Constantinos Simopoulos

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.

Hypoxia inducible factor 1α and 2α overexpression in inflammatory bowel disease

Aims: Hypoxia inducible factors 1α and 2α (HIF1α and HIF2α) are hypoxia regulated transcriptional factors, which control the expression of a variety of genes responsible for angiogenesis, glycolysis, and the inhibition of apoptosis. Because angiogenesis and tissue regeneration are integral components of the inflammatory process, this study was designed to investigate the role of HIFα molecules in inflammatory bowel disease. Methods: Surgical specimens from patients with active ulcerative colitis (UC) and Crohn’s disease (CD) were assessed immunohistochemically for HIF1α and HIF2α reactivity, and the expression of these molecules was compared with the expression of the angiogenic factors thymidine phosphorylase (TP), vascular endothelial growth factor (VEGF), and VEGF–KDR activated vasculature. The vascular density of the lesions was also assessed using anti-CD31 immunostaining. Results: HIF1α was expressed focally (epithelial cells, stromal fibroblasts, and myocytes) in both UC and CD, whereas HIF2α was expressed focally in UC and diffusely in CD. TP expression was uniformly positive in both diseases. VEGF expression was absent in CD, and weakly positive in UC. The VEGF–KDR reactivity of the submucosal vasculature was only slightly increased in UC and CD compared with normal tissue. The inflammatory cells stained with HIF2α and TP in all cases, but the reactivity was generalised in CD and focal in UC. In both diseases, vascular density was significantly higher than that seen in normal tissue. Conclusions: The discordant expression of HIF2α and VEGF in CD suggests an inherent deficiency of the intestine to respond to various stresses by the induction of VEGF. This finding should be investigated further.

The Influence of Platelet-Rich Plasma on Angiogenesis During the Early Phase of Tendon Healing

Background: The poor vascularity of tendons is a major factor in their limited healing capacity. The aim of this study was to assess the effect of Platelet Rich Plasma (PRP) on angiogenesis during tendon healing. Materials and Methods: Forty-eight skeletally mature New Zealand White rabbits were used. The Achilles tendon was transected transversely and 0.5 ml of PRP was injected into the tendon mass on each side of the incision on both limbs. The injection in the control group consisted of saline. Six animals from each group (12 tendons each) were sacrificed after 1, 2, 3, and 4 weeks following treatment. Three sections from each Achilles were stained with hematoxylinosin for microscopic examination. Further three sections were immunostained with a monoclonal antibody against CD31 (Daco Co), followed by image analysis to count new vessel numbers and statistical analysis was performed. Results: There was significantly more angiogenesis in the PRP group compared to the control group during the first two weeks of the healing process, i.e., inflammatory and proliferative phase (p < 0.0001). The orientation of collagen fibers in the PRP group was better organized. The number of the newly formed vessels in the PRP group were significantly reduced at 4 weeks compared to the controls (p < 0.0001) suggesting the healing process was shortened. Conclusion: PRP seems to enhance neovascularization which may accelerate the healing process and promote scar tissue of better histological quality. Clinical Relevance: Although these results need replication and further biomechanical research, PRP may promote tendon healing acceleration.

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.

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.

Laparoscopic Cholecystectomy in Obese Patients

Background: Laparoscopic cholecystectomy (LC) is the treatment of choice for gallstones. Obesity was initially considered a contraindication to this approach. The aim of this report is to review our experience with LC, to evaluate the role of BMI in the outcome. Methods: The records of 1,804 patients who underwent LC for symptomatic cholelithiasis from May 1992 to January 2004 were analyzed retrospectively. Patients were divided into 5 groups according to their BMI: ≤24.9, 25.0-29.9, 30.0-34.9, 35.0-39.9 and ≥40 kg/m2. Results: Of the 1,804 patients [1,379 females (76.4%) and 425 males (23.6%)] who underwent LC, 431(23.9%), 924 (51.2%), 355 (19.7%), 68 (3.8%) and 26 (1.4%) had BMI values of ≤24.9, 25.0-29.9, 30.0-34.9, 35.0-39.9 and ≥40 kg/m2, respectively. Conversion to open cholecystectomy was required in 94 patients (5.2%), and complications occurred in 39 patients (2.2%). There was no correlation between BMI and the conversion rate (P=0.593) and complication rate (P=0.944), while the hospital stay was similar between the groups with successful LC. The only significant difference was the longer operating time in the two obesity groups (P<0.001). Conclusions: LC is effective and safe in patients with morbid obesity. As it carried low risks of conversion and perioperative complications, we suggest that LC is the select approach for these patients. Moreover, the rapid mobilization and hospital discharge following LC may provide extra benefit to these patients.

Prophylactic intravenous ondansetron and dolasetron in intrathecal morphine-induced pruritus: a randomized, double-blinded, placebo-controlled study.

Pruritus is the most common side effect of intrathecal morphine for postoperative pain relief. Activation of central 5-hydroxytryptamine subtype 3 (5-HT3) receptors is one of its possible mechanisms. The role of 5-HT3 antagonists in the prevention of pruritus has not been clearly established. In a prospective, randomized, double-blind, placebo-controlled study, we evaluated the efficacy of prophylactic administration of ondansetron and dolasetron for the prevention of intrathecal morphine-induced pruritus. The patients were randomized into 3 groups to receive either 4 mg ondansetron IV (group O, n = 35), 12.5 mg dolasetron IV (group D, n = 35) or 5 mL placebo (group P, n = 35) 30 min before administration of spinal anesthesia with 10 to 17.5 mg of 0.5% hyperbaric bupivacaine and 0.25 mg of morphine for urologic, orthopedic, or vascular surgery. Patients were evaluated for incidence and severity of pruritus at arrival to the postanesthesia care unit and at 2, 4, 8, and 24 h postoperatively. The incidence and severity of pruritus was significantly less frequent in the ondansetron and dolasetron groups compared with placebo (34%, 20%, and 66% respectively, P < 0.01). Patients who received 5-HT3 antagonist reported significantly less total severity of pruritus compared with placebo during the first 8 h and the severe pruritus was observed only in patients within P group (P group: 4 of 35; 11%, O or D group: 0 of 35; 0%, P < 0.05). We conclude that the prophylactic use of ondansetron and dolasetron helps to reduce the incidence and severity of intrathecal morphine-induced pruritus.