Expression of E-cadherin repressors SNAIL, ZEB1 and ZEB2 by tumour and stromal cells influences tumour-budding phenotype and suggests heterogeneity of stromal cells in pancreatic cancer.

BACKGROUND: There is evidence that tumour-stroma interactions have a major role in the neoplastic progression of pancreatic ductal adenocarcinoma (PDAC). Tumour budding is thought to reflect the process of epithelial-mesenchymal transition (EMT); however, the relationship between tumour buds and EMT remains unclear. Here we characterize the tumour-budding- and stromal cells in PDAC at protein and mRNA levels concerning factors involved in EMT. METHODS: mRNA in situ hybridisation and immunostaining for E-cadherin, ß-catenin, SNAIL1, ZEB1, ZEB2, N-cadherin and TWIST1 were assessed in the main tumour, tumour buds and tumour stroma on multipunch tissue microarrays from 120 well-characterised PDACs and associated with the clinicopathological features, including peritumoural (PTB) and intratumoural (ITB) budding. RESULTS: Tumour-budding cells showed increased levels of ZEB1 (P<0.0001) and ZEB2 (P=0.0119) and reduced E-cadherin and ß-catenin (P<0.0001, each) compared with the main tumour. Loss of membranous ß-catenin in the main tumour (P=0.0009) and tumour buds (P=0.0053), without nuclear translocation, as well as increased SNAIL1 in tumour and stromal cells (P=0.0002, each) correlated with high PTB. ZEB1 overexpression in the main tumour-budding and stromal cells was associated with high ITB (P=0.0084; 0.0250 and 0.0029, respectively) and high PTB (P=0.0005; 0.0392 and 0.0007, respectively). ZEB2 overexpression in stromal cells correlated with higher pT stage (P=0.03), lymphatic invasion (P=0.0172) and lymph node metastasis (P=0.0152). CONCLUSIONS: In the tumour microenvironment of phenotypically aggressive PDAC, tumour-budding cells express EMT hallmarks at protein and mRNA levels underlining their EMT-type character and are surrounded by stromal cells expressing high levels of the E-cadherin repressors ZEB1, ZEB2 and SNAIL1, this being strongly associated with the tumour-budding phenotype. Moreover, our findings suggest the existence of subtypes of stromal cells in PDAC with phenotypical and functional heterogeneity.

Trends and outcomes in the use of surgery and radiation for the treatment of locally advanced esophageal cancer: a propensity score adjusted analysis of the surveillance, epidemiology, and end results registry from 1998 to 2008.

We examined outcomes and trends in surgery and radiation use for patients with locally advanced esophageal cancer, for whom optimal treatment isn't clear. Trends in surgery and radiation for patients with T1-T3N1M0 squamous cell or adenocarcinoma of the mid or distal esophagus in the Surveillance, Epidemiology, and End Results database from 1998 to 2008 were analyzed using generalized linear models including year as predictor; Surveillance, Epidemiology, and End Results doesn't record chemotherapy data. Local treatment was unimodal if patients had only surgery or radiation and bimodal if they had both. Five-year cancer-specific survival (CSS) and overall survival (OS) were analyzed using propensity-score adjusted Cox proportional-hazard models. Overall 5-year survival for the 3295 patients identified (mean age 65.1 years, standard deviation 11.0) was 18.9% (95% confidence interval: 17.3-20.7). Local treatment was bimodal for 1274 (38.7%) and unimodal for 2021 (61.3%) patients; 1325 (40.2%) had radiation alone and 696 (21.1%) underwent only surgery. The use of bimodal therapy (32.8-42.5%, P = 0.01) and radiation alone (29.3-44.5%, P < 0.001) increased significantly from 1998 to 2008. Bimodal therapy predicted improved CSS (hazard ratios [HR]: 0.68, P < 0.001) and OS (HR: 0.58, P < 0.001) compared with unimodal therapy. For the first 7 months (before survival curve crossing), CSS after radiation therapy alone was similar to surgery alone (HR: 0.86, P = 0.12) while OS was worse for surgery only (HR: 0.70, P = 0.001). However, worse CSS (HR: 1.43, P < 0.001) and OS (HR: 1.46, P < 0.001) after that initial timeframe were found for radiation therapy only. The use of radiation to treat locally advanced mid and distal esophageal cancers increased from 1998 to 2008. Survival was best when both surgery and radiation were used.

Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07.

BACKGROUND: We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS: Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS: The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

Tumour budding is a strong and independent prognostic factor in pancreatic cancer.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that escapes detection and resists treatment. Tumour budding, defined as the presence of de-differentiated single tumour cells or small cell clusters at the invasive front of gastrointestinal carcinomas like colorectal, oesophageal, gastric and ampullary, is linked to adverse prognosis. Tumour budding has not yet been reported in PDAC. AIM: To assess the frequency and prognostic impact of tumour budding in PDAC. METHODS: Whole-tissue sections of 117 PDACs with full clinico-pathological and follow-up information, including postoperative therapy, were stained using a pancytokeratin marker. Tumour budding was assessed in 10 high-power fields (HPFs) by two pathologists. High-grade budding was defined as an average of >10buds across 10HPFs. Measurements were correlated to patient and tumour characteristics. The study was performed according to the REMARK guidelines. RESULTS: Inter-observer agreement was considered strong (ICC=0.72). Low-grade budding was observed in 29.7% and high-grade budding in 70.3% cases. High-grade budding was linked to advanced pT classification (p=0.0463), lymphatic invasion (p=0.0192) and decreased disease-free (p=0.0005) and overall survival (p<0.0001). There was no association with pN, pM, R-status or blood vessel invasion. In multivariate analysis, the prognostic effect of tumour budding was independent of lymph node metastasis, lymphatic invasion and R-status (p<0.0001; HR (95% CI): 3.65 (2.1-6.4)). CONCLUSIONS: Our results show that high-grade tumour budding occurs frequently in PDAC and is a strong, independent and reproducible, highly unfavourable prognostic factor that could be used to guide future individualised therapeutic approaches.

Appendiceal mucocele in an elderly patient: how much surgery?

Appendiceal mucoceles are rare cystic lesions with an incidence of 0.3-0.7% of all appendectomies. They are divided into four subgroups according to their histology. Even though the symptoms may vary - depending on the level of complication - from right lower quadrant pain, signs of intussusception, gastrointestinal bleeding to an acute abdomen with sepsis, most mucoceles are asymptomatic and found incidentally. We present the case of a 70-year-old patient with an incidentally found appendiceal mucocele. He was seen at the hospital for backache. The CT scan showed a vertebral fracture and a 7-cm appendiceal mass. A preoperative colonoscopy displayed several synchronous adenomas in the transverse and left colon with high-grade dysplasia. In order to lower the cancer risk of this patient, we performed a subtotal colectomy. The appendiceal mass showed no histopathological evidence of malignancy and no sign of perforation. The follow-up was therefore limited to 2 months. In this case, appendectomy would have been sufficient to treat the mucocele alone. The synchronous high-grade dysplastic adenomas were detected in the preoperative colonoscopy and determined the therapeutic approach. Generally, in the presence of positive lymph nodes, a right colectomy is the treatment of choice. In the histological presence of mucinous peritoneal carcinomatosis, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is indicated. In conclusion, mucoceles of the appendix are detected with high sensitivity by CT scan. If there is no evidence of synchronous tumor preoperatively and no peritoneal spillage, invasion or positive sentinel lymph nodes during surgery, a mucocele is adequately treated by appendectomy.

Systematic review of atraumatic splenic rupture.

BACKGROUND: Atraumatic splenic rupture (ASR) is an ill defined clinicopathological entity. METHODS: The aim was to characterize aetiological and risk factors for ASR-related mortality in order to aid disease classification and treatment. A systematic literature review (1980-2008) was undertaken and logistic regression analysis employed. RESULTS: Some 632 publications reporting 845 patients were identified. The spleen was normal in 7.0 per cent (atraumatic-idiopathic rupture). One, two or three aetiological factors were found in 84.1, 8.2 and 0.7 per cent respectively (atraumatic-pathological rupture). Six major aetiological groups were defined: neoplastic (30.3 per cent), infectious (27.3 per cent), inflammatory, non-infectious (20.0 per cent), drug- and treatment-related (9.2 per cent) and mechanical (6.8 per cent) disorders, and normal spleen (6.4 per cent). Treatment comprised total splenectomy (84.1 per cent), organ-preserving surgery (1.2 per cent) or conservative measures (14.7 per cent). The ASR-related mortality rate was 12.2 per cent. Splenomegaly (P = 0.040), age above 40 years (P = 0.007) and neoplastic disorders (P = 0.008) were associated with increased ASR-related mortality on multivariable analysis. CONCLUSION: The condition can be classified simply into atraumatic-idiopathic (7.0 per cent) and atraumatic-pathological (93.0 per cent) splenic rupture. Splenomegaly, advanced age and neoplastic disorders are associated with increased ASR-related mortality.

Roux-en-Y drainage of the pancreatic stump decreases pancreatic fistula after distal pancreatic resection.

Clinically relevant fistula after distal pancreatic resection occurs in 5-30% of patients, prolonging recovery and considerably increasing in-hospital stay and costs. We tested whether routine drainage of the pancreatic stump into a Roux-en-Y limb after distal pancreatic resection decreased the incidence of fistula. From October 2001, data of all patients undergoing pancreatic distal resection were entered in a prospective database. From June 2003 after resection, the main pancreatic duct and the pancreatic stump were oversewn, and in addition, anastomosed into a jejunal Roux-en-Y limb by a single-layer suture (n = 23). A drain was placed near the anastomosis, and all patients received octreotide for 5-7 days postoperatively. The volume of the drained fluid was registered daily, and concentration of amylase was measured and recorded every other day. Patient demographics, hospital stay, pancreatic fistula incidence (> or =30 ml amylase-rich fluid/day on/after postoperative day 10), perioperative morbidity, and follow-up after discharge were compared with our initial series of patients (treated October 2001-May 2003) who underwent oversewing only (n = 20). Indications, patient demographics, blood loss, and tolerance of an oral diet were similar. There were four (20%) pancreatic fistulas in the "oversewn" group and none in the anastomosis group (p < 0.05). Nonsurgical morbidity, in-hospital stay, and follow-up were comparable in both groups.

[Positive ibopamine provocative test in normal-tension glaucoma suspects]. / Positiver Ibopamin Provokationstest bei Verdacht auf Niederdruckglaukom.

BACKGROUND: Ibopamine is an alpha-adrenergic agent and causes an elevation of intraocular pressure in eyes with increased outflow resistance. It has been proposed as a test substance for the detection of early ocular hydrodynamic disorders. PATIENTS AND METHODS: A total of 64 normal-tension glaucoma suspect eyes without anti-hypertensive treatment were enrolled. A daily pressure curve was registered with measurements at 7:00 am, 8:00 am, 12:00 am, 17:00 pm using an applanation tonometer and a contour tonometer followed by instillation of ibopamine 2% in both eyes. Tonometry was performed every 15 minutes during the following hour. An IOP increase of > 2.0 mmHg was considered positive. RESULTS: The positive test group showed a significant pressure increase from 18.04 to 22.06 mmHg. Ocular pulse amplitude increased from 2.96 to 3.97 mmHg and was positively correlated with the pressure. Intraocular pressure was unchanged in the negative test group. Central corneal thickness was not significantly different in the two groups (p = 0.32). CONCLUSIONS: Ibopamine 2% eye drops have a positive pressure effect in 50% of suspected normal-tension glaucoma eyes and may differentiate between eyes with normal trabecular outflow capacity and eyes with increased resistance in the trabecular meshwork that are prone to pressure peaks and deterioration to glaucoma.

Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer.

N-myc downstream-regulated gene-1 (NDRG1) is a recently described hypoxia-inducible protein that is upregulated in various human cancers. Pancreatic ductal adenocarcinoma, called pancreatic cancer, is a highly aggressive cancer that is characterised by its avascular structure, which results in a severe hypoxic environment. In this study, we investigated whether NDRG1 is upregulated in these tumours, thus providing a novel marker for malignant cells in the pancreas. By immunohistochemistry, we observed that NDRG1 was highly expressed in well-differentiated cells of pancreatic cancer, whereas the poorly differentiated tumour cells were negative. In addition, hyperplastic islets and ducts of nonquiescent pancreatic tissue were positive. To further explore its selective expression in tumours, two well-established pancreatic cancer cell lines of unequal differentiation status were exposed to 2% oxygen. NDRG1 mRNA and protein were upregulated by hypoxia in the moderately differentiated Capan-1 cells; however, its levels remained unchanged in the poorly differentiated Panc-1 cell line. Taken together, our data suggest that NDRG1 will not serve as a reliable marker of tumour cells in the pancreas, but may serve as a marker of differentiation. Furthermore, we present the novel finding that cellular differentiation may be an important factor that determines the hypoxia-induced regulation of NDRG1.

Laparoscopic ventral hernia repair is safe and cost effective.

BACKGROUND: Ventral hernia repair is increasingly performed by laparoscopic means since the introduction of dual-layer meshes. This study aimed to compare the early complications and cost effectiveness of open hernia repair with those associated with laparoscopic repair. METHODS: Open ventral hernia repair was performed for 92 consecutive patients using a Vypro mesh, followed by laparoscopic repair for 49 consecutive patients using a Parietene composite mesh. RESULTS: The rate of surgical-site infections was significantly higher with open ventral hernia repair (13 vs 1; p = 0.03). The median length of hospital stay was significantly shorter with laparoscopic surgery (7 vs 6 days; p = 0.02). For laparoscopic repair, the direct operative costs were higher (2,314 vs 2,853 euros; p = 0.03), and the overall hospital costs were lower (9,787 vs 7,654 euros; p = 0.02). CONCLUSIONS: Laparoscopic ventral hernia repair leads to fewer surgical-site infections and a shorter hospital stay than open repair. Despite increased operative costs, overall hospital costs are lowered by laparoscopic ventral hernia repair.

[Preserving vision in the elderly: a survey to start a quality development program in general practice]. / Erhaltung des Sehvermögens im Alter: Eine Patienten- und Hausarztbefragung zur Einleitung eines Qualitätsentwicklungsprojektes in der Hausarztpraxis.

The study examined the rate of patients, who do not follow recommendations for routine screening, do not visit physicians for eye-symptoms and when suffering from diabetes or glaucoma do not adhere to follow-up. To what extent can primary care physicians impact on these deficits of ophthalmologic care? 4918 consecutive, > or = 40 old patients of 107 primary care physicians of 9 networks participated. Of these patients 15% had never, 43% not within the last 3 years, consulted an ophthalmologist. 16% were diabetics, 7% had glaucoma and 46% had observed subjective eye symptoms. A quarter of these patients turn to their primary care physician, when having eye problems. Primary care physicians do not frequently suggest routine ophthalmologic controls nor do they use diagnostic tools like the Amsler-grid or the Swinging-Flash-Light Test.

Predictive value of complement activation fragments C3a and sC5b-9 for development of severe disease in patients with acute pancreatitis.

BACKGROUND: Complement activation has been shown to occur in patients with acute pancreatitis. However, the diagnostic potential of complement activation products in plasma for predicting severe disease remains unclear to date. METHODS: The daily levels of the complement anaphylatoxin C3a and the soluble terminal complement complex sC5b-9 were determined by ELISA in plasma of patients with mild (n = 16) or severe (n = 14) acute pancreatitis during the first week after onset of symptoms, and in healthy control subjects (n = 14). RESULTS: Both C3a and sC5b-9 were significantly elevated during the first 7 days in plasma of patients with severe acute pancreatitis (C3a: 459.3 +/- 407.5 ng/mL (mean +/- s); sC5b-9: 617.9 +/- 297.7 ng/mL), as compared to patients with mild disease (C3a: 172 +/- 149.5 ng/mL; sC5b-9: 306.7 +/- 167.3 ng/mL) or controls (C3a: 102.3 +/- 19.7 ng/mL; sC5b-9: 40.64 +/- 19.7 ng/mL; P < 0.001, repeated measures ANOVA). The analysis of both parameters in combination during the first week after onset of symptoms revealed a high sensitivity (0.93) and specificity (0.88) as well as high negative and positive predictive values (0.93 and 0.87, respectively) with an odds ratio of 91.0 for the development of pancreatic necrosis (P < 0.0001, Fisher exact test). CONCLUSION: In patients with acute pancreatitis, the plasma levels of complement C3a and sC5b-9 measured daily during the first week after onset of symptoms represent highly specific and sensitive parameters for the prediction of severe acute pancreatitis.

[Technique of pancreatic anastomosis]. / Technik der Pankreasanastomose.

Postoperative morbidity after pancreatic resection is primarily due to leakage of the pancreatic anastomosis. The duct-to-mucosa pancreatico-jejunostomy either as an end-to-end or end-to-side anastomosis is the preferred technique in our hands. The use of a temporarily catheter to drain the main pancreatic duct is optimal. The pancreatic leakage rate depends in many series on the consistence of the pancreatic parenchyma, the diameter of the major pancreatic duct and the local perfusion. A meticulous, standardized technique, the possibility to adapt the technique in case of unexpected findings and the operative routine of the surgeon are of paramount importance for achieving a low leakage rate. In so called "high volume" centers the pancreatic fistula rate today is in the range of 3 to 13% and the mortality of pancreatic head resection varies between 0.5 and 3%.

Role of laparoscopy in hepatic cyst surgery.

BACKGROUND: Hepatic cysts are detected incidentally in 2.5-5% of the population. Only about 15% of such cysts are symptomatic. Since laparoscopic deroofing for liver cysts was first described in 1991 there have been a number of reports of successful laparoscopic management of hepatic cysts, including the laparoscopic management of complex and parasitic cysts. METHODS: A systematic review of English-language articles on the subject appearing in journals through May 2002 was conducted using the Medline database. RESULTS: Only a minority of cystic liver lesions need treatment, and the therapeutic approach is guided by the type of cyst. Laparoscopic deroofing (combined with omentoplasty and/or oversewing) of uncomplicated liver cysts is associated with a recurrence rate of 10-25%, with less morbidity and mortality as compared to open surgery. On the other hand, treatment of complex liver cysts and hydatid cysts by laparoscopy is not considered a standard approach. CONCLUSION: The laparoscopic approach in uncomplicated but symptomatic liver cysts is effective, with low morbidity and mortality. Additional omentoplasty or oversewing appears to reduce the recurrence rate.

Therapeutic concept for acute leg and pelvic venous thrombosis.

Combination treatment in acute deep venous thrombosis essentially consists of a highly dosed locoregional thrombolysis of the valve-carrying crurofemoral axis and a mechanical thrombectomy of the valveless pelvic axis by Fogarty catheter. The success of this method is due to the fact that it largely eliminates the disadvantages of systemic thrombolysis, as well as those at conventional surgical thrombectomy, whilst retaining the advantages. Using combination treatment in acute leg and pelvic venous thrombosis within the first 7 days can result in restitutio ad integrum, i.e. complete desobliteration with maintained valve function in more than 80% of the cases.

Pancreatic stellate cells contribute to regeneration early after acute necrotising pancreatitis in humans.

BACKGROUND AND AIM: The aim of this study was to systematically analyse the pattern of regeneration in human acute pancreatitis by testing whether pancreatic stellate cells, their myofibroblastic offspring, and pancreatic ductules are involved in the regenerative process. PATIENTS AND METHODS: Between January 1994 and November 2000, 24 necrosectomy specimens containing vital tissue were obtained for pathological examination. Formalin fixed tissue samples were routinely processed and immunostained for cytokeratins 7 and 19, smooth muscle actin, desmin, Ki-67, and CD68. Pancreatic tissue from organ donors served as normal controls. RESULTS: Necrosectomy specimens were obtained between 11 and 41 days after the onset of symptoms. In vital areas of necrosectomy samples, spherical hypercellular spheres consisting of loose vascular connective tissue occurred, in part showing duct-like profiles which sprouted from remnant exocrine tissue almost perpendicular to the periphery of the spheres. In normal tissue, only a few stellate cells and myofibroblasts were present around ducts and ductules. In contrast, numerous stellate cells and myofibroblasts were detected in the hypercellular regenerative spheres after acute pancreatitis, both being situated within the loose tissue and forming compact periductular sheaths. Stellate cells/myofibroblasts and ductule cells exhibited increased proliferative activity. CONCLUSIONS: Pancreatic stellate cells and their activated myofibroblastic offspring may participate in regeneration after acute necrotising pancreatitis in humans. Time course studies are needed to further strengthen this regeneration concept.