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Summary It is unknown whether Ivor Lewis (IL) or McKeown (McK) esophagectomy is preferred in patients with potentially curable esophageal or gastro-esophageal junction (GEJ) cancer. Patients with mid- and distal esophageal and GEJ cancer without distant metastases who underwent IL or McK esophagectomy in the Netherlands between 2015 and 2017, were selected from the Netherlands Cancer Registry. Patients were propensity score matched for sex, age, American Society of Anesthesiologist classification, comorbidity, tumor type, tumor location, clinical stage, neoadjuvant treatment and year of diagnosis. The primary outcome was a 3-year relative survival (RS). Secondary outcome parameters were number of lymph nodes examined, number of positive lymph nodes, radical resection rate, tumor regression grade, post-operative complications and mortality. A total of 1627 patients who underwent IL (n = 1094) or McK (n = 533) esophagectomy were included. Patient and tumor characteristics were balanced after propensity score matching, leaving 658 patients to be compared. The 3-year RS was 54% after IL and 50% after McK esophagectomy, P = 0.140. The median number of lymph nodes examined, median number of positive lymph nodes, radical resection rate and tumor regression grade were comparable between both groups. Recurrent laryngeal nerve palsy (2 vs. 5%, P = 0.006) occurred less frequently after IL esophagectomy. No differences were observed in post-operative anastomotic leakage rate, pulmonary complication rate and mortality rates. There was no statistically significant difference in the 3-year RS between IL and McK esophagectomy. Based on these results, both IL and McK esophagectomy can be performed in patients with mid to distal esophageal and GEJ cancer.

BACKGROUND: The optimal anastomotic techniques in esophagectomy to minimize rates of anastomotic leakage and conduit necrosis are not known. The aim of this study was to assess whether the anastomotic technique was associated with anastomotic failure after esophagectomy in the international Oesophago-Gastric Anastomosis Audit cohort.METHODS: This prospective observational multicenter cohort study included patients undergoing esophagectomy for esophageal cancer over 9 months during 2018. The primary exposure was the anastomotic technique, classified as handsewn, linear stapled, or circular stapled. The primary outcome was anastomotic failure, namely a composite of anastomotic leakage and conduit necrosis, as defined by the Esophageal Complications Consensus Group. Multivariable logistic regression modeling was used to identify the association between anastomotic techniques and anastomotic failure, after adjustment for confounders.RESULTS: Of the 2238 esophagectomies, the anastomosis was handsewn in 27.1%, linear stapled in 21.0%, and circular stapled in 51.9%. Anastomotic techniques differed significantly by the anastomosis sites (P < .001), with the majority of neck anastomoses being handsewn (69.9%), whereas most chest anastomoses were stapled (66.3% circular stapled and 19.3% linear stapled). Rates of anastomotic failure differed significantly among the anastomotic techniques (P < .001), from 19.3% in handsewn anastomoses, to 14.0% in linear stapled anastomoses, and 12.1% in circular stapled anastomoses. This effect remained significant after adjustment for confounding factors on multivariable analysis, with an odds ratio of 0.63 (95% CI, 0.46-0.86; P = .004) for circular stapled versus handsewn anastomosis. However, subgroup analysis by anastomosis site suggested that this effect was predominantly present in neck anastomoses, with anastomotic failure rates of 23.2% versus 14.6% versus 5.9% for handsewn versus linear stapled anastomoses versus circular stapled neck anastomoses, compared with 13.7% versus 13.8% versus 12.2% for chest anastomoses.CONCLUSIONS: Handsewn anastomoses appear to be independently associated with higher rates of anastomotic failure compared with stapled anastomoses. However, this effect seems to be largely confined to neck anastomoses, with minimal differences between techniques observed for chest anastomoses. Further research into standardization of anastomotic approach and techniques may further improve outcomes.

Surgical resection remains the cornerstone of curative treatment for patients with esophageal cancer. Transthoracic minimally invasive esophagectomies have reduced the occurrence of pulmonary complications, however it is still associated with significant morbidity. The Minimally Invasive Cervical Esophagectomy (MICE) is a novel surgical technique. To date this technique is not routinely performed in European esophageal cancer patients. We aim to assess the safety and efficacy of the MICE procedure in Dutch patients with esophageal carcinoma. The MICE is a recently developed surgical technique in Japan. The procedure combines a laparoscopic transhiatal and single-port transcervical mediastinal dissection and aims to ensure a radical oncological resection with a reduction of pulmonary complications because a thoracotomy/scopy is avoided. A prospective pilot study was performed including consecutive patients undergoing MICE for esophageal cancer. Twenty patients were included. The male/female ratio was 16:4 with a median age of 71 years (IQR 52-85). Median operation time and blood loss was 350 minutes (IQR 326-360) and 100 ml (IQR 50-175). Conversion occurred in five patients (20%). Recurrent laryngeal nerve paralysis was seen in seven patients (35%), at least six of which were temporary. Anastomotic leakage occurred in three patients (15%, 2 ECCG grade 1 and 1 ECCG grade 3). Pneumonia, chyle leakage and hemothorax all occurred once in different patients (Clavien-Dindo grade 2, 4 and 3a, respectively). The median length-of-stay was 10 days (IQR 7-10). MICE is a novel minimally invasive surgical technique which seems safe and effective to perform in Dutch patients with esophageal carcinoma. As expected, a higher incidence of RLNP was seen, in most cases only temporarily. Long-term safety and effectiveness will be prospectively evaluated in a larger population.

Five-year overall survival of patients with locally advanced esophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery is 40%. Better understanding of histopathological factors that influence treatment response is necessary to identify patients with expected poor prognosis. Aim of the study was to assess whether pre- and post-treatment presence of excessive (≥1%) extracellular mucus accumulation, signet-ring cells (SRC) and/or poorly cohesive cells were associated with poor response to nCRT, independent of tumor differentiation grade. This was a retrospective cohort study. Patients included were diagnosed with an adenocarcinoma of the esophagus or GEJ, who underwent CROSS and were planned to undergo esophagectomy between 2001–2019 at two university hospitals. Percentages of the factors extracellular mucus, SRC and poorly cohesive cells were scored by experienced pathologists in pre-treatment biopsies and resection specimen slides relative to the primary tumor area. Multivariable logistic regression models and Cox proportional-hazards models were used to evaluate the histopathological factors in relation to tumor regression grade (TRG) 1–2 (10% tumor), overall survival (OS) and disease-free survival (DFS). Some 325 patients were included (median age 65 years, 280/325 (86%) male). In pre-treatment biopsies, ≥1% extracellular mucus was present in 66/325 (20%); ≥1% SRC 43/325 (13%); ≥1% poorly cohesive cells 126/325 (39%). In patients undergoing esophagectomy, 150/284 (53%) had TRG 3–4. Median OS in all patients was 44 months (95%CI: 36–62). Factors in pre-treatment biopsies were not associated with outcomes independent of differentiation grade. Only patients with ≥1% SRC in the resection specimen had poorer OS (Fig 1): HR for death 1.71, 95%CI: 1.06–2.76, adjusted for age, sex, pre-treatment pathological tumor and nodal stage (pre-pT/pre-pN), ypN and tumor differentiation grade. Extracellular mucus accumulation, SRC and/or poorly cohesive cells in pre-treatment biopsies in patients with esophageal adenocarcinoma treated with nCRT are not associated with response to nCRT, OS or DFS. Their presence should not be a reason to refrain from CROSS nCRT. However, persistence of SRC in the resection specimen after nCRT is an indicator of poor prognosis.

Shared decision making (SDM) is the cornerstone of patient-centered care and is associated with improved treatment outcomes. Making a well-informed decision can be challenging. Patients have to weigh possible outcomes and take into account a certain level of uncertainty. This study investigated patients’ information and supportive needs during the decision-making process to prefer active surveillance or standard surgery after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. Patients who underwent nCRT for carcinoma of the esophagus or esophagogastric junction and refused participation in a randomized trial on active surveillance versus standard surgery were included. Patients were interviewed about their need for information and support and received questionnaires on information- and decision-making preferences and health literacy 3 months after completion of nCRT or before surgery. Interviews were audiotaped and transcribed verbatim. Data were analyzed according to the principles of grounded theory. Forty patients were included of which 20 preferred surgery and 20 preferred active surveillance. Overall, patients’ information needs were met. Patients highly value support received from their loved ones and appreciate emphatic doctors who actively involved them in the decision-making process while paying attention to their individual needs and values. Information resources as the internet and conversations with others were largely used to confirm the treatment decision. Patients prefer to receive information from doctors first and they predominantly rely on this information to make a treatment decision. The importance of shared decision making and the role of doctors in this process is underlined by patients’ wish to be guided in decision-making. The role of healthcare professionals is essential at the initial phase of the decision-making process. After patients seem to have made a treatment decision, the influence of extern resources (including doctors) is limited.

Interaction between currents and semi-submerged structures in coastal areas is a problem of interest in naval and ocean engineering. CFD commercial codes capable of solving these problems have the drawbacks of the high cost of computational resources and time, making them unsuitable for real-time applications in ship maneuvering simulators. This work presents a mathematical model that includes semi-submerged structures in the shallow water equations with hydrostatic assumption. The inclusion of a semi-submerged structure implies the addition of a subdomain with no free surface, replaced by the structure surface. The elevation unknown is replaced by the pressure on the structure surface, which is also unknown. Within this subdomain (for the parcel of fluid under the semi-submerged structure), the 2D-integrated continuity equation is replaced by a Poisson-type equation for the pressure on the structure. This new model is implemented computationally using the finite element method for spatial discretization, and second order schemes for temporal discretization. The results show promising optimization of calculation time per time step, which can lead to the feasibility of real-time applications of hydrodynamic models in ship maneuvering simulators, for example. The numerical results are compared to simulations performed with a CFD commercial code. It shows fairly good agreement in the current magnitude calculations. The elevation and structure surface results are more discrepant, albeit physically realistic. The analysis of CFD results allows concluding that the inclusion of a 3D module and dynamic pressure estimations may improve the results.

Background and aim Transthoracic minimally invasive oesophagectomy (MIO) is increasingly performed as part of curative multimodality treatment. There is no robust evidence on the preferred location of the anastomosis after transthoracic MIO. The aim of this study was to compare an intrathoracic with a cervical anastomosis in a randomised controlled trial. Methods An open multicentre randomised controlled superiority trial was performed. Patients with mid to distal oesophageal or gastro-oesophageal junction cancer planned for curative resection were included. Patients were randomly assigned (1:1) to transthoracic MIO with intrathoracic or cervical anastomosis. The primary endpoint was anastomotic leakage requiring endoscopic, radiologic or surgical intervention. Secondary outcomes were overall anastomotic leak rate, other postoperative complications, length of stay, mortality and quality of life. The ICAN trial is registered in the Dutch trial register under number NTR4333. Results Two hundred and sixty-two patients were randomised and 245 were eligible for analysis. Anastomotic leakage necessitating re-intervention occurred in 15 of 122 (12.3%) patients with intrathoracic anastomosis and in 39 of 123 (31.7%) patients with cervical anastomosis (risk difference − 19.4%, 95% CI -29.5%—-9.3%). Overall anastomotic leak rate was 12.3% in the intrathoracic anastomosis group and 34.1% in the cervical anastomosis group (risk difference − 21.9%, 95% CI -32.1%—-11.6%). ICU length of stay, mortality rates and overall quality of life were comparable between groups, but intrathoracic anastomosis was associated with less severe complications, lower incidence of recurrent laryngeal nerve palsy and better quality of life in three subdomains. Conclusion Intrathoracic anastomosis is the preferred technique for patients treated with transthoracic MIO for mid to distal oesophageal or gastro-oesophageal junction cancer.

Background and aim Anastomotic leakage (AL) is a common and severe complication after esophagectomy. It is largely unknown which primary treatments are most effective for which type of leak. We aimed to investigate the effectiveness of different primary treatments of AL after esophagectomy. Methods The TENTACLE—Esophagus study is an international retrospective cohort study, in which 1509 patients with AL after esophagectomy between 2011 and 2019 were included. Detailed data were collected regarding case mix, resection (e.g. minimally invasive resection), leakage characteristics (e.g. organ failure, leak circumference, intrathoracic contamination) and leakage treatment (e.g. hours from diagnosis to treatment, primary and secondary treatment modalities such as endoscopic, radiologic and surgical treatment). An elaborate data quality validation and data accuracy assessment were performed. Primary outcome was 90-day mortality and secondary outcomes included length of stay and leak healing time. Regression analysis will be used to analyze the effectiveness of primary treatments after correction for patient-, surgery-, and leakage characteristics, and leakage severity. Different clinically relevant leakage groups have been defined. Efficacy of different treatment strategies adjusted for leakage severity will be analyzed in these clinical groups. The full study protocol is accessible at www.tentaclestudy.com. Results Detailed data of 1509 patients with AL was collected from 71 centers in 20 countries. Data accuracy was 96.5%. Preliminary results showed that the overall 90-day mortality was 11.7%. The analysis of TENTACLE—Esophagus data is currently being performed and efficacy of different leakage treatment strategies is being assessed. The efficacy of initial leakage treatment strategies will be ready to be presented at the ESDE meeting. Conclusion This is the largest study on effectiveness of AL treatments. The final results on efficacy of primary leak treatments, which will be available for presentation at the ESDE meeting, could provide an evidence-based basis that can be used by clinicians to determine the preferred primary treatment strategy in patients with a given type of anastomotic leakage after esophagectomy.

Background and aim MICE is an innovative Japanese surgical technique, combining a laparoscopic transhiatal and a single port cervical mediastinal dissection in patients operated for esophageal cancer. This complex surgical techniques aims to reduce pulmonary morbidity without compromising oncological radicality by avoiding thoracic access, prevailing pleural integrity and facilitating cervical or abdominal instead of pleural drainage of mediastinal infections in case of anastomotic leakage. Potential drawbacks are an increased risk of recurrent laryngeal nerve injury and learning associated morbidity during the implementation phase. Up to date this technique is not routinely performed in European esophageal cancer patients. Methods In order to explore the feasibility and safe implementation of the MICE procedure in Dutch esophageal cancer patients, the evidence based IDEAL-framework will be followed. This framework describes 6 stages of evolution for new surgical therapeutic interventions: Pre-clinical, First in human, Development, Exploration, Assessment and Long-term Study. Outcomes of the first two phases will be described. Results The Pre-clinical phase consisted of on-site visits to a Japanese expert center, protocol development, prospective risk assessment, instrument collection and extensive cadaveric training on six fresh frozen human bodies. A ‘virtual supervision platform’ has been developed to proceed with the implementation process despite the COVID pandemic. After thorough evaluation with Dutch upper GI surgical experts and esophageal cancer patients, we have proceeded to the ‘First in Human’ phase. Conclusion The IDEAL framework was used as an evidence based tool for safe implementation of the MICE procedure. We will present the results of the ‘pre-clinical’ and ‘first in human’ stage as well as the surgical technique of the MICE procedure.

Differences in cell wall components between two BNF-contrasting sugarcane genotypes might result from genetic variations particular to the genotype and from the efficiency in diazotrophic bacteria association. Sugarcane is a plant of the grass family (Poaceae) that is highly cultivated in Brazil, as an important energy resource. Commercial sugarcane genotypes may be successfully associated with beneficial endophytic nitrogen-fixing bacteria, which can influence several plant metabolic pathways, such as cell division and growth, synthesis of hormones, and defense compounds. In this study, we investigated how diazotrophic bacteria associated with sugarcane plants could be involved in the regulation of cell wall formation pathways. A molecular and structural characterization of the cell wall was compared between two genotypes of sugarcane with contrasting rates of Biological Nitrogen Fixation (BNF): SP70-1143 (high BNF) and Chunee (low BNF). Differentially expressed transcripts were identified in transcriptomes generated from SP70-1143 and Chunee. Expression profiles of cellulose and lignin genes, which were more expressed in SP70-1134, and callose genes, which were more expressed in Chunee, were validated by RT-qPCR and microscopic analysis of cell wall components in tissue sections. A similar expression profile in both BNF-contrasting genotypes was observed in naturally colonized plants and in plants inoculated with G. diazotrophicus. Cell walls of the high BNF genotype have a greater cellulose content, which might contribute to increase biomass. In parallel, callose was concentrated in the vascular tissues of the low BNF genotype and could possibly represent a barrier for an efficient bacterial colonization and dissemination in sugarcane tissues. Our data show a correlation between the gene profiles identified in the BNF-contrasting genotypes and a successful association with endophytic diazotrophic bacteria.

Differences in cell wall components between two BNF-contrasting sugarcane genotypes might result from genetic variations particular to the genotype and from the efficiency in diazotrophic bacteria association. Sugarcane is a plant of the grass family (Poaceae) that is highly cultivated in Brazil, as an important energy resource. Commercial sugarcane genotypes may be successfully associated with beneficial endophytic nitrogen-fixing bacteria, which can influence several plant metabolic pathways, such as cell division and growth, synthesis of hormones, and defense compounds. In this study, we investigated how diazotrophic bacteria associated with sugarcane plants could be involved in the regulation of cell wall formation pathways. A molecular and structural characterization of the cell wall was compared between two genotypes of sugarcane with contrasting rates of Biological Nitrogen Fixation (BNF): SP70-1143 (high BNF) and Chunee (low BNF). Differentially expressed transcripts were identified in transcriptomes generated from SP70-1143 and Chunee. Expression profiles of cellulose and lignin genes, which were more expressed in SP70-1134, and callose genes, which were more expressed in Chunee, were validated by RT-qPCR and microscopic analysis of cell wall components in tissue sections. A similar expression profile in both BNF-contrasting genotypes was observed in naturally colonized plants and in plants inoculated with G. diazotrophicus. Cell walls of the high BNF genotype have a greater cellulose content, which might contribute to increase biomass. In parallel, callose was concentrated in the vascular tissues of the low BNF genotype and could possibly represent a barrier for an efficient bacterial colonization and dissemination in sugarcane tissues. Our data show a correlation between the gene profiles identified in the BNF-contrasting genotypes and a successful association with endophytic diazotrophic bacteria.

Contains fulltext : 251509.pdf (Publisher’s version ) (Open Access) BACKGROUND: Intraoperative adverse events (iAEs) are frequent in visceral surgery, but severity and related postoperative outcome are poorly investigated. A novel classification of intraoperative adverse events, ClassIntra, includes surgical and anesthesiologic intraoperative adverse events using 5 severity grades and showed a high criterion and construct validity across all surgical disciplines. ClassIntra was studied for reproducibility in a prespecified group of patients undergoing visceral surgery. METHODS: iAEs were recorded in all patients enrolled in the ClassIntra validation study (NCT03009929). Postoperative complications were assessed daily according to the Clavien-Dindo classification. Results of the visceral group were compared with those of the non-visceral group and the full cohort. The risk-adjusted association between most severe intra and postoperative complications was investigated in a multivariable proportional odds model. Second, risk-adjusted association between ClassIntra grade and Comprehensive Complication Index, and postoperative length of stay was investigated. RESULTS: In total, 1,270 out of 2,520 patients (50%) underwent visceral surgery. Compared with the nonvisceral group and full cohort, more intraoperative (337/1270 [27%] vs 273/1250 [22%] vs 610/2520 [24%] patients) and postoperative complications (457/1270 [36%] vs 381/1250 [30%] vs 838/2520 [33%] patients) occurred. The risk for a more severe postoperative complication increased with each ClassIntra grade (odds ratio [95% confidence interval] I vs 0 1.10 [0.73 to 1.66], II vs 0 1.69 [1.10 to 2.60], III vs 0 2.31 [1.21 to 4.41], IV vs 0 2.35 [0.69 to 8.06]). Accordingly, CCI and postoperative length of stay increased with each ClassIntra grade in the visceral group, comparable with the nonvisceral and full cohort. CONCLUSION: Consistent results for the association of intraoperative adverse events and patient outcomes render ClassIntra a valuable instrument in visceral surgery.

Background Quality assurance is acknowledged as a crucial factor in the assessment of oncological surgical care. The aim of this study was to develop a composite measure of multiple outcome parameters defined as ‘textbook outcome’, to assess quality of care for patients undergoing oesophagogastric cancer surgery. Methods Patients with oesophagogastric cancer, operated on with the intent of curative resection between 2011 and 2014, were identified from a national database (Dutch Upper Gastrointestinal Cancer Audit). Textbook outcome was defined as the percentage of patients who underwent a complete tumour resection with at least 15 lymph nodes in the resected specimen and an uneventful postoperative course, without hospital readmission. Hospital variation in textbook outcome was analysed after adjustment for case-mix factors. Results In total, 2748 patients with oesophageal cancer and 1772 with gastric cancer were included in this study. A textbook outcome was achieved in 29·7 per cent of patients with oesophageal cancer and 32·1 per cent of those with gastric cancer. Adjusted textbook outcome rates varied from 8·5 to 52·4 per cent between hospitals. The outcome parameter ‘at least 15 lymph nodes examined’ had the greatest negative impact on a textbook outcome both for patients with oesophageal cancer and for those with gastric cancer. Conclusion Most patients did not achieve a textbook outcome and there was wide variation between hospitals.

Global temperature is predicted to increase in the end of the century and one of the primary consequences of this warming is the sea level rise. Considering the vulnerabilities on coastal systems and water resources, it is important to evaluate the potential effects of this rising in coastal areas, since the saline intrusion on rivers would be intensified, leading to problems related to water quality. In this context, the present work aimed to verify saline intrusion changes along an important river, S&#227o Francisco Canal, located in Rio de Janeiro State, Brazil. For this purpose, a hydrodynamic modeling was performed using SisBaHiA, considering different sea levels and tide conditions. According to the results, it was verified the intensification on saline intrusion and higher salinity values due to a sea level rise of 0.5 m. These results show that new licenses for water withdrawals must be carefully analyzed as the fluvial flow plays an important role to contain the saltwater intrusion on the studied river. Accordingly, it is recommended the evaluation of climate change effects in order to choose best strategies to reduce coastal vulnerability, and the use of this theme on environmental licensing and territorial planning, integrating water planning with coastal management.

Zika virus (ZIKV) is an emerging virus involved in recent outbreaks in Brazil. The association between the virus and Guillain-Barré syndrome (GBS) or congenital disorders has raised a worldwide concern. In this work, we investigated a rare Zika case, which was associated with GBS and spontaneous retained abortion. Using specific anti-ZIKV staining, the virus was identified in placenta (mainly in Hofbauer cells) and in several fetal tissues, such as brain, lungs, kidneys, skin and liver. Histological analyses of the placenta and fetal organs revealed different types of tissue abnormalities, which included inflammation, hemorrhage, edema and necrosis in placenta, as well as tissue disorganization in the fetus. Increased cellularity (Hofbauer cells and TCD8+ lymphocytes), expression of local pro-inflammatory cytokines such as IFN-γ and TNF-α, and other markers, such as RANTES/CCL5 and VEGFR2, supported placental inflammation and dysfunction. The commitment of the maternal-fetal link in association with fetal damage gave rise to a discussion regarding the influence of the maternal immunity toward the fetal development. Findings presented in this work may help understanding the ZIKV immunopathogenesis under the rare contexts of spontaneous abortions in association with GBS.

Background Studies comparing laparoscopic and open appendicectomy are difficult to interpret owing to several types of bias, and the results often seem of limited clinical importance. National audits can be valuable to provide insight into outcomes following appendicectomy at a population level. Methods A prospective, observational, resident-led, nationwide audit was carried out over a period of 2 months, including all consecutive adult patients who had surgery for suspected acute appendicitis. Complications after laparoscopic and open appendicectomy were compared by means of logistic regression analysis; subgroup analyses were performed for patients with complicated appendicitis. Results A total of 1975 patients were included from 62 participating Dutch hospitals. A normal appendix was seen in 3·3 per cent of patients. Appendicectomy was performed for acute appendicitis in 1378 patients, who were analysed. All but three patients underwent preoperative imaging. Laparoscopy was used in 79·5 per cent of patients; the conversion rate was 3·4 per cent. A histologically normal appendix was found in 2·2 per cent. Superficial surgical-site infection was less common in the laparoscopic group (odds ratio 0·25, 95 per cent c.i. 0·14 to 0·44; P < 0·001). The rate of intra-abdominal abscess formation was not significantly different following laparoscopic or open surgery (odds ratio 1·71, 0·80 to 3·63; P = 0·166). Similar findings were observed in patients with complicated appendicitis. Conclusion Management of acute appendicitis in the Netherlands is preferably performed laparoscopically, characterized by a low conversion rate. Fewer superficial surgical-site infections occurred with laparoscopy, although the rate of abscess formation was no different from that following open surgery. A low normal appendix rate is the presumed effect of a mandatory preoperative imaging strategy.

Immunotherapy can revolutionize anti-cancer therapy if specific targets are available. Recurrent somatic mutations in the exome can create highly specific neo-antigens. However, especially pediatric cancers are oligo-mutated and hardly exhibit recurrent neo-antigens. Yet, immunogenic peptides encoded by cancer-specific genes (CSGs), which are virtually not expressed in normal tissues, may enable a targeted immunotherapy of such cancers. Here, we describe an algorithm and provide a user-friendly software named RAVEN (Rich Analysis of Variable gene Expressions in Numerous tissues), which automatizes the systematic and fast identification of CSG-encoded peptides highly affine to Major Histocompatibility Complexes (MHC) starting from publicly available gene expression data. We applied RAVEN to a dataset assembled from more than 2,700 simultaneously normalized gene expression microarrays comprising 50 tumor entities, with a focus on sarcomas and pediatric cancers, and 71 normal tissue types. RAVEN performed a transcriptome-wide scan in each cancer entity for gender-specific CSGs. As a proof-of-concept we identified several established CSGs, but also many novel candidates potentially suitable for targeting multiple cancer types. The specific expression of the most promising CSGs was validated by qRT-PCR in cancer cell lines and by immunohistochemistry in a comprehensive tissue-microarray comprising 412 samples. Subsequently, RAVEN identified likely immunogenic peptides encoded by these CSGs by predicting the affinity to MHCs. Putative highly affine peptides were automatically crosschecked with the UniProt protein-database to exclude sequence identity with abundantly expressed proteins. The predicted affinity of selected peptides was validated in T2-cell peptide-binding assays in which many showed similar kinetics to a very immunogenic influenza control peptide.Collectively, we provide a comprehensive, exquisitely curated and validated catalogue of cancer-specific and highly MHC-affine peptides across 50 cancer entities. In addition, we developed an intuitive and freely available software to easily apply our algorithm to any gene expression dataset (https://github.com/JSGerke/RAVENsoftware). We anticipate that our peptide libraries and software constitute a rich resource to accelerate the development of novel immunotherapies.

Background: Complex surgical procedures such as esophagectomy and gastrectomy for cancer are associated with substantial morbidity and mortality. The purpose of this study was to evaluate trends in postoperative morbidity, mortality, and associated failure-to-rescue (FTR), in patients who underwent a potentially curative resection for esophageal or gastric cancer in the Netherlands, and to investigate differences between the two groups. Methods: All patients with esophageal or gastric cancer who underwent a potentially curative resection, registered in the Dutch Upper GI Cancer Audit (DUCA) between 2011 and 2014, were included. Primary outcomes were (major) postoperative complications, postoperative mortality and FTR. To investigate groups' effect on the outcomes of interest a mixed model was used. Results: Overall, 2644 patients with esophageal cancer and 1584 patients with gastric cancer were included in this study. In patients with gastric cancer, postoperative mortality (7.7% in 2011 vs. 3..8% in 2014) and FTR (38% in 2011 and 19% in 2014) decreased significantly over the years. The adjusted risk of developing a major postoperative complication was lower (OR 0.54; 95% CI 0.42-0.70), but the risk of FTR was higher (OR 1.85; 95% CI 1.05-3.27) in patients with gastric cancer compared to patients with esophageal cancer. Conclusion: Once a postoperative complication occurred, patients with gastric cancer were more likely to die compared to patients with esophageal cancer. Underlying mechanisms like patient selection, and differences in structure and organization of care should be investigated. Next to morbidity and mortality, failure-to-rescue should be considered as an important outcome measure after esophagogastric cancer resections. (C) 2017 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved

Background In 2011, the Dutch Upper Gastrointestinal Cancer Audit (DUCA) group began nationwide registration of all patients undergoing surgery with the intention of resection for oesophageal or gastric cancer. The aim of this study was to describe the initiation and implementation of this process along with an overview of the results. Methods The DUCA is part of the Dutch Institute for Clinical Auditing. The audit provides (surgical) teams with reliable, weekly updated, benchmarked information on process and (case mix-adjusted) outcome measures. To accomplish this, a web-based registration was designed, based on a set of predefined quality measures. Results Between 2011 and 2014, a total of 2786 patients with oesophageal cancer and 1887 with gastric cancer were registered. Case ascertainment approached 100 per cent for patients registered in 2013. The percentage of patients with oesophageal cancer starting treatment within 5 weeks of diagnosis increased significantly over time from 32·5 per cent in 2011 to 41·0 per cent in 2014 (P < 0·001). The percentage of patients with a minimum of 15 examined lymph nodes in the resected specimen also increased significantly for both oesophageal cancer (from 50·3 per cent in 2011 to 73·0 per cent in 2014; P < 0·001) and gastric cancer (from 47·5 per cent in 2011 to 73·6 per cent in 2014; P < 0·001). Postoperative mortality remained stable (around 4·0 per cent) for patients with oesophageal cancer, and decreased for patients with gastric cancer (from 8·0 per cent in 2011 to 4·0 per cent in 2014; P = 0·031). Conclusion Nationwide implementation of the DUCA has been successful. The results indicate a positive trend for various process and outcome measures.

Although the incidence of perforation after endoscopic procedures of the colon is low, the rising number of procedures could pose relevant health problems. Recognizing risk factors and optimizing treatment may reduce perforation incidence and the probability of (severe) complications. This study aimed to determine perforation frequency and the management of endoscopic colonoscopic perforation. A retrospective review of patient records was performed for all patients with iatrogenic colonic perforations after sigmoido/colonoscopy between 1990 and 2005. The patients’ demographic data, endoscopic procedural information, perforation location, therapy, and outcome were recorded. In the 16-year period, 30,366 endoscopic colonic procedures were performed. In total, 35 colonic perforations occured (0.12%). All the patients underwent a laparotomy: for primary repair in 18 cases (56%), for resection with anastomosis in 8 cases (25%), and for resection without anastomosis in 6 cases (19%). In three patients (8.6%), no perforation was found. The postoperative course was uncomplicated in 21 cases (60%) and complicated in 14 cases (40%), including mortality for 3 patients (8.6% resulting from perforations and 0.01% resulting from total endoscopic colon procedures). The relative risk ratio of colonoscopic and sigmoidoscopic procedures for perforations was 4. Therapeutic procedures show a delay in presentation and diagnosis compared with diagnostic procedures. Of the 35 perforations, 26 (74%) occurred in the sigmoid colon. Iatrogenic colonic perforation is a serious but rare complication of colonoscopy. A perforation risk of 0.12% was found. The perforation risk was higher for colonoscopic procedures than for sigmoidoscopic procedures. The sigmoid colon is the area at greatest risk for perforation. Immediate operative management, preferably primary repair and sometimes resection, appears to be a good strategy for most patients.

Ons doel was evaluatie van de frequentie en de manier van overleg tussen bedrijfs-/verzekeringsartsen enerzijds en fysiotherapeuten anderzijds. Tevens werd in beide groepen de persoonlijke ervaring van genoemde aspecten geevalueerd. In het totaal zonden 64 bedrijfs-/verzekeringsartsen en 407 fysiotherapeuten in de regio Rijnmond een vragenlijst betreffende bovenstaande aspecten ingevuld terug. De vragenlijst werd gevalideerd, gebruikmakend van constructvaliditeit en contentvaliditeit. Bovendien werd de test interne consistentie verricht om de betrouwbaarheid van de vragenlijst te verzekeren. Beide groepen stellen onderling overleg op prijs. Fysiotherapeuten hebben echter behoefte aan meer overleg. Het initiatief om de andere groep te benaderen ligt veelal bij de artsen. De bijdrage van de therapeuten aan reintegratie in arbeid van hun clienten wordt door de therapeuten hoger geschat dan door de artsen. De frequentie van overleg tussen bedrijfs-/verzekeringsartsen enerzijds en fysiotherapeuten anderzijds is vrij gering. De kwaliteit daarvan wordt door de meerderheid van beide groepen als vrij goed aangegeven. In tegenstelling tot de fysiotherapeuten zijn de artsen van mening dat de fysiotherapeutische interventie geen positieve invloed heeft op hervatting van werk en dat er voldoende overleg plaatsvindt.

Infective endocarditis is relatively uncommon in the pediatric population, but when it does occur, results in substantial morbidity and mortality. Children at risk for endocarditis are typically those with an underlying congenital heart condition. Furthermore, an endocardial abscess is a very rare yet serious complication of infective endocarditis. We describe a case of a 23-month-old previously healthy male infant with no known congenital heart disease who returned to the emergency department after a recent hospitalization for pneumococcal bacteremia, presenting acutely ill but without fever. He was found to be in congestive heart failure due to endocarditis and an aortic root abscess.

The first fatal case caused by the new genome type 7i is described in an 8-month-old boy requiring long-term respiratory support who developed Reye's syndrome, acute respiratory distress, and bronchiolitis obliterans with fatal evolution. Adenovirus was detected in nasopharyngeal secretions and was persistently positive during hospitalization. IgM and IgG adenovirus antibody titers measured in serum by enzyme-linked immunoassay (EIA) were 1:32 and 1:800, respectively. Serum interleukins (IL) and interferons (IFN) measured by EIA were as follows: IL-2, 110 pg/ml; IL-6, 300 pg/ml; IL-8, 7,000 pg/ml; TNF-alpha, 35 pg/ml, IL-1 and IL-4 undetectable, IFN-alpha 2,200 pg/ml, and IFN-gamma 700 pg/ml. Virologic studies showed that adenovirus isolated belonged to subgenus B, and digestion of viral DNA with Bam HI, Sma I, Bgl II, and Hind III identified the isolate as belonging to genome type 7i. Autopsy showed bronchiolitis obliterans with diffuse alveolar damage and perivenular fatty degeneration with polymorphonuclear infiltrates in the periportal spaces. The difficulty in obtaining adequate oxygenation with minimization of iatrogenic oxygen injury is discussed.

We present a comparative histopathological study of both acute and chronic human adenovirus pneumonia, with reference to the cellular and extracellular matrix components. Seventeen lungs from autopsied patients whose ages ranged from 2 to 60 months were studied. Adenovirus types 1, 2, 3, 5, and 7 were isolated from 15 patients with acute lung disease, and types 2 and 7 were isolated from the other two patients with chronic pulmonary illness. The results indicated the occurrence of two basic patterns of adenovirus interstitial pneumonia (1) classic pattern (acute), characterized by necrosis and degeneration and many type II pneumocytes with intranuclear inclusion bodies, which were positive for adenovirus DNA by in situ hybridization, and (2) proliferative or proliferative-productive pattern (chronic), which presented with diffuse pulmonary fibrosis and the interstitial proliferation of fibroblast-like cells, compatible with myofibroblasts (positive for vimentin and alpha smooth muscle actin), and increase in collagen types I and III, elastic fibers, and proteoglycans. Alveolar collapse appears to be an important pathogenetic mechanism in the development of this pattern.

During Schistosoma mansoni infection, there is morphological evidence of involvement of various hematopoietic growth factors, which cause eosinophil, neutrophil, megakaryocytic and erythroid extramedullary foci in the liver, lymph nodes and omental and mesenteric milky spots. While the eosinophil metaplasia in the periphery of hepatic granulomas roughly reproduced the intensity of the medullary eosinopoiesis, the neutrophil metaplasia, on the contrary, was more intense during the period of neutrophil depression in the bone marrow. This fact suggests that extramedullary hematopoietic foci are locally regulated, and amplify and/or compensate the systemic hematopoietic response during the infection.

Objectives To test the hypothesis that instituting a process of routine daily review of rhythm alarms in non-cardiac patients in the pediatric intensive care unit would yield clinically important disturbances that would otherwise go undetected. Study design A prospective observational study was performed over a consecutive 28-day period. Total bedside monitor alarms, rhythm alarms, and heart rate (HR) trends were recorded. Rhythm alarm recordings were reviewed independently by two study team members. Medical records for patients with critical arrhythmias were reviewed to evaluate for prior knowledge of the event and to correlate with clinical data. Results We evaluated 86 patients (343 patient-days). There were 54 656 total monitor alarms (159.3 alarms/patient-day), of which 19 970 (37%) were rhythm alarms, including 4032 (20%) critical arrhythmias. Fifty-six percent of the critical alarms were artifactual. Seventeen of the 1786 ventricular tachycardia alarms represented true episodes that occurred in 5 patients. Two patients' care were altered as a result of detection of the arrhythmia in the review process. Eight hundred sixty-five (98%) of the 883 true critical alarms reviewed were for extreme HR. Eighty-three percent (5172) of the 6239 true non-critical alarms reviewed were HR alarms. Conclusions Daily review of rhythm alarms improves detection of clinically relevant arrhythmias in non-cardiac pediatric intensive care unit patients.

Infection is a common problem in hepatobiliary surgery. Keighly and Lewis et al. reported infected bile in 31-33% of patients after an operation for biliary disease. Such patients had an increased risk of post-operative infections compared to patients with sterile bile1’2. These findings are confirmed by reports from Flemma et al. and Maddocks et al.. They found that bacteria are common in bile under pathological conditions like stones in the common bile duct, the presence of strictures especially partial strictures or cholangitis3’4. Keighly and Blenkhard also reported a strong relation between per-operative bile cultures and cultures from wound abscesses and blood after surgery on the biliary tract in patients with infected bile. In 64% of the wound abscesses and in 90% of the episodes of bacteraemia the same micro-organisms were observed as had previously been identified in the bile5. Micro-organisms frequently found in these cultures are gram-negative bacteria like E coli, Klebsiella spp or Pseudomonas spp. Sometimes gram-positives are found like Streptococcus faecalis. In patients with a biliodigestive anastomosis anaerobes may be found2’5. Intra-abdominal infections after liver resection are common. Incidences varying between 8 and 30% have been reported from different institutions6’7’8. Moreover, in liver transplant programs infection is 9 10 11 still the major cause of morbidity and mortality’ Therefore, the possible mechanisms of infection of the hepatobiliay system should be one of the major interests in hepatobiliary surgery. Bacteria may enter the liver and biliary tract in two ways. Either directly via the transsphincteric route or indirectly by translocation through the intestinal mucosa via the portal blood or the lymphatic system12’13, In both instances the gastrointestinal tract is the source of the invading micro-organisms. Normally, the upper part of the gastro-intestinal tract contains only few bacteria. This is due to the combined influence of acid secretion of the stomach and the inhibitory action of bile and pancreatic juices on many micro-organisms. The majority of the bacteria present are gram-negative cocci and baccilli. Occasionally

A 23-yr-old female presented with progressive dyspnoea and epigastrical pain after 2 days of severe upper abdominal pain with heavy, profuse vomiting. There was no history of dysphagia or gastric reflux. The patient was born with spina bifida, which was complicated with paralysis beneath L1, neurogenic bladder disease, hydrocephalus (for which a ventriculo-peritoneal shunt had been placed), and progressive thoracic scoliosis. Furthermore, she had a history of allergic bronchial asthma and had recently been treated with amoxycilline/clavulanicacid because of a urinary tract infection. Chronic medications included an oral contraconceptive and fluoxetine. On physical examination the patient was in severe respiratory distress. She was cyanotic, very agitated and was lying in a strange position with her head between her paralysed legs, making physical examination very difficult. Furthermore, the patient's body temperature was 35°C, with a blood pressure of 60/30 mmHg, a heart rate of 30 beats·min−1 and no signal on the pulse oximeter. On pulmonary examination there were diminished breathing sounds with hypersonore percussion on the right side. On the left-hand side there were normal …

Background: There is a growing interest in the use of local anaesthesia for inguinal hernia repair. It certainly seems to be an acceptable alternative for the elderly. Supporting intravenous sedation, however, still requires monitoring, anaesthetic personnel and some preparations for the patient. Therefore we set up a feasibility study of hernia repair under local anaesthesia without intravenous sedation or monitoring in elderly patients. Method: A total of 62 patients (aged 65 years or more) with unilateral inguinal hernia received a Mesh Plug Repair. Prospectively collected data included procedure-related complications and information on pain and quality of life as measured by Short Form 36. Results: No procedure-related complications were noted. Comparing the preoperative scores, the SF-36 on day 14 (n=61) did not differ significantly. After a median follow-up of ten months (n=54), significantly higher scores were found for scales of physical and emotional role and pain (all p

The first fatal case caused by the new genome type 7i is described in an 8-month-old boy requiring long-term respiratory support who developed Reye's syndrome, acute respiratory distress, and bronchiolitis obliterans with fatal evolution. Adenovirus was detected in nasopharyngeal secretions and was persistently positive during hospitalization. IgM and IgG adenovirus antibody titers measured in serum by enzyme-linked immunoassay (EIA) were 1:32 and 1:800, respectively. Serum interleukins (IL) and interferons (IFN) measured by EIA were as follows: IL-2, 110 pg/ml; IL-6, 300 pg/ml; IL-8, 7,000 pg/ml; TNF-alpha, 35 pg/ml, IL-1 and IL-4 undetectable, IFN-alpha 2,200 pg/ml, and IFN-gamma 700 pg/ml. Virologic studies showed that adenovirus isolated belonged to subgenus B, and digestion of viral DNA with Bam HI, Sma I, Bgl II, and Hind III identified the isolate as belonging to genome type 7i. Autopsy showed bronchiolitis obliterans with diffuse alveolar damage and perivenular fatty degeneration with polymorphonuclear infiltrates in the periportal spaces. The difficulty in obtaining adequate oxygenation with minimization of iatrogenic oxygen injury is discussed.

Objective: To determine if bacterial translocation and endotoxin absorption occur in organ donors with an anatomically intact gastrointestinal tract. Design: Case series. Setting: Intensive care units in general and university hospitals. Patients: Twenty-one (multiple) organ donors. Intervention: None. Main Outcome Measures: Occurrence of factors that may promote bacterial translocation and/or endotoxin absorption. Bacterial concentration in mesenteric lymph nodes, abdominal fluid, blood, liver, lung, and spleen. Endotoxin level in abdominal fluid, peripheral blood, and portal blood. Anatomical integrity of the bowel wall. Results: Factors that may promote bacterial translocation and/or endotoxin absorption were present in all organ donors. Culture specimens revealed bacteria in 14 organ donors (67%). In 210 (81%) of 260 culture specimens, the bacteria isolated were identical to those isolated from the bowel content, demonstrating bacterial translocation. Endotoxin was found in nine (53%) of 17 abdominal fluid samples, in four (19%) of 21 peripheral blood samples, and in two (10%) of 21 portal blood samples. Light- and electron-microscopic examination of the bowel wall showed no anatomical abnormalities. Conclusion: Bacterial translocation and endotoxin absorption are frequent among organ donors and may adversely influence organ function in transplant recipients and other critically ill patients. (Arch Surg. 1994;129:1063-1066)

To find out if fish oil given intraperitoneally would cause a reduction in the release of tumour necrosis factor and interleukin-6 in abdominal exudate and blood (experiment A), and if it reduces the incidence of organ failure in rats with peritonitis (experiment B).Laboratory experiment.University animal laboratory.Thirty-six selectively decontaminated rats in each experiment.All rats were pretreated with 2 ml fish oil, lecithin, or saline, intraperitoneally for one or six weeks before intraperitoneal injection of zymosan. Experiment A: Samples of abdominal exudate and plasma were taken regularly for 24 hours after the zymosan had been given. Experiment B: Clinical, biochemical, and histological variables were measured over a 12-day period after the zymosan had been given.Experiment A: Concentrations of tumour necrosis factor and interleukin-6 in abdominal exudate and plasma. Experiment B: Incidence of multiple organ failure.Experiment A: Concentrations of tumour necrosis factor and interleukin-6 in abdominal exudate and plasma were significantly higher in rats pretreated with fish oil, compared with control rats. This effect was more pronounced after six weeks of pretreatment. Experiment B: There were no significant differences between the groups for any variable.Fish oil given intraperitoneally increased rather than reduced local and systemic release of tumour necrosis factor and interleukin-6, and did not reduce the incidence of organ failure in rats with sterile peritonitis.

Background Since 1994 the ‘components separation technique’ has been used for the repair of large abdominal wall defects, thus avoiding the use of prosthetic material. Methods The results of the method were evaluated retrospectively in 40 patients. There were ten women and 30 men, of mean age 50·3 years and mean body mass index 27·4 kg m−2. All had midline hernias that could not be closed primarily. Hernias occurred in 25 patients after acute surgery of whom 11 had open treatment of generalized peritonitis. Reconstruction was performed under clean conditions in 27 patients, clean contaminated in seven and contaminated or dirty in six. In 13 patients the reconstruction was combined with bowel surgery. Results The postoperative course was complicated in 15 patients: one case of wound dehiscence, five haematomas, two seromas, six wound infections and one case of respiratory insufficiency. One patient died 6 days after operation from mesenteric thrombosis. After a mean follow-up of 8·5 (range 0–20) months recurrent hernias were found in eight patients. One patient had an enterocutaneous fistula in a newly created umbilicus. All recurrences appeared after clean operations. Conclusion The ‘components separation technique’ is useful for the reconstruction of large abdominal wall defects, especially under contaminated conditions where the use of prosthetic material is contraindicated. Moreover the technique can be used to close the abdomen at an early stage after open treatment of peritonitis. Devascularization of the skin and a large wound surface created by mobilization of the skin and subcutis are major drawbacks. Release of the external oblique muscle via separate skin incisions can prevent these problems and makes the method applicable for patients with an enterostomy.

Background Patients with secondary peritonitis are treated by surgery and intravenous antibiotics depending on the micro-organisms cultured from abdominal fluid samples. However, such samples may not be representative of the origin of the intra-abdominal infection. Therefore, this study determined (1) whether different micro-organisms are cultured from abdominal fluid, peritoneum and blood samples, and (2) whether fluorescence in situ hybridization (FISH), with 16S ribosomal RNA-targeted probes applied on peritoneum samples, is more efficient than standard culturing techniques. Methods In a pilot study, samples of abdominal fluid, peritoneum and blood were obtained from two groups of patients: six patients with secondary peritonitis (peritonitis group) and five patients without peritonitis (control group). Results Standard culturing techniques revealed coagulase-negative staphylococci (CNS) and yeast in abdominal fluid samples in three of six patients; Escherichia coli, enterococci, CNS and Citrobacter in peritoneum samples in five of six patients; and no micro-organisms in the blood samples from the peritonitis group. In the control group, CNS were cultured from the abdominal fluid samples in one of five patients, while no micro-organisms were cultured from peritoneum samples and CNS were cultured from the blood samples in one of five patients. The FISH technique revealed a large number of various anaerobic bacteria in peritoneum samples in one of six patients in the peritonitis group. In the control group no bacteria were detected. Conclusion Micro-organisms cultured from abdominal fluid differ from those cultured from peritoneum samples. The FISH technique confirmed these findings in only one case. However, it is a promising technique for the identification and localization of bacteria causing secondary peritonitis.