Refractory Cardiogenic Shock from Right Ventricular Infarction Successfully Managed with Inhaled Epoprostenol.

BACKGROUND Recognition and appropriate management of right ventricular (RV) infarction is essential, as RV injury increases mortality and substantially alters management during acute coronary syndrome. We report a case of RV infarction presenting with new right bundle branch block (RBBB), and therapeutic use of inhaled epoprostenol to reduce RV afterload and augment cardiac output during refractory cardiogenic shock. CASE REPORT A 53-year-old male presented to our institution in ventricular fibrillation with subsequent development of RBBB in the setting of proximal right coronary artery occlusion. Following percutaneous coronary intervention, the patient developed severe RV dysfunction with refractory cardiogenic shock. This was successfully managed with inhaled epoprostenol with normalization of right ventricular systolic function. CONCLUSIONS Although typically associated with anterior myocardial infarction, new RBBB should be recognized as a potential presenting sign of acute RV infarction. The use of inhaled epoprostenol in the setting of RV infarction has not been previously described, but it may augment right ventricular cardiac output via pulmonary vasodilatation.

Epidermal growth factor receptor controls flat dysplastic aberrant crypt foci development and colon cancer progression in the rat azoxymethane model.

PURPOSE: Colonic carcinogenesis deranges growth-regulating epidermal growth factor receptors (EGFR). We previously showed that EGFR signals were up-regulated in human aberrant crypt foci (ACF), putative colon cancer precursors. The azoxymethane model of colon cancer recapitulates many aspects of human colonic tumors. Recent studies indicate that flat dysplastic ACF with increased beta-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for flat dysplastic ACF development and cancer progression. EXPERIMENTAL DESIGN: Rats received azoxymethane or saline, and standard chow or chow supplemented with gefitinib, an EGFR inhibitor, for 44 weeks. EGFR signals were quantified in normal colon, flat ACF, and tumors by computerized analysis of immunostains and Western blots. K-ras mutations were assessed by PCR and mRNA for egfr ligands by quantitative real-time PCR. RESULTS: EGFR inhibition with gefitinib decreased the incidence of flat dysplastic ACF from 66% to 36% and tumors from 71% to 22% (P < 0.05). This inhibitor also reduced the overexpressions of cyclin D1 and Cox-2 in flat ACF. Furthermore, in flat ACF, EGFR blockade decreased the up-regulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-beta, potential regulators of cyclin D1 and Cox-2. In colonic tumors, EGFR blockade significantly decreased angiogenesis, proliferation, and progression while also increasing apoptosis (P < 0.05). Gefitinib also inhibited the activations of extracellular signal-regulated kinase, Src, and AKT pathways in tumors. CONCLUSIONS: We have shown for the first time that EGFR promotes the development of flat dysplastic ACF and the progression of malignant colonic tumors. Furthermore, we have mechanistically identified several transcription factors and their targets as EGFR effectors in colonic carcinogenesis.

A vitamin D analogue inhibits colonic carcinogenesis in the AOM/DSS model.

BACKGROUND: The azoxymethane (AOM) model recapitulates many features of human colon cancer, lacking an inflammatory component. Dextran sulfate sodium (DSS) induces colitis and promotes AOM-induced colon cancer in mice. Vitamin D analogues are anti-inflammatory and chemopreventive in models of colon cancer. Our aim was to evaluate the anti-inflammatory and chemopreventive efficacy of the vitamin D analogue Ro26-2198 in the AOM/DSS model and in vitro in HCA-7 colon cancer cells. MATERIALS AND METHODS: A/J mice received Ro26-2198 (0.01 microg/kg body wt/day x 28 days) or vehicle by mini-osmotic pump. Animals were treated with a single dose of AOM (5 mg/kg body wt) or vehicle 1 week after pump insertion. Mice received 3% DSS or water x 7 days beginning week 3. Animals were sacrificed after 8 weeks and colon segments were fixed in formalin or flash-frozen. Hematoxylin and eosin colonic sections were examined for dysplasia and colonic lysates were assessed for c-Myc, cyclooxygenase 2, and phospho-(active) extracellular signal regulated kinase (ERK) by Western blotting. For in vitro studies, HCA-7 cells were treated with Ro26-2198 followed by interleukin-1beta (IL-1beta). Proliferation was measured by WST-1 assay. RESULTS: Ro26-2198 delayed the onset of clinical colitis. Several dysplastic foci were present in the AOM/DSS group; none were found in the Ro26-2198 group. Compared with control, AOM/DSS significantly increased c-Myc (15-fold), cyclooxygenase 2 (COX-2) (2.5-fold), and pERK (10-fold), and Ro26-2198 abolished these increases. In vitro, Ro26-2198 inhibited IL-1beta-induced ERK activation and COX-2 induction and decreased HCA-7 cell proliferation. CONCLUSIONS: Ro26-2198 inhibited proliferative (ERK, c-Myc) and pro-inflammatory (COX-2) signals and progression to dysplasia, suggesting chemopreventive efficacy in this model of colitis-associated carcinogenesis.

Epidermal growth factor receptor signaling is required for microadenoma formation in the mouse azoxymethane model of colonic carcinogenesis.

Colonic carcinogenesis involves the progressive dysregulation of homeostatic mechanisms that control growth. The epidermal growth factor (EGF) receptor (EGFR) regulates colonocyte growth and differentiation and is overexpressed in many human colon cancers. A requirement for EGFR in colonic premalignancy, however, has not been shown. In the current study, we used a specific EGFR antagonist, gefitinib, to investigate this role of the receptor in azoxymethane colonic premalignancy. The azoxymethane model shares many clinical, histologic, and molecular features of human colon cancer. Mice received azoxymethane i.p. (5 mg/kg/wk) or saline for 6 weeks. Animals were also gavaged with gefitinib (10 mg/kg body weight) or vehicle (DMSO) thrice weekly for 18 weeks, a dose schedule that inhibited normal receptor activation by exogenous EGF. Compared with control colonocytes [bromodeoxyuridine (BrdUrd), 2.2+/-1.2%], azoxymethane significantly increased proliferation (BrdUrd, 12.6+/-2.8%), whereas gefitinib inhibited this hyperproliferation (BrdUrd, 6.2+/-4.0%; <0.005). Azoxymethane significantly induced pro-transforming growth factor-alpha (6.4+/-1.3-fold) and increased phospho-(active) EGFR (5.9+/-1.1-fold), phospho-(active) ErbB2 (2.3+/-0.2-fold), and phospho-(active) extracellular signal-regulated kinase (3.3+/-0.4-fold) in premalignant colonocytes. Gefitinib inhibited activations of these kinases by >75% (P<0.05). Gefitinib also significantly reduced the number of large aberrant crypt foci and decreased the incidence of colonic microadenomas from 75% to 33% (P<0.05). Gefitinib concomitantly decreased cell cycle-regulating cyclin D1 and prostanoid biosynthetic enzyme cyclooxygenase-2 in microadenomas, suggesting that these regulators are key targets of EGFR in colonic carcinogenesis. These results show for the first time that EGFR signaling is required for early stages of colonic carcinogenesis. Our findings suggest, moreover, that inhibitors of EGFR might be useful in chemopreventive strategies in individuals at increased risk for colonic malignancies.

Epidermal growth factor receptor signaling is up-regulated in human colonic aberrant crypt foci.

Aberrant crypt foci (ACF) are collections of abnormal colonic crypts with heterogeneous molecular and pathologic characteristics. Large and dysplastic ACF are putative precursors of colon cancer with neoplastic risk related to increased proliferation. In this study, we examined the role of epidermal growth factor receptor (EGFR) signaling in regulating ACF proliferation. Using magnification chromoendoscopy, we collected large ACF with endoscopic features of dysplasia and separately biopsied adjacent mucosa. Transcript levels were measured by real-time PCR, proteins were assessed by Western blotting, and levels were expressed as fold changes of adjacent mucosa. K-ras and B-Raf mutations were assessed by PCR and Ras activation by the ratio Ras-GTP / (Ras-GTP + Ras-GDP). At the RNA level, 38% of ACF were hyperproliferative, with proliferating cell nuclear antigen (PCNA) mRNA >/=2-fold of adjacent mucosa. Hyperproliferative ACF had significantly increased mRNA levels of EGFR (6.0 +/- 1.7-fold), transforming growth factor-alpha (14.4 +/- 5.0-fold), heparin-binding EGF-like growth factor (4.5 +/- 1.4-fold), cyclin D1 (4.6 +/- 0.7-fold), and cyclooxygenase-2 (COX-2; 9.3 +/- 4.2-fold; P < 0.05). At the protein level, 46% of ACF were hyperproliferative (PCNA, 3.2 +/- 1.2-fold). In hyperproliferative ACF, 44% possessed significant increases in four EGFR signaling components: EGFR (9.5 +/- 1.3-fold), phosphoactive ErbB2 (2.6 +/- 0.4-fold), phosphoactive extracellular signal-regulated kinase (3.7 +/- 1.1-fold), and cyclin D1 (3.4 +/- 0.8-fold; P < 0.05). Ras was activated in 46% of ACF (3.2 +/- 0.4-fold; P < 0.05), but K-ras mutations were present in only 7% of ACF. In contrast to COX-2 mRNA, the protein was not increased in hyperproliferative ACF. In summary, we have shown that ACF with up-regulated PCNA possess increased EGFR signaling components that likely contribute to the enhanced proliferative state of dysplastic-appearing ACF.