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.

Patient information ahead of thyroid surgery. Guidelines of the French Society of Oto-Rhino-Laryngology and Head and Neck Surgery (SFORL).

OBJECTIVE: The authors present the guidelines of the French Society of Oto-Rhino-Laryngology and Head and Neck Surgery (SFORL) on patient information ahead of thyroid surgery. METHODS: A multidisciplinary medical team was tasked with a scientific literature review on this topic. The texts retrieved were analyzed by an independent committee. A joint meeting drew up the final guidelines. The strength of the recommendations (grade A, B or C) was based on levels of evidence. RESULTS: It is recommended that the results of preoperative exploration and the indications for surgery should be explained to the patient. Patients should be informed as to the type of surgery, surgical objectives, risks and consequences. It is mandatory to obtain the patient's written consent before surgery. CONCLUSION: Appropriate medical information is a critical step in patient management.

[Arterial heterogeneity]. / Artériopathie et hétérogénéité artérielle.

More and more clinical observations and trials support the concept of heterogeneity of atheroma according to the arterial bed. In a pilot study named "Étude Comparative des Lésions Athéromateuses" (ECLA), we have shown that carotid and femoral plaques possess different characteristics. Carotid arteries display increased lipid content compared to femoral arteries whereas femoral arteries are more prone to calcify and to develop osteoid metaplasia. These observations should lead the researcher and the clinician to look at the cellular and molecular mechanisms governing the heterogeneity of atheromas. At last, a better understanding of the characteristics of plaques should help us to determine plaque stability, to prevent cardiovascular events and to choose the best medical, endovascular or surgical option.

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.

Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of solid pancreatic masses: the impact on patient-management strategy.

BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a safe and accurate technique for diagnosing pancreatic cancer. However, its impact for management of these patients is poorly investigated. AIMS: To investigate the diagnostic yield and the therapeutic impact of EUS-FNA in the management of solid pancreatic masses. METHODS: One hundred consecutive patients who underwent EUS-FNA for a solid pancreatic mass were included. Aspirates were placed onto glass slides for cytological examination and microbiopsies were fixed in formaldehyde for histology. The impact on clinical management was analysed retrospectively according to different endpoints, such as its impact on indications for chemotherapy, surgery or appropriate follow-up modality. RESULTS: Eight procedures were considered failures and two patients were lost to follow-up. A final diagnosis was obtained in 90 patients. The sensitivity, specificity and accuracy of combined cytology and histology for the diagnosis of malignant or potentially-malignant tumours were 78%, 75%, and 78% respectively. The sensitivity and accuracy of cytology alone were significantly higher than those of histology alone (P = 0.0003). By intention-to-diagnose analysis, EUS-FNA directly influenced the management strategy in 62 of 100 patients. CONCLUSIONS: In patients with pancreatic mass and suspected malignancy, EUS-FNA provides an accurate diagnosis in approximately 80% of cases. EUS-FNA directly influences the management in two-thirds of patients.

[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.

A new experimental rat model of osteosarcoma established by intrafemoral tumor cell inoculation, useful for biology and therapy investigations.

Satisfactory experimental models for preclinical cancer studies must follow several criteria: (1) reproducibility of the method used to induce the tumor and (2) clinical, pathological and kinetic similarity with the corresponding human tumors. We developed a model of osteosarcoma locally induced by the intrafemoral injection of osteosarcoma (OSR) cells in Sprague-Dawley rats. This method yields nearly 80% of bone tumors at the injection site. These tumors double their volume fairly slowly (in approximately 20 days) and lung metastases occur in 96% of the animals. The OSR cell-induced tumor is characterized by a direct production of mineralized matrix by the tumor cells themselves, as revealed by histochemical analysis. The microarchitectural parameters which were quantified by a microscanner show an increased trabecular bone volume (+238%) when OSR cells were injected in the femur, as compared to controls injected with vehicle. Osteoblastic markers such as alkaline phosphatase, osteopontin, osteocalcin and bone sialoprotein were expressed by the tumor in vivo, whereas the initially injected OSR cells did not express some of these markers, suggesting that OSR cells reacquired an osteoblastic phenotype in a favorable environment. The clinical, radiological and histological data show that this model shares high similarities with the osteocondensing forms of osteosarcoma in humans.

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.

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.

Neointimal hyperplasia after stenting in a human mammary artery organ culture.

Although the use of stents has limited the incidence of restenosis, in-stent restenosis remains an important problem. In-stent restenosis is the result of a healing process that induced neointimal hyperplasia through mechanisms that are still not understood. The aim of this study was to analyze the histological consequences of the healing process following stent implantation. Internal mammary arteries from atheroslerotic patients undergoing coronary artery bypass surgery were stented and maintained in culture for 0-28 days. Stent implantation after predilatation induced an extensive loss of endothelial cells whereas direct stenting preserved endothelium between the struts. Morphometric analysis shows that stent placement induced neointimal thickening. Smooth muscle alpha-actin labeling indicates that neo-intimal formation was mainly due to proliferation and migration of smooth muscle cells. Smooth muscle cell proliferation, assessed by MIB-1 staining, was maximal at day 14 after stent insertion. Human mammary artery organ culture thus provides valuable information on histological consequences of stent implantation with or without predilatation regarding endothelial cell disappearance and neointimal hyperplasia. These data also demonstrate that neointimal thickening induced by stent implantation comprises an intrinsic component resulting from the vessel wall response to stent insertion and suggest that blood factors could play an amplifying but not necessary role.

[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.

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.

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.

[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).

[Duodenal somatostatinoma. Anatomic/clinical study of 12 operated cases]. / Le somatostatinome duodénal. Etude anatomoclinique de 12 cas opérés.

STUDY AIM: Duodenal somatostatinomas (DS) are very rare neuro-endocrine tumours. The aim of this retrospective and multicentric study was to report the clinical and pathological characteristics of these neoplasms in a series of 12 patients and to compare them with the literature. PATIENTS AND METHODS: From 1987 to 1998, 12 patients were operated for a DS. There were seven women and five men ranging in age from 23 to 72 years (mean age: 56.6 years). Four patients had an associated von Recklinghausen's disease, one of them with multiple endocrine neoplasia (MEN type IIa) and medullary carcinoma of the thyroíd. The surgical procedures were pancreaticoduodenectomy (n = 8), small bowel resection (n = 2), inferior gastrectomy (n = 1) and gastrojejunostomy with hepatic metastases biopsies (n = 1). The tumour was mainly located on the 2nd duodenum (n = 10), with a mean size of 2.7 cm (ranging from 0.4 to 6 cm) and with a pancreatic invasion in three patients. A metastatic disease was present at the time of diagnosis in eight patients. There were, according to Capella's classification, two patients in the groups I and II, and ten patients in group III (83%), respectively. RESULTS: There was one postoperative death after a pancreaticoduodenectomy. Three patients secondarily died from tumoral progression. Eight patients were alive, with a mean follow-up of 84 months (ranging from 5 to 290 months), at the end-point of the study. CONCLUSION: Duodenal somatostatinomas are rare neuroendocrine, generally non-functioning, well-differentiated tumours with a low grade of malignancy. The association with the von Recklinghausen's disease is frequent. The clinical somatostatinoma syndrome with diabetes, diarrhea and biliary lithiasis is rare. The treatment is surgical even with a metastatic disease. The 5-year survival rate is better than those of the pancreatic somatostatinomas or the duodenal gastrinomas.

[Cutaneous metastases from follicular thyroid cancer]. / Métastase cutanée d'un carcinome vésiculaire de la thyroïde.

BACKGROUND: Cutaneous metastases from differentiated thyroid carcinoma are rare: only 41 cases have been reported in the literature. CASE REPORT: A 57-year-old woman underwent total thyroidectomy for a poor differentiated follicular thyroid carcinoma, with involvement of sternum and pulmonary metastases. Despite iodine-131 ablative therapy (> 1 Ci) she developed a skin metastasis of the scalp 9 years after the initial surgery. She died of widely metastatic thyroid carcinoma. DISCUSSION: Follicular carcinoma has a greater preponderance than papillary carcinoma for cutaneous metastases. The majority of skin metastases are localized to the head and neck. The development of a cutaneous metastasis is commonly associated with metastasis to other distant tissues and is followed by a deteriorating course and eventual death resulting from malignancy.

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.

Gene amplifications detected by fluorescence in situ hybridization in pure intraductal breast carcinomas: relation to morphology, cell proliferation and expression of breast cancer-related genes.

Investigation of early breast carcinogenesis is limited by the difficulty in obtaining cell cultures or adequate fresh frozen material and by the fact that available data from in situ techniques are interpreted in terms of various classification systems. Our studies in a series of pure ductal carcinomas in situ (DCIS) were conducted in accordance with the recommendations of the international Consensus Conference (Hum. Pathol., 28, 122-125, 1997) relative to processing, determination of lesion extent, and histological stratification primarily on nuclear grade (NG). A multifactorial study performed in 15 low- and 16 high-NG DCIS (68% detected by mammography) included the following: (1) morphological analysis of NG, necrosis, and architectural pattern; (2) detection of numerical genomic abnormalities at ERBB2, MYC, CCND1, Xq1.2 and 20q13 loci by fluorescence in situ hybridization on interphase nuclei; and (3) immunohistochemical determination of cell proliferation, p53 accumulation, hormonal receptors and bcl-2 expression on serial sections of formalin-fixed, paraffin-embedded specimens. High NG, comedo/solid pattern and necrosis were significantly associated with amplification at one or more loci, the number of amplified loci, amplification at the ERBB2 locus, absence of bcl-2 and hormonal receptor expression and high cell proliferation (p < 0.05). High NG and comedo/solid pattern were significantly associated with MYC amplification and p53 accumulation, and necrosis with CCND1 amplification (the only gene amplification detected in low NG DCIS). These data provide additional information on the early steps of breast carcinogenesis, in accordance with currently recognized criteria of histological classification.