Prognostic impact of activin subunit inhibin beta A in gastric and esophageal adenocarcinomas.

PURPOSE: Adenocarcinomas of the esophagus (AEG) and stomach (AS) are among the most common cancers worldwide. Novel markers for risk stratification and guiding treatment are strongly needed. Activin is a multi-functional cytokine with context specific pro- and anti-tumorigenic effects. We aimed to investigate the prognostic role of activin tumor protein expression in AEG/ASs. METHODS: Tissue from a retrospective cohort of 277 patients with AEG/AS treated primarily by surgery at the Charité - Universitätsmedizin Berlin was collected and analyzed by immunohistochemistry using a specific antibody to the activin homodimer inhibin beta A. Additionally, we evaluated T-cell infiltration and PD1 expression as well as expression of PD-L1 by immunohistochemistry as possible confounding factors. Clinico-pathologic data were collected and correlated with activin protein expression. RESULTS: Out of 277 tumor samples, 72 (26.0%) exhibited high activin subunit inhibin beta A protein expression. Higher expression was correlated with lower Union for International Cancer Control (UICC) stage and longer overall survival. Interestingly, activin subunit expression correlated with CD4+ T-cell infiltration, and the correlation with higher overall survival was exclusively seen in tumors with high CD4+ T-cell infiltration, pointing towards a role of activin in the tumor immune response in AEG/ASs. CONCLUSION: In our cohort of AEG/AS, higher activin subunit levels were correlated with longer overall survival, an effect exclusively seen in tumors with high CD4+ cell infiltration. Further mechanistic research is warranted discerning the exact effect of this context specific cytokine.

[Successful pembrolizumab therapy in metastasized adenosquamous carcinoma of the colon]. / Erfolgreiche Pembrolizumab-Therapie bei metastasiertem adenosquamösem Karzinom des Kolons.

Adenosquamous carcinoma (ASqC) is an exceedingly rare subtype of colorectal cancer without any known special guidelines for treatment. The biological behaviour and molecular background are widely unknown, although a few case studies report a worse prognosis compared to ordinary colorectal adenocarcinoma. We herein report for the first time the successful immune checkpoint inhibitor therapy in a 40-year-old patient suffering from metastasized right-sided colonic ASqC with unique molecular features, after having previously progressed under standard chemotherapy.

Volume-outcome relationship in pancreatic surgery.

BACKGROUND: Volume-outcome relationships related to major surgery may be of limited value if observation ends at the point of discharge without taking transfers and later events into consideration. METHODS: The volume-outcome relationship in patients who underwent pancreatic surgery between 2008 and 2010 was assessed using claims data for all inpatient episodes from Germany's largest provider of statutory health insurance covering about 30 per cent of the population. Multiple logistic regression models with random effects were used to analyse the effect of hospital volume (using volume quintiles) on 1-year mortality, adjusting for age, sex, primary disease, type of surgery and co-morbidities. Additional outcomes were in-hospital (including transfer to other hospitals until final discharge) and 90-day mortality. RESULTS: Of 9566 patients identified, risk-adjusted 1-year mortality was significantly higher in the three lowest-volume quintiles compared with the highest-volume quintile (odds ratio 1·73, 1·53 and 1·37 respectively). A similar, but less pronounced, effect was demonstrated for in-hospital and 90-day mortality. The effect of hospital volume on 1-year mortality was comparable to the effect of co-morbid conditions such as renal failure. CONCLUSION: Although mortality related to pancreatic surgery is influenced by many factors, this study demonstrated lower mortality at 1 year in high-volume centres in Germany.

Minimally Invasive Surgery for Pancreatic Disease - Current Status.

Laparoscopic procedures have advanced to represent the new gold standard in many surgical fields. Although application in pancreatic surgery is hampered by the friable nature of the gland and the difficulty of its exposure, advanced technology and surgeons' experience are leading to an expansion of minimally invasive pancreatic surgery. Addressing the whole range of main operative procedures, this review analyzes the literature data so far to give an overview about the current status of minimally invasive pancreatic surgery, its indications and limitations. In acute pancreatitis, a step-up approach from percutaneous drainage to retroperitoneoscopic necrosectomy seems beneficial. Transgastric necrosectomy also preserves the retroperitoneal compartment in contrast to the laparoscopic approach, which has widely been abandoned. In tumor pathology, laparoscopic access is adequate for small benign lesions in the pancreatic tail and body. Oncological outcome shows to be at least equal to the open procedure. Concerning laparoscopic pancreaticoduodenectomy, there is no evidence for a patients' benefit currently although several studies prove that it can be done.

Spine surgery in a state-of-the-art hybrid operating room: an experience of 1745 implanted pedicle screws in the thoracolumbar spine.

Hybrid-operating rooms (hybrid-OR) combine high-resolution 2D images and 3D-scans with the possibility of 3D-navigation and allow minimal invasive pedicle screw placement even in the upper thoracic spine. The disadvantage of high cost and increased radiation needs to be compensated with high accuracy and safety. The hybrid operating room consists of a floor-based flat-panel robotic C-arm with 3D-scan capability (Artis Zeego, Siemens; Germany) combined with navigation (BrainLAB Curve, BrainLAB; Germany). Through a minimally invasive incision, a Jamshidi needle was advanced through the pedicle and a K-wire was placed. If 2D image quality did not allow safe placement 3D-navigation was used to place the K-wire. Position was controlled through a 3D-Scan and corrected if necessary before screw placement. Postoperative CTs evaluated screw perforation grade with grade I when completely within the pedicle, II < 2 mm, III 2-4 mm, and IV > 4 mm outside the pedicle. Overall, 354 screws were placed in T1-T6, 746 in the lower thoracic spine T7-T12 and 645 in the L1-L5. Navigation was mainly used in upper thoracic spine cases (31 of 57). In 63 out of 326 cases K-wire was corrected after the 3D-Scan. Overall, 99.1% of the screws showed perforation less than 2 mm. Mean radiation was 13.3 ± 11.7 mSv and significantly higher in the upper thoracic spine and in navigated procedures. Despite higher costs and radiation, the hybrid-OR allows highest accuracy and therefore patient safety in minimal invasive pedicle screw placement in the thoracic and lumbar spine.

External multicentre validation of pseudomyxoma peritonei PSOGI-Ki67 classification.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignant disease. Adding of the Ki67 proliferation index to the PSOGI PMP classification provided two different subcategories of the extensive HG-PMP group (HG-PMP ≤15% and HG-PMP >15%) with different survival in a previous unicentric study. This study aims to carry out an external and multicentre validation of this new proposed classification. METHOD: It was a prospective analysis of samples from a historical and international cohort of patients. A representative area with higher cellular density was used to determine the Ki67%. The Ki67 proliferation index (%) was determined in all the HG-PMP patients. A Cox proportional hazard models and multivariable COX models were used. The Kaplan-Meier method and the two-tailed log-rank test were used to analyse the effect of different PSOGI-Ki67 categories on OS and DFS. Its predictive accuracy was analysed using Harrel's C-index and the ROC curve. The calibration was performed using the calibration plots matching. RESULTS: After exclusions, 349 patients were available for analysis. The 5-years OS were 86% for LG-PMP, 59% for HG-PMP≤15, 38% for HG-PMP>15 and 42% for SRC-PMP (p = 0.0001). The 5-years DFS were 49% for LG-PMP, 35% for HG-PMP≤15, 16% for HG-PMP>15 and 18% SRC-PMP (p = 0.0001). The discrimination capability of PSOGI-Ki67 was validated. CONCLUSION: the PSOGI-Ki67 classification discriminates and predicts the OS and DFS in patients with PMP dividing the HG-PMP category into two well-defined sub-categories. The Ki67 proliferation index should be incorporated routinely in the pathology report for these patients.

Feasibility of delayed hyperthermic intraperitoneal chemotherapy in case of unforeseen complications.

BACKGROUND: Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) can improve the prognosis of selected patients with peritoneal surface malignancy (PSM). Usually, treatment is performed as an extensive one-step approach. We investigated the feasibility of delayed HIPEC, if the one-step procedure was interrupted precociously. METHODS: 42 patients with PSM who underwent CRS and delayed HIPEC from 2006-2008 were studied. HIPEC was performed 5 days after treatment with mitomycin, cisplatin and hyperthermia. Perioperative complications and toxicity were analyzed. RESULTS: Delayed HIPEC was successfully completed in 40 of the 42 patients. In 2 cases, HIPEC was omitted because of complications during chemotherapy (anastomotic leakage and retroperitoneal edema). Minor and major surgical complications occurred in 18 and 9 of the 40 patients treated with HIPEC (45 vs. 22.5%), respectively. Toxicity grade II-IV (WHO criteria) was observed in 4 of them (10%). Median stay in the intensive care unit was 9 days (range 2-31) while the mean hospitalization time was 24 days (range 14-59). In this series, there was no mortality. CONCLUSION: Postponement of HIPEC after CRS (two-step approach) is feasible. Analysis of morbidity and mortality showed no significant difference to the one-step approach reported in the literature and no disadvantages for the patient. The two-step approach is an alternative option for patients who had to discontinue the one-step approach due to unpredictable intraoperative complications.

Initial results after implementation of a multimodal treatment for peritoneal malignancies.

INTRODUCTION: Peritoneal carcinomatosis represents a clinical condition with a limited perspective concerning long term survival. The combination of surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) represents a complex multimodal therapeutic management concept with promising results for prolongation of survival. For the identification of pitfalls during implementation of the HIPEC procedure into clinical practice an observational study was conducted. METHODS: Between 2005 and 2009 data from all patients treated with cytoreductive surgery and HIPEC for peritoneal carcinomatosis was prospectively collected and analysed. RESULTS: During the observational interval a total of 42 patients underwent surgical treatment for peritoneal carcinomatosis. In 34 patients the complete procedure with surgical cytoreduction and HIPEC was performed. Perioperative mortality (6%) and morbidity (35%) was similar to other reported series. Twenty-five patients (76%) survived the 18 months follow-up period after complete procedure. CONCLUSION: The multimodal therapeutic treatment concept of surgical cytoreduction and following HIPEC leads to promising results for patients suffering from peritoneal carcinomatosis. However this treatment concept is afflicted with a relevant risk of postoperative complications.

Prognostic impact of Claudin 18.2 in gastric and esophageal adenocarcinomas.

INTRODUCTION: The tight junction molecule Claudin 18.2 is selectively expressed in healthy and malignant gastric epithelial tissue and is a promising therapy target for high Claudin 18.2 expressing adenocarcinomas of the esophagogastric junction and stomach (AEG/S). METHODS: This study analyzed the prevalence, characteristics and prognostic impact of Claudin 18.2 expression in primary tumor, lymph node and distant metastasis in a large Caucasian AGE/S cohort with 414 patients. RESULTS: Claudin 18.2 was highly expressed in 17.1% of primary tumors, 26.7% of lymph node metastasis and 16.7% of distant metastasis. High Claudin 18.2 expression in lymph node metastasis and primary tumors correlated significantly (p < 0.001). High expression of Claudin 18.2 was neither associated with histomorphogical subtype, or tumor state, nor with overall survival. CONCLUSION: In Caucasian AEG/S patients, 17.1% appeared to be eligible for an anti-Claudin 18.2 therapy. Claudin 18.2 expression itself has no impact on prognosis and is not related to any tumor subtype.

Better prognosis of gastric cancer patients with high levels of tumor infiltrating lymphocytes is counteracted by PD-1 expression.

The prognostic potential of anti-tumor immune responses is becoming increasingly important in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S) especially regarding the use of immune checkpoint inhibitors. This study analyzes for the first time the prognostic impact of tumor-infiltrating lymphocytes (TILs) and checkpoint inhibitors in a large Caucasian cohort in patients with AGE/S. We screened tissue samples from 438 therapy-naïve patients with AGE/S undergoing surgery between 1992 and 2005, examined in a tissue microarray (TMA) and stained against human CD3, CD4, CD8, PD-1, and PD-L1. Out of 438 tissue samples, 210 were eligible for multivariate analysis. This revealed that high infiltration with CD3+, CD4+, or CD8+ TILs was associated with an increased overall survival in AGE/S patients, which could only be confirmed in multivariate analysis for CD3 (HR: 0.326; p = .023). Independent improved survival was limited to gastric cancer patients and to early tumor stages as long as TILs did not express PD-1 (HR: 1.522; p = .021). Subgroup analyses indicate that TIL-dependent anti-tumor immune response is only effective in gastric cancer patients in early stages of disease in PD-1 negative TILs. Combined analysis of PD-1 and CD3 could serve as a prognostic marker for the clinical outcome of gastric cancer patients and could also be of interest for immunotherapy.

Treatment of oesophageal anastomotic leaks by temporary stenting with self-expanding plastic stents.

BACKGROUND: Oesophageal anastomotic leakage is associated with considerable morbidity and mortality. The aim of the present study was to assess the feasibility of using temporary self-expanding plastic stents to treat postoperative oesophageal leaks. METHODS: Patients with anastomotic leakage after abdominothoracic oesophagectomy treated by endoscopic insertion of self-expanding plastic stents between 2001 and 2007 were studied. Clinical outcomes were analysed, including healing of the leak, morbidity and mortality. RESULTS: Stents were inserted successfully in all 22 patients without procedure-related complications. Ten patients also required computed tomography-guided drainage because surgical drains had been removed. Non-ventilated patients received oral nutrition a mean of 4 days after stent placement. Combined treatment with stenting and drainage resulted in resolution of the leak in 21 of 22 patients. The mean healing time (time to stent removal) was 23 days. Stent migration occurred in five of 22 patients, but endoscopic reintervention with placement of a new stent was successful in all patients. Repeat thoracotomy with intraoperative stent placement was necessary in one patient with an oesophagocolonic anastomosis. One patient died in hospital. CONCLUSION: In combination with effective drainage, self-expanding plastic stents are an option for the treatment of oesophageal anastomotic leaks, and may reduce leak-related morbidity and mortality.

Analysis of NTRK expression in gastric and esophageal adenocarcinoma (AGE) with pan-TRK immunohistochemistry.

Small molecule inhibitors such as Larotrectinib have been recently approved in the treatment of patients with fusions of the neurotrophic-tropomyosin receptor tyrosine kinase (NTRK) genes 1-3. These genomic rearrangements have been reported across different tumor subtypes with a high prevalence in rare tumors. However, in gastric and esophageal adenocarcinoma (AGE) NTRK fusions have also been described in a subset of Asian patients. In order to study the prevalence of this alteration in Caucasian patients with AGE we performed immunohistochemistry for pan-NTRK in 438 formalin-fixed paraffin embedded (FFPE) tumor samples. While we found NTRK expression in gastric glands and tumor adjacent nerve tissue, we did not detect this marker in the tumor compartment. Based on our findings NTRK fusions do not seem to play a role in the molecularpathology of Caucasian AEG patients, so that other treatment options are required.

Duodenum-preserving subtotal and total pancreatic head resections for inflammatory and cystic neoplastic lesions of the pancreas.

INTRODUCTION: For treatment of inflammatory and benign neoplastic lesions of the pancreatic head, a subtotal or total pancreatic head resection is a limited surgical procedure with the impact of replacing the application of a Whipple procedure. The objective of this work is to describe the technical modifications of subtotal and total pancreatic head resection for inflammatory and neoplastic lesions of the pancreas. The advantages of this limited surgical procedure are the preservation of the stomach, the duodenum and the extrahepatic biliary ducts for treatment of benign lesions of the pancreatic head, papilla, and intrapancreatic segment of the common bile duct. For chronic pancreatitis with an inflammatory mass complicated by compression of the common bile duct or causing multiple pancreatic main duct stenoses and dilatations, a subtotal pancreatic head resection results in a long-lasting pain control. Performing, in addition, a biliary anastomosis or a Partington Rochelle type of pancreatic main duct drainage, respectively, is a logic and simple extension of the procedure. The rationale for the application of duodenum-preserving total pancreatic head resection for cystic neoplastic lesions are complete exstirpation of the tumor and, as a consequence, interruption of carcinogenesis of the neoplasia preventing development of pancreatic cancer. Duodenum-preserving total head resection necessitates additional biliary and duodenal anastomoses. For mono-centric IPMN, MCN, and SCA tumors, located in the pancreatic head, total duodenum-preserving pancreatic head resection can be performed without hospital mortality and resurgery for recurrency. Based on controlled clinical trials, duodenum-preserving pancreatic head resection is superior to the Whipple-type resection with regard to lower postoperative morbidity, almost no delay of gastric emptying, preservation of the endocrine function, lower frequency of rehospitalization, early professional rehabilitation, and establishment of a predisease level of quality of life. CONCLUSION: The limited surgical procedures of subtotal or total pancreatic head resection are simple, safe, ensures free tumour margins and replace in the authors institution the application of a Whipple-type head resection.

[Surgical treatment of peritoneal metastases of gastric cancer]. / Chirurgische Therapie beim peritoneal metastasierten Magenkarzinom.

BACKGROUND: Up to 17% of all patients with gastric cancer are diagnosed with the presence of peritoneal metastases, which is associated with a poor prognosis. The most promising results were shown with multimodal treatment regimens including systemic chemotherapy and cytoreductive surgery (CRS). A subsequent hyperthermic intraperitoneal chemotherapy (HIPEC).possibly has a positive effect and is currently being tested. OBJECTIVES: This manuscript highlights the key role of CRS and HIPEC in patients with peritoneal metastases of gastric cancer and illustrates which patients benefit from this intensive therapy. METHODS: We performed a comprehensive review of the literature to demonstrate relevant aspects in the treatment of peritoneal metastases in gastric cancer. RESULTS: The use of CRS and HIPEC improves the overall survival to 11 months compared to best supportive care in selected patients. Patients who present with low volume peritoneal disease (peritoneal cancer index ≤6) have the best prognosis. This intensive treatment is associated with a relatively high morbidity (15-50%) and mortality (1-10%). Complete cytoreduction, i.e. a complete macroscopic absence of tumor tissue after resection is the most important prognostic factor. CONCLUSION: The CRS and HIPEC procedures have a proven survival benefit in selected patients. Due to the relatively high morbidity and mortality, the evaluation should be performed by an experienced team including a surgical oncologist, medical oncologist and intensive care physician, to achieve the highest rate of complete cytoreduction in combination with low morbidity; however, the effect of HIPEC has to be proven and the results of the randomized GASTRIPEC trial are awaited.

Cytoreductive surgery and HIPEC improve survival compared to palliative chemotherapy for biliary carcinoma with peritoneal metastasis: A multi-institutional cohort from PSOGI and BIG RENAPE groups.

BACKGROUND: Peritoneal metastasis from biliary carcinoma (PMC) is associated with poor prognosis when treated with chemotherapy. OBJECTIVE: To evaluate the impact on survival of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and compare with conventional palliative chemotherapy for patients with PMC. MATERIAL AND METHODS: A prospective multicenter international database was retrospectively searched to identify all patients with PMC treated with a potentially curative CRS/HIPEC (CRS/HIPEC group). The overall survival (OS) was compared to patients with PMC treated with palliative chemotherapy (systemic chemotherapy group). Survival was analyzed using Kaplan-Meier method and compared with Log-Rank test. RESULTS: Between 1995 and 2015, 34 patients were included in the surgical group, and compared to 21 in the systemic chemotherapy group. In the surgical group, median peritoneal cancer index was 9 (range 3-26), macroscopically complete resection was obtained for 25 patients (73%). There was more gallbladder localization in the surgical group compared to the chemotherapy group (35% vs. 18%, p = 0.001). Median OS was 21.4 and 9.3 months for surgical and chemotherapy group, respectively (p=0.007). Three-year overall survival was 30% and 10% for surgical and chemotherapy group, respectively. CONCLUSION: Treatment with CRS and HIPEC for biliary carcinoma with peritoneal metastasis is feasible and may provide survival benefit when compared to palliative chemotherapy.

Short-term effect of physiotherapy rehabilitation on functional performance of lower limb amputees.

The objective of the trial was to evaluate the effectiveness of a short and intensive physiotherapy programme versus usual care, mainly consisting of walking. Fifty-eight male unilateral lower limb amputees were randomised over intensive care (N = 29) and usual care (N = 29); this study was carried out in a clinical environment, within the premises of the International Committee of the Red Cross, in Southern Myanmar. The amputees in the experimental group received a three-day programme built around 7 specific exercises, lasting approximately one hour altogether. Effects were assessed on: 2-minute walk test, physiological cost index (PCI), amount of weight bearing on both legs, 5 questions of the Functional Measure for Amputees questionnaire and the timed up and go test. Trans-tibial amputees were tested the first day they were fitted and then 2 days later; trans-femoral amputees were tested when walking out of the parallel bars and 4 days later. The experimental group showed significant improvement in the 2-minute walk test (p = 0.02), in the PCI (p = 0.02) and in the maximal weight bearing test on the amputated leg (p = 0.04). Despite limited means, research remains feasible in a developing country; this study has demonstrated that physiotherapy is effective in improving functional performance of lower limb amputees and therefore has its place in every rehabilitation centre.

[The question of surgical therapy for necrolytic migratory erythema, a cutaneous disease]. / Erythema necrolyticum migrans: Chirurgische Therapie einer Hauterkrankung?

Necrolytic migratory erythema (NME) is a rare paraneoplastic dermatologic condition. Its underlying cause is usually a pancreatic islet cell tumour with marked glucagon secretion. The glucagonoma syndrome is characterised by pancreatic neuroendocrine neoplasm, NME, and diabetes mellitus. We present a case of glucagonoma syndrome in a 58-year-old woman with a history of recurrent cutaneous manifestations who was referred for surgical resection of a pancreatic neoplasm after the NME was finally diagnosed. We discuss diagnostic methods, differential diagnosis, and therapeutic management of this disease.