Publications by authors named "Thomas Hielscher"

156 Publications

Integrated Molecular-Morphologic Meningioma Classification: A Multicenter Retrospective Analysis, Retrospectively and Prospectively Validated.

J Clin Oncol 2021 Oct 7:JCO2100784. Epub 2021 Oct 7.

Department of Neurosurgery, NYU Langone Hospital, New York, NY.

Purpose: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established ( and ), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma.

Methods: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases.

Results: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively).

Conclusion: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.
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http://dx.doi.org/10.1200/JCO.21.00784DOI Listing
October 2021

Carfilzomib, Lenalidomide, and Dexamethasone Followed by Salvage Autologous Stem Cell Transplant with or without Maintenance for Relapsed or Refractory Multiple Myeloma.

Cancers (Basel) 2021 Sep 20;13(18). Epub 2021 Sep 20.

Hematology, Oncology and Rheumatology, University Hospital Heidelberg, 69121 Heidelberg, Germany.

Salvage high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a treatment option for relapsed and/or refractory multiple myeloma (RRMM). No data are available on salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens. We retrospectively report on 44 patients receiving salvage HDCT/ASCT following re-induction with carfilzomib/lenalidomide/dexamethasone (KRd). All patients received frontline HDCT/ASCT with median time to progression (TTP1) of 2.9 (1.2-13.5) years, enabling paired comparison of frontline and salvage HDCT/ASCT. After re-induction and before salvage transplant, 25/44 patients (57%) attained ≥ very good partial response (VGPR), which increased to 34/44 (77%) at best response after salvage HDCT/ASCT. Median progression-free survival (PFS) was 23.3 months from salvage HDCT/ASCT. Patients with ≥ VGPR at the time of salvage HDCT/ASCT and those receiving maintenance treatment post salvage HDCT/ASCT had significantly superior PFS (hazard ratio (HR) 0.19, = 0.001 and HR 0.20, = 0.009). In patients achieving at least an equal depth of response before salvage HDCT/ASCT as before frontline HDCT/ASCT, PFS after salvage HDCT/ASCT was comparable to the frontline situation ( = 0.3). This is the first report of state-of-the-art triplet re-induction and salvage HDCT/ASCT for RRMM after frontline transplantation. Deep remissions achieved with KRd translate into prolonged PFS following salvage HDCT/ASCT and are enhanced by maintenance treatment.
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http://dx.doi.org/10.3390/cancers13184706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472377PMC
September 2021

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.

Nat Commun 2021 09 22;12(1):5577. Epub 2021 Sep 22.

Division of Haematopathology, European Institute of Oncology IRCCS, Milan, Italy.

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.
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http://dx.doi.org/10.1038/s41467-021-25379-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458384PMC
September 2021

Local ablative treatment with surgery and/or radiotherapy in single-site and oligometastatic carcinoma of unknown primary.

Eur J Cancer 2021 Sep 11;157:179-189. Epub 2021 Sep 11.

Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; Department of Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany. Electronic address:

Background: Single-site carcinoma of unknown primary (CUP) is recognised as a distinct favourable subtype in the European Society of Medical Oncology (ESMO) classification. There is broad consensus that these patients are candidates for local ablative treatment strategies with surgery and/or radiotherapy, but data on their outcomes are scarce.

Patients And Methods: In this study, we have addressed the prospects of cure and prognostic factors in a retrospective cohort of 63 patients who were eligible for local treatment at our centre.

Results: Median event-free (EFS) and overall survival (OS) were 15.6 months and 52.5 months, respectively. Of 61 patients who received local treatment, 20 (32.8%) remained event-free over a median follow-up of 28 months. Baseline clinical parameters including affected organ, number, volume and histology of metastases had no significant impact on prognosis, whereas deleterious TP53 mutations and DNA copy number loss emerged as independent adverse risk factors with respect to EFS. Surgical treatment was associated with improved OS as compared to radiation-based therapy.

Conclusion: Our study advocates to pursue localised treatment with surgery and/or radiotherapy whenever feasible and implies that genetic parameters might additionally determine the clinical course of single-site CUP patients.
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http://dx.doi.org/10.1016/j.ejca.2021.08.019DOI Listing
September 2021

GTF2I Mutation in Thymomas: Independence From Racial-Ethnic Backgrounds. An Indian/German Comparative Study.

Pathol Oncol Res 2021 23;27:1609858. Epub 2021 Aug 23.

Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.

Thymomas are the most frequent adult mediastinal cancers. Their etiology is unknown and their pathogenesis poorly understood. Racial, ethnic and environmental factors influence tumorigenesis in many cancers, but their role in thymomas remains unclear to date. In this study that included pretreatment thymoma cases from India and Germany ( = 37 and = 77, respectively) we compared i) the prevalence of the thymoma-specific chromosome 7 c.74146970T > A mutation of the gene in type A and AB thymomas; ii) epidemiological features; and iii) the frequency of myasthenia gravis (MG). Due to a known predominance of GTF2I mutation in A and AB histotypes, we included only a marginal number of type B thymomas as a control group in both cohorts. While the distribution of histological types between the cohorts was similar ( = 0.1622), Indian patients were strikingly younger ( < 0.0001; median age 50 vs. 65 years) and showed significantly lower tumour stage (Masaoka-Koga stage I) at primary diagnosis ( = 0.0005) than the German patients. In patients with known MG status ( = 17 in Indian and = 25 in German cohort), a clear trend towards more frequent MG was observed in the Indian group ( = 0.0504; 48 vs. 82%). The prevalence of the mutation (analysed in = 34 Indian and = 77 German patients) was identical in the two cohorts. We conclude that racial-ethnic and environmental factors do not significantly influence the most common molecular feature of thymomas but may have an impact on the timing of clinical presentation.
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http://dx.doi.org/10.3389/pore.2021.1609858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419886PMC
August 2021

Consistent Major Differences in Sex- and Age-Specific Diagnostic Performance among Nine Faecal Immunochemical Tests Used for Colorectal Cancer Screening.

Cancers (Basel) 2021 Jul 16;13(14). Epub 2021 Jul 16.

German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Division of Preventive Oncology, 69120 Heidelberg, Germany.

Evidence on diagnostic performance of faecal immunochemical tests (FITs) by sex and age is scarce. We aimed to evaluate FIT performance for detection of advanced colorectal neoplasia (AN) by sex and age across nine different FIT brands in a colonoscopy-controlled setting. The faecal samples were obtained from 2042 participants of colonoscopy screening. All eligible cases with AN ( 216) and 300 randomly selected participants without AN were included. Diagnostic performance for detection of AN was assessed by sex and age (50-64 vs. 65-79 years for each of the nine FITs individually and for all FITs combined. Sensitivity was consistently lower, and specificity was consistently higher for females as compared with males (pooled values at original FIT cutoffs, 25.7% vs. 34.6%, = 0.12 and 96.2% vs. 90.8%, < 0.01, respectively). Positive predictive values (PPVs) were similar between both sexes, but negative predictive values (NPVs) were consistently higher for females (pooled values, 91.8% vs. 86.6%, < 0.01). Sex-specific cutoffs attenuated differences in sensitivities but increased differences in predictive values. According to age, sensitivities and specificities were similar, whereas PPVs were consistently lower and NPVs were consistently higher for the younger participants. A negative FIT is less reliable in ruling out AN among men than among women and among older than among younger participants. Comparisons of measures of diagnostic performance among studies with different sex or age distributions should be interpreted with caution.
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http://dx.doi.org/10.3390/cancers13143574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306133PMC
July 2021

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma.

Neuro Oncol 2021 Jul 7. Epub 2021 Jul 7.

Brain Tumor Translational Targets, DKFZ Junior Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Glioblastoma is the most common primary malignancy of the central nervous system with dismal prognosis. Genomic signatures classify isocitrate dehydrogenase 1 (IDH)-wildtype glioblastoma into three subtypes: proneural, mesenchymal and classical. Dasatinib, an inhibitor of proto-oncogene kinase Src (SRC), is one of many therapeutics which, despite promising preclinical results, has failed to improve overall survival in glioblastoma patients in clinical trials. We examined whether glioblastoma subtypes differ in their response to dasatinib and could hence be evaluated for patient enrichment strategies in clinical trials.

Methods: We carried out in silico analyses on glioblastoma gene expression (TCGA) and single-cell RNA-Seq data. In addition, in vitro experiments using glioblastoma stem-like cells (GSCs) derived from primary patient tumors were performed, with complementary gene expression profiling and immunohistochemistry analysis of tumor samples.

Results: Patients with the mesenchymal subtype of glioblastoma showed higher SRC pathway activation based on gene expression profiling. Accordingly, mesenchymal GSCs were more sensitive to SRC inhibition by dasatinib compared to proneural and classical GSCs. Notably, SRC phosphorylation status did not predict response to dasatinib treatment. Furthermore, serpin peptidase inhibitor clade H member 1 (SERPINH1), a collagen related heat-shock protein associated with cancer progression, was shown to correlate with dasatinib response and with the mesenchymal subtype.

Conclusion: This work highlights further molecular-based patient selection strategies in clinical trials and suggests the mesenchymal subtype as well as SERPINH1 to be associated with response to dasatinib. Our findings indicate that stratification based on gene expression subtyping should be considered in future dasatinib trials.
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http://dx.doi.org/10.1093/neuonc/noab158DOI Listing
July 2021

Fully Automatic Deep Learning in Bi-institutional Prostate Magnetic Resonance Imaging: Effects of Cohort Size and Heterogeneity.

Invest Radiol 2021 Jun 8. Epub 2021 Jun 8.

From the Division of Radiology, German Cancer Research Center Heidelberg University Medical School, Heidelberg, Germany Department of Radiology, Affiliated Hospital of Guilin Medical University Department of Radiology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, Guangxi, China Department of Urology, University of Heidelberg Medical Center Division of Biostatistics, German Cancer Research Center Institute of Pathology, University of Heidelberg Medical Center Division of Medical Physics in Radiology Medical Image Computing, German Cancer Research Center German Cancer Consortium, Heidelberg, Germany.

Background: The potential of deep learning to support radiologist prostate magnetic resonance imaging (MRI) interpretation has been demonstrated.

Purpose: The aim of this study was to evaluate the effects of increased and diversified training data (TD) on deep learning performance for detection and segmentation of clinically significant prostate cancer-suspicious lesions.

Materials And Methods: In this retrospective study, biparametric (T2-weighted and diffusion-weighted) prostate MRI acquired with multiple 1.5-T and 3.0-T MRI scanners in consecutive men was used for training and testing of prostate segmentation and lesion detection networks. Ground truth was the combination of targeted and extended systematic MRI-transrectal ultrasound fusion biopsies, with significant prostate cancer defined as International Society of Urological Pathology grade group greater than or equal to 2. U-Nets were internally validated on full, reduced, and PROSTATEx-enhanced training sets and subsequently externally validated on the institutional test set and the PROSTATEx test set. U-Net segmentation was calibrated to clinically desired levels in cross-validation, and test performance was subsequently compared using sensitivities, specificities, predictive values, and Dice coefficient.

Results: One thousand four hundred eighty-eight institutional examinations (median age, 64 years; interquartile range, 58-70 years) were temporally split into training (2014-2017, 806 examinations, supplemented by 204 PROSTATEx examinations) and test (2018-2020, 682 examinations) sets. In the test set, Prostate Imaging-Reporting and Data System (PI-RADS) cutoffs greater than or equal to 3 and greater than or equal to 4 on a per-patient basis had sensitivity of 97% (241/249) and 90% (223/249) at specificity of 19% (82/433) and 56% (242/433), respectively. The full U-Net had corresponding sensitivity of 97% (241/249) and 88% (219/249) with specificity of 20% (86/433) and 59% (254/433), not statistically different from PI-RADS (P > 0.3 for all comparisons). U-Net trained using a reduced set of 171 consecutive examinations achieved inferior performance (P < 0.001). PROSTATEx training enhancement did not improve performance. Dice coefficients were 0.90 for prostate and 0.42/0.53 for MRI lesion segmentation at PI-RADS category 3/4 equivalents.

Conclusions: In a large institutional test set, U-Net confirms similar performance to clinical PI-RADS assessment and benefits from more TD, with neither institutional nor PROSTATEx performance improved by adding multiscanner or bi-institutional TD.
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http://dx.doi.org/10.1097/RLI.0000000000000791DOI Listing
June 2021

The prognostic value of galactosylceramide-sulfotransferase (Gal3ST1) in human renal cell carcinoma.

Sci Rep 2021 05 25;11(1):10926. Epub 2021 May 25.

Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Renal cell carcinoma (RCC) is the deadliest primary genitourinary malignancy typically associated with asymptomatic initial presentation and poorly predictable survival. Next to established risk factors, tumor microenvironment may alter metastatic capacity and immune landscape. Due to their high concentrations, sulfoglycolipids (sulfatides) were among the first well-described antigens in RCC that are associated with worse prognosis. As sulfatide detection in routine diagnostics is not possible, we aimed to test the prognostic value of its protein counterpart, sulfatide-producing enzyme Gal3ST1. We performed retrospective long-term follow up analysis of Gal3ST1 expression as prognostic risk factor in a representative RCC patient cohort. We observed differentially regulated Gal3ST1 expression in all RCC types, being significantly more associated with clear cell RCC than to chromophobe RCC (p = 0.001). Surprisingly, in contrast to published observations from in vitro models, we could not confirm an association between Gal3ST1 expression and a malignant clinical behaviour of the RCC. In our cohort, Gal3ST1 did not significantly influence progression-free survival (Hazard Ratio (HR): 1.7 95% CI (0.6-4.9), p = 0.327). Particularly after adjusting for histology, T-stage, N-status and M-status at baseline, we observed no independent prognostic effect (HR = 1.0 95% CI (0.3-3.3), p = 0.96). The analysis of Gal3ST1 mRNA expression in a TCGA dataset supported the results of our cohort. Thus, Gal3ST1 might help to differentiate between chromophobe RCC and other frequent RCC entities but-despite previously published data from cell culture models-does not qualify as a prognostic marker for RCC. Further investigation of regulatory mechanisms of sulfatide metabolism in human RCC microenvironment is necessary to understand the role of this quantitatively prominent glycosphingolipid in RCC progression.
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http://dx.doi.org/10.1038/s41598-021-90381-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149814PMC
May 2021

Analyzing Longitudinal wb-MRI Data and Clinical Course in a Cohort of Former Smoldering Multiple Myeloma Patients: Connections between MRI Findings and Clinical Progression Patterns.

Cancers (Basel) 2021 Feb 25;13(5). Epub 2021 Feb 25.

Diagnostic and Interventional Radiology, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.

The purpose of this study was to analyze size and growth dynamics of focal lesions (FL) as well as to quantify diffuse infiltration (DI) in untreated smoldering multiple myeloma (SMM) patients and correlate those MRI features with timepoint and cause of progression. We investigated 199 whole-body magnetic resonance imaging (wb-MRI) scans originating from longitudinal imaging of 60 SMM patients and 39 computed tomography (CT) scans for corresponding osteolytic lesions (OL) in 17 patients. All FLs >5 mm were manually segmented to quantify volume and growth dynamics, and DI was scored, rating four compartments separately in T1- and fat-saturated T2-weighted images. The majority of patients with at least two FLs showed substantial spatial heterogeneity in growth dynamics. The volume of the largest FL ( = 0.001, c-index 0.72), the speed of growth of the fastest growing FL ( = 0.003, c-index 0.75), the DI score (DIS, = 0.014, c-index 0.67), and its dynamic over time (DIS dynamic, < 0.001, c-index 0.67) all significantly correlated with the time to progression. Size and growth dynamics of FLs correlated significantly with presence/appearance of OL in CT within 2 years after the respective MRI assessment ( = 0.016 and = 0.022). DIS correlated with decrease of hemoglobin ( < 0.001). In conclusion, size and growth dynamics of FLs correlate with prognosis and local bone destruction. Connections between MRI findings and progression patterns (fast growing FL-OL; DIS-hemoglobin decrease) might enable more precise diagnostic and therapeutic approaches for SMM patients in the future.
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http://dx.doi.org/10.3390/cancers13050961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956649PMC
February 2021

Comparison of single-scanner single-protocol quantitative ADC measurements to ADC ratios to detect clinically significant prostate cancer.

Eur J Radiol 2021 Mar 13;136:109538. Epub 2021 Jan 13.

Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Germany. Electronic address:

Background: Mean ADC has high predictive value for the presence of clinically significant prostate cancer (sPC). Measurement variability is introduced by different scanners, protocols, intra-and inter-patient variation. Internal calibration by ADC ratios can address such fluctuations however can potentially lower the biological value of quantitative ADC determination by being sensitive to deviations in reference tissue signal.

Purpose: To better understand the predictive value of quantitative ADC measurements in comparison to internal reference ratios when measured in a single scanner, single protocol setup.

Materials And Methods: 284 consecutive patients who underwent 3 T MRI on a single scanner followed by MRI-transrectal ultrasound fusion biopsy were included. A board-certified radiologist retrospectively reviewed all MRIs blinded to clinical information and placed regions of interest (ROI) on all focal lesions and the following reference regions: normal-appearing peripheral zone (PZNL) and transition zone (TZNL), the urinary bladder (BLA), and right and left internal obturator muscle (RIOM, LIOM). ROI-based mean ADC and ADC ratios to the reference regions were compared regarding their ability to predict the aggressiveness of prostate cancer. Spearman's rank correlation coefficient was used to estimate the correlation between ADC parameters, Gleason score (GS) and ADC ratios. The primary endpoint was presence of sPC, defined as a GS ≥ 3 + 4. Univariable and multivariable logistic regression models were constructed to predict sPC. Receiver operating characteristics curves (ROC) were used for visualization; DeLong test was used to evaluate the differences of the area under the curve (AUC). Bias-corrected AUC values and corresponding 95 %-CI were calculated using bootstrapping with 100 bootstrap samples.

Results: After exclusion of patients who received prior treatment, 259 patients were included in the final cohort of which 220 harbored 351 MR lesions. Mean ADC and ADC ratios demonstrated a negative correlation with the GS. Mean ADC had the strongest correlation with ρ of -0.34, followed by ADCratioPZNL (ρ=-0.32). All ADC parameters except ADCratioLIOM (p = 0.07) were associated with sPC p<0.05). Mean ADC and ADCratioPZNL had the highest ROC AUC of all parameters (0.68). Multivariable models with mean ADC improve predictive performance.

Conclusions: A highly standardized single-scanner mean ADC measurement could not be improved upon using any of the single ADC ratio parameters or combinations of these parameters in predicting the aggressiveness of prostate cancer.
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http://dx.doi.org/10.1016/j.ejrad.2021.109538DOI Listing
March 2021

Lenalidomide versus bortezomib maintenance after frontline autologous stem cell transplantation for multiple myeloma.

Blood Cancer J 2021 01 7;11(1). Epub 2021 Jan 7.

Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany.

Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1-21 of 28 day cycles) followed by 10-15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with
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http://dx.doi.org/10.1038/s41408-020-00390-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791127PMC
January 2021

HER3-Receptor-Mediated STAT3 Activation Plays a Central Role in Adaptive Resistance toward Vemurafenib in Melanoma.

Cancers (Basel) 2020 Dec 14;12(12). Epub 2020 Dec 14.

Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Melanoma is an aggressive form of skin cancer that is often characterized by activating mutations in the Mitogen-Activated Protein (MAP) kinase pathway, causing hyperproliferation of the cancer cells. Thus, inhibitors targeting this pathway were developed. These inhibitors are initially very effective, but the occurrence of resistance eventually leads to a failure of the therapy and is the major obstacle for clinical success. Therefore, investigating the mechanisms causing resistance and discovering ways to overcome them is essential for the success of therapy. Here, we observed that treatment of melanoma cells with the B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) inhibitor vemurafenib caused an increased cell surface expression and activation of human epidermal growth factor receptor 3 (HER3) by shed ligands. HER3 promoted the activation of signal transducer and activator of transcription 3 (STAT3) resulting in upregulation of the STAT3 target gene SRY-Box Transcription Factor 2 () and survival of the cancer cells. Pharmacological blocking of HER led to a diminished STAT3 activation and increased sensitivity toward vemurafenib. Moreover, HER blocking sensitized vemurafenib-resistant cells to drug treatment. We conclude that the inhibition of the STAT3 upstream regulator HER might help to overcome melanoma therapy resistance toward targeted therapies.
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http://dx.doi.org/10.3390/cancers12123761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764938PMC
December 2020

Comparison of Prostate MRI Lesion Segmentation Agreement Between Multiple Radiologists and a Fully Automatic Deep Learning System.

Rofo 2021 May 19;193(5):559-573. Epub 2020 Nov 19.

Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Purpose:  A recently developed deep learning model (U-Net) approximated the clinical performance of radiologists in the prediction of clinically significant prostate cancer (sPC) from prostate MRI. Here, we compare the agreement between lesion segmentations by U-Net with manual lesion segmentations performed by different radiologists.

Materials And Methods:  165 patients with suspicion for sPC underwent targeted and systematic fusion biopsy following 3 Tesla multiparametric MRI (mpMRI). Five sets of segmentations were generated retrospectively: segmentations of clinical lesions, independent segmentations by three radiologists, and fully automated bi-parametric U-Net segmentations. Per-lesion agreement was calculated for each rater by averaging Dice coefficients with all overlapping lesions from other raters. Agreement was compared using descriptive statistics and linear mixed models.

Results:  The mean Dice coefficient for manual segmentations showed only moderate agreement at 0.48-0.52, reflecting the difficult visual task of determining the outline of otherwise jointly detected lesions. U-net segmentations were significantly smaller than manual segmentations (p < 0.0001) and exhibited a lower mean Dice coefficient of 0.22, which was significantly lower compared to manual segmentations (all p < 0.0001). These differences remained after correction for lesion size and were unaffected between sPC and non-sPC lesions and between peripheral and transition zone lesions.

Conclusion:  Knowledge of the order of agreement of manual segmentations of different radiologists is important to set the expectation value for artificial intelligence (AI) systems in the task of prostate MRI lesion segmentation. Perfect agreement (Dice coefficient of one) should not be expected for AI. Lower Dice coefficients of U-Net compared to manual segmentations are only partially explained by smaller segmentation sizes and may result from a focus on the lesion core and a small relative lesion center shift. Although it is primarily important that AI detects sPC correctly, the Dice coefficient for overlapping lesions from multiple raters can be used as a secondary measure for segmentation quality in future studies.

Key Points:   · Intermediate human Dice coefficients reflect the difficulty of outlining jointly detected lesions.. · Lower Dice coefficients of deep learning motivate further research to approximate human perception.. · Comparable predictive performance of deep learning appears independent of Dice agreement.. · Dice agreement independent of significant cancer presence indicates indistinguishability of some benign imaging findings.. · Improving DWI to T2 registration may improve the observed U-Net Dice coefficients..

Citation Format: · Schelb P, Tavakoli AA, Tubtawee T et al. Comparison of Prostate MRI Lesion Segmentation Agreement Between Multiple Radiologists and a Fully Automatic Deep Learning System. Fortschr Röntgenstr 2021; 193: 559 - 573.
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http://dx.doi.org/10.1055/a-1290-8070DOI Listing
May 2021

Spatial Distribution of Focal Lesions in Whole-Body MRI and Influence of MRI Protocol on Staging in Patients with Smoldering Multiple Myeloma According to the New SLiM-CRAB-Criteria.

Cancers (Basel) 2020 Sep 7;12(9). Epub 2020 Sep 7.

Institute of Diagnostic and Interventional Radiology, Paediatric Radiology and Neuroradiology, University Medical Centre Rostock, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany.

The purpose of this study was to assess how different MRI protocols (spinal vs. spinal plus pelvic vs. whole-body (wb)-MRI) affect staging in patients with smoldering multiple myeloma (SMM), according to the SLiM-CRAB-criterion '>1 focal lesion (FL) in MRI'. In this retrospective study, a baseline cohort of 147 SMM patients with wb-MRI at initial diagnosis was investigated, including prognostic data regarding development of CRAB-criteria. Fifty-two patients formed a follow-up cohort with a median of three wb-MRIs. The locations of all FLs were determined and it was calculated how staging decisions regarding the criterion '>1 FL in MRI' would have been made if only a limited anatomic area (spine vs. spine plus pelvis) would have been covered by the MRI protocol. Furthermore, subgroups of patients selected by different cutoff-protocol-combinations were compared regarding their prognosis for development of CRAB-criteria. With an MRI protocol limited to spine/spine plus pelvis, only 28%/64% of patients who actually had >1 FL in wb-MRI would have been rated correctly as having '>1 FL in MRI'. Fifty-four percent/36% of patients with exactly 1 FL in spine/spine plus pelvis revealed >1 FL when the entire wb-MRI was analyzed. During follow-up, four more patients developed >1 FL in wb-MRI; both limited MRI protocols would have detected only one of these four patients as having >1 FL at the correct timepoint. Having >1 FL in spine/in spine plus pelvis/in the whole body was associated with a 43%/57%/49% probability of developing CRAB-criteria within 2 years. Patients with >3 FL in spine plus pelvis and patients with >4 FL in the whole body had an 80% probability to develop CRAB-criteria within 2 years. MRI protocols limited to the spine or to spine plus pelvis lead to substantial underdiagnoses of patients who actually have >1 FL in wb-MRI at baseline and during follow-up, which influences staging and treatment decisions according to the current SLiM-CRAB criteria. However, given the spatial distribution of FLs and the analysis on clinical course of patients indicates that the cutoff for the number of FLs should be adopted according to the MRI protocol when using MRI for staging in SMM.
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http://dx.doi.org/10.3390/cancers12092537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563298PMC
September 2020

IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.

Cell 2020 09 19;182(5):1252-1270.e34. Epub 2020 Aug 19.

Department of Cell Toxicology, Helmholtz Centre for Environmental Research-UFZ, 04318 Leipzig, Germany.

Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.
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http://dx.doi.org/10.1016/j.cell.2020.07.038DOI Listing
September 2020

Salvage autologous transplant and lenalidomide maintenance vs. lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE.

Leukemia 2021 04 21;35(4):1134-1144. Epub 2020 Jul 21.

Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The role of salvage high-dose chemotherapy and autologous stem cell transplantation (sHDCT/ASCT) for relapsed and/or refractory multiple myeloma (RRMM) in the era of continuous novel agent treatment has not been defined. This randomized, open-label, phase III, multicenter trial randomized patients with 1st-3rd relapse of multiple myeloma (MM) to a transplant arm (n = 139) consisting of 3 Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, and 22; 4-week cycles) reinduction cycles, sHDCT (melphalan 200 mg/m), ASCT, and lenalidomide maintenance (10 mg/day) or to a control arm (n = 138) of continuous Rd. Median PFS was 20.7 months in the transplant and 18.8 months in the control arm (HR 0.87; 95% CI 0.65-1.16; p = 0.34). Median OS was not reached in the transplant and 62.7 months in the control arm (HR 0.81; 95% CI 0.52-1.28; p = 0.37). Forty-one patients (29%) did not receive the assigned sHDCT/ASCT mainly due to early disease progression, adverse events, and withdrawal of consent. Multivariate landmark analyses from the time of sHDCT showed superior PFS and OS (p = 0.0087/0.0057) in patients who received sHDCT/ASCT. Incorporation of sHDCT/ASCT into relapse treatment with Rd was feasible in 71% of patients and did not significantly prolong PFS and OS on ITT analysis while patients who received sHDCT/ASCT may have benefitted.
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http://dx.doi.org/10.1038/s41375-020-0948-0DOI Listing
April 2021

A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in -Driven Pediatric Low-Grade Glioma Cells.

Mol Cancer Ther 2020 08 25;19(8):1736-1750. Epub 2020 May 25.

Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.

Pilocytic astrocytomas as well as other pediatric low-grade gliomas (pLGG) exhibit genetic events leading to aberrant activation of the MAPK pathway. The most common alterations are fusions and BRAF and mutations. Novel drugs targeting the MAPK pathway (MAPKi) are prime candidates for the treatment of these single-pathway diseases. We aimed to develop an assay suitable for preclinical testing of MAPKi in pLGGs with the goal to identify novel MAPK pathway-suppressing synergistic drug combinations. A reporter plasmid (pDIPZ) with a MAPK-responsive ELK-1-binding element driving the expression of destabilized firefly luciferase was generated and packaged using a lentiviral vector system. Pediatric glioma cell lines with a BRAF fusion (DKFZ-BT66) and a BRAF mutation (BT-40) background, respectively, were stably transfected. Modulation of the MAPK pathway activity by MAPKi was measured using the luciferase reporter and validated by detection of phosphorylated protein levels. A screening of a MAPKi library was performed, and synergy of selected combinations was calculated. Screening of a MAPKi library revealed MEK inhibitors as the class inhibiting the pathway with the lowest ICs, followed by ERK and next-generation RAF inhibitors. Combination treatments with different MAPKi classes showed synergistic effects in BRAF fusion as well as BRAF mutation backgrounds. Here, we report a novel reporter assay for medium- to high-throughput preclinical drug testing in pLGG cell lines. The assay confirmed MEK, ERK, and next-generation RAF inhibitors as potential treatment approaches for and BRAF-mutated pLGGs. In addition, the assay revealed that combination treatments synergistically suppressed MAPK pathway activity.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-1021DOI Listing
August 2020

Response Improvement Rather than Response Status after First Autologous Stem Cell Transplantation Is a Significant Prognostic Factor for Survival Benefit from Tandem Compared with Single Transplantation in Multiple Myeloma Patients.

Biol Blood Marrow Transplant 2020 07 16;26(7):1280-1287. Epub 2020 Mar 16.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) have provided effective treatment for patients with newly diagnosed multiple myeloma for more than 3 decades; however, which patients will benefit from tandem ASCT compared with single ASCT remains unclear. Here we retrospectively analyzed 978 trial and nontrial patients who underwent single or tandem ASCT in Heidelberg or other German-Speaking Myeloma Multicenter Group centers. Our results show that response improvement after first ASCT is a significant prognostic factor for progression-free survival benefit from tandem versus single ASCT (multivariable analysis, P = .002; hazard ratio, .64; 95% confidence interval, .48 to .85; P for interaction = .02). The depth of response after first ASCT and the cytogenetic profile did not have a significant prognostic effect on survival benefit from tandem ASCT. Our results suggest that it is not the response depth, but rather the response improvement after first ASCT is of prognostic significance regarding the benefit of tandem ASCT versus single ASCT.
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http://dx.doi.org/10.1016/j.bbmt.2020.03.006DOI Listing
July 2020

Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL.

Genome Med 2020 03 18;12(1):29. Epub 2020 Mar 18.

The German Cancer Consortium (DKTK), Heidelberg, Germany.

Background: In cancer, normal epigenetic patterns are disturbed and contribute to gene expression changes, disease onset, and progression. The cancer epigenome is composed of the epigenetic patterns present in the tumor-initiating cell at the time of transformation, and the tumor-specific epigenetic alterations that are acquired during tumor initiation and progression. The precise dissection of these two components of the tumor epigenome will facilitate a better understanding of the biological mechanisms underlying malignant transformation. Chronic lymphocytic leukemia (CLL) originates from differentiating B cells, which undergo extensive epigenetic programming. This poses the challenge to precisely determine the epigenomic ground state of the cell-of-origin in order to identify CLL-specific epigenetic aberrations.

Methods: We developed a linear regression model, methylome-based cell-of-origin modeling (Methyl-COOM), to map the cell-of-origin for individual CLL patients based on the continuum of epigenomic changes during normal B cell differentiation.

Results: Methyl-COOM accurately maps the cell-of-origin of CLL and identifies CLL-specific aberrant DNA methylation events that are not confounded by physiologic epigenetic B cell programming. Furthermore, Methyl-COOM unmasks abnormal action of transcription factors, altered super-enhancer activities, and aberrant transcript expression in CLL. Among the aberrantly regulated transcripts were many genes that have previously been implicated in T cell biology. Flow cytometry analysis of these markers confirmed their aberrant expression on malignant B cells at the protein level.

Conclusions: Methyl-COOM analysis of CLL identified disease-specific aberrant gene regulation. The aberrantly expressed genes identified in this study might play a role in immune-evasion in CLL and might serve as novel targets for immunotherapy approaches. In summary, we propose a novel framework for in silico modeling of reference DNA methylomes and for the identification of cancer-specific epigenetic changes, a concept that can be broadly applied to other human malignancies.
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http://dx.doi.org/10.1186/s13073-020-00724-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081711PMC
March 2020

T-type calcium channel inhibition restores sensitivity to MAPK inhibitors in de-differentiated and adaptive melanoma cells.

Br J Cancer 2020 03 17;122(7):1023-1036. Epub 2020 Feb 17.

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, D-68135, Mannheim, Germany.

Background: Drug resistance remains as one of the major challenges in melanoma therapy. It is well known that tumour cells undergo phenotypic switching during melanoma progression, increasing melanoma plasticity and resistance to mitogen-activated protein kinase inhibitors (MAPKi).

Methods: We investigated the melanoma phenotype switching using a partial reprogramming model to de-differentiate murine melanoma cells and target melanoma therapy adaptation against MAPKi.

Results: Here, we show that partially reprogrammed cells are a less proliferative and more de-differentiated cell population, expressing a gene signature for stemness and suppressing melanocyte-specific markers. To investigate adaptation to MAPKi, cells were exposed to B-Raf Proto-Oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors. De-differentiated cells became less sensitive to MAPKi, showed increased cell viability and decreased apoptosis. Furthermore, T-type calcium channels expression increased in adaptive murine cells and in human adaptive melanoma cells. Treatment with the calcium channel blocker mibefradil induced cell death, differentiation and susceptibility to MAPKi in vitro and in vivo.

Conclusion: In summary, we show that partial reprogramming of melanoma cells induces de-differentiation and adaptation to MAPKi. Moreover, we postulated a calcium channel blocker such as mibefradil, as a potential candidate to restore sensitivity to MAPKi in adaptive melanoma cells.
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http://dx.doi.org/10.1038/s41416-020-0751-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109069PMC
March 2020

Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial.

Leukemia 2020 07 7;34(7):1853-1865. Epub 2020 Feb 7.

Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany.

The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n = 502): arms A1:PAd + LEN-2Y (n = 125), B1:PAd + LEN-CR (n = 126), A2:VCD + LEN-2Y (n = 126), B2:VCD + LEN-CR (n = 125). In the LEN-CR group (B1 + B2), n = 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p = 0.60, primary endpoint) nor overall survival (OS) (p = 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p = 0.03) but not PFS (HR = 1.15, p = 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p = 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p = 0.01). LEN MT should be applied beyond CR for at least 2 years.
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http://dx.doi.org/10.1038/s41375-020-0724-1DOI Listing
July 2020

Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary.

Int J Cancer 2020 06 11;146(11):3053-3064. Epub 2020 Mar 11.

Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.

Cancer of unknown primary (CUP) denotes a malignancy with histologically confirmed metastatic spread while the primary tumor remains elusive. Here, we address prognostic and therapeutic implications of mutations and copy number variations (CNVs) detected in tumor tissue in the context of a comprehensive clinical risk assessment. Targeted panel sequencing was performed in 252 CUP patients. 71.8% of patients had unfavorable CUP according to ESMO guidelines. 74.7% were adeno- and 13.7% squamous cell carcinomas. DNA was extracted from microdissected formalin-fixed, paraffin-embedded tissues. For library preparation, mostly multiplex PCR-based Ion Torrent AmpliSeq™ technology with Oncomine comprehensive assays was used. Most frequent genetic alterations were mutations/deletions of TP53 (49.6%), CDKN2A (19.0%) and NOTCH1 (14.1%) as well as oncogenic activation of KRAS (23.4%), FGFR4 (14.9%) and PIK3CA (10.7%). KRAS activation was predominantly found in adenocarcinomas (p = 0.01), PIK3CA activation in squamous cell carcinomas (p = 0.03). Male sex, high ECOG score, unfavorable CUP, higher number of involved organs and RAS activation predicted decreased event-free and overall survival in multivariate analysis. Deletions of CDKN2A were prognostically adverse regarding overall survival. TP53 mutations did not significantly influence prognosis in the overall cohort, but worsened prognosis in otherwise favorable CUP subtypes. Although not standard in CUP, for 17/198 (8.6%) patients molecularly targeted treatment was recommended and 10 patients (5.1%) were treated accordingly. In conclusion, besides the identification of drug targets, panel sequencing in CUP is prognostically relevant, with RAS activation and CDKN2A deletion emerging as novel independent risk factors in a comprehensive assessment with clinicopathological data.
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http://dx.doi.org/10.1002/ijc.32882DOI Listing
June 2020

Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia.

Clin Epigenetics 2019 12 10;11(1):188. Epub 2019 Dec 10.

KiTZ Clinical Trial Unit, Hopp Children's Cancer Center Heidelberg (KiTZ), German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Background: Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3-18 years) with relapsed or therapy-refractory malignancies.

Results: A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m/day with weekly dose escalations of 50 mg/m until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m/day was determined (maximum, 580 mg/m/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher C. Five patients achieved prolonged disease control (> 12 months) and showed a higher C (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome.

Conclusion: An SDR of 130 mg/m/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker.

Trial Registration: ClinicalTrials.gov, NCT01422499. Registered 24 August 2011.
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http://dx.doi.org/10.1186/s13148-019-0775-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902473PMC
December 2019

cMyc and ERK activity are associated with resistance to ALK inhibitory treatment in glioblastoma.

J Neurooncol 2020 Jan 28;146(1):9-23. Epub 2019 Nov 28.

Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Anaplastic lymphoma kinase (ALK) is expressed in ~ 60% of glioblastomas and conveys tumorigenic functions. Therefore, ALK inhibitory strategies with alectinib are conceivable for patients with glioblastoma. The aims of this preclinical study were to investigate efficacy as well as to understand and potentially overcome primary and acquired resistance mechanisms of alectinib in glioblastoma.

Methods: Efficacy of alectinib was analyzed dependent on ALK expression in different glioblastoma initiating cells and after lentiviral knockdown of ALK. Alectinib resistant cells were generated by continuous treatment with increasing alectinib doses over 3 months. M-RNA, phospho-protein and protein regulation were analyzed to decipher relevant pathways associated to treatment or resistance and specifically inhibited to evaluate rational salvage therapies.

Results: Alectinib reduced clonogenicity and proliferation and induced apoptosis in ALK expressing glioblastoma initiating cells, whereas cells without ALK expression or after ALK depletion via knockdown showed primary resistance against alectinib. High expression of cMyc and activation of the ERK1/2 pathway conferred resistance against alectinib in ALK expressing glioblastoma cells. Pharmacological inhibition of these pathways by cMyc inhibitor or MEK inhibitor, trametinib, overcame alectinib resistance and re-sensitized resistant cells to continued alectinib treatment. The combination of alectinib with radiotherapy demonstrated synergistic effects in inhibition of clonogenicity in non-resistant and alectinib resistant glioblastoma cells.

Conclusion: The data offer rationales for alectinib treatment in ALK expressing glioblastoma and for the use of ALK expression status as potential biomarker for alectinib treatment. In addition, the results propose MEK inhibition or radiotherapy as reasonable salvage treatments after acquired alectinib resistance.
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http://dx.doi.org/10.1007/s11060-019-03348-zDOI Listing
January 2020

Asymmetric distribution of TLR3 leads to a polarized immune response in human intestinal epithelial cells.

Nat Microbiol 2020 01 4;5(1):181-191. Epub 2019 Nov 4.

Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany.

Intestinal epithelial cells (IECs) act as a physical barrier separating the commensal-containing intestinal tract from the sterile interior. These cells have found a complex balance allowing them to be prepared for pathogen attacks while still tolerating the presence of bacterial or viral stimuli present in the lumen of the gut. Using primary human IECs, we probed the mechanisms that allow for such a tolerance. We discovered that viral infections emanating from the basolateral side of IECs elicit a stronger intrinsic immune response in comparison to lumenal apical infections. We determined that this asymmetric immune response is driven by the clathrin-sorting adaptor AP-1B, which mediates the polarized sorting of Toll-like receptor 3 (TLR3) towards the basolateral side of IECs. Mice and human IECs lacking AP-1B showed an exacerbated immune response following apical stimulation. Together, these results suggest a model where the cellular polarity program plays an integral role in the ability of IECs to partially tolerate apical commensals while remaining fully responsive to invasive basolateral pathogens.
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http://dx.doi.org/10.1038/s41564-019-0594-3DOI Listing
January 2020
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