Immuno-histochemical correlation of fibrosis-related markers with the desmoplastic reaction of the mesentery in small intestine neuroendocrine neoplasms

INTRODUCTION Small intestine neuroendocrine neoplasms (siNENs) will attain more importance due to their increasing incidence. Moreover, siNENs might lead to a desmoplastic reaction (DR) of the mesentery causing severe complications and deteriorating prognosis. The expression of fibrosis-related proteins appears to be the key mechanisms for the development of this desmoplastic reaction. Therefore, this study aimed to investigate the association of the desmoplastic mesentery with specific fibrosis-related protein expression levels. MATERIALS AND METHODS By immunohistochemistry, the protein expression levels of four fibrosis-related markers (APLP2, BNIP3L, CD59, DKK3) were investigated in primary tumors of 128 siNENs. The expression levels were correlated with the presence of a desmoplastic reaction and clinico-pathological parameters. RESULTS In the primary tumor, APLP2, BNIP3L, CD59 and DKK3 were highly expressed in 29.7% (n = 38), 64.9% (n = 83), 92.2% (n = 118) and 80.5% (n = 103), respectively. There was no significant correlation of a single marker or the complete marker panel to the manifestation of a desmoplastic mesentery. The desmoplastic mesentery was significantly associated with clinical symptoms, such as flushing and diarrhea. However, neither the fibrosis-related marker panel nor single marker expressions were associated with clinical symptoms. DISCUSSION The expression rates of four fibrosis-related markers in the primary tumor display a distinct pattern. However, the expression patterns are not associated with desmoplastic altered mesenteric lymph node metastases and the expression patterns did not correlate with prognosis. These findings suggest alternative mechanisms being responsible for the desmoplastic reaction

Distinct expression patterns of VEGFR 1-3 in gastroenteropancreatic neuroendocrine neoplasms: supporting clinical relevance, but not a prognostic factor

Introduction: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are an increasing tumor entity. Since many patients are diagnosed at an advanced stage, treatment is still challenging and dependent on many tumor and patient specific factors. Therefore, the aim of the present study was to elucidate the expression rates and the prognostic value of vascular endothelial growth factor receptor (VEGFR) 1-3 in GEP-NENs. A potential association to immune checkpoint markers was further investigated. Material and Methods: The expression levels of VEGFR 1-3 were analyzed by immunohistochemistry and correlated with the expression of the checkpoint markers PD-1 and PD-L1. Furthermore, the tumor samples of 249 GEP-NEN patients were studied and correlated with overall survival rates and clinicopathological features. Kaplan–Meier analyses and the log rank test were used for survival analyses. Categorical variables were compared by the χ2 test. Results: The most common primary tumor site was the small intestine (50.6%), followed by the pancreas (25.7%). VEGFR 1 was highly expressed in 59%, VEGFR 2 in 6.4%, and VEGFR 3 in 61.8% of the analyzed samples. The expression of VEGFR 1-3 was not significantly associated with survival rates. Pancreatic NENs had the highest expression of VEGFR 1 and 3 in 80% of the cases. VEGFR 1-3 positivity correlated with the expression levels of immune checkpoint markers. Discussion: VEGFR 1-3 show a distinct expression pattern in different subgroups of neuroendocrine neoplasias indicating a conceivable target. Moreover, there was a substantial association between VEGFRs andimmune checkpoint markers. Taken together, anti-VEGFR therapy represents a promising therapeutic approach in GEP-NEN patients and should be addressed in future studies

EMT-Related Genes Have No Prognostic Relevance in Metastatic Colorectal Cancer as Opposed to Stage II/III: Analysis of the Randomised, Phase III Trial FIRE-3 (AIO KRK 0306; FIRE-3)

Introduction: There is no standard treatment after resection of colorectal liver metastases and the role of systemic therapy remains controversial. To avoid over- or undertreatment, proper risk stratification with regard to postoperative treatment strategy is highly needed. We recently demonstrated the prognostic relevance of EMT-related (epithelial-mesenchymal transition) genes in stage II/III CRC. As EMT is a major step in CRC progression, we now aimed to analyse the prognostic relevance of EMT-related genes in stage IV CRC using the study cohort of the FIRE-3 trial, an open-label multi-centre randomised controlled phase III trial of patients with metastatic CRC. Methods: Overall and progression free survival were considered as endpoints (n = 350). To investigate the prognostic relevance of EMT-related genes on either endpoint, we compared predictive performance of different models using clinical data only to models using gene data in addition to clinical data, expecting better predictive performance if EMT-related genes have prognostic value. In addition to baseline models (Kaplan Meier (KM), (regularised) Cox), Random Survival Forest (RSF), and gradient boosted trees (GBT) were fit to the data. Repeated, nested five-fold cross-validation was used for hyperparameter optimisation and performance evaluation. Predictive performance was measured by the integrated Brier score (IBS). Results: The baseline KM model showed the best performance (OS: 0.250, PFS: 0.251). None of the other models were able to outperform the KM when using clinical data only according to the IBS scores (OS: 0.253 (Cox), 0.256 (RSF), 0.284 (GBT); PFS: 0.254 (Cox), 0.256 (RSF), 0.276 (GBT)). When adding gene data, performance of GBT improved slightly (OS: 0.262 vs. 0.284; PFS: 0.268 vs. 0.276), however, none of the models performed better than the KM baseline. Conclusion: Overall, the results suggest that the prognostic relevance of EMT-related genes may be stage-dependent and that EMT-related genes have no prognostic relevance in stage IV CRC

Treatment with somatostatin analogs induces differentially expressed let-7c-5p and mir-3137 in small intestine neuroendocrine tumors

Background Distant metastases frequently occur in gastroenteropancreatic neuroendocrine tumors. If hepatic surgery is not feasible, patients are treated with somatostatin analogs. However, the underlying mechanisms of action of this treatment remain to be defined. The aim of the present study was to analyze the micro-RNA expression profile inter-individually before and after the treatment with somatostatin analogs. Material and methods Tumor specimens of all included patients (n = 8) before and after the onset of a therapy with somatostatin analogs were analyzed and a micro-RNA expression profile (754 micro-RNAs) of each probe was generated. This analysis in an intra-individual setting was selected to avoid bias from inter-individual differences. The micro-RNA expression profiles were validated by qPCR. Patients with any other systemic treatment were excluded from the present study. Results Eight patients were included in the present study of which all had neuroendocrine tumors of the small intestine with diffuse hepatic metastases. Grouped analyses revealed that 15 micro-RNAs were differentially expressed (3 up- and 12 downregulated) after the exposure to somatostatin analogs. Additionally, let-7c-5p and mir-3137 are concordantly regulated in the inter-individually analysis. Conclusions This is the first study analyzing the individual micro-RNA expression profile before and after a therapy with somatostatin analogs. Data from this study reveal that somatostatin analogs may in part exert their beneficial effects through an alteration in the micro-RNA expression profile

Effective biodiversity monitoring needs a culture of integration

Despite conservation commitments, most countries still lack large-scale biodiversity monitoring programs to track progress toward agreed targets. Monitoring program design is frequently approached from a top-down, data-centric perspective that ignores the socio-cultural context of data collection. A rich landscape of people and organizations, with a diversity of motivations and expertise, independently engages in biodiversity monitoring. This diversity often leads to complementarity in activities across places, time periods, and taxa. In this Perspective, we propose a framework for aligning different efforts to realize large-scale biodiversity monitoring through a networked design of stakeholders, data, and biodiversity schemes. We emphasize the value of integrating independent biodiversity observations in conjunction with a backbone of structured core monitoring, thereby fostering broad ownership and resilience due to a strong partnership of science, society, policy, and individuals. Furthermore, we identify stakeholder-specific barriers and incentives to foster joint collaboration toward effective large-scale biodiversity monitoring

Hidden Ecological Potentials in the Production of Materials for Swiss Road Pavements

Sustainability has become a major concern in the field of civil infrastructures in recent years. Developing road construction projects with lower ecological impacts over a project’s entire life cycle can help in making road infrastructure contribute to sustainable development. This study focuses on the ecological potentials in the production of road materials used in Swiss road pavements. The environmental assessment was performed using a cradle-to-gate life-cycle assessment (LCA) approach in which all processes from the raw material extraction to the finished product were considered. The comparison of the results of the best-case asphalt pavement and the standard asphalt pavement for Swiss highway construction shows ecological potentials of up to 55%. Use of the best-case concrete pavement lowers the environmental impact by up to 53% in comparison to the worst-case concrete pavement for Swiss highways. Concerning composite pavements, the best-case variant offers an ecological potential 38% higher than the standard pavement