Publications by authors named "Sebastian Bauer"

302 Publications

Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study.

J Clin Oncol 2021 Aug 3:JCO2100217. Epub 2021 Aug 3.

Department of Medical Oncology, Sarcoma Center, West German Cancer Center, DKTK-Partner-Site, University of Duisburg-Essen, Essen, Germany.

Purpose: Primary or secondary mutations in or platelet-derived growth factor receptor alpha () underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study (NCT02508532), avapritinib showed clinical activity against PDGFRA D842V-mutant and later-line KIT-mutant GIST. VOYAGER (NCT03465722), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST.

Patients And Methods: VOYAGER randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression.

Results: Four hundred seventy-six patients were randomly assigned (avapritinib, n = 240; regorafenib, n = 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 5.6 months; = .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade ≥ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%).

Conclusion: Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST.
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http://dx.doi.org/10.1200/JCO.21.00217DOI Listing
August 2021

Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor.

Front Oncol 2021 12;11:672500. Epub 2021 Jul 12.

Department of Medicine, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR, United States.

The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resistance is further complicated by extensive clonal heterogeneity, even within single patients. To combat these limitations, next-generation TKIs were developed and clinically tested, leading to 2 new USA FDA drug approvals in 2020. Ripretinib, a broad-spectrum KIT/PDGFRA inhibitor, was recently approved for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Avapritinib, a type I kinase inhibitor that targets active conformation, was approved for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. In this review, we will discuss how resistance mutations have driven the need for newer treatment options for GIST and compare the original GIST TKIs with the next-generation KIT/PDGFRA kinase inhibitors, ripretinib and avapritinib, with a focus on their mechanisms of action.
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http://dx.doi.org/10.3389/fonc.2021.672500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313277PMC
July 2021

Correction to: Therapeutic Options for Patients with Refractory Status Epilepticus in Palliative Settings or with a Limitation of Life‑Sustaining Therapies: A Systematic Review.

CNS Drugs 2021 Jul 27. Epub 2021 Jul 27.

Epilepsy Center Frankfurt Rhine‑Main, Center of Neurology and Neurosurgery, Goethe-University Frankfurt, Schleusenweg 2‑16, 60528, Frankfurt am Main, Germany.

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http://dx.doi.org/10.1007/s40263-021-00845-6DOI Listing
July 2021

Clinical Benefit of Ripretinib Dose Escalation After Disease Progression in Advanced Gastrointestinal Stromal Tumor: An Analysis of the INVICTUS Study.

Oncologist 2021 Jul 27. Epub 2021 Jul 27.

Centre Léon Bérard & Université Claude Bernard, Lyon, France.

Background: Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumor (GIST) as ≥fourth-line therapy. In INVICTUS, ripretinib intra-patient dose escalation (IPDE) to 150 mg twice daily (BID) was allowed after progressive disease (PD) on 150 mg QD by blinded independent central review using modified RECIST 1.1. We report the efficacy and safety of ripretinib IPDE to 150 mg BID after PD among patients randomized to ripretinib 150 mg QD in the INVICTUS study.

Materials And Methods: Tumor imaging was performed every 28-day cycle for the first 4 cycles in the ripretinib 150 mg QD period and then every other cycle, including the 150 mg BID period. Among the ripretinib IPDE patients, progression-free survival (PFS)1 was the time from randomization until PD; PFS2 was the time from the first dose of ripretinib 150 mg BID to PD or death.

Results: Among 43 ripretinib IPDE patients, median PFS1 was 4.6 months (95% confidence interval [CI], 2.7-6.4) and median PFS2 was 3.7 months (95% CI, 3.1-5.3). Median overall survival was 18.4 months (95% CI, 14.5-not estimable). Ripretinib 150 mg BID (median duration of treatment 3.7 months) was well tolerated with new or worsening Grade 3-4 TEAEs of anemia in 6 (14%) and abdominal pain in 3 (7%) patients. Ripretinib 150 mg BID was discontinued due to TEAEs in 7 (16%) patients.

Conclusion: Ripretinib 150 mg BID after PD on 150 mg QD may provide additional clinically meaningful benefit with an acceptable safety profile in patients with ≥fourth-line GIST. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT03353753 (INVICTUS) IMPLICATIONS FOR PRACTICE: Of the 85 patients with advanced gastrointestinal stromal tumor having received ≥3 prior anticancer therapies randomized to ripretinib 150 mg once daily (QD) in the phase 3 INVICTUS study, 43 underwent ripretinib intra-patient dose escalation (IPDE) to 150 mg twice daily (BID) after progressive disease (PD). Median progression-free survival was 4.6 months before and 3.7 months after ripretinib IPDE. The safety profile of ripretinib 150 mg BID was acceptable. These findings indicate ripretinib IPDE to 150 mg BID may provide additional clinical benefit in patients with PD on ripretinib 150 mg QD, for whom limited treatment options exist.
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http://dx.doi.org/10.1002/onco.13917DOI Listing
July 2021

The effect of adjuvant therapies on long-term outcome for primary resected synovial sarcoma in a series of mainly children and adolescents.

J Cancer Res Clin Oncol 2021 Jul 17. Epub 2021 Jul 17.

Hospital for Children and Adolescents, Goethe-University Frankfurt (Main), Frankfurt, Germany.

Background: The benefit of adjuvant therapy in synovial sarcoma (SS) treatment is under debate. Long-term follow-up data are missing.

Methods: SS patients treated in the consecutive trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P, and the SoTiSaR-registry till 2013 were analyzed.

Results: Median age of 185 patients was 13.9 years (0.1-56)-with median follow-up of 7.4 years for 163 survivors. Most tumors (76%) were located in extremities. Size was < 3 cm in 58 (31%), 3-5 cm in 59 (32%), 5-10 cm in 42 (23%), and > 10 cm in 13 (7%) (13 missing). In 84 (45%) tumors, first excision was complete (R0 corresponding to IRS-I-group) and in 101 (55%) marginal (R1 corresponding to IRS-II-group). In a subsequent surgical intervention during chemotherapy, R0-status was accomplished in 23 additional IRS-II-group patients with secondary surgery. Radiotherapy was administered to 135 (73%), thereof 62 with R0-status and 67 R1-status (6 missing information). Adjuvant chemotherapy was administered to all but six patients. 5-year event-free (EFS) and overall survival (OS) was 82.9% ± 5.7 (95%CI) and 92.5% ± 3.9. Local and metastatic relapse-free survival was 91.3% ± 4.3 and 92.3% ± 4.1 at 5 years, respectively. In the multivariate analysis, tumor size and no chemotherapy were independently associated with EFS. Size and site were associated with OS. In a detailed analysis of local and metastatic events, tumor size was associated with an independent risk for developing metastases. No independent factor for suffering local recurrence could be identified.

Discussion: Omission of chemotherapy in a non-stratified way seems not justified. Size governs survival due to high linear association with risk of suffering metastatic recurrence in a granular classification.
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http://dx.doi.org/10.1007/s00432-021-03614-6DOI Listing
July 2021

Evaluation of the Predictive Potential of 18F-FDG PET and DWI Data Sets for Relevant Prognostic Parameters of Primary Soft-Tissue Sarcomas.

Cancers (Basel) 2021 Jun 1;13(11). Epub 2021 Jun 1.

Department of Diagnostic and Interventional Radiology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.

Background: To evaluate the potential of simultaneously acquired 18F-FDG PET- and MR-derived quantitative imaging data sets of primary soft-tissue sarcomas for the prediction of neoadjuvant treatment response, the metastatic status and tumor grade.

Methods: A total of 52 patients with a high-risk soft-tissue sarcoma underwent a 18F-FDG PET/MR examination within one week before the start of neoadjuvant treatment. For each patient, the maximum tumor size, metabolic activity (SUVs), and diffusion-restriction (ADC values) of the tumor manifestations were determined. A Mann-Whitney-U test was used, and ROC analysis was performed to evaluate the potential to predict histopathological treatment response, the metastatic status or tumor grade. The results from the histopathological analysis served as reference standard.

Results: Soft-tissue sarcomas with a histopathological treatment response revealed a significantly higher metabolic activity than tumors in the non-responder group. In addition, grade 3 tumors showed a significant higher 18F-FDG uptake than grade 2 tumors. Furthermore, no significant correlation between the different outcome variables and tumor size or calculated ADC-values could be identified.

Conclusion: Measurements of the metabolic activity of primary and untreated soft-tissue sarcomas could non-invasively deliver relevant information that may be used for treatment planning and risk-stratification of high-risk sarcoma patients in a pretherapeutic setting.
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http://dx.doi.org/10.3390/cancers13112753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199532PMC
June 2021

Transcutaneous auricular vagus nerve stimulation influences gastric motility: A randomized, double-blind trial in healthy individuals.

Brain Stimul 2021 Jun 26. Epub 2021 Jun 26.

Epilepsy Center Hessen and Department of Neurology, Philipps-University Marburg, Marburg, Germany; Center for Mind, Brain and Behavior, CMBB, Philipps-University Marburg, Marburg, Germany; Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Germany. Electronic address:

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated regarding its therapeutic properties in several several conditions such as epilepsy, migraine and major depressive disorder and was shown to access similar neural pathways as invasive vagus nerve stimulation. While the vagus nerve's role in gut motility is physiologically established, the effect of taVNS has scarcely been investigated in humans and yielded conflicting results. Real-time gastric magnetic resonance imaging (rtMRI) is an established reproducible method to investigate gastric motility non-invasively.

Objective: To investigate the influence of taVNS on gastric motility of healthy participants using rtMRI.

Methods: We conducted a randomized, double-blind study using high-frequency (HF) stimulation at 25Hz or low-frequency (LF) taVNS at 1Hz after ingestions of a standardized meal in 57 healthy participants. The gastric motility index (GMI) was determined by measuring the amplitude and velocity of the peristaltic waves using rtMRI.

Results: After HF taVNS, GMI was significantly higher than after LF stimulation (p = 0.005), which was mainly attributable to a higher amplitude of the peristaltic waves (p = 0.003).

Conclusion: We provide evidence that 4-h of taVNS influences gastric motility in healthy human participants for the first time using rtMRI. HF stimulation is associated with higher amplitudes of peristaltic waves in the gastric antrum compared to LF stimulation. Further studies are needed to investigate the effect of different frequencies of taVNS and its therapeutic properties in conditions with impaired gastric motility.
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http://dx.doi.org/10.1016/j.brs.2021.06.006DOI Listing
June 2021

Pharmacokinetic-pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies.

Br J Cancer 2021 Jun 17. Epub 2021 Jun 17.

Department of Medical Oncology, Centre Léon Bérard, Lyon, France.

Background: CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525).

Methods: Fifty-one patients received oral treatment with CGM097 10-400 mg 3qw (n = 31) or 300-700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics.

Results: No dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined.

Conclusions: Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors.

Translational Relevance: Haematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity.
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http://dx.doi.org/10.1038/s41416-021-01444-4DOI Listing
June 2021

Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers.

Cancer Discov 2021 Jun 10. Epub 2021 Jun 10.

Omics IT and Data Management Core Facility, German Cancer Research Center.

The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. Based on 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared to previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0126DOI Listing
June 2021

Predictive impact of the inflammation-based indices in uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion.

Radiol Oncol 2021 May 31. Epub 2021 May 31.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Background: The aim of the study was to evaluate pretreatment inflammatory markers as prognostic factors in patients with unresectable uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion.

Patients And Methods: 54 patients (44% male, median age: 61 years) were retrospectively assessed. A median of 3 (range: 1-11) treatment sessions were performed with melphalan (92%) or fotemustin (8%). Inflammatory indices were calculated as follows: neutrophils/nl to lymphocytes/nl ratio (NLR), systemic immune-inflammation index ([platelets/nl × neutrophils/nl]/[lymphocytes/nl]; SII), and platelets/nl to lymphocytes/nl ratio (PLR). The cut-off for dichotomization purposes was set at the median (inflammatory indices, hepatic tumor burden) or the upper level of normal. Kaplan Meier analysis was performed for median overall survival (OS) in months, and Cox proportional hazard model for uni(UVA) and multivariate (MVA) hazard ratio (HR, 95%CI) analyses were performed.

Results: Median OS of the study cohort was 7.7 (6.3-10.9) months. In UVA OS was prolonged for low C reactive protein (CRP) (13.5 . 5.2; p = 0.0005), low SII (10.8 . 5.6; p = 0.0005), low NLR (11.1 . 6.3; p = 0.0045), low aspartate aminotransferase (AST) (11.5 . 5.6; p = 0.015), alanine aminotransferases (ALT) (11.5 . 5.6; p = 0.01), and tumor burden ≦ 50% (8.2 . 4.8; p = 0.007). MVA confirmed low CRP (HR: 0.29, 0.11-0.7; p = 0.005), low SII (HR: 0.19, 0.11-0.7; p = 0.008), and low ALT (HR: 0.13, 0.02-0.63; p = 0.011) as independent predictors for prolonged OS. Patients with ≦ 1, 2, 3 elevated significant MVA-factors survived a median of 14.9, 7.7, and 3.9 months, respectively (p = 0.0001).

Conclusions: Pretreatment inflammatory markers (CRP, SII) and AST were independent prognostic survival markers in patients with uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. A combination of factors may help to identify patients potentially benefitting from treatment.
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http://dx.doi.org/10.2478/raon-2021-0027DOI Listing
May 2021

GNA14, GNA11, and GNAQ Mutations Are Frequent in Benign but Not Malignant Cutaneous Vascular Tumors.

Front Genet 2021 30;12:663272. Epub 2021 Apr 30.

Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Essen, Germany.

Cutaneous vascular tumors consist of a heterogeneous group of benign proliferations, including a range of hemangiomas and vascular malformations, as well as heterogeneous groups of both borderline and malignant neoplasms such as Kaposi's sarcoma and angiosarcomas. The genetics of these tumors have been assessed independently in smaller individual cohorts making comparisons difficult. In our study, we analyzed a representative cohort of benign vascular proliferations observed in a clinical routine setting as well as a selection of malignant vascular proliferations. Our cohort of 104 vascular proliferations including hemangiomas, malformations, angiosarcomas and Kaposi's sarcoma were screened by targeted next-generation sequencing for activating genetic mutations known or assumed to be potentially relevant in vascular proliferations. An association analysis was performed for mutation status and clinico-pathological parameters. Frequent activating hotspot mutations in genes, including Q205, and Q209 were identified in 16 of 64 benign vascular tumors (25%). gene mutations were particularly frequent (52%) in cherry (senile) hemangiomas (13 of 25). In angiosarcomas, activating mutations ( and ) were identified in three samples (16%). No activating or gene mutations were identified in Kaposi's sarcomas. Our study identifies Q205, and Q209 mutations as being the most common and mutually exclusive mutations in benign hemangiomas. These mutations were not identified in malignant vascular tumors, which could be of potential diagnostic value in distinguishing these entities.
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http://dx.doi.org/10.3389/fgene.2021.663272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141909PMC
April 2021

Wada test results contribute to the prediction of change in verbal learning and verbal memory function after temporal lobe epilepsy surgery.

Sci Rep 2021 May 26;11(1):10979. Epub 2021 May 26.

Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, University Hospital Frankfurt and Goethe University, Schleusenweg 2-16, 60528, Frankfurt am Main, Germany.

In recent years, the clinical usefulness of the Wada test (WT) has been debated among researchers in the field. Therefore, we aimed to assess its contribution to the prediction of change in verbal learning and verbal memory function after epilepsy surgery. Data from 56 patients with temporal lobe epilepsy who underwent WT and subsequent surgery were analyzed retrospectively. Additionally, a standard neuropsychological assessment evaluating attentional, learning and memory, visuospatial, language, and executive function was performed both before and 12 months after surgery. Hierarchical linear regression analyses were used to determine the incremental value of WT results over socio-demographic, clinical, and neuropsychological characteristics in predicting postsurgical change in patients' verbal learning and verbal memory function. The incorporation of WT results significantly improved the prediction models of postsurgical change in verbal learning (∆R = 0.233, p = .032) and verbal memory function (∆R = 0.386, p = .005). Presurgical performance and WT scores accounted for 41.8% of the variance in postsurgical change in verbal learning function, and 51.1% of the variance in postsurgical change in verbal memory function. Our findings confirm that WT results are of significant incremental value for the prediction of postsurgical change in verbal learning and verbal memory function. Thus, the WT contributes to determining the risks of epilepsy surgery and, therefore, remains an important part of the presurgical work-up of selected patients with clear clinical indications.
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http://dx.doi.org/10.1038/s41598-021-90376-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154896PMC
May 2021

Tropomyosin receptor kinases in sarcomas - of joy and despair.

Curr Opin Oncol 2021 Jul;33(4):336-344

Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen.

Purpose Of Review: The relatively recent discovery of neurotrophic tropomyosin receptor kinase (NTRK) gene arrangements as pan-tumor predictive biomarkers has led to impressive novel treatments for patients with TRK fusions. Although the number of patients who qualify for treatment is vanishingly small for cancer patients in general, a few histological subsets of sarcomas exhibit NTRK fusions more commonly leading to large expectations within the sarcoma community.

Recent Findings: Larotrectenib and entrectenib have recently been approved based on durable responses in TRK positive cancers with nonresectable or metastatic disease, including many sarcomas. Identification of resistance mutations to TRKi has led to the development of novel salvage therapies which may soon further expand the armamentarium of treatments. The greatest barrier and frustration to date is the actual identification of patients who harbor the fusion. The dimension of rarity in sarcomas remains difficult to comprehend for both patients and caregivers. Diagnosis of NTRK fusions is complex, particularly in the context of sarcomas and can involve immunohistochemistry as a screening tool but frequently requires fluorescence-in-situ hybridization or next-generation sequencing (NGS) to confirm the diagnosis.

Summary: The growing evidence on subtype-specific incidence of NTRK fusions will help to improve strategic prioritization or exclusion of subtypes to reduce the burden of negative testing. Next-generation inhibitors provide potential salvage treatment options for patients failing first-line therapy.
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http://dx.doi.org/10.1097/CCO.0000000000000752DOI Listing
July 2021

Data of a high temperature heat injection test.

Data Brief 2021 Jun 3;36:107035. Epub 2021 Apr 3.

Institute of Geosciences, Christian-Albrechts-University Kiel, Kiel, Germany.

This document compiles the data related to a high temperature heat injection test, which was carried out at an injection temperature of 74 °C in a shallow aquifer and is presented by Heldt et al. [1]. The data set contains transient measurements of temperatures at 18 wells in 10 depths and measurements of the experimental boundary conditions (injection temperature and flow rate) at a temporal resolution of up to 1 min. The spatial configuration and the technical details about where and how the data have been measured are provided. In addition, data of a multilevel multi well pumping test are shown. The presented data is useful to gain insights into the thermohydraulic processes induced by a high temperature heat injection test and can furthermore be used for the development and verification of numerical models of the presented experiment and similar applications like high temperature aquifer thermal energy storage.
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http://dx.doi.org/10.1016/j.dib.2021.107035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082194PMC
June 2021

Ga-68-FAPI as diagnostic tool in sarcoma: Data from the FAPI-PET prospective observational trial.

J Nucl Med 2021 Apr 30. Epub 2021 Apr 30.

Department of Medical Oncology, West-German Cancer Center, University of Duisburg-Essen, Germany.

Bone and soft tissue sarcomas express fibroblast activation protein (FAP) on tumor cells and associated fibroblast. Therefore, FAP is a promising therapeutic and diagnostic target. Novel radio-labelled FAP-Inhibitors (e.g. Ga-FAPI46) have shown high tumor uptake in positron emission tomography (PET) in sarcoma patients. Here we report endpoints of the FAPI-PET prospective observational trial. Forty-seven patients with bone or soft tissue sarcomas undergoing clinical Ga-FAPI-PET were eligible for enrollment into the FAPI-PET observational trial. Of these patients, 43 patients also underwent F-Fluordesoxyglucose PET (FDG). The primary study endpoint was the association of Ga-FAPI-PET uptake intensity and histopathological FAP-expression analyzed with Spearman's r correlation. Secondary endpoints were detection rate, positive predictive value (PPV), interreader reproducibility, and change in management. Datasets were interpreted by two blinded readers. Primary endpoint was met and the association between FAPI-PET uptake intensity and histopathological FAP-expression was significant (Spearman's r = 0.43; = 0.03). By histopathological validation PPV was 1.00 (95% CI, 0.87-1.00) on a per-patient and 0.97 (95% CI, 0.84-1.00) on a per-region basis. In cases with histopathologic validation, 27 of 28 (96%) confirmed patients and 32 of 34 (94%) confirmed regions were PET positive resulting in an SE of 0.96 (95%CI, 0.82-1.00) on a per-patient and 0.94 (95%CI, 0.80-0.99) on a per-region basis. The detection rate on a per-patient basis in FAPI- and FDG-PET was 76.6% and 81.4%, respectively. In 8 (18.6%) patients FAPI-PET resulted in an upstaging compared to FDG-PET. FAPI-PET readers showed substantial to almost perfect agreement for the defined regions (Fleiss kappa: primary κ = 0.78; local nodal κ = 0.54; distant nodal κ = 0.91; lung κ = 0.86; bone κ = 0.69 and other κ = 0.65). Clinical management changed in 13 (30%) patients after FAPI-PET. We confirm an association of tumoral FAPI-PET uptake intensity and histopathological FAP expression in sarcoma patients. Further, using blinded reads and independent histopathological validation we report high PPV and sensitivity of FAPI-PET for sarcoma staging.
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http://dx.doi.org/10.2967/jnumed.121.262096DOI Listing
April 2021

The diffuse-type tenosynovial giant cell tumor (dt-TGCT) patient journey: a prospective multicenter study.

Orphanet J Rare Dis 2021 04 29;16(1):191. Epub 2021 Apr 29.

Department of Orthopaedic Surgery, Leiden University Medical Center, Leiden, The Netherlands.

Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm arising from the synovium of joints, bursae, and tendon sheaths affecting small and large joints. It represents a wide spectrum ranging from minimally symptomatic to massively debilitating. Most findings to date are mainly from small, retrospective case series, and thus the morbidity and actual impact of this rare disease remain to be elucidated. This study prospectively explores the management of TGCT in tertiary sarcoma centers.

Methods: The TGCT Observational Platform Project registry was a multinational, multicenter, prospective observational study involving 12 tertiary sarcoma centers in 7 European countries, and 2 US sites. This study enrolled for 2 years all consecutive ≥ 18 years old patients, with histologically diagnosed primary or recurrent cases of diffuse-type TGCT. Patient demographic and clinical characteristics were collected at baseline and every 6 months for 24 months. Quality of life questionnaires (PROMIS-PF and EQ-5D) were also administered at the same time-points. Here we report baseline patient characteristics.

Results: 166 patients were enrolled between November 2016 and March 2019. Baseline characteristics were: mean age 44 years (mean age at disease onset: 39 years), 139/166 (83.7%) had prior treatment, 71/166 patients (42.8%) had ≥ 1 recurrence after treatment of their primary tumor, 76/136 (55.9%) visited a medical specialist ≥ 5 times, 66/116 (56.9%) missed work in the 24 months prior to baseline, and 17/166 (11.6%) changed employment status or retired prematurely due to disease burden. Prior treatment consisted of surgery (i.e., arthroscopic, open synovectomy) (128/166; 77.1%) and systemic treatments (52/166; 31.3%) with imatinib (19/52; 36.5%) or pexidartinib (27/52; 51.9%). Treatment strategies at baseline visits consisted mainly of watchful waiting (81/166; 48.8%), surgery (41/166; 24.7%), or targeted systemic therapy (37/166; 22.3%). Patients indicated for treatment reported more impairment compared to patients indicated for watchful waiting: worst stiffness NRS 5.16/3.44, worst pain NRS 6.13/5.03, PROMIS-PF 39.48/43.85, and EQ-5D VAS 66.54/71.85.

Conclusion: This study confirms that diffuse-type TGCT can highly impact quality of life. A prospective observational registry in rare disease is feasible and can be a tool to collect curated-population reflective data in orphan diseases. Name of registry: Tenosynovial Giant Cell Tumors (TGCT) Observational Platform Project (TOPP).

Trial Registration Number: NCT02948088. Date of registration: 10 October 2016. URL of Trial registry record: https://clinicaltrials.gov/ct2/show/NCT02948088?term=NCT02948088&draw=2 .
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http://dx.doi.org/10.1186/s13023-021-01820-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086070PMC
April 2021

Ewing Sarcoma-Diagnosis, Treatment, Clinical Challenges and Future Perspectives.

J Clin Med 2021 Apr 14;10(8). Epub 2021 Apr 14.

Pediatrics III, University Hospital Essen, 45147 Essen, Germany.

Ewing sarcoma, a highly aggressive bone and soft-tissue cancer, is considered a prime example of the paradigms of a translocation-positive sarcoma: a genetically rather simple disease with a specific and neomorphic-potential therapeutic target, whose oncogenic role was irrefutably defined decades ago. This is a disease that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease. International collaborations have defined the current standard of care in prospective studies, delivering multiple cycles of systemic therapy combined with local treatment; both are associated with significant morbidity that may result in strong psychological and physical burden for survivors. Nevertheless, the combination of non-directed chemotherapeutics and ever-evolving local modalities nowadays achieve a realistic chance of cure for the majority of patients with Ewing sarcoma. In this review, we focus on the current standard of diagnosis and treatment while attempting to answer some of the most pressing questions in clinical practice. In addition, this review provides scientific answers to clinical phenomena and occasionally defines the resulting translational studies needed to overcome the hurdle of treatment-associated morbidities and, most importantly, non-survival.
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http://dx.doi.org/10.3390/jcm10081685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071040PMC
April 2021

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020).

Front Hum Neurosci 2020 23;14:568051. Epub 2021 Mar 23.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.
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http://dx.doi.org/10.3389/fnhum.2020.568051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040977PMC
March 2021

Number of metastases and their response to chemotherapy impact survival of patients with isolated lung metastases from bone-derived sarcoma.

BMC Cancer 2021 Apr 7;21(1):375. Epub 2021 Apr 7.

Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Ruhrlandklinik, Tüschener Weg 40, 45239, Essen, Germany.

Background: Pulmonary metastasectomy (PM) is an established treatment for selected patients with metastatic sarcomas. The aim of this study was to examine our institutional experience and evaluate factors predicting outcome.

Methods: We retrospectively reviewed all patients undergoing PM for bone sarcoma in our center from 2001 to 2019. Survival was calculated from the date of PM. Impact on survival of clinical parameters was assessed.

Results: Thirty-eight patients (27 males, 71%) were included. Histology was osteosarcoma (n = 20, 53%), Ewing sarcoma (n = 13, 34%) and chondrosarcoma (n = 5, 13%). Twelve patients (31.5%) had synchronous metastases, all received chemotherapy before PM. Median number of metastases was 3 (1 to 29). Twenty (53%) patients had mediastinal lymph node sampling. One patient had positive lymph nodes. Ninety-day mortality was 0%. Three and 5-year PFS were 24.5 and 21%, respectively. Three and 5-year OS were 64.5 and 38.5%, respectively. More than three metastases and progression under chemotherapy were significant independent predictors for OS.

Conclusion: PM is a safe procedure and encouraging long-term outcome can be achieved. Patients with progression of pulmonary metastases under chemotherapy as well as patients with more than three metastases had significantly worse OS.
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http://dx.doi.org/10.1186/s12885-021-08073-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028220PMC
April 2021

Treatment of Angiosarcoma with Pazopanib and Paclitaxel: Results of the EVA (Evaluation of Votrient in Angiosarcoma) Phase II Trial of the German Interdisciplinary Sarcoma Group (GISG-06).

Cancers (Basel) 2021 Mar 11;13(6). Epub 2021 Mar 11.

Division of Surgical Oncology and Thoracic Surgery, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany.

We aimed to evaluate the efficacy and toxicity of paclitaxel combined with pazopanib in advanced angiosarcoma (AS). The primary end point was progression-free survival (PFS) rate at six months (PFSR6). Planned accrual was 44 patients in order to detect a PFSR6 of >55%, with an interim futility analysis of the first 14 patients. The study did not meet its predetermined interim target of 6/14 patients progression-free at 6 months. At the time of this finding, 26 patients had been enrolled between July 2014 and April 2016, resulting in an overrunning of 12 patients. After a median follow-up of 9.5 (IQR 7.7-15.4) months, PFSR6 amounted to 46%. Two patients had a complete and seven patients a partial response. Patients with superficial AS had a significantly higher PFSR6 (61% vs. 13%, = 0.0247) and PFS (11.3 vs. 2.7 months, < 0.0001) compared to patients with visceral AS. The median overall survival in the entire cohort was 21.6 months. A total of 10 drug-related serious adverse effects were reported in 5 patients, including a fatal hepatic failure. Although our study did not meet its primary endpoint, the median PFS of 11.6 months in patients with superficial AS appears to be promising. Taking recent reports into consideration, future studies should evaluate the safety and efficacy of VEGFR and immune checkpoint inhibitors with or without paclitaxel in a randomized, multiarm setting.
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http://dx.doi.org/10.3390/cancers13061223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000466PMC
March 2021

Relationships between highly recurrent tumor suppressor alterations in 489 leiomyosarcomas.

Cancer 2021 Aug 31;127(15):2666-2673. Epub 2021 Mar 31.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Leiomyosarcoma (LMS) is the most common soft tissue and uterine sarcoma, but no standard therapy is available for recurrent or metastatic LMS. TP53, p16/RB1, and PI3K/mTOR pathway dysregulations are recurrent events, and some LMS express estrogen receptor (ER) and/or progesterone receptor (PR). To characterize relationships between these pathway perturbations, the authors evaluated protein expression in soft tissue and uterine nonprimary leiomyosarcoma (np-LMS), including local recurrences and distant metastases.

Methods: TP53, RB1, p16, and PTEN expression aberrations were determined by immunohistochemistry (IHC) in tissue microarrays (TMAs) from 227 np-LMS and a comparison group of 262 primary leiomyosarcomas (p-LMS). Thirty-five of the np-LMS had a matched p-LMS specimen in the TMAs. Correlative studies included differentiation scoring, ER and PR IHC, and CDKN2A/p16 fluorescence in situ hybridization.

Results: Dysregulation of TP53, p16/RB1, and PTEN was demonstrated in 90%, 95%, and 41% of np-LMS, respectively. PTEN inactivation was more common in soft tissue np-LMS than uterine np-LMS (55% vs 31%; P = .0005). Moderate-strong ER expression was more common in uterine np-LMS than soft tissue np-LMS (50% vs 7%; P < .0001). Co-inactivation of TP53 and RB1 was found in 81% of np-LMS and was common in both soft tissue and uterine np-LMS (90% and 74%, respectively). RB1, p16, and PTEN aberrations were nearly always conserved in p-LMS and np-LMS from the same patients.

Conclusions: These studies show that nearly all np-LMS have TP53 and/or RB1 aberrations. Therefore, therapies targeting cell cycle and DNA damage checkpoint vulnerabilities should be prioritized for evaluations in LMS.
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http://dx.doi.org/10.1002/cncr.33542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277678PMC
August 2021

Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patients.

J Immunother Cancer 2021 Mar;9(3)

Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: Some sarcomas respond to immune checkpoint inhibition, but predictive biomarkers are unknown. We analyzed tumor DNA methylation profiles in relation to immunological parameters and response to anti-programmed cell death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy in patients with sarcoma.

Patients And Methods: We retrospectively identified adult patients who had received anti-PD-1 ICI therapy for recurrent sarcoma in two independent centers. We performed (1) blinded radiological response evaluation according to immune response evaluation criteria in solid tumors (iRECIST) ; (2) tumor DNA methylation profiling of >850,000 probes using Infinium MethylationEPIC microarrays; (3) analysis of tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and intratumoral expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) using immunohistochemistry; and (4) evaluation of blood-based systemic inflammation scores (neutrophil-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio). Response to anti-PD-1 ICI therapy was bioinformatically and statistically correlated with DNA methylation profiles and immunological data.

Results: 35 patients (median age of 50 (23-81) years; 18 females, 17 males; 27 soft tissue sarcomas; 8 osteosarcomas) were included in this study. The objective response rate to anti-PD-1 ICI therapy was 22.9% with complete responses in 3 out of 35 and partial responses in 5 out of 35 patients. Adjustment of DNA methylation data for tumor-infiltrating immune cells resulted in identification of methylation differences between responders and non-responders to anti-PD-1 ICI. 2453 differentially methylated CpG sites (DMPs; 2043 with decreased and 410 with increased methylation) were identified. Clustering of sarcoma samples based on these DMPs revealed two main clusters: methylation cluster 1 (MC1) consisted of 73% responders and methylation cluster 2 (MC2) contained only non-responders to anti-PD-1 ICI. Median progression-free survival from anti-PD-1 therapy start of MC1 and MC2 patients was 16.5 and 1.9 months, respectively (p=0.001). Median overall survival of these patients was 34.4 and 8.0 months, respectively (p=0.029). The most prominent DNA methylation differences were found in pathways implicated in Rap1 signaling, focal adhesion, adherens junction Phosphoinositide 3-kinase (PI3K)-Akt signaling and extracellular matrix (ECM)-receptor interaction.

Conclusions: Our data demonstrate that tumor DNA methylation profiles may serve as a predictive marker for response to anti-PD-1 ICI therapy in sarcoma.
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http://dx.doi.org/10.1136/jitc-2020-001458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993298PMC
March 2021

Enrichment of Circular RNA Expression Deregulation at the Transition to Recurrent Spontaneous Seizures in Experimental Temporal Lobe Epilepsy.

Front Genet 2021 28;12:627907. Epub 2021 Jan 28.

Affiliated Partner of the European Reference Network EpiCARE, Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Mesial temporal lobe epilepsy (mTLE) is a common form of epilepsy and is characterized by recurrent spontaneous seizures originating from the temporal lobe. The majority of mTLE patients develop pharmacoresistance to available anti-epileptic drugs (AEDs) while exhibiting severe pathological changes that can include hippocampal atrophy, neuronal death, gliosis and chronic seizures. The molecular mechanisms leading to mTLE remain incompletely understood, but are known to include defects in post-transcriptional gene expression regulation, including in non-coding RNAs (ncRNAs). Circular RNAs (circRNAs) are a class of recently rediscovered ncRNAs with high levels of expression in the brain and proposed roles in diverse neuronal processes. To explore a potential role for circRNAs in epilepsy, RNA-sequencing (RNA-seq) was performed on hippocampal tissue from a rat perforant pathway stimulation (PPS) model of TLE at different post-stimulation time points. This analysis revealed 218 differentially expressed (DE) circRNAs. Remarkably, the majority of these circRNAs were changed at the time of the occurrence of the first spontaneous seizure (DOFS). The expression pattern of two circRNAs, circ_Arhgap4 and circ_Nav3, was further validated and linked to and target regulation, respectively. This is the first study to examine the regulation of circRNAs during the development of epilepsy. It reveals an intriguing link between circRNA deregulation and the transition of brain networks into the state of spontaneous seizure activity. Together, our results provide a molecular framework for further understanding the role and mechanism-of-action of circRNAs in TLE.
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http://dx.doi.org/10.3389/fgene.2021.627907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876452PMC
January 2021

Postoperative outcomes and surgical ratio at a newly established epilepsy center: The first 100 procedures.

Epilepsy Behav 2021 03 22;116:107715. Epub 2021 Jan 22.

Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany.

Purpose: To describe the patients' characteristics, surgical ratio, and outcomes following epilepsy surgery at the newly established Epilepsy Center Frankfurt Rhine-Main.

Methods: We retrospectively studied the first 100 consecutive patients, including adult (n = 77) and pediatric (n = 23) patients, with drug-resistant epilepsy who underwent resective or ablative surgical procedures at a single, newly established epilepsy center. Patient characteristics, seizure and neuropsychological outcomes, histopathology, complications, and surgical ratio were analyzed.

Results: The mean patient age was 28.8 years (children 10.6 years, adults 34.2 years). The mean epilepsy duration was 11.9 years (children 3.9 years, adults 14.3 years), and the mean follow-up was 1.5 years. At the most recent visit, 64% of patients remained completely seizure free [Engel IA]. The rates of perioperative complications and unexpected new neurological deficits were 5%, each. The proportion of patients showing deficits in one or more cognitive domains increased six months after surgery and decreased to presurgical proportions after two years. Symptoms of depression were significantly decreased and quality of life was significantly increased after surgery. The surgical ratio was 25.3%.

Conclusion: Similar postsurgical outcomes were achieved at a newly established epilepsy center compared with long-standing epilepsy centers. The lower time to surgery may reflect a general decrease in time to surgery over the last decade or the improved accessibility of a new epilepsy center in a previously underserved area. The surgical ratio was not lower than reported for established centers.
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http://dx.doi.org/10.1016/j.yebeh.2020.107715DOI Listing
March 2021

Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial.

Eur J Cancer 2021 Mar 16;145:132-142. Epub 2021 Jan 16.

Department of Medical Oncology, University Hospital Essen, Sarcoma Center, University of Duisburg-Essen, Essen, Germany.

Background: PDGFRA D842V mutations occur in 5-10% of gastrointestinal stromal tumours (GISTs), and previously approved tyrosine kinase inhibitors (TKIs) are inactive against this mutation. Consequently, patients have a poor prognosis. We present an updated analysis of avapritinib efficacy and long-term safety in this patient population.

Methods: NAVIGATOR (NCT02508532), a two-part, open-label, dose-escalation/dose-expansion phase I study, enrolled adult patients with unresectable GISTs. Patients with PDGFRA D842V-mutant GIST were a prespecified subgroup within the overall safety population, which included patients who received ≥1 avapritinib dose. Primary end-points were overall response rate (ORR) and avapritinib safety profile. Secondary end-points were clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS). Overall survival (OS) was an exploratory end-point.

Results: Between 7 October 2015 and 9 March 2020, 250 patients enrolled in the safety population; 56 patients were included in the PDGFRA D842V population, 11 were TKI-naïve. At data cut-off, median follow-up was 27.5 months. Safety profile was comparable between the overall safety and PDGFRA D842V populations. In the PDGFRA D842V population, the most frequent adverse events were nausea (38 [68%] patients) and diarrhoea (37 [66%]), and cognitive effects occurred in 32 (57%) patients. The ORR was 91% (51/56 patients). The CBR was 98% (55/56 patients). The median DOR was 27.6 months (95% confidence interval [CI]: 17.6-not reached [NR]); median PFS was 34.0 months (95% CI: 22.9-NR). Median OS was not reached.

Conclusion: Targeting PDGFRA D842V-mutant GIST with avapritinib resulted in an unprecedented, durable clinical benefit, with a manageable safety profile. Avapritinib should be considered as first-line therapy for these patients.
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http://dx.doi.org/10.1016/j.ejca.2020.12.008DOI Listing
March 2021

Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following at Least Three Prior Lines of Therapy.

Oncologist 2021 04 1;26(4):e639-e649. Epub 2021 Feb 1.

Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

Background: Most gastrointestinal stromal tumors (GIST) driven by KIT or platelet-derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two-part, single-arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST.

Materials And Methods: Eligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy.

Results: As of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment-related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response-evaluable patients with GIST harboring KIT or non-D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10-25). Median duration of response was 10.2 months (95% CI, 7.2-10.2), and median progression-free survival was 3.7 months (95% CI, 2.8-4.6).

Conclusion: Avapritinib has manageable toxicity with meaningful clinical activity as fourth-line or later treatment in some patients with GIST with KIT or PDGFRA mutations.

Implications For Practice: In the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet-derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist.
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http://dx.doi.org/10.1002/onco.13674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018324PMC
April 2021

Reply to E. Younger et al, V. Sharma et al, and M. Uchihara et al.

J Clin Oncol 2021 Mar 13;39(7):864-865. Epub 2021 Jan 13.

Viktor Grünwald, MD, Interdisciplinary Genitourinary Oncology at the West-German Cancer Center, Clinic for Internal Medicine (Tumor Research) and Clinic for Urology, University Hospital Essen, Germany; Xiaofei Liu, MSc, Institute for Biostatistics, Medical School Hanover, Hanover, Germany; Markus Schuler, MD, Helios Clinic, Berlin, Germany; and Sebastian Bauer, MD, Clinic for Internal Medicine (Tumor Research), University Hospital Essen, Germany.

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http://dx.doi.org/10.1200/JCO.20.03272DOI Listing
March 2021

Creating a regular array of metal-complexing molecules on an insulator surface at room temperature.

Nat Commun 2020 Dec 21;11(1):6424. Epub 2020 Dec 21.

Physical Chemistry I, Department of Chemistry, Bielefeld University, Universitätsstraße 25, 33615, Bielefeld, Germany.

Controlling self-assembled nanostructures on bulk insulators at room temperature is crucial towards the fabrication of future molecular devices, e.g., in the field of nanoelectronics, catalysis and sensor applications. However, at temperatures realistic for operation anchoring individual molecules on electrically insulating support surfaces remains a big challenge. Here, we present the formation of an ordered array of single anchored molecules, dimolybdenum tetraacetate, on the (10.4) plane of calcite (CaCO). Based on our combined study of atomic force microscopy measurements and density functional theory calculations, we show that the molecules neither diffuse nor rotate at room temperature. The strong anchoring is explained by electrostatic interaction of an ideally size-matched molecule. Especially at high coverage, a hard-sphere repulsion of the molecules and the confinement at the calcite surface drives the molecules to form locally ordered arrays, which is conceptually different from attractive linkers as used in metal-organic frameworks. Our work demonstrates that tailoring the molecule-surface interaction opens up the possibility for anchoring individual metal-complexing molecules into ordered arrays.
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http://dx.doi.org/10.1038/s41467-020-20189-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752910PMC
December 2020

Lactate Dehydrogenase Prior to Transarterial Hepatic Chemoperfusion Predicts Survival and Time to Progression in Patients with Uveal Melanoma Liver Metastases.

Rofo 2021 Jun 21;193(6):683-691. Epub 2020 Dec 21.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Germany.

Purpose:  To assess serum lactate dehydrogenase (LDH) as a pretreatment prognostic factor in patients with uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion (THC).

Materials And Methods:  56 patients (48 % male, median age: 63.5 years) underwent a median of 4 THC sessions. Kaplan-Meier for median overall survival (OS) and time to hepatic progression (TTP; 95 %CI) in months and Cox proportional hazards model for uni- (UVA) & multivariate analyses (MVA) for hazard ratio (HR) evaluation were calculated.

Results:  The median OS was 9.4 months. The pretreatment LDH value before 1st THC was the strongest OS predictor with 19.8 months for normal (≦ 280 units per liter (U/L)), 9.7 for intermediate (> 280-< 1000 U/L), and 3.84 months for high (≧ 1000 U/L) LDH. LDH significantly predicted a median TTP with 8 months, 4 months, and 1 month for normal, intermediate, and high LDH, respectively. UVA revealed intermediate (16.5) and high (77.3) LDH, bilirubin > the upper limit of normal (ULN) (2.89), alkaline phosphatase > 1.5 ULN (6.8), leukocytes > ULN (4.2), gamma-glutamyl transferase (GGT) > ULN (7), extrahepatic metastases (1.8) and liver lesions ≥ 5 cm (3.6) as significant predictors for worse OS. MVA confirmed intermediate (5) and high (27.1) LDH, bilirubin (5.7), GGT (2.9), and tumor size ≥ 5 cm (3.7) as significant independent predictors for worse OS. Patients with decreasing vs. increasing LDH > 10 % between 1st and 2nd THC (median: 38 days) survived longer (14.6 vs. 4.3 months) and progressed later (7 months vs. 1 month).

Conclusion:  Elevated pretreatment serum LDH is an essential and robust OS and TTP predictor, potentially allowing for the identification of patients benefiting most from transarterial hepatic chemoperfusion.

Key Points: · Pretherapeutic LDH is the most reliable prognosticator for OS and TTP. · Therapy-related LDH decrease > 10 % between 1st and 2nd THC had prolonged OS and TTP. · Lower Values of LDH, bilirubin, gamma-glutamyl transferase, and tumor size are independent pretherapeutic predictors for longer OS. · Extrahepatic metastases do not have an independent influence on overall survival.

Citation Format: · Ludwig J, Haubold J, Heusner T et al. Lactate Dehydrogenase Prior to Transarterial Hepatic Chemoperfusion Predicts Survival and Time to Progression in Patients with Uveal Melanoma Liver Metastases. Fortschr Röntgenstr 2021; 193: 683 - 691.
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http://dx.doi.org/10.1055/a-1299-1627DOI Listing
June 2021

Surgical Treatment for Primary Chest Wall Sarcoma: A Single-Institution Study.

J Surg Res 2021 Apr 16;260:149-154. Epub 2020 Dec 16.

Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Center Essen, Essen, Germany. Electronic address:

Background: Primary sarcomas of the chest wall are rare aggressive tumors. Surgery is part of the multimodal treatment. We describe our institutional patient cohort and evaluate prognostic factors.

Methods: All patients who had curative intent surgery for primary chest wall sarcoma from 2004 to 2019 were retrospectively reviewed. Impact on survival-calculated from the date of surgery until last follow-up- was assessed for the following variables: age, gender, type of resection, size, grading, stage, completeness of resection, and neoadjuvant and adjuvant therapy.

Results: Twenty-three patients (15 males, 65%) with a median age of 54 y (4 to 82) were included. Most common histology was chondrosarcoma (n = 5, 22%). Seven patients (30%) received neoadjuvant and 13 patients (57%) received adjuvant treatment. R0 resection was achieved in 83%. Extended chest wall resection was performed in 14 patients (61%), including lung (n = 13, 57%), diaphragm (n = 2, 9%) and pericardium (n = 1, 4%). Morbidity and 90-day mortality were 23% and 0%, respectively. Three- and 5-year overall survival was 53% and 35%, respectively. R0 resection was predictor of overall survival (P = 0.029). Tumor grade and extended resections were predictors for recurrence (P = 0.034 and P = 0.018, respectively).

Conclusions: Surgical resection of primary chest wall sarcoma is a safe procedure even when extended resection is required.
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http://dx.doi.org/10.1016/j.jss.2020.11.078DOI Listing
April 2021
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