Costantinos Simopoulos

Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer.

Lactate dehydrogenase 5 (LDH5) is one of the five LDH isoenzymes and, apparently, the most important for promoting anaerobic glycolysis. LDH5 is transcriptionally regulated by the hypoxia inducible factors (HIF) 1α and 2α. In this study, the possible aggressive advantages that colorectal tumours may gain from a high LDH5 content was investigated. To this end, 75 colorectal adenocarcinomas were studied immunohistochemically for the expression of LDH5, and the results were related to tumor differentiation, lymph node and distant metastases, the expression of HIF1α and HIF2α, vascular density (VD) and vascular endothelial growth factor (VEGF). A high LDH5 content was noted in 51 of 75 (68%) colorectal adenocarcinomas. The reactivity was nuclear and/or cytoplasmic. Nuclear LDH5 reactivity was correlated with lymph node involvement and distant metastases. There was a direct association between LDH5 up-regulation and HIF1α and HIF2α accumulation. HIF1α was linked with VEGF, VD and also with extramural invasion, nodal and distant metastases. It is concluded that a high LDH5 content in tumor cells is directly related to an up-regulated HIF pathway and is lnked with an aggressive phenotype in colorectal adenocarcinomas.

LYVE-1 immunohistochemical assessment of lymphangiogenesis in endometrial and lung cancer

Aims/Methods: Normal and malignant pulmonary and endometrial tissues were analysed for lymphatic vessels to assess the process of lymphangiogenesis and its role at these sites, using specific immunostaining for LYVE-1 and the panendothelial marker CD31. Results: Lymphatics were clearly demonstrated in some normal tissues (myometrium, bronchial submucosa, and intestinal submucosa), but not in others (endometrium and alveolar tissue). LYVE-1 positive lymphatic vessels were detected at the tumour periphery of endometrial and lung carcinomas, but not within the main tumour mass. Double staining for LYVE-1 and the MIB1 proliferation marker revealed a higher proliferation index in lymphatic endothelial cells at the invading front of endometrial carcinomas, compared with myometrial areas distal to the tumour. Lung and endometrial carcinomas did not have an intratumorous lymphatic network. Conclusions: Although lymphangiogenesis may occur at the invading tumour front, incorporated lymphatics do not survive. Therefore, the dissemination of cancer cells through the lymphatics may occur by invasion of peripheral cancer cells into the adjacent normal lymphatics, or through shunts eventually produced at the invading tumour front as a consequence of active angiogenesis and lymphangiogenesis.

c-erbB-2 Related Aggressiveness in Breast Cancer Is Hypoxia Inducible Factor-1α Dependent

c-erbB-2–positive breast carcinomas are highly aggressive tumors. In vitro data on breast cell lines showed that c-erbB-2 enhanced translational efficiency of hypoxia inducible factor-1α (HIF1α) production (Laughner et al., Mol Cell Biol 2001;21:3995–4005). We investigated the clinical correlate of this observation to assess whether c-erbB-2 expression was related to HIF1α expression, angiogenesis, and prognosis. A series of 180 breast carcinomas of known c-erbB-2 status (90 c-erbB-2–positive and 90 c-erbB-2–negative carcinomas) were stained immunohistochemically for HIF1α and CD31 endothelial cell antigen. c-erbB-2 positivity was clearly related to HIF1α protein expression and high angiogenesis. However, prognosis was decreased only in cases with simultaneous c-erbB-2 and HIF1α expression. If activation of c-erbB-2 in humans results in overexpression of HIF1α independently of conditions of hypoxia, as occur in experimental studies, this interaction may represent a main pathway conferring clinical aggressiveness to c-erbB-2–positive breast tumors.

Endogenous markers of hypoxia/anaerobic metabolism and anemia in primary colorectal cancer

Anemia has been implicated in the decreased oxygen tension noted within the tumor environment. In a series of 79 colorectal adenocarcinomas we investigated the role of anemia in activating molecular pathways regulated by hypoxia. Preoperative Hb levels were correlated with the immunohistochemical expression of HIF1α and HIF2α, LDH5, GLUT1, VEGF, DEC1 and BNIP3, and with angiogenesis and the cancer cell proliferation index. Upregulation of HIF1α and HIF2α proteins, found in 43% and 44.3% of cases, respectively, was not related to anemia (Hb < 10 g%). This is in agreement with other studies suggesting that HIF activation occurs for various reasons, such as poor or irregular vascularity, or oncogene activation. Nevertheless, low Hb levels (<10 g%) were linked to activated anaerobic metabolism (LDH5 overexpression) in a subset of tumors not expressing HIF1α (P < 0.01). Overexpression of HIFs, whether linked to anemia or not, was associated with a number of factors related to tumor aggressiveness (assessed as local invasion and nodal metastasis), anaerobic metabolism and intratumoral acidosis (LDH5, GLUT1; increased glucose metabolism to lactate), activation of genes related to necrosis (BNIP3) and angiogenesis (VEGF). Expression of BNIP3 emerged as the strongest independent factor related to transmural invasion and metastasis to lymph nodes. Identification of specific patterns of the hypoxia molecular cascade activated in cancer cells might help in developing specific therapeutic policies. (Cancer Sci 2006; 97: 582–588)

Early antivascular effects of bevacizumab anti-VEGF monoclonal antibody on colorectal carcinomas assessed with functional CT imaging.

Background:The complex effect on anti-VEGF (vascular endothelial growth factor) monoclonal antibodies on the tumor vasculature urges studies to identify the optimal time frames for the administration of such agents with chemotherapy and radiotherapy. Patients and Methods:Using CT scan functional imaging, we examined the perfusion changes of contrast medium induced 7 days following administration of bevacizumab (5 mg/kg iv) in 12 patients with colorectal cancer. Results:CT imaging 7 days after the administration of bevacizumab confirmed tumor shrinkage in 3 of 12 cases. The mean Haunsfield units after the injection of contrast medium were significantly lower 7 days following the administration of bevacizumab (P = 0.002). The “perfusion score” significantly decreased after the administration of bevacizumab (P = 0.01). In 5 of 12 cases the perfusion score was by 45% to 75% decreased, in 3 of 12 minor drop of the perfusion score was noted, in 1 of 12 a slight increase was noted, and in 3 of 12 remained unchanged. Conclusion:It is concluded that the antivascular effects of bevacizumab are evident within 7 days from administration in 40% of colorectal carcinomas. The mechanisms by which this early antivascular effect may favor the antitumor efficacy of radiotherapy and chemotherapy require further investigation.

Oxygen and glucose consumption in gastrointestinal adenocarcinomas: Correlation with markers of hypoxia, acidity and anaerobic glycolysis

This study gives an insight into tumor metabolic activity by investigating oxygen and glucose content, together with their metabolic products carbon dioxide and acids‐pH, in the arterial and venous blood of a tumor. Nineteen patients with gastrointestinal adenocarcinomas undergoing surgery were studied. Biochemical analysis showed that in a large subgroup of tumors, oxygen consumption was reduced while that of glucose was increased in malignant, as compared to normal tissues; these features were more evident in tumors overexpressing lactate dehydrogenase (LDH‐5) and hypoxia inducible factors (HIF1α/2α). An increase in carbon dioxide production in the tumor environment was linked with overexpression of carbonic anhydrase 9 (CA9). The simultaneous overexpression of CA9 and LDH‐5 was related to very low pH levels in the veins draining the tumor, suggesting an intense acidification of the tumor microenvironment in such cases. These in vivo data confirm the importance of HIFs and their downstream regulated genes in tumor metabolism, particularly in glycolysis and carbon dioxide buffering. (Cancer Sci 2006; 97: 1056 –1060)

Laparoscopic cholecystectomy in a patient with situs inversus totalis and previous abdominal surgery

Sims inversus totalis is a rare congenital defect that can present difficulties during laparoscopic surgery due to the mirror-image anatomy. We report a patient with symptomatic cholelithiasis and previous abdominal surgery in whom a chest X-ray revealed a right-sided heart, whereas abdominal ultrasound revealed that his gallbladder was located in the left hypochondrium. At surgery, the surgeon and the camera assistant were standing on the right-hand side of the patient, and the first assistant was standing on the left. The camera was introduced through an umbilical incision, and laparos-copy confirmed the sims inversus. The other 10-mm trocar was placed in the midline left of the falciform ligament and two 5-mm trocars were placed in the left subcostal midclavicular line and anterior axillary line, respectively. After dissection of multiple adhesions caused by previous abdominal surgery, a standard laparoscopic cholecystectomy was performed successfully. This report suggests that sims inversus is not a contraindication for laparoscopic surgery. However, the procedure is more difficult and potentially hazardous due to the mirror-image anatomy (particularly the transposition of biliary ducts) causing difficulties in orientation, so that extreme care is required to avoid iatrogenic injuries. Despite these factors, laparoscopic cholecystectomy can be performed safely in patients with sims inversus totalis.

Laparoscopic Cholecystectomy in a Patient with Situs Inversus Using Ultrasonically Activated Coagulating Scissors. Report of a Case and Review of the Literature

Abstract Situs inversus totalis is a rare defect with a genetic predisposition, which can present difficulties in the management of abdominal pathology, especially in laparoscopic surgery, due to the mirror-image anatomy. Herein, we report on a patient with situs inversus totalis and symptomatic cholelithiasis. The patient had a successful laparoscopic cholecystectomy, using ultrasonically activated coagulating scissors. Diagnostic pitfalls and technical details of the laparoscopic cholecystectomy are discussed and a review of the relevant literature is presented.

Serum E-cadherin concentrations and their response during laparoscopic and open cholecystectomy

AbstractsBackground: Elevated serum levels of the cell adhesion molecule E-cadherin have been associated with the presence of tissue injury and inflammation. We compared soluble E-cadherin response during laparoscopic and open cholecystectomy. Methods: The E-cadherin response to surgery was studied in 16 patients undergoing laparoscopic cholecystectomy and 12 patients undergoing open cholecystectomy. Serum E-cadherin levels were measured by an enzyme immunoassay (ELISA) preoperatively, 10 and 30 min after the commencement of surgery, and at 6 and 24 h following the operation. Results: Serum E-cadherin levels decreased progressively during laparoscopic cholecystectomy; their concentrations at 24 h after surgery were significantly lower when compared with preoperative values. In the open cholecystectomy group, serum E-cadherin levels did not differ from preoperative values at any time point. Serum E-cadherin concentrations at 24 h after surgery and the cumulative E-cadherin response were significantly higher in the open cholecystectomy group than in the laparoscopic group. Conclusion: Compared with open cholecystectomy, the cumulative E-cadherin response is significantly reduced following laparoscopic cholecystectomy.

Rectal endometriosis causing colonic obstruction and concurrent endometriosis of the appendix: a case report

IntroductionEndometriosis is a clinical entity which presents with functioning endometrial tissue at sites outside the uterus. Bowel endometriosis is usually asymptomatic, but it may show non-specific symptoms. The presence and/or association of appendiceal endometriosis, concomitant with rectal endometriosis, is possible.Case presentationA 36-year-old Greek woman was admitted to the emergency room of our hospital with signs of acute abdomen. On physical examination, our patient had a painful distended abdomen. Digital examination revealed an empty rectum and bowel obstruction was diagnosed. Our patient underwent exploratory laparotomy and rectum stenosis (almost complete obstruction) was observed. The bowel stenosis was resected, and temporary colostomy and appendectomy were performed. The pathology report showed endometriosis of the colon and the appendix, and our patient received medical treatment for endometriosis. Six months after this operation our patient had another surgery for restoration of large bowel continuity. No endometriosis was found. Our patient was doing well at the one-year follow up.ConclusionEndometriosis of the bowel is a disease that may cause large bowel obstruction. In women of reproductive age, the surgeon should consider endometriosis as a differential diagnosis in case of various gastrointestinal symptoms.