Probabilistic Autoencoder Using Fisher Information.

Neural networks play a growing role in many scientific disciplines, including physics. Variational autoencoders (VAEs) are neural networks that are able to represent the essential information of a high dimensional data set in a low dimensional latent space, which have a probabilistic interpretation. In particular, the so-called encoder network, the first part of the VAE, which maps its input onto a position in latent space, additionally provides uncertainty information in terms of variance around this position. In this work, an extension to the autoencoder architecture is introduced, the FisherNet. In this architecture, the latent space uncertainty is not generated using an additional information channel in the encoder but derived from the decoder by means of the Fisher information metric. This architecture has advantages from a theoretical point of view as it provides a direct uncertainty quantification derived from the model and also accounts for uncertainty cross-correlations. We can show experimentally that the FisherNet produces more accurate data reconstructions than a comparable VAE and its learning performance also apparently scales better with the number of latent space dimensions.

Endoscopic anterior fundoplication with the Medigus Ultrasonic Surgical Endostapler (MUSE™) for gastroesophageal reflux disease: 6-month results from a multi-center prospective trial.

BACKGROUND: Both long-term proton pump inhibitor (PPI) use and surgical fundoplication have potential drawbacks as treatments for chronic gastroesophageal reflux disease (GERD). This multi-center, prospective study evaluated the clinical experiences of 69 patients who received an alternative treatment: endoscopic anterior fundoplication with a video- and ultrasound-guided transoral surgical stapler. METHODS: Patients with well-categorized GERD were enrolled at six international sites. Efficacy data was compared at baseline and at 6 months post-procedure. The primary endpoint was a ≥ 50 % improvement in GERD health-related quality of life (HRQL) score. Secondary endpoints were elimination or ≥ 50 % reduction in dose of PPI medication and reduction of total acid exposure on esophageal pH probe monitoring. A safety evaluation was performed at time 0 and weeks 1, 4, 12, and 6 months. RESULTS: 66 patients completed follow-up. Six months after the procedure, the GERD-HRQL score improved by >50 % off PPI in 73 % (48/66) of patients (95 % CI 60-83 %). Forty-two patients (64.6 %) were no longer using daily PPI medication. Of the 23 patients who continued to take PPI following the procedure, 13 (56.5 %) reported a ≥ 50 % reduction in dose. The mean percent of total time with esophageal pH <4.0 decreased from baseline to 6 months (P < 0.001). Common adverse events were peri-operative chest discomfort and sore throat. Two severe adverse events requiring intervention occurred in the first 24 subjects, no further esophageal injury or leaks were reported in the remaining 48 enrolled subjects. CONCLUSIONS: The initial 6-month data reported in this study demonstrate safety and efficacy of this endoscopic plication device. Early experience with the device necessitated procedure and device changes to improve safety, with improved results in the later portion of the study. Continued assessment of durability and safety are ongoing in a three-year follow-up study of this patient group.

The current evidence in support of multimodal treatment of locally advanced, potentially resectable esophageal cancer.

BACKGROUND: Treatment of locally advanced resectable esophageal cancer is challenging. In the past three decades surgical treatment has become safer, chemotherapy more powerful and radiation techniques more precise. Today's stage-dependent treatment relies on modern diagnostic tools such as multidetector helical CT, high-frequency endoscopic ultrasound, PET, image fusion techniques and MRI. Specialists cooperate on multidisciplinary tumor boards that follow transparent decision trees based on the newest evidence. METHODS: Results of recent randomized controlled trials are examined with emphasis on their reliability and comparability. RESULTS: Patients with esophagogastric cancer undergoing neoadjuvant chemotherapy, perioperative chemotherapy and neoadjuvant radiochemotherapy plus esophagectomy had a higher R-0 resection rate, fewer involved lymph nodes and better overall survival than with esophagectomy alone. While perioperative morbidity and mortality were not remarkably enhanced by neoadjuvant chemotherapy, several trials showed an increase of mortality after neoadjuvant radiochemotherapy. Adenocarcinoma seems to respond better to chemotherapy than squamous cell cancer, and squamous cell cancer seems to respond better to radiochemotherapy than adenocarcinoma. CONCLUSION: On the basis of the results of randomized trials, preoperative treatment of esophageal cancer shows a survival benefit and should be recommended as the standard treatment strategy in advanced esophageal cancer. While preoperative radiochemotherapy is the standard for advanced squamous cell cancer, both chemotherapy and radiochemotherapy may be adopted for neoadjuvant/perioperative treatment of adenocarcinoma depending on the patient's general condition. Markers to predict response are urgently needed since only responders benefit from multimodal treatment and nonresponders suffer potential harm when surgery is delayed.

Influence of resection extent on morbidity in surgery for squamous cell cancer at the pharyngoesophageal junction.

PURPOSE: Squamous cell cancer (SCC) of the pharyngoesophageal junction area has a poor prognosis mainly due to late symptom manifestation and diagnosis. Treatment of choice is still pharyngolaryngoesophagectomy, substantially affecting quality of life. Limited surgical procedures have been adopted as well. The aim of this retrospective study was to evaluate whether the extent of resection influences postoperative safety and mortality. METHODS: From 1984 to 2006, 66 patients were operated at a single tertiary referral center. Nineteen patients (28.8 %) had SCC of the hypopharynx and 47 patients (71.2 %) had SCC of the cervical and cervicothoracic esophagus. Thirty-five patients (53.0 %) underwent cervical esophageal resection (CE) and 31 underwent total esophagectomy (TE). In 39 patients (59.1 %), the larynx was preserved. Thirteen patients (19.7 %) underwent multimodal treatment. RESULTS: Overall postoperative morbidity was 69.7 % and reoperation rate reached 28.8 %. TE (P = 0.03) and larynx preservation (P = 0.02) were followed by a higher rate of non-lung infections compared with CE and pharyngolaryngectomy, respectively. Pulmonary complications have been observed more frequently after larynx preservation (P = 0.02). Hospital mortality was 9.1 %. Four patients died after TE (12.9 %) and two patients died after CE (5.7 %). In all of them, the larynx had been preserved (15.4 %). Overall, 53 patients (80.3 %) died until follow-up. One-year and 5-year survival in patients with the major tumor burden at the cervicothoracic site was 35.7 and 0 %. CONCLUSIONS: CE can be recommended as long as R0 resection is warranted. The advantage of larynx preservation is gained by higher morbidity and mortality rates and may not be recommended as standard procedure. Surgery may not be appropriate for advanced SCC in the cervicothoracic region.

Gastrointestinal stromal tumors: diagnosis, therapy and follow-up care in Austria.

Optimal treatment for patients suffering from gastrointestinal stromal tumors (GIST) is based on an interdisciplinary treatment approach. Austrian representatives of Medical and Surgical Oncology, Pathology, Radiology, Nuclear Medicine, Gastroenterology, and Laboratory Medicine issued this manuscript on a consensual base within the context of currently available and published literature. This paper contains guidelines and recommendations for diagnosis, therapy, and follow-up of GIST patients in Austria.

Expression of podoplanin is a rare event in sporadic gastrointestinal stromal tumors and does not influence prognosis.

AIMS: Podoplanin overexpression is associated with worse prognosis in several human cancers. In gastrointestinal stromal tumors (GISTs) very few data on the expression of podoplanin exist, but it seems to be frequently overexpressed in pediatric/syndromic GISTs. We investigated podoplanin expression and its clinical relevance in a large series of sporadic GISTs. METHODS: Podoplanin expression was determined immunohistochemically in 145 sporadic adult GISTs. Aneuploidies of 1p36 and 1q25 were investigated using FISH, and KIT and PDGFRA genes were investigated by sequencing. RESULTS: Overexpression of podoplanin was observed in eight (5.6%) GISTs and no association with amplification of 1p36 or KIT or PDGFRA mutations was seen. The amount of podoplanin expression was not associated with clinical risk factors or patient survival. CONCLUSION: Overexpression of podoplanin is a rare event in sporadic GISTs and is not associated with amplification of 1p36 or with KIT or PDGFRA mutations, which indicates limited pathobiological or clinical relevance.

Carbonic anhydrase IX overexpression is associated with diminished prognosis in esophageal cancer and correlates with Her-2 expression.

BACKGROUND: Carbonic anhydrase IX (CAIX), a transmembrane glycoprotein, seems to play a key role in the adaption of tumor cells to hypoxia. This study was designed to investigate the clinical role of CAIX and its association with Her-2 in a large cohort of adeno- (AC) and squamous cell carcinomas (SCC) of the esophagus and their metastases. METHODS: Expression of CAIX and Her-2 was investigated immunohistochemically in formalin fixed, paraffin-embedded tissue from 330 esophageal cancers (182 ACS, 148 SCCs). Corresponding lymph node metastases in 137 cases, distant metastases in 34 cases, and local recurrences in 14 cases were analyzed for CAIX expression. RESULTS: A total of 147 cases (44.5%) showed strong CAIX expression (AC: 46.7%; ACC: 41.9%). CAIX status of the primary tumor influenced CAIX expression in corresponding lymph node metastases (P<0.001, linear regression). High CAIX-expression was an independent prognostic factor for shorter overall and disease-free survival (P≤0.05, Cox regression). Twenty-nine ACs (15.9%) and 6 SCCs (4.1%) showed Her-2 overexpression. In AC, a significant positive correlation between the Her-2 status and CAIX expression was found (P=0.009, chi-square test). CONCLUSIONS: High CAIX expression is associated with shorter survival in esophageal cancer, and the hypoxic phenotype seems to be preserved at least during formation of lymph node metastases. Inhibition of CAIX might reduce the ability of tumor cells to establish disseminated disease. In Her-2 overexpressing ACs, blocking of this tyrosine kinase, e.g., by monoclonal antibodies, might induce this effect.

Accuracy of hydro-multidetector row CT in the local T staging of oesophageal cancer compared to postoperative histopathological results.

OBJECTIVE: To evaluate the accuracy of multidetector computed tomography with water filling (Hydro-MDCT) in the T-staging of patients with oesophageal cancer. MATERIALS AND METHODS: There were 131 consecutive patients who were preoperatively and prospectively examined in the prone position on arterial phase contrast-enhanced MDCT, after ingestion of 1,000-1,500 ml tap water and effervescent granules. Two readers staged the local tumour growth (T-staging) independently. They assessed tumour location, size, presence of stenosis, and morphology of the outer border of the oesophageal wall and perioesophageal fat planes on CT. CT findings were compared with histopathological results from resected specimens. Data were analyzed using the SPSS statistical package. RESULTS: Both readers obtained a high sensitivity of 95% and a high positive predictive value of 96%. Accurate local staging was achieved in 76.3% and 68.7% for readers 1 and 2, respectively. Inter-reader agreement was excellent (weighted κ value of 0.93 and un-weighted κ of 0.89). CONCLUSION: Using the hydro-technique and applying specific assessment criteria, MDCT appears to be an accurate, non-invasive diagnostic tool for local tumour staging of oesophageal cancer.

Surgery for liver metastases originating from sarcoma-case series.

INTRODUCTION: Liver metastases originating from various types of sarcoma are a rare reason for hepatic resection. So far, even multicentre studies do hardly provide statistically relevant sample sizes. Thus, review of available data can provide surgeons with useful information in similar cases. Therefore, this study can be regarded more as a contribution to this pool of data than as a stand-alone paper. PATIENTS AND METHODS: The study includes 10 women and five men who underwent subtotal hepatic resection for solitary (n = 4) and multiple (n = 11) liver metastases originating from sarcoma. The median tumour diameter was 60 mm (range 20-200 mm). RESULTS: Morbidity was 33%. One patient died within 30 days after surgery. Resection was complete (R0) in 67%. Median overall survival was 33.6 months, 5-year survival 27%. The use of Pringle manoeuvre was significantly associated with poorer outcome (p = 0.014) and shorter period of recurrence-free survival (p = 0.012). Diameter of liver lesion over 50 mm showed significantly shorter recurrence-free survival (p = 0.042). CONCLUSION: Hepatic resection may be beneficial in patients with isolated sarcoma metastasis in the liver.

Temporary placement of self-expanding oesophageal stents as bridging for neo-adjuvant therapy.

BACKGROUND: Placement of self-expanding stents is an effective palliation for dysphagia in non-resectable oesophageal or proximal gastric cancer. The aim of this analysis was to assess the efficacy of temporary stent placement for dysphagia relief during neo-adjuvant treatment for locally advanced disease. METHODS: A total of 38 patients scheduled for neo-adjuvant chemo(radio)therapy for locally advanced oesophageal cancer (n = 29), cardia cancer (n = 8) or subcardial gastric cancer (n = 1) underwent placement of self-expanding plastic stents (n = 13) or covered metal stents (n = 25) due to severe dysphagia and weight loss. RESULTS: Instant dysphagia relief was achieved in 37 (97.4%) of 38 patients. Dysphagia scores declined from mean 3.0 +/- 0.7 before stent placement to 0.6 +/- 0.9 at restaging. After completion of the neo-adjuvant therapy 20 (52.6%) of the 38 patients underwent resection of the tumour, 5 patients (13.2%) underwent primary resection without receiving chemotherapy while 12 patients (31.6%) did not undergo surgery. Stent-related complications were observed as perforation (n = 1), mediastinitis (n = 1), tracheo-oesophageal fistula (n = 2), bleeding (n = 1) and jejunal perforation caused by a migrated stent (n = 1). Serum albumin significantly decreased in patients with progressive disease despite successful stenting (40.0 +/- 4.9 mg/dl versus 29.7 +/- 6.4 mg/dl, p < 0.05) while stable albumin levels were found in patients who underwent surgery (39.9 +/- 4.3 mg/dl versus 39.1 +/- 3.8 mg/dl, p = 0.484). CONCLUSION: Placement of self-expanding stents is highly effective for instant dysphagia relief, enabling adequate oral nutrition during neo-adjuvant therapy, but is limited by a high re-intervention rate.

Open versus minimally invasive esophagectomy: a single-center case controlled study.

BACKGROUND: Recent advances in laparoscopic and thoracoscopic surgery have made it possible to perform esophagectomy using minimally invasive techniques. Although technically complex, recent case studies showed that minimally invasive approaches to esophagectomy are feasible and have the potential to improve mortality, hospital stay, and functional outcome. METHODS: We have performed a case controlled pair-matched study comparing 62 patients who had undergone either minimally invasive (MIE) or open esophagectomy (OE) between 2004 and 2007. Patients were matched by tumor stage and localization, sex, age, and preoperative ASA score. Pathologic stage, operative time, blood loss, transfusion requirements, hospital length of stay, postoperative morbidity, and mortality were recorded. RESULTS: Statistically significant differences were seen in the overall number of patients with surgical morbidity (MIE: 25% vs. OE: 74%, p = 0.014), the transfusion rate (MIE: 12.9% vs. OE: 41.9%, p = 0.001), and the rate of postoperative respiratory complications (MIE: 9.7% vs. OE: 38.7%, p = 0.008). There was no difference with respect to the duration of surgery. The number of resected lymph nodes and rate of pathologic complete resection were comparable. ICU stay [MIE: 3 days (range = 0-15) vs. OE: 6 days (range = 1-40), p = 0.03] and hospital stay [MIE: 12 days (range = 8-46) vs. OE: 24 days (range = 10-79), p = 0.001] were significantly shorter in the MIE group. CONCLUSION: The results of this case-controlled study provide further evidence for the feasibility and possible improvements in the postoperative morbidity of minimally invasive esophagectomy. Our data are comparable to those from other centers and lead us to initiate the first prospectively randomized study comparing the morbidity of total minimally invasive esophagectomy with the open technique.

Ramucirumab plus paclitaxel or FOLFIRI in platinum-refractory advanced or metastatic gastric or gastroesophageal junction adenocarcinoma-experience at two centres.

BACKGROUND: Ramucirumab is a VEGFR-2 antibody that has proven to prolong overall survival (OS) in patients with pretreated metastatic gastric/gastrooesophageal junction (GEJ) adenocarcinoma. We present data from patients treated with ramucirumab and paclitaxel or FOLFIRI after failure of at least one platinum- and 5-FU-containing chemotherapy (CHT) regimen. METHODS: In this retrospective two-center study, 56 patients with metastatic gastric cancer (47%) or adenocarcinoma of the GEJ (53%) were treated with paclitaxel and ramucirumab (n=38) as second-line (75%) or beyond second-line (25%) therapy. FOLFIRI-ramucirumab (FOLFIRI-R) (n=16) was given to patients with a short interval between taxane-based perioperative CHT and occurrence of metastatic disease or to those ineligible for paclitaxel. RESULTS: The median progression-free survival (PFS) and OS for patients treated with paclitaxel-ramucirumab (pacl-R) were 2.9 (95% CI: 2.3-3.6) and 4.4 (4.1-4.7) months, respectively, and those for patients treated with FOLFIRI-R were 5.9 (95% CI: 0.35-11.4) and 8.3 (6.6-10) months, respectively (P=0.05). We observed a trend towards prolonged PFS after perioperative taxane-based FLOT CHT (n=12) with FOLFIRI-R compared with pacl-R. Adverse events were manageable, with neutropenia and polyneuropathy (PNP) being the most common events. More than two treatment lines were given to 48.2% of patients. CONCLUSIONS: The use of ramucirumab in combination with FOLFIRI showed favourable PFS and OS in patients with prior treatments with platinum and/or taxane-based agents and allows further treatment lines after progression. In patients with taxane pretreatment or persistent high-grade PNP, the combination of FOLFIRI-R might be a promising combination.

The value of protecting the longitudinal staple line with invaginating sutures during esophageal reconstruction by gastric tube pull-up.

BACKGROUND: Radical surgery with lymphadenectomy offers the best chance of curing esophageal cancer, but it carries considerable risks. Generally, the resected esophagus is replaced with a gastric tube. Rupture of the gastric tube staple line is a rare but serious surgical complication. One unresolved issue is whether oversewing of the longitudinal gastric staple line is necessary to avoid staple line rupture or insufficiency. PATIENTS AND METHODS: Between 2000 and February 2008, 199 patients underwent esophageal resection for cancer or perforation at the Vienna General Hospital, Medical University of Vienna. Data were collected prospectively. Of these patients, 151 (75.9%) underwent reconstruction by pulling up a gastric tube. These comprised the study population. In 83 patients (55.0%) the longitudinal gastric staple line was not oversewn (group A). In 68 patients (45.0%) the staple line was reinforced by invaginating sutures (group B). RESULTS: The mean age of the patients was 62.0 +/- 10.6 years (median: 63.1 years). Males comprised 75.5% of the population. Adenocarcinoma was diagnosed in 77 patients (51.0%), 63 patients (41.7%) suffered from a squamous cell carcinoma, 10 patients (6.6%) had esophageal perforation, and in 1 patient (0.7%) a gastrointestinal stromal tumor was diagnosed. In group A, a leak within the staple line was observed in 4 of 83 patients (4.9%). No leak was found in group B (p = 0.09). Major surgical complications included anastomotic leakage (21 patients; 13.9%), gastric tip necrosis (3 patients; 2%), postoperative ileus (3 patients; 2.0%) and chylothorax (7 patients; 4.6%). Two major intraoperative complications (1.3%) were splenic injury and aortic bleeding. CONCLUSION: A remarkable but not statistically significant difference was found regarding staple line rupture between study groups. However, all leaks were seen in patients without a staple line suture.

Dedicated multi-detector CT of the esophagus: spectrum of diseases.

Multi-detector computed tomography (CT) offers new opportunities in the imaging of the gastrointestinal tract. Its ability to cover a large volume in a very short scan time, and in a single breath hold with thin collimation and isotropic voxels, allows the imaging of the entire esophagus with high-quality multiplanar reformation and 3D reconstruction. Proper distention of the esophagus and stomach (by oral administration of effervescent granules and water) and optimally timed administration of intravenous contrast material are required to detect and characterize disease. In contrast to endoscopy and double-contrast studies of the upper GI tract, CT provides information about both the esophageal wall and the extramural extent of disease. Preoperative staging of esophageal carcinoma appears to be the main indication for MDCT. In addition, MDCT allows detection of other esophageal malignancies, such as lymphoma and benign esophageal tumors, such as leiomyma. A diagnosis of rupture or fistula of the esophagus can be firmly established using MDCT. Furthermore, miscellaneous esophageal conditions, such as achalasia, esophagitis, diverticula, and varices, are incidental findings and can also be visualized with hydro-multi-detector CT. Multi-detector CT is a valuable tool for the evaluation of esophageal wall disease and serves as an adjunct to endoscopy.

[Surgical treatment of gastrointestinal stromal tumors]. / Chirurgie des gastrointestinalen Stromatumors.

Interdisciplinary management is required in the therapy of gastrointestinal stromal tumors, in consideration of complex strategies in the treatment of patients with GIST. Endoscopy, histopathology - mutation analysis included - but also radio diagnostic, surgery and oncology are topics in treating patients suffering from GIST. Especially in cases of advanced gastrointestinal stromal tumor or metastatic disease our multidisciplinary knowledge is required, because information about these entities are rather rare.

[Gastrointestinal stromal tumors: recommendations for diagnosis, treatment and aftercare in Austria]. / Klinische Empfehlungen. Gastrointestinale Stromatumore: Empfehlungen zu Diagnose, Behandlung und Nachsorge in Osterreich.

Diagnosis and treatment of gastrointestinal stromal tumors (GIST) requires an interdisciplinary treatment approach. This strategy should be reflected by the content of this article. Austrian representatives of 'GIST relevant' specialties authored this publication on a consensual base. This manuscript should be regarded as a guideline for 'GIST involved' colleagues in Austria.

Complications of central venous port systems: a pictorial review.

Central venous port devices are indicated for patients, who need long-term intravenous therapy. Oncologic patients may require intermittent administration of chemotherapy, parenteral nutrition, infusions, or blood transfusions. A venous port system is composed of a port chamber attached to a central catheter, which is implanted into the central venous system. The subcutaneous location of the catheter chamber improves the patients' quality of life and the infection rate is lower than in non-totally implantable central venous devices. However, proper implantation, use, and care of a port system are important to prevent short- and long-term complications. Most common early complications (< 30 days) include venous malpositioning of catheter and perforation with arterial injury, pneumothorax, hemothorax, thoracic duct injury, or even cardiac tamponade. Delayed complications include infection, catheter thrombosis, vessel thrombosis and stenosis, catheter fracture with extravasation, or fracture with migration or embolization of catheter material. Radiologic imaging has become highly relevant in intra-procedural assessment and postoperative follow-up, for detection of possible complications and to plan intervention, e.g., in case of catheter migration. This pictorial review presents the normal imaging appearance of central venous port systems and demonstrates imaging features of short- and long-term complications.

The combination of 5-fluorouracil, leukovorin, etoposide, and cisplatin (FLEP) in patients with metastatic esophageal cancer. A single-institution experience.

BACKGROUND: A retrospective analysis was carried out on the efficacy and toxicity of the combination of 5-fluorouracil, leucovorin, etoposide and cisplatin (FLEP) in patients with metastatic esophageal cancer treated at our institution. PATIENTS AND METHODS: Patients received intravenous 5-fluorouracil 500 mg/m2, leucovorin 300 mg/m2, etoposide 100 mg/m2 and cisplatin 30 mg/m2, on days 1 to 3. Courses were repeated every 4 weeks until progression or up to a maximum of 6 courses. Patients were evaluated for response after every three courses using computed tomography. RESULTS: Eighteen patients received a total of 76 courses (median 4, range 1-6). The median time to progression was 9.2 months and the overall response rate was 22% (one complete response i.e. 5%, and three partial responses i.e. 17%). Seven patients (39%) had stable disease, while another 7 progressed during therapy. The median survival for all patients was 10.2 months. The most common hematological toxicities were leukocytopenia and neutropenia grade 3, which occurred in two patients (11%) each, while grade 3 and 4 infection was seen in one patient each (5%). Anemia grade 3 occurred in 2 patients (11%). Nonhematological toxicities consisted of nausea/vomiting grade 3 in 3 (17%), diarrhea grade 3 in one (5%) and mucositis grade 3 in 3 patients (17%). CONCLUSION: We conclude that the FLEP combination is a safe and active regimen for patients with metastatic esophageal cancer.

Chemotherapy in gastric cancer.

Although treatment of gastric cancer has improved substantially during the last decade there is still controversy about the best way and sequence of treatment. An early interdisciplinary treatment plan is mandatory before therapy is started. In this multidisciplinary expert statement we review current literature and give treatment recommendations for neoadjuvant, adjuvant, and palliative treatment of gastric cancer.