Repeat liver resection after a hepatic or extended hepatic trisectionectomy for colorectal liver metastasis

Objective: A right and left hepatic trisectionectomy and an extended trisectionectomy are the largest liver resections performed for malignancy. This report analyses a series of 23 patients who had at least one repeat resection after a hepatic trisectionectomy for colorectal liver metastasis (CRLM).Methods: A retrospective analysis of a single-centre prospective liver resection database from May 1996 to April 2009 was used for patient identification. Full notes, radiology and patient reviews were analysed for a variety of factors with respect to survival.Results: Twenty-three patients underwent up to 3 repeat hepatic resections after 20 right and 3 left hepatic trisectionectomies. In 18 patients the initial surgery was an extended trisectionectomy. Overall 1-, 3- and 5-year survival rates after a repeat resection were 100%, 46% and 32%, respectively. No factors predictive for survival were identified.Conclusion: A repeat resection after a hepatic trisectionectomy for CRLM can offer extended survival and should be considered where appropriate.     

The changing profile of esophageal cancer presentation and its implication for diagnosis

CONTEXT: The incidence of esophageal adenocarcinoma is rising and has surpassed squamous cell carcinoma. OBJECTIVE: To determine how the increasing incidence of esophageal adenocarcinoma alters the classic clinical presentation and the implications of these changes for diagnosis. DESIGN AND SETTING: A five-year retrospective review (1991-1996) was made. PARTICIPANTS: All patients were identified by a computerized registry search with a diagnosis of esophageal carcinoma. MAIN OUTCOME MEASURES: Clinical presentation; duration of symptoms; and correlation with diagnosis, pathology, treatment and outcome. RESULTS: One-hundred-eight (35%) patients had squamous cell carcinoma and 199 (65%) had adenocarcinoma. Dysphagia and weight loss were more common among patients with squamous cell carcinoma (93% and 68%), when compared to adenocarcinoma (79% and 53%). Twenty-one percent of adenocarcinoma patients had other symptoms presentation, including gastroesophageal reflux disease. Once dysphagia was present, there was no correlation between the duration.of symptoms and survival. However, cancers detected in patients who presented with reflux symptoms without dysphagia showed an improved prognosis over patients who presented with both. CONCLUSIONS: Esophageal adenocarcinoma has surpassed squamous cell carcinoma. Gastroesophageal reflux was associated with an earlier stage of presentation compared to the "classic" presentation of esophageal cancer.     

Analysis of genetic events that modulate the oncogenic and growth suppressive activities of the PAX3-FKHR fusion oncoprotein

Alveolar rhabdomyosarcoma (ARMS) is associated with chromosomal translocations that generate PAX3-FKHR and PAX7-FKHR fusion oncoproteins. Based on studies demonstrating that high PAX3-FKHR expression causes growth suppression, the hypothesis is proposed that, during ARMS tumorigenesis, the translocations cause low oncoprotein expression and are followed by collaborating events that block growth suppression pathways and permit upregulation of oncoprotein expression. To investigate oncogenic function at low expression levels, PAX3-FKHR was introduced into NIH3T3 cells in the pBabe retroviral vector. Compared to high expression systems, PAX3-FKHR expression from pBabe was lower and did not suppress growth, but showed transforming activity in the soft agar assay. As a possible collaborating event, PAX3-FKHR paired box mutations were previously shown in high expression systems to reverse growth suppressive effects. In the low expression system, the paired box mutation enhanced transformation in soft agar and focus formation assays. Although these mutations are candidate collaborating events, sequencing of paired box regions in ARMS tumors did not identify mutations. Finally, genes from known genetic alterations in ARMS were introduced, alone or combined, into NIH3T3 cells with high PAX3-FKHR expression and did not rescue growth suppression. In summary, these studies provide a model for an event in ARMS tumorigenesis that enhances PAX3-FKHR oncogenicity and abrogates growth suppression, but do not demonstrate a known event occurring in ARMS tumors that fulfills these criteria.     

Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability

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Inhibition of matrix metalloproteinase-2 improves endothelial function and prevents hypertension in insulin-resistant rats

BACKGROUND AND PURPOSE

Insulin resistance is often found to be associated with high blood pressure. We propose that in insulin-resistant hypertension, endothelial dysfunction is the consequence of increased activity of vascular MMP-2. As MMP-2 proteolytically cleaves a number of extracellular matrix proteins, we hypothesized that MMP-2 impairs endothelial function by proteolytic degradation of endothelial NOS (eNOS) or its cofactor, heat shock protein 90 (HSP90).

EXPERIMENTAL APPROACH

We tested our hypothesis in bovine coronary artery endothelial cells and fructose-fed hypertensive rats (FHR), a model of acquired systolic hypertension and insulin resistance.

KEY RESULTS

Treatment of FHRs with the MMP inhibitor doxycycline, preserved endothelial function as well as prevented the development of hypertension, suggesting that MMPs impair endothelial function. Furthermore, incubating endothelial cells in vitro with a recombinant MMP-2 decreased NO production in a dose-dependent manner. Using substrate cleavage assays and immunofluorescence microscopy studies, we found that MMP-2 not only cleaves and degrades HSP90, an eNOS cofactor but also co-localizes with both eNOS and HSP90 in endothelial cells, suggesting that MMPs functionally interact with the eNOS system. Treatment of FHRs with doxycycline attenuated the decrease in eNOS and HSP90 expression but did not improve insulin sensitivity.

CONCLUSIONS AND IMPLICATIONS

Our data suggest that increased activity of MMP-2 in FHRs impairs endothelial function and promotes hypertension. Inhibition of MMP-2 could be a potential therapeutic strategy for the management of hypertension.