Peritoneal adhesions are a common complication following abdominal surgery and contribute substantially to long-termmorbidity, including bowel obstruction, chronic pain, and infertility. Their diverse clinical presentation, ranging from thin strands todense obstructive bands, suggests multiple underlying pathomechanisms. We propose a histopathological framework for classifyingperitoneal adhesions based on extracellular matrix characteristics, providing a microscopic correlation to clinical heterogeneity andsupporting translational research on adhesion prevention. In this study, adhesions from 77 patients were examined histologically. Masson's Trichrome staining was used to visualize the extracellular matrix, enabling classification into five clusters based on qualitative histological analysis: stringy, dense, loose, fatty, and mixed. The "stringy" and "dense" clusters exhibited the highest extracellular matrix fraction and vessel area, whereas the"loose" and "fatty" clusters displayed lower ECM density and vascularity. Immunohistochemical staining for αSMA (myofibroblasts) and PGP9.5 (nerve fibers) further revealed cluster-specific differences in myofibroblast presence and innervation. Cluster distribution was significantly associated with clinical parameters, including adhesion load and prior peritonitis. This is the first study to systematically categorize peritoneal adhesions byextracellular matrix characteristics, identifying five distinct histopathological phenotypes. Our findings highlight the structural andcellular diversity of adhesions, offering new insights with potential implications for understanding adhesion pathophysiology andguiding future therapeutic strategies. Validation in larger cohorts will be essential to confirm this framework and establish its clinicalutility.

Accurate cancer staging is essential for cancer research and treatment evaluation; however, real-world data (RWD) often include incomplete or inconsistent UICC classifications. We present the development, optimization, demonstration, and release of the Munich UICC Staging Tool (MUST), an open-source R script that automates UICC staging based on TNM classifications and tumor characteristics, improving data completeness and consistency. MUST incorporates official UICC staging rules (6th-8th editions). A key feature is the application of RWD-specific rules to handle missing values and incomplete information. The tool is transparent, highly customizable, and adaptable to future TNM versions and diverse applications. MUST was validated using anonymized clinical tumor registry data from two Munich university hospitals (analyzed independently, n > 100,000), focusing on pancreatic and stomach cancers. Compared to documented UICC stages, MUST increased staging completeness from 60% to 72% in Clinic-1 and from 20% to 74% in Clinc-2. Agreement rates between documented and MUST-generated UICC stages were 90% in Clinic-1 and 95% in Clinic-2. To assess reliability, a Confidence Level metric summarizes the proportion of original versus additional rules applied. 70% of MUST-derived stages in Clinic-1 and 48% in Clinic-2 were classified as "Assured," with the remaining cases relying on RWD-specific rules. The results demonstrate that RWD-specific rules substantially improve completeness, while the differences between clinics highlight variations in documentation and coding practices. MUST offers a reliable solution for UICC staging, addressing documentation gaps and improving data quality. Its adaptability makes it valuable for clinical documentation, registries, and large-scale oncology studies.

Background: Anastomotic leakage (AL) is a major concern following esophagectomy due to the associated morbidity and mortality. The impact of hospital volume on postoperative outcomes after esophagectomy has previously been reported. The aim of this study was to analyze the current trends in postoperative anastomotic leakage and associated failure-to-rescue after esophagectomy in relation to hospital volume in German acute care hospitals using real-world data from the German Diagnosis-Related Groups (G-DRG) database. Materials and methods: A retrospective secondary data analysis of the G-DRG database was performed for all in-hospital cases of patients undergoing esophagectomy from 2013 to 2021. AL and in-house mortality rates were assessed in relation to hospital case volume and endoscopic treatment modalities. Results: The study included 32 335 cases. The mean reported AL rate was 17.1% with a mean failure-to-rescue rate of 18.9%. AL rates did not differ between hospitals with an annual case-volume ≤ 25 procedures/year vs. >25 procedures/year (16.8% vs. 17.6%, OR 1.06, P = 0.07). However, in high-volume centers (> 25 procedures/year), in-hospital mortality for cases with AL (failure-to-rescue) was lower compared to medium-volume (10-25 cases/year) and low-volume (1-9 cases/year) centers (14.2% vs. 21.5% vs. 25.1%). The use of EVT increased over time, reaching 58.1% of AL cases in 2021 compared to 14.2% in 2013, while the use of self-expanding metal stents (SEMS) decreased from 37.0% in 2013 to 9.3% in 2021. Conclusions: AL rates after esophagectomy remain high. In-house mortality is significantly lower in high-volume hospitals highlighting the importance to consider improvements in centralization of procedures. Further efforts are needed to reduce AL rates and improve outcomes after esophagectomy.

Esophageal anastomotic leaks (EAL) after esophagectomy strongly increase postoperative mortality and morbidity. Identifying, addressing, and improving risk factors are pivotal. In this article, we conducted a systematic review with meta-analysis, comparing findings with our 13-year experience in a German high-volume esophageal surgery center. Databases of Pubmed, Scopus, and Cochrane were systematically screened for publications prior to 2025, and all patients undergoing esophageal resection surgery from 2010 to 2022 were analyzed for EAL occurrence, incorporating the review data into our analysis. Among 14,163 studies screened, 202 were included, with 123 studies providing sufficient information on risk factors’ impact on EAL. Our patient register revealed 144 out of 787 with EAL. Cardiopulmonary factors such as hypertension (RR 1.44; p = 0.0004), coronary artery disease (RR 1.28; p = 0.0004), heart insufficiency (RR 1.56; p = 0.05), peripheral artery disease (RR 1.65; p = 0.0009), pulmonary disease (RR 1.5; p = 0.01), COPD (RR 1.39; p = 0.13), renal insufficiency (RR 1.61; p = 0.03), diabetes mellitus (RR 1.51; p < 0.00001), obesity (BMI > 25; RR 1.31; p = 0.009; BMI > 30; RR 1.49; p = 0.006), smoking (former smoker: RR 1.54; p < 0.0001; active smoker: RR 1.25; p < 0.0001), and frequent alcohol intake (RR 1.7; p = 0.003) were all associated with an increased risk of EAL following esophagectomy. We show that preoperative management targeting these risk factors result in a significant reduction of EAL. Our extensive review underscores the critical role of cardiovascular, pulmonary, and renal conditions in EAL development, emphasizing the importance of prehabilitation to mitigate risks associated with EAL after esophagectomy.

Objective The aim of this study was to evaluate whether the configuration of anastomotic doughnuts from upper gastrointestinal surgeries was associated with anastomotic leakage (AL). Background AL is a severe postoperative complication after upper gastrointestinal cancer surgeries. AL is associated with an increase in overall and cancer-related morbidity and mortality in patients with esophageal and gastric cancer. New intraoperative biomarkers are needed to predict the risk of AL to implement early preventive measures. Materials and methods Anastomotic doughnuts from 102 patients undergoing surgery for esophageal or gastric cancer using circular staplers were examined. The minimal and maximal height and width of the anastomotic doughnuts were measured and correlated with the postoperative AL rate. Results The AL rate in our study collective was 15,7%. The minimal width (Wmin) of the oral and aboral anastomotic doughnuts was significantly lower in patients with AL compared to patients without AL (p=0.002 and p=0.041 respectively). The Wmin of the esophageal anastomotic doughnut was an independent risk factor for AL in the multivariable analysis (p=0.034). Negative predictive values for the measurements of anastomotic doughnuts (Wmin) with regard to the risk of AL were higher than for the commonly used postoperative biomarker C-reactive protein. Conclusion Minimal anastomotic doughnut width was statistically significantly associated with AL. Thus, not only the evaluation of the completeness of the anastomotic doughnuts but also intraoperative measurements could be used to predict the risk of AL to initiate early preventive measures to prevent the development of AL and/or reduce AL-associated morbidity.

Introduction Anastomotic leaks (AL) crucially affect clinical course after esophagectomy by increasing postoperative mortality and complications. Although intraoperatively offered to the majority of patients, the impact of intraoperative fluid management and catecholamine therapy is not well known.

Background Malignant tumors of the esophagus are the sixth leading cause of cancer-related deaths worldwide. Postoperative leakage of the esophago-gastrostomy leads to mediastinal sepsis, which is still associated with a high morbidity and mortality rate. The aim of this study was to describe the endoscopic view of the different severity grades of an anastomotic leakage. MethodsPatients Between June 2016 and September 2018, 144 patients were operated upon in the Department of Surgery, University of Munich, Germany. Among these patients, 34 (23.6%) presented with a leakage of the anastomosis. EndoscopyIn this retrospective analysis the focus is to describe different patterns of leakage of the anastomosis.Results We studied 34 patients in whom post-esophagectomy leakage of the anastomosis was detected and treated with an endoluminal vacuum sponge system. The leakage healed in 26 of 29 patients (success rate 89.7%). With increasing severity of leakage, the treatment time and the in-hospital mortality correspondingly increased. Furthermore, the incidence of development of a fistula to the tracheobronchial system increased with higher grades of leakage.ConclusionsExact descriptions of leakage are necessary to compare the cases and to prove post-treatment improvement. This is, to our knowledge, the first publication to present a leakage grading score in patients after esophagectomy including reconstruction with a gastric tube. This new grading system needs to be tested in further analyses, with special focus on prospective analysis.

Purpose The incidence of esophageal adenocarcinoma (EAC) has been increasing for decades without significant improvements in treatment. Barrett’s esophagus (BE) is best established risk factor for EAC, but current surveillance with random biopsies cannot predict progression to cancer in most BE patients due to the low sensitivity and specificity of high-definition white light endoscopy. Methods Here, we evaluated the membrane-bound highly specific Hsp70-specific contrast agent Tumor-Penetrating Peptide (Hsp70-TPP) in guided fluorescence molecular endoscopy biopsy. Results Hsp70 was significantly overexpressed as determined by IHC in dysplasia and EAC compared with non-dysplastic BE in patient samples ( n = 12) and in high-grade dysplastic lesions in a transgenic (L2-IL1b) mouse model of BE. In time-lapse microscopy, Hsp70-TPP was rapidly taken up and internalized by human BE dysplastic patient–derived organoids. Flexible fluorescence endoscopy of the BE mouse model allowed a specific detection of Hsp70-TPP-Cy5.5 that corresponded closely with the degree of dysplasia but not BE. Ex vivo application of Hsp70-TPP-Cy5.5 to freshly resected whole human EAC specimens revealed a high (> 4) tumor-to-background ratio and a specific detection of previously undetected tumor infiltrations. Conclusion In summary, these findings suggest that Hsp70-targeted imaging using fluorescently labeled TPP peptide may improve tumor surveillance in BE patients.

The response to neoadjuvant therapy can vary widely between individual patients. Histopathological tumor regression grading (TRG) is a strong factor for treatment response and survival prognosis of esophageal adenocarcinoma (EAC) patients following neoadjuvant treatment and surgery. However, TRG systems are usually based on the estimation of residual tumor but do not consider stromal or metabolic changes after treatment. Spatial metabolomics analysis is a powerful tool for molecular tissue phenotyping but has not been used so far in the context of neoadjuvant treatment of esophageal cancer. We used imaging mass spectrometry to assess the potential of spatial metabolomics on tumor and stroma tissue for evaluating therapy response of neoadjuvant-treated EAC patients. With an accuracy of 89.7%, the binary classifier trained on spatial tumor metabolite data proved to be superior for stratifying patients when compared with histopathological response assessment, which had an accuracy of 70.5%. Sensitivities and specificities for the poor and favorable survival patient groups ranged from 84.9% to 93.3% using the metabolic classifier and from 62.2% to 78.1% using TRG. The tumor classifier was the only significant prognostic factor (HR 3.38, 95% CI 1.40-8.12, p = 0.007) when adjusted for clinicopathological parameters such as TRG (HR 1.01, 95% CI 0.67-1.53, p = 0.968) or stromal classifier (HR 1.86, 95% CI 0.81-4.25, p = 0.143). The classifier even allowed us to further stratify patients within the TRG1-3 categories. The underlying mechanisms of response to treatment have been figured out through network analysis. In summary, metabolic response evaluation outperformed histopathological response evaluation in our study with regard to prognostic stratification. This finding indicates that the metabolic constitution of the tumor may have a greater impact on patient survival than the quantity of residual tumor cells or the stroma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Tumor regression following neoadjuvant treatment can be observed in lymph node (LN) metastases similar to the primary tumor in esophageal adenocarcinomas (EAC). We evaluated the prognostic significance of tumor regression in LN metastases of locally advanced EAC of 239 patients treated with neoadjuvant radiochemotherapy (RCTX) or chemotherapy (CTX) followed by esophagectomy. We examined retrospectively the LN for histopathologic signs of regression, i.e., nodular fibrosis and acellular mucin. LN classification was performed according to two parameters: presence (−) or absence (+) of residual tumor and regression characteristics in the LN, resulting in four categories: LN−/REG−, LN−/REG+, LN+/REG+, LN+/REG−. In total, LN metastases with residual tumor were detectable in 117/239 (49%) cases. Regression in LN were observed in 85/239 cases (35.5%). The distribution of the LN/REG categories were as follows: 97 patients (40.6%) were LN−/REG−. A total of 25 patients (10.5%) were LN−/REG+. A total of 60 (25.1%) were LN+/REG+ and 57 (23.8%) LN+/REG−. The LN/Reg categorization had a significant prognostic value in univariate analysis (p < 0.001) and multivariate analysis (HR = 1.326; p = 0.002) with similar results for the subgroups of patients treated with RCTX or CTX. The prognosis of LN−/REG+ was worse than LN−/REG− but better than both LN+ categories, which was demonstrated in the Kaplan–Meier curves but did not reach statistical significance (p = 0.104 and p = 0.090, respectively). In contrast, there was no difference between LN+/REG+ and LN+/REG− (p = 0.802). In summary, regression in LN metastases of EAC can be observed in a significant number of patients after neoadjuvant therapy. Complete regression of former LN metastases in comparison to “true” negative LN seems to be of prognostic relevance but additional studies are needed to confirm this trend seen in our study.

Revascularization strategies for chronic mesenteric ischemia (CMI) include open (OR) and endovascular (ER) modalities. The primary objective of this study was to analyze the safety and effectiveness of OR and ER and the impact of clinical and morphological variables on early and midterm outcomes in a consecutive series of CMI patients in a tertiary referral center. From 2004 to 2017, all CMI patients treated with OR and ER were retrospectively identified. Patient records, preoperative imaging, as well as peri- and postoperative outcomes were analyzed. Univariable and multivariable analysis was performed to identify clinical or morphological variables affecting reintervention rates within 2 years. In total, 63 patients (33% male; mean age 71, range 60–76 years) were treated by ER (41 patients) or OR (22 patients) for CMI. Mean follow-up was 26 (10–71) months. 30-day mortality was 0.0% after ER and 4.5% after OR (p = 0.069); 30-day morbidity was 9.8% vs. 31.8%, respectively (p = 0.030). Length of stay was significantly longer after OR (14 vs. 4 days; p < 0.001). Freedom from reintervention rate after 2 years was 82% after OR and 73% after ER (p = 0.14). Overall survival did not differ after 2 years (OR 85% vs. ER 86%; p = 0.35). Multivariable analysis revealed that smoking was associated with higher risk of reintervention (hazard ratio, HR: 4.14; 95% confidence interval, CI 1.11–15.53; p = 0.03). Additionally, a nonsignificant trend of lower reintervention rates after OR was detected (HR 0.23 95% CI 0.05–1.08; p = 0.06). Due to a lower invasiveness, despite the higher reintervention rate, an “endovascular first” strategy is justified and recommended.

Esophageal carcinoma (EC) is one of the most aggressive human malignancies with high rates of resistance to conventional anticancer treatment. Cancer-associated fibroblasts (CAFs) are an important part of the tumor microenvironment and associated with tumor progression. COL11A1, SPARC, and CD90 have been identified as rather specific CAF markers, with COL11A1 expression particularly shown to influence response to chemotherapy. We investigated the impact of CAFs in esophageal cancer with a special focus on response to neoadjuvant treatment (nTX). Two collections of esophageal carcinomas were investigated: 164 cases treated with primary resection and 256 cases receiving nTX before resection. The expression of CAF markers was determined using next-generation tissue microarray (ngTMA®) technology and immunohistochemistry. The presence of COL11A1 and SPARC in fibroblasts within both primary resected cases and nTX-treated cases was associated with unfavorable clinicopathological variables such as higher (y)pT category and lymphatic invasion (p<0.001 each). The presence of COL11A1-positive CAFs was associated with worse overall survival in primary resected cases (HR: 2.162, p = 0.004, CI 95% 1.275–3.686). While in tumors showing regression after nTX, COL11A1-positive CAFs were detected less frequently, SPARC-positive CAFs were enriched after nTX, in both responding and non-responding patients (p < 0.001). Our results support the concept of CAFs as an important factor of tumor promotion and maintenance in EC. The population of CAFs increases with tumor progression and decreases, partly depending on the subtype, after regression following nTX. CAFs may serve as potential target for future therapeutic approaches for these highly aggressive tumors.

Multimodal treatment with neoadjuvant chemoradiation followed by surgery (nCRT + S) is the treatment of choice for patients with locally advanced or node-positive esophageal squamous cell carcinoma (E-SCC). Those who are unsuitable or who decline surgery can be treated with definitive chemoradiation (dCRT). This study compares the oncologic outcome of nCRT + S and dCRT in E-SCC patients. Between 2011 and 2017, 95 patients with E-SCC were scheduled for dCRT or nCRT+ S with IMRT at our department. Patients undergoing dCRT received at least 50 Gy and those undergoing nCRT + S received at least 41.4 Gy. All patients received simultaneous chemotherapy with either carboplatin and paclitaxel or cisplatin and 5-fluoruracil. We retrospectively compared baseline characteristics and oncologic outcome including overall survival (OS), progression-free survival (PFS) and site of failure between both treatment groups. Patients undergoing dCRT were less likely to have clinically suspected lymph node metastases (85% vs. 100%, p = 0.019) than patients undergoing nCRT + S and had more proximally located tumors (median distance from dental arch to cranial tumor border 20 cm vs. 26 cm, p < 0.001). After a median follow up of 25.6 months for surviving patients, no significant differences for OS and PFS were noticed comparing nCRT + S and dCRT. However, the rate of local tumor recurrence was significantly higher in patients treated with dCRT than in those treated with nCRT + S (38% vs. 10%, p = 0.002). Within a multivariate Cox regression model, age, tumor location, and tumor grading were the only independent parameters affecting OS and PFS. In addition to that, proximal tumor location was the only parameter independently associated with an increased risk for local treatment failure. In E-SCC patients treated with either dCRT or nCRT + S, a higher rate of local tumor recurrence was seen in patients treated with dCRT than in patients treated with nCRT + S. There was at least a trend towards an improved OS and PFS in patients undergoing nCRT + S. However, this should be interpreted with caution, because proximal tumor location was the only parameter independently affecting the risk of local tumor recurrence.

Background Cellular Dissociation Grade (CDG) composed of tumour budding and cell nest size has been shown to independently predict prognosis in pre-therapeutic biopsies and primary resections of oesophageal squamous cell carcinoma (ESCC). Here, we aimed to evaluate the prognostic impact of CDG in ESCC after neoadjuvant therapy. Methods We evaluated cell nest size and tumour budding activity in 122 post-neoadjuvant ESCC resections, correlated the results with tumour regression groups and patient survival and compared the results with data from primary resected cases as well as pre-therapeutic biopsies. Results CDG remained stable when results from pre-therapeutic biopsies and post-therapeutic resections from the same patient were compared. CDG was associated with therapy response and a strong predictor of overall, disease-specific (DSS) and disease-free (DFS) survival in univariate analysis and—besides metastasis—remained the only significant survival predictor for DSS and DFS in multivariate analysis. Multivariate DFS hazard ratios reached 3.3 for CDG-G2 and 4.9 for CDG-G3 neoplasms compared with CDG-G1 carcinomas ( p = 0.016). Conclusions CDG is the only morphology-based grading algorithm published to date, which in concert with regression grading, is able to contribute relevant prognostic information in the post-neoadjuvant setting of ESCC.

[This corrects the article DOI: 10.1371/journal.pone.0197610.].

Paclitaxel is a powerful chemotherapeutic drug, used for the treatment of many cancer types, including esophageal adenocarcinomas (EAC). Autophagy is a lysosome-dependent degradation process maintaining cellular homeostasis. Defective autophagy has been implicated in cancer biology and therapy resistance. We aimed to assess the impact of autophagy on chemotherapy response in EAC, with a special focus on paclitaxel. Responsiveness of EAC cell lines, OE19, FLO-1, OE33 and SK-GT-4, to paclitaxel was assessed using Alamar Blue assays. Autophagic flux upon paclitaxel treatment in vitro was assessed by immunoblotting of LC3B-II and quantitative assessment of WIP1 mRNA. Immunohistochemistry for the autophagy markers LC3B and p62 was applied on tumor tissue from 149 EAC patients treated with neoadjuvant chemotherapy, including pre- and post-therapeutic samples (62 matched pairs). Tumor response was assessed by histology. For comparison, previously published data on 114 primary resected EAC cases were used. EAC cell lines displayed differing responsiveness to paclitaxel treatment; however this was not associated with differential autophagy regulation. High p62 cytoplasmic expression on its own (p ≤ 0.001), or in combination with low LC3B (p = 0.034), was associated with nonresponse to chemotherapy, regardless of whether or not the regiments contained paclitaxel, but there was no independent prognostic value of LC3B or p62 expression patterns for EAC after neoadjuvant treatment. p62 and related pathways, most likely other than autophagy, play a role in chemotherapeutic response in EAC in a clinical setting. Therefore p62 could be a novel therapeutic target to overcome chemoresistance in EAC.

Following publication of the original article [1], the authors reported that for one of the authors, Stephanie E. Combs, the middle name was accidentally omitted. They also reported that for two of the authors, Daniel Habermehl and Stephanie E. Combs, two affiliations were accidentally omitted. In this Correction the incorrect and correct author name are shown and the two omitted affiliations are listed.

Background: Neoadjuvant chemotherapy (neoCTx) improves survival outcomes of patients with localised esophagogastric adenocarcinoma (EGA). This analysis evaluates the predictive value of histopathological response after neoCTx. Methods: A total of 461 patients with locally advanced EGA (>= T2 and/or N+) who received neoCTx followed by surgery were analysed: 314 (68.1%) with intestinal, 94 (20.4%) with diffuse and 53 (11.5%) with mixed histological type according to Lauren classification. Histopathological response evaluation was available for 363 patients and performed locally. This analysis evaluates the predictive value of histopathological subtype on histopathological response after neoCTx. Response was correlated with survival. Results: Median patients' age was 63 years, 79.8% were male. Tumours were localised in the stomach in 32.5% and EG junction in 67.5% of the patients. With a median follow-up of 49.4 months, median disease-free (DFS) and overall survival (OS) were 38.0 and 66.4 months, respectively. Pathological complete response (TRG1a) was 8.8% and combined complete and subtotal regression (TRG1a/b) was 27.3% for all patients. Around 9.2% of patients with intestinal type had a TRG1a compared with 6.2% with diffuse and 10.8% with mixed type. TRG1a/b rate was higher in intestinal (31.0%) than in diffuse (15.4%) and in mixed type (21.6%). For patients with intestinal type, 3-year DFS was 78.4% with TRG1a and 54.3% with other regression grades (p = 0.031). All patients with diffuse and mixed type and TRG1a were disease free after 3 years compared with 31.1% (p = 0.056) and 47.7% (p = 0.044) with other regression grades. Conclusion: Histopathological subtype is predictive for histopathological response and outcome after neoCTx, with the highest response rates in intestinal differentiated EGA. (C) 2017 Elsevier Ltd. All rights reserved.

Neoadjuvant chemoradiation (nCRT) is the treatment of choice for patients with locally advanced squamous cell carcinoma of the esophagus (SCC). Today radiation oncologists can choose between two different therapy regimes including chemoradiation with cisplatin and 5-fluoruracil (CDDP/5FU) and chemoradiation analogue to the CROSS-regime with carboplatin and paclitaxel (Carb/TAX). However, there is a lack of studies comparing these regimes, especially for the subgroup of patients with SCC. In this study, we want to compare nCRT with CDDP/5FU and nCRT with Carb/TAX for patients with locally advanced SCC.