Fibroblast activation protein and its prognostic significance in correlation with vascular endothelial growth factor in pancreatic adenocarcinoma.

Fibroblast activation protein (FAP), a selective protein for tumor stromal fibroblasts, is expressed in >90% of human epithelial carcinomas. A characteristic feature of pancreatic cancer is an extensive fibrotic or desmoplastic reaction surrounding the primary tumor. The present study aimed to evaluate the expression levels of FAP and vascular endothelial growth factor (VEGF) and determine their correlation in pancreatic adenocarcinoma. Confocal laser scanning microscopy and conventional immunohistochemical analysis were used to quantify FAP and VEGF expression levels in formalin­fixed and paraffin­embedded tissue biopsies from 46 patients (male, 26; female, 20; mean age, 66 years; age range, 53­80 years) with pancreatic adenocarcinoma stage IIA or IIB. The expression levels of FAP in the neoplastic and adjacent normal tissue were significantly higher in stage IIB patients, compared with stage IIA patients. FAP expression was correlated with positive lymph nodes, resulting in poor prognosis for stage IIB patients. The partial correlation coefficient between FAP and VEGF expression levels was 0.39 (P=0.007), and the two factors had an effect on patient survival. Multivariate analysis demonstrated the prognostic superiority of FAP over VEGF, which is considered to be the most consistently reproducible molecular marker with prognostic value in resected pancreatic adenocarcinoma. Due to the limited beneficial effect of current systemic therapies for pancreatic adenocarcinoma, targeting FAP may be a potential therapeutic strategy and requires further investigation.

Repair of gastric defects with an equine pericardial patch.

PURPOSES: The objective of this study was to test the efficacy of an equine pericardial patch for repairing full-thickness defects of the stomach wall. METHODS: Circular defects, 1.5 cm in diameter, were created on the anterior wall of the stomach of 12 female New Zealand rabbits. The defects were repaired by an equine pericardial patch. After euthanasia at different time intervals (3 days to 8 weeks) a macroscopic evaluation of the abdominal cavity (including adhesion scoring), mechanical testing and a histological examination of the stomach were performed. RESULTS: The animals survived the surgical procedure and underwent an uneventful recovery until euthanasia. None of the patches failed. Adhesions were observed in all animals and were significant in 3/12 animals. Bursting pressure testing indicated that the repair was durable and that adequate strength to prevent patch failure was achieved by the second week. A histological examination showed gradual narrowing of the perforation site by mucosal and limited muscular regeneration. CONCLUSIONS: The equine pericardial patch was successfully used to repair a gastric defect in our experimental model, and it seems that it could have potential as a material suitable for further research concerning the repair of upper gastrointestinal defects.

DNA methylation profile of genes involved in inflammation and autoimmunity in inflammatory bowel disease.

The contribution of epigenetic alterations to disease pathogenesis is emerging as a research priority. In this study, we aimed to seek DNA methylation changes in peripheral blood and tissue biopsies from patients with inflammatory bowel disease. The promoter methylation status of genes involved in inflammation and autoimmunity was profiled using the Human Inflammatory Response and Autoimmunity EpiTect Methyl II Signature PCR Array profiles. Methylation was considered to be hypermethylated if >20% according to the instructions of the manufacturer. The microarrays were validated with Quantitative Real-time PCR. Regarding Crohn disease (CD) no gene appeared hypermethylated compared to healthy controls. In ulcerative colitis (UC) 5 genes (CXCL14, CXCL5, GATA3, IL17C, and IL4R) were hypermethylated compared to healthy controls. Some of the examined genes show different methylation patterns between CD and UC. Concerning tissue samples we found that all hypermethylated genes appear the same methylation pattern and confirmed a moderate-strong correlation between methylation levels in colon biopsies and peripheral blood (Pearson coefficients r=0.089-0.779, and r=0.023-0.353, respectively). The epigenetic changes observed in this study indicate that CD and UC exhibit specific DNA methylation signatures with potential clinical applications in IBD non-invasive diagnosis and prognosis.

DNA methylation changes in inflammatory bowel disease.

The cause of inflammatory bowel disease, encompassing Crohn's disease and ulcerative colitis, remains a mystery but evidence is accumulating that complex interactions between the genetic background and the gut microbiota of the host and environmental factors associated with rapid industrialization and westernized life styles may underlie its pathogenesis. Recent epigenetic studies have suggested that interactions between environment and host DNA may play a leading role in the phenotypical expression of both diseases, explaining amongst others the differences in disease expression in monozygotic twins. DNA methylation is the most studied epigenetic modification and during the last decade its correlation to IBD pathogenesis has been well established. Genes from different molecular pathways have been studied but till now there is no standardized database of methylated genes in IBD. Thus, a thorough and in depth study of DNA methylation, its potential relation to IBD and its interaction with the available pharmaceutical armamentarium is of great interest.

Combined side-to-end anastomosis with temporary end colostomy for the management of selected left-sided colonic emergencies.

Management of surgical emergencies of the left colon commonly requires excision of the colonic segment bearing the lesion, creation of an end colostomy, and closure of the rectosigmoid stump. Closure of the end stoma may be technically challenging. During this study, we used a new surgical technique involving the creation of an end-to-side anastomosis of the rectosigmoid stump to the base of the proximal colonic segment in association with an end colostomy. During a 15-year period, 23 patients were offered this type of surgery. Mortality was zero. Complications were observed in seven patients (morbidity, 7/23). Mean hospitalization time was 12.3 days. Closure of the colostomy was performed approximately 1 month after initial surgery and was easily performed using a mechanical stapler, either intraperitoneally or even extraperitoneally. No complications were observed after closure of the colostomy. The described technique is a useful alternative for the management of selected patients with left-sided colonic surgical emergencies. Its main advantage is that it greatly facilitates colostomy closure, which is performed earlier compared with the colostomy closure after a typical Hartmann's procedure.

Carcinoid tumors of the duodenum and the ampulla of Vater: current diagnostic and therapeutic approach in a series of 8 patients. Case series.

AIM: To describe the specific characteristics of duodenal/perivaterian carcinoids and to analyze the diagnostic/therapeutic approach. MATERIAL AND METHODS: Eight patients were included in our study. Symptoms on admission included dyspepsia, upper gastrointestinal (GI) bleeding and anemia. All patients underwent upper GI endoscopy and gastrointestinal peptides (gastrin) and neuroendocrine markers (Chromogranin-A, CgA) measurement. Imaging studies were performed in all patients, including OCTREOSCAN, while in patients with ACs MRCP or ERCP was also performed, when necessary. Definite diagnosis was confirmed by histopathologic examination. RESULTS: Polypoid masses (carcinoids) were revealed at duodenal bulb and ampulla of Vater, in 5 and 3 patients, respectively. Serum gastrin was moderately increased in 4 patients, while in one patient it was more than 1000 pg/ml. Serum CgA was moderately increased in one patient, in whom OCTREOSCAN detected a solitary hepatic metastasis. Two patients with DC, of less than 1 cm of diameter, were treated by endoscopic polypectomy, while all the other patients underwent surgery. The patient with hepatic metastasis and positive OCTREOSCAN received also Octreotide LAR, resulting in stabilization of disease. No recurrence or metastases were observed during follow-up (range : 1.5-9.6 years). CONCLUSIONS: In DC tumors <1 cm endoscopic excision with close follow-up is an adequate treatment, while in tumors >1 cm and in AC, surgical resection is the treatment of choice. In metastatic tumors, resection of the primary lesion with administration of somatostatin analogues may stabilize the disease and improve patient's quality of life.

Controversies and challenging therapeutic modalities in gastric cancer.

Gastric cancer is still the fourth common neoplasm worldwide. Gastric ulcers, adenomatous polyps, and intestinal metaplasia have been associated with an increased relative risk. Tissue diagnosis and anatomic localization of the primary tumor are best obtained by upper gastrointestinal endoscopy. Despite new screening techniques peritoneal tumor spread and occult liver and lymph node metastases are only detected intra-operatively. Therapy is becoming more and more complex comprising surgical resection, investigational neoadjuvant, adjuvant or palliative chemotherapy, or supportive care. Complete surgical eradication of a tumor with resection of adjacent lymph nodes represents the best chance for long-term survival. The choice of operation depends upon the location of the tumor, the clinical stage, and the histologic type. Chemotherapy can provide symptom palliation, improve quality of life, and prolong survival in patients with advanced gastric cancer. Preoperative radiation therapy may allow for tumor downstaging and reduced probability of residual microscopic disease at surgery.

Recapitulation of ras oncogene mutations in breast cancer.

Several human breast cancer cell lines have been shown to contain mutational activation of Ras oncogenes. The goal of this review is to clarify the physiology and biochemical pathways of Ras family oncogenes in order to understand thoroughly the mechanisms behind Ras gene mutations. Ras genes are involved in the early stages of mammary oncogenesis through augmented expression of the normal p21 protein. Recognition of the mechanisms resulting in aberrant expression of Ras, as well as unveiling the influence of the Ras family gene activation in the Ras signaling pathway, should have a major impact on clarifying the oncogenetic process, possibly offering candidate therapy and prevention strategies.

Stapled cholecystojejunostomy for palliative treatment of the malignant jaundice; an effective and feasible alternative to hand-sewn method.

Unresectable periampullary cancer is commonly characterized by painless jaundice and has a rapid evolution with dismal prognosis. Biliary drainage can be achieved by various techniques and approaches, with the endoscopic drainage being the preferred method. However, when open surgery is performed with the intent to resect a tumor which is finally found to be unresectable, open drainage of the biliary tree is indicated. We present a new technique of cholecystojejunostomy using a circular mechanical stapler, which could be used in patients with intact gallbladder and widely patent the cystic duct. The described cholecystoenterostomy with the use of a circular mechanical stapler is the first reported in the literature. The procedure has been successfully used in 6 patients with excellent results. No early recurrence of biliary obstruction, cholangitis or post-operative anastomotic complications were observed. The relative simplicity of the procedure, the shorter operative time and the effective relief of jaundice, are the main advantages of the proposed technique. We believe that this method needs further investigation and can be proved effective in reducing hospitalization and anastomotic complications, compared to hand-sewn techniques.

Retained surgical sponges: what the practicing clinician should know.

Retained surgical sponges (RSS) are an avoidable complication following surgical operations. RSS can elicit either an early exudative-type reaction or a late aseptic fibrous tissue reaction. They may remain asymptomatic for long time; when present, symptomatology varies substantially and includes septic complications (abscess formation, peritonitis) or fibrous reaction resulting in adhesion formation or fistulation into adjacent hollow organs or externally. Plain radiograph may be useful for the diagnosis; however, computed tomography is the method of choice to establish correct diagnosis preoperatively. Removal of RSS is always indicated to prevent further complications. This is usually accomplished by open surgery; rarely, endoscopic or laparoscopic removal may be successful. Prevention is of key importance to avoid not only morbidity and even mortality but also medicolegal consequences. Preventive measures include careful counting, use of sponges marked with a radiopaque marker, avoidance of use of small sponges during abdominal procedures, careful examination of the abdomen by the operating surgeon before closure, radiograph in the operating theater (either routinely or selectively), and recently, usage of barcode and radiofrequency identification technology.

Facing the challenge of treating gallbladder carcinoma. Review of the literature.

Gallbladder carcinoma (GBC) remains the most common biliary tract malignancy and is characterized as an aggressive and highly lethal disease. There is also a wide discrepancy among sources regarding the epidemiology of the tumor. Despite recent research on the therapeutic strategies against gallbladder neoplastic disorders, surgical resection appears the only potentially curative approach. Unfortunately, a mere minority of patients is eligible to undergo surgical intervention. In addition, surgical removal of gallbladder tumor does not necessarily guarantee patient's long-term recovery. Alternative therapies, such as radio and chemotherapy proved insufficient. The aim of this review was to evaluate the results of surgical treatment for GBC with special reference to the extent of its histological spread and to present the recent literature in order to provide an update on the current concepts of surgical management of the disease.

Walled-off pancreatic necrosis.

Walled-off pancreatic necrosis (WOPN), formerly known as pancreatic abscess is a late complication of acute pancreatitis. It can be lethal, even though it is rare. This critical review provides an overview of the continually expanding knowledge about WOPN, by review of current data from references identified in Medline and PubMed, to September 2009, using key words, such as WOPN, infected pseudocyst, severe pancreatitis, pancreatic abscess, acute necrotizing pancreatitis (ANP), pancreas, inflammation and alcoholism. WOPN comprises a later and local complication of ANP, occurring more than 4 wk after the initial attack, usually following development of pseudocysts and other pancreatic fluid collections. The mortality rate associated with WOPN is generally less than that of infected pancreatic necrosis. Surgical intervention had been the mainstay of treatment for infected peripancreatic fluid collection and abscesses for decades. Increasingly, percutaneous catheter drainage and endoscopic retrograde cholangiopancreatography have been used, and encouraging results have recently been reported in the medical literature, rendering these techniques invaluable in the treatment of WOPN. Applying the recommended therapeutic strategy, which comprises early treatment with antibiotics combined with restricted surgical intervention, fewer patients with ANP undergo surgery and interventions are ideally performed later in the course of the disease, when necrosis has become well demarcated.

Sentinel lymph node biopsy in breast cancer: a systematic review.

Lymphatic mapping and sentinel lymphadenectomy have become an important tool for axillary lymph node staging in women with early-stage breast cancer. Many issues such as indications, usefulness, or best method of performing a sentinel node biopsy need to be addressed. Multiple studies now confirm that sentinel lymphadenectomy accurately stages the axilla and is associated with less morbidity than axillary dissection. Blue dye, radiocolloid, or both can be used to identify the sentinel node, and several injection techniques may be used successfully. Many patient factors previously thought to affect accuracy of the procedure have now been shown to be of limited significance. This paper's main purpose is to present the pros and cons of the sentinel lymph node biopsy, and to elucidate all questions regarding to the matter by reviewing the current medical literature.

Small (<10 mm) thyroid nodules; how aggressively should they be managed?

Most commonly, an aggressive management (including surgery) is recommended for thyroid nodules measuring >10 mm. The aim of this review is to present currently available data regarding indications for aggressive treatment of small (<10 mm) thyroid nodules. Clinical factors (history of neck irradiation; extremes of age, i.e. children or elderly patients; family history of thyroid cancer, specifically medullary thyroid cancer, and MEN 2 A or B or familial medullary thyroid cancer; rapid growth of nodule), findings from routine laboratory investigation (increased thyroglobulin or calcitonin levels) or genetic testing (specific RET gene mutations), echomorphological characteristics of the suspicious nodule, and the result of fine-needle aspiration (FNA) should be combined to select those patients with small thyroid nodules, who should be treated surgically. In conclusion, nodule size per se is not an absolute criterion of safety. Aggressive treatment may be indicated in the presence of suspicious clinical/laboratory and/or ultrasound (US) findings. US-guided FNA should be performed when malignancy is a concern, regardless of nodule size, to avoid missing or undertreating a curable cancer.

Current trends in the management of infected necrotizing pancreatitis.

Severe acute pancreatitis is a potentially life-threatening disease. Pancreatic necrosis is associated with an aggravated prognosis, while superimposed infection is almost always lethal without surgery. Bacterial translocation mainly from the gut is the most widely accepted mechanism in the pathogenesis of infected pancreatic necrosis. Infected pancreatic necrosis should be suspected in the presence of the usual markers of systemic inflammation (i.e., fever and leukocytosis), organ failure, or a protracted severe clinical course. The diagnostic method of choice to confirm the diagnosis of pancreatic necrosis is contrast-enhanced computed tomography, where necrotic areas are evidenced as regions without enhancement. The presence of pancreatic necrotic infection should be based on a combination of clinical manifestations, results of laboratory investigation (mainly increased levels of CRP and / or procalcitonin), and can be confirmed by image-guided fine-needle aspiration and gram stain /culture of the aspirates. Surgery remains the treatment of choice for the management of infected pancreatic necrosis and involves open necrosectomy (debridement) and wide drainage of the peripancreatic areas, often in association with continuous irrigation. Planned reoperations may be required to achieve complete removal of the necrotic / infected material. The timing of surgery is of paramount importance; ideally, surgery should be performed after 2 or 3 weeks from the onset of pancreatitis. Recently, various minimally invasive approaches have been described, but they have not been compared in prospective trials with the classical open surgery. Antibiotic therapy is routinely used in patients with infected necrotizing pancreatitis, in conjunction with surgical debridement; its role, however, in the management of patients with sterile necrosis is recently questioned. Nutritional support should be taken into consideration in these patients; enteral nutrition should be preferred over total parenteral nutrition to improve the anatomical and functional integrity of the gut mucosa, thereby preventing bacterial translocation.

A case of signet ring carcinoma of the appendix: dilemmas in differential diagnosis and management.

PURPOSE: Signet ring carcinoma (SRC) of the appendix consists one of the most biologically virulent cancers. We present the case of a patient with primary SRC complicated by the development of acute inflammation of the appendix. CASE REPORT: A 78-year-old man was admitted due to a 5-day history of increasing colicky abdominal pain and vomiting. Clinical examination revealed a firm, tender mass in the right ileac fossa. Laparotomy confirmed a tumor mass which appeared to originate from the appendix. The affected part of the bowel was resected and a right hemicolectomy with an end-to-side ileotransverse anastomosis was performed. The appendix was notably thickened with an ulcerated wall containing sinus tracts, chronic inflammation, and scarring. Moreover, a focus of SRC was detected. CONCLUSIONS: Appendiceal SRC is a rare entity, which may sometimes be confused with other pathologies providing difficulties in differential diagnosis, having an impact on therapeutic decisions and affecting prognosis.