European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4).

INTRODUCTION: The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD). METHODS: Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD. RESULTS: Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended. DISCUSSION: These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment.

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.

Upregulation of the histone γ-H2AX correlates with worse patient survival and basal-like subtype in pancreatic ductal adenocarcinoma.

PURPOSE: Patients with pancreatic ductal adenocarcinoma (PDAC) have yet to experience significant benefits from targeted therapy. Olaparib is currently the only active substance in BRCA-mutated PDACs that successfully influences the DNA repair of carcinoma cells. H2AX belongs to the histone family and is known as a part of the DNA repair system. The inhibition of γ-H2AX could lead to the inhibition of mitotically active tumor cells. Therefore, we aimed to evaluate the predictive value of the γ-H2AX in patients with PDAC. METHODS: All included patients (n = 311) received a pancreatic resection with curative intention in one of our PANCALYZE study centers. Subsequently, they were enrolled in a standardized follow-up protocol. Immunohistochemical stainings for γ-H2AX were conducted on tissue microarrays. RESULTS: Patients exhibiting high levels of γ-H2AX expression experience more frequent R1 resections, indicating advanced tumor stages in this subgroup. Additionally, patients with high γ-H2AX expression demonstrated significantly poorer survival compared to those with low expression (median OS: 15 vs. 25 months, p < 0.001). In multivariate analyses, high γ-H2AX expression could be identified as an independent risk factor for worse patient survival. Moreover, high γ-H2AX expression could be more frequently observed in the more aggressive basal-like subtype. CONCLUSION: γ-H2AX can be characterized as a predictive biomarker for poorer patient survival. Consequently, upcoming clinical trials focused on the efficacy of targeted therapies influencing the DNA repair system and radiotherapy should evaluate γ-H2AX as a potential biomarker for therapy response. Furthermore, γ-H2AX may serve as a viable target for treatment in the future.

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.

Correlation of primary tumor volume and histopathologic response following neoadjuvant treatment of esophageal adenocarcinoma.

INTRODUCTION: In esophageal cancer, histopathologic response following neoadjuvant therapy and transthoracic esophagectomy is a strong predictor of long-term survival. At the present, it is not known whether the initial tumor volume quantified by computed tomography (CT) correlates with the degree of pathologic regression. METHODS: In a retrospective analysis of a consecutive patient cohort with esophageal adenocarcinoma, tumor volume in CT prior to chemoradiotherapy or chemotherapy alone was quantified using manual segmentation. Primary tumor volume was correlated to the histomorphological regression based on vital residual tumor cells (VRTC) (Cologne regression scale, CRS: grade I, >50% VRTC; grade II, 10-50% VRTC; grade III, <10% VRTC and grade IV, complete response without VRTC). RESULTS: A total of 287 patients, 165 with neoadjuvant chemoradiotherapy according to the CROSS protocol and 122 with chemotherapy according to the FLOT regimen, were included. The initial tumor volume for patients following CROSS and FLOT therapy was measured (CROSS: median 24.8 ml, IQR 13.1-41.1 ml, FLOT: 23.4 ml, IQR 10.6-37.3 ml). All patients underwent an Ivor-Lewis esophagectomy. 180 patients (62.7 %) were classified as minor (CRS I/II) and 107 patients (37.3 %) as major or complete responder (CRS III/IV). The median tumor volume was calculated as 24.2 ml (IQR 11.9-40.3 ml). Ordered logistic regression revealed no significant dependence of CRS from tumor volume (OR = 0.99, p-value = 0.99) irrespective of the type of multimodal treatment. CONCLUSION: The initial tumor volume on diagnostic CT does not aid to differentiate between potential histopathological responders and non-responders to neoadjuvant therapy in esophageal cancer patients. The results emphasize the need to establish other biological markers of prediction.

[Tailored surgery in the treatment of gastroesophageal cancer]. / Maßgeschneiderte Chirurgie in der Behandlung gastroösophagealer Tumoren.

The surgical options and particularly perioperative treatment, have significantly advanced in the case of gastroesophageal cancer. This progress enables a 5-year survival rate of nearly 50% to be achieved through curative multimodal treatment concepts for locally advanced cancer. Therefore, in tumor boards and surgical case discussions the question increasingly arises regarding the type of treatment that provides optimal oncological and functional outcomes for individual patients with pre-existing diseases. It is therefore essential to carefully assess whether organ-preserving treatment might also be considered in the future or in what way minimally invasive or robotic surgery can offer advantages. Simultaneously, the boundaries of surgical and oncological treatment are currently being shifted in order to enable curative forms of treatment for patients with pre-existing conditions or those with oligometastatic diseases. With the integration of artificial intelligence into decision-making processes, new possibilities for information processing are increasingly becoming available to incorporate even more data into making decisions in the future.

[The "surgical track"-Innovative approaches to counteract the shortage of young recruits in surgery]. / Der "Surgical Track" ­ innovative Ansätze gegen den Nachwuchsmangel in der Chirurgie.

Surgery faces significant challenges resulting from changes in medical education and the declining attractiveness of the surgical career path for aspiring doctors in the western world. For example, students' expectations of their future workplace have changed, with issues such as career planning uncertainties, an unbalanced work-life balance, and a lack of compatibility of family and occupation becoming increasingly more relevant. The entry of Generation Z into the workforce will also impact surgery. Although women comprise the largest proportion of graduates only a few opt for a career in surgery. The resulting shortage of young surgeons will negatively impact medical care in German surgical units. Intense competition for talents is already emerging in all medical specialties. Thus, hospitals and academic centers are taking various measures to counteract the impending staff shortage, such as summer schools or scholarships with work commitments. Furthermore, regional funding laws are being established. In addition, as there is a declining interest in surgical training, particularly during the course of medical studies, early integration of surgical skills is crucial to counteract this trend. For this reason, we have developed the "surgical track", designed to offer targeted innovative teaching concepts to get students attracted to surgery at an early stage. The "surgical track" is based on virtual reality (VR) and robotics. Students can practice operations and emergency scenarios through VR simulations and complete practical exercises with robotic systems. High-quality training concepts such as the "surgical track" can help to promote enthusiasm for surgery and impart knowledge at the same time, even if the long-term benefits still need to be evaluated. Through virtual simulations, robotic surgery and innovative teaching, students gain insights into visceral surgery that combine theoretical understanding and practical experience.

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.

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.

Copy-number-gain of telomerase reverse transcriptase (hTERT) is associated with an unfavorable prognosis in esophageal adenocarcinoma.

Esophageal adenocarcinoma exhibits one of the highest mortality rates among all cancer entities. Multimodal therapy strategies have improved patients' survival significantly. However, patients in early stages are currently limited to receiving only local therapies, even though some patients within this group showcase short survival periods. Until now, there has been no widely established clinically used biomarker to detect these high-risk patients. Telomerase reverse transcriptase (TERT), a gene encoding a crucial subunit of the telomerase enzyme, plays a significant role in establishing cancer cell immortality and is under suspicion for its potential contribution to tumor progression. Therefore, we aimed to evaluate the clinical relevance of the TERT amplification status. We included 643 patients with esophageal adenocarcinoma, who underwent Ivor-Lewis esophagectomy at the University Hospital of Cologne. The TERT amplification status was characterized using fluorescence in situ hybridization. Clinicopathological values and patients' overall survival were compared between patients with and without TERT amplification. Further sub-cohort analyses were conducted for patients with pT1N0-3 tumor stage. Eighty-One patients (12.6%) exhibited TERT amplification. Patients with amplified TERT showed significantly worse overall survival (median OS: 22.6 vs. 36.8 months, p = 0.009). Interestingly, TERT amplification could be characterized as an independent risk factor for worse overall survival in multivariate analysis in patients with pT1N0-3 tumor stage (HR = 2.440, 95% CI 1.095-5.440, p = 0.029). In this study, we describe the TERT amplification status as an independent risk factor for worse survival in patients diagnosed with esophageal adenocarcinoma at pT1N0-3 tumor stage, encompassing cases involving tumor infiltration of the lamina propria, muscularis mucosae, and/or submucosa. Based on our findings, we put forth the proposition that evaluating the TERT amplification status may serve as a valuable tool in identifying a specific subgroup of patients, namely those with TERT amplification and pT1N0-3 tumor-stage esophageal adenocarcinoma. The patients of this subgroup could potentially benefit from enhanced follow-up protocols, more aggressive treatment approaches, or possible targeted TERT inhibition therapies, all aimed at improving their overall clinical outcomes.

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.

Postesophagectomy Diaphragmatic Prolapse after Robot-Assisted Minimally Invasive Esophagectomy (RAMIE).

BACKGROUND: Postesophagectomy diaphragmatic prolapse (PDP) is a major complication after esophagectomy with significant mortality and morbidity. However, in the current literature, treatment and outcomes are not evaluated for patients undergoing an Ivor Lewis Robot-assisted minimally invasive esophagectomy (IL-RAMIE). The aim of this study is to evaluate the incidence of PDP after IL-RAMIE. Moreover, the study aims to determine whether using a minimally invasive approach in the management of PDP after an IL-RAMIE procedure is safe and feasible. MATERIALS AND METHODS: This study includes all patients who received an IL-RAMIE at our high-volume center (>200 esophagectomies/year) between April 2017 and December 2022 and developed PDP. The analysis focuses on time to prolapse, symptoms, treatment, surgical method, and recurrence rates of these patients. RESULTS: A total of 185 patients underwent an IL-RAMIE at our hospital. Eleven patients (5.9%) developed PDP. Patients presented with PDP after a medium time of 241 days with symptoms like reflux, nausea, vomiting, and pain. One-third of these patients did not suffer from any symptoms. In all cases, a CT scan was performed in which the colon transversum always presented as the herniated organ. In one patient, prolapse of the small intestine, pancreas, and greater omentum also occurred. A total of 91% of these patients received a revisional surgery in a minimally invasive manner with a mean hospital stay of 12 days. In four patients, PDP recurred (36%) after 13, 114, 119 and 237 days, respectively. CONCLUSION: This study shows that a minimally invasive approach in repositioning PDP is a safe and effective option after IL-RAMIE.

Combination of the biomarkers for aging and cancer? - Challenges and current status.

The proportion of patients diagnosed with cancer has been shown to rise with the increasing aging global population. Advanced age is a major risk factor for morbidity and mortality in older adults. As individuals experience varying health statuses, particularly with age, it poses a challenge for medical professionals in the cancer field to obtain standardized treatment outcomes. Hence, relying solely on chronological age and disease-related parameters is inadequate for clinical decision-making for elderly patients. With functional, multimorbidity-related, and psychosocial changes that occur with aging, oncologic diseases may develop and be treated differently from younger patients, leading to unique challenges in treatment efficacy and tolerance. To overcome this challenge, personalized therapy using biomarkers has emerged as a promising solution. Various categories of biomarkers, including inflammatory, hematological, metabolic, endocrine, and DNA modification-related indicators, may display features related to both cancer and aging, aiding in the development of innovative therapeutic approaches for patients with cancer in old age. Furthermore, physical functional measurements as non-molecular phenotypic biomarkers are being investigated for their potential complementary role in structured multidomain strategies to combat age-related diseases such as cancer. This review provides insight into the current developments, recent discoveries, and significant challenges in cancer and aging biomarkers, with a specific focus on their application in advanced age.

[Surgical treatment of pseudomyxoma peritonei-Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy]. / Chirurgische Therapie des Pseudomyxoma-peritonei-Syndroms ­ zytoreduktive Chirurgie und hypertherme intraperitoneale Chemotherapie.

BACKGROUND: Pseudomyxoma peritonei syndrome (PMP) is an orphan disease. Surgery is the fundament of treatment. METHOD: Short review summarizing the state of the art treatment. RESULTS: Cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) form the foundations of treatment for PMP. The peritoneal cancer index should be preoperatively determined based on imaging and/or laparoscopy, intraoperatively validated and both should be documented. An extraperitoneal surgical preparation technique leads to effective en bloc resection of the peritoneum and the affected abdominal area. The HIPEC technique should be performed with mitomycin C for 60-90 min. Complete CRS (CC = 0, CC = 1) and the histological subtype are relevant for the prognosis. Structured educational programs and mentoring can optimize the learning curve. The aftercare should be performed at the surgical center. After follow-up imaging at 3 months after CRS, in the first 2 years a control should be carried out every 6 months. Thereafter, the intervals can be extended to 1 year. CONCLUSION: Standardized surgical treatment and HIPEC, optimized specific surgical training and structured follow-up at the center lead to an excellent long-term prognosis for patients with PMP.