Population-based cohort follow-up study of all patients operated for borderline ovarian tumor in western Sweden during an 11-year period.

Borderline ovarian tumors (BOTs) make up around 10-20% of all epithelial ovarian tumors. The aim of the present study was to investigate the outcome of a complete large population-based cohort of patients treated for BOT. All patients (n= 399) treated for BOT in the western part of Sweden (population around 1.6 million) between 1993 and 2004 were followed. The treatment consisted of primary staging surgery with addition of platinum-based adjuvant chemotherapy for the majority of aneuploid tumors. Data relating to the surgical procedure, FIGO stage, histopathology, ploidy status, adjuvant chemotherapy, and disease state (recurrence or death) at follow-up visits were continuously entered into a cancer quality registry. Data concerning cases and deaths were also controlled against the Swedish National Cancer Registry. The median age of the BOT patients was 55 years (range 16-90). The relative 5- and 10-year survivals were 99.9% (95% CI 96.3-102.4) and 103.5% (95% CI 97.2-108.2), respectively. Aneuploidy was found in 63 (17%) patients, with significantly more aneuploid tumors found among patients of older (>60 years) age. Out of the 399 patients, 8 had recurrence of the disease. Three of the eight patients died from the disease. Five patients with recurrence are alive, three of these patients with no signs of disease after additional treatment. This complete long-term follow-up of a large population-based cohort of BOT patients shows that there is a good overall survival in this patient group.

Prostate adenocarcinoma cells release the novel proinflammatory polypeptide EMAP-II in response to stress.

The proinflammatory protein endothelial monocyte-activating polypeptide II (EMAP-II) was first detected in supernatants of murine tumor cells by virtue of its ability to stimulate endothelial-dependent coagulation in vitro. The purified protein has pleiotropic effects on endothelial cells, monocytes, and neutrophils; however, its function in vivo is unknown, and the mechanism whereby it is released from cells is poorly understood. We investigated the expression of EMAP-II in human prostate adenocarcinoma specimens by immunohistochemistry and in LNCaP and DU-145 human prostate adenocarcinoma cells by reverse transcription-PCR, flow cytometry, and Western blotting. We then examined the effects of chemical and physiological stress on release and processing of EMAP-II by LNCaP and DU-145 cells. These cells constitutively express a Mr 34,000 form of EMAP-II that is retained intracellularly. Exposure to agents that induce apoptosis or, in some cases, necrosis induces the release of the Mr 34,000 form and further processing to the Mr 27,000 and Mr 22,000 forms. Hypoxia, but not heat shock, is a potent inducer of release and processing of biologically active EMAP-II by LNCaP and DU-145 cells. We suggest that release of EMAP-II by prostate adenocarcinoma cells as a consequence of treatment with anticancer agents or as a result of constitutive hypoxia may potentiate the effects of those agents through the localized activation of host effector mechanisms.

NESP55, a novel chromogranin-like peptide, is expressed in endocrine tumours of the pancreas and adrenal medulla but not in ileal carcinoids.

Neuroendocrine secretory protein 55, NESP55, is an acidic protein belonging to the chromogranin family. The distribution of NESP55 in human tumours is not known. The aim of the present study was to study the expression of NESP55 in human gastrointestinal, pancreatic and adrenal tumours. A total of 118 human endocrine and nonendocrine tumours were examined by immunocytochemistry, and compared to the expression of chromogranin A (CgA) in the same tumours. Pancreatic endocrine tumours (14 out of 25), pheochromocytomas (19 out of 19), and neuroblastomas (seven out of 14) expressed NESP55, with the same strong labelling pattern in both benign and malignant tumours. Expression of NESP55 in pancreatic endocrine tumours and pheochromocytomas was confirmed by Western and Northern blot analysis. Immunocytochemical analysis demonstrated no labelling in ileal carcinoids (zero out of 15), and adrenocortical adenomas (zero out of 15). The majority of gastrointestinal and pancreatic carcinomas were negative for NESP55, with focal staining observed in two out of 30 tumours. In contrast, CgA was present in all neuroendocrine tumours examined (25 out of 25 pancreatic endocrine tumours, 19 out of 19 pheochromocytomas, 14 out of 14 neuroblastomas and 15 out of 15 ileal carcinoids). Thus, the expression of NESP55 in endocrine tumours of the gastrointestinal tract, pancreas and adrenals differs from that of CgA. Neuroendocrine secretory protein 55 is found in a subset of neuroendocrine tumours showing differentiation towards adrenal chromaffin cells and pancreatic islets cells.

Cloning and expression of human endothelial-monocyte-activating polypeptide 2 (EMAP-2) and identification of its putative precursor.

Endothelial-monocyte-activating polypeptide 2 (EMAP-2) modulates a range of properties of endothelial cells, monocytes and neutrophils in vitro, and induces an acute inflammatory reaction and tumour regression in vivo. We generated the full-length human cDNA sequences of EMAP-2 and its putative precursor pro-EMAP-2 as PCR products. These were cloned into the pCR3 vector and subcloned into pGEX-2T for expression as fusion products with glutathione-S-transferase (GST). Recombinant EMAP-2 (rEMAP-2) was isolated by thrombin cleavage of the fusion protein, followed by affinity chromatography. rEMAP-2 retained biological activity, which was blocked by polyclonal antibodies raised against GST-EMAP-2. By Western blotting, a 34-kDa product corresponding to the predicted precursor proEMAP-2 was detected in lysates of the U937 monocytic cell line, while supernatants contained higher levels of the mature 22-kDa molecule.

Differential expression of vesicular monoamine transporter (VMAT) 1 and 2 in gastrointestinal endocrine tumours.

Neuroendocrine tumours are characterized by their capacity to produce hormones, which are stored in vesicles and secretory granules. Demonstration of granule/vesicle proteins in tumours is taken as evidence of neuroendocrine differentiation. Vesicular monoamine transporters (VMAT1 and VMAT2) mediate the transport of amines into vesicles of neurons and endocrine cells. The expression of VMAT1 and VMAT2 and the usefulness of VMAT1 and VMAT2 in the histopathological diagnosis of gastrointestinal endocrine tumours have not been fully explored. This study therefore investigated the expression of VMAT1 and VMAT2 in 211 human gastrointestinal tumours by immunocytochemistry and western blotting. VMAT1 and/or VMAT2 were demonstrated in the majority of amine-producing endocrine tumours of gastric, ileal, and appendiceal origin. Serotonin-producing endocrine tumours (ileal and appendiceal carcinoids) expressed predominantly VMAT1, while histamine-producing endocrine tumours (gastric carcinoids) expressed VMAT2 almost exclusively. In peptide-producing endocrine tumours such as rectal carcinoids and endocrine pancreatic tumours, only a small number of immunopositive tumour cells were observed. No labelling was found in non-endocrine tumours, including gastric, colorectal and pancreatic adenocarcinomas and gastrointestinal stromal tumours. In conclusion, VMAT1 and VMAT2 are differentially expressed by gastrointestinal endocrine tumours, with a pattern specific for each tumour type, reflecting their neuroendocrine differentiation and origin. VMAT1 and VMAT2 may therefore become valuable markers in the classification of neuroendocrine tumours and may also indicate patients suitable for radioisotope treatment operating via these transporter systems.

Uptake of meta-iodobenzylguanidine in neuroendocrine tumours is mediated by vesicular monoamine transporters.

The radio-iodinated noradrenaline analogue meta-iodobenzylguanidine (MIBG) can be used for scintigraphy and radiation therapy of neuroendocrine (NE). The aim of the present study was to study the importance of vesicular monoamine transporters (VMATs) for the uptake of (123)I-MIBG in NE tumours. In nude mice, bearing the human transplantable midgut carcinoid GOT1, all organs and xenografted tumours accumulated (123)I after i.v. injection of (123)I-MIBG. A high concentration of (123)I was maintained in GOT1 tumours and adrenals, which expressed VMATs, but rapidly decreased in all other tissues. In the VMAT-expressing NE tumour cell lines GOT1 and BON and in VMAT-expressing primary NE tumour cell cultures (carcinoids, n=4 and pheochromocytomas, n=4), reserpine significantly reduced the uptake of (123)I-MIBG. The membrane pump inhibitor clomipramine had no effect on the uptake of (123)I-MIBG in GOT1 and BON cells, but inhibited the uptake in one out of four primary carcinoid cell cultures and three out of four primary pheochromocytoma cell cultures. In conclusion, VMATs and secretory granules are of importance for the uptake and retention of (123)I-MIBG in NE tumours. Information about the type and degree of expression of VMATs in NE tumours may be helpful in future to select patients suitable for radiation therapy with radio-iodinated MIBG.