Julia Christina Kuehn

All Publications

• Non-invasive Mantle Cell Lymphoma risk stratification by inference of tumor proliferation from cfDNA Ashtari, A., Mutter, J., Tessoulin, B., Rossi, C., Boegeholz, J., Goldstein, J., Klanova, M., Kuehn, J., Alig, S., Schroers-Martin, J., Liu, C., Olsen, M., Kang, X., Trneny, M., Le Gouill, S., Diehn, M., Esfahani, M., Alizadeh, A. ELSEVIER. 2025: 1789-1790

  View details for DOI 10.1182/blood-2025-1789

  View details for Web of Science ID 001660185400040

• Comprehensive molecular profiling of urologic tumors presented in a molecular tumor board: insights from a real-world precision oncology cohort. Frontiers in oncology Glienke, M., Himmelsbach, R., Zirngibl, M., Metzger, P., Kühn, J., Miething, C., Sigle, A., Gratzke, C., Nientiedt, C., Rassner, M., Becker, H., Duyster, J., Lassmann, S., Werner, M., Börries, M., Grabbert, M. 2025; 15: 1688779

  Abstract

  Molecular tumor boards (MTBs) have become an integral component of precision oncology, yet data on their real-world impact in urologic cancers are limited. This study aimed to characterize the molecular landscape of urologic malignancies presented to the MTB at the University Medical Center Freiburg and to evaluate the frequency and clinical relevance of genomic alterations across tumor entities.We retrospectively analyzed 118 patients with histologically confirmed urologic tumors presented at the Freiburg MTB between Januar 2019 and December 2024. Comprehensive molecular profiling was performed using next-generation sequencing (TruSight Oncology 500 or whole exome sequencing). Data were analyzed for mutation frequency, tumor mutational burden (TMB), and co-occurrence patterns, and integrated with clinical data to guide therapy recommendations.Somatic mutations were identified in 90.6% of cases. Frequent alterations included TP53, BRCA2, KMT2D, and ATM, with DNA damage response and chromatin remodeling pathways commonly affected. Prostate cancers showed high rates of BRCA2 and APC co-mutations, indicating potential benefit from combined PARP and Wnt-targeted therapies. In bladder and upper tract urothelial carcinomas (UTUC), KMT2C co-occurred with genes such as SPTA1 and LRP1B, suggesting a hypermutated, immunoresponsive phenotype. Renal tumors frequently harbored alterations in VHL, PBRM1, and SETD2. Rare entities such as penile and testicular tumors displayed distinct mutation patterns, including BRCA1/2 and MMR gene alterations.Comprehensive molecular profiling in a MTB setting reveals distinct and therapeutically relevant mutational patterns across urologic cancers. These data support the integration of MTBs into clinical workflows and highlight the potential of co-mutational signatures to guide personalized treatment strategies.

  View details for DOI 10.3389/fonc.2025.1688779

  View details for PubMedID 41395625

  View details for PubMedCentralID PMC12695579

• Tracing malignant precursor mutations and their cellular origins in blood and bone marrow of primary central nervous system lymphomas by ultrasensitive genomic profiling Kuehn, J., Klingler, C., Weinschenk, S., Mutter, J., Hummel, F., Rapp, J., Lauer, E., Ranganathan, L., Bleul, S., Alig, S., Prinz, M., Duyster, J., Sankowski, R., Diehn, M., Alizadeh, A., Schorb, E., Reinacher, P., Scherer, F. ELSEVIER. 2025: 458-459

  View details for DOI 10.1182/blood-2025-458

  View details for Web of Science ID 001659530100009

• The effect of ibrutinib on the myeloid cell compartment in CNS lymphoma. Leukemia Kuehn, J. C., Neidert, N. N., Zhang, J., Mutter, J., Alig, S., Klingler, C., Hummel, F., Ranganathan, L., Bleul, S., Beck, J., Prinz, M., Diehn, M., Alizadeh, A., Duyster, J., Sankowski, R., Heiland, D. H., Scherer, F. 2025

  View details for DOI 10.1038/s41375-025-02600-y

  View details for PubMedID 40210767

  View details for PubMedCentralID 3795457

• Intraoperative classification of CNS lymphoma and glioblastoma by AI-based analysis of Stimulated Raman Histology (SRH). Brain & spine Scheffler, P., Straehle, J., El Rahal, A., Erny, D., Mizaikoff, B., Vasilikos, I., Prinz, M., Coenen, V. A., Kühn, J., Scherer, F., Heiland, D. H., Schnell, O., Roelz, R., Beck, J., Reinacher, P. C., Neidert, N. 2025; 5: 104187

  Abstract

  Early diagnosis is important to differentiate central nervous system lymphomas (CNSL) from the main differential diagnosis, glioblastoma (GBM), because of different primary treatment modalities for these entities. Due to neurological deficits, diagnostic stereotactic biopsies often need to be performed urgently. In this setting the availability of an intraoperative neuropathological assessment is limited.This study uses AI-based analysis of Stimulated Raman Histology (SRH) to establish a classifier distinguishing CNSL from glioblastoma in an intraoperative setting.We collected 126 intraoperative SRH images from 40 patients diagnosed with CNSL. These SRH images were divided into patches, measuring 224 x 224 pixels each. Additionally, we used a comparative dataset of 87 SRH images from 31 patients with GBM as a control group to train and validate a neural network based on the CTransPath architecture. Two distinct diagnostic categories were established: "Lymphoma" and "Glioblastoma".Our model demonstrated an accuracy rate of 92.5% in distinguishing between lymphoma and glioblastoma. Analysis of our test dataset showed a sensitivity of 84.2% and a specificity of 100% in the detection of CNSL, demonstrating performance comparable to standard intraoperative histopathological analysis.The use of AI-driven analysis of SRH images holds promise for intraoperative tissue examination of stereotactic biopsies with suspected CNSL en par with the current gold standard. This study could improve the management of these cases especially in the emergency setting when conventional intraoperative neuropathological evaluation is unavailable.

  View details for DOI 10.1016/j.bas.2025.104187

  View details for PubMedID 40027294

  View details for PubMedCentralID PMC11868944

• Modulation of the Tumor Microenvironment By CCL19 in Primary CNS Lymphomas Kuehn, J. C., Md, R., Neidert, N. N., Mutter, J. A., Grabis, E., Alig, S. K., Zhang, J., Klingler, C., Bleul, S., Hummel, F., Ranganathan, L., Lauer, E. M., Heiland, D., Prinz, M., Mueller, K. J., von Baumgarten, L., Duyster, J., Schorb, E., Diehn, M., Alizadeh, A. A., Reinacher, P. C., Scherer, F. ELSEVIER. 2024: 856-857

  View details for DOI 10.1182/blood-2024-199257

  View details for Web of Science ID 001412608600049

• Guiding Treatment and Clinical Management of Patients with CNS Lymphomas By Minimal-Invasive Detection of Circulating Tumor DNA in Cerebrospinal Fluid Weinschenk, S., Philipp, U., Kuehn, J. C., Mueller, K. J., Fauser, J., Boeckle, D., Gebhard, I., Hinz, M., Neidert, N. N., Bleul, S., Lauer, E. M., Mutter, J. A., Alig, S. K., Kurtz, D., Finke, J., Marks, R., Diehn, M., Alizadeh, A. A., Reinacher, P. C., Wehrle, J., Wolf, D., Kocher, F., Chapuy, B., Beck, J., Prinz, M., von Baumgarten, L., Schorb, E., Duyster, J., Scherer, F. ELSEVIER. 2024: 1583-1584

  View details for DOI 10.1182/blood-2024-202943

  View details for Web of Science ID 001410640300038

• The Effect of Ibrutinib on the Myeloid Cell Compartment in Central Nervous System Lymphoma Slice Cultures Kuehn, J. C., Neidert, N. N., Zhang, J., Mutter, J. A., Alig, S. K., Klingler, C., Hummel, F., Bleul, S., Ranganathan, L., Beck, J., Prinz, M., Diehn, M., Alizadeh, A. A., Duyster, J., Sankowski, R., Heiland, D., Scherer, F. ELSEVIER. 2024: 4374-4375

  View details for DOI 10.1182/blood-2024-199125

  View details for Web of Science ID 001409330600009

• Comprehensive genetic profiling and molecularly guided treatment for patients with primary CNS tumors. NPJ precision oncology Kuehn, J. C., Metzger, P., Neidert, N., Matysiak, U., Gräßel, L., Philipp, U., Bleul, S., Pauli, T., Falkenstein, J., Bertemes, H., Cysar, S., Hess, M. E., Frey, A. V., Duque-Afonso, J., Schorb, E., Machein, M., Beck, J., Schnell, O., von Bubnoff, N., Illert, A. L., Peters, C., Brummer, T., Prinz, M., Miething, C., Becker, H., Lassmann, S., Werner, M., Börries, M., Duyster, J., Heiland, D. H., Sankowski, R., Scherer, F. 2024; 8 (1): 180

  Abstract

  Despite major advances in molecular profiling and classification of primary brain tumors, personalized treatment remains limited for most patients. Here, we explored the feasibility of individual molecular profiling and the efficacy of biomarker-guided therapy for adult patients with primary brain cancers in the real-world setting within the molecular tumor board Freiburg, Germany. We analyzed genetic profiles, personalized treatment recommendations, and clinical outcomes of 102 patients with 21 brain tumor types. Alterations in the cell cycle, BRAF, and mTOR pathways most frequently led to personalized treatment recommendations. Molecularly informed therapies were recommended in 71% and implemented in 32% of patients with completed molecular diagnostics. The disease control rate following targeted treatment was 50% and the overall response rate was 30%, with a progression-free survival 2/1 ratio of at least 1.3 in 31% of patients. This study highlights the efficacy of molecularly guided treatment and the need for biomarker-stratified trials in brain cancers.

  View details for DOI 10.1038/s41698-024-00674-y

  View details for PubMedID 39143272

  View details for PubMedCentralID PMC11324882

• Liquid biopsy for improving diagnosis and monitoring of CNS lymphomas: A RANO review. Neuro-oncology Nayak, L., Bettegowda, C., Scherer, F., Galldiks, N., Ahluwalia, M., Baraniskin, A., von Baumgarten, L., Bromberg, J. E., Ferreri, A. J., Grommes, C., Hoang-Xuan, K., Kühn, J., Rubenstein, J. L., Rudà, R., Weller, M., Chang, S. M., van den Bent, M. J., Wen, P. Y., Soffietti, R. 2024; 26 (6): 993-1011

  Abstract

  The utility of liquid biopsies is well documented in several extracranial and intracranial (brain/leptomeningeal metastases, gliomas) tumors.The RANO (Response Assessment in Neuro-Oncology) group has set up a multidisciplinary Task Force to critically review the role of blood and cerebrospinal fluid (CSF)-liquid biopsy in CNS lymphomas, with a main focus on primary central nervous system lymphomas (PCNSL).Several clinical applications are suggested: diagnosis of PCNSL in critical settings (elderly or frail patients, deep locations, and steroid responsiveness), definition of minimal residual disease, early indication of tumor response or relapse following treatments, and prediction of outcome.Thus far, no clinically validated circulating biomarkers for managing both primary and secondary CNS lymphomas exist. There is need of standardization of biofluid collection, choice of analytes, and type of technique to perform the molecular analysis. The various assays should be evaluated through well-organized central testing within clinical trials.

  View details for DOI 10.1093/neuonc/noae032

  View details for PubMedID 38598668

  View details for PubMedCentralID PMC11145457

• Improved early outcome prediction by MRI-based 3D tumor volume assessment in patients with CNS lymphomas. Neuro-oncology Lauer, E. M., Riegler, E., Mutter, J. A., Alig, S. K., Bleul, S., Kuehn, J., Ranganathan, L., Klingler, C., Demerath, T., Wurtemberger, U., Rau, A., WeiSS, J., Eisenblaetter, M., Bamberg, F., Prinz, M., Finke, J., Duyster, J., Illerhaus, G., Diehn, M., Alizadeh, A. A., Schorb, E., Reinacher, P. C., Scherer, F. 2023

  Abstract

  BACKGROUND: Central nervous system lymphomas (CNSL) display remarkable clinical heterogeneity, yet accurate prediction of outcomes remains challenging. The IPCG criteria are widely used in routine practice for the assessment of treatment response. However, the value of the IPCG criteria for ultimate outcome prediction is largely unclear, mainly due to the uncertainty in delineating complete from partial responses during and after treatment.METHODS: We explored various MRI features including semi-automated 3D tumor volume measurements at different disease milestones and their association with survival in 93 CNSL patients undergoing curative-intent treatment.RESULTS: At diagnosis, patients with more than three lymphoma lesions, periventricular involvement, and high 3D tumor volumes showed significantly unfavorable PFS and OS. At first interim MRI during treatment, the IPCG criteria failed to discriminate outcomes in responding patients. Therefore, we randomized these patients into training and validation cohorts to investigate whether 3D tumor volumetry could improve outcome prediction. We identified a 3D tumor volume reduction of ≥97% as the optimal threshold for risk stratification (=3D early response, 3D_ER). Applied to the validation cohort, patients achieving 3D_ER had significantly superior outcomes. In multivariate analyses, 3D_ER was independently prognostic of PFS and OS. Finally, we leveraged prognostic information from 3D MRI features and circulating biomarkers to build a composite metric that further improved outcome prediction in CNSL.CONCLUSIONS: We developed semi-automated 3D tumor volume measurements as strong and independent early predictors of clinical outcomes in CNSL patients. These radiologic features could help improve risk stratification and help guide future treatment approaches.

  View details for DOI 10.1093/neuonc/noad177

  View details for PubMedID 37713267

• Circulating Tumor DNA Profiling for Detection, Risk Stratification, and Classification of Brain Lymphomas. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Mutter, J. A., Alig, S. K., Esfahani, M. S., Lauer, E. M., Mitschke, J., Kurtz, D. M., Kühn, J., Bleul, S., Olsen, M., Liu, C. L., Jin, M. C., Macaulay, C. W., Neidert, N., Volk, T., Eisenblaetter, M., Rauer, S., Heiland, D. H., Finke, J., Duyster, J., Wehrle, J., Prinz, M., Illerhaus, G., Reinacher, P. C., Schorb, E., Diehn, M., Alizadeh, A. A., Scherer, F. 2022: JCO2200826

  Abstract

  Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL.We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL.Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, P < .0001, log-rank test) and overall survival (OS, P = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; P = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; P = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, P = .0002; OS, P = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value.We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL.

  View details for DOI 10.1200/JCO.22.00826

  View details for PubMedID 36542815

• Adult-onset temporal lobe epilepsy suspicious for autoimmune pathogenesis: Autoantibody prevalence and clinical correlates. PloS one Kuehn, J. C., Meschede, C., Helmstaedter, C., Surges, R., von Wrede, R., Hattingen, E., Vatter, H., Elger, C. E., Schoch, S., Becker, A. J., Pitsch, J. 2020; 15 (10): e0241289

  Abstract

  Temporal lobe adult-onset seizures (TAOS) related to autoimmunity represent an increasingly recognized disease syndrome within the spectrum of epilepsies. In this context, certain autoantibodies (autoABs) were often associated with limbic encephalitis (LE). Here, we aimed to gain insights into (a) the distribution of 'neurological' autoABs (neuroABs, defined as autoABs targeting neuronal surface structures or 'onconeuronal' ABs or anti-glutamate acid decarboxylase 65 (GAD65) autoABs) in a large consecutive TAOS patient cohort, to characterize (b) clinical profiles of seropositive versus seronegative individuals and to find (c) potential evidence for other autoABs. Blood sera/cerebrospinal fluid (CSF) of TAOS patients (n = 800) and healthy donors (n = 27) were analyzed for neuroABs and screened for other autoABs by indirect immunofluorescence on hippocampal/cerebellar sections and immunoblots of whole brain and synaptosome lysates. Serological results were correlated with clinico-neuropsychological features. 13% of TAOS patients (n = 105) were neuroAB+, with anti-GAD65 and anti-N-methyl-D-aspartate receptors (NMDAR) as most frequent autoABs in this group. In our screening tests 25% of neuroAB- patients (n = 199) were positive (screening+), whereas all control samples were negative (n = 27). Intriguingly, key clinico-neuropsychological characteristics including magnetic resonance imaging (MRI) findings, epileptiform electroencephalographic (EEG) activity, and inflammatory cellular infiltrates in CSF were shared to a greater extent by neuroAB+ with neuroAB-/screening+ patients than with neuroAB-/screening- patients. Serological testing in a large consecutive TAOS patient series revealed seropositivity for anti-GAD65 autoABs as the most frequent neuroAB. Intriguingly, neuroAB+ individuals were virtually indistinguishable from neuroAB-/screening+ patients in several major clinical features. In contrast, neuroAB-/screening- TAOS patients differed in many parameters. These data support the potential presence of so far unrecognized autoABs in patients with TAOS.

  View details for DOI 10.1371/journal.pone.0241289

  View details for PubMedID 33119692

  View details for PubMedCentralID PMC7595292

• Drebrin Autoantibodies in Patients with Seizures and Suspected Encephalitis. Annals of neurology Pitsch, J., Kamalizade, D., Braun, A., Kuehn, J. C., Gulakova, P. E., Rüber, T., Lubec, G., Dietrich, D., von Wrede, R., Helmstaedter, C., Surges, R., Elger, C. E., Hattingen, E., Vatter, H., Schoch, S., Becker, A. J. 2020; 87 (6): 869-884

  Abstract

  Assess occurrence of the dendritic spine scaffolding protein Drebrin as a pathophysiologically relevant autoantibody target in patients with recurrent seizures and suspected encephalitis as leading symptoms.Sera of 4 patients with adult onset epilepsy and suspected encephalitis of unresolved etiology and equivalent results in autoantibody screening were subjected to epitope identification. We combined a wide array of approaches, ranging from immunoblotting, immunoprecipitation, mass spectrometry, subcellular binding pattern analyses in primary neuronal cultures, and immunohistochemistry in brains of wild-type and Drebrin knockout mice to in vitro analyses of impaired synapse formation, morphology, and aberrant neuronal excitability by antibody exposure.In the serum of a patient with adult onset epilepsy and suspected encephalitis, a strong signal at ∼70kDa was detected by immunoblotting, for which mass spectrometry revealed Drebrin as the putative antigen. Three other patients whose sera also showed strong immunoreactivity around 70kDa on Western blotting were also anti-Drebrin-positive. Seizures, memory impairment, and increased protein content in cerebrospinal fluid occurred in anti-Drebrin-seropositive patients. Alterations in cerebral magnetic resonance imaging comprised amygdalohippocampal T2-signal increase and hippocampal sclerosis. Diagnostic biopsy revealed T-lymphocytic encephalitis in an anti-Drebrin-seropositive patient. Exposure of primary hippocampal neurons to anti-Drebrin autoantibodies resulted in aberrant synapse composition and Drebrin distribution as well as increased spike rates and the emergence of burst discharges reflecting network hyperexcitability.Anti-Drebrin autoantibodies define a chronic syndrome of recurrent seizures and neuropsychiatric impairment as well as inflammation of limbic and occasionally cortical structures. Immunosuppressant therapies should be considered in this disorder. ANN NEUROL 2020;87:869-884.

  View details for DOI 10.1002/ana.25720

  View details for PubMedID 32196746

• A 64-Year-Old Patient With a Mesiotemporal Mass and Symptomatic Epilepsy. Brain pathology (Zurich, Switzerland) Kuehn, J. C., Scheuerle, A., Bauer, J., Becker, A. J., Wirtz, R., Lewerenz, J. 2020; 30 (2): 413-414

  View details for DOI 10.1111/bpa.12818

  View details for PubMedID 32100436

  View details for PubMedCentralID PMC8018108

• Anti-epileptogenic and Anti-convulsive Effects of Fingolimod in Experimental Temporal Lobe Epilepsy. Molecular neurobiology Pitsch, J., Kuehn, J. C., Gnatkovsky, V., Müller, J. A., van Loo, K. M., de Curtis, M., Vatter, H., Schoch, S., Elger, C. E., Becker, A. J. 2019; 56 (3): 1825-1840

  Abstract

  Temporal lobe epilepsy (TLE) represents a devastating neurological condition, in which approximately 4/5 of patients remain refractory for anti-convulsive drugs. Epilepsy surgery biopsies often reveal the damage pattern of "hippocampal sclerosis" (HS) characterized not only by neuronal loss but also pronounced astrogliosis and inflammatory changes. Since TLE shares distinct pathogenetic aspects with multiple sclerosis (MS), we have here scrutinized therapeutic effects in experimental TLE of the immunmodulator fingolimod, which is established in MS therapy. Fingolimod targets sphingosine-phosphate receptors (S1PRs). mRNAs of fingolimod target S1PRs were augmented in two experimental post status epilepticus (SE) TLE mouse models (suprahippocampal kainate/pilocarpine). SE frequently induces chronic recurrent seizures after an extended latency referred to as epileptogenesis. Transient fingolimod treatment of mice during epileptogenesis after suprahippocampal kainate-induced SE revealed substantial reduction of chronic seizure activity despite lacking acute attenuation of SE itself. Intriguingly, fingolimod exerted robust anti-convulsive activity in kainate-induced SE mice treated in the chronic TLE stage and had neuroprotective and anti-gliotic effects and reduced cytotoxic T cell infiltrates. Finally, the expression profile of fingolimod target-S1PRs in human hippocampal biopsy tissue of pharmacoresistant TLE patients undergoing epilepsy surgery for seizure relief suggests repurposing of fingolimod as novel therapeutic perspective in focal epilepsies.

  View details for DOI 10.1007/s12035-018-1181-y

  View details for PubMedID 29934763