Oncogenic role and target properties of the lysine-specific demethylase KDM1A in chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), epigenetic alterations are considered to centrally shape the transcriptional signatures that drive disease evolution and underlie its biological and clinical subsets. Characterizations of epigenetic regulators, particularly histone-modifying enzymes, are very rudimentary in CLL. In efforts to establish effectors of the CLL-associated oncogene T-cell leukemia 1A (TCL1A), we identified here the lysine-specific histone demethylase KDM1A to interact with the TCL1A protein in B cells in conjunction with an increased catalytic activity of KDM1A. We demonstrate that KDM1A is upregulated in malignant B cells. Elevated KDM1A and associated gene expression signatures correlated with aggressive disease features and adverse clinical outcomes in a large prospective CLL trial cohort. Genetic Kdm1a knockdown in Eµ-TCL1A mice reduced leukemic burden and prolonged animal survival, accompanied by upregulated p53 and proapoptotic pathways. Genetic KDM1A depletion also affected milieu components (T, stromal, and monocytic cells), resulting in significant reductions in their capacity to support CLL-cell survival and proliferation. Integrated analyses of differential global transcriptomes (RNA sequencing) and H3K4me3 marks (chromatin immunoprecipitation sequencing) in Eµ-TCL1A vs iKdm1aKD;Eµ-TCL1A mice (confirmed in human CLL) implicate KDM1A as an oncogenic transcriptional repressor in CLL which alters histone methylation patterns with pronounced effects on defined cell death and motility pathways. Finally, pharmacologic KDM1A inhibition altered H3K4/9 target methylation and revealed marked anti-B-cell leukemic synergisms. Overall, we established the pathogenic role and effector networks of KDM1A in CLL via tumor-cell intrinsic mechanisms and its impacts in cells of the microenvironment. Our data also provide rationales to further investigate therapeutic KDM1A targeting in CLL.

German, Austrian, and Swiss guidelines for systemic treatment of gastric cancer.

The updated edition of the German, Austrian and Swiss Guidelines for Systemic Treatment of Gastric Cancer was completed in August 2023, incorporating new evidence that emerged after publication of the previous edition. It consists of a text-based "Diagnosis" part and a "Therapy" part including recommendations and treatment algorithms. The treatment part includes a comprehensive description regarding perioperative and palliative systemic therapy for gastric cancer and summarizes recommended standard of care for surgery and endoscopic resection. The guidelines are based on a literature search and evaluation by a multidisciplinary panel of experts nominated by the hematology and oncology scientific societies of the three involved countries.

Treatment of local recurrence of esophageal cancer following Ivor-Lewis esophagectomy-Experiences of a high-volume center.

PURPOSE: Patients with local recurrence of esophageal cancer have a highly decreased overall survival. There is currently no standardized treatment algorithm for this group. This retrospective cohort study aimed to evaluate the survival of patients with local recurrence, despite receiving individualized treatment options. METHODS: 241 of 1791 patients were diagnosed with a local recurrence following Ivor-Lewis esophagectomy at the University Hospital of Cologne. 59 patients, who were diagnosed only with a local recurrence of adeno- or squamous cell carcinoma and received their individualized therapy regimes at our high-volume center, were included. RESULTS: The study included 52 patients with adenocarcinoma and 7 with squamous cell carcinoma. Among these, 6 patients underwent resection, 19 received solely chemotherapy, 29 received chemoradiotherapy, and 5 were provided with best supportive care. Patients who underwent resection showed a better survival outcome compared to patients without resection (median OS: not reached vs. 15.1 months, p = 0.012). Best supportive care and palliative care were found to be independent risk factors for shorter overall survival compared to curative intended treatment options like local resection or chemoradiotherapy. CONCLUSION: In this study, different treatment strategies for patients with local recurrence of esophageal cancer were depicted. Resection as well as chemoradiotherapy could play a role in selected patients. Further prospective studies are needed to improve the selection of eligible patients.

Sex- and gender-specific differences in symptoms and health-related quality of life among patients with gastroesophageal reflux disease.

Gastroesophageal Reflux Disease (GERD) is a common chronic gastrointestinal disorder affecting both men and women. Nonerosive reflux disease generally affects more women, whereas GERD complications such as Barrett's esophagus (BE) or esophageal cancer affect more men. The aim of this study was to evaluate sex- and gender-specific symptoms and health-related quality of life (HRQoL) among men and women with GERD. Patients with clinical signs of reflux and completion of 24-hour pH-Impedance testing at the University Hospital Cologne were included into the study. Evaluation of symptoms and HRQoL included the following validated questionnaires: GERD-Health-Related Quality of Life (GERD HRQL), Gastrointestinal Quality of Life Index (GIQLI), and Hospital Anxiety and Depression Scale (HADS). In all, 509 women and 355 men with GERD were included. Men had a significantly higher DeMeester score (60.2 ± 62.6 vs. 43 ± 49.3, P < 0.001) and a higher incidence of BE (18.6 vs. 11.2%, P = 0.006). Women demonstrated significantly higher levels of anxiety (30.9 vs. 14.5%, P = 0.001), more severely impacting symptoms (45.3 ± 11.3 vs. 49.9 ± 12.3, P < 0.001), as well as physical (14.2 ± 5.7 vs. 16.7 ± 5.6, P < 0.001) and social dysfunction (13.3 ± 4.8 vs. 14.8 ± 4.3, P = 0.002). Women further reported a lower HRQoL (85.3 ± 22.7 vs. 92.9 ± 20.8, P < 0.001). Men and women differ on biological, psychological, and sociocultural levels.

A senior surgical resident can safely perform complex esophageal cancer surgery after surgical mentoring program-experience of a European high-volume center.

Previous studies have shown that surgical residents can safely perform a variation of complex abdominal surgeries when provided with adequate training, proper case selection, and appropriate supervision. Their outcomes are equivalent when compared to experienced board-certified surgeons. Our previously published training curriculum for robotic assisted minimally invasive esophagectomy already demonstrated a possible reduction in time to reach proficiency. However, esophagectomy is a technically challenging procedure and comes with high morbidity rates of up to 60%, making it difficult to provide opportunities to train surgical residents. We aimed to investigate if a surgical resident could safely perform complex esophageal surgery when a structured modular teaching curriculum is applied. A structured teaching program based on our previously published modular step-up approach was applied by two experienced board-certified esophageal surgeons. Our IRB-approved (Institutional Review Board) database was searched to identify all Ivor-Lewis esophagectomies performed by the selected surgical resident from August 2019 to July 2021. The cumulative sum method was used to analyze the learning curve of the surgical resident. Outcomes of patients operated by the resident were then compared to our overall cohort of open, hybrid, and robotic Ivor-Lewis esophagectomies from May 2016 to May 2020. The total cohort included 567 patients, of which 65 were operated by the surgical resident and 502 patients were operated by experienced esophageal cancer surgeons as the control group. For baseline characteristics, a significant difference for BMI (Body mass index) was observed, which was lower in the resident's group (25.5 kg/m2 vs. 26.8 kg/m2 (P = 0.046). A significant difference of American Society of Anesthesiologists- and Eastern Cooperative Oncology Group-scores was seen, and a subgroup analysis including all patients with American Society of Anesthesiologists I and Eastern Cooperative Oncology Group 0 was performed revealing no significant differences. Postoperative complications did not differ between groups. The anastomotic leak rate was 13.8% in the resident's cohort and 12% in the control cohort (P = 0.660). Major complications (Clavien-Dindo ≥ IIIb) occurred in 16.9% of patients in both groups. Oncological outcome, defined by harvested lymph nodes (35 vs. 32.33, P = 0.096), proportion of lymph node compliant performed operations (86.2% vs. 88.4%, P = 0.590), and R0-resection rate (96.9% vs. 96%, P = 0.766), was not compromised when esophagectomies were performed by the resident. The resident completed the learning curves after 39 cases for the total operating time, 38 cases for the thoracic operating time, 26 cases for the number of harvested lymph nodes, 29 cases for anastomotic leak rate, and finally 58 cases for the comprehensive complication index. For postoperative complications, no significant difference was seen between patients operated in the resident group versus the control group, with a third of patients being discharged with a textbook outcome in both cohorts. Furthermore, no difference in oncological quality of the resection was found, emphasizing safety and feasibility of our training program. A structured modular step-up for training a surgical resident to perform complex esophageal cancer surgery can successfully maintain patient safety and outcomes.

GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level.

OBJECTIVE: Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling. DESIGN: We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. RESULTS: The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models. CONCLUSION: Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

Predicting the HER2 status in oesophageal cancer from tissue microarrays using convolutional neural networks.

BACKGROUND: Fast and accurate diagnostics are key for personalised medicine. Particularly in cancer, precise diagnosis is a prerequisite for targeted therapies, which can prolong lives. In this work, we focus on the automatic identification of gastroesophageal adenocarcinoma (GEA) patients that qualify for a personalised therapy targeting epidermal growth factor receptor 2 (HER2). We present a deep-learning method for scoring microscopy images of GEA for the presence of HER2 overexpression. METHODS: Our method is based on convolutional neural networks (CNNs) trained on a rich dataset of 1602 patient samples and tested on an independent set of 307 patient samples. We additionally verified the CNN's generalisation capabilities with an independent dataset with 653 samples from a separate clinical centre. We incorporated an attention mechanism in the network architecture to identify the tissue regions, which are important for the prediction outcome. Our solution allows for direct automated detection of HER2 in immunohistochemistry-stained tissue slides without the need for manual assessment and additional costly in situ hybridisation (ISH) tests. RESULTS: We show accuracy of 0.94, precision of 0.97, and recall of 0.95. Importantly, our approach offers accurate predictions in cases that pathologists cannot resolve and that require additional ISH testing. We confirmed our findings in an independent dataset collected in a different clinical centre. The attention-based CNN exploits morphological information in microscopy images and is superior to a predictive model based on the staining intensity only. CONCLUSIONS: We demonstrate that our approach not only automates an important diagnostic process for GEA patients but also paves the way for the discovery of new morphological features that were previously unknown for GEA pathology.

Impact of the Surgical Approach for Neoadjuvantly Treated Gastroesophageal Junction Type II Tumors: A Multinational, High-volume Center Retrospective Cohort Analysis.

OBJECTIVE: The aim of this study was to explore oncologic outcomes of transhiatal gastrectomy (THG) or transthoracic esophagectomy (TTE) for neoadjuvantly treated gastroesophageal junction (GEJ) Siewert type II adenocarcinomas, a multinational, high-volume center cohort analysis was undertaken. BACKGROUND: Neoadjuvant radiochemotherapy or perioperative chemotherapy (CTx) followed by surgery is the standard therapy for locally advanced GEJ. However, the optimal surgical approach for type II GEJ tumors remains unclear, as the decision is mainly based on individual experience and assessment of operative risk. METHODS: A retrospective analysis of 5 prospectively maintained databases was conducted. Between 2012 and 2021, 800 patients fulfilled inclusion criteria for type II GEJ tumors and neoadjuvant radiochemotherapy or CTx. The primary endpoint was median overall survival (mOS). Propensity score matching was performed to minimize selection bias. RESULTS: Patients undergoing THG (n=163, 20.4%) had higher American Society of Anesthesiologists (ASA) classification and cT stage ( P <0.001) than patients undergoing TTE (n=637, 79.6%). Neoadjuvant therapy was different as the THG group were mainly undergoing CTx (87.1%, P <0.001). The TTE group showed higher tumor regression ( P =0.009), lower ypT/ypM categories (both P <0.001), higher nodal yield ( P =0.009) and higher R0 resection rate ( P =0.001). The mOS after TTE was longer (78.0 vs 40.0 months, P =0.013). After propensity score matching a higher R0 resection rate ( P =0.004) and mOS benefit after TTE remained ( P =0.04). Subgroup analyses of patients without distant metastasis ( P =0.037) and patients only after neoadjuvant chemotherapy ( P =0.021) confirmed the survival benefit of TTE. TTE was an independent predictor of longer survival. CONCLUSION: Awaiting results of the randomized CARDIA trial, TTE should in high-volume centers be considered the preferred approach due to favorable oncologic outcomes.

Long-Term Postsurgical Outcomes of Neoadjuvant Chemoradiation (CROSS) Versus Chemotherapy (FLOT) for Multimodal Treatment of Adenocarcinoma of the Esophagus and the Esophagogastric Junction.

BACKGROUND: The question of the ideal neoadjuvant therapy for locally advanced esophagogastric adenocarcinoma has not been answered to date. Multimodal treatment has become a standard treatment for these adenocarcinomas. Currently, perioperative chemotherapy (FLOT) or neoadjuvant chemoradiation (CROSS) is recommended. METHODS: A monocentric retrospective analysis compared long-term survival after CROSS versus FLOT. The study enrolled patients with adenocarcinoma of the esophagus (EAC) or the esophagogastric junction type I or II undergoing oncologic Ivor-Lewis esophagectomy between January 2012 and December 2019. The primary objective was to determine the long-term outcome in terms of overall survival. The secondary objectives were to determine differences regarding the histopathologic categories after neoadjuvant treatment and the histomorphologic regression. RESULTS: The findings showed no survival advantage for one or the other treatment in this highly standardized cohort. All the patients underwent open (CROSS: 9.4% vs. FLOT: 22%), hybrid (CROSS: 82% vs. FLOT: 72%), or minimally invasive (CROSS: 8.9% vs. FLOT: 5.6%) thoracoabdominal esophagectomy. The median post-surgical follow-up period was 57.6 months (95% confidence interval [CI] 23.2-109.7 months), and the median survival was longer for the CROSS patients (54 months) than for the FLOT patients (37.2 months) (p = 0.053). The overall 5-years survival was 47% for the entire cohort (48% for the CROSS and 43% for the FLOT patients). The CROSS patients showed a better pathologic response and fewer advanced tumor stages. CONCLUSION: The improved pathologic response after CROSS cannot be translated into longer overall survival. To date, the choice of which neoadjuvant treatment to use can be made only on the basis of clinical parameters and the patient's performance status.

Prediction of postoperative complications after oesophagectomy using machine-learning methods.

BACKGROUND: Oesophagectomy is an operation with a high risk of postoperative complications. The aim of this single-centre retrospective study was to apply machine-learning methods to predict complications (Clavien-Dindo grade IIIa or higher) and specific adverse events. METHODS: Patients with resectable adenocarcinoma or squamous cell carcinoma of the oesophagus and gastro-oesophageal junction who underwent Ivor Lewis oesophagectomy between 2016 and 2021 were included. The tested algorithms were logistic regression after recursive feature elimination, random forest, k-nearest neighbour, support vector machine, and neural network. The algorithms were also compared with a current risk score (the Cologne risk score). RESULTS: 457 patients had Clavien-Dindo grade IIIa or higher complications (52.9 per cent) versus 407 patients with Clavien-Dindo grade 0, I, or II complications (47.1 per cent). After 3-fold imputation and 3-fold cross-validation, the overall accuracies were: logistic regression after recursive feature elimination, 0.528; random forest, 0.535; k-nearest neighbour, 0.491; support vector machine, 0.511; neural network, 0.688; and Cologne risk score, 0.510. For medical complications, the results were: logistic regression after recursive feature elimination, 0.688; random forest, 0.664; k-nearest neighbour, 0.673; support vector machine, 0.681; neural network, 0.692; and Cologne risk score, 0.650. For surgical complications, the results were: logistic regression after recursive feature elimination, 0.621; random forest, 0.617; k-nearest neighbour, 0.620; support vector machine, 0.634; neural network, 0.667; and Cologne risk score, 0.624. The calculated area under the curve of the neural network was 0.672 for Clavien-Dindo grade IIIa or higher, 0.695 for medical complications, and 0.653 for surgical complications. CONCLUSION: The neural network scored the highest accuracies compared with all of the other models for the prediction of postoperative complications after oesophagectomy.

The human gullet or stomach can develop tumours. Surgery can help to cure patients with these tumours. But the operation is risky because sometimes adverse events can happen afterwards. So far, there is no reliable prediction model. It may help to predict the risk of adverse events accurately. For example, patients with a high risk could be observed more thoroughly. Patients with a low risk may not need unnecessary procedures. The information of all patients with an operation at a specialized hospital was collected. Machine learning is a complex mathematical method and was used in this study. It is able to analyse big data sets of information. One machine-learning method called neural network was best in predicting adverse events. Right now, the performance may not be strong enough to fully rely on the prediction. However, refinement of the prediction and more data could improve the neural network in the future.

High NANOG expression correlates with worse patients' survival in esophageal adenocarcinoma.

BACKGROUND: Patients diagnosed with esophageal cancer demonstrate a low overall survival even despite the established multimodal therapy as the current standard of care. Therefore, further biomarkers for patients with high-risk and additional therapy options are needed. NANOG is a transcription factor, which can be found in stem cells and is known to support tumorigenesis. METHODS: Six hundred sixty patients with esophageal adenocarcinoma, who were operated at the University of Cologne with a curative intent, were included. Immunohistochemical stainings for NANOG were performed. The study population was divided into NANOG-positive and -negative subgroups. RESULTS: Positive NANOG expression correlates significantly with worse overall survival (p = 0.002) and could be confirmed as an independent risk factor for worse patient survival in multivariate analysis (HR = 1.40, 95%CI = 1.09-1.80, p = 0.006). This effect could be detected in the subgroup of primarily operated patients, but not in patients after neoadjuvant therapy. CONCLUSIONS: We describe a NANOG-positive subgroup of patients with esophageal cancer, who exhibit worse overall survival in a large patient cohort. This discovery suggests the potential use of NANOG as a biomarker for both intensified therapy and stricter follow-up regimes. Additionally, NANOG-positive stem cell-like cancer cells could be used as a new antitumoral treatment target if validated in mechanistic and clinical studies.

Time to endoscopic vacuum therapy-lessons learned after > 150 robotic-assisted minimally invasive esophagectomies (RAMIE) at a German high-volume center.

OBJECTIVE OF THE STUDY: In esophageal surgery, anastomotic leak (AL) remains one of the most severe and critical adverse events after oncological esophagectomy. Endoscopic vacuum therapy (EVT) can be used to treat AL; however, in the current literature, treatment outcomes and reports on how to use this novel technique are scarce. The aim of this study was to evaluate the outcomes of patients with an AL after IL RAMIE and to determine whether using EVT as an treatment option is safe and feasible. MATERIAL AND METHODS: This study includes all patients who developed an Esophagectomy Complications Consensus Group (ECCG) type II AL after IL RAMIE at our center between April 2017 and December 2021. The analysis focuses on time to EVT, duration of EVT, and follow up treatments for these patients. RESULTS: A total of 157 patients underwent an IL RAMIE at our hospital. 21 patients of these (13.4%) developed an ECCG type II AL. One patient died of unrelated Covid-19 pneumonia and was excluded from the study cohort. The mean duration of EVT was 12 days (range 4-28 days), with a mean of two sponge changes (range 0-5 changes). AL was diagnosed at a mean of 8 days post-surgery (range 2-16 days). Closure of the AL with EVT was successful in 15 out of 20 patients (75%). Placement of a SEMS (Self-expandlable metallic stent) after EVT was performed in four patients due to persisting AL. Overall success rate of anastomotic sealing independently of the treatment modality was achieved in 19 out of 20 Patients (95%). No severe EVT-related adverse events occurred. CONCLUSION: This study shows that EVT can be a safe and effective endoscopic treatment option for ECCG type II AL.

Analysis of training pathway to reach expert performance levels based on proficiency-based progression in robotic-assisted minimally invasive esophagectomy (RAMIE).

BACKGROUND: Robotic-assisted minimally invasive esophagectomy (RAMIE) was first introduced in 2003 and has since then shown to significantly improve the postoperative course. Previous studies have shown that a structured training pathway based on proficiency-based progression using individual skill levels as measures of reach of competence can enhance surgical performance. The aim of this study was to evaluate and help understand our pathway to reach surgical expert levels using a proficiency-based approach introducing RAMIE at our German high-volume center. METHODS: All patients undergoing RAMIE performed by two experienced surgeons for esophageal cancer since the introduction of the robotic technique in 2017 was included in this analysis. Intraoperative outcomes and postoperative outcomes were included in the analysis. The cumulative sum method was used to analyze how many cases are needed to reach expert levels for different performance characteristics and skill sets during robotic-assisted minimally invasive esophagectomy. RESULTS: From 06/2017 to 03/2022, a total of 154 patients underwent RAMIE at our facility and were included in the analysis. An advancement in performance level was observed for total operating time after 70 cases and for thoracic operative time after 79 cases. Lymph node yield showed an increase up until case 60 in the CUSUM analysis. Length of hospital stay stabilized after case 55. The CCI score inflection point was at case 55 in both CUSUM and regression analyses. Anastomotic leak rate stabilized at case 38 and showed another inflection point after case 83. CONCLUSION: Our data and analysis showed the progression from proficient to expert performance levels during the implementation of RAMIE at a European high-volume center. Further analysis of surgeons, especially with a different training status has yet to reveal if the caseloads found in this study are universally applicable. However, skill acquisition and respective measures of such are diverse and as a great range of number of cases was observed, we believe that the learning curve and ascent in performance levels cannot be defined by one parameter alone.

Hybrid laparoscopic versus fully robot-assisted minimally invasive esophagectomy: an international propensity-score matched analysis of perioperative outcome.

BACKGROUND: Currently, little is known regarding the optimal technique for the abdominal phase of RAMIE. The aim of this study was to investigate the outcome of robot-assisted minimally invasive esophagectomy (RAMIE) in both the abdominal and thoracic phase (full RAMIE) compared to laparoscopy during the abdominal phase (hybrid laparoscopic RAMIE). METHODS: This retrospective propensity-score matched analysis of the International Upper Gastrointestinal International Robotic Association (UGIRA) database included 807 RAMIE procedures with intrathoracic anastomosis between 2017 and 2021 from 23 centers. RESULTS: After propensity-score matching, 296 hybrid laparoscopic RAMIE patients were compared to 296 full RAMIE patients. Both groups were equal regarding intraoperative blood loss (median 200 ml versus 197 ml, p = 0.6967), operational time (mean 430.3 min versus 417.7 min, p = 0.1032), conversion rate during abdominal phase (2.4% versus 1.7%, p = 0.560), radical resection (R0) rate (95.6% versus 96.3%, p = 0.8526) and total lymph node yield (mean 30.4 versus 29.5, p = 0.3834). The hybrid laparoscopic RAMIE group showed higher rates of anastomotic leakage (28.0% versus 16.6%, p = 0.001) and Clavien Dindo grade 3a or higher (45.3% versus 26.0%, p < 0.001). The length of stay on intensive care unit (median 3 days versus 2 days, p = 0.0005) and in-hospital (median 15 days versus 12 days, p < 0.0001) were longer for the hybrid laparoscopic RAMIE group. CONCLUSIONS: Hybrid laparoscopic RAMIE and full RAMIE were oncologically equivalent with a potential decrease of postoperative complications and shorter (intensive care) stay after full RAMIE.

Clinical utility and applicability of the,Esophagus Complication Consensus Group' (ECCG) classification of anastomotic leakage following hybrid Ivor-Lewis esophagectomy.

BACKGROUND: Anastomotic leakage (AL) remains the leading surgical complication following Ivor-Lewis (IL) esophagectomy. Different treatment options of AL exist but outcome is difficult to compare due to a lack of generally accepted classifications. This retrospective study was conducted to analyze the clinical significance of a recently proposed classification based on the management of AL. PATIENTS AND METHODS: A cohort of 954 consecutive patients undergoing hybrid IL esophagectomy (laparoscopy/thoracotomy) was analysed. AL was defined according to the,Esophagus Complication Consensus Group' (ECCG) criteria depending on its treatment: conservative (AL type I), interventional endoscopic (AL type II), and surgical (AL type III). Primary outcome was single or multiple organ failure (Clavien-Dindo IVA/B) associated with AL. RESULTS: Overall morbidity was 63.0% and 8.8% (84/954 patients) developed an AL postoperatively. Three patients (3.5%) had an AL type I, 57 patients (67.9%) an AL type II and 24 patients (28.6%) an AL type III. For patients managed surgically, AL was diagnosed significantly earlier (median days: AL type III: 2 vs AL type II: 6, p < 0.001). Associated organ failure (CD IVA/B) was significantly lower for AL type II as compared to AL type III (21.1% versus 45.8%, p < 0.0001). In-hospital mortality was 3.5% for AL type II and 8.3% for AL type III (p = 0.789). There was no difference for re-admission to ICU and overall length of hospital stay. CONCLUSION: The proposed ECCG classification is simply to apply and discriminates the post-treatment severity of AL but does not aid to implement a treatment algorithm.

Oligometastatic disease and visceral resections in advanced malignant melanoma: a propensity-matched analysis.

PURPOSE: Malignant melanoma is among the tumours with the highest increase in incidence of solid tumours in Germany. While most patients are diagnosed at an early stage and show a good prognosis, advanced stages of malignant melanoma are accompanied with a poor prognosis and limited treatment options. Comparable to other tumour entities, the resection of visceral metastases could lead to a better prognosis. Supplementary, the subgroup of oligometastatic patients might benefit from surgical therapy to a greater extent. METHODS: This retrospective study analysed 351 patients treated between 2006 and 2017 at the University Hospital of Cologne. A total of 121 patients showed visceral metastases, with which we compared patients with a diffuse tumour spread to patients in an oligometastatic state. Furthermore, we evaluated the effect of visceral resection of oligometastatic, malignant melanoma. RESULTS: Our analysis showed that patients with an oligometastatic malignant melanoma had a significantly better prognosis than patients with a diffuse pattern of metastases, if they showed visceral metastases. Furthermore, the resection of visceral metastases leads to a significant gain in median overall survival time (13.6 vs. 34.2 months) and in progression-free survival (9.6 vs. 3.8 months). CONCLUSION: The resection of visceral metastases is a rational treatment option in advanced malignant melanoma. Although our study is limited by a small cohort of patients (n = 18), we believe that the resection of visceral metastases will be fundamental in the treatment of malignant melanoma. In particular, patients in an oligometastatic stage could be an eligible group for surgical treatment.

Cancer-Associated Fibroblast Heterogeneity and Its Influence on the Extracellular Matrix and the Tumor Microenvironment.

The tumor microenvironment comprises multiple cell types, like cancer cells, endothelial cells, fibroblasts, and immune cells. In recent years, there have been massive research efforts focusing not only on cancer cells, but also on other cell types of the tumor microenvironment, thereby aiming to expand and determine novel treatment options. Fibroblasts represent a heterogenous cell family consisting of numerous subtypes, which can alter immune cell fractions, facilitate or inhibit tumor growth, build pre-metastatic niches, or stabilize vessels. These effects can be achieved through cell-cell interactions, which form the extracellular matrix, or via the secretion of cytokines or chemokines. The pro- or antitumorigenic fibroblast phenotypes show variability not only among different cancer entities, but also among intraindividual sites, including primary tumors or metastatic lesions. Commonly prescribed for arterial hypertension, the inhibitors of the renin-angiotensin system have recently been described as having an inhibitory effect on fibroblasts. This inhibition leads to modified immune cell fractions and increased tissue stiffness, thereby contributing to overcoming therapy resistance and ultimately inhibiting tumor growth. However, it is important to note that the inhibition of fibroblasts can also have the opposite effect, potentially resulting in increased tumor growth. We aim to summarize the latest state of research regarding fibroblast heterogeneity and its intricate impact on the tumor microenvironment and extracellular matrix. Specifically, we focus on highlighting recent advancements in the comprehension of intraindividual heterogeneity and therapy options within this context.

Worldwide Techniques and Outcomes in Robot-assisted Minimally Invasive Esophagectomy (RAMIE): Results From the Multicenter International Registry.

OBJECTIVE: This international multicenter study by the Upper GI International Robotic Association aimed to gain insight in current techniques and outcomes of RAMIE worldwide. BACKGROUND: Current evidence for RAMIE originates from single-center studies, which may not be generalizable to the international multicenter experience. METHODS: Twenty centers from Europe, Asia, North-America, and South-America participated from 2016 to 2019. Main endpoints included the surgical techniques, clinical outcomes, and early oncological results of ramie. RESULTS: A total of 856 patients undergoing transthoracic RAMIE were included. Robotic surgery was applied for both the thoracic and abdominal phase (45%), only the thoracic phase (49%), or only the abdominal phase (6%). In most cases, the mediastinal lymphadenectomy included the low paraesophageal nodes (n=815, 95%), subcarinal nodes (n = 774, 90%), and paratracheal nodes (n = 537, 63%). When paratracheal lymphadenectomy was performed during an Ivor Lewis or a McKeown RAMIE procedure, recurrent laryngeal nerve injury occurred in 3% and 11% of patients, respectively. Circular stapled (52%), hand-sewn (30%), and linear stapled (18%) anastomotic techniques were used. In Ivor Lewis RAMIE, robot-assisted hand-sewing showed the highest anastomotic leakage rate (33%), while lower rates were observed with circular stapling (17%) and linear stapling (15%). In McKeown RAMIE, a hand-sewn anastomotic technique showed the highest leakage rate (27%), followed by linear stapling (18%) and circular stapling (6%). CONCLUSION: This study is the first to provide an overview of the current techniques and outcomes of transthoracic RAMIE worldwide. Although these results indicate high quality of the procedure, the optimal approach should be further defined.

Long-Term Outcome After Histopathological Complete Response with and Without Nodal Metastases Following Multimodal Treatment of Esophageal Cancer.

BACKGROUND: This study analyzed the long-term survival after pathological complete response (pCR) with and without nodal metastases and associated recurrence following multimodal treatment of esophageal cancer. The recurrence pattern after pCR is of importance for different postoperative surveillance strategies. METHODS: A cohort of 890 patients with esophageal cancer received neoadjuvant therapy followed by transthoracic esophagectomy. Only patients with pCR of the primary tumor with and without nodal metastasis were analyzed. A clinicopathological database was set up and completed with long-term follow up information on recurrent disease. RESULTS: The specimen of 201 patients (23%) demonstrated pCR, 84% without (ypT0N0) and 16% with residual nodal disease (ypT0N+). For ypT0N0 patients, the 5-year overall survival was significantly higher than for patients with metastatic nodes (77% vs. 24%) (p < 0.0001). Sixty-eight percent of patients had no evidence of tumor recurrence, whereas 32% had proven relapse. For patients with and without tumor recurrence, 5-year survival rates were 14% and 93%, respectively (p < 0.0001). For patients with recurrent disease, median survival time was 27 for locoregional, 44 for distant, and 24 months for combined recurrence (p = 0.302). In the multivariable Cox-regression analysis, node-positive disease predicted both locoregional and metastatic recurrence. CONCLUSIONS: Pathological CR offers long-term survival in patients without nodal metastases but outcome significantly deteriorates with the presence of nodal metastases. Follow-up recommendations may therefore be adopted in patients with pCR. Furthermore, "watch-and-wait" surveillance strategies with suspected clinical complete response have to be considered with caution.

Robot-assisted minimally invasive esophagectomy (RAMIE) vs. hybrid minimally invasive esophagectomy: propensity score matched short-term outcome analysis of a European high-volume center.

INTRODUCTION: Transthoracic esophagectomy is a highly complex and sophisticated procedure with high morbidity rates and a significant mortality. Surgical access has consistently become less invasive, transitioning from open esophagectomy to hybrid esophagectomy (HE) then to totally minimally invasive esophagectomy (MIE), and most recently to robot-assisted minimally invasive esophagectomy (RAMIE), with each step demonstrating improved patient outcomes. Aim of this study with more than 600 patients is to complete a propensity-score matched comparison of postoperative short-term outcomes after highly standardized RAMIE vs. HE in a European high volume center. PATIENTS AND METHODS: Six hundred and eleven patients that underwent transthoracic Ivor-Lewis esophagectomy for esophageal cancer between May 2016 and May 2021 were included in the study. In January 2019, we implemented an updated robotic standardized anastomotic technique using a circular stapler and ICG (indocyanine green) for RAMIE cases. Data were retrospectively analyzed from a prospectively maintained IRB-approved database. Outcomes of patients undergoing standardized RAMIE from January 2019 to May 2021 were compared to our overall cohort from May 2016-April 2021 (HE) after a propensity-score matching analysis was performed. RESULTS: Six hundred and eleven patients were analyzed. 107 patients underwent RAMIE. Of these, a total of 76 patients underwent a robotic thoracic reconstruction using the updated standardized circular stapled anastomosis (RAMIE group). A total of 535 patients underwent HE (Hybrid group). Seventy patients were propensity-score matched in each group and analysis revealed no statistically significant differences in baseline characteristics. RAMIE patients had a significantly shorter ICU stay (p = 0.0218). Significantly more patients had no postoperative complications (Clavien Dindo 0) in the RAMIE group [47.1% vs. 27.1% in the HE group (p = 0.0225)]. No difference was seen in lymph node yield and R0 resection rates. Anastomotic leakage rates when matched were 14.3% in the hybrid group vs. 4.3% in the RAMIE group (p = 0.07). CONCLUSION: Our analysis confirms the safety and feasibility of RAMIE and HE in a large cohort after propensity score matching. A regular postoperative course (Clavien-Dindo 0) and a shorter ICU stay were seen significantly more often after RAMIE compared to HE. Furthermore it shows that both procedures provide excellent short-term oncologic outcomes, regarding lymph node harvest and R0 resection rates. A randomized controlled trial comparing RAMIE and HE is still pending and will hopefully contribute to ongoing discussions.