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Data on Mesothelin expression in human normal and cancerous tissues is controversial. We employed immunohistochemistry on a tissue microarray from 599 pancreatic cancers and 12 large tissue sections of pancreatitis. Mesothelin expression was highest in pancreatic adenocarcinomas (89%) and adenocarcinomas of the ampulla Vateri (79%), infrequent in pancreatitis and absent in 6 acinus cell carcinomas and normal pancreas. Mesothelin expression was unrelated to pathological tumor stage, grade, metastasis, and tumor infiltrating CD8+ lymphocytes. In conclusion, pancreatic cancer may be ideally suited for putative anti-mesothelin therapies, and mesothelin may represent a suitable biomarker for pancreatic cancer diagnosis, especially on small biopsies.

BACKGROUND Immune checkpoint-inhibitors targeting the PD-1/PD-L1 system are FDA approved in microsatellite instable (MSI) or mismatch repair deficient (dMMR) colorectal cancer (CRC). PD-L1 expression is tightly linked to features connected to immune checkpoint inhibitor response, but studies on large subsets of cancers analyzing the correlation between different status of MSI/dMMR, tumor infiltrating lymphocytes and PD-L1 expression are still lacking. METHODS More than 1800 CRC were analyzed for PD-L1 by immunohistochemistry in a tissue microarray format. Data were compared to MMR, the number of intratumoral CD8+ cytotoxic T-cells, and adverse clinico-pathological parameters. Different cutoff levels for defining PD-L1 positivity in tumor cells (1%, 5%, 10%, and 50%) yielded comparable results. RESULTS At a cutoff level of 5%, PD-L1 positivity was seen in 5.1% of tumors. PD-L1 was more often positive in dMMR (18.6%) than in MMR proficient (pMMR) cancers (4.1%; p

Introduction: Mucin 5AC (MUC5AC) belongs to the family of secreted gel-forming mucins. It is physiologically expressed in some normal mucin producing epithelial cells but also in pancreatic, ovarian, and colon cancer cells. The role of MUC5AC expression in cancer is not fully understood. This study was designed to explore the role of MUC5AC for pancreatic cancer progression, its association to microsatellite instability, and its diagnostic utility. Methods: Mucin 5AC expression was studied immunohistochemically in a tissue microarray (TMA) from 532 pancreatic cancers, 61 cancers of the ampulla Vateri, six acinar cell carcinomas and 12 large sections of pancreatitis. Results: Mucin 5AC staining was interpretable in 476 of 599 (79%) arrayed cancers. Staining was completely absent in normal pancreas and pancreatitis, but frequent in pancreatic cancer. Membranous and cytoplasmic MUC5AC expression was most common in pancreatic adenocarcinomas (71% of 423), followed by carcinomas of the ampulla Vateri (43% of 47), and absent in six acinar cell carcinomas. Mucin 5AC expression was unrelated to tumor phenotype (tumor stage, tumor grade, lymph node, and distant metastasis), and microsatellite instability in ductal adenocarcinomas and carcinomas of the ampulla Vateri. Conclusion: Our study indicates that MUC5AC is an excellent biomarker for pancreatic cancer diagnosis, especially to support the sometimes-difficult diagnosis on small biopsies. Mucin 5AC expression is unrelated to pancreatic cancer aggressiveness.

The transmembrane channel protein DOG1 (Discovered on GIST1) is normally expressed in the gastrointestinal interstitial cells of Cajal and also in gastrointestinal stroma tumors arising from these cells. However, there is also evidence for a relevant role of DOG1 expression in colorectal cancers. This study was undertaken to search for associations between DOG1 expression and colon cancer phenotype and key molecular alterations.A tissue microarray containing samples from more than 1,800 colorectal cancer patients was analyzed by immunohistochemistry.DOG1 immunostaining was detected in 503 (30.2%) of 1,666 analyzable colorectal cancers and considered weak in 360 (21.6%), moderate in 78 (4.7%), and strong in 65 (3.9%). Strong DOG1 immunostaining was associated with advanced pT stage (p=0.0367) and nodal metastases (p=0.0145) but these associations were not retained in subgroups of 1,135 mismatch repair proficient and 86 mismatch repair deficient tumors. DOG1 positivity was significantly linked to several molecular tumor features including mismatch repair deficiency (p=0.0034), BRAF mutations (p0.0001), nuclear p53 accumulation (p=0.0157), and PD-L1 expression (p=0.0199) but unrelated to KRAS mutations and the density of tumor infiltrating CD8 positive lymphocytes.Elevated DOG1 expression is frequent in colorectal cancer and significantly linked to important molecular alterations. However, DOG1 overexpression is largely unrelated to histopathological parameters of cancer aggressiveness and may thus not serve as a prognostic parameter for this tumor entity.

Mucin 5AC (MUC5AC) is a secreted gel-forming mucin expressed by several epithelia. In the colon, MUC5AC is expressed in scattered normal epithelial cells but can be abundant in colorectal cancers. To clarify the relationship of MUC5AC expression with parameters of tumor aggressiveness and mismatch repair deficiency (dMMR) in colorectal cancer, a tissue microarray containing 1812 colorectal cancers was analyzed by immunohistochemistry. MUC5AC expression was found in 261 (15.7%) of 1,667 analyzable colorectal cancers. MUC5AC expression strongly depended on the tumor location and gradually decreased from proximal (27.4% of cecum cancers) to distal (10.6% of rectal cancers; p p p

Background Microsatellite instability (MSI) has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in pancreatic cancer, but data on the possible extent of intratumoral heterogeneity are lacking. Methods To study MSI heterogeneity in pancreatic cancer, a tissue microarray (TMA) comprising 597 tumors was screened by immunohistochemistry with antibodies for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. Results In six suspicious cases, large section immunohistochemistry and microsatellite analysis (Bethesda panel) resulted in the identification of 4 (0.8%) validated MSI cases out of 480 interpretable pancreatic ductal adenocarcinomas. MSI was absent in 55 adenocarcinomas of the ampulla of Vater and 7 acinar cell carcinomas. MMR deficiency always involved MSH6 loss, in three cases with additional loss of MSH2 expression. Three cancers were MSI-high and one case with isolated MSH6 loss was MSS in PCR analysis. The analysis of 44 cancer-containing tumor blocks revealed that the loss of MMR protein expression was always homogeneous in affected tumors. Automated digital image analysis of CD8 immunostaining demonstrated markedly higher CD8 + tumor infiltrating lymphocytes in tumors with (mean = 685, median = 626) than without (mean = 227; median = 124) MMR deficiency (p Conclusions Our data suggest that MSI occurs early in a small subset of ductal adenocarcinomas of the pancreas and that immunohistochemical MMR analysis on limited biopsy or cytology material may be sufficient to estimate MMR status of the entire cancer mass.

Transvaginal specimen removal has been introduced 20 years ago but then abandoned. With the advent of transvaginal interventions following the introduction of natural orifice transluminal endoscopic surgery, renewed interest was generated for hybrid procedures with minimal access for the intervention and use of transvaginal (TV) specimen removal. We present the first such series after laparoscopic distal pancreatectomy.In seven subsequent women (median age 48 years) with body and tail pancreatic tumors undergoing laparoscopic distal pancreatectomy, the new method of TV specimen removal was applied. The patients' data and the technical successes as well as intra- and postprocedural complications were recorded prospectively. The patients were followed after discharge for gynecological examination.Specimen removal consisting of the pancreas and spleen in five and the pancreas only in two cases was technically successful; no intraoperative complications were encountered. Postoperative complications consisted of one case of intra-abdominal hemorrhage and one case of pancreatic fistula, attributable to the resection and not to TV specimen removal. Gynecological follow-up was normal in all seven patients.The technique of TV specimen removal is feasible and safe also after laparoscopic distal pancreatectomy. It may help to further diminish the access trauma of laparoscopic pancreatic surgery.

The evaluation of cardiopulmonary parameters is an essential factor for ascertaining of functional operability prior to anatomical lung resection. A predictive formulae for estimating of functional operability based on analysis of cardiorespiratory parameters have not yet been described. In marginal cases, a precise assessment is an important decisive factor under fear of postoperative complication regarding more radical parenchymal resection.The functional tests such as spirometry, spiroergometry, stair climbing exercise, 6-Minute walk test, echocardiography, stress echocardiography and lung perfusion scintigram under consideration of general health situation could provide predictive postoperative information for ascertaining of functional operability.We describe in this review the meaningful cardiorespiratory tests for estimating of the outcome prior to anatomical lung resection.

BACKGROUND: In the recent years natural orifice transluminal endoscopic surgery (NOTES) has been an increasingly popular topic with rising numbers of papers and surgeries. We have developed in 2007 a technique of hybrid transvaginal cholecystectomy (TVC) that can be used in daily routine. METHODS: From June 2007 until September 2010, 165 female patients underwent TVC. Data about patients, indications, operations and follow-up were collected prospectively. RESULTS: One hundred and sixty-four TVC could be performed successfully. We had one case of conversion to conventional laparoscopic cholecystectomy. We report about one intraoperative complication and one postoperative complication. All other postoperative courses were uneventful and the gynecological examination one week postoperatively without pathological findings. CONCLUSIONS: This technique of TVC is as successful as the conventional laparoscopic cholecystectomy and can be used in daily routine.

Background and study aims Natural orifice transluminal endoscopic surgery (NOTES) has been tested in the animal model for a multitude of procedures including cholecystectomy. Clinical experience using flexible endoscopes is, however, very limited. Transvaginal cholecystectomy has been shown to be the most feasible approach in which rigid instruments can be used. We report our experience in all patients treated over a 1-year period. Patients and methods Between June 2007 and June 2008, 68 patients (mean age 50 years) underwent transvaginal cholecystectomy with an additional 5-mm umbilical trocar using rigid laparoscopic instruments. Data about symptoms, operation, and postoperative course were prospectively collected, as were findings of a gynecological follow-up examination 1 week after surgery and the results of an interview at least 3 months after surgery. Results All 68 operations were finished successfully without conversion, with a mean operation time of 51 minutes; in three additional cases severe pelvic adhesions prevented further transvaginal progress. There were no intraoperative or immediately postoperative complications, but one patient presented with a Douglas pouch abscess 3 weeks after surgery. Gynecologic follow-up exams 1 week after surgery were unremarkable. All patients were interviewed 3-10 months after surgery and had no abdominal or gynecological complaints including in relation to sexual intercourse. Conclusion Transvaginal NOTES cholecystectomy with rigid instruments can be safely and effectively performed in daily routine.

The use of natural orifices for operations in the abdominal cavity (natural orifice transluminal endoscopic surgery, or NOTES) could be a conclusive development in the field of minimally invasive surgery. Early in the 1990s we had experiences with posterior colpotomy for removal of specimens in laparoscopic surgery. This is why we use the transvaginal approach in NOTES and combine it with a trocar hidden in the umbilicus. With this technique we could perform cholecystectomy without a visible scar. The operation could become routine also because of the use of our well-known rigid optics and instruments. From June 2007 until April 2008 we operated on 57 patients using this method. All operations finished successfully, and the mean operation time was 54 min. There was one complication. An abscess in the Douglas room had to be evacuated laparoscopically. All other postoperative courses were uneventful. After a minimum follow-up of 3 months, none of the patients had symptoms in the vagina or during sexual intercourse.

Laparoscopic surgery has dramatically improved surgical care of patients reducing postoperative pain, wound infection rate, hospital stay, inability to work, risk of hernia, and cosmetic result. Natural orifice transluminal endoscopic surgery (NOTES) is even less traumatic to the abdominal wall and might further improve minimal invasive surgery of patients, but might also increase surgical risk when used by a transgastric or transcolonic approach with flexible endoscopes. Therefore we decided to use a transvaginal approach using rigid laparoscopic instruments for cholecystectomies.Through a 5-mm incision deep in the umbilicus a pneumoperitoneum was created. The optic and a dissector were inserted through the posterior fornix of the vagina under laparoscopic control from the umbilicus and a transvaginal gallbladder removal was performed.20 patients were successfully operated in a 4.5-month period. Operating time was 62 (35-100) min. No intra- or postoperative complications occurred in any patient. Gynecological examination after 8 days showed no negative findings and the cosmetic result was ideal with no visible scars.In our series we showed that cholecystectomies can be routinely performed in a NOTES technique without visible scar. The transvaginal approach is the safe in NOTES and common laparoscopic instruments can be used as long as there are no better flexible endoscopes for this purpose.

Laparoscopic surgery has decreased trauma and improved results and natural orifice transluminal endoscopic surgery (NOTES) should be a further step in this direction. However the use of flexible gastroscopes in the abdomen is difficult and the generally chosen transgastric approach is not without risk. Therefore we have carried out a cholecystectomy with a combined transvaginal and transumbilical approach, using laparoscopic instruments. The optic and a dissector were inserted in the posterior fornix of the vagina, and a 5-mm trocar was inserted deep in the umbilicus. After dissection the gallbladder was removed through the vagina. The operation was done without problems within 85 minutes and left no visible scar. The postoperative course was uneventful. In NOTES the transvaginal approach has important advantages over the transgastric method (e. g. regarding sterilization and closure); standard laparoscopic instruments can be used whilst there are no flexible endoscopes that are easier to handle.

The EURO-NOTES Clinical Registry (ECR) was established as a European database to allow the monitoring and safe introduction of Natural Orifice Transluminal Endoscopic Surgery (NOTES). The aim of this study was to analyze different techniques applied and relative results during the first 2 years of the ECR.The ECR was designed as a voluntary database with online access. All members of the European Society for Gastrointestinal Endoscopy and the European Association for Endoscopic Surgery were requested to participate in the registry. Demographic and therapy data as well as data on the postoperative course are recorded in the ECR in an anonymous way.A total of 533 patients who underwent NOTES procedures were included in the study. Four different hybrid techniques for 435 cholecystectomies were described, registering postoperative complications in 2.8% of patients, addition of a single trocar in 5.3%, and conversions to laparoscopy in 0.5%. Both flexible endoscopic and rigid laparoscopic cholecystectomy techniques proved to be safe and effective with minor differences. There was a shorter operative time in the rigid laparoscopic group. Thirty-three appendectomies were reported by transgastric and transvaginal techniques, with transvaginal techniques scoring shorter operative time and hospital stay, but with a frequent need to add more trocars. Overall complications occurred in 14.7% of patients but they did not differ significantly among the different techniques. One transvaginal and 31 transanal sigmoidectomies were included for prolapse and diverticulitis, with four postoperative complications (12.5%), but none needing further treatment. Twenty peroral esophageal myotomies were included with three postoperative complications (15.0%), but none needing further treatment.Five years since the introduction of NOTES into clinical practice, hybrid techniques have gained considerable clinical application. Several NOTES hybrid cholecystectomy and appendectomy techniques are practicable and safe alternatives to laparoscopic procedures. Also, sigmoidectomies and peroral esophageal myotomies were described, proving feasibility and safety. Nevertheless, the real benefit of NOTES for patients still needs to be assessed.

Since 2007, natural orifice transluminal endoscopic surgery (NOTES) has been applied in humans. We performed this prospective study to evaluate the transvaginal route in terms of risks, complication rate, and long-term side effects such as dyspareunia. From June 2007 to September 2011, we performed 222 transvaginal hybrid NOTES procedures: 220 transvaginal cholecystectomies (TVC) and 2 transvaginal appendectomies (TVA). All patients were asked to present to our associated gynecologists within 1 week for an examination. After at least 3 months, the patients were interviewed using a standard questionnaire. All operations could be successfully performed in this technique except two cases, which were converted to conventional laparoscopic cholecystectomy. The only intraoperative complication was the puncture of the urine bladder. We observed two postoperative complications: one biliary fistula 3 days after TVC, and one abscess in the Douglas pouch 3 weeks after TVC. The gynecological examinations revealed no abnormalities. The interview (median postoperative time, 6 months) with a follow-up rate of 93 % revealed no pain in the pelvis, dyspareunia, or sexual dysfunction after TVC. The transvaginal route is appropriate for NOTES procedures; there is only a minor and acceptable rate of intra- and postoperative morbidity.

Natural orifice transluminal endoscopic surgery (NOTES) is currently a very important topic for both gastroenterologists and surgeons. We have developed a technique of transvaginal hybrid NOTES cholecystectomy (TVC) that leaves no visible scar and is applicable to daily use. This technique is compared to the conventional laparoscopic cholecystectomy (CLC) in a matched-pair analysis. From June 2007 until February 2009, 108 NOTES cholecystectomies were performed. For a matched-pair analysis we first selected a group of 192 female patients who had undergone CLC and who were operated on by the same group of surgeons in the same time period. Then 108 pairs who had TVC were matched according to the degree of inflammation of the gallbladder and age. We were able to contact 208 patients at least 3 months after surgery. Hence, the study analysis was performed with 100 complete pairs. All 200 cholecystectomies were performed successfully without conversion. The TVC procedure was significantly longer than CLC (52 vs. 35 min, p

Background The EURO-NOTES Clinical Registry (ECR) was established as a European database to allow the monitoring and safe introduction of Natural Orifice Transluminal Endoscopic Surgery (NOTES). The aim of this study was to analyze different techniques applied and relative results during the first 2 years of the ECR.