understood. Recent investigations involving somatostatin receptors in normal and neoplastic human tissues suggest that the action is complex and involves both direct and indirect mechanisms. In this article, Jean-Claude Reubi and Jean Laissue describe the variety of biological mechanisms involved in neoplasia that are associated with somatostatin, and illustrate the therapeutic potential and present limitations of somatostatin analogues.

Clinical applications of somatostatin analogs.

The somatostatin analog Sandostatin is successfully used in the treatment of metastatic endocrine pancreatic tumors, carcinoids, and acromegaly. In addition, somatostatin receptors are also present on other tumors in man, therefore making it possible to demonstrate these tumors by the administration of (123)I-coupled to a somatostatin analog.

Locoregional regulatory peptide receptor targeting with the diffusible somatostatin analogue 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC): a pilot study in human gliomas.

Human gliomas, especially of low-grade type, have been shown to express high-affinity somatostatin receptor type 2 (J-C. Reubi et al., Am. J. Pathol, 134: 337-344, 1989). We enrolled seven low-grade and four anaplastic glioma patients in a pilot study using the diffusible peptidic vector 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC) for receptor targeting. The radiopharmakon was locoregionally injected into a stereotactically inserted Port-a-cath. DOTATOC competes specifically with somatostatin binding to somatostatin receptor type 2 in the low nanomolar range as shown by a displacement curve of 125I-[Tyr3]-octreotide in tumor tissue sections. Diagnostic (111)In-labeled DOTATOC-scintigraphy following local injection displayed homogeneous to nodular intratumoral vector distribution. The cumulative activity of regionally injected peptide-bound 90Y amounted to 370-3300 MBq, which is equivalent to an effective dose range between 60 +/- 15 and 550 +/- 110 Gy. Activity was injected in one to four fractions according to tumor volumes; 1110 MBq of 90Y-labeled DOTATOC was the maximum activity per single injection. We obtained six disease stabilizations and shrinking of a cystic low-grade astrocytoma component. The only toxicity observed was secondary perifocal edema. The activity:dose ratio (MBq:Gy) represents a measure for the stability of peptide retention in receptor-positive tissue and might predict the clinical course. We conclude that SR-positive human gliomas, especially of low-grade type, can be successfully targeted by intratumoral injection of the metabolically stable small regulatory peptide DOTATOC.