Lapo Bencini

herg1 Gene and HERG1 Protein Are Overexpressed in Colorectal Cancers and Regulate Cell Invasion of Tumor Cells

The acquisition of the capacity to invade surrounding tissues confers a more malignant phenotype to tumor cells and is necessary for the establishment of metastases. The understanding of the molecular mechanisms underlying cell invasion in human solid tumors such as colorectal cancers could provide not only more sensitive prognostic analyses but also novel molecular targets for cancer therapy. We report in this article that K+ ion channels belonging to the HERG family are important determinants for the acquisition of an invasive phenotype in colorectal cancers. The herg1 gene and HERG1 protein are expressed in many colon cancer cell lines, and the activity of HERG channels modulates colon cancer cell invasiveness. Moreover, the amount of HERG1 protein expressed on the plasma membrane is directly related to the invasive phenotype of colon cancer cells. Finally, both the herg1 gene and HERG1 protein were expressed in a high percentage of primary human colorectal cancers, with the highest incidence occurring in metastatic cancers, whereas no expression could be detected either in normal colonic mucosa or in adenomas.

Helicobacter pylori secreted peptidyl prolyl cis, trans-isomerase drives Th17 inflammation in gastric adenocarcinoma.

Helicobacter pylori infection is characterized by an inflammatory infiltrate, consisting mainly of neutrophils and T cells. This study was undertaken to evaluate the type of gastric T cell response elicited by the secreted peptidyl prolyl cis, trans-isomerase of H. pylori (HP0175) in patients with distal gastric adenocarcinoma. The cytokine profile and the effector functions of gastric tumor-infiltrating lymphocytes (TILs) specific for HP0175 was investigated in 20 patients with distal gastric adenocarcinoma and H. pylori infection. The helper function of HP0175-specific TILs for monocyte MMP-2, MMP-9, and VEGF production was also investigated. TILs cells from H. pylori infected patients with distal gastric adenocarcinoma produced Interleukin (IL)-17 and IL-21 in response to HP0175. HP0175-specific TILs showed poor cytolytic activity while expressing helper activity for monocyte MMP-2, MMP-9 and VEGF production. These findings indicate that HP0175 is able to drive gastric Th17 response. Thus, HP0175, by promoting pro-inflammatory low cytotoxic TIL response, matrix degradation and pro-angiogenic pathways, may provide a link between H. pylori and gastric cancer.

Predictors of recurrence after laparoscopic ventral hernia repair.

Laparoscopic ventral hernia repair (LVHR) is widely used to manage ventral hernias, but predictors of hernia recurrence have been poorly investigated. This retrospective study investigated the influence of common risk factors on hernia recurrence. Data from 146 consecutive, unselected patients who underwent LVHR between 2000 and 2006 were collected. Demographic, clinical, and perioperative parameters were analyzed to identify predictable risk factors for hernia recurrence. Both univariate and multivariate Coxs regression analysis were employed. The overall recurrence rate was 8% (12 patients) after an average follow-up of 45 months. On univariate analysis, smoking (P=0.01) and earlier repair (P<0.00) were significantly different in recurred patients. However, only earlier repair was an independent predictor of multivariate Coxs regression analysis (hazard ratio 0.085, 95% confidence interval: 0.020-0.355; P=0.001). LVHR is a safe technique to repair ventral hernias. However, smokers with earlier failed repair attempts have a higher risk of recurrence.

Modular branched neurotensin peptides for tumor target tracing and receptor-mediated therapy: a proof-of-concept.

The aim of this study was to demonstrate that oligo-branched peptides can be effective either for spotlighting tumor cells that overexpress peptide receptors, or for killing them, simply by exchanging the functional moiety coupled to the conserved receptor-targeting core. Tetra-branched peptides containing neurotensin (NT) sequence are described here as selective targeting agents for human colon, pancreas and prostate cancer. Fluorophore-conjugated peptides were used to measure tumor versus healthy tissue binding in human surgical samples, resulting in validation of neurotensin receptors as highly promising tumor-biomarkers. Drug-armed branched peptides were synthesized with different conjugation methods, resulting in uncleavable adducts or drug-releasing molecules. Cytotoxicity on human cell lines from colon (HT-29), pancreas (PANC-1) or prostate (PC-3) carcinoma indicated branched NT conjugated with MTX and 5-FdU as the most active agents on PANC-1 (EC(50) 4.4e-007 M) and HT-29 (1.1e-007 M), respectively. Tetra-branched NT armed with 5-FdU was used for in vivo experiments in HT-29-xenografted mice and produced a 50% reduction in tumor growth with respect to animals treated with the free drug. An unrelated branched peptide carrying the same drug was completely ineffective. In vitro and in vivo results indicated that branched peptides are valuable tools for tumor selective targeting.

Laparoscopic treatment of ventral hernias: prospective evaluation.

We describe 50 patients who recently underwent laparoscopic surgery. Early results, complications, and follow-up data were collected prospectively. Of 50 patients, 34 had an incisional hernia, whereas 16 had a primary defect. Three trocars were inserted. EndoShears or Ultracision was used for tissue manipulation. The prosthetic mesh used was an expanded polytetrafluoroethylene (ePTFE) mesh, inserted through the first trocar and fixed with a helicoidal stapler. Patients were followed-up in the outpatient clinic (mean, 14 months). Every operation was successfully completed, and mean operative time was 103 minutes. There were two small bowel injuries (4%) repaired by minilaparotomy. Postoperative pain was limited. Bowel movements, ambulation, and discharge were prompt. We noted 4 cases of urinary retention (8%), 8 seromas (16%), and 1 prolonged ileus, which resolved on day 5 spontaneously. Mean postoperative stay was 4 days. One patient was readmitted after 4 weeks because of incomplete obstruction, resolved conservatively. There has been only 1 recurrence (2%), 8 months after the operation. The technique appears safe and efficacious.

Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.

Modern approach to cholecysto-choledocholithiasis

Gallstones and common bile duct calculi are found to be associated in 8%-20% of patients, leading to possible life-threatening complications, such as acute biliary pancreatitis, jaundice and cholangitis. The gold standard of care for gallbladder calculi and isolated common bile duct stones is represented by laparoscopic cholecystectomy and endoscopic retrograde cholangiopancreatography, respectively, while a debate still exists regarding how to treat the two diseases at the same time. Many therapeutic options are also available when the two conditions are associated, including many different types of treatment, which local professionals often administer. The need to limit maximum discomfort and risks for the patients, combined with the economic pressure of reducing costs and utilizing resources, favors single-step procedures. However, a multitude of data fail to strongly demonstrate the superiority of any technique (including a two or multi-step approach), while rigorous clinical trials that include so many different types of treatment are still lacking, and it is most likely unrealistic to conduct them in the future. Therefore, the choice of the best management is often led by the local presence of professional expertise and resources, rather than by a real superiority of one strategy over another.

Comparison of laparoscopic and open repair for primary ventral hernias.

We designed a retrospective clinical trial comparing laparoscopic primary ventral hernia repair (LPVHR) and open traditional repair (OPVHR). Demographics, perioperative data, results, and follow-up were examined to determine if there was any difference in the main outcomes. From January 2000 to December 2006, 28 consecutive, unselected patients, who successfully underwent LPVHR, were matched with 36 patients, who received OPVHR (with mesh) during the same period. The operating room records, clinical files, and outpatient sheets were examined. Patient demographics, results, and follow-up were compared in the 2 groups. Demographic characteristics, site of hernia, concomitant surgery, and defect size were comparable between the 2 groups, but the proportion of urgent procedures was higher in OPVHR patients (25% vs. 4%; P=0.03). The overall complication rates were similar, with some specific differences, whereas analgesic requirement and hospital stay were also comparable. The operative times were significantly longer for the LPVHR group (70 min vs. 35 min; P<0.000). Four recurrences were noted in both OPVHR and LPVHR patients, 11% versus 14%, respectively, with no significant difference (P=0.67). LPVHR seemed to be as safe as the OVHR in this study, although LPVHR increased operative time. The complications of each method should be taken into consideration before making the choice of the surgical approach.

Laparoscopic cholecystectomy: retrospective comparative evaluation of titanium versus absorbable clips.

We present a retrospective study of the use of titanium and absorbable clips during laparoscopic cholecystectomy. The aim was to determine any differences in outcome and costs. From January 1999 to February 2002, 690 patients who had successfully undergone a laparoscopic cholecystectomy were reviewed. According to the type of clip, we retrospectively identified two groups of patients: 199 in whom the surgeons had used absorbable clips (absorbable clip group, ACG) and 491 in whom the surgeons had used titanium nonabsorbable clips (titanium clip group, TCG). Data about demographics, operation, results, complications, and follow-up were collected and matched in the two groups. Demographics, concomitant surgery, and the American Society of Anesthesiologists (ASA) status were comparable between the two groups. Although the proportions of cases requiring urgent operation, intraoperative cholangiography, use of a fourth trocar, and use of drainage suction were similar, the difficulty score of the operation was lower (6.3 vs. 7.0, P =.03) and the operative time was shorter (44 vs. 61 minutes, P <.0001) in the ACG than in the TCG. Complications, hospital stay, and long-term results were satisfactory and comparable between the two groups. No correlation was found between clip type and the incidence of biliary tree injuries, bleeding, wound infection, or readmission. The cost of the two types of clips varied slightly (90 euros for each procedure). Despite the fact that absorbable clips are theoretically less likely to cause complications than metallic ones, we were not able to demonstrate any clinical advantage during laparoscopic cholecystectomy in this retrospective study. Furthermore, the results suggest that absorbable clips are preferred when the cholecystectomy presents fewer difficulties.

Minimally invasive surgical approach to pancreatic malignancies

Pancreatic surgery for malignancy is recognized as challenging for the surgeons and risky for the patients due to consistent perioperative morbidity and mortality. Furthermore, the oncological long-term results are largely disappointing, even for those patients who experience an uneventfully hospital stay. Nevertheless, surgery still remains the cornerstone of a multidisciplinary treatment for pancreatic cancer. In order to maximize the benefits of surgery, the advent of both laparoscopy and robotics has led many surgeons to treat pancreatic cancers with these new methodologies. The reduction of postoperative complications, length of hospital stay and pain, together with a shorter interval between surgery and the beginning of adjuvant chemotherapy, represent the potential advantages over conventional surgery. Lastly, a better cosmetic result, although not crucial in any cancerous patient, could also play a role by improving overall well-being and patient self-perception. The laparoscopic approach to pancreatic surgery is, however, difficult in inexperienced hands and requires a dedicated training in both advanced laparoscopy and pancreatic surgery. The recent large diffusion of the da Vinci(®) robotic platform seems to facilitate many of the technical maneuvers, such as anastomotic biliary and pancreatic reconstructions, accurate lymphadenectomy, and vascular sutures. The two main pancreatic operations, distal pancreatectomy and pancreaticoduodenectomy, are approachable by a minimally invasive path, but more limited interventions such as enucleation are also feasible. Nevertheless, a word of caution should be taken into account when considering the increasing costs of these newest technologies because the main concerns regarding these are the maintenance of all oncological standards and the lack of long-term follow-up. The purpose of this review is to examine the evidence for the use of minimally invasive surgery in pancreatic cancer (and less aggressive tumors), with particular attention to the oncological results and widespread reproducibility of each technique.