Hexokinase 2 as an independent risk factor for worse patient survival in esophageal adenocarcinoma and as a potential therapeutic target protein: A retrospective, single­center cohort study.

Cancer cells exhibit a distinct metabolic profile that features an upregulation of less efficient glycolysis accompanied by lactate production for energy generation, in contract to the characteristic metabolism of normal cells. Consequently, cancer research has focused on the enzymes that participate in these cancer metabolic pathways. Among them, hexokinase 2 (HK2) has an important position as the initial enzyme in the glycolytic pathway. Increased expression levels of HK2 have been correlated with an increased risk of poor patient outcomes and advanced tumor stages in a number of malignant tumors, such as gastric carcinoma. The present study aimed to investigate the specific role of HK2 in patients diagnosed with esophageal adenocarcinoma. A total of 643 patients with esophageal adenocarcinoma were included. Immunohistochemical staining and HK2 mRNA in situ probes were used to investigate the association of HK2 expression levels with clinical and molecular tumor characteristics. Patients who exhibited high HK2 expression levels demonstrated significantly reduced overall survival (OS) times compared with patients who exhibited low HK2 expression levels (29.6 vs. 39.9 months, respectively; P=0.027). Furthermore, high HK2 expression levels were demonstrated to be an independent risk factor for reduced patient survival (hazard ratio, 1.65; 95% CI, 1.09-2.50; P=0.018). Significantly reduced patient survival was also demonstrated in the subgroups of male patients, patients with primarily resected tumors, patients with HER2-negative tumors and patients with tumors exhibiting Y chromosome loss. Elevated expression of HK2 was identified as a risk factor for unfavorable patient survival in esophageal adenocarcinoma. This revelation suggests the potential for future diagnostic and therapeutic avenues tailored to this specific patient subset. Identifying patients with high HK2 expression may pinpoint a higher-risk cohort, paving the way for comprehensive prospective studies that could advocate for intensified monitoring and more aggressive therapeutic regimens. Furthermore, the targeted inhibition of HK2 could hold promise as a strategy to potentially enhance patient outcomes.

Role of preexisting right ventricular remodeling in symptoms and prognosis after transcatheter tricuspid valve repair.

BACKGROUND: Severe tricuspid regurgitation (TR) is associated with chronic volume overload and right ventricular remodeling (RVR). Transcatheter tricuspid valve repair (TTVr) reduces TR and can improve quality of life (QoL), but the role of preprocedural RVR on TTVr outcomes remains unclear. AIMS: To investigate the role of RVR on outcomes after TTVr for severe TR. METHODS: Consecutive patients undergoing TTVr (61% edge-to-edge vs. 39% direct annuloplasty) for severe TR were retrospectively compared by preexisting RVR which was defined as dilation of RV mid-level diameter (> 35 mm) according to guidelines. QoL was evaluated using NYHA class, Minnesota Living with Heart Failure Questionnaire (MLHFQ), 36-Item Short Form Health Survey (SF-36), and 6-min walking distance (6MWD) 1-month after TTVr. Mid-term mortality and heart failure (HF) hospitalization were assessed through 1 year. RESULTS: RVR was present in 137 of 223 patients (61%). Symptoms and QoL improved equally in both groups: ≥ 1 NYHA class (57% vs. 65% of patients with vs. without RVR, respectively), 6MWD (36% vs. 34%), MLHFQ (81% vs. 69%), and SF-36 (68% vs. 65%) improvement. One-year mortality and HF hospitalization were significantly higher in patients with RVR (24% and 30%, respectively) than in patients without (8% and 13%, both p < 0.05). In multivariable analysis, RVR was independently associated with mortality (HR 2.3, 95%CI (1.0-5.0), p = 0.04) and the combined endpoint of mortality or rehospitalization (HR 2.0, 95%CI (1.1-3.8), p = 0.03). CONCLUSIONS: TTVr was associated with significant QoL improvement after 1 month, irrespective of RVR. Despite increased mortality and rehospitalization for heart failure, TTVr in the presence of RVR still provides substantial symptomatic benefit for patients with severe TR.

Extent and clinical significance of the therapy-relevant tight junction protein Claudin 18.2 in pancreatic ductal adenocarcinoma - real-world evidence.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

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.

Co-expression patterns of cancer associated fibroblast markers reveal distinct subgroups related to patient survival in oropharyngeal squamous cell carcinoma.

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rapidly increasing in high income countries due to its association with persistent high-risk human papilloma virus (HPV) infection. Recent scientific advances have highlighted the importance of the tumor microenvironment in OPSCC. In this study, including 216 OPSCC patients, we analyze the composition of four established markers of cancer associated fibroblasts (CAFs) in the context of intratumoral CD8 T-cell infiltration. Methods: Immunohistochemical staining for fibroblast activation protein (FAP), platelet-derived growth factor receptor beta (PDGFRb), periostin, alpha smooth muscle actin (α-SMA) and CD8 were analyzed digitally and their association with survival, tumor- and patient characteristics was assessed. Results: Co-expression of CAF markers was frequent but not associated with HPV status. FAPhigh and PDGFRbhigh expression were associated with increased CD8 T-cell infiltration. Low expression of PDGFRb improved patient survival in female patients but not in male patients. We identified PDGFRblow periostinlow α-SMAlow status as an independent predictor of improved survival (hazard ratio 0.377, p = 0.006). Conclusion: These findings elucidate the co-expression of four established CAF markers in OPSCC and underscore their association with T-cell infiltration and patient survival. Future analyses of CAF subgroups in OPSCC may enable the development of individualized therapies.

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.