Adjuvant early breast cancer systemic therapies according to daily used technologies.

Prognosis of early breast cancer patients is significantly improved with the use of adjuvant therapies. Various guidelines have been proposed to select patients who will derive the most benefit from such treatments. However, classifications have limited usefulness in subsets of patients such as those with node negative breast cancer. The 2007 St. Paul de Vence Clinical Practice Recommendations proposed to consider adjuvant therapy in accordance with the 10-year relapse-free survival reduction estimated by Adjuvant! Online. However, many limitations remain regarding the use of Adjuvant! Online. Among them, adverse prognostic and/or predictive factors such as vascular invasion, mitotic activity, progesterone receptor negativity, and HER-2 expression are not incorporated in the routine clinical decision process. Our group has therefore issued guidelines based on the consideration of both Adjuvant! Online calculations and the prognostic and/or predictive effects of these markers. In addition, web-accessible comprehensive tables summarizing these recommendations are provided.

Atteintes cardiaques dans les connectivites: l'exemple du lupus érythémateux systémique [Cardiac involvement in connective tissue disease: the example of systemic lupus erythematosus]

When we think of cardiac affection in the context of systemic lupus erythematosus (SLE), we usually refer to pericarditis first. As frequent as this affection is, it is actually not the only cardio-vascular problem that occurs with this systemic inflammatory disease. Are the cardiac events--ranging from multiple heart valve involvements to increased cardiovascular risks--clinically significant? And are they involving a specific follow-up, treatment or support? We are therefore trying to evaluate these questions in order to give some recommendations to any practitioners following up a lupus patient, or a patient suffering from any other inflammatory systemic disease.

Reversibility of cardiac fibrosis in mice chronically infected with Trypanosoma cruzi, under specific chemotherapy

This investigation was performed to verify the effect of specific chemotherapy (Benznidazole or MK-346) on the inflammatory and fibrotic cardiac alterations in mice chronically infected with the strains 21 SF (Type II) and Colombian (Type III) of Trypanosoma cruzi. To obtain chronically infected mice, two groups of 100 Swiss mice each, were infected with either the 21 SF or the Colombian strain (2x 10 [raised to the power of] 4 and 5x 10 [raised to the power of] 4 blood forms respectively). The rate of morality in the acute phase was of 80% for both groups. Twenty surviving mice chronically infected with the 21 SF strain and 20 with the Colombian strain were then divided in treated and untreated groups. Excluding those that died during the course of treatment, 14 mice chronically infected with the 21 SF strain and 15 with the Colombian strain were evaluated in the present study. Chemotherapy was performed with Benznidazole (N-benzil-2-nitro-1-imidazolacetamide) in the dose of 100mg/k.b.w/day, for 60 days, or with the MK-436(3(1-methyl-5 nitroimidazol-2-yl) in two daily doses of 250 mg/k.b.w, for 20 days. Parasitological cure tests were performed (xenodiagnosis, haemoculture, subinovulation of the blood into newborn mice), and serological indirect immunofluorescence test. The treated and untreated mice as well as intact controls were killed at different periods after treatment and the heart were submitted to histopathological study with hematoxilineosin and picrosirius staining; ultrastructural study; collagen immunotyping, fibronectin and laminin identification by immunofluorescence tests. Results: the untreated controls either infected with 21 SF or Colombian strain, showed inflammatory and fibrotic alterations that were mild to moderate with the 21 SF strain and intense with the Colombian strain. Redpicrosirius staining showed bundles of collagen in the interstitial space and around cardiac fibers. Increased deposits of mitritial components and collagen fibers, macrophages and fibroblasts appeared at the ultra structural examination. Deposits of fibronectin, laminin, pro-III and IV collagens were seen, most intense in those infected with the Colombian strain. Treated nice, parasitologically cured, presented clear-cut regression of the inflammatory lesions and of the interstitial matrix thickening. Mice infected with the Colombian strain and treated with MK-436, was parasitologically cured in 5/6 cases and showed mild inflammatory infiltration and fibrosis. The mice treated with Benznidazole (Colombian strain) did not cure and showed moderate fibrosis and inflammation. Treatment of the nice infected with the 21 SF with Benznidazole determined parasitological cure of all animals, that showed mild inflammation and fibrosis of the myocardium. The cured mice of all groups and treated but uncured showed collagen degradation at electronmicroscopy and decrease of immunofluorescence pattern of the matrix.

Hyperplasia of elastic tissue in hepatic schistosomal fibrosis

Elastic tissue hyperplasia, revealed by means of histological, immunocytochemical and ultrastructural methods, appeared as a prominent change in surgical liver biopsies taken from 61 patients with schistosomal periportal and septal fibrosis. Such hyperplasia was absent in ecperimental murine schistosomiasis, including mice with "pipe-stem" fibrosis. Displaced connective tissue cells in periportal areas, such as smooth muscle cells, more frequently observed in human material, could be the site of excessive elastin synthesis, and could explain the differences observed in human and experimental materials. Elastic tissue, sometimes represented by its microfibrillar components, also appeared to be more condensed in areas of matrix (collagen) degradation, suggesting a participation of this tissue in the remodelling of the extracellular matrix. By its rectratile properties elastic tissue hyperplasia in hepatic schistosomiasis can cause vascular narrowing and thus play a role in the pathogenesis of portal hypeertension.

Dynamics of fibrosis production and resorption in intestinal schistosomiasis of mice

A histological, morphometric and immunocytochemical study of schistosomal periovular granulomas in the liver and intestines of mice revealed that intestinal granulomas are smaller and contain less collagen than those in the liver. After curative treatment intestinal granulomas undergo a relatively more rapid resorption, although the general pattern of collagen degradation apparently does not differ from that observed in the liver. Tendency to form scattered, usually isolated granulomas that are only mildly fibrogenic, coupled with a well-balanced process of resorption appear as the explanation why intestinal fibrosis is not an outstanding feature of schistosomiasis as it is in the liver.

Connective tissue growth factor, steatosis and fibrosis in patients with chronic hepatitis C.

BACKGROUND/AIM: Both steatosis and insulin resistance have been linked to accelerated fibrosis in chronic hepatitis C. Connective tissue growth factor (CTGF) plays a major role in extracellular matrix production in fibrotic disorders including cirrhosis, and its expression is stimulated in vitro by insulin and glucose. We hypothesized that CTGF may link steatosis, insulin resistance and fibrosis. METHODS: We included 153 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study and for whom a liver biopsy and plasma samples were available. CTGF expression was assessed quantitatively by immunohistochemistry. In 94 patients (57 with genotypes non-3), plasma levels of glucose, insulin and leptin were also measured. CTGF synthesis was investigated by immunoblotting on LX-2 stellate cells. RESULTS: Connective tissue growth factor expression was higher in patients with steatosis (P=0.039) and in patients with fibrosis (P=0.008) than those without these features. CTGF levels were neither associated with insulinaemia or with glycaemia, nor with inflammation. By multiple regression analysis, CTGF levels were independently associated with steatosis, a past history of alcohol abuse, plasma leptin and HCV RNA levels; when only patients with genotypes non-3 were considered, CTGF levels were independently associated with a past history of alcohol abuse, plasma leptin levels and steatosis. Leptin stimulated CTGF synthesis in LX-2 cells. CONCLUSIONS: In patients with chronic hepatitis C and steatosis, CTGF may promote fibrosis independently of inflammation. CTGF may link steatosis and fibrosis via increased leptin levels.

Isolation of Pseudomonas cepacia in cystic fibrosis patient

Pulmonary infection on cystic fibrosis (CF) patients are associated with a limited qualitative number of microorganisms. During the colonization process, Staphylococcus aureus usually preceedes Pseudomonas aeruginosa. This latter is at first non-mucoid, being replaced or associated to a mucoid morphotype which is rare in other diseases. In 1980, Pseudomonas cepacia appeared as an important agent in CF pulmonary infections with a mean frequency of about 6.1% isolations in different parts of the world. The primus colonization mainly occurs in the presence of pre-existent tissue lesions and the clinical progress of the disease is variable. In some patients it can be fulminant; in others it can cause a gradual and slow decrease in their pulmonary functions. The concern with this germ isolation is justified by its antibiotic multiple resistence and the possibility of direct transmission from a colonized patient to a non-colonized one. We reported the first case of P. cepacia infection in a CF patient in our area. The microbiological attendance to this patient had been made from 1986 to 1991 and the first positive culture appeared in 1988. The sensitivity profile showed that the primus colonization strain was sensitive to 9 of 17 tested antibiotics, however in the last culture the strain was resistent to all antibiotics. These data corroborate the need for monitoring the bacterial flora on CF patients respiratory system.

Use of PCR for the determination of the frequency of the deltaF508 mutation in Brasilian cistic fibrosis patients

The [Delta]F508 mutation in the cystic fibrosis (CF) gene was studied in a population of 18 Brazilian CF patients and their 17 families by use of PCR and differential hybridization with oligonucleotides. In a total of 34 chromosomes considered, 12 (35%) carried the F508 deletion, a frequency much lower than that reported in most other populations. As a consequence, CF in Brazil would be predominantly caused by mutations different from the F508 deletion

Capillaria hepatica: a cause of septal fibrosis of the liver

Fine, long, fibrous septa were observed as a late change developing in the acinar zone III of the liver of rats experimentally infected with the helminth Capillaria hepatica. Hepatic septal fibrosis begun 30 days after inoculation of embryonated eggs into the stomach of rats and became clearly evident from the 40th day onwards. Experimental observation was undertaken for 170 days. Septal fibrosis increased progressively with time and was most marked when the parasitic nodules formed around larvae, disintegrating worms and eggs were involving. Septal fibrosis of the liver has not been previously recognized as a manifestation of hepatic capillariasis. The presence of sequestered parasite antigens, probably being slowly released within the liver, appears to be a major factor in the pathogenesis of hepatic septal fibrosis observed in rats with C. hepatica infection.

Morphological aspects of the myocarditis and myositis in Calomys callosus experimentally infected with Trypanosoma cruzi: fibrogenesis and spontaneous regression of fibrosis

Calomys callosus a wild rodent, is a natural host of Trypanosoma cruzi. Twelve C. callosus were infected with 10(5) trypomastigotes of the F strain (a myotropic strain) of T. cruzi. Parasitemia decreased on the 21 st day becoming negative around the 40th day of infection. All animals survived but had positive parasitological tests, until the end of the experiment. The infected animals developed severe inflammation in the myocardium and skeletal muscle. This process was pronounced from the 26 th to the 30th day and gradually subsided from the 50 th day becoming absent or residual on the 64 th day after infection. Collagen was identified by the picro Sirius red method. Fibrogenesis developed early, but regression of fibrosis occurred between the 50th and 64th day. Ultrastructural study disclosed a predominance of macrophages and fibroblasts in the inflammatory infiltrates, with small numbers of lymphocytes. Macrophages had active phagocytosis and showed points of contact with altered muscle cells. Different degrees of matrix expansion were present, with granular and fibrilar deposits and collagen bundles. These alterations subsided by the 64th days. Macrophages seem to be the main immune effector cell in the C. callosus model of infection with T. cruzi. The mechanisms involved in the rapid fibrogenesis and its regression deserve further investigation.

Esophagogastric cancer: integration of targeted therapies into systemic chemotherapy.

Although combination chemotherapy has been shown to be more effective than single agents in advanced esophagogastric cancer, the better response rates have not fulfilled their promise as overall survival times from best combination still range between 8 to 11 months. So far, the development of targeted therapies stays somewhat behind their integration into treatment concepts compared to other gastrointestinal diseases. Thus, the review summarizes the recent advances in the development of targeted therapies in advanced esophagogastric cancer. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors EGFR1 and HER2. For trastuzumab and bevacizumab, phase III trial results have been presented recently. While addition of trastuzumab to cisplatin/5-fluoropyrimidine-based chemotherapy results in a clinically relevant and statistically significant survival benefit in HER 2+ patients, the benefit of the addition of bevacizumab to chemotherapy was not significant. Thus, all patients with metastatic disease should be tested for HER-2 status in the tumor. Trastuzumab in combination with cisplatin/5-fluoropyrimidine-based chemotherapy is the new standard of care for patients with HER2-positive advanced gastric cancer.

Systemic effects of epidural Methylprednisolone injection on glucose tolerance in diabetic patients.

ABSTRACT: BACKGROUND: Several studies have shown that in diabetic patients, the glycemic profile was disturbed after intra-articular injection of corticosteroids. Little is known about the impact of epidural injection in such patients. The goal of this study was double, at first comparing the glycaemic profile in diabetic patients after a unique injection of 80 mg of acetate methylprednisolone either intra-articular or epidural and secondly to compare the amount of systemic diffusion of the drug after both procedures. METHODS: Seventeen patients were included. Glycemic changes were compared in 9 diabetic patients following intra-articular (4 patients) and epidural injections (5 patients). Epidural injections were performed using the sacral route under fluoroscopic control in patients with lumbar spinal stenosis. Diabetes control had to stable for more than 10 days and the renal function to be preserved. Blood glucose was monitored using a validated continuous measuring device (GMS, Medtronic) the day before and for two days following the injection. Results were expressed in the form of daily glycemic profiles and as by mean, peak and minimal values +/ SD. The urinary excretion of methylprednisolone after the 2 routes of injection was analyzed in 8 patients (4 in each group). Urine samples were cropped one hour before the injections, then 4 times during the first day and 3 times a week for 2 weeks. The measurements included the free and conjugated fraction RESULTS: The glycaemic profile remains unchanged with no significant changes in the group of the 5 diabetic patients receiving epidural injections. On the other end, the average peak and mean values were enhanced up to 3 mmol/l above baseline two days after the infiltration in the groups of the 4 diabetic patients infiltrated intra-articular. The mean urinary excretion of the steroid was about ten times higher in the intra-articular versus epidural group: 7000 ng/ml versus 700 ng/ml. Looking at each individual there were marked differences especially after intra-articular injections. CONCLUSION: This is the first study to show that a single epidural steroid injection of 80 mg depot methylprednisolone had no effect on the glycemic control in diabetic patients. The absence of glycemic control changes correlated well with the very low urinary excretion of the drug after epidural injection. Trial registration NCT01420497.

Calomys callosus: an alternative model to study fibrosis in Schistosomiasis mansoni: the pathology of the acute phase

Twenty Calomys callosus, Rengger, 1830 (Rodentia-Cricetidae) were studied in the early stage of the acute schistosomal mansoni infection (42nd day). The same number of Swiss Webster mice were used as a comparative standard. Liver and intestinal sections, fixed in formalin-Millonig and embedded in paraffin, were stained with hematoxilin and eosin, PAS-Alcian Blue, pH = 1.0 and 2.5, Lennert's Giemsa, Picrosirius plus polarization microscopy, Periodic acid methanamine silver, Gomori's silver reticulin and resorcin-fuchsin. Immunohistological study (indirect immunofluorescence and peroxidase labeled extravidin-biotin methods) was done with antibodies specific to pro-collagen III, fibronectin, elastin, condroitin-sulfate, tenascin, alpha smooth muscle actin, vimentin and desmin. The hepatic granulomas were small, reaching only 27 of the volume of the hepatic Swiss Webster granuloma. They were composed mainly by large immature macrophages, often filled by schistosomal pigment, characterizing an exsudative-macrophage granuloma type. The granulomas were situated in the parenchyma and in the portal space. They were often intravascular, poor of extracellular matrix components, except fibronectin and presented, sometimes alpha smooth muscle actin and vimentin positive cells. The C. callosus intestinal granulomas were similar to Swiss Webster, showing predominance of macrophages. Therefore, the C. callosus acquire very well the Schistosoma mansoni infection, without developing strong hepatic acute granulomatous reaction, suggesting lack of histopathological signs of hypersensitivity.