vasoactive-intestinal-peptide and Liver-Neoplasms

A 53-year-old man presented with diarrhoea and hypokalaemia and was diagnosed with a neuroendocrine tumour of unknown origin with multiple liver metastases. Somatostatin analogues led to a reduction in the size of the tumours and improvement of his symptoms. However, after several years, the tumours grew in size, and the patient's clinical symptoms recurred. The patient underwent transcatheter arterial embolization (TAE) of the hepatic artery to treat the liver metastases. Immediately after embolization, the symptoms disappeared. Although the patient had an unresectable vasoactive intestinal polypeptide-producing neuroendocrine tumour, the endocrine symptoms were able to be controlled with chemotherapy and TAE, resulting in a long-term survival.

Topics: Combined Modality Therapy; Embolization, Therapeutic; Endosonography; Hepatic Artery; Humans; Liver Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide

VIPomas are rare pancreatic endocrine tumors associated with a well-defined clinical syndrome characterized by watery diarrhea, hypokalemia, and metabolic acidosis. The objective of this study was to review a single institution's experience with VIPomas, as well as to review the English literature. A retrospective review of the Johns Hopkins pancreatic database revealed four cases of VIPoma, with three patients being male. All patients presented with watery diarrhea, hypokalemia, hypercalcemia, and acidosis. All patients had no family history of multiple endocrine neoplasia. Computed tomography revealed the primary pancreatic tumor in all patients, with three tumors located in the tail of the pancreas. One tumor involved the entire pancreas. Computed tomography and/or octreotide radionuclide scans identified hepatic metastasis in three patients. Mean serum vasoactive intestinal polypeptide levels were 683 pg/ml (range 293 to 1,500 pg/ml). All patients underwent resection of the pancreatic primary tumor. Two patients also had simultaneous liver resections. All patients had evidence of malignancy as defined by the presence of metastatic lymph nodes and/or hepatic metastases. Two patients had complete resolution of symptoms after surgical resection. One patient required radioablation of liver metastases and adjuvant octreotide therapy for control of symptoms. One patient died of progressive metastatic disease 96 months after surgery, whereas the other three remain alive. Extended, meaningful survival can be achieved for VIPoma patients, combining an aggressive surgical approach with additional strategies for treatment of unresected disease.

Topics: Algorithms; Diagnosis, Differential; Diarrhea; Humans; Liver Neoplasms; Pancreatectomy; Pancreatic Neoplasms; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Topics: Aged; Humans; Liver Neoplasms; Male; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

This review has focused on the unique role of radionuclide scintigraphy in characterization of hepatic mass lesions. Radionuclide scintigraphy, unlike most other imaging modalities, is based on specific physiological and biochemical properties of each pathological entity that affects the liver. Hepatic scintigraphy, with its widespread availability, noninvasive nature, and relatively low cost is a powerful adjunct to other imaging techniques in the investigation of hepatic mass lesions. We have reviewed clinical presentation and characteristic findings of most hepatic lesions and have described reported findings with all available imaging modalities with particular emphasis on hepatic scintigraphy (Table 1) as well as a suggested algorithm for workup of solid hepatic masses (Fig 6). Additionally, the role of newer, more specialized techniques including PET scanning, 123I-labeled VIP, and 111In-labeled DTPA-D-Phe-octreotide scanning are reviewed. Hepatic nuclear scintigraphy continues to play an important role in the management of patients with solid hepatic masses.

Topics: Algorithms; Carcinoma, Hepatocellular; Costs and Cost Analysis; Hemangioma, Cavernous; Humans; Indium Radioisotopes; Iodine Radioisotopes; Liver Diseases; Liver Neoplasms; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Terbium; Tomography, Emission-Computed; Vasoactive Intestinal Peptide

A 5-year-old child presented with an unresectable liver neoplasm, the histology of which resembled a malignant rhabdoid tumor. Clinical course was unrelenting despite therapy, and the child died four months later. During the course of her illness, she developed watery diarrhea and was found to have a high serum level of vasointestinal peptide (VIP). This is the first report of a childhood tumor with rhabdoid features to secrete VIP.

Topics: Child, Preschool; Fatal Outcome; Female; Humans; Liver Neoplasms; Rhabdoid Tumor; Vasoactive Intestinal Peptide

Recently, we have shown that the expression of receptors for vasoactive intestinal peptide (VIP) on intestinal adenocarcinomas can be used for in vivo targeting of primary or metastatic tumor sites using 123I-labeled VIP. Several other receptors and antigens including the TAG-72 protein have also been implemented for in vivo localization purposes. In this study, we have compared the in vitro and in vivo binding of 123I-VIP and of the 111In-labeled monoclonal antibody (MAb) directed against TAG-72 (OncoScint; 111In-CR-103) in patients with intestinal adenocarcinomas in a single-blinded, prospectively randomized trial.. Twenty patients were administered either 123I-VIP (150-200 MBq; 1 microgram) or 111In-CYT-103 (150 MBq; 1 mg) for one imaging study. After interim analysis demonstrated superior imaging with 123I-VIP, the next 10 patients (accounting for a total of 50 patients) enrolled in this trial underwent both studies in random order to allow for a direct comparison.. In total, 123I-VIP scans were true-positive in 28 of 30 patients (93%) versus 17 of 30 patients administered 111In-CYT-103 (56%). In the subgroup of 10 patients enrolled in the second part of the study, primary intestinal adenocarcinomas were imaged in five of five patients with 123I-VIP and in only two of these patients with 111In-CYT-103. Liver metastases were visualized in five of six patients by 123I-VIP receptor scanning and in four of these patients with 111In-CYT-103. The in vitro results indicated significant binding of 123I-VIP to primary colorectal tumors as well as to HT29 and COLO320 adenocarcinoma cells. In vitro, adenocarcinoma cells also expressed abundant numbers of the TAG-72 antigen.. Intestinal adenocarcinomas co-express VIP receptors and the IAG-72 antigen. Despite significant in vitro binding of both agents, however, the VIP receptor scan is more sensitive in localizing intestinal adenocarcinomas and metastatic spread.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Female; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Iodine Radioisotopes; Liver Neoplasms; Male; Middle Aged; Oligopeptides; Pancreatic Neoplasms; Pentetic Acid; Prospective Studies; Radioimmunodetection; Receptors, Vasoactive Intestinal Peptide; Single-Blind Method; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Monoclonal antibodies have not been evaluated in metastasizing endocrine tumors, even though these lesions may induce severe morbidity of hormone excess in absence of considerable tumor burden.. A murine monoclonal antibody of the IgG2a subtype was generated by immunization with dispersed tumor cells from an endocrine pancreatic carcinoma associated with liver and peritoneal metastases as well as a therapy-resistant Verner-Morrison's syndrome.. Immunohistochemical staining disclosed selective tissue reactivity of the antibody and conspicuous immunostaining on the surface of the tumor cells. Infusion of 100 mg antibody over 2 days into the common hepatic artery of the patient was accompanied by reduced diarrhea volume until death 6 weeks later and transient elevation of total plasma immunoreactivity for vasoactive intestinal peptide due to large molecular forms of the peptide. Postmortem examination demonstrated disappearance of peritoneal metastases as well as absence of immunostaining for the injected antibody and the transferrin receptor within residual hepatic tumors.. The results substantiate that symptomatic alleviation and perhaps interference with tumor cell mass may be obtained with monoclonal antibodies in patients with endocrine tumors and that the antiidiotypic immunoglobulin response may play a role herein.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Neoplasm; Humans; Immunohistochemistry; Immunotherapy; Infusions, Intra-Arterial; Liver Neoplasms; Male; Mice; Mice, Inbred DBA; Middle Aged; Pancreatic Neoplasms; Peritoneal Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Topics: Cholangiopancreatography, Magnetic Resonance; Diarrhea; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Humans; Liver Neoplasms; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Topics: Humans; Liver Neoplasms; Male; Middle Aged; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Radiopharmaceuticals; Receptors, Peptide; Treatment Outcome; Vasoactive Intestinal Peptide; Vipoma

Topics: Animals; Apoptosis; bcl-X Protein; Carcinoma, Hepatocellular; Cell Line, Tumor; Cells, Cultured; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Hep G2 Cells; Humans; Liver Neoplasms; Phosphorylation; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Signal Transduction; Vasoactive Intestinal Peptide

Gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) are increasing in incidence, and accurate staging is important for selecting the appropriate treatment. (68)Ga-DOTATATE imaging is a promising approach for detecting GEPNETs and could help in selecting optimal therapeutic strategies. The aim of this study was to prospectively determine the clinical utility of (68)Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) in detecting unknown primary and metastatic GEPNETs.. One hundred thirty-one patients were enrolled in a prospective study of patients undergoing (68)Ga-DOTATATE PET/CT, (111)In-pentetreotide single-photon emission computed tomography (SPECT)/CT and multiphasic CT scan, and/or magnetic resonance imaging in a blinded fashion with comprehensive biochemical testing. The primary outcome measure was the detection of lesions by each imaging study.. (68)Ga-DOTATATE PET/CT imaging detected 95.1% of lesions (95% CI, 92.4% to 96.8%) with an average maximum standardized uptake value of 65.4 ± 47 (range, 6.9 to 244), anatomic imaging detected 45.3% of lesions (95% CI, 37.9% to 52.9%), and (111)In-pentetreotide SPECT/CT detected 30.9% of lesions (95% CI, 25.0% to 37.5%), with a significant difference between imaging modalities (P < .001). In four of 14 patients (28.6%), (68)Ga-DOTATATE PET/CT found a previously unknown primary tumor, and detected primary GEPNET, lymph node, and distant metastases correctly in 72 of 113 lesions (63.7%) when compared with histopathology, with 22.1% and 38.9% detected by using (111)In-pentetreotide SPECT/CT and anatomic imaging, respectively. On the basis of findings with (68)Ga-DOTATATE PET/CT, 43 of 131 patients (32.8%) had a change in management recommendation. In patients with carcinoid symptoms but negative biochemical testing, (68)Ga-DOTATATE PET/CT detected lesions in 65.2% of patients, 40% of which were detected neither by anatomic imaging nor by (111)In-pentetreotide SPECT/CT.. (68)Ga-DOTATATE PET/CT imaging provides important information for accurate staging of GEPNETs and selection of appropriate treatment interventions even in the absence of biochemical evidence of disease in symptomatic patients.

Topics: Adult; Aged; Aged, 80 and over; Chromogranin A; Female; Humans; Hydroxyindoleacetic Acid; Intestinal Neoplasms; Liver Neoplasms; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Neoplasms, Unknown Primary; Neuroendocrine Tumors; Organometallic Compounds; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Positron-Emission Tomography; Prospective Studies; Somatostatin; Stomach Neoplasms; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Young Adult

Topics: Adenocarcinoma; Carcinoma, Neuroendocrine; Cell Differentiation; Colonic Neoplasms; Fatal Outcome; Humans; Leukemia, Hairy Cell; Liver Neoplasms; Male; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Vasoactive Intestinal Peptide; Vipoma

VIPoma is an exceedingly unusual neuroendocrine neoplasm that autonomously secretes vasoactive intestinal polypeptide (VIP). Its reported incidence is approximately 1 per 10 million individuals per year. Herein, we report the case of sporadic pancreatic VIPoma in a 47-year-old male who presented with a six-month history of chronic, plentiful, watery diarrhea. On physical examination, the patient looked sick, lethargic and had signs of dehydration. Laboratory investigations revealed high VIP hormone level (989pg/mL), hypokalemia, hypercalcemia, hyperglycemia, high blood urea nitrogen, high creatinine, and metabolic acidosis on arterial blood gas. Contrast-enhanced computed tomography (CT) scan showed a 3.1×3.3×4.7cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component. Moreover, a 5.7×6.1×6.8cm metastatic hepatic lesion was identified. The patient underwent distal pancreatectomy with splenectomy, hepatic lesion resection, and lymph node dissection. Histopathological and immunohistochemical examination of the pancreatic and hepatic lesions revealed neuroendocrine tumor (VIPoma). Postoperatively, the patient received radiofrequency ablation for the hepatic lesion. A post-operative six-month follow-up showed significant symptomatic relief, reduced VIP hormone level (71pg/mL) and normalized electrolyte and acid-base profiles. However, a magnetic resonance imaging (MRI) scan showed a small residual metastatic liver lesion which was considered for hepatic artery embolization (HAE). The patient is still alive with a residual hepatic disease at 18months. We also present a brief literature review on VIPoma.

Topics: Humans; Liver; Liver Neoplasms; Male; Middle Aged; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Splenectomy; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

VIPomas are rare neuroendocrine tumours, with metastases often confined to the liver. Orthotopic liver transplantation may be considered in patients with metastases confined to the liver, however the long term benefits have yet to be shown.. To discuss the role of orthotopic liver transplantation for neuroendocrine tumours including VIPomas.. We describe the case of a very rare pancreatic VIPoma, the therapeutic modalities employed, including orthotopic liver transplantation, and present the results of a relevant literature search.. This case is the longest (25 years) reported in the literature for survival from a VIPoma after initial diagnosis and long term survival after liver transplantation (9 years).. Liver transplantation for metastatic VIPomas confined to the liver may be justified in selected patients to provide symptomatic hormonal control and pain from tumour bulk, provided there is no extra hepatic disease and medical treatment has been exhausted.

Topics: Humans; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Topics: Antineoplastic Agents, Hormonal; Diagnosis, Differential; Diarrhea; Female; Humans; Hypokalemia; Indium Radioisotopes; Irritable Bowel Syndrome; Liver; Liver Neoplasms; Middle Aged; Octreotide; Pancreatic Neoplasms; Radionuclide Imaging; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Hepatocellular carcinoma (HCC) is an aggressive and often fatal neoplasm. HepG2 cells are a cell line derived from HCC. This investigation shows that vasoactive intestinal peptide (VIP) inhibits HepG2 cell proliferation in vitro. In addition, VIP decreases the expression of signal transducers and activators of transcription-3 (STAT-3) and phosphorylated STAT-3 (pSTAT-3). Transfection of HepG2 cells with STAT-3 siRNA also dose-dependently inhibits proliferation. These findings suggest that VIP-mediated inhibition of HepG2 proliferation may be mediated by STAT-3. Further studies demonstrate that VIP increases HepG2 cAMP levels and 8-cl-cAMP inhibits HepG2 proliferation as well as pSTAT-3 and STAT-3 levels, suggesting that cAMP is also involved in the inhibition of HepG2 proliferation. VIP also attenuates the proliferative effects of hepatocyte growth factor (HGF) and interleukin-6 (IL-6) on HepG2 cells. These preliminary studies suggest that the antiproliferative actions of VIP may offer a new and promising means of suppressing HCC.

Topics: Blotting, Western; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Vasoactive Intestinal Peptide

In June 1999, a 62-year-old man is hospitalised to evaluate the sonographic suspicion of liver metastases. The biopsy of the liver shows a malignant neuroendocrine tumour. Further diagnostic investigation including gastroscopy, colonoscopy, enteroclysis, thoracal and abdominal CT and somatostatin-receptor-scintigraphy does not localise the primary tumour. In the absence of clinical symptoms a wait and see procedure with clinical and imaging controls at regular intervals is arranged. Beginning in spring of 2001--nearly two years after the initial diagnosis--the patient suffers from progredient diarrhoea and weight loss leading to hospitalisation in September 2001. The existence of secretory diarrhoea, hypokalaemia and hypercalcaemia arouses suspicion of vipoma. This is proven by a remarkably elevated plasma concentration of vasoactive intestinal peptide (VIP). Once more, an accurate investigation is started but no primary tumour can be discovered despite extensive liver metastases. A vipoma is a rare differential diagnosis of secretory diarrhoea. This case report describes the remarkable constellation of liver metastases of a malignant neuroendocrine neoplasm without a primary tumour and the clinical presentation of a W.D.H.A. syndrome (watery diarrhoea, hypokalaemia and hypo- or achlorhydria). Despite extensive disease, therapy with octreotide and prednisolone provides a good clinical response.

Topics: Biopsy, Needle; Diagnosis, Differential; Diagnostic Imaging; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasms, Unknown Primary; Octreotide; Prednisolone; Radioligand Assay; Receptors, Somatostatin; Vasoactive Intestinal Peptide; Vipoma; Water-Electrolyte Balance

Paraneoplastic syndromes are frequently associated with various types of malignant tumors but are fairly rare in the course of hepatocellular carcinoma (HCC). We describe the clinical case of a 76 year old man with chronic hepatitis C infection related to liver disease who had suffered for several months from chronic runny but blood and mucus-free diarrhea, together with progressive weight loss and flushing of the face. Serological tests made on admission confirmed the chronic liver disease and showed an increase of serum levels of some neuroendocrine hormones, i.e. 5-hydroxytryptamine and vasoattive intestinal peptide. Ultrasound and CT scans led to the diagnosis of HCC. The diarrhea and the increase in some neuroendocrine hormones were therefore interpreted as expression of a paraneoplastic-like neuroendocrine syndrome that had preceded the onset of HCC by some months. The patient died a few months after the diagnosis of HCC, from total portal vein thrombosis and consequent liver and renal failure. This clinical report draws the attention to the possibility of paraneoplastic syndrome expression before the clinical onset of HCC and to the role that neuroendocrine hormones may have on the growth and spread of HCC.

Topics: Aged; Carcinoma, Hepatocellular; Diarrhea; Hepatitis C, Chronic; Humans; Liver Neoplasms; Male; Paraneoplastic Syndromes; Radiography, Abdominal; Serotonin; Time Factors; Tissue Polypeptide Antigen; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide

Tissue from a vasoactive intestinal peptide (VIP)-secreting human tumor has been used to establish and characterize human neuroendocrine primary cell cultures from which permanent, clone-derived cell lines have been established. Viable cells were obtained by enzymatic and mechanical dissociation of freshly resected pancreatic islet tumor and hepatic metastatic tumor tissues. Aliquots of tumor cells were established ex vivo under culture conditions including porous substrata coated with type IV collagen and laminin and a low serum, hormonally defined culture medium. The small (<10 microm) rounded, grape-like cells had a very slow growth rate of doubling times estimated at several weeks or more. After several passages, morphologically uniform cells were derived that strongly expressed neuroendocrine markers of synaptophysin and synaptobrevin. Although chromogranin A and VIP had somewhat weaker expression, both demonstrated phorbol ester-stimulated secretion. The morphologic and secretory properties were maintained by the cells for nearly 2 years in culture. The establishment of this novel VIP-secreting human neuroendocrine cell line (HuNET) makes available a culture model with which to study a transformed version of this pancreatic islet cell type and offers approaches by which to establish islet tumor cell lines.

Topics: Adult; Carcinoma, Islet Cell; Cell Separation; Chromogranin A; Chromogranins; Cryopreservation; Fluorescent Antibody Technique, Indirect; Humans; Immunoenzyme Techniques; Liver Neoplasms; Male; Pancreatic Neoplasms; Synaptophysin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide-secreting tumors (VIPomas) are extremely rare and difficult to diagnose. The authors describe a patient who was found to have a VIPoma after 3 years of symptoms. Somatostatin receptor scintigraphy using indium-labeled octreotide localized her tumor and prompted a surgical resection. This is the preferred imaging study for the earliest, most accurate, and cost-effective identification of VIPomas and their metastases.

Topics: Female; Humans; Liver Neoplasms; Magnetic Resonance Imaging; Middle Aged; Octreotide; Organotechnetium Compounds; Pancreatic Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide

Recent data demonstrated a high sensitivity (>90%) in the visualization of primary/recurrent pancreatic cancer as well as metastases by means of 123I-labeled vasoactive intestinal peptide (VIP). The aim of this study was to investigate the diagnostic value of radioiodinated VIP in patients suffering from adenocarcinoma of the exocrine pancreas.. Sixty consecutive patients (26 women, 34 men; mean age 59 yr) with histologically verified pancreatic cancer were investigated in this study. Twenty-one patients presented with organ-confined malignancy (19 at study entry and 2 during follow-up after initial surgery developed tumor recurrence), while 25 patients had distant metastases along with the local malignancy, and 7 patients had liver metastases after resection of the primary lesion (6 on study entry and 1 during follow-up showed tumor development). In 5 of these patients, abdominal lymph node metastases were present at the time of scanning. Of 10 patients, who had undergone potentially curative surgery for their cancer, 7 remained free of disease during follow-up until death or for at least 6 mo. Iodine-123-VIP (150-200 MBq; approximately 1 microg VIP) was administered to all patients. Scintigraphic results were evaluated as compared to conventional radiologic imaging methods and surgical exploration.. Primary pancreatic tumors were visualized by 123I-VIP in 19/21 patients (90%) with disease confined to the pancreas and in 8/25 patients (32%) suffering both from locoregional and disease metastatic to the liver. The overall 123I-VIP scan sensitivity for primary pancreatic adenocarcinomas was 58% (27/46 scans). Liver metastases were imaged in 29/32 patients (scan sensitivity 90%) and abdominal lymph node metastases in 4/5 patients. In 5 patients, the VIP receptor scan indicated the malignant lesion before CT. In vitro results confirmed specific binding of 123I-VIP to primary pancreatic tumor cells as well as to PANC1 adenocarcinoma cells.. Iodine-123-VIP receptor scanning has the potential to offer additional information to augment diagnostic standard methods and could influence the decision-making process in the treatment of pancreatic cancer.

Topics: Adenocarcinoma; Female; Humans; Iodine Radioisotopes; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Radionuclide Imaging; Receptors, Vasoactive Intestinal Peptide; Sensitivity and Specificity; Vasoactive Intestinal Peptide

We report an optimized in situ hybridization (ISH) protocol with a rapid signal amplification procedure based on catalyzed reporter deposition (CARD) to increase the sensitivity of non-isotopic mRNA ISH on formaldehyde-fixed and paraffin-embedded tissue. The CARD method is based on the deposition of haptenized tyramide molecules in the vicinity of hybridized probes catalyzed by horseradish peroxidase. Commercially available and newly synthesized haptenized tyramides, including digoxigenin-, biotin-, di- and trinitrophenyl- as well as fluorescein-tyramide, were compared. The haptenized tyramides were visualized using peroxidase conjugated anti-hapten antibodies followed by the diaminobenzidine reaction. As a test system, we applied digoxigenin-labeled oligonucleotides to detect insulin and vasoactive intestinal polypeptide mRNA in pancreatic endocrine tumors and liver metastases. Our results indicate that specificity, sensitivity, and applicability of oligonucleotide mRNA ISH can be significantly improved by using chemically digoxigenin-labeled oligonucleotide probes and signal amplification by CARD. Furthermore, all tested tyramides provided approximately equal amplification efficiency. In conclusion, CARD signal amplification should further promote mRNA ISH studies on paraffin-embedded tissues and allow for multiple-target nucleic acid detection in situ.

Topics: Dinitrophenols; Formaldehyde; Gene Amplification; Haptens; Humans; In Situ Hybridization; Insulin; Liver; Liver Neoplasms; Oligonucleotide Probes; Pancreas; Pancreatic Neoplasms; Paraffin Embedding; RNA, Messenger; Sensitivity and Specificity; Tissue Fixation; Tyramine; Vasoactive Intestinal Peptide

We previously reported that vasoactive intestinal polypeptide (VIP) significantly inhibited Matrigel invasion and haptotactic migration of murine colon 26-L5 carcinoma in vitro. To extend our study, we investigated the inhibitory mechanisms of VIP on Matrigel invasion of colon 26-L5 carcinoma, and the effect on metastatic properties of the tumor cells. VIP inhibited the invasion of the tumor cells in a concentration-dependent manner without affecting their growth, and achieved approximately 50% reduction at 10(-6) M. VIP also suppressed cell motility with a similar inhibition rate to the invasion assay. Time course study revealed that the motility was reduced by 40% when the tumor cells were preincubated with 10(-6) M VIP for 3 h. In contrast, 6-h pretreatment with 10(-6) M VIP caused the increased ability of the adhesion to both fibronectin and laminin with a 50% enhancement. A large amount of VIP1 receptor transcripts was expressed in the cells, whereas VIP2 receptor was undetectable, by RT-PCR and subsequent Southern blot hybridization. A specific antagonist for VIP1 receptor reversed the suppressed motility induced by VIP. Cryostat sections showed that the 3-h pretreatment of tumor cells with VIP caused the reduction of the arrest in the livers at 6 h after the tumor inoculation into a portal vein of mice. VIP could prevent the experimental liver metastasis of the tumor cells in a dose-dependent manner. The cells pretreated with 10(-6) M VIP for 3 h also showed the reduced ability of the liver metastasis. These results suggest that VIP could block the invasion and the metastasis of colon 26-L5 carcinoma through suppression of their motility.

Topics: Animals; Blotting, Southern; Cell Adhesion; Cell Movement; Colonic Neoplasms; Dose-Response Relationship, Drug; Fibronectins; Laminin; Liver Neoplasms; Mice; Mice, Inbred BALB C; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

A 35-yr-old male presented with a 3-yr history of voluminous watery diarrhea. He had episodes of severe generalized weakness which responded to fluid and electrolyte replacement therapy. Investigations revealed a solitary liver mass and an elevated vasoactive intestinal polypeptide level. An extensive work-up did not show any other extrahepatic primary lesion. Surgical resection ameliorated all of his symptoms, accompanied by a decrease in the vasoactive intestinal polypeptide level. We believe that this patient represents a case of primary hepatic vipoma syndrome. To our present knowledge, this has not been reported previously. We discuss the clinical manifestations, investigations, and management of the case.

Topics: Adult; Biopsy; Combined Modality Therapy; Embolization, Therapeutic; Hepatectomy; Humans; Liver; Liver Neoplasms; Male; Octreotide; Vasoactive Intestinal Peptide; Vipoma

A patient with metastatic VIP-producing pancreatic tumor was successfully treated with subcutaneous octreotide, an analogue of somatostatin, for more than 4 years. The profuse diarrhea was rapidly controlled and the plasma concentrations of the hormones (VIP, neurotensin, gastrin, pancreatic polypeptide) fell to nearly normal within 2 months. Because of asymptomatic increase in tumor size, we added chemotherapy 2 years later. Since the drug is rapidly effective and well tolerated, it will probably become the therapy of choice in this syndrome.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Liver Neoplasms; Male; Neurotensin; Octreotide; Pancreatic Neoplasms; Streptozocin; Vasoactive Intestinal Peptide; Vipoma

Hypercalcitoninemia in gastroenteropancreatic tumors associated with calcitonin immunoreactivity is rare.. We report here two patients in whom pancreatic neuroendocrine tumors both contained and secreted immunoreactive calcitonin. Both patients experienced elevated basal calcitonin immunoreactivity.. The peak responses of immunoreactive calcitonin occurred 5 minutes after pentagastrin administration in these two patients and were 30% and 180% above basal concentrations corresponding to peak increments of 0.39 and 8.78 ng/ml, respectively. The immunoreactive calcitonin response to pentagastrin in these two patients was not significantly different from that seen among five patients with medullary carcinoma of the thyroid gland.. It does not appear that immunoreactive calcitonin responses to pentagastrin stimulation will discriminate between patients with medullary carcinoma of the thyroid gland and those with nonfamilial, gastroenteropancreatic neuroendocrine tumors that express calcitonin immunoreactivity. In patients with secretory diarrhea and/or flushing, an elevated level of immunoreactive calcitonin, in the absence of a thyroid mass in the neck, may herald the presence of a gastroenteropancreatic neuroendocrine tumor.

Topics: Adenoma, Islet Cell; Aged; Calcitonin; Female; Humans; Liver Neoplasms; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Pentagastrin; Stomach Neoplasms; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Thirty primary liver neoplasms (16 hepatocellular, nine biliary, and five epithelioid haemangioendotheliomas) were studied for the expression of the general 'neuroendocrine' markers, neurone specific enolase (NSE) and protein gene product 9.5 (PGP 9.5). Grimelius silver staining for neurosecretory granules and immunostaining for S100 protein, HMB-45, vasoactive intestinal polypeptide (VIP), and calcitonin were also performed. Eleven of the 16 hepatocellular carcinomas stained positively for PGP 9.5, four for NSE, six for HMB-45, and two for S100 protein. Seven exhibited granular staining by the Grimelius method; eight showed immunostaining for VIP, and two for calcitonin. Three of the five haemangioendotheliomas demonstrated positive immunostaining for PGP 9.5, and two for NSE; of the nine biliary carcinomas, two showed staining for PGP 9.5 and NSE, and four contained cells staining with the Grimelius technique. Primary neoplasms of liver may show 'neuroendocrine' differentiation and this aspect of their phenotypic expression has to be considered before predicting the site of origin of a tumour in the liver.

Topics: Bile Duct Neoplasms; Biomarkers, Tumor; Calcitonin; Carcinoma, Hepatocellular; Cell Differentiation; Hemangioendothelioma; Humans; Liver Neoplasms; Neuropeptides; Phosphopyruvate Hydratase; S100 Proteins; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

We describe a case of a tumour of the sigmoid colon with hepatic metastases in a patient with previously documented ulcerative colitis. A diagnosis of metastatic vipoma was made on the basis of high plasma levels of vasoactive intestinal polypeptide (VIP). Profuse diarrhoea and profound metabolic upset were corrected by the use of a somatostatin analogue SMS 201-995, whilst conventional cytotoxic therapy produced a significant tumour response with return of the plasma VIP level to normal.

Topics: Adenoma, Islet Cell; Adult; Antineoplastic Combined Chemotherapy Protocols; Colitis, Ulcerative; Colostomy; Combined Modality Therapy; Female; Humans; Liver Neoplasms; Octreotide; Pancreatic Neoplasms; Sigmoid Neoplasms; Streptozocin; Vasoactive Intestinal Peptide; Vipoma

Ten patients with metastatic pancreatic endocrine tumours were treated with the long-acting somatostatin analogue octreotide (SMS 201-995). Three patients showed no response, clinically or biochemically, and treatment was therefore withdrawn. The seven remaining patients continued treatment for a median period of 28 months (range 13-54 months). Treatment was initially effective, symptoms improved and the concentrations of tumour-related hormones were reduced. Worsening of symptoms and rising levels of tumour-related hormone concentrations occurred a median of 5 months (range 1-6 months) after the start of therapy and were initially reversed by increasing the dose of octreotide over a median of 10 months (range 6-16 months). However, after a median of 13 months (range 5-34 months) at the maximum dosage, symptoms recurred and were no longer responsive to a further increase in dosage of octreotide or other therapeutic measures. All patients died within a period of 5 months once this resistant phase of their illness had been reached.

Topics: Adenoma, Islet Cell; Gastrins; Glucagon; Humans; Liver Neoplasms; Octreotide; Pancreatic Neoplasms; Time Factors; Vasoactive Intestinal Peptide

Long-acting somatostatin analogues such as SMS 201-995 (Sandoz) are being evaluated in a wide range of clinical indications, including gut neuroendocrine tumours and acrogemaly. Long-term continuous SMS 201-995 treatment has achieved useful symptomatic improvement in diarrhoea in 4 patients with metastatic VIPomas who had relapsed following previous treatment. Clinical improvement has outlasted suppression of VIP secretion (suggesting an additional direct antisecretory action of SMS 201-995) and has occurred despite expansion of hepatic metastases. In 6 patients with tumours secreting gastrin and/or glucagon, secretion of these peptides was acutely inhibited by SMS 201-995. However, endocrine and clinical responses to chronic treatment have been less consistent. SMS 201-995 is active orally at doses of 4-8 mg and when given thrice-daily to 6 patients with active acromegaly, suppressed mean 24-h growth hormone levels by 51-88%. Despite significantly reduced plasma insulin concentrations, glucose tolerance did not deteriorate. SMS 201-995 was also effective in suppressing thyroid-stimulating hormone (TSH) and thyroid hormone secretion in a patient with mild thyrotoxicosis due to non-tumoural inappropriate TSH hypersecretion. In all cases SMS 201-995 treatment has been well tolerated and has few side-effects.

Topics: Acromegaly; Adenoma; Adult; Aged; Diarrhea; Female; Gastrointestinal Neoplasms; Glucagonoma; Growth Hormone; Humans; Hyperthyroidism; Liver Neoplasms; Male; Middle Aged; Neoplasms, Glandular and Epithelial; Octreotide; Pancreatic Neoplasms; Pituitary Neoplasms; Somatostatin; Streptozocin; Thyrotropin; Vasoactive Intestinal Peptide; Vipoma; Zollinger-Ellison Syndrome

The effect of oral lidamidine hydrochloride and subcutaneous long acting somatostatin analogue, SMS 201-995, on stool output and salt and water transport in the small intestine was investigated in a patient with gross secretory diarrhoea caused by a vasoactive intestinal polypeptide (VIP) secreting tumour in the liver. Transport in the jejunum and ileum were assessed by steady state perfusion techniques. Under basal conditions, the patient was absorbing fluid and electrolytes from the jejunum and ileum, but at rates that were abnormally low. Lidamidine had no effect on either intestinal transport or stool frequency and output. SMS 201-995 increased intestinal absorption in the jejunum and ileum, reduced plasma VIP concentrations, daily stool frequency and weight, and enabled the patient to resume a normal diet without oral or intravenous fluid and electrolyte supplements. After two months of treatment, medical control was becoming increasingly difficult and stool output had risen again to 2 litres per day. Surgical resection, fortunately, was possible and led to resolution of symptoms and normal plasma VIP concentrations.

Topics: Adult; Biological Transport; Body Fluids; Diarrhea; Electrolytes; Humans; Intestinal Absorption; Liver Neoplasms; Male; Octreotide; Phenylurea Compounds; Somatostatin; Vasoactive Intestinal Peptide

A 44-year-old woman with hepatocellular carcinoma presented with intractable watery diarrhea and her condition was evaluated angiographically. Surgical ablation of the tumor resulted in complete resolution of the diarrhea. The tumor cells of the hepatocellular carcinoma were found to contain vasoactive intestinal polypeptide, gastrin, and prostaglandinlike immunoactivity. To our knowledge, this is the first report of such an association.

Topics: Adult; Carcinoma, Hepatocellular; Diarrhea; Dinoprostone; Female; Gastrins; Histocytochemistry; Humans; Liver Neoplasms; Paraneoplastic Endocrine Syndromes; Prostaglandins E; Radiography; Vasoactive Intestinal Peptide

A 43-yr-old-man with metastatic VIPoma in whom the conventional measures of surgery, chemotheraphy, and hepatic artery embolization ultimately failed to control his severe diarrhea, resulting from vasoactive intestinal polypeptide hypersecretion, was treated with a new long-acting somatostatin analogue, SMS 201-995, for 14 mo. SMS 201-995 not only controlled the diarrhea without side effects but appeared to have possibly induced a reduction in metastatic tumor size.

Topics: Adenoma, Islet Cell; Adult; Delayed-Action Preparations; Drug Evaluation; Humans; Liver Neoplasms; Male; Octreotide; Pancreatic Neoplasms; Somatostatin; Time Factors; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Contrast Media; Diarrhea; Diatrizoate; Humans; Iodine; Iopanoic Acid; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Prednisone; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Adult; Aged; Diabetes Mellitus; Diagnosis, Differential; Female; Glucagonoma; Humans; Insulinoma; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Skin Diseases; Somatostatinoma; Vasoactive Intestinal Peptide

Thirty-two tumors (31 pancreatic and one jejunal) all associated with severe watery diarrhea, increased VIP levels in blood and most with hypokalemia, were investigated. The VIP content of tumor tissue ranged from 23 to 15,000 pmol/g. VIP immunoreactive cells were detected histochemically in 24 of 28 tumors investigated, PP immunoreactive cells in 11 of 28 tumors, hCG (alpha chain) immunoreactive cells in 12 of 25 tumors, and neuron specific enolase (NSE) immunoreactive cells in 24 of 26 tumors (the 2 negative results were due to inadequate fixation). All cases showed light microscopic features of epithelial endocrine tumors. Electron microscopy demonstrated a prevalence of agranular, poorly granulated and a minority of well granulated cells. Most secretory granules were round, small (150+/- 30 nm diameter) and of moderate electron density, resembling those of the so-called D1 cells. By electron immunocytochemistry, PP was directly localized in a subpopulation of relatively larger granules (154 +/- 22 nm core diameter) showing closely applied membranes. VIP-storing granules, directly identified only in the jejunal tumor, appear to correspond to a subpopulation of slightly smaller P-type granules (126 +/- 37 nm core diameter) showing a narrow, clear halo. The origin, behavior, and diagnostic criteria of VIPomas are discussed.

Topics: Adult; Aged; Antibody Formation; Chorionic Gonadotropin; Cytoplasmic Granules; Female; Histocytochemistry; Humans; Liver Neoplasms; Male; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Potassium; Radioimmunoassay; Vasoactive Intestinal Peptide

In three families with the multiple endocrine adenomatosis type I (MEA I) trait, 51 members were investigated by measurement of circulating peptide hormones as tumor markers. Twenty-five of 51 members (49 percent) were considered to be affected by MEA I disorders. The incidence rose with age (75 percent in generation II). Both sexes were affected equally. Hyperparathyroidism was present in 20 of 25 affected members (80 percent), and pituitary tumors (prolactinomas) were found in four of 25 (16 percent). Endocrine pancreatic tumors were found in nine of 25 affected members (36 percent), but when "probable" tumors (seven) are included the frequency rises to 72 percent. Hyperparathyroidism was found in all except one member with proved lesions in other organs. Among patients with proved and possible endocrine pancreatic tumors, elevated serum levels of gastrin and pancreatic polypeptide were frequently found, 78 percent and 67 percent, respectively, and we suggest that serum gastrin and pancreatic polypeptide levels are the most useful screening markers at present for pancreatic lesions in MEA I.

Topics: Adenoma; Adolescent; Adult; Age Factors; Aged; Female; Gastrins; Humans; Hyperparathyroidism; Insulinoma; Liver Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Parathyroid Neoplasms; Pedigree; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Dactinomycin; Female; Humans; Indomethacin; Liver Neoplasms; Middle Aged; Pancreatic Neoplasms; Prednisolone; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Aged; Diabetes Mellitus, Type 1; Humans; Hypokalemia; Liver Neoplasms; Male; Pancreatic Neoplasms; Streptozocin; Syndrome; Vasoactive Intestinal Peptide; Vipoma

A case of pancreatic cholera (Verner-Morrison syndrome) associated with a pancreatic endocrine tumor and hepatic metastases is presented. VIP and HPP plasma levels, initially elevated, were accurately followed in various conditions: during corticosteroid therapy, after pancreatic tumor excision, during and after streptozotocin therapy (1.5 g/m2) by repeated intraarterial route). Only streptozotocin therapy resulted in a reduction of the stool volume with concomitant decrease in VIP plasma levels. However, the size of the hepatic metastases was unchanged and HPP plasma levels remained elevated. It is suggested that VIP represents the tumoral secretion and HPP a marker of the residual malignant tissue.

Topics: Adenoma, Islet Cell; Adult; Humans; Liver Neoplasms; Male; Outcome and Process Assessment, Health Care; Pancreatic Neoplasms; Streptozocin; Tissue Extracts; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Diarrhea; Gastrointestinal Hormones; Humans; Hypokalemia; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Syndrome; Ultrasonics; Vasoactive Intestinal Peptide

A 57-year-old male patient with metastasizing non-beta islet cell carcinoma of the pancreas is described. Both gastrin and VIP levels were elevated and the patient suffered from a syndrome of pancreatic cholera and hyperacidity. The tumour contained gastrin and VIP as demonstrated by immunofluorescence. The patient also had a history of familial renal stone formation and parathyroid nodular hyperplasia. Resection of pancreatic tumour in 1973 resulted in four years without symptoms. In 1977 definite signs of multiple hepatic metastases appeared. These signs disappeared after streptozotocin given in a dosage of 2 g three times at weekly intervals. The patient had remained well for 20 months after this treatment. The causative agents for the clinical syndrome in this case are discussed in view of circulating hormone levels.

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Dehydration; Gastrins; Gastrointestinal Hormones; Humans; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Streptozocin; Syndrome; Vasoactive Intestinal Peptide

In animals, the effects of vasoactive intestinal polypeptide (VIP) include peripheral vasodilation, hyperdynamic circulation, hyperglycemia, and hyperventilation. Because these phenomena are noted in patients with cirrhosis, it has been postulated that VIP might be escaping hepatic inactivation and entering the systemic circulatory system and contributing to these abnormalities. The major purpose of this study is to establish whether or not VIP levels are elevated in patients with cirrhosis. Additional goals are to determine if VIP levels are elevated in acute liver disease and in chronic illnesses with secondary liver involvement. The data demonstrate that patients with cirrhosis and those with acute liver disease or chronic illnesses with secondary hepatic involvement have a wide range of VIP levels with mean values significantly above that of normal individuals and patients with chronic illness and no liver involvement.

Topics: Acute Disease; Chronic Disease; Gastrointestinal Hormones; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Neoplasm Metastasis; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Antigens; Calcitonin; Gastrointestinal Hormones; Hormones, Ectopic; Humans; Liver Neoplasms; Neoplasm Metastasis; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

Vaso-active intestinal polypeptide (VIP) is a recently discovered polypeptide widely distributed throughout the gastro-intestinal tract and nervous system. Elevated plasma VIP levels are found in gut and neural endocrine tumours producing the watery diarrhoea syndrome. Fifty per cent of these tumours are intrinsically malignant and the mortality rate may be as high as 30% even from the bening growths owing to the serious metabolic sequelae of the syndrome. The plasma VIP level is not elevated in any other non-tumourous diarrhoeal condition. The biological action of VIP closely resembles the clinical features of the Verner-Morrison syndrome and experimental evidence strongly suggests that VIP is the causal agent. The measurement of plasma VIP is of exceptional diagnostic value, since detection of elevated levels enables early removal of the tumour and may be life-saving.

Topics: Adrenal Gland Neoplasms; Diagnosis, Differential; Diarrhea; Ganglioneuroma; Gastrointestinal Hormones; Humans; Hypokalemia; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

A 61-year-old woman had watery diarrhea, hypochlorhydria, hypokalemia, and elevated serum gastrin levels. She had islet cell carcinoma of the body of the pancreas with multiple metastases to the liver. Radioimmunoassay and immunofluorescence demonstrated both vasoactive intestinal polypeptide (VIP) and gastrin in the surgically removed carcinoma and in a metastatic focus. Electron microscopical findings confirmed the presence of two cell types whose secretory granules had characteristics ascribed to these two hormones. Plasma prostaglandin E levels were also elevated above normal. Serum VIP levels became elevated to the Verner-Morrison range prior to her death of a bleeding duodenal ulcer two years after initial symptoms.

Topics: Adenoma, Islet Cell; Female; Gastrins; Gastrointestinal Hormones; Humans; Liver Neoplasms; Middle Aged; Neoplasm Metastasis; Pancreas; Pancreatic Neoplasms; Vasoactive Intestinal Peptide