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.

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis, wherefore targeted therapies have experienced increasing interest. Zolbetuximab is a novel targeted therapy under investigation in patients with PDAC and targets Claudin 18.2 (CLDN18.2), which is a component of tight junctions and is of significance in various solid tumors. As its role in PDAC is not definitively elucidated, this study aims to clarify the significance of CLDN18.2 expression in PDAC in a real-world setting. All patients (n = 309) were recruited at one of the PANCALYZE study centers and received pancreatic resection with curative intention. Paraffin samples were analyzed using an antibody against CLDN18.2, which is known to be comparable to the antibody used by the SPOTLIGHT and GLOW studies. 94 PDACs are positive for CLDN18.2 (30.4 %). Positive CLDN 18.2 expression was associated with significantly better cancer differentiation (p < 0.001). Patients with positive CLDN18.2 expression showed significantly better overall survival when compared to patients with negative expression (median OS: 30 versus 18 months, p = 0.003). Additionally, in multivariable analyses, CLDN18.2 expression was identified as an independent factor for better survival in patients with PDAC (HR = 0.686, 95 %CI = 0.492-0.956, p = 0.026). Significant improvement in survival could be demonstrated by adding Zolbetuximab to known chemotherapy regimes in patients with gastro-esophageal junction adenocarcinoma with at least 75 % CLDN18.2 positive cancer cells. Our findings demonstrate, that 30.4 % of the included patients with PDAC would potentially be eligible for therapy with Zolbetuximab in a real-world patient cohort. Results of trials targeting Claudin 18.2 are pending in patients with PDAC.

Purpose: The pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer entities. Effective therapy options are still lacking. The tumor microenvironment possibly bears further treatment possibilities. This study aimed to describe the expression patterns of four established carcinoma-associated fibroblast (CAFs) markers and their correlation in PDAC tissue samples. Methods: This project included 321 patients with PDAC who underwent surgery with a curative intent in one of the PANCALYZE study centers. Immunohistochemical stainings for FAP, PDGFR, periostin, and SMA were performed. The expression patterns of each marker were divided into low- and high-expressing CAFs and correlated with patients’ survival. Results: Tumors showing SMA^high-, Periostin^highSMA^high-, or Periostin^highSMA^lowPDGFR^lowFAP^high-positive CAFs demonstrated significantly worse survival. Additionally, a high expression of SMA in PDAC tissue samples was shown to be an independent risk factor for worse survival. Conclusion: This project identified three subgroups of PDAC with different expression patterns of CAF markers which showed significantly worse survival. This could be the base for the further characterization of the fibroblast subgroups in PDAC and contribute to the development of new targeted therapy options against CAFs.

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.

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.

Objective: To evaluate short-term outcomes and identify predictors of morbidity and mortality following multivisceral oncologic resections involving the pancreas. Summary background data: Multivisceral resections including the pancreas are required for locally advanced abdominal malignancies but are associated with considerable perioperative risk. While smaller series suggest acceptable outcomes in selected patients, large-scale international data are lacking to guide surgical decision-making and risk stratification. Methods: This was a retrospective cohort study of 1283 patients from 31 international centers who underwent multivisceral oncologic resections involving the pancreas. Patient demographics, tumor characteristics, operative details, and 90-day postoperative outcomes were analyzed. Results: The cohort had a mean age of 64.7 years, and 54.7% were male. Distal pancreatectomy was the most frequent procedure (60.5%), and R0 resection was achieved in 60.9% of cases. The 90-day mortality was 6.9%, highest in patients with gastric adenocarcinoma (16.7%). Major complications (Clavien–Dindo grade III–V) occurred in 34.4% of patients. Higher ASA classification and open surgical approach were independently associated with increased morbidity and mortality. Prolonged operative time was associated with morbidity only. Female gender and treatment at high-volume centers were protective. In patients with pancreatic tumors, resection involving the colon (OR: 1.78, P < 0.001), stomach (OR: 1.33, P = 0.042), or three or more organs (OR: 1.75, P = 0.006) significantly increased complication rates. Conclusions: Multivisceral resections involving the pancreas are associated with relevant perioperative risk. Optimizing patient selection, favoring minimally invasive techniques when feasible in selected patients, and centralizing care to high-volume centers may help improve outcomes for these complex surgical procedures.