Alexandros Polychronidis

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.

Circulating VEGF levels in the serum of gastric cancer patients: Correlation with pathological variables, patient survival, and tumor surgery

ObjectiveTo evaluate the clinical usefulness of serum vascular endothelial growth factor (VEGF) levels in gastric cancer patients. Summary Background DataVascular endothelial growth factor plays an important role in the formation of new blood vessels involved in the growth and metastatic spread of solid tumors, but there is limited information regarding the clinical significance of serum VEGF levels in cancer patients. MethodsSerum VEGF concentrations were measured by an enzyme linked immunosorbent assay in 61 healthy controls and in 58 gastric cancer patients before surgery, and then again at 7 and 30 days after surgery. The association between preoperative serum VEGF levels, clinicopathological features and patient survival, and their changes following surgery were evaluated. ResultsSerum VEGF levels in gastric cancer patients were significantly higher than those in controls. There was a significant association between serum VEGF levels and disease stage, as well as invasion depth of the tumor and the presence of distant metastases. Serum VEGF levels decreased significantly after radical resection of the primary tumor and increased in patients with unresectable tumors. Multivariate regression analysis showed that serum VEGF level is an independent prognostic factor for survival. ConclusionsSerum VEGF levels in gastric patients are significantly higher compared with normal controls and correlate with local tumor extent, disease stage, and the presence of distant metastases. Preoperative serum VEGF concentration decreases significantly after radical resection of the primary tumor and is an independent prognostic factor for patient survival suggesting that determination of serum VEGF levels may be clinically useful.

Risk factors for conversion of laparoscopic cholecystectomy to open cholecystectomy

BackgroundConversion to open cholecystectomy is still required in some patients. The aim of this study was to evaluate preoperative factors associated with conversion to open cholecystectomy in elective cholecystectomy and acute cholecystitis.MethodsThe records of 1,804 patients who underwent cholecystectomy from May 1992 to January 2004 were reviewed retrospectively. The demographics and preoperative data of patients who required conversion to laparotomy were compared to those with successful laparoscopic cholecystectomy.ResultsConversion to open cholecystectomy was needed in 94 patients (5.2%),of which 44 (2.8%) had no inflammation and 50 (18.4%) had acute inflammation of the gallbladder. Male gender, age older than 60 years, previous upper abdominal surgery, diabetes, and severity of inflammation were all significantly correlated with an increased conversion rate to laparotomy. Also, the conversion from laparoscopic to open cholecystectomy in acute cholecystitis patients was associated with greater white blood cell count, fever, elevated total bilirubin, aspartate transaminase, and alanine transaminase levels, and the various types of inflammation.ConclusionsNone of these risk factors were contraindications to laparoscopic cholecystectomy. This may help predict the difficulty of the procedure and permit the surgeon to better inform patients about the risk of conversion from laparoscopic to open cholecystectomy.

Serum vascular endothelial growth factor levels in pancreatic cancer patients correlate with advanced and metastatic disease and poor prognosis

The serum concentrations of vascular endothelial growth factor (VEGF) were measured by an enzyme linked immunosorbent assay in 51 healthy controls and in 58 patients with pancreatic cancer before and 30 days after surgery. Pancreatic cancer patients had significantly higher serum VEGF levels compared with healthy controls with a significant association between serum VEGF levels, disease stage and the presence of both lymph node and distant metastases. Serum levels of VEGF decreased significantly after radical resection of the tumor. Elevated preoperative serum VEGF level was a significant prognostic factor, although not independent of stage, for patient survival. These findings suggest that serum VEGF concentrations may reflect pancreatic cancer progression and that their determination may be clinically useful.

Laparoscopic cholecystectomy in patients with previous upper or lower abdominal surgery

Background: Previous abdominal surgery has been reported as a relative contraindication to laparoscopic cholecystectomy. This study specifically examined the effect of previous intraabdominal surgery on the feasibility and safety of laparoscopic cholecystectomy. Methods: Data from 1,638 consecutive patients who underwent laparoscopic cholecystectomy were reviewed and analyzed for open conversion rates, operative times, intra- and postoperative complications, and hospital stay. Results: Of the 1,638 study patients 473 (28.9%) had undergone previous abdominal surgery: 58 upper and 415 lower abdominal operations. The 262 patients who had undergone only a previous appendectomy were excluded from further analysis. Adhesions were found in 70.7%, 58.8% and 2.1% of patients respectively, who had previous upper, lower or no previous abdominal surgery with adhesiolysis required, respectively, in 78%, 30% and 0% of these cases. There were no complications directly attributable to adhesiolysis. Patients with previous upper abdominal surgery had a longer operating time (66.4 ± 34.2 min), a higher open conversion rate (19%), a higher incidence of postoperative wound infection (5.2%), and a longer postoperative stay (3.4 ± 2.1 days) than those who had undergone previous lower abdominal surgery (50.8 ± 24 min, 3.3%, 0.7%, and 2.6 ± 1.4 days, respectively) and those without prior abdominal surgery (47.4 ± 25.6 min, 5.4%, 1.2%, and 2.8 ± 1.9 days, respectively). Conclusions: Previous abdominal operations, even in the upper abdomen, are not a contraindication to safe laparoscopic cholecystectomy. However, previous upper abdominal surgery is associated with an increased need for adhesiolysis, a higher open conversion rate, a prolonged operating time, an increased incidence of postoperative wound infection, and a longer postoperative stay.

Human leptin induces angiogenesis in vivo

Leptin is an adipocyte-produced peptide, which plays a crucial role in the regulation of body weight. There is also evidence that leptin stimulates endothelial cell proliferation and the formation of capillary-like tubes in vitro. The disc angiogenesis system was used to measure the angiogenic effect of leptin in vivo. Discs containing 25, 50, 100 and 250ng/ml of leptin were implanted subcutaneously in Wistar rats, removed after a growth period of 7 and 14 days, and compared with spontaneous growth controls and with positive controls containing equivalent doses of vascular endothelial growth factor (VEGF). Discs were examined morphologically for stroma and vessel development and by immunohistochemistry for quantitative evaluation of angiogenesis. The specificity of the angiogenic effect of leptin was tested by blocking leptin with a polyclonal anti-leptin antibody. Leptin induced a significant level of angiogenesis in a dose-dependent manner both at 7 and 14 days, with a peak at the dose of 100ng/ml. The angiogenic activity of leptin was completely abolished by the anti-leptin neutralizing antibody. VEGF also induced significant dose-dependent angiogenesis at the same time points with a peak observed at a concentration of 100ng/ml. The angiogenic response to leptin was significantly higher at 7 days compared with VEGF but not at the 14-day time point. In conclusion, leptin has a specific angiogenic effect in vivo, which is dose- and time-dependent in a concentration range of 25-250ng/ml. This effect is equivalent to the angiogenic effect of VEGF but is evident earlier compared with VEGF.

Prognostic relevance of light chain 3 (LC3A) autophagy patterns in colorectal adenocarcinomas

Aims The microtubule-associated protein 1 light chain 3 (LC3A) is an essential component of the autophagic vacuoles, forming a reliable marker of autophagic activity. In a previous study, the authors showed that LC3A immunohistochemistry renders three patterns of autophagic expression in breast carcinomas: diffuse cytoplasmic, perinuclear and ‘stone-like’ intracellular structures (SLS), each with a distinct prognostic relevance. Methods Tumour tissues from 155 patients with stage IIA–III colorectal adenocarcinomas, treated with surgery alone, were assessed immunohistochemically for LC3A. Median values were used as cut-off points to separate groups into low and high autophagic activity. Associations with prognosis and with lactate dehydrogenase-5 (LDH5) were sought. Results High SLS counts were associated with metastases and poor prognosis, while the prominence of the perinuclear pattern was linked to localised disease and good prognosis. The cytoplasmic pattern was irrelevant. Furthermore, patients with increased SLS numbers, but suppressed perinuclear expression, were associated with LDH5 overexpression and had an extremely poor prognosis (3-year survival 16.5%). The prognosis improved considerably when high SLS counts were accompanied by intense perinuclear expression (3-year survival 67%) and were optimal when SLS numbers dropped below median values, irrespective of perinuclear status (3-year survival 94–100%). Multivariate analysis showed that SLS and perinuclear patterns were independent predictors of death events. Conclusions Perinuclear LC3A accumulation in colorectal tumour cells is a marker of good prognosis, presumably reflecting a basal autophagic activity. An abnormal or excessive autophagic response, as indicated by increased numbers of SLS, is linked to metastasis and poor prognosis.

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)

Hydatid Disease of the Abdomen and Other Locations

We present patients treated for hydatid disease in our hospital (in northeastern Greece) over the last 20 years. In the period from 1984 to 2003, a total of 135 patients (54 male, 81 female) were treated for echinococcal disease (age 15–85 years). In 111 (82.2%) patients only the liver was affected; 9 (6.7%) patients had concomitant hepatic and extrahepatic hydatid disease; and 15 (11.1%) patients had only extrahepatic disease. Clinical symptoms in patients with hepatic locations of the disease included abdominal pain localized in the epigastrium or right upper quadrant of the abdomen, tenderness, hepatomegaly with palpable abdominal mass, jaundice, fever, and anaphylactic reaction. All the patients were treated surgically. Surgical techniques included partial cystectomy and drainage, cystectomy and capitonage, cystectomy and omentoplasty, only drainage, left lateral hepatectomy, total pericystectomy, and laparoscopic pericystectomy. Rupture into the bile duct was managed by T-tube drainage or biliodigestive anastomosis. Symptoms and surgical treatment for extrahepatic cysts varied according to the location of the cyst. The median cyst diameter of all patients was 11 cm. The postoperative complication rate was 17.0%. Two patients died (1.5%). The median hospital stay was 18 days. The recurrence rate was 6.7%. The study suggests that treatment of this benign disease should be the less radical surgical technique combined with pre- and postoperative anthelmintic administration. The surgical treatment should be combined with careful use of scolicidal fluids and aspiration of the cyst to avoid contamination and minimize the risk of recurrence.