Platelet glycoprotein VI promotes metastasis through interaction with cancer cell-derived galectin-3.

Increasing evidence suggests that platelets play a predominant role in colon and breast cancer metastasis, but the underlying molecular mechanisms remain elusive. Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin that triggers platelet activation through immunoreceptor tyrosine-based activation motif (ITAM) signaling and thereby regulates diverse functions, including platelet adhesion, aggregation, and procoagulant activity. GPVI has been proposed as a safe antithrombotic target, because its inhibition is protective in models of arterial thrombosis, with only minor effects on hemostasis. In this study, the genetic deficiency of platelet GPVI in mice decreased experimental and spontaneous metastasis of colon and breast cancer cells. Similar results were obtained with mice lacking the spleen-tyrosine kinase Syk in platelets, an essential component of the ITAM-signaling cascade. In vitro and in vivo analyses supported that mouse, as well as human GPVI, had platelet adhesion to colon and breast cancer cells. Using a CRISPR/Cas9-based gene knockout approach, we identified galectin-3 as the major counterreceptor of GPVI on tumor cells. In vivo studies demonstrated that the interplay between platelet GPVI and tumor cell-expressed galectin-3 uses ITAM-signaling components in platelets and favors the extravasation of tumor cells. Finally, we showed that JAQ1 F(ab')2-mediated inhibition of GPVI efficiently impairs platelet-tumor cell interaction and tumor metastasis. Our study revealed a new mechanism by which platelets promote the metastasis of colon and breast cancer cells and suggests that GPVI represents a promising target for antimetastatic therapies.

[Single port transumbilical cholecystectomy [SILS] -- 30 non-selected cases]. / Single port transumbilicalis cholecystectomia (SILS) -- Nem szelektált 30 eset összehasonlító elemzése.

Single port laparoscopic surgery became popular all over the world, and cholecystectomy represents the most frequent intervention with this technique. We compared transumbilical single port laparoscopic cholecystectomies (SILS) to conventional three-port laparoscopic cholecystectomies (LC), which were performed by the same surgeon between 2008-2010. As regards SILS cases, they represent a non-selected series. Transabdominal sutures were not applied in any of those, but one additional 5 mm port was inserted in two SILS cases. Only straight instruments were used in all but two SILS cholecystectomies. Mean age of patients was lower in the SILS group, however male:female ratio and BMI were similar. While none of the procedures were converted in the SILS group, one needed to be done so in the LC patients. One of the SILS patients underwent a transumbilical laparoscopic wash-out for an intrabdominal haematoma, which developed due to non-surgical reasons. Mean operative time and postoperative hospitalisation was 75.9 ± 25 minutes and two days in the SILS group, while 55.7 ± 17 minutes and 2.8 days in the LC group, respectively. We concluded that transumbilical single port cholecystectomy can be performed safely by using conventional straight instruments. We could not identify any publication about non-selected SILS cholecystectomy series in the English language literature.

[Laparoscopic transhiatal resection of esophageal cancer]. / Nyelôcsôtumor miatt végzett laparoscopos transhiatalis nyelôcsô-exstirpatio.

INTRODUCTION: Minimally invasive oesophageal resection is a real alternative to the conventional open operative techniques in the surgical treatment of oesophageal tumours. PATIENT AND METHOD: The authors present a case of a 51 year-old female patient who initially underwent an upper GI endoscopy for vague stomach symptoms. The examination revealed an oesophageal tumour of approximately 2 cm in length, located at 32 cm from the incisors. Abdominal ultrasound and CT scans were carried out, which showed that the tumour had breached the submucosa, but regional lymph node metastasis was not detected. Since an intraluminal flexible endoscopic ablation of the tumour could not have been carried out, a laparoscopic transhiatal oesophagus excision was done. The oesophagus was replaced by an intracorporal tubulated stomach in the posterior mediastinum. RESULT: In the postoperative period a gastro-pleural fistula developed in the middle third of the stomach, which was treated conservatively (thoracic drainage, Salem probe). A phlegmone developed next to the feeding jejunostomy - at the site of one of the trocars - required exploration, the re-suturing of the jejunostomy due to persisting leakage of the small intestine. 3 months after the operation the patient was asymptomatic and gained 2 kg weight. CONCLUSION: Laparoscopic transhiatal oesophagus resection has all the benefits of the minimally invasive techniques; in addition, it makes possible to do a more radical surgery than with the traditional transhiatal operation. The authors review the relevant literature and present other minimal invasive techniques, discussing the results on lymph node dissection, pyloroplasty, as well as replacement.

Effect of bioactive polypeptides on leaking large bowel anastomosis and intestines in the rat.

Anastomotic leakage and postoperative adhesions represent major complications after colorectal surgery. We have previously shown a positive effect on both anastomotic strength and abdominal adhesions by the use of differently charged bioactive polypeptides. The present study aimed to investigate the effect of the same polypeptides on the healing of an insufficient intestinal anastomosis, as well as on accidental intestinal injury, in addition to measuring the preventive effect against the development of abdominal adhesions. An insufficient, and thereby potentially leaking, intestinal anastomosis and punctures of the intestine ("accidental intestinal injury model") were performed in rats. The treatment groups received intraperitoneal administration of poly-L-lysine and poly-L-glutamate, while controls received sodium chloride. Burst pressure, extent of abdominal adhesions, and postoperative complications were analyzed in both experimental models. A significant decrease of adhesions was seen in all animals treated with polypeptides (p < .05). Burst pressure was significantly higher (p < .001) in animals with intestinal perforation as seen on day 1 and then decreasing. A significant decrease in the incidence of peritonitis was also noted early (day 1) in this model (p = .002). The mortality and complications were high in the intestinal anastomosis model, though not affected by treatment with polypeptides. Intraabdominal adhesions were significantly reduced using polypeptides in this study, with no observed effect on other postsurgical complications. There were signs of less infectious complications in polypeptide treated animals. In animals with accidental intestinal injury, a higher burst pressure was noted in treated animals.

Differently charged polypeptides in the prevention of post-surgical peritoneal adhesions.

OBJECTIVE: Peritoneal adhesions develop after almost all surgical interventions in the abdomen. We have developed an efficient treatment against post-surgical adhesions consisting of a combination of positively charged poly-L-lysine and negatively charged poly-L-glutamate. The aim of the present study was to further develop the concept of applying oppositely charged polypeptides in the prevention of adhesion formation, by evaluating different doses of the peptides, alterations in the way of administration, and also testing alternative components. MATERIAL AND METHODS: Eighty-five NMRI mice were divided into six groups. A standardized peritoneal injury model was used. The groups received physiologic sodium chlorine, poly-L-lysine+poly-L-glutamate, low molecular weight poly-L-lysine+poly-L-glutamate, locally administered poly-L-lysine+poly-L-glutamate, in vitro mixed poly-L-lysine+poly-L-glutamate and poly-L-arginine+poly-L-glutamate, respectively. After 7 days, the extent of adhesion formation was determined during relaparotomy and was expressed as the mean percentage of the total wound length. RESULTS: A significant decrease (p <0.001) in the peritoneal adhesion rate was detected in all groups, with the exception of the group administered poly-L-arginine. Among those animals that received poly-L-lysine and poly-L-glutamate, the low dose of poly-L-lysine administration resulted in the most pronounced anti-adhesive effect. CONCLUSIONS: The most effective polypeptide combination was poly-L-lysine and poly-L-glutamate, also showing effectiveness when used at low doses and by local application. The differences in adhesion prevention and the possible underlying mechanisms are discussed and the key role of poly-L-lysine is elucidated.

Efficacy of bioactive polypeptides on bleeding and intra-abdominal adhesions.

BACKGROUND: Perioperative bleeding and postoperative adhesions are two problems encountered in abdominal surgery. Commercial products are available that decrease both bleeding and development of abdominal adhesions, but no products are effective in both situations. The combination of differently charged bioactive polypeptides, administered intraperitoneally, has previously been shown effective in decreasing postoperative adhesions. The present study is a pilot examination of the effects on perioperative bleeding and postoperative adhesions, applying the polypeptide concept. METHODS: Standardized wounds in the liver and spleen were induced in 52 NMRI mice. The amounts of bleeding and postoperative adhesions were measured after 1 and 7 days, respectively. Separate animals were examined after 8 weeks for long-term healing of the parenchymal wounds. RESULTS: Both parenchymal bleeding and the extent of adhesions significantly decreased (p = 0.001 and p = 0.029, respectively) as compared to controls. Histology after 8 weeks showed no clear signs of impaired or altered healing. CONCLUSION: Intraperitoneal administration of differently charged polypeptides significantly decreased postoperative bleeding and postoperative adhesions. Bioactive polypeptides appear promising in the promotion of peritoneal healing and merits further studies.

Novel treatment in peritoneal adhesion prevention: protection by polypeptides.

OBJECTIVE: To evaluate a novel antiadhesive polypeptide complex containing a combination of poly-L-glutamate and poly-L-lysine in order to study its effectiveness and mechanisms in the prevention of postoperative abdominal adhesions in mice. MATERIAL AND METHODS: The length of peritoneal adhesions was measured and expressed in percentage of the wound length in a standardized peritoneal injury model and evaluated 7 days and 4 weeks after adhesion induction. The test compound was administered intraperitoneally following surgery. Peritoneal swabs, including the wound area, were stained in order to determine the peritoneal location and clearance of the polypeptides. Electron microscopy was performed to analyze the wound surface and the ultra-structural changes of the phagocytes in cell culture. Moreover, flow cytometry was used to evaluate the effect on macrophage phagocytic function. RESULTS: The poly-L-lysine and poly-L-glutamate combination significantly decreased peritoneal adhesions both at 7 days' (p < 0.001) and 4 weeks' (p < or = 0.001) follow-up. From the first day, the compound was found in the wound, after which this was gradually rebuilt, and covered with mesothelial cells. The macrophages phagocytosed the test compound particles, resulting in significant cell growth, and large phagocytic vacuoles. CONCLUSIONS: The intraperitoneal administration of poly-L-lysine and poly-L-glutamate resulted in a significant decrease in experimental postoperative peritoneal adhesions.

Increasing anastomosis safety and preventing abdominal adhesion formation by the use of polypeptides in the rat.

BACKGROUND AND AIMS: Postoperative adhesions can potentially be reduced using different anti-adhesive agents, though these drugs tend to compromise healing of an intestinal anastomosis. No method that significantly increases anastomosis safety is known at present. The aim of the study was to develop a concept of preventing postoperative adhesions using differently charged bioactive polypeptides, also considering healing and safety of an intestinal anastomosis. METHODS: An ileocolic anastomosis was performed under both "clean" and "septic" conditions in the rat. The treatment group received intraperitoneal poly-L-lysine and poly-L-glutamate, while controls received sodium chloride. Abdominal adhesions, anastomosis leakage and burst pressure were analysed after 1, 3, 5 and 7 days in the clean anastomosis model and after 7 days in the septic model. RESULTS: A significant decrease (p<0.01) in the amount of adhesions was seen in animals treated with polypeptides after 1, 3 and 5 days, while no difference was seen after 7 days. The anastomosis demonstrated a significantly higher burst pressure as evaluated at days 1 and 3 (p<0.05 and p<0.01, respectively) in the polypeptide-treated animals, while no difference was seen between the groups at day 5 or 7. CONCLUSION: The use of differently charged polypeptides administered intraperitoneally after surgery resulted in a significant decrease in the extent of postoperative adhesions. Furthermore, an increase in intestinal anastomosis safety, based on improved burst pressure during the first 3 days, i.e. the critical period during the healing process, was noted. No adverse effects were seen in surgery during septic conditions.

[Laparoscopic transhiatal resection of epiphrenic diverticulum of the esophagus]. / Epiphrenalis nyelocsogurdély transhiatalis laparoszkópos resectiója.

The operation of the epiphrenic diverticulum of the esophagus--due to its anatomical position--is feasible either with thoracotomy or with laparotomy. The advantages of the first method are the possibility of better exploration and a technically easier operation. At the same time, the disadvantage of the surgical procedure imposed on the patient by opening his/her thoracic cavity is not to be underestimated, either. In case of an abdominal approach, the diverticulum in the mediastinum causes difficulties. The laparoscopic method combines the advantages of both solutions. The authors report the case of a 62 years old woman with a history of regurgitation and swallowing problems accompanied by a 20-kilogram weight loss. Barium esophagography and esophagogastroduodenoscopy showed a typically positioned 11-cm large epiphrenic diverticulum. As an operative solution transhiatal laparoscopic resection of the diverticulum with Heller cardiomyotomy and Dor fundoplication using an endoscopic stapler was performed. The postoperative period was uneventful; the patient was discharged on the 8th post-operative day with unhindered swallow. In the international literature 79 cases treated with minimally invasive therapy have been published so far. Based on own experience, the authors state that the laparoscopic transhiatal resection of the epiphrenic diverticulum of the esophagus is successful and might be the method of choice.

Prevention of postoperative peritoneal adhesions: effects of lysozyme, polylysine and polyglutamate versus hyaluronic acid.

OBJECTIVE: Intraperitoneal adhesions are an important cause of postoperative intestinal obstruction, abdominal discomfort and infertility. In the present study we hypothesized that a combination of polypeptides with different surface properties, resulting in fine disperse low-soluble complexes, could be of benefit in the prevention of abdominal adhesions. MATERIAL AND METHODS: Various polypeptides including lysozyme, polyglutamate, polylysine and combinations of all three were evaluated as compared to hyaluronic acid. A standard wound on the parietal peritoneum in mice was used and the evaluated agents were administered immediately postoperatively. The extent of peritoneal adhesions to the injured area was measured and expressed as a percentage of the wound length as evaluated after 7 days. Flow cytometry was performed to evaluate the effect on peritoneal macrophage survival and phagocytic function and the Pick test was used to determine peroxide production in order to estimate toxicity and potential impairment of macrophage function caused by the chemicals. RESULTS: Significant differences were seen among the treatment groups (p<0.001). Both polyglutamate and lysozyme, and polyglutamate together with polylysine significantly decreased adhesion formation as compared to hyaluronic acid. The polylysine-polyglutamate combination was still visible macroscopically on the peritoneal surface after 1 week, though not after 1 month. The polyglutamate-lysozyme mixture was less effective than these individual components alone. The chemicals did not show any toxic effects or altered function in macrophage cell culture. CONCLUSIONS: Lysozyme, polyglutamate and, most effectively, a polyglutamate-polylysine combination significantly decreased experimental abdominal adhesion formation. A strong mechanical connection to the wound and prolonged attendance in the surface were noted. Peritoneal phagocyte function did not seem to be influenced by the chemicals.

Late abdominal complaints after appendectomy--readmissions during long-term follow-up.

BACKGROUND/AIMS: The postoperative risk of small bowel obstruction is a recognized complication following appendectomy. Few studies have reconsidered the whole extent of abdominal complaints and problems following appendectomy. This study tries to evaluate the long-term outcome describing abdominal complaints requiring readmission following appendectomy. METHODS: A retrospective study of 3,230 patients undergoing open appendectomy at a single center university hospital in Sweden between 1981 and 1996. Late (>30 days) readmissions were noted and the cause for readmission and need for surgical intervention were analyzed. RESULTS: Overall, late readmissions occurred in 2.94% during a median follow-up of 10 years after appendectomy. Females predominated among those readmitted, as did patients with complicated appendicitis or a 'normal' appendix. Nonspecific abdominal pain with no sign of small bowel obstruction caused almost half of the readmissions (45%). To a large extent this group consisted of females (76%). Small bowel obstruction was seen in 1.24% and was surgically treated in 0.68% of all appendectomies. Incisional hernias were also seen (0.4% of all appendectomies). CONCLUSION: The magnitude of readmissions due to abdominal complaints is more pronounced than previously reported with as many patients with signs of small bowel obstruction managed nonoperatively as surgically, and frequent readmissions due to nonspecific abdominal pain.

[Reoperations for early recurrent occlusions following femoropopliteal and femorocrural bypasses]. / Femoropoplitealis és femorocruralis bypass mútéteket követóen korai elzáródás miatt végzett reoperációink.

We analyse the early results of 333 patients who had been operated on because of femoropopliteal occlusions between 1996 and 2000. Most interventions (90.4%) were below knee reconstructions. The rate of crural bypasses was high (40.5%). We examined whether the length and type of the graft influenced the outcome of the primary operation. If below knee bypass was necessary in every operation autologous grafts were preferred either partially or entirely (saphenous vein or arm vein). The number of reocclusions and amputations was significantly higher if the distal anastomosis involved the crural arteries (p < 0.02), or the graft was not autologous (p < 0.01). There was no statistical difference between early results of saphena and arm vein bypasses (p = 0.2). Thirty-six reoperations were performed for early graft failures. Either the patient's general condition or local findings did not allow reoperations in 17 patients with occluded graft, they were treated conservatively. Nine patients died after surgery (2.7%). In the postoperative period 21 major amputations were necessary (6.3%), in six cases the graft was patient. After reoperations 7 patients needed amputations (19.4%), in the 17 patients not reoperated on the second time, 8 amputations were necessary (47%), the difference is significant (p < 0.05). We are convinced about the importance of urgent reoperation in case of early graft occlusion. If the run-off to the distal arteries was doubtful intraoperative angiography was performed. When distal extension of the operation was necessary we tried to use autologous grafts. The amputation rate was significantly lower after reoperations if the cause of graft occlusion was found and corrected compared to simple thrombectomies (p < 0.05).