Bone Like Arterial Calcification in Femoral Atherosclerotic Lesions: Prevalence and Role of Osteoprotegerin and Pericytes.

OBJECTIVE/BACKGROUND: Arterial calcification, a process that mimics bone formation, is an independent risk factor of cardiovascular morbidity and mortality, and has a significant impact on surgical and endovascular procedures and outcomes. Research efforts have focused mainly on the coronary arteries, while data regarding the femoral territory remain scarce. METHODS: Femoral endarterectomy specimens, clinical data, and plasma from a cohort of patients were collected prospectively. Histological analysis was performed to characterize the cellular populations present in the atherosclerotic lesions, and that were potentially involved in the formation of bone like arterial calcification known as osteoid metaplasia (OM). Enzyme linked immunosorbent assays and cell culture assays were conducted in order to understand the cellular and molecular mechanisms underlying the formation of OM in the lesions. RESULTS: Twenty-eight of the 43 femoral plaques (65%) displayed OM. OM included osteoblast and osteoclast like cells, but very few of the latter exhibited the functional ability to resorb mineral tissue. As in bone, osteoprotegerin (OPG) was significantly associated with the presence of OM (p = .04). Likewise, a high plasma OPG/receptor activator for the nuclear factor kappa B ligand (RANKL) ratio was significantly associated with the presence of OM (p = .03). At the cellular level, there was a greater presence of pericytes in OM+ compared with OM- lesions (5.59 ± 1.09 vs. 2.42 ± 0.58, percentage of area staining [region of interest]; p = .04); in vitro, pericytes were able to inhibit the osteoblastic differentiation of human mesenchymal stem cells, suggesting that they are involved in regulating arterial calcification. CONCLUSION: These results suggest that bone like arterial calcification (OM) is highly prevalent at femoral level. Pericyte cells and the OPG/RANK/RANKL triad seem to be critical to the formation of this ectopic osteoid tissue and represent interesting potential therapeutic targets to reduce the clinical impact of arterial calcification.

Interleukin 34 expression is associated with synovitis severity in rheumatoid arthritis patients.

OBJECTIVES: Interleukin (IL) 34 is a new cytokine implicated in macrophage differentiation and osteoclastogenesis. This study assessed IL-34 expression in the tissue of patients with rheumatoid arthritis (RA). METHODS: Immunohistochemistry was performed in synovial biopsies from patients with RA (n=20), osteoarthritis (n=3) or other inflammatory arthritis (n=4). IL-34 was detected in the synovial fluid by ELISA and its messenger RNA expression was studied by quantitative PCR in rheumatoid synovial fibroblasts after stimulation by tumour necrosis factor α (TNFα) and IL-1ß. Wild-type, jnk1(-/-)-jnk2(-/-) and nemo(-/-) murine fibroblasts and pharmacological inhibition were used to determine the involvement of nuclear factor kappa B (NF-κB) and JNK in that effect. RESULTS: IL-34 was expressed in 24/27 biopsies, with three samples from RA patients being negative. A significant association was found between IL-34 expression and synovitis severity. Levels of IL-34 and the total leucocyte count in synovial fluid were correlated. TNFα and IL-1ß stimulated IL-34 expression by synovial fibroblasts in a dose/time-dependent manner through the NF-κB and JNK pathway. CONCLUSION: This work for the first time identifies IL-34 expression in the synovial tissue of patients with arthritis. This cytokine, as a downstream effector of TNFα and IL-1ß, may contribute to inflammation and bone erosions in RA.

The Bone Niche of Chondrosarcoma: A Sanctuary for Drug Resistance, Tumour Growth and also a Source of New Therapeutic Targets.

Chondrosarcomas are malignant cartilage-forming tumours representing around 20% of malignant primary tumours of bone and affect mainly adults in the third to sixth decade of life. Unfortunately, the molecular pathways controlling the genesis and the growth of chondrosarcoma cells are still not fully defined. It is well admitted that the invasion of bone by tumour cells affects the balance between early bone resorption and formation and induces an "inflammatory-like" environment which establishes a dialogue between tumour cells and their environment. The bone tumour microenvironment is then described as a sanctuary that contributes to the drug resistance patterns and may control at least in part the tumour growth. The concept of "niche" defined as a specialized microenvironment that can promote the emergence of tumour stem cells and provide all the required factors for their development recently emerges in the literature. The present paper aims to summarize the main evidence sustaining the existence of a specific bone niche in the pathogenesis of chondrosarcomas.

[Hemoperitoneum due to rupture of an omental arterial aneurysm]. / Hémopéritoine par rupture spontanée d'un anévrisme de l'arcade vasculaire omentale.

We report a case of spontaneous hemoperitoneum due to rupture of an omental arterial aneurysm. This source of bleeding is unusual (2 cases published); the diagnosis was made preoperatively by doppler ultrasound and CT scan with IV contrast. Omental resection was performed and histological analysis confirmed the diagnosis. A literature review of the rare cases of hemoperitoneum due to rupture of a digestive arterial aneurysm is done.

Tk, a new colon tumor-associated antigen resulting from altered O-glycosylation.

Erythrocyte polyagglutination antigens T and Tn are truncated O-glycan chains that are also carcinoma-associated antigens. We investigated whether Tk polyagglutination antigen could similarly be a carcinoma-associated marker and a target of immunotherapy. Monoclonal antibody LM389 was raised against Tk erythrocytes and tested by immunohistochemistry. LM389 strongly reacted with 48% human colorectal carcinomas. Labeling of normal tissues was visible on epithelial cells, mainly digestive, but was confined at a supranuclear level. Expression of the antigen on cloned human carcinoma cells correlated with sialosyl-Tn expression. O-Sialoglycoprotein endopeptidase treatment revealed that on carcinomas and cell lines, the epitope was present on O-glycans. Antibody specificity was determined using synthetic carbohydrates. Direct binding and inhibition studies indicated that LM389 best ligands were terminated by two branched N-acetylglucosamine units. Screening of murine cellular cell lines with LM389 allowed development of an experimental model with Tk-positive and -negative cells in syngeneic BDIX rats. Vaccination of rats with Tk erythrocytes provided a protection against growth of rat Tk-positive, but not of Tk-negative, tumor cells in association with the development of antibodies. Taken together, the results indicate that Tk polyagglutination antigen is a new colorectal carcinoma-associated antigen, absent from the normal cell surface, resulting from alteration of O-glycans biosynthesis and with potential as a target of immunotherapy.

Enhanced tumor regression and tissue repair when zoledronic acid is combined with ifosfamide in rat osteosarcoma.

The efficacy of zoledronic acid (ZOL), with or without the anticancer drug ifosfamide (IFO), was tested on primary bone tumor growth using a rat-transplantable model of osteosarcoma. The effects on bone remodeling and tumor growth were analyzed by radiography, micro-computed tomography (micro-CT), and histological staining. The in vitro effects of ZOL were studied by proliferation, apoptosis, and cell cycle analyses on the osteosarcoma cells OSRGA compared to rat primary osteoblasts. Treatment with ZOL was effective in preventing the formation of osteolytic lesions that developed in bone sites and in reducing the local tumor growth, as compared to the untreated rats. The combination of ZOL and IFO was more effective than each agent alone in preventing tumor recurrence, improving tissue repair, and increasing bone formation as revealed by the analysis of trabecular architecture. In vitro studies demonstrated that ZOL was more potent against the OSRGA cell line than osteoblasts (with a half-maximal inhibitory effect on proliferation seen at 0.2 and 20 microM, respectively), the ZOL-induced inhibition of OSRGA proliferation being due to cell cycle arrest in S-phase. No effect on OSRGA apoptosis could be observed in vitro, as assessed by Hoechst staining and caspase-1 and -3 activation. In situ cell death was determined by TUNEL staining on tumor tissue sections. No significant difference in TUNEL-positive cells could be observed between ZOL-treated and -untreated rats. This is the first report of the anti-bone resorption and antitumoral activities of zoledronic acid in a rat model of osteosarcoma, and its beneficial association with an antitumoral chemotherapeutic drug in preventing tumor recurrence.

Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I.

One hundred pancreatic tumors ranging in size from 0.3 to 7 cm were studied in 28 patients (17 male and 11 female patients; mean age 35 years) with multiple endocrine neoplasia, type I. An immunohistochemical study was performed on deparaffinized sections using the following antibodies: neuron-specific enolase, chromogranin A or synaptophysin, insulin, glucagon, somatostatin, pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP), gastrin, adrenocorticotropic hormone, alpha-subunit of human chorionic gonadotropin, gonadotropin-releasing factor, serotonin, and calcitonin. Among the 100 tumors (all multiple), seven were unclassified, 10 were plurihormonal, and 83 produced a predominant hormonal secretion (with 50-90% of the same cell type), including 37 "A-cell tumors" (glucagon), 27 "B-cell tumors" (insulin), 11 PP-cell tumors, one G-cell tumor (gastrin) and one vasoactive intestinal peptide (VIP)-cell tumor. These multiple tumors had a different predominant hormonal secretion in the same patient in 23 of the 28 cases. There was a preferential association of A-cell tumor and B-cell tumor. Hyperplasia of the islets of Langerhans was not detected in adjacent pancreas. Nesidioblastosis was observed in 30% of cases.

Cyclo-oxygenase-2 over-expression in sporadic colorectal carcinoma without lymph node involvement.

BACKGROUND: Cyclo-oxygenase-2 over-expression has been reported in most advanced human colorectal cancers. AIMS: To assess the prevalence of cyclo-oxygenase-2 over-expression in non-advanced colorectal cancers, to investigate the correlation between cyclo-oxygenase-2 status and tumour clinicopathological features and molecular phenotype, and to determine the impact of cyclo-oxygenase-2 status on long-term clinical outcome. METHODS: Sixty-one patients who had undergone surgery for colorectal cancer without lymph node involvement were evaluated retrospectively. Cyclo-oxygenase-2 expression was determined by immunohistochemistry. The tumour replication error phenotype was assessed by amplification of the two microsatellites, BAT-25 and BAT-26. RESULTS: Thirty-six tumours were classified as cyclo-oxygenase-2 positive and 25 as cyclo-oxygenase-2 negative. No correlation was found between cyclo-oxygenase-2 over-expression and clinicopathological features or molecular phenotype. Cyclo-oxygenase-2 over-expression was an independent predictor of a poor prognosis. Indeed, the relative risk of tumour recurrence or death for patients with cyclo-oxygenase-2-positive tumours was 2.13 times that of patients with cyclo-oxygenase-2-negative tumours (P=0.008; 95% confidence interval, 1.22-3.73). This difference remained significant when post-operative deaths were censored in the multivariate analysis (P=0.014). CONCLUSION: Cyclo-oxygenase-2 over-expression is not associated with tumour phenotype, but is indicative of a poorer clinical outcome in patients with non-advanced colorectal carcinoma.

Molecular mechanisms involved in the antiproliferative effect of two COX-2 inhibitors, nimesulide and NS-398, on colorectal cancer cell lines.

BACKGROUND: Cyclooxygenase (COX)-2 is up-regulated in most colorectal cancers. Chronic use of non-steroidal anti-inflammatory drugs, which target cyclooxygenases, have been shown to reduce the risk of these cancers. However, the mechanisms underlying this protective effect remain unclear. AIMS: The aim of our study was to characterize the effects of two COX-2 selective inhibitors, NS-398 and nimesulide, on colorectal cancer cell proliferation, and to describe the molecular mechanisms involved. MATERIALS AND METHODS: HT-29 and SW-1116 cell lines were cultured with either NS-398 or nimesulide. Cell proliferation was assessed by staining DNA with crystal violet. Cell cycle repartition and apoptosis were analysed by flow cytometry. The expression of COX-1 and COX-2. and of two cyclin dependent kinase inhibitors, p21Cip1 and p27Kip1, was analysed by Western blotting and RT-PCR. RESULTS: Both drugs dose-dependently inhibited cell proliferation and induced G1 cell cycle blockade. HT-29 cells were more sensitive to both drugs than SW-1116 cells. p21Cip1 and p27Kip1 were induced on both cell lines. Concomitant induction of p21Cip1 mRNA indicates transcriptional modulation, whereas induction of p27Kip1 only at the protein level suggests post-translational modulation. CONCLUSION: NS-398 and nimesulide inhibit colorectal cell proliferation through induction of p21Cip1 and p27Kip1.

Endocrine tumors of the duodenum. A study of 55 cases relative to clinicopathological features and hormone content.

BACKGROUND/AIMS: Study of prognosis of duodenal endocrine tumors. METHODOLOGY: Retrospective study concerned 55 duodenal endocrine tumors discovered in biopsy or surgical specimens. Follow-up records available for 49 patients indicated that inconspicuous associated clinical manifestations were often found subsequently. Seven patients were classified as Zollinger-Ellison syndrome and seven as multiple endocrine neoplasia (6 MEN I and 1 MEN II). RESULTS: Tumors were small (mean 1.28cm) and located preferentially in the first and second part of the duodenum. Fifty-four were well-differentiated and one poorly differentiated. Immunochemistry revealed 30 G-cell tumors (54.6%), 15 D-cell (27.3%), two plurihormonal (EC cell and G cell), and one GRH-cell, whereas seven could not be classified. Fifteen patients died (five in relation to their disease). Twenty-one had metastases (liver, nodes, lung), eight of whom are still alive. CONCLUSIONS: Eighty-eight percent of duodenal endocrine tumors were gastrinomas, small plurifocal tumors and somatostatinomas preferentially located in the ampullar region and diagnosed because of hematemesis or icterus. Size is an important prognostic factor in determining whether surgery is required. The prognosis is better for D- and G-cell tumors than pancreatic endocrine tumors. Duodenal endocrine tumors in multiple endocrine neoplasia have a good prognosis, but can be associated with pancreatic plurihormonal tumors and metastases.

[Right atrial intracardiac varices. Review of the literature and case report]. / Varices intracardiaques auriculaires droites. Revue de la littérature à propos d'une observation.

Right atrial varices are rare. They were described for the first time by anatomo-pathologists at the end of the 19th century and beginning of the 20th century. They are situated in the lower part of the inter-atrial septum and rarely exceed 2 cm in diameter. Descriptions have been from post-mortem studies which have led to epidemiological analyses and have given rise to nosological controversies. The authors report a case characterised by the exceptional volume of the varices. This could have enabled the diagnosis to be suspected at transoesophageal echocardiography before surgery. Thoracic CT scan and MRI completed the iconography. In the literature, two other cases of cardiac varices diagnosed at echocardiography have been published: they were small tumours on the lower part of the interatrial septum and the diagnosis before surgery was that of a myxoma. These formations seem to correspond to chance findings and do not appear to give rise to symptoms.

[A rare cause of myocardial infarction: papillary fibroelastoma of the aortic valve]. / Cause rare d'infarctus du myocarde: le fibro-élastome papillaire de la valve aortique.

Papillary fibroelastoma is a rare, benign endocardial tumour usually located on the cardiac valves. Before echocardiography, these tumours were chance findings either at surgery or at autopsy. With the advent of echocardiography, the diagnosis has become commoner and they are often the cause of systemic embolism justifying surgical ablation. In this case, an aortic valve papillary fibroelastoma presented with myocardial infarction in a 78 year old woman with normal coronary angiography. The diagnosis was strongly suspected at echocardiography and confirmed by histological analysis of the surgically excised tumour.

[Extension of an acinar cell pancreatic carcinoma with cystic changes invading the Wirsung canal]. / Carcinome à cellules acineuses pancréatique d'allure kystique, envahissant le canal de Wirsung.

We report a case of acinar cell carcinoma of the pancreas with misleading cystic changes. A 32-year-old woman presented with symptoms suggesting acute pancreatitis on chronic pancreatitis. The abdominal computed tomography and the endoscopic retrograde pancreatography demonstrated hypertrophy of the pancreatic head associated with global dilatation of main pancreatic duct and secondary canals and a 5 cm communicating cyst. A intraductal papillary-mucinous tumor was suggested. Microscopic findings showed a poorly differentiated adenocarcinoma. Six months later, a liver metastasis was detected. The microscopic appearance was different, suggesting acinar cell carcinoma, confirmed by immunohistochemistry. Only two other cases of acinar cell carcinoma with cystic component have been reported in the literature.

[Immunohistochemical study of 17 cases of rectal neuroendocrine tumors]. / Etude immunohistochimique de 17 cas de tumeurs neuro-endocrines rectales.

Seventeen rectal neuroendocrine tumors ("Rectal Carcinoids") were studied by immunohistochemistry using antibodies directed against neuroendocrine markers: chromogranin A, neuron-specific enolase, synaptophysin, neuroendocrine peptides (ACTH, glicentin, glucagon, pancreatic polypeptide, somatostatin, vasoactive intestinal peptide) and antibody against serotonin. All patients with tumors measuring 1 cm or less had no specific symptoms and survived between fifteen months and eight years. Only one patient with a 6 cm poorly differentiated neuroendocrine carcinoma died less than one year after diagnosis. Only five out of seventeen tumors secreted serotonin. Most tumors were derived from L cell secreting glucagon, glicentin or pancreatic polypeptide.

[Duodenal somatostatinomas associated with von Recklinghausen's neurofibromatosis. Apropos of 2 cases]. / Somatostatinomes duodénaux et neurofibromatose de von Recklinghausen.

Somatostatinomas are rare neuroendocrine tumors; they are essentially located in the pancreas and in the duodenum. The association with a neurofibromatosis type I is especially observed when the tumor is located in the ampulla of Vater. These tumors are not associated with a "somatostatin syndrome", but often present with gastrointestinal bleeding, abdominal pain and obstructive jaundice. The diagnosis is confirmed by immunohistochemical studies. The aim of this study is to report 2 cases of metastazing duodenal periampullary somatostatinomas associated with von Recklinghausen's disease and to discuss the prognosis of these tumors. Future genetic research are necessary as point out the familial feature of this association in one of our cases.

[Histopathologic features of cytomegalovirus lymphadenitis in the "immunocompetent" patient. Report of 7 cases]. / Aspects histopathologiques de la lymphadénite à cytomégalovirus chez le sujet "immunocompétent". A propos de 7 observations.

The authors report seven cases of cytomegalovirus lymphadenitis in apparently immunocompetent patients. One patient presented with an infectious mononucleosis-like illness. The main presentation of the others was isolated cervical lymphadenopathies. The lymph node pathology showed aspecific lymphoid hyperplasia, resembling the human immunodeficiency virus related lymphadenopathy, associated with diagnostic inclusion cells. Infected cells were confined to areas of monocytoid B cell hyperplasia in all cases whereas exceptionally observed in germinal centers. Because of their variable appearance, serial sectioning was frequently necessary to disclose their characteristic features. In all cases, immunohistochemistry using an anti-cytomegalovirus antibody was positive and revealed more infected cells than detected by morphology alone. Except for the endothelial cell, the nature of infected cells remained undetermined. An alteration of the antigenic expression as a consequence of cell infection might be responsible for immunohistochemistry failure in the cell characterization.

[Pathologic study with immunohistochemistry of 61 pancreatic endocrine tumors in 16 patients suffering from multiple endocrine neoplasia type I (MEN I). Review of the literature]. / Etude anatomopathologique avec immunohistochimie de 61 tumeurs endocrines pancréatiques chez 16 patients atteints de néoplasies endocriniennes multiples de type I (NEM I). Revue de la littérature.

The Multiple Endocrine Neoplasia (MEN I) or Wermer's syndrome is an uncommon disease which is most often inherited and affects mainly parathyroid glands, pancreatic islets and pituitary gland. The aim of this study concerning 61 pancreatic tumors in 16 patients suffering from MEN I was to define the macroscopic, histological and immunohistochemical characteristics of these tumors. The pancreatic endocrine tumors as part of the MEN I syndrome concern multiple tumors of small size, localized most often to the pancreas's tail. In 79% of cases, these tumors have a different predominating peptidic hormonal secretion in a same patient though most of them have plurihormonal secretions. The pancreatic polyendocrinopathy detection imposes a family investigation to look for a type I polyendocrinopathy.

[Post-transplantation of Hodgkin's disease. Clinico-pathologic study of 3 cases]. / Maladie de Hodgkin après transplantation d'organè. Etude anatomoclinique de 3 observations.

As a frequent complication of immunosuppression, lymphoproliferative disorders affect approximately 2 % of allorgan transplant recipients. Most of them are EBV-associated-B-cell-lymphoproliferations. Other types of non Hodgkin's lymphomas and Hodgkin's disease, as observed in general population, have only rarely been reported in this group of patients. We report three cases of Hodgkin's disease, which were diagnosed in two renal transplant recipients and one heart transplant patient. They were associated with Epstein-Barr virus, as demonstrated by immunohistochemistry and in situ hybridization. EBV is frequently associated with Hodgkin's disease in the general population, and always implicated in AIDS-related Hodgkin's disease. However in transplant patients the rarity of Hodgkin's disease argues against a direct oncogenic role of this virus.

[Pulmonary endodermal tumor resembling fetal lung. Low grade adenocarcinoma of the fetal lung type]. / Tumeur pulmonaire endodermique ressemblant au poumon foetal. Adénocarcinome de type poumon foetal de bas grade.

Pulmonary endodermal tumor resembling fetal lung is a rare pulmonary neoplasm, classified either within the pulmonary blastomas spectrum or as a subtype of adenocarcinoma. We report a case revealed by a fever in a 24-year-old woman. The tumor measured 9 cm and extended into the lower right bronchus. The diagnosis was done on a biopsy performed during fiberoptic endoscopy. The patient was treated by lobectomy. She is well without disease 6 years after surgery. This type of predominantly epithelial tumor with neuroendocrine differentiation and a scanty non malignant stromal component should be identified in young women because of its favorable outcome after surgical resection. It must not be confused with ordinary adenocarcinoma nor metastatic adenocarcinoma, especially endometrioid type.

[Parathyroid cyst. Report of ten cases]. / Les kystes parathyroïdiens. A propos de dix observations.

AIM OF THE STUDY: To evaluate the characteristics of the parathyroid cysts (PC). PATIENTS AND METHOD: Ten patients with PC were included in this retrospective study. The PC were discovered as follows: cervical mass (n = 3), hyperparathyroidism (n = 3), incidentally during thyroid surgery (n = 3) and screening for obesity (n = 1). Intracystic parathormone determination was performed after fine needle aspiration in 2 cases. RESULTS: Mean cyst measurements were 27 mm (ext: 5-70 mm) to 22 mm (5-45 mm). Nine cysts were cervical (resection by cervicotomy), and one was mediastinal (resection by sternotomy). In addition to the resection of the PC, 3 adenomas, 1 hyperplasia of the parathyroid glands and 3 benign thyroid diseases were recognized and treated during the cervicotomies. CONCLUSION: The diagnosis of PC is not common and must be based primarily on the study of the cyst liquid obtained by percutaneous puncture (intracystic parathormone measurement).