Effect of LDHA Inhibition on TNF-α-Induced Cell Migration in Esophageal Cancers.

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.

New classifications of axillary lymph nodes and their anatomical-clinical correlations in breast surgery.

BACKGROUND: In the last decade, two research groups, the French group by Clough et al. (Br J Surg. 97:1659-65, 2010) and the Chinese one by Li et al. (ISRN Oncol 2013:279013, 2013), proposed two types of classification of axillary lymph nodes in breast cancer, identifying novel anatomic landmarks for dividing the axillary space in lymph node dissection. MAIN BODY: Knowledge of the exact location of the sentinel node helps to focus the surgical dissection and to reduce the morbidity of sentinel lymph node biopsy procedures, in particular the risk of arm lymphedema, without compromising sensitivity. CONCLUSION: In this article, we aimed at focusing on the clinical impact that the most recent classifications of axillary lymph nodes have obtained in literature, highlighting the importance of defining new demarcations to preserve the axillary lymph nodes as much as possible in breast surgery.

The Effect of Neddylation Inhibition on Inflammation-Induced MMP9 Gene Expression in Esophageal Squamous Cell Carcinoma.

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.

The usefulness of lactate dehydrogenase measurements in current oncological practice.

One of the hallmarks of cancer cells is increased energy requirements associated with the higher rate of cellular proliferative activity. Metabolic changes in rapidly dividing cancer cells are closely associated with increased uptake of glucose and abnormal activity of lactate dehydrogenase (LDH), which regulates the processing of glucose to lactic acid. As serum LDH levels were found to be commonly increased in cancer patients and correlated with poor clinical outcome and resistance to therapy, the determination of LDH has become a standard supportive tool in diagnosing cancers or monitoring the effects of cancer treatment. The aim of this review is to summarize the current knowledge about methods and the practical utility for measuring both the total LDH and LDH isoenzymatic activities in the diagnosis, prognosis and prediction of cancer diseases.

Surgery for colorectal cancer in elderly: a comparative analysis of risk factor in elective and urgency surgery.

INTRODUCTION: 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. MATERIALS AND METHODS: 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. DISCUSSION: 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. CONCLUSIONS: The surgical choice should be made case by case (custom-made), not based on age only.

Is it safe and useful, laparoscopic peritoneal lavage in the treatment of acute diverticulitis of octogenarian patients? A multicenter retroprospective observational study.

BACKGROUND: 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. PATIENTS AND METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Postoperative mortality and morbidity in older patients undergoing emergency right hemicolectomy for colon cancer.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: We observed that particularly lethal combination is older age, perforation with peritonitis and advanced stage of the cancer.

Urgency surgical treatment for duodenal GISTs: analysis of aged patients and review of the literature.

INTRODUCTION: 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. CASES: 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. DISCUSSION: 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. CONCLUSION: 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.

A systematic review of the management and outcome of ERCP related duodenal perforations using a standardized classification system.

INTRODUCTION: The incidence of duodenal perforation after ERCP ranges from 0.09% to 1.67% and mortality up to 8%. METHODS: This systematic review was registered in Prospective Register of Systematic Reviews, PROSPERO. Stapfer classification of ERCP-related duodenal perforations was used. RESULTS: 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. CONCLUSIONS: 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.

Achalasia--balloon dilation or surgery?

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 AND 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.

Colon micro- and macrooesofagisation in interposed pedicled colonic right half segments for esophagus reconstruction.

Treatment of esophageal burns may require surgical transplantation (interposition) of the colon or stomach. The interposed parts change their function and morphology. To investigate the macro- and microchanges in the transplanted colonic segment we analyzed in long-term follow-up (up to 29 years) the group of 21 patients in a retrospective study who underwent surgical interposition of pedicled colonic right half segments for esophageal burns. The data were analyzed statistically with the software package Statistica 13 (StatSoft Polska, Cracow). All calculations were performed with a significant level of P = .05. We evaluated the macro- and microanatomy of the grafts using radiology, endoscopy and histology. The adaptation of the transplanted tube was excellent. The diameter of the colonic tube was normal (35-60 mm) in 60% of females and 100% of males. Typical macrooesophagisation was found in all patients, while microoesophagisation involved inflammation, which gradually resolved over a period of about 5 years to be replaced by edema without fibrosis. Only in few patients persistent reflux was present, leading to erosions or ulcerations. All symptoms subsided after conservative treatment. We concluded macrooesophagization developed gradually after surgery, and was fully developed after 15 to 20 years. Microoesophagization appeared soon after interposition, and was obvious after 5 years. No metaplasia or dysplasia were observed (except in 1 patient), and the number of goblet cell remained constant.

A middle mesenteric artery.

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.

MMP9: A Tough Target for Targeted Therapy for Cancer.

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.

Invadopodia: clearing the way for cancer cell invasion.

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.

A rare case of acute pancreatitis: a diagnostic conundrum and unusual complications.

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 bacteremia. 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.

A rare case of acute pancreatitis: a diagnostic conundrum and unusual complications.

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 bacteremia. 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.

Modified Paul-Mikulicz jejunostomy in frail geriatric patients undergoing emergency small bowel resection.

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.

Immunohistochemical study of decorin expression in polyps and carcinomas of the colon.

BACKGROUND: 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. MATERIAL/METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Non-epithelial tumors of the large intestine]. / Nienablonkowe nowotwory jelita grubego.

UNLABELLED: Colorectal cancer may arise from any kind of tissue constituting normal wall of the large intestine, however, in majority of cases, it is of epithelial origin. Endocrine, mesenchymal neoplasms and non-granulomatic lymphomas belong to rarely occurring cancers of the large intestine. Mesenchymal neoplasms may derive from muscles, nervous system, fibrous connective tissue, fat tissue and from blood and lymphatic vessels. The paper presents 3 cases of non-epithelial neoplasms of the large intestine (myosarcoma and 2 myomas). All cancers concerned women older than 50 years (mean age 64.6 +/- 11.4 years) and were localized in the right hemicolon. In all cases episodes of hemorrhage from the lower part of the digestive tract triggered the diagnostic procedures. Surgical treatment varied from hemicolectomy with lymphadenectomy to endoscopic excision of a small lipoma. Histopathological verification and immunohistochemical staining were obtained after their removal. Clinical course and intraoperative situation were decisive as to type of surgery. Although mesenchymal tumors are very rare among large intestine neoplasms, one should consider their occurrence while carrying preoperative diagnosis. CONCLUSION: Occurrence of other tumors than neoplasms should be taken into consideration while carrying preoperative diagnosis.