@article{LapaHerrmannSchirbeletal.2017, author = {Lapa, Constantin and Herrmann, Ken and Schirbel, Andreas and H{\"a}nscheid, Heribert and L{\"u}ckerath, Katharina and Schottelius, Margret and Kircher, Malte and Werner, Rudolf A. and Schreder, Martin and Samnick, Samuel and Kropf, Saskia and Knop, Stefan and Buck, Andreas K. and Einsele, Hermann and Wester, Hans-Juergen and Kort{\"u}m, K. Martin}, title = {CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed multiple myeloma}, series = {Theranostics}, volume = {7}, journal = {Theranostics}, number = {6}, doi = {10.7150/thno.19050}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172095}, pages = {1589-1597}, year = {2017}, abstract = {C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM). Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival. ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive. CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted.}, language = {en} } @article{LapaSchrederSchirbeletal.2017, author = {Lapa, Constantin and Schreder, Martin and Schirbel, Andreas and Samnick, Samuel and Kort{\"u}m, Klaus Martin and Herrmann, Ken and Kropf, Saskia and Einsele, Herrmann and Buck, Andreas K. and Wester, Hans-J{\"u}rgen and Knop, Stefan and L{\"u}ckerath, Katharina}, title = {[\(^{68}\)Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - comparison to [\(^{18}\)F]FDG and laboratory values}, series = {Theranostics}, volume = {7}, journal = {Theranostics}, number = {1}, doi = {10.7150/thno.16576}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172106}, pages = {205-212}, year = {2017}, abstract = {Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [\(^{68}\)Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies. Thirty-five patients with MM underwent [\(^{68}\)Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [\(^{18}\)F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity. [\(^{68}\)Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66\%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [\(^{18}\)F]FDG was available, [\(^{68}\)Ga]Pentixafor-PET detected more lesions in 4/19 (21\%) subjects, [\(^{18}\)F]FDG proved superior in 7/19 (37\%). In the remaining 8/19 (42\%) patients, both tracers detected an equal number of lesions. [\(^{18}\)F]FDG-PET positivity correlated with [\(^{68}\)Ga]Pentixafor-PET positivity (p=0.018). [\(^{68}\)Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.}, language = {en} } @article{MunawarZhouPrommersbergeretal.2023, author = {Munawar, Umair and Zhou, Xiang and Prommersberger, Sabrina and Nerreter, Silvia and Vogt, Cornelia and Steinhardt, Maximilian J. and Truger, Marietta and Mersi, Julia and Teufel, Eva and Han, Seungbin and Haertle, Larissa and Banholzer, Nicole and Eiring, Patrick and Danhof, Sophia and Navarro-Aguadero, Miguel Angel and Fernandez-Martin, Adrian and Ortiz-Ruiz, Alejandra and Barrio, Santiago and Gallardo, Miguel and Valeri, Antonio and Castellano, Eva and Raab, Peter and Rudert, Maximilian and Haferlach, Claudia and Sauer, Markus and Hudecek, Michael and Martinez-Lopez, J. and Waldschmidt, Johannes and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, K. Martin}, title = {Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma}, series = {Communications Biology}, volume = {6}, journal = {Communications Biology}, doi = {10.1038/s42003-023-05683-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357609}, year = {2023}, abstract = {The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.}, language = {en} } @article{LapaGarciaVellosoLueckerathetal.2017, author = {Lapa, Constantin and Garcia-Velloso, Maria J. and L{\"u}ckerath, Katharina and Samnick, Samuel and Schreder, Martin and Otero, Paula Rodriguez and Schmid, Jan-Stefan and Herrmann, Ken and Knop, Stefan and Buck, Andreas K. and Einsele, Hermann and San-Miguel, Jesus and Kort{\"u}m, Klaus Martin}, title = {\(^{11}\)C-methionine-PET in multiple myeloma: a combined study from two different institutions}, series = {Theranostics}, volume = {7}, journal = {Theranostics}, number = {11}, doi = {10.7150/thno.20491}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172038}, pages = {2956-2964}, year = {2017}, abstract = {\(^{11}\)C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to \(^{18}\)F-2`-deoxy-2`-fluoro-D-glucose (FDG). 78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of W{\"u}rzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available. MET-PET detected focal lesions (FL) in 59/78 subjects (75.6\%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3\%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases. MET depicted more FL in 44 patients (56.4\%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0\%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (κ = 0.82 vs κ = 0.72). This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra- and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM.}, language = {en} } @article{LodaKrebsDanhofetal.2019, author = {Loda, Sophia and Krebs, Jonathan and Danhof, Sophia and Schreder, Martin and Solimando, Antonio G. and Strifler, Susanne and Rasche, Leo and Kort{\"u}m, Martin and Kerscher, Alexander and Knop, Stefan and Puppe, Frank and Einsele, Hermann and Bittrich, Max}, title = {Exploration of artificial intelligence use with ARIES in multiple myeloma research}, series = {Journal of Clinical Medicine}, volume = {8}, journal = {Journal of Clinical Medicine}, number = {7}, issn = {2077-0383}, doi = {10.3390/jcm8070999}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197231}, pages = {999}, year = {2019}, abstract = {Background: Natural language processing (NLP) is a powerful tool supporting the generation of Real-World Evidence (RWE). There is no NLP system that enables the extensive querying of parameters specific to multiple myeloma (MM) out of unstructured medical reports. We therefore created a MM-specific ontology to accelerate the information extraction (IE) out of unstructured text. Methods: Our MM ontology consists of extensive MM-specific and hierarchically structured attributes and values. We implemented "A Rule-based Information Extraction System" (ARIES) that uses this ontology. We evaluated ARIES on 200 randomly selected medical reports of patients diagnosed with MM. Results: Our system achieved a high F1-Score of 0.92 on the evaluation dataset with a precision of 0.87 and recall of 0.98. Conclusions: Our rule-based IE system enables the comprehensive querying of medical reports. The IE accelerates the extraction of data and enables clinicians to faster generate RWE on hematological issues. RWE helps clinicians to make decisions in an evidence-based manner. Our tool easily accelerates the integration of research evidence into everyday clinical practice.}, language = {en} } @article{ZhouRascheKortuemetal.2020, author = {Zhou, Xiang and Rasche, Leo and Kort{\"u}m, K. Martin and Danhof, Sophia and Hudecek, Michael and Einsele, Hermann}, title = {Toxicities of Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma: An Overview of Experience From Clinical Trials, Pathophysiology, and Management Strategies}, series = {Frontiers in Immunology}, volume = {11}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2020.620312}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219911}, year = {2020}, abstract = {In the last few years, monoclonal antibodies (mAbs) such as elotuzumab and daratutumab have brought the treatment of multiple myeloma (MM) into the new era of immunotherapy. More recently, chimeric antigen receptor (CAR) modified T cell, a novel cellular immunotherapy, has been developed for treatment of relapsed/refractory (RR) MM, and early phase clinical trials have shown promising efficacy of CAR T cell therapy. Many patients with end stage RRMM regard CAR T cell therapy as their "last chance" and a "hope of cure". However, severe adverse events (AEs) and even toxic death related to CAR T cell therapy have been observed. The management of AEs related to CAR T cell therapy represents a new challenge, as the pathophysiology is not fully understood and there is still no well-established standard of management. With regard to CAR T cell associated toxicities in MM, in this review, we will provide an overview of experience from clinical trials, pathophysiology, and management strategies.}, language = {en} } @phdthesis{Kortuem2007, author = {Kort{\"u}m, Klaus Martin}, title = {Analyse der Behandlungssituation in der Rektumkarzinomchirurgie der Chirurgischen Universit{\"a}tsklinik W{\"u}rzburg - Aufbau und Auswertung einer Datenbank im Rahmen der Qualit{\"a}tssicherung}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-25499}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2007}, abstract = {In der vorliegenden Arbeit wurde eine Datenbank entwickelt,um die Behandlungssituation in der Rektumkarzinomchirurgie beurteilen zu k{\"o}nnen. Mit Hilfe dieser Datenbank wurden retrospektiv die Akten von 179 an einem Rekumkarzinom erkrankten Patienten an der Chirurgischen Universit{\"a}tsklinik W{\"u}rzburg ausgewertet. Anhand dieser Daten konnten die W{\"u}rzburger Behandlungsergebnisse mit denjenigen, welche in der internationalen Literatur zu finden sind, verglichen werden.}, subject = {Mastdarmchirurgie}, language = {de} } @article{ZhouDierksKertelsetal.2020, author = {Zhou, Xiang and Dierks, Alexander and Kertels, Olivia and Kircher, Malte and Schirbel, Andreas and Samnick, Samuel and Buck, Andreas K. and Knorz, Sebastian and B{\"o}ckle, David and Scheller, Lukas and Messerschmidt, Janin and Barakat, Mohammad and Kort{\"u}m, K. Martin and Rasche, Leo and Einsele, Hermann and Lapa, Constantin}, title = {18F-FDG, 11C-Methionine, and 68Ga-Pentixafor PET/CT in patients with smoldering multiple myeloma: imaging pattern and clinical features}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {8}, issn = {2072-6694}, doi = {10.3390/cancers12082333}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211240}, year = {2020}, abstract = {This study aimed to explore the correlation between imaging patterns and clinical features in patients with smoldering multiple myeloma (SMM) who simultaneously underwent 18F-FDG, 11C-Methionine, and 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT). We retrieved and analyzed clinical characteristics and PET imaging data of 10 patients with SMM. We found a significant correlation between bone marrow (BM) plasma cell (PC) infiltration and mean standardized uptake values (SUV\(_{mean}\)) of lumbar vertebrae L2-L4 on 11C-Methionine PET/CT scans (r = 0.676, p = 0.031) and 68Ga-Pentixafor PET/CT scans (r = 0.839, p = 0.002). However, there was no significant correlation between BM involvement and SUV\(_{mean}\) of lumbar vertebrae L2-L4 on 18F-FDG PET/CT scans (r = 0.558, p = 0.093). Similarly, mean target-to-background ratios (TBR\(_{mean}\)) of lumbar vertebrae L2-L4 also correlated with bone marrow plasma cell (BMPC) infiltration in 11C-Methionine PET/CT (r = 0.789, p = 0.007) and 68Ga-Pentixafor PET/CT (r = 0.724, p = 0.018) PET/CT. In contrast, we did not observe a significant correlation between BMPC infiltration rate and TBR\(_{mean}\) in 18F-FDG PET/CT (r = 0.355, p = 0.313). Additionally, on 11C-Methionine PET/CT scans, we found a significant correlation between BMPC infiltration and TBR\(_{max}\) of lumbar vertebrae L2-L4 (r = 0.642, p = 0.045). In conclusion, 11C-Methionine and 68Ga-Pentixafor PET/CT demonstrate higher sensitivity than 18F-FDG PET/CT in detecting BM involvement in SMM.}, language = {en} } @article{HaertleBuenacheCuestaHernandezetal.2023, author = {Haertle, Larissa and Buenache, Natalia and Cuesta Hern{\´a}ndez, Hip{\´o}lito Nicol{\´a}s and Simicek, Michal and Snaurova, Renata and Rapado, Inmaculada and Martinez, Nerea and L{\´o}pez-Mu{\~n}oz, Nieves and S{\´a}nchez-Pina, Jos{\´e} Mar{\´i}a and Munawar, Umair and Han, Seungbin and Ruiz-Heredia, Yanira and Colmenares, Rafael and Gallardo, Miguel and Sanchez-Beato, Margarita and Piris, Miguel Angel and Samur, Mehmet Kemal and Munshi, Nikhil C. and Ayala, Rosa and Kort{\"u}m, Klaus Martin and Barrio, Santiago and Mart{\´i}nez-L{\´o}pez, Joaqu{\´i}n}, title = {Genetic alterations in members of the proteasome 26S subunit, AAA-ATPase (PSMC) gene family in the light of proteasome inhibitor resistance in multiple myeloma}, series = {Cancers}, volume = {15}, journal = {Cancers}, number = {2}, issn = {2072-6694}, doi = {10.3390/cancers15020532}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305013}, year = {2023}, abstract = {For the treatment of Multiple Myeloma, proteasome inhibitors are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients. The proteasome is a large and complex machinery. Here, we focus on the AAA ATPases of the 19S proteasome regulator (PSMC1-6) and their implication in PI resistance. As an example of cancer evolution and the acquisition of resistance, we conducted an in-depth analysis of an index patient by applying FISH, WES, and immunoglobulin-rearrangement sequencing in serial samples, starting from MGUS to newly diagnosed Multiple Myeloma to a PI-resistant relapse. The WES analysis uncovered an acquired PSMC2 Y429S mutation at the relapse after intensive bortezomib-containing therapy, which was functionally confirmed to mediate PI resistance. A meta-analysis comprising 1499 newly diagnosed and 447 progressed patients revealed a total of 36 SNVs over all six PSMC genes that were structurally accumulated in regulatory sites for activity such as the ADP/ATP binding pocket. Other alterations impact the interaction between different PSMC subunits or the intrinsic conformation of an individual subunit, consequently affecting the folding and function of the complex. Interestingly, several mutations were clustered in the central channel of the ATPase ring, where the unfolded substrates enter the 20S core. Our results indicate that PSMC SNVs play a role in PI resistance in MM.}, language = {en} } @article{ZhouBaiMeckeletal.2021, author = {Zhou, Xiang and Bai, Tao and Meckel, Katharina and Song, Jun and Jin, Yu and Kort{\"u}m, Martin K. and Eisele, Hermann and Hou, Xiaohua and Rasche, Leo}, title = {COVID-19 infection in patients with multiple myeloma: a German-Chinese experience from W{\"u}rzburg and Wuhan}, series = {Annals of Hematology}, volume = {100}, journal = {Annals of Hematology}, issn = {0939-5555}, doi = {10.1007/s00277-020-04184-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235108}, pages = {843-846}, year = {2021}, abstract = {No abstract available.}, language = {en} }