Xiang Zhou, Seungbin Han, Nadine Cebulla, Larissa Haertle, Maximilian J. Steinhardt, Daniel Schirmer, Eva Runau, Leon Flamm, Calvin Terhorst, Laura Jähnel, Cornelia Vogt, Silvia Nerreter, Eva Teufel, Emilia Stanojkovska, Julia Mersi, Umair Munawar, Magnus Schindehütte, Robert Blum, Ann-Kristin Reinhold, Oliver Scherf-Clavel, Heike L. Rittner, Mirko Pham, Leo Rasche, Hermann Einsele, Claudia Sommer and K. Martin Kortüm
Bortezomib induced peripheral neuropathy and single nucleotide polymorphisms in PKNOX1.
Biomarker Research 2023 May 16; 11(1):52
Multiple myeloma is the second most common malignant bone marrow disorder in Germany. A crucial component in the treatment of this disorder is bortezomib (BTZ), a well-established chemotherapy drug. Almost all individuals affected by multiple myeloma receive BTZ, however, a significant number of them develop peripheral neuropathy, a dose-limiting side effect of BTZ. The pathomechanisms underlying peripheral neuropathy in these conditions are not yet fully understood. A genome-wide association study (GWA study) suggested that specific nucleotide polymorphisms (SNPs) in PKNOX1 gene correlate with an increased risk of developing bortezomib-induced peripheral neuropathy (BIPN). In the present study, we investigated this possible correlation in myeloma patients treated with BTZ at the University Hospital Würzburg.
Individuals carrying a homozygous genotype mutation in PKNOX1 (rs2839629) and/or within the intergenic region between PKNOX1 and CBS (rs915854) have a notably higher risk of developing a painful bortezomib-induced peripheral neuropathy (BIPN). Conducting a genetic screening for these specific SNPs before initiating BTZ therapy could offer an improved means of assessing a patient's likelihood of experiencing a painful polyneuropathy, potentially serving as a valuable biomarker for tailoring personalized treatment strategies in the future.
Information about the authors of this study and the whole project 1 team, led by Prof. Martin Kortum, MD, Prof. Claudia Sommer, MD, and Prof Einsele, can be found on the project's respective side.
Previous Paper of the Month
Cebulla N, Schirmer D, Runau E, Flamm L, Gommersbach S, Stengel H, Zhou X, Einsele H, Reinhold AK, Rogalla von Bieberstein B, Zeller D, Rittner H, Kortüm KM, Sommer C.
Neurofilament light chain levels indicate acute axonal damage under bortezomib treatment
Journal of Neurology. 2023 Feb 18
Multiple myeloma (MM) is a plasma cell disorder, responsible for 13% of all hematological malignancies. Bortezomib (BTZ), a well-established chemotherapy drug, is the first-line therapy for this disease. However, despite the efficacy of bortezomib, some patients experience side effects such as Bortezomib-induced peripheral neuropathy (BIPN). Symptoms may regress after the end of the treatment, but BIPN is commonly a dose limiting complication of BTZ treatment, and in some cases, treatment needs to be discontinued. Until now there is no biomarker, which can predict this side effect and its severity. In Project 1 of this Clinical Research Unit, we are investigating the development and regression of peripheral neuropathy and pain under BTZ treatment.
In our study, we provided a cross-sectional analysis of our cohort, in which we assessed the levels of neurofilament light chain (NfL). NfL levels were further correlated with several clinical parameters. We found that the axonal damage acutely triggered by BTZ is accompanied by an increase in NfL levels.
Furthermore, these increased levels of NfL correlate with a decreasing amplitude of the nerve action potential on electrophysiological measurements and with the cumulative dose of BTZ: The higher the sum of the BTZ doses administered during therapy, the higher the NfL level and the lower the electrical conductivity of the nerves.
After discontinuing BTZ, NfL levels continually drop over time and approach normal levels again. The next steps of our research are to further investigate the aforementioned alterations in comparison with the clinical course of the disease.
We achieved, through the close cooperation of the interdisciplinary and translational team of the KFO 5001, a first step towards understanding BIPN. By analyzing the effect of BTZ on NfL levels, we were able to better characterize and quantify the extent of damage present in BIPN patients. Our aim now is to test whether NfL can be established as a biomarker and be incorporated into daily clinical practice.
Prof. Dr. Claudia Sommer, MD, is the speaker of the KFO 5001 and one of the principal investigators of Projects 1, 5 and Z.
Nadine Cebulla is a doctoral candidate working under the supervision of Prof. Dr. Claudia Sommer, MD, in Project 1.
Appeltshauser L, Junghof H, Messinger J, Linke J, Haarmann A, Ayzenberg I, Baka P, Dorst J, Fisse AL, Grüter T, Hauschildt V, Jörk A, Leypoldt F, Mäurer M, Meinl E, Michels S, Motte J, Pitarokoili K, Stettner M, Villmann C, Weihrauch M, Welte GS, Zerr I, Heinze KG, Sommer C, Doppler K
Anti-pan-neurofascin antibodies induce subclass-related complement activation and nodo-paranodal damage
Brain. Published online Nov 8 2022
In this clinical-experimental study, we described for the first time the effects of pan-neurofascin antibodies on the formation and integrity of the Ranvier Nodes. The Ranvier Nodes, that form gaps within the myelin-sheath, are crucial for the rapid conduction of action potentials. In patients with inflammatory polyneuropathies, neurofascin antibodies destroy the nodal architecture leading to impaired nerve conduction.
Our work includes a detailed description of the clinical consequences of these disorders: Affected patients suffer from an acute and severe polyneuropathy with complete paralysis of the entire musculature, including the respiratory muscles, and often need to be assisted with mechanical ventilation for prolonged periods. However, with immunomodulatory and B-cell-directed therapy, the disease is potentially reversible and usually goes into complete remission after the acute phase.
In order to better identify and efficiently treat affected patients, the accurate description of the clinical aspects of this disease is essential to everyday clinical practice. Likewise, understanding the pathomechanism of this disease allows physicians and scientists to use and further develop specific therapies for the disease. Furthermore, a cell culture model established in this study could be easily used in future studies to screen for other antibody-mediated polyneuropathies.
New biomarkers: Antibodies and neurofilament-light chain
In addition to the antibody titer, the authors also identified the neurofilament-light chain as a new biomarker of disease severity, as well as a good marker for assessing the response to long-term therapy. This will help to monitor the disease in a long term, to adjust therapies faster and to identify a possible relapse at an early stage.
Dr Kathrin Doppler, MD, is the principal investigator of Project 3, in which neuropathic pain caused by anti-Caspr2 autoantibodies is being investigated.
Dr Luise Appeltshauser, MD, works as a Clinician Scientist in the working group of Dr Kathrin Doppler and Univ.-Prof. Claudia Sommer, MD, on autoantibody-mediated neuropathies.
Schulte A, Lohner H, Degenbeck J, Segebarth D, Rittner H, Blum R, Aue A
Unbiased analysis of the dorsal root ganglion after peripheral nerve injury: no neuronal loss, no gliosis, but satellite glial cell plasticity
Pain. Published online Aug 15 2022
In this paper, we describe the cellular composition of the dorsal root ganglia in an animal model of sciatic nerve injury. For the first time, deep learning (AI-based) image analysis has been applied to a large dataset of microscopy images of dorsal root ganglia. This allowed automatic evaluation of more than 2,500 immunohistochemical images of dorsal root ganglia after nerve injury - something that would have never been possible with previously used methods. As a result, we found that the nerve injury does not lead to a loss of neurons or uncontrolled growth of glial cells, as previously suspected, but only activates the cellular plasticity of glial cells.
The data published by our group sets new standards for the objective analysis of microscopic images, here representative in the research area "Molecular Pain Research". This methodology is the basis for describing the multicellular processes of pain resolution with greater precision.
In project 9 we study the multicellular processes of pain resolution. At present, even cellular processes in human dorsal root ganglia are being studied using deep learning.
Weiner S, Strinitz M, Herfurth J, Hessenauer F, Nauroth-Kreß C, Kampf T, Homola GA, Üçeyler N, Sommer C, Pham M, Schindehütte M.
Dorsal Root Ganglion Volumetry by MR Gangliography
American Journal of Neuroradiology, Vol 43, No 5 (Mai), 2022: pp 769-775. Epub 2022 Apr 21.
Several pain disorders are associated with volume changes of dorsal root ganglia which contain the cell bodies of all sensory peripheral nerve cells. They are significantly involved in pain perception and processing. In this paper, we evaluated a refined method to determine more accurately the volume of the lumbosacral dorsal root ganglia by magnetic resonance imaging (MRI). By ground-truth segmentation, the dorsal root ganglia volume in the individual segments can be determined significantly better and the DRG can be delineated more precise. In parallel, the new method was validated in a cohort of 64 healthy subjects to determine normal values of volume of dorsal root ganglia.
The investigation of the dorsal root ganglia using magnetic resonance Gangliography (MRG) provides information on the condition and function of the nervous system in humans. An improved volume determination allows early detection of changes in the dorsal root ganglia. Therefore, on the one hand, the method can play an increasingly important role in the research of painful conditions, and, on the other hand, it can also be used for diagnostics and therapy planning in the care of patients with pain disorders.
Magnetic resonance imaging of nerves is part of the projekt Z.