Current status of prognostic immunohistochemical markers for urothelial bladder cancer.

The management and prognostication of patients with urothelial carcinomas (UCs), the most common histological type of bladder cancer, is mainly based on clinicopathological parameters. Several markers have been proposed to monitor this disease, including individual cell cycle-related proteins such as p53, pRb, p16, p21 and p27. Other putative markers are the oncogene products of FGFR3 and the ErbB family, proliferation markers including Ki-67, Aurora-A and survivin and different components within the immune system. In this review, a total of 12 parameters were evaluated and their discriminatory power compared. It is concluded that, in single-marker analyses, the proliferation markers Ki-67, survivin and Aurora-A offer the best potential to predict disease progression since they were all able to demonstrate independent prognostic power in repeated studies. Markers related to the immune system (e.g. CD8+ cells, regulatory T cells and cyclooxygenase-2 expression) or oncogene products of the ErbB family and FGFR3 are less powerful predictors of outcome or have not been equally well studied. The cell cycle-related proteins p53, pRb, p16, p21 and p27 have been extensively studied, but their usefulness as single prognostic markers remains unclear. However, in multimarker analyses, these markers appear to add prognostic information, indicating that they may contribute to more accurate treatment of UC.

Octreotide scintigraphy and Chromogranin A do not predict clinical response in patients with octreotide acetate-treated hormone-refractory prostate cancer.

In this pilot study, the predictive value of Octreotide scintigraphy (Octreoscan) and/or Chromogranin-A (CgA) was investigated in patients with hormone-refractory prostate cancer treated with Octreotide acetate. In total, 20 patients with progressive disease and bone metastases entered the trial. At baseline Octreoscan, CgA, PSA, alkaline phosphates (ALP) and two self-administered questionnaires (EORTC QLQ C-30 (v3) and brief pain index) were performed and a diary of the pharmaceutical was started. The treatment consisted of Octreotide (Sandostatin LAR) acetate 30 mg intramuscular injection every month. The blood samples and questionnaires were repeated every month until 3 months. Clinical responder was defined as a patient with increased global health score more than 10 units and stable or decreased pain score without an increase in analgesic. In all, 17 patients were treated per protocol, and four were assessed as clinical responders. Six patients developed a reduction in ALP (median -26%, range -5 to -78%). All patients increased in PSA. At baseline, three patients had a negative Octreoscan and the patients with positive lesions, demonstrated uptake of low intensity. At baseline the CgA was elevated above the normal range in 15 of the patients, and during treatment five patients decreased their CgA to the normal range. Neither baseline Octreoscan nor CgA could identify the clinical reponders. A minority of patients improves their health-related quality of life. The decrease and normalization of CgA levels in five patients during therapy indicates therapeutic activity but Octreoscan and CgA could not identify clinical responders.

Angiogenic factors: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) are not necessarily elevated in patients with advanced renal cell carcinoma.

Serum analysis of Vascular Endothelial Growth Factor (VEGF) and basic Fibroblast Growth Factor (b-FGF) levels were studied in 53 patients with renal cell carcinoma (RCC). Approximately 2/3 of the patients had disseminated disease at diagnosis, the remainder had no evidence of metastases. The results confirmed that VEGF has a major role in the angiogenesis of RCC. No correlation was observed between VEGF and/or b-FGF and the presence or absence of metastases, nor was any correlation observed between VEGF and/or b-FGF and patient survival. Thus, to utilise VEGF and/or b-FGF as a tumour marker at the time of diagnosis to predict patients with a high risk of progression, where an adjuvant therapeutic approach would be of great value, seems to be limited. Not all patients with RCC exhibited elevated serum levels of VEGF and/or b-FGF. No correlation was observed between tumour stage and serum levels of these angiogenic peptides.

89Strontium in the management of painful sceletal metastases.

PURPOSE: To make a review of the literature of 89strontium-chloride and a retrospective study of time to palliative intended external irradiation, number of portals and overall-survival after 89strontium-chloride therapy. RESULTS: In total 93 patients were treated 116 times with 89strontium. The patients with prostatic carcinoma received 91% of all 89strontium therapies. Median over-all survival was 10 months after injection. In those cases when 89strontium was given before palliative radiotherapy, the average of total number of local fields was significantly lower (1.1 versus 4.1) compared to those cases where local fields preceded 89strontium therapy. However, time to 89new external irradiation after 89strontium injection was equal between these groups (3.8 versus 2.9 months). CONCLUSION: A review of literature conclude that 89strontium is effective for the reduction of pain originating from osteoblastic metastases. It also reduce the need for external radiotherapy and therefore is cost-effective. However, 89strontium is more effective in an early phase of the metastatic disease and preferably as an adjuvance to external radiotherapy.

Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) are elevated in advanced stages of non-Hodgkin's lymphomas.

The serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in 116 patients with non-Hodgkin's lymphomas (NHL) tested previously for soluble intercellular adhesion molecule-1 (sICAM-1). In contrast to Hodgkin's disease and chronic lymphocytic leukaemia, the sVCAM-1 levels in NHL patients were not significantly different from the levels of healthy controls (n = 31). However, sVCAM-1 was elevated in advanced stage disease, i.e. stages III + IV. Elevated serum levels of sVCAM-1 were associated with significantly poorer disease-free (p = 0.024) and overall (p = 0.02) survival. sVCAM-1 correlated poorly with other known prognostic variables (LDH, sTK and beta 2m) and with sICAM-1. None of the tested markers added prognostic information for disease-free survival independently of Ann Arbor stage and B-symptoms. The expression of VCAM-1 and ICAM-1 in tumour biopsies from 15 patients representing 7 different histologies were examined and compared with the serum levels of the soluble adhesion molecules. No correlation was found between the adhesion molecule expression by vascular endothelium and the corresponding serum levels.

[111In-DPTA-D-Phe1]-octreotide scintigraphy in the management of patients with advanced renal cell carcinoma.

Somatostatin receptor scintigraphy using the 111In-labelled somatostatin analogue octreotide (Octreoscan) was performed in 9 patients with metastatic renal cell carcinoma. In total 11 scintigraphies were performed. Positive tumor uptakes were observed in 9 patients. The results of the octreotide scans were correlated to diagnostic CT and/or X-ray images. Forty (59%) out of 68 known tumor localizations were visualized with the octreotide scan. A second scan following therapy was performed in two patients. These patients showed progressive disease despite treatment and also exhibited intensified uptakes at octreotide scintigraphy. One false positive lesion was observed in the 40 lesions visualized in scintigraphy. It was concluded that renal cell carcinoma expresses somatostatin receptors, as could be visualized with Octreoscan scintigraphy. The scintigraphic technique can be used as an instrument for in vivo characterization of the disease. The data could also form a basis for future investigations regarding the possible therapeutic effect of octreotide in the management of renal cell cancer.

Somatostatin receptor scintigraphy during treatment with lanreotide in patients with neuroendocrine tumors.

To investigate possible changes in somatostatin receptor expression during treatment with high dose lanreotide, eight patients with neuroendocrine tumors were investigated by [(111)In-DTPA-D-Phe1]-octreotide scintigraphy before and during treatment. The spleen-to-background ratio decreased in all patients, whereas tumor-to-background ratio revealed a heterogeneous pattern with an average increase of 50% (-79% to +1,087%). This finding indicates that lanreotide treatment may influence the binding of radioactively labeled somatostatin to the spleen, while changes in the binding to functioning somatostatin receptors in tumor cells are more complex and not clearly related to treatment.

Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) are elevated in advanced stages of non-Hodgkin's lymphomas.

The serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in 116 patients with non-Hodgkin's lymphomas (NHL) tested previously for soluble intercellular adhesion molecule-1 (sICAM-1). In contrast to Hodgkin's disease and chronic lymphocytic leukaemia, the sVCAM-1 levels in NHL patients were not significantly different from the levels of healthy controls (n=31). However, sVCAM-1 was elevated in advanced stage disease, i.e. stages III+IV. Elevated serum levels of sVCAM-1 were associated with significantly poorer disease-free (p = 0.024) and overall (p = 0.02) survival. sVCAM-1 correlated poorly with other known prognostic variables (LDH, sTK and beta2m) and with sICAM-1. None of the tested markers added prognostic information for disease-free survival independently of Ann Arbor stage and B-symptoms. The expression of VCAM-1 and ICAM-1 in tumour biopsies from 15 patients representing 7 different histologies were examined and compared with the serum levels of the soluble adhesion molecules. No correlation was found between the adhesion molecule expression by vascular endothelium and the corresponding serum levels.

Antibodies against double-stranded DNA and development of polymyositis during treatment with interferon.

Alpha interferons have become effective palliative treatments for patients with neuroendocrine tumours such as carcinoids and endocrine pancreatic tumours. However, several reports indicate an increased incidence of both autoantibodies and autoimmune diseases in patients treated with interferon-alpha (IFN-alpha). We studied the development of antibodies against double-stranded DNA (dsDNA) and clinical signs of autoimmune disease in 214 patients with malignant carcinoids or endocrine pancreatic tumours consecutively admitted for treatment with IFN-alpha. Seventeen patients (8%) developed antibodies against dsDNA, predominantly females (12 females and 5 males). One patient had clinical and laboratory signs of polymyositis. Among the other 16 patients, three developed hypothyroidism and in six patients the anti-dsDNA autoantibodies normalized despite continuing therapy. Although a significant number of patients developed autoantibodies against dsDNA, overt autoimmune disease related to these antibodies is a rare event and many patients spontaneously normalize these titres despite continuing IFN-alpha treatment.

Pain figures are unsuitable for determination of palliative radiotherapy portals in patients with hormone refractory prostatic cancer.

We aimed to compare bone scintigraphy with pain extension and other quality of life (QoL) factors in order to evaluate QoL and the appropriateness of using pain figures and a subjective pain description as the basis for palliative radiotherapy (RT) portals. Twenty-three patients with progressive hormone-refractory prostatic adenocarcinoma were investigated with bone scintigraphy and completed pain figures, VAS (visual analogue scales) and a comprehensive self-questionnaire concerning QoL. The Soloway score was significantly correlated with Impaired overall QoL (p = 0.05), and especially with questions regarding restriction of movements (p = 0.001). Weight bearing regions were significantly more often affected at bone scintigraphy than other locations in the group of patients reporting incidental pain during exercise. Surprisingly, a poor level of correlation existed when comparing location of pain with location of uptake on bone scintigraphy, even if an adjacent region was included in the comparison. The subjective description of pain extension in pain figures correlates poorly with the uptake patterns at bone scintigraphy--an interesting finding since pain extensions is regularly used for the definition of palliative RT portals. Furthermore, it appears that the tumour burden itself is not and indicator of the pain score at rest, but affects aspects of QoL. Moreover, it would appears as though the location of metastases in the skeleton significantly affects physical quality of life aspects. It is probably more important to irradiate weight bearing regions of skeleton in order to increase QoL.

Clinical significance of circulating CD44 in non-Hodgkin's lymphoma.

Soluble isoforms of various adhesion molecules have recently been observed in the blood circulation, but the physiological effects of such molecules remain unsettled. Our earlier results indicate that soluble CD44 can be detected in sera of healthy individuals and that significantly higher levels of serum CD44 (s-CD44) can be found in lymphoma patients. The serum level of the standard form of CD44 parallels the clinical treatment response in patients with lymphoma. In the present study, we have investigated the clinical significance of s-CD44 in non-Hodgkin's lymphoma measured at the time of the diagnosis. S-CD44 was measured from the sera of 123 patients with non-Hodgkin's lymphoma by dot blotting high levels of s-CD44 were associated with high serum levels of lactate dehydrogenase and thymidine kinase, high histological grade of malignancy and poor overall survival. However, s-CD44 level did not have independent prognostic value in a multivariate analysis. In conclusion, a high s-CD44 level at the time of diagnosis was associated with poor survival and several other adverse prognostic factors. Our previous and present studies taken together suggest that measurement of s-CD44 is a valuable tool to monitor treatment response in lymphoma patients. However, it may not be an improved prognostic marker.

[111In-DTPA-D-Phe1]-octreotide scintigraphy in patients with hormone-refractory prostatic adenocarcinoma can predict therapy outcome with octreotide treatment: a pilot study.

A pilot study to evaluate the predictive value of Indium-111-labelled somatostatin analogue [DTPA-D-Phe1]-octreotide scintigraphy (OctreoScan111) in the Octreotide treatment of hormone-refractory prostatic adenocarcinoma was initiated. Ten patients were investigated with OctreoScan111 with regard to disease extension and tumor-to-background ratio. Subsequently, the patients were treated with Octreotide (Sandoz, Basel, Schweiz) at a dose of 100 micrograms twice a day subcutaneously. Three patients experienced symptomatic relief, and two of these responded with a decrease in PSA. Three patients did not notice any difference after 6 months of treatment and two of them developed an increase in their PSA value. One patient progressed after five months as regards both PSA and symptoms. Three patients were not able to complete treatment. Of the seven evaluable patients, the three with the highest tumour-to-background ratios at OctreoScan111 were those patients with reduced or stable PSA levels, and none of these progressed during treatment. Previous reports along with this study demonstrate that only a minority of patients with hormone-refractory prostatic adenocarcinoma benefit from Octreotide treatment. However, OctreoScan111 investigations may identify patients who will respond to Octreotide therapy.

Infradiaphragmatic Hodgkin's disease: the Swedish National Care Programme experience. The Swedish Lymphoma Study Group.

A Swedish national care programme has provided guidelines for staging, treatment and follow-up of all patients with Hodgkin's disease (HD) since 1985. Between January 1985 and December 1992, 920 patients were reported and followed prospectively. Of a total of 533 patients with stage I and II disease, 484 presented with supradiaphragmatic HD and 49 (9%) with infradiaphragmatic HD. The median follow-up time was 4.3 yr (3.3-10 yr). Significant differences in average age (45 +/- 21 yr and 55 +/- 19 yr), male:female ratio (1.1:1 and 2.8:1) and B-symptoms (25% and 47%) were observed in patients with supra- and infradiaphragmatic HD, respectively. Forty-six patients with infradiaphragmatic HD were treated with a curative intention and 40 (87%) achieved a complete response. Eleven (28%) of the 40 patients have recurred and 8 patients have died of HD. Complete response rates and recurrence frequencies did not differ from those observed in patients with supradiaphragmatic HD. Mortality was, however, significantly higher (p = 0.001) in the infradiaphragmatic group; this was due mainly to poorer effects of salvage treatment in a elderly population. In this population-based study, patients with peripheral disease in stage IA respond well to inverted Y irradiation alone, whereas it appears to be important to give stage II patients chemotherapy or a combined modality treatment in order to avoid unacceptably high recurrence rates.

Positron emission tomography (PET) with 11C-5-hydroxytryptophan (5-HTP) in patients with metastatic hormone-refractory prostatic adenocarcinoma.

The discovery of neuroendocrine differentiation in hormone-refractory prostatic adenocarcinoma has opened a potentially new therapeutic approach in this group of patients with a poor prognosis and few effective therapy modalities. Based on previous findings of increased uptake of 11C-5-hydroxytryptophan (11C-5-HTP) in neuroendocrine tumours using the PET technique, this tracer was applied in the study of 10 patients with metastatic hormone-refractory prostatic adenocarcinoma. In three patients, the study was repeated after treatment. An increased uptake of 11C-5-HTP was observed in all investigated skeletal lesions, although the magnitude of the uptake was moderate. The difference between the standard uptake values (SUV) in normal bone and metastatic lesions was significant (p < 0.001). A kinetic analysis of the uptake of 11C-5-HTP demonstrates an increase during the first minutes followed by a wash-out and a stabilization of the tissue/blood ratio at about 2. The Patlak plots demonstrated a gradual increase in the transport rate during the first 20 to 30 min, after which a constant level was observed. The SUV varied between patients and between lesions over time and treatment. The uptake of 11C-5-HTP discriminates metastatic lesions from normal bone and may thus aid in the diagnosis and, potentially, in treatment monitoring of metastatic hormone-refractory prostatic adenocarcinoma. Uptake kinetics are characterized by a wash-out and cannot alone be used as proof of neuroendocrine differentiation in hormone-refractory prostatic adenocarcinoma.

Comparison between transversal SPECT, 3-dimensional rendering and 3-dimensional rendering plus clipping in the diagnosis of somatostatin receptor distribution in malignancies using 111In-DTPA-D-Phe1-octreotide scintigraphy.

Two hundred and seven patients were investigated with [111In-DTPA-D-Phe1]-octreotide Single Photon Emission Computerized Tomography (SPECT) scintigraphy. A comparison was carried out of the diagnostic accuracy of the three display modalities, viz. transversal SPECT (trvSPECT), three dimensional volume rendering (3Dvr) and three dimensional volume rendering plus clipping (3Dvr + c) in the rendered volume. TrvSPECT could visualize a greater number of lesions in 85 (41%) cases when compared with 3Dvr. In 48 (23%) cases, trvSPECT could visualize a greater number of lesions when compared with 3Dvr + c. The differences were caused by radioactivity in intestines and the gallbladder and in lesions shaped like an hour-glass. In conclusion, 3Dvr + c imaging was regarded as the reference since it combines both transversal and volume information. An overall sensitivity of 0.998 was found for trvSPECT and the corresponding value for 3Dvr was 0.75. The specificity was 0.45 for trvSPECT and 0.80 for 3Dvr. The accuracy was 0.87 for trvSPECT and 0.76 for 3Dvr, when compared with 3Dvr + c. The value of 3Dvr is in high-contrast images, where it provides additional anatomical information, whereas in low-contrast images, 3Dvr was found to have low accuracy. In low-contrast images, trvSPECT was found to be almost equal in accuracy to 3Dvr + c imaging. However, in high-contrast images, trvSPECT was found to give more false positives than 3Dvr + c in the assessment of SPECT studies using [111In-DTPA-D-Phe1]-octreotide. The interpretation was that trvSPECT has to be used in conjunction with 3Dvr + c and, in high-contrast images, 3Dvr provides additional value.

PET with hydroxytryptophan as tracer in hormone-refractory prostatic adenocarcinoma: evaluation of decarboxylation in vivo.

Position emission tomography (PET) was performed on two patients with hormone-refractory prostatic adenocarcinoma in order to characterize the mechanism behind an earlier observed increased uptake of tracer hydroxytryptophan (5-HTP) in bone metastases. The osseous metastases were investigated with 5-hydroxytryptophan, radio-labelled with 11C in the carboxyl group (5-HTC), and with 5-HTP in order to elucidate in vivo the presence of hydroxytryptophan decarboxylation. An increased uptake, measured as standard uptake value (SUV), in the metastatic lesions was observed using 5-HTP. The uptake varied between lesions. Using 5-HTC a corresponding uptake was observed. The time-activity rates were similar. The congruence in uptake patterns between 5-HTP and 5-HTC in the investigated lesions, demonstrates that decarboxylation of 5-hydroxytryptophan to serotonin is not a dominant factor in the uptake. It was concluded that 5-HTC could be used in vivo to investigate the chemical event of decarboxylation of 5-hydroxytryptophan and provide information about characteristics in metastatic lesions.

A comparison between the efficacy of somatostatin receptor scintigraphy and that of in situ hybridization for somatostatin receptor subtype 2 messenger RNA to predict therapeutic outcome in carcinoid patients.

Predictive tests for treatment with somatostatin analogues have been asked for by clinicians. We have shown previously that somatostatin receptor (sstr) scintigraphy may be used to predict therapeutic outcomes for carcinoid patients receiving somatostatin analogues. However, almost 20% of patients with pathological tracer uptake fail to respond to such treatment. To increase further the reliability and prognostic value of sstr identification, we investigated the presence of mRNA for the subtypes sstr1 and sstr2 by in situ hybridization on tumor specimen from 25 carcinoid patients (22 midgut, 2 foregut, and 1 hindgut), all receiving somatostatin analogue treatment (12 lanreotide, 8 octreotide, and 5 octastatin) and compared this to the therapeutic response evaluated as inhibition of hormone secretion. Expression of sstr2 mRNA could be detected in 15 patients, all responding to somatostatin analogue treatment and showing pathological tracer uptake in tumor lesions at sstr scintigraphy. In the remaining 10 patients, no sstr2 mRNA could be detected, and none of the patients responded to somatostatin analogue treatment. Three of these 10 patients failed to accumulate tracer activity at sstr scintigraphy, whereas 7 had a pathological uptake of [(111)In-DTPA-D-Phe(1)]-octreotide. We conclude that in this group of carcinoid patients, there was complete agreement between the presence of mRNA for sstr2 detected by in situ hybridization and therapeutic outcome. In patients with pathological tracer accumulation without expression of somatostatin sstr2 mRNA, other sstr may be present that can bind the somatostatin analogue but not inhibit hormone secretion.

Elevated serum levels of soluble ICAM-1 in non-Hodgkin's lymphomas correlate with tumour burden, disease activity and other prognostic markers.

The serum levels of soluble ICAM-1 (CD54) were significantly elevated in patients with non-Hodgkin's lymphomas (NHL, n=127) and hairy cell leukaemia (HCL, n=15) compared with healthy controls (n=31). In high-grade malignant NHL (n=79) the sICAM-1 levels correlated with the tumour mass as reflected in the Ann Arbor staging system but not with bulky disease. Further, the sICAM-1 levels correlated with disease activity as reflected by the presence of B symptoms and with other known prognostic markers. In particular serum thymidine kinase (sTK). In patients with low-grade malignant NHL (n=48) a trend towards higher serum levels of sICAM-1 was found in patients with advanced stage and B symptoms. In both low and high-grade malignant NHL, elevated levels of sICAM-1 were associated with poorer overall and disease-free survival. The present results indicated that sICAM-1 levels have a prognostic power equal to that of other serum markers claimed to be of prognostic value in NHL, namely serum lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), beta-2-microglobulin (beta2m), serum thymidine kinase (sTK), albumin and orosomucoid. The cellular origin and the possible interactions between soluble and surface ICAM-1 and its ligands needs further exploration.

Estramustine-binding protein (EMBP) in renal cell carcinoma immunohistochemistry, immunoscintigraphy and in vitro estramustine effects.

The present report shows that the human renal cell carcinoma (RCC) cell lines, A498 and CAKI-2, express the estramustine-binding protein (EMBP). The RCC cell lines investigated were highly sensitive for estramustine, with cell arrest in atypical metaphase. In vitro experiments using a fluorimetric cytotoxicity assay (FMCA) showed a pronounced cytotoxic effect mediated by estramustine. Immunohistochemical analysis of tumour specimens from patients with RCC showed positive staining for EMBP in 12/16 cases. Immunoscintigraphy was performed in an experimental system in nude mice, heterotransplanted with the CAKI-2 cell line. A radiolabelled monoclonal anti-EMBP antibody was used. The results show a specific uptake of the antibody in the RCC tumour, expressed as a percentage of the injected dose per gram tissue, which ranged from 4.03 to 6.9. The results obtained form the basis for clinical studies on the feasibility of utilizing estramustine in the management of RCC. Immunoscintigraphy using the monoclonal anti-EMBP antibody is of potential use for in vivo characterization of the malignancy and in the selection patients suitable for treatment with estramustine.

Somatostatin receptor scintigraphy in patients with carcinoid tumors: comparison between radioligand uptake and tumor markers.

We have performed 100 scintigraphic investigations using [111In-diethylenetriaminepentaacetic acid-D-Phe1]octreotide (111In-octreotide) single photon emission tomography (SPECT) in patients with carcinoid tumors. One or several lesions could be detected in 77 cases, and true negative results were obtained in 11 cases. There were false-negative results in 12 cases compared with results from conventional radiological methods. The ratio between the SPECT signals from the area with the highest uptake and normal lung was used as a tumor:background ratio. An attenuation correction was made in all investigations. We found that lesions in untreated patients had lower tumor:background ratios compared with those in patients treated with somatostatin analogues (medians, 10 and 40, respectively; P < 0.001) or IFN (median, 23; P = 0.03). In untreated patients, there was a correlation between the tumor:background ratio and the levels of urinary 5-hydroxyindoleacetic acid (U-5HIAA) and p-chromogranin A. The data obtained in the present investigation indicate that somatostatin receptor expression might be influenced by the treatment; i.e., a higher tumor:background ratio is found in patients treated with either somatostatin analogues or IFN. Furthermore, it was found that somatostatin receptor expression correlates with the levels of U-5HIAA and p-chromogranin A in untreated patients, and that 111In-octreotide SPECT scintigraphy is more likely positive in patients with elevated U-5HIAA values. This indicates that somatostatin receptor expression and elevated U-5HIAA are more likely present in patients with highly differentiated tumors and, thus, could be of prognostic value.