Mutational Landscape and Expression of PD-L1 in Patients with Non-Small Cell Lung Cancer Harboring Genomic Alterations of the MET gene

BACKGROUND Mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations and MET gene amplification occur in 3-5% of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) targeting MET alterations have shown promising results in these patients. OBJECTIVE The aim of this study was to describe the genomic profile, PD-L1 expression and clinicopathological features of MET dysregulated NSCLC. PATIENTS AND METHODS We identified 188 patients with advanced-stage NSCLC with data on MET expression by immunohistochemistry (IHC). IHC for PD-L1 expression was performed in 131 patient samples, and next-generation sequencing (NGS) analysis was performed in 109 patient samples. RESULTS MET exon 14 skipping alterations were identified in 16 (14.7%) samples, MET amplifications with cut-off ≥4 copy number variations were identified in 11 (10.1%) samples, and an oncogenic MET mutation (MET p.D1228N) was identified in 1 (0.9%) sample. 12/15 tumors (80.0%) harboring MET exon 14 alterations and 7/11 (63.6%) MET-amplified tumors expressed PD-L1 in ≥1% of tumor cells. Tumors harboring MET exon 14 skipping alterations expressed PD-L1 more frequently than MET wild-type IHC-positive tumors (p = 0.045). Twenty-five percent of MET exon 14-altered cases and 33% of MET-amplified cases harbored potentially targetable oncogenic co-mutations in KRAS, BRAF, and EGFR. The most frequent co-occurring mutations in all MET-altered tumors were TP53, KRAS, BRAF, and CDK4. CONCLUSIONS We demonstrated that MET exon 14 skipping alterations and MET amplification are not mutually exclusive to other oncogenic co-mutations, and report the association of genomic MET alterations with PD-L1 expression. Since genomic MET alterations are emerging targets requiring upfront treatment, optimal understanding of the co-mutational landscape for this patient population is needed

PD-L1 and HIF-2α Upregulation in Head and Neck Paragangliomas after Embolization

Hypoxia activates pathways associated with tumor progression, metastatic spread, and alterations in the immune microenvironment leading to an immunosuppressive phenotype. In particular, the upregulation of PD-L1, a target for therapy with checkpoint inhibitors, is well-studied in several tumors. However, the relationship between hypoxia and PD-L1 regulation in pheochromocytomas and paragangliomas (PPGL), and especially in paragangliomas treated with embolization, is still largely unexplored. We investigated the expression of the hypoxia-marker HIF-2α and of PD-L1 in a PPGL-cohort with and without embolization as potential biomarkers that may predict the response to treatment with HIF-2α and checkpoint inhibitors. A total of 29 tumor samples from 25 patients who were operated at a single center were included and analyzed utilizing immunohistochemistry (IHC) for PD-L1 and HIF-2α. Embolization prior to surgery was performed in seven (24%) tumors. PD-L1 expression in tumor cells of head and neck paragangliomas (HNPGLs) receiving prior embolization (median PD-L1 positivity: 15%) was significantly higher as compared to PD-L1 expression in HNPGLs without prior embolization (median PD-L1 positivity: 0%) (p = 0.008). Consistently, significantly more HNPGLs with prior embolization were positive for HIF-2α (median nuclear HIF-2α positivity: 40%) as compared to HNPGLs without prior embolization (median nuclear HIF-2α positivity: 0%) (p = 0.016). Our results support the hypothesis that embolization with subsequent hypoxia leads to the upregulation of both PD-L1 and HIF-2α in HNPGLs, and could thus facilitate targeted treatment with HIF-2α and checkpoint inhibitors in the case of inoperable, locally advanced, or metastatic disease

Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. OBJECTIVE: Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. METHODS: Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs. RESULTS: Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx). CONCLUSION: SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs

Influencing the European Union from Outside. Switzerland, the European Water Framework Directive, and Micropollution Regulation in the Rhine River Basin

This paper sheds light on an unusual political influence mechanism, i.e. the influence of a non-EU member state on agendas and policies at the level of the EU and EU members states. Borrowing both from the literatures on policy diffusion as well as on the influence of small member states in EU decision-making, we argue that such an influence is fostered by both structural and agency-related factors. We illustrate this potential influence with a case study on the regulation of micropollutants in waterbodies. Adopting a mixed-method approach, we show that the upstream location of Switzerland, its integration into transnational networks as well as joint water basin institutions provides the country with structural opportunities to diffuse policy innovation to the EU’s policy agenda and member states’ policies. In addition, agency-related factors matter as the EU or member states can point to Switzerland as a successful example or pioneer, especially since the Swiss policy is in line with an overall EU strategy on reducing negative impacts of chemicals on humans and the environment

Policy Diffusion in the Context of International River Basin Management

This paper deals with policy diffusion across countries in the context of collaborative river basin management. Borrowing from the literature on policy diffusion and ‘smart strategies’ of small European Union member states, we argue that policy diffusion is fostered by structural and agency-related factors. We illustrate our theoretical ideas with a case study on the new Swiss policy on micropollutants in surface waters. Based on a rich set of documents and interviews with key actors, we show that the integration of Switzerland into formal and informal transnational networks fosters the diffusion of its micropollutants policy to other Rhine riparian countries. In addition, we analyse agency-related factors favouring policy diffusion in river basins, such as a country's pioneer role, its expertise, the fact that its policy is in line with general policy goals in other countries and the political acceptance of the policy at home. Our analysis suggests that policy diffusion can be an important phenomenon in integrated water resources management. Copyright © 2016 John Wiley & Sons, Ltd and ERP Environment

Interactions among Sustainable Development Goals:: Knowledge for identifying multipliers and virtuous cycles

Developed to be interconnected by design, the 17 sustainable development goals (SDGs) and their 169 targets have attracted a growing scientific community committed to exploring the systemic interactions inherent to the 2030 Agenda. Understanding which SDGs influence one another (positively or negatively) is critical to prioritize and implement policies that maximize synergies between goals while navigating trade‐offs. In this way, the need for informed decision‐making urgently requires knowledge of context‐specific SDG interactions. Drawing on an extensive literature review (including scientific reports and scholarly articles), we collected, synthesized, and analyzed data about negative and positive interactions among SDG goals and targets. Based on this unique dataset, our analysis focused on three key elements of the resulting network of SDG interactions: First, we identified the most dominant SDGs in the network. Second, we identified systemic multipliers, defined as nodes with higher weighted amounts of outgoing than incoming influence. Third, we identified critical sub‐networks of strongly interconnected SDG targets, highlighting possible virtuous cycles that could serve as concrete entry points to realize the 2030 Agenda. Building on our results, a collaborative effort to add and refine data on behalf of an open‐knowledge platform could provide a solid basis for further analysis and enhanced usability in concrete contexts

Novel PSCA targeting scFv-fusion proteins for diagnosis and immunotherapy of prostate cancer

Purpose Despite great progress in the diagnosis and treatment of localized prostate cancer (PCa), there remains a need for new diagnostic markers that can accurately distinguish indolent and aggressive variants. One promising approach is the antibody-based targeting of prostate stem cell antigen (PSCA), which is frequently overexpressed in PCa. Here, we show the construction of a molecular imaging probe comprising a humanized scFv fragment recognizing PSCA genetically fused to an engineered version of the human DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT), the SNAP-tag, enabling specific covalent coupling to various fluorophores for diagnosis of PCa. Furthermore, the recombinant immunotoxin (IT) PSCA(scFv)-ETA' comprising the PSCA(scFv) and atruncated version of Pseudomonas exotoxin A (PE, ETA') was generated. Methods We analyzed the specific binding and internalization behavior of the molecular imaging probe PSCA(scFv)SNAP in vitro by flow cytometry and live cell imaging, compared to the corresponding IT PSCA(scFv)-ETA'. The cytotoxic activity of PSCA(scFv)-ETA' was tested using cell viability assays. Specific binding was confirmed on formalin-fixed paraffin-embedded tissue specimen of early and advanced PCa. Results Alexa -Fluor (R) 647 labeling of PSCA(scFv)-SNAP confirmed selective binding to PSCA, leading to rapid internalization into the target cells. The recombinant IT PSCA(scFv)-ETA' showed selective binding leading to internalization and efficient elimination of target cells. Conclusions Our data demonstrate, for the first time, the specific binding, internalization, and cytotoxicity of a scFv-based fusion protein targeting PSCA. Immunohistochemical staining confirmed the specific ex vivo binding to primary PCa material