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Cell migration is an essential part of the complex and multistep process that is the development of cancer, a disease that is the second most common cause of death in humans. An important factor promoting the migration of cancer cells is TNF-α, a pro-inflammatory cytokine that, among its many biological functions, also plays a major role in mediating the expression of MMP9, one of the key regulators of cancer cell migration. It is also known that TNF-α is able to induce the Warburg effect in some cells by increasing glucose uptake and enhancing the expression and activity of lactate dehydrogenase subunit A (LDHA). Therefore, the aim of the present study was to investigate the interrelationship between the TNF-α-induced promigratory activity of cancer cells and their glucose metabolism status, using esophageal cancer cells as an example. By inhibiting LDHA activity with sodium oxamate (SO, also known as aminooxoacetic acid sodium salt or oxamic acid sodium salt) or siRNA-mediated gene silencing, we found using wound healing assay and gelatin zymography that LDHA downregulation impairs TNF-α-dependent tumor cell migration and significantly reduces TNF-α-induced MMP9 expression. These effects were associated with disturbances in the activation of the ERK1/2 signaling pathway, as we observed by Western blotting. We also reveal that in esophageal cancer cells, SO effectively reduces the production of lactic acid, which, as we have shown, synergizes the stimulating effect of TNF-α on MMP9 expression. In conclusion, our findings identified LDHA as a regulator of TNF-α-induced cell migration in esophageal cancer cells by the ERK1/2 signaling pathway, suggesting that LDHA inhibitors that limit the migration of cancer cells caused by the inflammatory process may be considered as an adjunct to standard therapy in esophageal cancer patients.

A 63-year-old man with a history of recurrent idiopathic acute pancreatitis (AP) was admitted to our surgical ward due to severe abdominal pain. He denied chronic excessive alcohol use. Other typical causes of AP, such as gallstones, hypertriglyceridemia, and trauma, were ruled out. After considering all possible etiologies, the most likely factor producing AP was medication that had been administered to him two weeks before the very first episode of the disease. Medication should always be considered as a possible trigger of AP, especially if the first episode occurs shortly after drug administration and the etiology is unclear. During patient’s hospitalization, laboratory reports revealed significant fluctuations in the serum levels of pancreatic enzymes, which can be attributed to recurrent bacteriemia. After the 30-day period of hospitalization and long-lasting antibiotic therapy, he was discharged in a good condition with normal levels of serum pancreatic enzymes.

Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, cell migration, new blood vessel formation, and immune response. In this review, we present the current state of knowledge on MMP9 and its role in cancer growth in the context of cell adhesion/migration, cancer-related inflammation, and tumor microenvironment formation. We also summarize recent achievements in the development of selective MMP9 inhibitors and the limitations of using them as anticancer drugs.

Inhibition of the protein neddylation process by the small-molecule inhibitor MLN4924 has been recently indicated as a promising direction for cancer treatment. However, the knowledge of all biological consequences of MLN4924 for cancer cells is still incomplete. Here, we report that MLN4924 inhibits tumor necrosis factor-alpha (TNF-α)-induced matrix metalloproteinase 9 (MMP9)-driven cell migration. Using real-time polymerase chain reaction (PCR) and gelatin zymography, we found that MLN4924 inhibited expression and activity of MMP9 at the messenger RNA (mRNA) and protein levels in both resting cells and cells stimulated with TNF-α, and this inhibition was closely related to impaired cell migration. We also revealed that MLN4924, similar to TNF-α, induced phosphorylation of inhibitor of nuclear factor kappa B-alpha (IκB-α). However, contrary to TNF-α, MLN4924 did not induce IκB-α degradation in treated cells. In coimmunoprecipitation experiments, nuclear IκB-α which formed complexes with nuclear factor kappa B p65 subunit (NFκB/p65) was found to be highly phosphorylated at Ser32 in the cells treated with MLN4924, but not in the cells treated with TNF-α alone. Moreover, in the presence of MLN4924, nuclear NFκB/p65 complexes were found to be enriched in c-Jun and cyclin dependent kinase inhibitor 1 A (CDKN1A/p21) proteins. In these cells, NFκB/p65 was unable to bind to the MMP9 gene promoter, which was confirmed by the chromatin immunoprecipitation (ChIP) assay. Taken together, our findings identified MLN4924 as a suppressor of TNF-α-induced MMP9-driven cell migration in esophageal squamous cell carcinoma (ESCC), likely acting by affecting the nuclear ubiquitin–proteasome system that governs NFκB/p65 complex formation and its DNA binding activity in regard to the MMP9 promoter, suggesting that inhibition of neddylation might be a new therapeutic strategy to prevent invasion/metastasis in ESCC patients.

This systematic review and meta-analysis investigates current evidence on the therapeutic role of laparoscopic lavage in the management of diverticular peritonitis. A systematic review of the literature was performed on PubMed until June 2016, according to preferred reporting items for systematic reviews and meta-analyses guidelines. All randomised controlled trials comparing laparoscopic lavage with surgical resection, irrespective of anastomosis or stoma formation, were analysed. After assessment of titles and full text, 3 randomised trials fulfilled the inclusion criteria. Overall the quality of evidence was low because of serious concerns regarding the risk of bias and imprecision. In the laparoscopic lavage group, there was a statistically significant higher rate of postoperative intra-abdominal abscess (RR 2.54, 95% CI 1.34-4.83), a lower rate of postoperative wound infection (RR 0.10, 95% CI 0.02-0.51), and a shorter length of postoperative hospital stay during index admission (WMD = -2.03, 95% CI -2.59 to -1.47). There were no statistically significant differences in terms of postoperative mortality at index admission or within 30 days from intervention in all Hinchey stages and in Hinchey stage III, postoperative mortality at 12 months, surgical reintervention at index admission or within 30-90 days from index intervention, stoma rate at 12 months, or adverse events within 90 days of any Clavien-Dindo grade. The surgical reintervention rate at 12 months from index intervention was significantly lower in the laparoscopic lavage group (RR 0.57, 95% CI 0.38-0.86), but these data included emergency reintervention and planned intervention (stoma reversal). This systematic review and meta-analysis did not demonstrate any significant difference between laparoscopic peritoneal lavage and traditional surgical resection in patients with peritonitis from perforated diverticular disease, in terms of postoperative mortality and early reoperation rate. Laparoscopic lavage was associated with a lower rate of stoma formation. However, the finding of a significantly higher rate of postoperative intra-abdominal abscess in patients who underwent laparoscopic lavage compared to those who underwent surgical resection is of concern. Since the aim of surgery in patients with peritonitis is to treat the sepsis, if one technique is associated with more postoperative abscesses, then the technique is ineffective. Even so, laparoscopic lavage does not appear fundamentally inferior to traditional surgical resection and this technique may achieve reasonable outcomes with minimal invasiveness.

Diverticular disease of the colon also affects older people. Generally, older patients with diverticulitis may be regarded as too risky to undergo surgery. This retroprospective multicentric observational study aims to assess the safety and benefits of laparoscopic peritoneal lavage (LPL) in elderly patients with perforated sigmoid diverticulitis. We hospitalized in urgency 100 patients, aged over 75, for sigmoid diverticulitis. Sixty-nine patients were treated with conservative medical therapy, while 31 were treated surgically, in which the surgery was performed in urgency in 18 cases, while in election in 13 cases. Laparoscopic peritoneal lavage was made in urgency in five cases. The mean age of the sample was 81.72. Thirty-one patients underwent surgery, and five patients were treated in urgency with laparoscopic peritoneal lavage. Perioperative mortality was zero. None of the patients who underwent laparoscopic peritoneal lavage showed recurrent disease. Diagnostic laparoscopy can be useful in elderly patient, since these patients may benefit from a more conservative surgical strategy. The selection of patients to be subjected to laparoscopic lavage must be very rigorous.

The invasive nature of many cancer cells involves the formation of F-actin-based, lipid-raft-enriched membrane protrusions known as invadopodia or, more broadly, invadosomes. Invadopodia are specialized adhesive structures arising from ventral cell surface within cell-extracellular matrix (ECM) contacts and concentrate high proteolytic activities that allow cells to overcome the dense scaffold of local microenvironment, comprising a natural barrier to cell spreading. This degradative activity distinguishes invadopodia from other adhesive structures like focal adhesions, lamellipodia or filopodia, and is believed to drive cancer progression.

Background Proximal or extended bowel resections are sometimes necessary during emergency surgery of the small bowel and call for creating a high small bowel stomy as a part of damage control surgery. Secondary restoration of intestinal continuity in the frail geriatric patient, further weakened by subsequent severe malabsorption may be prohibitive. Methods Six patients underwent emergency small bowel resection for proximal jejunal disease (83.3% high-grade adhesive SBO and 16.7% jejunal diverticulitis complicated with perforation). With the intention to avoid end jejunostomy and the need for repeat laparotomy for bowel continuity restoration we modified the classic Paul-Mikulicz jejunostomy. Results The postoperative course was uneventful in four patients whose general condition improved considerably. At six-month follow-up, neither patients required parenteral nutrition. Conclusions This modified stoma can have the advantage of allowing a partial passage of the enteric contents, reducing the degree of malabsorption, and rendering jejunostomy reversal easy to perform later.

Rationale Retroperitoneal colonic perforation is a rare cause of retroperitoneal abscess. It presents, more frequently in frail elderly patients, with heterogeneous signs and symptoms which hamper the clinical diagnosis. Subcutaneous emphysema with pneumomediastinum and iliopsoas muscle abscess are unusual signs. Colonic retroperitoneal perforation may be consequent to diverticulitis or locally advanced colon cancer. Due to the anatomy of the retroperitoneal space and different physiopathology, diverticular perforation may present with air and pus collection; on the other hand perforated colon cancer may cause groin mass and psoas abscess. We reported 2 cases of colonic retroperitoneal perforation from diverticulitis and locally advanced colon cancer, respectively. Aim of this report is to improve differential diagnosis based on clinical signs. Patients' concerns A 71-year-old man presented with pain in his left side, fatigue, fever, nausea, massive subcutaneous emphysema of the neck, and Blumberg sign in the left iliac fossa. A 67-year-old man presented with abdominal pain, sub-occlusion, left groin mass, left groin, and lower limb pain during walking, negative Blumberg sign. Diagnosis In the first patient the computerized tomography revealed pneumoperitoneum, gas in the mesosigma, pneumomediastinum, wall thickening of the descending colon, and retroperitoneal collection from diverticular perforation. In the second patient abdominal CT scan found thickening of the sigmoid colon adherent to the iliopsoas and fluid collection. Interventions In the first patient, a left hemicolectomy extending to the transverse colon, followed by a toilette and debridement of the retroperitoneum were performed. In the second patient, tumor of descending colon perforated in the retroperitoneum with iliopsoas abscess was treated with left hemicolectomy and a drainage of the abscess. Outcomes The first patient underwent right colectomy with ileostomy in the 7 postoperative day for large bowel necrosis. He died of sepsis 2 days after. The second patient had regular postoperative and he is still alive. Lessons The spread of retroperitoneal abscess in complicated colonic diverticulitis is different from that in advanced colonic cancer. The former can present with a subcutaneous emphysema, the latter with a groin mass. Hence a thorough clinical examination and radiological studies are needed to diagnose these conditions.

Background: Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumours in the digestive tract. The duodenal GIST (dGIST) is the rarest subtype, representing only 4–5% of all GIST, but up to 21% of the resected ones. The diagnostic and therapeutic management of dGIST may be difficult due to the rarity of this tumor, its anatomical location, and the clinical behavior that often mimic a variety of conditions; moreover, there is lack of consent for their treatment. This study has evaluated the scientific literature to provide consensus on the diagnosis of dGIST and to outline possible options for surgical treatment. Methods: An extensive research has been carried out on the electronic databases MEDLINE, Scopus, EMBASE and Cochrane to identify all clinical trials that report an event or case series of dGIST. Results: Eighty-six studies that met the inclusion criteria were identified with five hundred forty-nine patients with dGIST: twenty-seven patients were treated with pancreatoduodenectomy and ninety-six with only local resection (segmental/wedge resections); in four hundred twenty-six patients it is not possible identify the type of treatment performed (pancreatoduodenectomy or segmental/wedge resections). Conclusions: dGISTs are a very rare subset of GISTs. They may be asymptomatic or may involve symptoms of upper GI bleeding and abdominal pain at presentation. Because of the misleading clinical presentation the differential diagnosis may be difficult. Tumours smaller than 2 cm have a low biological aggressiveness and can be followed annually by endoscopic ultrasound. The biggest ones should undergo radical surgical resection (R0). In dGIST there is no uniformly adopted surgical strategy because of the low incidence, lack of experience, and the complex anatomy of the duodenum. Therefore, individually tailored surgical approach is recommended. R0 resection with 1–2 cm clear margin is required. Lymph node dissection is not recommended due to the low incidence of lymphatic metastases. Tumor rupture should be avoided.

The role of laparoscopy in the diagnosis and treatment of stable abdominal trauma patients is still a matter of serious debate and only incomplete data are available.We performed a systematic review and meta-analysis of the literature between January 1990 and August 2016.Overall, 9817 laparoscopies were performed for abdominal trauma; only 26.2% of the cases were converted to a laparotomy. The incidence of therapeutic laparotomies showed a reduction from 69% to 47.5%, whereas the incidence of therapeutic laparoscopies increased from 7.2% to 22.7%.The overall perioperative mortality rate was significantly lower in the laparoscopy group [odds ratio (M-H, random); 95% confidence interval, 0.35 (0.26-0.48)]. The same group showed shorter length of hospital stay [odds ratio (M-H, random); 95% confidence interval, -3.48 (-8.91 to 1.96)].This systematic review shows a significant decrease in the use of laparoscopy in trauma patients. Most likely the widespread use of imaging techniques allows a more accurate selection of patients for diagnostic laparoscopy. Infact, a reduction in incidence of nontherapeutic laparotomies is evident in these selected patients undergoing diagnostic laparoscopy. Moreover, the literature reported an increasing trend of therapeutic laparoscopy, demonstrating that it is safe and effective. The small number and poor quality of the studies identified, the retrospective observational nature of the studies (low level of evidence), the high risk of bias, and the high heterogeneity of some outcomes make the applicability of the results of this meta-analysis unclear.

Metastasis is the leading cause of mortality in patients with highly invasive cancers and, as such, is a major problem for medicine. It has been increasingly recognized that cancer-related inflammation plays an important role in promoting invasion and the metastatic process in which cell motility and upregulation of proteolytic enzymes are crucial events. TNFα is a proinflammatory cytokine known to stimulate synthesis of MMP9, a zinc- and calcium-dependent endopeptidase contributing to the regulation of ECM remodeling and cell signaling. However, the precise molecular mechanism of TNFα-induced MMP9 gene expression in cancers is still not fully understood. This study shows that TNFα-induced cell migration and invasion involve ERK1/2-dependent up-regulation of CDKN1A/p21 expression in highly aggressive breast cancer cells and that CDKN1A/p21 plays an important regulatory role in TNFα-induced MMP9 gene expression, indicating an unknown function of CDKN1A/p21 as a regulator of proteolytic activity in cancer cells.

There are numerous reports suggesting that fibroblast activating protein-α (FAP-α) plays an important role in invasion of various tumor types. We studied the expression pattern of FAP-α in esophageal squamous cell carcinoma (ESCC) patients who had not been treated primarily and those who had received neoadjuvant radiochemotherapy. Our goal was to establish whether readily available tissue specimens fixed in formalin and stored in paraffin blocks for years might still be a source of FAP-α RNA for PCR analysis. The study included 20 patients divided into two groups, 10 patients in each group. We evaluated the expression of FAP-α by PCR techniques in fresh frozen and in paraffin-embedded tissues, and compared it to the expression in non-cancer tissues. To detect the protein expression level of FAP-α in paraffin-embedded tissues we used chromogenic immunohistochemical (IHC) staining. Data were analyzed by t-test or the nonparametric Wilcoxon matched pair test using Statistica 12.5 software. We observed an increased level of the FAP-alpha gene and protein expression in cancer tissues when compared with their corresponding normal tissues. However, statistically significant differences were found only in the group of patients untreated before surgery. RNA extracted from paraffin-embedded tissue sections had very low quality, especially in the context of degradation. FAP-α remains a highly altered participant of a complex microenvironment in esophageal squamous cell carcinoma, and its role in cell signaling requires further study. In this paper, we conclude that the use of a regular RT-PCR method for diagnostic purposes, which we have presented in an earlier paper, can be as good as qRT-PCR. Also, immunohistochemistry proved to be very useful and the only reliable method that can be used on formalin-fixed, paraffin-embedded tissues stored long term.

To better understand the role of membrane-associated proteolytic systems in the development of esophageal cancer, we studied the expression of two serine proteases, fibroblast activation protein-α (FAP-α) and dipeptidyl peptidase IV (DPPIV) and three metalloproteinases, matrix metalloproteinase (MMP)-2, MMP-9 and MT1-MMP in 24 primary esophageal squamous cell carcinoma (ESCC) tissues and paired non-cancer tissues. Using reverse-transcription PCR, western blotting and zymography, we showed that both serine proteases and all three metalloproteinases were highly altered in ESCC. A positive correlation between the expression of FAP-α and DPPIV and the activity of both gelatinases was found. This may indicate that these proteolytic systems are tightly linked to each other and collectively are involved in the process of ECM degradation that facilitates cancer cell invasion and metastasis.

Anastomotic leak following colorectal surgery can be a devastating adverse event. The ideal stapling device should be capable of rapid creation of an anastomosis with serosal apposition without the persistence of a foreign body or a foreign body reaction which potentially contribute to early anastomotic dehiscence or late anastomotic stricture. A systematic review was performed examining available data on controlled randomized and non-randomized trials assessing the NiTi compression anastomosis ring—(NiTi CAR™) (NiTi Solutions, Netanyah Israel) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) standards. A protocol for this meta-analysis has been registered on PROSPERO (CRD42016050934). The initial search yielded 45 potentially relevant articles. After screening titles and abstracts for relevance and assessment for eligibility, 39 of these articles were eventually excluded leaving 6 studies for analysis in the review. Regarding the primary outcome measure, the overall anastomotic leak rate was 2.2% (5/230) in the compression anastomosis group compared with 3% (10/335) in the conventional anastomosis group; this difference was not statistically significant (RR 0.75, 95% CI 0.25–2.24; participants = 565; studies = 6; I 2 = 0%). There were no statistically significant differences between compression and conventional anastomoses in any of the secondary outcomes. This review was unable to demonstrate any statistically significant differences in favor of the compression anastomosis technique over conventional manual or stapled mechanical anastomoses.

Colon cancer therapy is primarily surgical. Advanced age does not represent a contraindication to surgery. We analyse the results of surgery in ultra 75 patients undergoing surgery for colorectal cancer by examining the correlation between the comorbidity and any post-operative complications. We surgically treated 66 patients for colorectal cancer, aged over 75. The examined subjects were compromised for various reasons. We have evaluated the different influences of risk factors in elective and urgency operation. Several studies have shown that age alone is not a significant prognostic factor in survival after colonic surgery. The assessment of general conditions in elderly patients, as demonstrated by the literature, is a fundamental moment in the management of colorectal cancer. The surgical choice should be made case by case (custom-made), not based on age only.

The management of patients with colonic diverticular perforation is still evolving. Initial lavage with or without simple suture and drainage was suggested in the late 19th century, replaced progressively by the three-stage Mayo Clinic or the two-stage Mickulicz procedures. Fears of inadequate source control prompted the implementation of the resection of the affected segment of colon with formation of a colostomy (Hartman procedure) in the 1970’s. Ensuing development of the treatment strategies was driven by the recognition of the high morbidity and mortality and low reversal rates associated with the Hartman procedure. This led to the wider use of resection and primary anastomosis during the 1990’s. The technique of lavage and drainage regained popularity during the 1990’s. This procedure can also be performed laparoscopically with the advantage of faster recovery and shorter hospital stay. This strategy allows resectional surgery to be postponed or avoided altogether in many patients; and higher rates of primary resection and anastomosis can be achieved avoiding the need for a stoma. The three recent randomized controlled trials comparing laparoscopic peritoneal lavage alone to resectional surgery reported inconsistent outcomes. The aim of this review is to review the historical evolution and future reflections of surgical treatment modalities for diffuse purulent and feculent peritonitis. In this review we classified the various surgical strategies according to Krukowski et al. and Vermeulen et al. and reviewed the literature related to surgical treatment separately for each period.

Background: A Spigelian Hernia (SH) is an uncommon clinical entity comprising 0.12% to 2% of all the abdominal wall hernias. Usually the symptoms of the hernia are non-specific and therefore a diagnosis based only on the clinical examination is difficult. Imaging studies are particularly useful during the diagnostic process, but sometimes do not give the proper presurgical diagnosis. Case presentation: We present the case of a 77-year-old woman with a suspected tumor of the blind gut, where only a more accurate preoperative examination later enabled the identification of the presence of a SH. Furthermore, during the less conventional classical surgery it was revealed that the appendix, which is an event that rarely occurs, was found incarcerated within the hernia contents. Conclusion: We present the clinical difficulty with diagnosis of SH with incarcerated appendix and the variety of the symptoms. Additionally, we present a brief literature review with a concomitant description of the clinical appearance, diagnostic approach, and treatment options concerning SH.

The incidence of duodenal perforation after ERCP ranges from 0.09% to 1.67% and mortality up to 8%.This systematic review was registered in Prospective Register of Systematic Reviews, PROSPERO. Stapfer classification of ERCP-related duodenal perforations was used.The systematic search yielded 259 articles. Most frequent post-ERCP perforation was Stapfer type II (58.4%), type I second most frequent perforation (17.8%) followed by Stapfer type III in 13.2% and type IV in 10.6%. Rate of NOM was lowest in Stapfer type I perforations (13%), moderate in type III lesions (58.1%) and high in other types of perforations (84.2% in type II and 84.6% in IV). In patients underwent early surgical treatment (24 h from ERCP) the most frequent operation was simple duodenal suture with or without omentopexy (93.7%). In patients undergoing late surgical treatment (24 h from ERCP) interventions performed were more complex. In type I lesions post-operative mortality rate was higher in patients underwent late operation (24 h). In type I lesions, failure of NOM occurred in 42.8% of patients. In type II failure of NOM occurred in 28.9% of patients and in type III there was failure of NOM in only 11.1%, none in type IV. Postoperative mortality after NOM failure was 75% in type I, 22.5% in type II and none died after surgical treatment for failure of NOM in type III perforations.This systematic review showed that in patients with Stapfer type I lesions, early surgical treatment gives better results, however the opposite seems true in Stapfer III and IV lesions.

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms (85%) of the gastrointestinal (GI) tract; duodenal GISTs constitute 3–5% of all GISTs and represent 10–30% of all malignant tumours of the duodenum. Rarely, patients present severe bowel obstruction, perforation or severe bleeding. The radical resection with complete removal of the tumour remains the main therapeutic approach. We performed a local resection in patients with suspected GIST admitted for emergency treatment for GI bleeding. We present three cases of patients admitted for GI bleeding. The cause could be a GIST bleeding. In all cases, local resection was performed without a pancreaticoduodenectomy. Histological examination on surgical preparations showed that in two cases it was a GIST and in one case, it was a leiomyoma. Surgery remains the treatment of choice in the case of a GIST primitive without evidence of metastases, even for patients who are hospitalized for a bleeding emergency. Wide resections are not needed; it is important to remove completely the disease. In the case of duodenal GIST, it is important to get negative margins near the head of the pancreas, and this could take a PD. According to our experience and to the literature review, we believe that if the duodenal papilla or the periampullary region is not interested, you must perform a local resection. This is also because non-malignant tumours may present as GISTs and in these cases it is not recommended to run a PD. The treatment of choice for duodenal GISTs is complete surgical resection with negative resection margins. When the papilla or the periampullary region is involved we choose to perform pancreaticoduodenectomy; otherwise it is better to perform a local resection. In fact, local resection has lower morbidity and mortality, with a comparable outcome.

Background The optimal therapeutic schedule in patients with achalasia is still under discussion. The aim of this study was to review our institution’s experience with myotomy and dilation in patients with achalasia. Material/Methods Clinical data were available for 59 patients who had ever had myotomy (n=38), dilation (n=21), or both procedures (n=8) between 2000 and 2007. Patients were followed prospectively with objective (a barium esophagogram) and subjective (a simple survey that scored dysphagia and overall patient satisfaction with the procedure) diagnostic tools. In the group of patients after pneumatic dilatations, frequency of interventions was higher (1, 2) than in the myotomy group (0, 2) at 2-year follow-up. Patients after myotomy with recurrence of dysphagia were treated with dilations. Results Mean time of dysphagia occurrence was similar in both groups (10 months). The statistically significant differences in treatment outcomes in both groups were in favor of myotomy during 2-year follow-up. Conclusions The data indicates that both methods of treatment might be useful in dysphagia control, but better results are obtained after myotomy. Repeat interventions are more frequent after endoscopic dilation. One method of treatment does not exclude the other. A short period of symptom relief after myotomy may suggest the myotomy was incomplete.

Even with the advances in surgical technique and perioperative care, morbidity and mortality after colorectal cancer surgery remain considerable, and patients (pt) who present as an emergency have an even higher mortality and morbidity rate. A total of 35 pt with caecum or ascending colon cancer between January 2007 and June 2015, three departments in Italy and in Poland, were included in the study. The intention of surgery in all cases was curative resection with ileo-colic anastomosis. Comparative statistical analysis was performed. Acute bowel obstruction was the major complication of CRC that led to an emergency hemicolectomy. Postoperative mortality and morbidity rates were in total 12.5 and 28.1%, respectively. All the deaths happened in Poland. Of the pt, 42.8% had morbidity in Poland and 16.6% in Italy. Out of the pt, 25% presenting with perforation: 25% died, 25% had wound dehiscence, 12.5% had pulmonary oedema, and 12.5% had an intra-abdominal abscess. The mean age of the pt with complications in Poland and in Italy was 79.3 and 72.0 years, respectively. We observed that particularly lethal combination is older age, perforation with peritonitis and advanced stage of the cancer.

A two-stage esophagectomy with an interval for reconstruction of the esophagus creates an opportunity for the esophageal stump to recover from vessel injury and allows the formation of granulation tissue rich in proangiogenic factors, including transforming growth factor β (TGF-β) and vascular endothelial growth factor A (VEGF-A), which may have an impact on anastomosis healing. The present study comprised 25 patients (27 in total, 2 succumbed to complications following surgery) who underwent two-stage esophagectomy for squamous cell carcinoma in the Department of Gastrointestinal and General Surgery, Wroclaw Medical University (Wroclaw, Poland) between January 2007 and December 2012. Immunohistochemical staining for VEGF-A and TGF-β was performed to evaluate esophageal wall specimens at the time of esophagostomy construction and prior to anastomosis, in which the cervical esophagus was connected with the colon or ileum. At the time of reconstructive surgery, a significant increase in microvessel density was observed in all esophageal specimens (P

The purpose of this retrospective study is to show that transcervical diverticulectomy (TD) in treatment of Zenker diverticulum (ZD) can still be a first choice procedure in selected patients and in experienced hands its safety might be compared to the minimally invasive endoscopic diverticulostomy. The study cohort consisted of 44 patients (18 male, 26 female) operated for (ZD). All the patients underwent open diverticulectomy. The decision to choose open surgical repair depended on surgical risk, age of the patient, size of the diverticular septum (the distance between the top of the diverticulum and its bottom on barium study), and patient's preference. Mean age of patients was 64.6 ± 11.9 years; range: 26 to 88 years. A total of 36.4% out of them finished 70 years. Postoperative mortality was nil. Two major complications (4.5%) requiring surgical intervention occurred: leak and hematoma. Data were analyzed by t test for independent samples using Statistica 12.5 software. P value

To determine the role of the reactive stroma in cancer progression, we investigated decorin (DCN) and transforming growth factor-beta (TGF-beta expression, and matrix metalloproteinase-2 (MMP-2) activity in the tumorous esophagus. We found statistically insignificantly decreased levels of DCN expression in the pathological tissues. No obvious alterations in TGF-beta expression were noticed. The highly significant increase in MMP-2 activity in cancers did not result in elevated levels of TGF-beta dimers. Therefore, the system of TGF-beta liberation from its complex with DCN by activated MMP-2 does not seem to contribute to esophageal cancerogenesis, although this hypothesis should be reevaluated with a larger study group.

Colonic diverticular disease is the most common cause of lower gastrointestinal bleeding. In the past, this condition was usually managed with urgent colectomy. Recently, the development of endoscopy and interventional radiology has led to a change in the management of colonic diverticular bleeding. The aim of this systematic review is to define the best treatment for colonic diverticular bleeding. A systematic bibliographic research was performed on the online databases for studies (randomized controlled trials [RCTs], observational trials, case series, and case reports) published between 2005 and 2014, concerning patients admitted with a diagnosis of diverticular bleeding according to the PRISMA methodology. The outcomes of interest were: diagnosis of diverticulosis as source of bleeding; incidence of self-limiting diverticular bleeding; management of non self-limiting bleeding (endoscopy, angiography, surgery); and recurrent diverticular bleeding. Fourteen studies were retrieved for analysis. No RCTs were found. Eleven non-randomized clinical controlled trials (NRCCTs) were included in this systematic review. In all studies, the definitive diagnosis of diverticular bleeding was always made by urgent colonoscopy. The colonic diverticular bleeding stopped spontaneously in over 80% of the patients, but a re-bleeding was not rare. Recently, interventional endoscopy and angiography became the first-line approach, thus relegating emergency colectomy to patients presenting with hemodynamic instability or as a second-line treatment after failure or complications of hemostasis with less invasive treatments. Colonoscopy is effective to diagnose diverticular bleeding. Nowadays, interventional endoscopy and angiographic treatment have gained a leading role and colectomy should only be entertained in case of failure of the former.

Purpose Dupuytren's contracture is a fibroproliferative disorder of the hand characterized by an abnormal myofibroblast and fibroblast proliferation and extracellular matrix deposition leading to retraction and deformation of the palm. Recent studies have shown that molecules of extracellular matrix may coordinate morphogenesis, cell differentiation, and most importantly, fibrogenesis in tissue. Gelatinase A (MMP-2) is a member of the matrix metalloproteinase family of proteolytic enzymes that contribute to remodeling the extracellular matrix by degrading its components. The aim of this study was to determine the level of MMP-2 activation in the palmar fascia of patients with Dupuytren's contracture with reference to the clinical stages of disease progression and recurrence of the contracture after surgery. Methods The level of relative MMP-2 activation, expressed by the active to latent MMP-2 ratio, was investigated with use of zymography and computerized densitometry in 16 normal and 71 pathologic tissues characterizing different clinical stages of the disease progression. Results We found that the level of MMP-2 activation was significantly elevated in the palmar fascias with Dupuytren's contracture compared with normal tissues. We did not find statistically significant differences between groups with different stages of the disease progression. We also did not find a relation between a high level of MMP-2 activation and the recurrence in the area of surgically treated Dupuytren's contracture. Conclusions The differences in MMP-2 activation between contractured and normal fascia suggest a participation of this enzyme in the promotion of Dupuytren's disease. We did not find a relationship, however, between the level of MMP-2 activation and the secondary contracture.

A hallmark of most cancer cells is an altered metabolism involving a shift to aerobic glycolysis with lactate production coupled with a higher uptake of glucose as the main source of energy. Lactate dehydrogenase 5 (LDH-5) catalyzes the reduction of pyruvate by NADH to form lactate, thus determining the availability of NAD(+) to maintain the continuity of glycolysis. It is therefore an important control point in the system of cellular energy release. Its upregulation is common in many malignant tumors. Inhibiting LDH-5 activity has an anti-proliferative effect on cancer cells. It may reverse their resistance to conventional chemo- and radiotherapy. Recent research has renewed interest in LDH-5 as an anticancer drug target. This review summarizes recent studies exploring the role of LDH-5 in cancer growth, its utility as a tumor marker, and developments made in identifying and designing anti-LDH-5 therapeutic agents.

Acute pancreatitis is the inflammatory condition of a gland, including an invasion into, to a lesser or greater extent, the surrounding tissues, and also the contiguous or distant organs (Braganza, 2001; Frossard et al., 2008). The analysis of the processes, occurring in the course of acute pancreatitis, has made it possible to define this disease as the one which comprises of two phases. Initially, the hyperstimulation of the immunological system with the excessive local activation of the cells of inflammatory focus in the pancreas occurs, and later on, as a result, the systemic response, expressed as Systemic Inflammatory Response Syndrome (SIRS), develops. Compensatory Anti-inflammatory Response Syndrome (CARS) causes early organic complications (Gamaste, 1994; Toouli et al., 2002; Yousaf & McCallion, 2003). The intensification of an inflammatory response, hypoxia and the occurrence of oligovolemic shock may result in the clinical development of Multi-Organ Dysfunction Syndrome (MODS), which is defined as the more advanced stage of SIRS. In this period, greater susceptibility to bacterial infections and fungal infections and, consequently, an increased mortality rate, caused by blood poisoning, is observed. Multi-Organ Dysfunction Syndrome requires the application of the powerful methods of supporting the organism of a patient (Song et al., 2003). Acute pancreatitis is a disease of an unpredictable course. It is, usually, a reversible process, in which the pain ailments of the abdomen undergo regression and the activity of pancreatic enzymes returns to its normal level. In 70 75% of cases, this process becomes subjected to the self-limitation and has the properties of interstitial inflammation. However, in 5 – 15%, a form characterized by severe, necrotic course may develop. In this case, local complications and multi-organic complications are alike present The morbidity rate in case of acute pancreatitis in Poland is estimated to be at the level of 240 cases per 1 million in a year. The mortality rate amounts to 5 10% in total. However, in the cases of severe course, it amounts to approximately 35% (Baillie, 1997; Balthazar et al., 2002; Beger et al., 1997; Lund

Recent studies showed that a small leucine-rich proteoglycan, decorin, may suppress tumor progression as a natural anticancer agent negatively controlling cellular growth. It was hypothesized that physiological expression of decorin may be associated with cellular senescence of the colorectal mucosa and that its down-regulation, promoting an increase in cellular proliferation, could participate in the progression of adenoma to adenocarcinoma. Therefore the expression of decorin in hyperplastic and neoplastic polyps of the colorectum was examined and compared with normal colonic mucosa and colon cancer tissues.Tissue samples were obtained from 41 patients with different types of colonic polyps (6 hyperplastic adenomas, 34 neoplastic adenomas, and 1 adenomatous polyp with focal carcinoma) and 12 patients with colon cancer. Seven samples of normal colon tissue were used as controls. Paraffin-embedded samples were used for immunohistochemical study.Normal and hyperplastic tissues and the majority of tubular adenomas showed strong expression of decorin in the stroma. Adenomas with a villous component showed moderate and very low decorin immunoreactivity. The decrease in decorin reactivity in tubulo-villous adenomas was significant as compared with other polyps and controls. Weak decorin immunoreactivity in stroma adjacent to clusters of cancerous cells was also found in most cases of common types of adenocarcinoma, but not in adenocarcinoma mucinosum.The expression of decorin may be involved in the differentiation of colonic polyps and reduced expression of decorin may abrogate the defensive potential of stromal tissue and promote the development of common types of colon carcinoma.

The aim of this paper was to examine participation of the epidermal growth factor receptor (EGF-R) signal pathway in the pathogenesis of Dupuytren’s disease. The study showed changes in the ratio of membrane EGF-R to its intracellular level during the different clinical stages of Dupuytren’s contracture progression. Our observations of a high ratio of surface to intracellular EGF-R in the palmar aponeurosis of patients with second degree of Dupuytren’s disease (Iselin’s classification), which was significantly higher than this ratio in control palmar fascia ( P = 0.022), would suggest that EGF-R has a role in the involutional phase of the disease.

To invade adjacent tissues, cancer cells form special membrane protrusions with high proteolytic activity, named invadopodia. To better understand the role of invadopodia-associated proteolytic systems in the growth of esophageal cancer, we studied the expression of two serine proteases, FAP-alpha and DPPIV, and three metalloproteinases, MMP-2, MMP-9 and MT1-MMP, in a primary ESCC. The enzyme profile was evaluated in relation to the synthesis of cortactin as an important control factor in invadopodia formation and function. The expression and activity of proteases and cortactin in cancer tissues paired with non-cancer tissues were analyzed by RT-PCR, WB and zymography. Tissue samples were obtained from 24 patients who were undergoing surgical resection for esophageal carcinoma. All the tumors had been classified as ESCC and diagnosed as T3 or T4, N1-N3, and M0-M1 according to the TNM classification. The non-cancer tissue samples were taken from the distal area (5-10 cm from the macroscopic changes) and confirmed in histological examinations to be R0. We found an average 3-fold increase in DPPIV expression and an average five-fold higher level of FAP-alpha expression in ESCC over the control tissues. Up-regulation of DPPIV positively correlates with the FAP-alpha expression ratio. FAP-alpha transcripts and DPPIV mRNAs were observed in all the analyzed cancer and non-cancer tissue samples. We found a much higher level of the active MT1-MMP form in cancers relative to paired non-cancer tissues. The correlation between the level of MT1-MMP active form and MMP-2 activity observed in this study shows a tight connection between the two enzymes. We observed enhanced synthesis and activation of both MMP-2 and MMP-9 in cancer tissues. The cancer to normal ratios of the two active gelatinases correlated positively with the expression levels of both serine proteases. We examined the levels of CTTN in the cancer and non-cancer tissues of esophagus in order to find out if CTTN expression is associated with the expression and/or activity of invadopodia proteases. The increased level of CTTN was identified in 35% of ESCC tissues but the differences between groups were not statistically significant. No significant correlation was found between CTTN expression level and any other factors evaluated in our study. In conclusion, we showed that invadopodia-associated proteases, including FAP-alpha, DPPIV, MT1-MMP, MMP-2 and MMP-9, are significantly up-regulated in ESCC and that it might contribute to a more aggressive esophageal cancer. The presence of FAP-alpha in the cancer-free surgical margin suggests that alterations in the stromal environment may extend much father into surrounding tumor tissues than is usually considered. Citation Format: Katarzyna Augoff, Anita Hryniewicz-Jankowska, Renata Tabola, Leszek Czapla, Piotr Szelachowski, Krzysztof Grabowski, Aleksander F. Sikorski. Up-regulated expression and activation of invadopodia-associated proteases in esophageal squamous cell carcinoma (ESCC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5056. doi:10.1158/1538-7445.AM2013-5056

Purpose Tumor progression is associated with cell migration, invasion and metastasis. These processes are accompanied by the activation of specific proteases that are either linked to cellular membranes or are secreted into extracellular spaces. TNF-α is known to play an important role in various aspects of tumor progression. The aim of this work was to assess the effect of TNF-α on the migration of breast cancer cells and, in addition, to assess its association with the location of membrane-associated proteases in lipid rafts. Methods Wound scratch healing and Transwell migration assays were used to study the effect of TNF-α on the migration of both hormone-dependent and hormone-independent breast cancer-derived cells, i.e., MCF7 and MDA-MB-231, respectively. The expression and secretion of three matrix metalloproteases, MMP9, MMP2 and MT1-MMP, and two dipeptidyl peptidases, CD26 and FAP-α, was investigated using RT-PCR, Western blotting and gelatin zymography. In addition, activation of the MAPK/ERK signaling pathway was investigated by Western blotting. Results We found that a TNF-α-induced enhancement of breast cancer cell migration was accompanied by an increased secretion of MMP9, but not MMP2, into the culture media. We also found that TNF-α upregulated the expression of the dipeptidyl peptidases CD26 and FAP-α in a dose-dependent manner and, in addition, enhanced the concentration of all five proteases in lipid rafts in the breast cancer-derived cells tested, regardless of cell type. Furthermore, we found that TNF-α activated the MAPK/ERK signaling pathway by increasing the ERK1/2 phosphorylation level. Application of the MEK/ERK1/2 inhibitor U-0126 resulted in down-regulation of TNF-α-induced MMP9 secretion and abrogation of the enhanced concentration of proteases in the lipid rafts. Conclusions From our results we conclude that TNF-α-induced activation of the MAPK/ERK signaling pathway may promote breast cancer cell migration via both upregulation of MMP9, CD26 and FAP-α and concentration of these proteases, as also MT1-MMP and MMP2, in the lipid rafts. TNF-α may serve as a potential therapeutic target in breast cancers susceptible to TNF-α stimulation.

In 114 cases of the transverse colon isolated from cadavers (50 male, 64 female), anatomical examinations of the arterial system of the colon were performed. Arteriograms were obtained after dissecting and contrasting the colonic vessels with Mixobar contrast. In one case, on arteriography of the colon with its mesentery isolated from a 55-year-old male cadaver, a rare anatomical variant was found. The third mesenteric artery originated directly from the aorta-halfway between the superior and inferior mesenteric arteries and ascended obliquely in the direction of the hepatic flexure of the colon. Supply area of the artery was typical for the middle colic branch of the superior mesenteric artery: the distal segment of the ascending colon and the transverse colon. Such a variation, although very rare, may have particular impact on diagnosis and even the method and range of surgery.