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Abstract Anastomotic leakage (AL) is a potentially life-threatening complication following colorectal cancer (CRC) resection. In this study, we aimed to unravel longitudinal changes in microbial structure before, during, and after surgery and to determine if microbial alterations may be predictive for risk assessment between sufficient anastomotic healing (AS) and AL prior surgery. We analysed the microbiota of 134 colon mucosal biopsies with 16S rRNA V1-V2 gene sequencing. Samples were collected from three location sites before, during, and after surgery, and patients received antibiotics after the initial collection and during surgery. The microbial structure showed dynamic surgery-related changes at different time points. Overall bacterial diversity and the abundance of some genera such as Faecalibacterium or Alistipes decreased over time, while the genera Enterococcus and Escherichia_Shigella increased. The distribution of taxa between AS and AL revealed significant differences in the abundance of genera such as Prevotella, Faecalibacterium and Phocaeicola. In addition to Phocaeicola, Ruminococcus2 and Blautia showed significant differences in abundance between preoperative sample types. ROC analysis of the predictive value of these genera for AL revealed an AUC of 0.802 (p = 0.0013). In summary, microbial composition was associated with postoperative outcomes, and the abundance of certain genera may be predictive of postoperative complications.

Abstract For many cancers there are only a few well-established risk factors. Here, we use summary data from genome-wide association studies (GWAS) in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify potentially causal relationships for over 3,000 traits. Our outcome datasets comprise 378,142 cases across breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, as well as 485,715 controls. We complement this analysis by systematically mining the literature space for supporting evidence. In addition to providing supporting evidence for well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we also find sex steroid hormones, plasma lipids, and telomere length as determinants of cancer risk. A number of the molecular factors we identify may prove to be potential biomarkers. Our analysis, which highlights aetiological similarities and differences in common cancers, should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app to visualise findings.

Abstract Background Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease. Methods We describe an integrated whole‐exome sequencing and transcriptomic study of 37 iCCAs patients in Germany. Results We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke‐associated Asian iCCAs. Conclusions By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.

Background: Colorectal cancer (CRC) prognosis is determined by the disease stage with low survival rates for advanced stages. Current CRC screening programs are mainly using colonoscopy, limited by its invasiveness and high cost. Therefore, non-invasive, cost-effective, and accurate alternatives are urgently needed. Objective and design: This retrospective multi-center plasma proteomics study was performed to identify potential blood-based biomarkers in 36 CRC patients and 26 healthy volunteers by high-resolution mass spectrometry proteomics followed by the validation in an independent CRC cohort (60 CRC patients and 44 healthy subjects) of identified selected biomarkers. Results: Among the 322 identified plasma proteins, 37 were changed between CRC patients and healthy volunteers and were associated with the complement cascade, cholesterol metabolism, and SERPIN family members. Increased levels in CRC patients of the complement proteins C1QB, C4B, and C5 as well as pro-inflammatory proteins, lipopolysaccharide-binding protein (LBP) and serum amyloid A4, constitutive (SAA4) were revealed for first time. Importantly, increased level of C5 was verified in an independent validation CRC cohort. Increased C4B and C8A levels were correlated with cancer-associated inflammation and CRC progression, while cancer-associated inflammation was linked to the acute-phase reactant leucine-rich alpha-2-glycoprotein 1 (LRG1) and ceruloplasmin. Moreover, a 4-protein signature including C4B, C8A, apolipoprotein C2 (APO) C2, and immunoglobulin heavy constant gamma 2 was changed between early and late CRC stages. Conclusion: Our results suggest that C5 could be a potential biomarker for CRC diagnosis. Further validation studies will aid the application of these new potential biomarkers to improve CRC diagnosis and patient care.

Abstract Background T-cell retargeting to eliminate CEACAM5-expressing cancer cells via CEACAM5xCD3 bispecific antibodies (BsAbs) showed limited clinical activity so far, mostly due to insufficient T-cell activation, dose-limiting toxicities, and formation of anti-drug antibodies (ADA). Methods We present here the generation and preclinical development of NILK-2301, a BsAb composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format). Results NILK-2301 binds CD3ɛ on T-cells with its lambda light chain arm with an affinity of ≈100 nM, and the CEACAM5 A2 domain on tumor cells by its kappa light chain arm with an affinity of ≈5 nM. FcγR-binding is abrogated by the “LALAPA” mutation (Leu234Ala, Leu235Ala, Pro329Ala). NILK-2301 induced T-cell activation, proliferation, cytokine release, and T-cell dependent cellular cytotoxicity of CEACAM5-positive tumor cell lines (5/5 colorectal, 2/2 gastric, 2/2 lung), e.g., SK-CO-1 (E max = 89%), MKN-45 (E max = 84%), and H2122 (E max = 97%), with EC50 ranging from 0.02 to 0.14 nM. NILK-2301 binds neither to CEACAM5-negative or primary colon epithelial cells nor to other CEACAM family members. NILK-2301 alone or in combination with checkpoint inhibition showed activity in organotypic tumor tissue slices and colorectal cancer organoid models. In vivo, NILK-2301 at 10 mg/kg significantly delayed tumor progression in colon- and a pancreatic adenocarcinoma model. Single-dose pharmacokinetics (PK) and tolerability in cynomolgus monkeys at 0.5 or 10 mg/kg intravenously or 20 mg subcutaneously showed dose-proportional PK, bioavailability ≈100%, and a projected half-life in humans of 13.1 days. NILK-2301 was well-tolerated. Data were confirmed in human FcRn TG32 mice. Conclusions In summary, NILK-2301 combines promising preclinical activity and safety with lower probability of ADA-generation due to its format compared to other molecules and is scheduled to enter clinical testing at the end of 2023.

Abstract Burst abdomen (BA) remains a severe postoperative complication after abdominal surgery. Obesity is a known risk factor for postoperative complications but objective parameters such as body mass index fail to predict BA after abdominal surgery. In recent literature, CT-derived body composition assessment could predict obesity-related diseases and surgical site infections. We report data from the institutional wound register, comparing patients with BA to a subgroup of patients without BA. The CT images were evaluated for intraabdominal and subcutaneous fat tissues. Univariate and multivariate risk factor analysis was performed in order to evaluate CT-derived obesity parameters as risk factor for BA. 92 patients with BA were compared to 32 controls. Patients with BA had significantly more visceral obesity (VO; p

Abstract Background Exercise training is beneficial in enhancing physical function and quality of life in cancer patients. Its comprehensive implementation remains challenging, and underlying cardiopulmonary adaptations are poorly investigated. This randomized controlled trial examines the implementation and effects of home-based online training on cardiopulmonary variables and physical activity. Methods Of screened post-surgical patients with breast, prostate, or colorectal cancer, 148 were randomly assigned (1:1) to an intervention (2 × 30 min/week of strength-endurance training using video presentations) and a control group. All patients received activity feedback during the 6-month intervention period. Primary endpoint was change in oxygen uptake after 6 months. Secondary endpoints included changes in cardiac output, rate pressure product, quality of life (EORTC QoL-C30), C-reactive protein, and activity behavior. Results One hundred twenty-two patients (62 intervention and 60 control group) completed the study period. Change in oxygen uptake between intervention and control patients was 1.8 vs. 0.66 ml/kg/min (estimated difference after 6 months: 1.24; 95% CI 0.23 to 2.55; p = 0.017). Rate pressure product was reduced in IG (estimated difference after 6 months: − 1079; 95% CI − 2157 to − 1; p = 0.05). Physical activity per week was not different in IG and CG. There were no significant interaction effects in body composition, cardiac output, C-reactive protein, or quality of life. Conclusions Home-based online training among post-surgery cancer patients revealed an increase of oxygen uptake and a decrease of myocardial workload during exercise. The implementation of area-wide home-based training and activity feedback as an integral component in cancer care and studies investigating long-term effects are needed. Trial registration DRKS-ID: DRKS00020499 ; Registered 17 March 2020.

Abstract Hyperspectral Imaging (HSI) is a relatively new medical imaging modality that exploits an area of diagnostic potential formerly untouched. Although exploratory translational and clinical studies exist, no surgical HSI datasets are openly accessible to the general scientific community. To address this bottleneck, this publication releases HeiPorSPECTRAL ( https://www.heiporspectral.org ; https://doi.org/10.5281/zenodo.7737674 ), the first annotated high-quality standardized surgical HSI dataset. It comprises 5,758 spectral images acquired with the TIVITA® Tissue and annotated with 20 physiological porcine organs from 8 pigs per organ distributed over a total number of 11 pigs. Each HSI image features a resolution of 480 × 640 pixels acquired over the 500–1000 nm wavelength range. The acquisition protocol has been designed such that the variability of organ spectra as a function of several parameters including the camera angle and the individual can be assessed. A comprehensive technical validation confirmed both the quality of the raw data and the annotations. We envision potential reuse within this dataset, but also its reuse as baseline data for future research questions outside this dataset. Measurement(s) Spectral Reflectance Technology Type(s) Hyperspectral Imaging Sample Characteristic - Organism Sus scrofa

Abstract Background Colon conduit is an alternative approach to reconstructing the alimentary tract after esophagectomy. Hyperspectral imaging (HSI) has been demonstrated to be effective for evaluating the perfusion of gastric conduits, but not colon conduits. This is the first study to describe this new tool addressing image-guided surgery and supporting esophageal surgeons to select the optimal colon segment for the conduit and anastomotic site intraoperatively. Patients and methods Of 10 patients, eight who underwent reconstruction with a long-segment colon conduit after esophagectomy between 01/05/2018 and 01/04/2022 were included in this study. HSI was recorded at the root and tip of the colon conduit after clamping the middle colic vessels, allowing us to evaluate the perfusion and appropriate part of the colon segment. Results Anastomotic leak (AL) was detected in only one (12.5%) of all the enrolled patients (n = 8). None of the patients developed conduit necrosis. Only one patient required re-anastomosis on postoperative day 4. No patient needed conduit removal, esophageal diversion, or stent placement. There was a change in the anastomosis site to proximal in two patients intraoperatively. There was no need to change the side of colon conduit intraoperatively in any patient. Conclusion HSI is a promising and novel intraoperative imaging tool to objectively assess the perfusion of the colon conduit. It helps the surgeon to define the best perfused anastomosis site and the side of colon conduit in this type of operation.

Abstract Background Oesophageal cancer (EC) is the sixth leading cause of cancer death worldwide. Oesophageal resection is the only curative treatment option for EC which is frequently performed via an abdominal and right thoracic approach (Ivor-Lewis operation). This 2-cavity operation is associated with a high risk of major complications. To reduce postoperative morbidity, several minimally invasive techniques have been developed that can be broadly classified into either hybrid oesophagectomy (HYBRID-E) via laparoscopic/robotic abdominal and open thoracic surgery or total minimally invasive oesophagectomy (MIN-E). Both, HYBIRD-E and MIN-E, compare favourable to open oesophagectomy. However, there is still an evidence gap comparing HYBRID-E with MIN-E with regard to postoperative morbidity. Methods The MICkey trial is a multicentre randomized controlled superiority trial with two parallel study groups. A total of 152 patients with oesophageal cancer scheduled for elective oesophagectomy will be randomly assigned 1:1 to the control group (HYBRID-E) or to the intervention group (MIN-E). The primary endpoint will be overall postoperative morbidity assessed via the comprehensive complication index (CCI) within 30 days after surgery. Specific perioperative parameters, as well as patient-reported and oncological outcomes, will be analysed as secondary outcomes. Discussion The MICkey trial will address the yet unanswered question whether the total minimally invasive oesophagectomy (MIN-E) is superior to the HYBRID-E procedure regarding overall postoperative morbidity. Trial registration DRKS00027927 U1111-1277-0214. Registered on 4th July 2022

BackgroundAurora kinase A (AURKA) plays a pivotal role in regulating cell mitosis and tumor progression. However, its prognostic significance across diverse cancer types remains relatively unexplored.MethodsWe conducted a comprehensive analysis of AURKA expression in various cancers using data from The Cancer Genome Atlas, Genotype-Tissue Expression, and The Human Protein Atlas databases. Our investigation encompassed an exploration of the associations between AURKA expression and clinical characteristics, shedding light on potential functional roles of AURKA. Additionally, we delved into the relationship between AURKA and the tumor microenvironment. To substantiate the role of AURKA, we carried out in vitro experiments in esophageal adenocarcinoma (EAC), prostate cancer (PRAD), and pancreatic cancer (PAAD) cells.ResultsOur analysis revealed that AURKA is prominently overexpressed in a majority of the cancer types under investigation. Elevated AURKA expression correlated closely with poorer prognosis and advanced tumor stages. AURKA was found to be associated with key pathways involved in the cell cycle and arachidonic acid metabolism. Moreover, AURKA expression exhibited significant correlations with immunoregulatory genes and immune cell profiles. Notably, in vitro experiments demonstrated that silencing AURKA expression resulted in reduced cell viability in EAC, PRAD, and PAAD cells, as well as a decrease in clone formation, cell cycle elongation, diminished cell invasion and reduced spheroid size in EAC cells (OE33 and OE19).ConclusionOur study elucidates the oncogenic role of AURKA and underscores its prognostic value across a spectrum of cancers, including EAC. These findings suggest that AURKA holds promise as a predictive biomarker for EAC and various other tumor types.

IntroductionObesity and physical inactivity are known to affect cancer's development and prognosis. In this context, physical aerobic and resistance training as well as a Mediterranean nutrition have been proven to have many positive health effects. The aim of this study was therefore to investigate the effect of home-based training on body composition and certain metabolic laboratory parameters.MethodsPatients with breast, colorectal and prostate cancer who underwent curative surgery at stages T1N0M0–T3N3M0 were eligible for this trial and randomized to an intervention and control group. In the intervention group the patients carried out online-based strength-endurance home training during the 6-month study period. Body composition was assessed via bioelectrical impedance analysis (baseline, 3 months and 6 months). Metabolic blood parameters were also analyzed and nutrition behavior determined using the Mediterranean Diet Adherence Screener (MEDAS).ResultsThe intervention group's fat mass decreased while their lean body mass increased (time effect p = 0.001 and p = 0.001, respectively). We found no interaction effect in body weight (p = 0.19), fat mass [p = 0.06, 6-months estimates −0.9 (95% CI −1.8 to −0.1)] and lean body mass (p = 0.92). Blood samples also failed to show a statistically significant interaction effect between time × group for HbA1c% (p = 0.64), Insulin (p = 0.33), Adiponectin (p = 0.87), Leptin (p = 0.52) and Triglycerides (p = 0.43). Only Adiponectin revealed significance in the time effect (p < 0.001) and Leptin in the group effect (p = 0.03). Dietary behavior during the study period was similar in patients in the intervention and control groups (interaction p = 0.81; group p = 0.09 and time p = 0.03).DiscussionIndividualized online-based home training in postoperative cancer patients revealed only minor changes, with no group differences in body composition or metabolic laboratory parameters, which were predominantly in the reference range at baseline. More studies investigating effects of online-based home training on body composition and nutrition behavior are needed.Trial registrationhttps://drks.de/search/en/trial/DRKS00020499, DRKS-ID: DRKS00020499.

Abstract Laparoscopic procedures can be assisted by intraoperative modalities, such as quantitative perfusion imaging based on fluorescence or hyperspectral data. If these modalities are not available at video frame rate, fast image registration is needed for the visualization in augmented reality. Three feature-based algorithms and one pre-trained deep homography neural network (DH-NN) were tested for single and multi-homography estimation. Fine-tuning was used to bridge the domain gap of the DH-NN for non-rigid registration of laparoscopic images. The methods were validated on two datasets: an open-source record of 750 manually annotated laparoscopic images, presented in this work, and in-vivo data from a novel laparoscopic hyperspectral imaging system. All feature-based single homography methods outperformed the fine-tuned DH-NN in terms of reprojection error, Structural Similarity Index Measure, and processing time. The feature detector and descriptor ORB1000 enabled video-rate registration of laparoscopic images on standard hardware with submillimeter accuracy.

Summary: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett’s oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. Funding: German Research Foundation (DFG).

Hyperspectral imaging (HSI) is a non-invasive and contactless technique that enables the real-time acquisition of comprehensive information on tissue within the surgical field. In this pilot study, we investigated whether a new HSI system for minimally-invasive surgery, TIVITA® Mini (HSI-MIS), provides reliable insights into tissue perfusion of the proximal and distal esophagogastric anastomotic sites during 21 laparoscopic/thoracoscopic or robotic Ivor Lewis esophagectomies of patients with cancer to minimize the risk of dreaded anastomotic insufficiency. In this pioneering investigation, physiological tissue parameters were derived from HSI measurements of the proximal site of the anastomosis (esophageal stump) and the distal site of the anastomosis (tip of the gastric conduit) during the thoracic phase of the procedure. Tissue oxygenation (StO2), Near Infrared Perfusion Index (NIR-PI), and Tissue Water Index (TWI) showed similar median values at both anastomotic sites. Significant differences were observed only for NIR-PI (median: 76.5 vs. 63.9; p = 0.012) at the distal site (gastric conduit) compared to our previous study using an HSI system for open surgery. For all 21 patients, reliable and informative measurements were attainable, confirming the feasibility of HSI-MIS to assess anastomotic viability. Further studies on the added benefit of this new technique aiming to reduce anastomotic insufficiency are warranted.

Over the last few years, diffusion-weighted imaging (DWI) has become increasingly relevant in the diagnostic assessment of peritoneal carcinomatosis. The aim of this study was to investigate the benefits of high-b DWI (c-DWI) compared to standard DWI in patients with peritoneal carcinomatosis. A cohort of 40 patients with peritoneal carcinomatosis were included in this retrospective study. DWI was performed with b-values of 50, 400, and 800 or 1000 s/mm² on a 1.5-T magnetic resonance imaging (MRI) scanner. C-DWI was calculated using a mono-exponential model with high b-values of 1000, 2000, 3000, 4000, and 5000 s/mm². All c-DWI images with high b-values were compared in terms of volume, detectability of peritoneal lesions, and image quality with the DWI sequence acquired with a b-value of 800 or 1000 s/mm² by two readers. In the group with a b-value of 800 s/mm², there was no statistically significant difference in terms of lesion volume. In the second group with a b-value of 1000 s/mm², peritoneal carcinomatosis lesions were statistically significantly larger than in the c-DWI with a- high b-value of 2000 s/mm² (median 7 cm³, range 1–26 cm³vs. median 6 cm³, range 1–83 cm³, p < 0.05). In both groups, there was a marked decrease in the detectability of peritoneal lesions starting at b = 2000 s/mm². In addition, image quality decreased noticeably from c-DWI at b = 3000 s/mm². In both groups, all images with high b-values at b = 4000 s/mm² and 5000 s/mm² were not diagnostically valuable due to poor image quality. The c-DWI technique offers good diagnostic performance without additional scanning time. High c-DWI b-values up to b = 1000 s/mm² provide comparable detectability of peritoneal carcinomatosis compared to standard DWI. Higher b-values over 1500 s/mm² result in lower image quality, which might lead to misdiagnosis.

Abstract Excessive levels of anxiety may negatively influence treatment outcomes and likely increase patient suffering. We designed a prospective observational study to assess whether preoperative patient-reported anxiety affects major general surgery outcomes. We prospectively administered the State-Trait Anxiety Inventory (STAI) to measure preoperative anxiety in patients awaiting major general surgical procedures. Patients were grouped by STAI scores according to established cutoffs: no anxiety (STAI

Abstract Esophageal cancer is the sixth leading cause of cancer-related death worldwide. Histopathological confirmation is a key step in tumor diagnosis. Therefore, simplification in decision-making by discrimination between malignant and non-malignant cells of histological specimens can be provided by combination of new imaging technology and artificial intelligence (AI). In this work, hyperspectral imaging (HSI) data from 95 patients were used to classify three different histopathological features (squamous epithelium cells, esophageal adenocarcinoma (EAC) cells, and tumor stroma cells), based on a multi-layer perceptron with two hidden layers. We achieved an accuracy of 78% for EAC and stroma cells, and 80% for squamous epithelium. HSI combined with machine learning algorithms is a promising and innovative technique, which allows image acquisition beyond Red–Green–Blue (RGB) images. Further method validation and standardization will be necessary, before automated tumor cell identification algorithms can be used in daily clinical practice.

Abstract To investigate, whether hyperspectral imaging (HSI) is able to reliably differentiate between healthy and damaged cartilage tissue. A prospective diagnostic study was performed including 21 patients undergoing open knee surgery. HSI data were acquired during surgery, and the joint surface’s cartilage was assessed according to the ICRS cartilage injury score. The HSI system records light spectra from 500 to 1000 nm and generates several parameters including tissue water index (TWI) and the absorbance at 960 nm and 540 nm. Receiver operating characteristic curves were calculated to assess test parameters for threshold values of HSI. Areas with a cartilage defect ICRS grade ≥ 3 showed a significantly lower TWI (p = 0.026) and higher values for 540 nm (p 0.74, a cartilage defect ICRS grade ≥ 3 could be detected with a sensitivity of 0.81 and a specificity of 0.81. TWI was not suitable for cartilage defect detection. HSI can provide reliable parameters to differentiate healthy and damaged cartilage. Our data clearly suggest that the difference in absorbance at 540 nm would be the best parameter to achieve accurate identification of damaged cartilage.

ObjectiveAchalasia is associated with reduced quality of life in affected patients but research regarding the psychological burden of achalasia in terms of depression and anxiety is scarce. The current study therefore aims to investigate rates of depression and anxiety in patients with achalasia in relation to prevalence rates in the general population and to examine the extent to which achalasia-related characteristics (time since diagnosis, symptom load, achalasia-related quality of life, treatment history) predict symptoms of depression and anxiety.MethodsUsing validated screening instruments, rates of depression and anxiety were assessed in a cross-sectional survey of a sample of 993 patients with achalasia and compared to population controls stratified by age and sex. Associations between depression and anxiety and achalasia-related factors were explored using linear regression.ResultsCompared to population controls, screening rates of female patients with achalasia were between 3.04 (p = .004) and 7.87 (p < .001) times higher for depression and 3.10 (p < .001) times higher for anxiety, respectively. No significant differences were found for male patients with achalasia. Both achalasia-related quality of life and symptom load were independently related to impaired mental health.ConclusionWomen appear to be specifically affected by the psychological burden of achalasia, pointing to sex-specific or gendered experiences of the disease. In addition to symptom reduction, psychological support may prove beneficial for improving the well-being of patients with achalasia.

Introduction The only curative treatment for most gastric cancer is radical gastrectomy with D2 lymphadenectomy (LAD). Minimally invasive total gastrectomy (MIG) aims to reduce postoperative morbidity, but its use has not yet been widely established in Western countries. Minimally invasivE versus open total GAstrectomy is the first Western multicentre randomised controlled trial (RCT) to compare postoperative morbidity following MIG vs open total gastrectomy (OG).Methods and analysis This superiority multicentre RCT compares MIG (intervention) to OG (control) for oncological total gastrectomy with D2 or D2+LAD. Recruitment is expected to last for 2 years. Inclusion criteria comprise age between 18 and 84 years and planned total gastrectomy after initial diagnosis of gastric carcinoma. Exclusion criteria include Eastern Co-operative Oncology Group (ECOG) performance status >2, tumours requiring extended gastrectomy or less than total gastrectomy, previous abdominal surgery or extensive adhesions seriously complicating MIG, other active oncological disease, advanced stages (T4 or M1), emergency setting and pregnancy.The sample size was calculated at 80 participants per group. The primary endpoint is 30-day postoperative morbidity as measured by the Comprehensive Complications Index. Secondary endpoints include postoperative morbidity and mortality, adherence to a fast-track protocol and patient-reported quality of life (QoL) scores (QoR-15, EUROQOL EuroQol-5 Dimensions-5 Levels (EQ-5D), EORTC QLQ-C30, EORTC QLQ-STO22, activities of daily living and Body Image Scale). Oncological endpoints include rate of R0 resection, lymph node yield, disease-free survival and overall survival at 60-month follow-up.Ethics and dissemination Ethical approval has been received by the independent Ethics Committee of the Medical Faculty, University of Heidelberg (S-816/2021) and will be received from each responsible ethics committee for each individual participating centre prior to recruitment. Results will be published open access.Trial registration number DRKS00025765.

Objective:. This Delphi exercise aimed to gather consensus surrounding risk factors, diagnosis, and management of chyle leaks after esophagectomy and to develop recommendations for clinical practice. Background:. Chyle leaks following esophagectomy for malignancy are uncommon. Although they are associated with increased morbidity and mortality, diagnosis and management of these patients remain controversial and a challenge globally. Methods:. This was a modified Delphi exercise was delivered to clinicians across the oesophagogastric anastomosis collaborative. A 5-staged iterative process was used to gather consensus on clinical practice, including a scoping systematic review (stage 1), 2 rounds of anonymous electronic voting (stages 2 and 3), data-based analysis (stage 4), and guideline and consensus development (stage 5). Stratified analyses were performed by surgeon specialty and surgeon volume. Results:. In stage 1, the steering committee proposed areas of uncertainty across 5 domains: risk factors, intraoperative techniques, and postoperative management (ie, diagnosis, severity, and treatment). In stages 2 and 3, 275 and 250 respondents respectively participated in online voting. Consensus was achieved on intraoperative thoracic duct ligation, postoperative diagnosis by milky chest drain output and biochemical testing with triglycerides and chylomicrons, assessing severity with volume of chest drain over 24 hours and a step-up approach in the management of chyle leaks. Stratified analyses demonstrated consistent results. In stage 4, data from the Oesophagogastric Anastomosis Audit demonstrated that chyle leaks occurred in 5.4% (122/2247). Increasing chyle leak grades were associated with higher rates of pulmonary complications, return to theater, prolonged length of stay, and 90-day mortality. In stage 5, 41 surgeons developed a set of recommendations in the intraoperative techniques, diagnosis, and management of chyle leaks. Conclusions:. Several areas of consensus were reached surrounding diagnosis and management of chyle leaks following esophagectomy for malignancy. Guidance in clinical practice through adaptation of recommendations from this consensus may help in the prevention of, timely diagnosis, and management of chyle leaks.

Background: Safe values for quantitative perfusion parameters of indocyanine green (ICG) angiography have not been fully defined, and interpretation remains at the surgeon’s discretion. This prospective observational study aimed to establish the safe values for the quantitative perfusion parameters by comparing tissue oxygenation levels from HSI images in laparoscopic colorectal surgery. Methods: ICG angiography was performed using a laparoscopic near-infrared (NIR) camera system with ICG diluted in 10 mL of distilled water. For quantitative perfusion parameters, the changes in fluorescence intensity with perfusion times were analyzed to plot a time–fluorescence intensity graph. To assess real-time tissue oxygen saturation (StO2) in the colon, the TIVITA® Tissue System was utilized for hyperspectral imaging (HSI) acquisition. The StO2 levels were compared with the quantitative perfusion parameters derived from ICG angiography at corresponding points to define the safe range of ICG parameters reflecting good tissue oxygenation. Results: In the regression analysis, T1/2MAX, TMAX, slope, and NIR perfusion index were correlated with tissue oxygen saturation. Using this regression model, the cutoff values of quantitative perfusion parameters were calculated as T1/2MAX ≤ 10 s, TMAX ≤ 30 s, slope ≥ 5, and NIR perfusion index ≥50, which best reflected colon StO2 higher than 60%. Diagnostic values were analyzed to predict colon StO2 of 60% or more, and the ICG perfusion parameters T1/2MAX, TMAX, and perfusion TR showed high sensitivity values of 97% or more, indicating their ability to correctly identify cases with acceptable StO2. Conclusion: The safe values for quantitative perfusion parameters derived from ICG angiography were T1/2MAX ≤ 10 s and TMAX ≤ 30 s, which were associated with colon tissue oxygenation levels higher than 60% in the laparoscopic colorectal surgery.

Objective:. This study investigates the effects of PVE and vascular inflow control (VIC) on liver microperfusion and tissue oxygenation using hyperspectral imaging (HSI) technology. Background:. Mechanisms triggering future liver remnant (FLR) augmentation introduced by PVE have not been sufficiently studied in humans. Particularly, the arterial buffer response (ABR) of the liver might play a vital role. Methods:. Hyperspectral datacubes (TIVITA) acquired during 58 major liver resections were qualitatively and quantitatively analyzed for tissue oxygenation (StO2%), near-infrared (NIR) perfusion, organ-hemoglobin indices (OHI), and tissue-water indices (TWI). The primary study endpoint was measurement of hyperspectral differences in liver parenchyma subject to PVE and VIC before resection. Results:. HSI revealed parenchyma specific differences in StO2% with regard to the underlying disease (P < 0.001). Preoperative PVE (n = 23, 40%) lead to arterial hyperoxygenation and hyperperfusion of corresponding liver segments (StO2: 77.23% ± 11.93%, NIR: 0.46 ± 0.20[I]) when compared with the FLR (StO2: 66.13% ± 9.96%, NIR: 0.23 ± 0.12[I]; P < 0.001). In a case of insufficient PVE and the absence of FLR augmentation hyperspectral StO2 and NIR differences were absent. The hyperspectral assessment demonstrated increased liver tissue-oxygenation and perfusion in PVE-segments (n = 23 cases) and decreased total VIC in nonembolized FLR hemilivers (n = 35 cases; P < 0.001). Intraoperative HSI analysis of tumor tissue revealed marked tumor specific differences in StO2, NIR, OHI, and TWI (P < 0.001). Conclusions:. HSI allows intraoperative quantitative and qualitative assessment of microperfusion and StO2% of liver tissue. PVE lead to ABR-triggered tissue hyperoxygenation and cross-talk FLR augmentation. HSI furthermore facilitates intraoperative tumor tissue identification and enables image-guided liver surgery following VIC.

Abstract Background Burst abdomen (BA) is a severe complication after abdominal surgery, which often requires urgent repair. However, evidence on surgical techniques to prevent burst abdomen recurrence (BAR) is scarce. Methods We conducted a retrospective analysis of patients with BA comparing them to patients with superficial surgical site infections from the years 2015 to 2018. The data was retrieved from the institutional wound register. We analyzed risk factors for BA occurrence as well as its recurrence after BA repair and surgical closure techniques that would best prevent BAR. Results We included 504 patients in the analysis, 111 of those suffered from BA. We found intestinal resection (OR 172.510; 22.195–1340.796, p

Abstract Objectives Free flap surgery is an essential procedure in soft tissue reconstruction. Complications due to vascular compromise often require revision surgery or flap removal. We present hyperspectral imaging (HSI) as a new tool in flap monitoring to improve sensitivity compared to established monitoring tools. Methods We performed a prospective observational cohort study including 22 patients. Flap perfusion was assessed by standard clinical parameters, Doppler ultrasound, and HSI on t0 (0 h), t1 (16–28 h postoperatively), and t2 (39–77 h postoperatively). HSI records light spectra from 500 to 1000 nm and provides information on tissue morphology, composition, and physiology. These parameters contain tissue oxygenation (StO2), near-infrared perfusion- (NIR PI), tissue hemoglobin- (THI), and tissue water index (TWI). Results Total flap loss was seen in n = 4 and partial loss in n = 2 cases. Every patient with StO2 or NIR PI below 40 at t1 had to be revised. No single patient with StO2 or NIR PI above 40 at t1 had to be revised. Significant differences between feasable (StO2 = 49; NIR PI = 45; THI = 16; TWI = 56) and flaps with revision surgery [StO2 = 28 (p

Abstract Background Physical training is recommended in various national and international guidelines for patients with cancer. Observational studies have shown that physical activity leads to reduced recurrence and mortality rates by 20–40% in colorectal, breast, and prostate cancer. Despite existing evidence, a systematic care structure is still lacking. The primary aim of this study is to implement and evaluate an online training platform to strengthen physical performance and patient empowerment after cancer surgery. Methods The evaluation will be conducted as a prospective multicenter randomized controlled trial with three subgroups (colorectal-, breast-, and prostate cancer). Each group will include 100 patients (total 300 patients including dropouts; clinical stages T1–3 and/or N+; M0 after surgery intervention) and the primary endpoint (13% increase in the maximal oxygen consumption during exercise) will be examined. The intervention group will receive a 6-month home-based online training (2–3 times per week strength-endurance training using video presentations), bidirectional activity feedback information, online communication, and online counseling. The control group (usual care) will be advised lifestyle improvement. In-hospital testing will be performed before, during, and after the intervention. In addition to cardiopulmonary capacity, tumor specific diagnostics (liquid biopsy, depression and fatigue assessment, metabolic and endothelial screening) will be applied. Discussion Due to the increasing incidence of cancer, associated with considerable mortality, morbidity and impaired quality of life, there is an imperative requirement for improved cancer care, of which structured physical training may become an integral component. Trial registration DRKS-ID: DRKS00020499 ; Registered 17 March 2020.

Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.

BackgroundThe near-infrared/indocyanine green imaging fluorescence (NIR/ICG) technology is showing promising results in several fields of surgical oncology. The clinical value of NIR/ICG technology in the surgical treatment of advanced gastric cancer (AGC) is not clearly established.MethodsThis is the protocol of the “iGreenGO” (indocyanine Green Gastric Observation) Study, a national prospective multicenter study. Western patients who undergo curative-intent gastrectomy with D2 lymphadenectomy for AGC constitute the study cohort. All the patients undergo preoperative upper gastrointestinal endoscopy for submucosal peritumoral ICG injection at the most 20 h before surgery. Intraoperative endoscopic injection before starting surgical dissection is also allowed. The primary endpoint is the “change in the surgical conduct” (CSC), i.e., the need to perform further dissection after intraoperative NIR/ICG technology activation at the end of D2 lymphadenectomy. Secondary endpoints include the pattern of abdominal fluorescence distribution according to tumor and patient characteristics, the preoperative clinical variables potentially associated with CSC, and the incidence of stage migration due to NIR/ICG application.DiscussionThe iGreenGO Study is the first study to investigate the clinical role of NIR/ICG technology for the surgical treatment of AGC in a large cohort of Western patients. Results from the present study can further clarify the role of NIR/ICG technology in surgical lymphadenectomy for AGC.

Problem: Similarity measures are widely used as an approved method for spectral discrimination or identification with their applications in different areas of scientific research. Even though a range of works have been presented, only a few showed slightly promising results for human tissue, and these were mostly focused on pathological and non-pathological tissue classification. Methods: In this work, several spectral similarity measures on hyperspectral (HS) images of in vivo human tissue were evaluated for tissue discrimination purposes. Moreover, we introduced two new hybrid spectral measures, called SID-JM-TAN(SAM) and SID-JM-TAN(SCA). We analyzed spectral signatures obtained from 13 different human tissue types and two different materials (gauze, instruments), collected from HS images of 100 patients during surgeries. Results: The quantitative results showed the reliable performance of the different similarity measures and the proposed hybrid measures for tissue discrimination purposes. The latter produced higher discrimination values, up to 6.7 times more than the classical spectral similarity measures. Moreover, an application of the similarity measures was presented to support the annotations of the HS images. We showed that the automatic checking of tissue-annotated thyroid and colon tissues was successful in 73% and 60% of the total spectra, respectively. The hybrid measures showed the highest performance. Furthermore, the automatic labeling of wrongly annotated tissues was similar for all measures, with an accuracy of up to 90%. Conclusion: In future work, the proposed spectral similarity measures will be integrated with tools to support physicians in annotations and tissue labeling of HS images.

Summary: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.

A poor preoperative functional capacity increases the perioperative risk. Therefore, a web-based exercise approach has been initiated for a careful supervision and individual support of patients during their perioperative cancer therapy. Here, we present the data of a 57-year-old patient, scheduled for esophagectomy. Beside a five-week neoadjuvant chemoradiotherapy (CRT), the patient performed 10 weeks of a web-based prehabilitation exercise training (preconditioning) and continued the exercise program for 14 weeks after surgery. The patient performed 42 of 44 recommended training sessions in the preconditioning period in his home environment. This corresponds to a mean of 131 (±38) min of total training per week. The patient performed 52 of 48 recommended training sessions in the postconditioning period. This corresponds to a mean of 165 (±87) min of total training per week. The patient could maintain his functional capacity during CRT and enhanced his submaximal performance level to the end of the intervention. The patient’s adherence to the program was noteworthy. The most important features of this approach are the personalized design and the flexible scheduling precisely in tune with the patient’s needs, concerns, and therapy related downtimes. Thus, the patient nearly fulfilled the exercise guidelines at a sufficient exercise intensity even during the neoadjuvant therapy. The preconditional exercise prevented a presumed CRT-induced and tumor-associated loss of functional capacity. The postoperative exercise led to a structured and adequate return into regular physical activities after surgery. Finally, this approach complements a comprehensive clinical care, in a health-promoting, cost-effective, and patient-safely manner.

Gastroesophageal reflux disease (GERD) is a major risk factor for Barret’s esophagus (BE) and esophageal adenocarcinoma (EA). Here, An et al. report 25 genetic loci for GERD, many of which associate with BE and EA or with other traits such as BMI.

Abstract Background An altered Wnt-signaling activation has been reported during Barrett’s esophagus progression, but with rarely detected mutations in APC and β-catenin (CTNNB1) genes. Methods In this study, a robust in-depth expression pattern analysis of frizzled receptors, co-receptors, the Wnt-ligands Wnt3a and Wnt5a, the Wnt-signaling downstream targets Axin2, and CyclinD1, as well as the activation of the intracellular signaling kinases Akt and GSK3β was performed in an in vitro cell culture model of Barrett’s esophagus. Representing the Barrett’s sequence, we used normal esophageal squamous epithelium (EPC-1, EPC-2), metaplasia (CP-A) and dysplasia (CP-B) to esophageal adenocarcinoma (EAC) cell lines (OE33, OE19) and primary specimens of squamous epithelium, metaplasia and EAC. Results A loss of Wnt3a expression was observed beginning from the metaplastic cell line CP-A towards dysplasia (CP-B) and EAC (OE33 and OE19), confirmed by a lower staining index of WNT3A in Barrett’s metaplasia and EAC, than in squamous epithelium specimens. Frizzled 1–10 expression analysis revealed a distinct expression pattern, showing the highest expression for Fzd2, Fzd3, Fzd4, Fzd5, Fzd7, and the co-receptor LRP5/6 in EAC cells, while Fzd3 and Fzd7 were rarely expressed in primary specimens from squamous epithelium. Conclusion Despite the absence of an in-depth characterization of Wnt-signaling-associated receptors in Barrett’s esophagus, by showing variations of the Fzd- and co-receptor profiles, we provide evidence to have a significant role during Barrett’s progression and the underlying pathological mechanisms.

The original article [1] contains slight errors whereby several terms in the first column of Tables 1, 2, and 3 have an erroneous ‘p’ preceding them.

Abstract Background Estimation of lymph node status is essential in order to determine precise therapy for patients with non-small cell lung cancer (NSCLC). Furthermore, lymph node involvement is a very powerful prognostic factor in these patients. In this analysis, we aim to evaluate the predictive factors for lymph node metastasis in NSCLC-patients. Methods In a prospectively-established database, we analyzed all data of patients with NSCLC, who underwent oncological surgical resections from 01/2007 to 12/2016, retrospectively. The correlation between clinicopathological parameters and lymph node metastasis was investigated by using univariate and binary logistic regression analysis. Results In this study, we operated on 204 consecutive patients, 142 men (71.7%) and 56 women (28.3%). Lymph node metastases were detected in 38.2% (78/204). Preoperatively, central tumor localization (OR = 2.6, 95% CI = 1.3–5.1, P = 0.005) and tumor size > 3 cm (OR = 2.5, 95% CI = 1.3–4.4, P = 0.005) were found to be significant predictive factors for lymph node metastasis. Postoperatively, multivariate analysis showed that intratumoral lymph vessel invasion (L1-status) (OR = 17.3, 95% CI = 5.1–58.4, P

Emerging immunotherapies quest for better patient stratification in cancer treatment decisions. Moderate response rates of PD-1 inhibition in gastric and esophagogastric junction cancers urge for meaningful human model systems that allow for investigating immune responses ex vivo. Here, the standardized patient-derived tissue culture (PDTC) model was applied to investigate tumor response to the PD-1 inhibitor Nivolumab and the CD3/CD28 t-lymphocyte activator ImmunoCultTM. Resident t-lymphocytes, tumor proliferation and apoptosis, as well as bulk gene expression data were analyzed after 72 h of PD-1 inhibition either as monotherapy or combined with Oxaliplatin or ImmunoCultTM. Individual responses to PD-1 inhibition were found ex vivo and combination with chemotherapy or t-lymphocyte activation led to enhanced antitumoral effects in PDTCs. T-lymphocyte activation as well as the addition of pre-cultured peripheral blood mononuclear cells improved PDTC for studying t-lymphocyte and tumor cell communication. These data support the potential of PDTC to investigate immunotherapy ex vivo in gastric and esophagogastric junction cancer.

Innovations and new advancements in intraoperative real-time imaging have gained significant importance in the field of gastric cancer surgery in the recent past. Currently, the most promising procedures include indocyanine green fluorescence imaging (ICG-FI) and hyperspectral imaging or multispectral imaging (HSI, MSI). ICG-FI is utilized in a broad range of clinical applications, e.g., assessment of perfusion or lymphatic drainage, and additional implementations are currently investigated. HSI is still in the experimental phase and its value and clinical relevance require further evaluation, but initial studies have shown a successful application in perfusion assessment, and prospects concerning non-invasive tissue and tumor classification are promising. The application of machine learning and artificial intelligence technologies might enable an automatic evaluation of the acquired image data in the future. Both methods facilitate the accurate visualization of tissue characteristics that are initially indistinguishable for the human eye. By aiding surgeons in optimizing the surgical procedure, image-guided surgery can contribute to the oncologic safety and reduction of complications in gastric cancer surgery and recent advances hold promise for the application of HSI in intraoperative tissue diagnostics.

There are approximately 1.8 million diagnoses of colorectal cancer, 1 million diagnoses of stomach cancer, and 0.6 million diagnoses of esophageal cancer each year globally. An automatic computer-assisted diagnostic (CAD) tool to rapidly detect colorectal and esophagogastric cancer tissue in optical images would be hugely valuable to a surgeon during an intervention. Based on a colon dataset with 12 patients and an esophagogastric dataset of 10 patients, several state-of-the-art machine learning methods have been trained to detect cancer tissue using hyperspectral imaging (HSI), including Support Vector Machines (SVM) with radial basis function kernels, Multi-Layer Perceptrons (MLP) and 3D Convolutional Neural Networks (3DCNN). A leave-one-patient-out cross-validation (LOPOCV) with and without combining these sets was performed. The ROC-AUC score of the 3DCNN was slightly higher than the MLP and SVM with a difference of 0.04 AUC. The best performance was achieved with the 3DCNN for colon cancer and esophagogastric cancer detection with a high ROC-AUC of 0.93. The 3DCNN also achieved the best DICE scores of 0.49 and 0.41 on the colon and esophagogastric datasets, respectively. These scores were significantly improved using a patient-specific decision threshold to 0.58 and 0.51, respectively. This indicates that, in practical use, an HSI-based CAD system using an interactive decision threshold is likely to be valuable. Experiments were also performed to measure the benefits of combining the colorectal and esophagogastric datasets (22 patients), and this yielded significantly better results with the MLP and SVM models.

Abstract Background Cost reduction measures in medicine are gaining greater importance nowadays, especially in high-volume procedures such as laparoscopic appendectomy (LAE). Currently there are two common methods of dissecting the appendix from the caecal pole: linear stapler and endoloops. The endoloop is the cheaper device but can only be used in uncomplicated cases of appendicitis. Therefore both methods are used in LAE depending on intraoperative findings. The goal of this study was to retrospectively evaluate possible cost reduction due to increased use of endoloop in LAE in our general surgery department of a tertiary referral university hospital. Methods We previously used the stapler for appendix dissection in LAE as our local protocol but introduced the endoloop as standard method in 2015 to reduce intraoperative costs. We conducted a retrospective analysis of patients who underwent LAE between June 2014 and October 2015 in our department. Our purpose is to show the effects on cost reduction during the introductory period adjusting for a potential bias due to the individual learning curve of every surgeon. We estimated costs for LAE by taking into account average device costs and duration of operation (DO) as well as patient outcome. Results A total of 177 patients underwent LAE, 73 in 2014 (phase I) and 104 in 2015 (phase II). The median DO was 61 (± 24 SD) min during the entire period, and increased by 14 min from phase I to II (from 51 (±23 SD) min to 65 (±24 SD) min respectively, p

Abstract Background Patients undergoing surgery for esophageal cancer have a high risk for postoperative deterioration of lung function and pulmonary complications. This is partly due to one-lung ventilation during thoracotomy. This often accounts for prolonged stay on intensive care units, delayed postoperative reconvalescence and reduced quality of life. Socioeconomic disadvantages can result from these problems. Physical preconditioning has become a crucial leverage to optimize fitness and lung function in patients scheduled for esophagectomy, in particular during the time period of neoadjuvant therapy. Methods/Study design We designed a prospective multicenter randomized-controlled trial. The objective is to evaluate the impact of an internet-based exercise program on postoperative respiratory parameters and pneumonia rates in patients with Barrett’s carcinoma scheduled for esophagectomy. Patients are randomly assigned to either execute internet-based perioperative exercise program (iPEP), including daily endurance, resistance and ventilation training or treatment as usual (TAU). During neoadjuvant therapy and recovery, patients in the intervention group receive an individually designed intensive exercise program based on functional measurements at baseline. Personal feedback of the supervisor with customized training programs is provided in weekly intervals. Discussion This study will evaluate if an intensive individually adapted training program via online supervision during neoadjuvant therapy will improve cardiorespiratory fitness and reduce pulmonary complications following esophagectomy for Barrett’s cancer. Trial registration NCT02478996 , registered 26 May 2015.

Abstract Background Transabdominal Preperitoneal (TAPP) and Lichtenstein operation are established methods for inguinal hernia repair in clinical practice. Meta-analyses of randomized controlled studies, comparing those two methods for repair of primary inguinal hernia, are still missing. In this study, a systematic review and meta-analysis of published randomized controlled trials was performed to compare early and long term outcomes of the two methods. Methods A literature search was carried out to identify randomized controlled trials, which compared TAPP and Lichtenstein repair for primary inguinal hernia. Outcome measures included duration of operation, length of hospital stay, acute postoperative and chronic pain, time to return to work, hematoma, wound infection, neuralgia, numbness, scrotal swelling, seroma and hernia recurrence. A quantitative meta-analysis was performed, using Odds Ratios (OR) or Standardized Mean Difference (SMD), and Confidence Interval (CI). Results Eight controlled randomized studies were identified suitable for the analysis. The mean duration of the operation was shorter in Lichtenstein repair (SMD = 6.79 min, 95% CI, −0.68 – 14.25), without significant difference. Comparing both techniques, patients of the laparoscopic group showed postoperatively significantly less chronic inguinal pain (OR = 0.42; 95% CI, 0.23–0.78). Analyses of the remaining outcome measures did not show any significant differences between the two techniques. Conclusion The results of this analysis indicate that complication rate and outcome of both procedures are comparable. TAPP operation demonstrated only one advantage over Lichtenstein operation with significantly less chronic inguinal pain postoperatively.

Esophageal adenocarcinoma (EA) and its precancerous condition Barrett's esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta-analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic association data. eQTL data from two BE/EA-relevant tissues (esophageal mucosa and gastroesophageal junction) generated within the context of the GTEx project were cross-referenced with the GWAS meta-analysis data. Variants representing an eQTL in at least one of the two tissues were categorized into genome-wide significant loci (P < 5×10-8) and novel candidate loci (5×10-8 ≤ P ≤ 5×10-5). To follow up these novel candidate loci, a genetic association study was performed in a replication cohort comprising 1,993 cases and 967 controls followed by a combined analysis with the GWAS meta-analysis data. The cross-referencing of eQTL and genetic data yielded 2,180 variants that represented 25 loci. Among the previously reported genome-wide significant loci, 22 eQTLs were identified in esophageal mucosa and/or gastroesophageal junction tissue. The regulated genes, most of which have not been linked to BE/EA etiology so far, included C2orf43/LDAH, ZFP57, and SLC9A3. Among the novel candidate loci, replication was achieved for two variants (rs7754014, Pcombined = 3.16×10-7 and rs1540, Pcombined = 4.16×10-6) which represent eQTLs for CFDP1 and SLC22A3, respectively. In summary, the present approach identified candidate genes whose expression was regulated by risk variants in disease-relevant tissues. These findings may facilitate the elucidation of BE/EA pathophysiology.

Background. Loss of LLGL1 has been associated with loss of cellular adhesion and dissemination of cells from colorectal cancer and malignant melanoma. Regulation and relevance of LLGL1 were analyzed in gastric cancer patients with lymphatic and distant dissemination. Furthermore, LLGL1 expression was analyzed in relation to the cellular adhesion protein E-cadherin. Methods. LLGL1 and E-cadherin transcription levels were evaluated in 56 gastric cancer patients and five gastric cancer cell lines. IHC staining for LLGL1 was performed on 39 gastric cancer specimens. LLGL1 was stably transfected into LLGL1 negative gastric cancer cell line SNU16 (del(17) (p11.2)) for functional in vitro assays and a xenograft bioassay. Results. Gastric cancer specimens and cell lines displayed LLGL1 and E-cadherin expression levels with variable intensity. In gastric mucosa, LLGL1 exhibited weak cytoplasmic and strong cortical staining. Loss of LLGL1 expression occurred in 65% of gastric cancers and significantly correlated with loss of E-cadherin expression (P=0.00009). Loss of LLGL1 expression was associated with the diffuse type of gastric cancer (P=0.029) with peritoneal carcinomatosis (M1; P=0.006) and with female gender (P=0.017). Stable reexpression of LLGL1 in SNU16 cells significantly increased both plastic surface adhesion and extracellular matrix proteins laminin and fibronectin, but had no impact on in vitro proliferation, apoptosis, or invasion or on in vivo proliferation or differentiation in our xenograft bioassay. Conclusion. LLGL1 is coexpressed with E-cadherin. Loss of expression of either protein is associated with diffuse gastric cancer and peritoneal metastases. LLGL1 does not impact on proliferation or epithelial-mesenchymal transition (EMT) rather increasing cellular adhesion.

Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

[This corrects the article DOI: 10.1371/journal.pone.0189514.].

Cancer resistance is a major cause for longevity of the naked mole-rat. Recent liver transcriptome analysis in this animal compared to wild-derived mice revealed higher expression of alpha2-macroglobulin (A2M) and cell adhesion molecules, which contribute to the naked mole-rat's cancer resistance. Notably, A2M is known to dramatically decrease with age in humans. We hypothesize that this might facilitate tumour development. Here we found that A2M modulates tumour cell adhesion, migration and growth by inhibition of tumour promoting signalling pathways, e.g. PI3K / AKT, SMAD and up-regulated PTEN via down-regulation of miR-21, in vitro and in tumour xenografts. A2M increases the expression of CD29 and CD44 but did not evoke EMT. Transcriptome analysis of A2M-treated tumour cells, xenografts and mouse liver demonstrated a multifaceted regulation of tumour promoting signalling pathways indicating a less tumorigenic environment mediated by A2M. By virtue of these multiple actions the naturally occurring A2M has strong potential as a novel therapeutic agent.