Impact of Borderline Resectability in Pancreatic Head Cancer on Patient Survival: Biology Matters According to the New International Consensus Criteria

Background: International consensus criteria (ICC) have redefined borderline resectability for pancreatic ductal adenocarcinoma (PDAC) according to three dimensions: anatomical (BR-A), biological (BR-B), and conditional (BR-C). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumour and vessels but that biological and conditional dimensions also are important. Methods: Patients’ tumours were retrospectively defined b

The WERA cancer center matrix: strategic management of patient access to precision oncology in a large and mostly rural area of Germany

Purpose Providing Patient Access to Precision Oncology (PO) is a major challenge of clinical oncologists. Here, we provide an easily transferable model from strategic management science to assess the outreach of a cancer center. Methods As members of the German WERA alliance, the cancer centers in Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact. Specifically, we examined the provenance of patients from WERA´s molecular tumor boards (MTBs) between 2020 and 2022 (n = 2,243). As second dimension, we added the provenance of patients receiving general cancer care by WERA. Clustering our catchment area along these two dimensions set up a four-quadrant matrix consisting of postal code areas with referrals towards WERA. These areas were re-identified on a map of the Federal State of Bavaria. Results The WERA Matrix overlooked an active screening area of 821 postal code areas – representing about 50% of Bavaria´s spatial expansion and more than six million inhabitants. The WERA Matrix identified regions successfully connected to our outreach structures in terms of subsidiarity – with general cancer care mainly performed locally but PO performed in collaboration with WERA. We also detected postal code areas with a potential PO backlog – characterized by high levels of cancer care performed by WERA and low levels or no MTB representation. Conclusions The WERA Matrix provided a transparent portfolio of postal code areas, which helped assessing the geographical impact of our PO program. We believe that its intuitive principle can easily be transferred to other cancer centers

Soluble B-cell maturation antigen in lacrimal fluid as a potential biomarker and mediator of keratopathy in multiple myeloma

Belantamab mafodotin (belantamab) is a first-in-class anti-BCMA antibody-drug conjugate approved for the treatment of triple-class refractory multiple myeloma. It provides a unique therapeutic option for patients ineligible for CAR-T and bispecific antibody therapy, and/or patients progressing on anti-CD38 treatment where CAR-T and bispecifics might be kept in reserve. Wider use of the drug can be challenged by its distinct ocular side effect profile, including corneal microcysts and keratopathy. While dose reduction has been the most effective way to reduce these toxicities, the underlying mechanism of this BCMA off-target effect remains to be characterized. In this study, we provide the first evidence for soluble BCMA (sBCMA) in lacrimal fluid and report on its correlation with tumor burden in myeloma patients. We confirm that corneal cells do not express BCMA, and show that sBCMA-belantamab complexes may rather be internalized by corneal epithelial cells through receptor-ligand independent pinocytosis. Using an hTcEpi corneal cell-line model, we show that the pinocytosis inhibitor EIPA significantly reduces belantamab-specific cell killing. As a proof of concept, we provide detailed patient profiles demonstrating that, after belantamab-induced cell killing, sBCMA is released into circulation, followed by a delayed increase of sBCMA in the tear fluid and subsequent onset of keratopathy. Based on the proposed mechanism, pinocytosis-induced keratopathy can be prevented by lowering the entry of sBCMA into the lacrimal fluid. Future therapeutic concepts may therefore consist of belantamab-free debulking therapy prior to belantamab consolidation and/or concomitant use of gamma-secretase inhibition as currently evaluated for belantamab and nirogacestat in ongoing studies

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Anti-Tumor-Effekte von murinen Zytokin-stimulierten Natürlichen-Killer-Zellen

Hintergrund und Ziele Bei Tumorerkrankungen können durch die Transplantation von Stammzellen heute neue Therapiefortschritte erzielt werden. Für den Therapieerfolg der allogenen Knochenmarktransplantation (KMT) bei hämatologischen Neoplasien sind neben der hochdosierten Radio- und Chemotherapie auch Donorimmunzellen verantwortlich. Natürliche Killer (NK)-Zellen sind hierbei wichtige Effektorzellen der angeborenen Immunität gegen infizierte oder maligne Zellen. Die im Rahmen einer Stammzelltransplantation auftretenden schwerwiegendsten Komplikationen sind die Entwicklung von Graft-versus-Host Erkrankungen (GvHD) des Empfängers. Neue Erkenntnisse deuten auf eine protektive Wirkung von NK-Zellen bei der Entwicklung der akuten GvHD hin. NK-Zellen vermögen das adaptive Immunsystem zu regulieren. Sie scheinen die reaktiven T-Zellen, welche gegenwärtig als Auslöser der GvHD angesehen werden, möglicherweise indirekt herunter zu regulieren. Daher sind NK-Zellen eine vielversprechende Zellpopulation für einen adoptiven Transfer bei der Therapie von Patienten mit GvHD. Die biologischen Grundlagen beim Einsatz von Zytokin-stimulierten NK-Zellen in der Immuntherapie sind aktuell noch wenig bekannt. Der Fokus dieser Arbeit liegt auf der Verwendbarkeit von Zytokin-stimulierten NK-Zellen in der Immuntherapie mit dem Ziel, präklinische Grundlagen für den Einsatz in der onkologischen Zelltherapie zu erarbeiten. Methoden Im ersten Teil wurde die Zellkultur und Zytokin-Stimulation bearbeitet. Dabei wurden MACS separierte C57Bl/6 Milz-NK-Zellen in Zellkultur genommen und mit Zytokinen stimuliert. Anschließend wurden die Veränderungen im Phänotyp und in den Effektorzellfunktionen mit Durchflusszytometrie, ELISA und Zellzytotoxischem Assay evaluiert. Im zweiten Teil wurde eine Methode der in vivo Biolumineszenz-Bildgebung (Bioluminescence Imaging, BLI) der Maus inklusive eines selbst programmierten Auswertungsmoduls etabliert, was innerhalb der Arbeitsgruppe zuvor noch nicht durchgeführt worden war. Zusammenführend konnten im dritten Teil die Zytokin-Stimulation und das BLI in einem neuen Graft-versus-Lymphom (GvL-) und GvHD-Tiermodell kombiniert werden. Lymphom-tragende Balb/c Mäuse erhielten eine allogene Knochenmarktransplantation und parallel eine Immunzelltherapie. Das Ausmaß der GvHD wurde anhand eines etablierten Scores ermittelt. Ergebnisse und Beobachtungen Interleukin-2 (IL-2) und Interleukin-15 (IL-15) zeigen in der in vitro Anwendung auf NK-Zellen vergleichbare Ergebnisse. Mit IL-2 ist die Viabilität von NK-Zellen nach Stimulation signifikant erhöht. Dabei zeigen die murinen Subpopulationen einen Shift zu CD11b exprimierenden NK-Zellen. Die Zytotoxizität scheint nach IL-2 Stimulation erhöht. Anhand der Biolumineszenz konnte der GvL-Effekt nach allogener Knochenmarkstammzelltransplantation inklusive NK-Zell-/T-Zell-Transfer nicht-invasiv beobachtet werden. Es zeigte sich eine signifikante Tumorreduktion nach Knochenmarktransplantation und T-Zell-Transfer. Auf Grund der T-Zellen war die GvHD jedoch gesteigert. Praktische Schlussfolgerungen Die vorliegenden Ergebnisse tragen zum grundlegenden Verständnis der biologischen Prozesse von NK-Zellen im Kontext der GvL- und GvH-Reaktion bei. Ein möglicher adoptiver Einsatz von NK-Zellen in der Immuntherapie ist vielversprechend. Zukünftig sind weitere Versuche mit besser überlebenden IL-15-stimulierten NK-Zellen gerechtfertigt, um sichere Aussagen über Effektorzellfunktionen und die Auswirkungen derer auf die GvL und GvHD treffen zu können. Somit ließen sich weitere Erkenntnisse über den Nutzen einer NK-Zell-Therapie gewinnen.Background New approaches in haematopoietic therapy increasingly show a better outcome to allogeneic stem cell transplantation. For that Graft-versus-Host disease (GvHD) is the limiting factor. Natural Killer (NK) cells are main effector cells in innate immunity against viruses and malignant cells. New data show a possible reduction of GvHD mediated by NK cells. Possibly they could suppress T cells. Meanwhile they could also maintain the desired Graft-versus-Lymphoma (GvL) effect. Thus, they are a valuable option for adoptive cell therapy. There are still many unknown mechanisms regarding the role of cytokine stimulated NK cells in GvL and GvHD. This thesis is focused on the preclinical analysis and development of adoptive NK cell immunotherapy in a setting of allogeneic stem cell transplantation. Methods First, cell culture and cytokine stimulation were tested. MACS separated spleen NK cells from C57Bl/6 mice were stimulated with IL-2 or IL-15. Changes in phenotype and function were measured via FACS, ELISA and cellcytotoxic assay. Next, a new in vivo bioluminescence imaging method together with quantification and interpretation was established. An own software module (macro) for analysis of the results was created. In the third part, the results were converted into a new established GvL/ GvHD animal model. BCL-1-Luc+gfp+ bearing mice were sublethal irradiated and allogen transplanted. An adoptive T cell transfer was administered in some animals. Results IL-2 and IL-15 showed comparable results in vitro. After IL-2 stimulation viability of NK cells was significantly higher. Murine NK cell subpopulations shifted more to CD11b+ cells. IL-2 stimulation leaded to higher cytotoxicity. The GvL effect was impressingly observed via bioluminescence imaging. T cells are the main effector cells of GvL after hematopoietic stem cell transplantation, but can cause GvHD.� Summary and future prospects These results lead to a better understanding of the basic biological processes in the immunotherapy with NK cells in a setting of allogeneic stem cell transplantation. The clinical use is promising. In future experiments the use of IL-15 in the immunotherapy could be addressed. Effector cell function and cytotoxicity could be observed further. Thus, a better understanding of NK cells in GvL and GvHD biology can lead to better prospects in clinical use

The urgent need for precision medicine in cancer and its microenvironment: the paradigmatic case of multiple myeloma

No abstract availabl