Publications by authors named "Martin Werner"

235 Publications

Transitioning the Molecular Tumor Board from Proof of Concept to Clinical Routine: A German Single-Center Analysis.

Cancers (Basel) 2021 Mar 8;13(5). Epub 2021 Mar 8.

Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of the Comprehensive Cancer Center Freiburg (Germany) including workflows and process optimizations. This retrospective single-center study includes data on 488 patients enrolled in the MTB from February 2015 through December 2018. Recommendations include individual molecular diagnostics, molecular stratified therapies, assessment of treatment adherence and patient outcomes including overall survival. The majority of MTB patients presented with stage IV oncologic malignancies (90.6%) and underwent an average of 2.1 previous lines of therapy. Individual diagnostic recommendations were given to 487 patients (99.8%). A treatment recommendation was given in 264 of all cases (54.1%) which included a molecularly matched treatment in 212 patients (43.4%). The 264 treatment recommendations were implemented in 76 patients (28.8%). Stable disease was observed in 19 patients (25.0%), 17 had partial response (22.4%) and five showed a complete remission (6.6%). An objective response was achieved in 28.9% of cases with implemented recommendations and for 4.5% of the total population (22 of 488 patients). By optimizing the MTB workflow, case-discussions per session increased significantly while treatment adherence and outcome remained stable over time. Our data demonstrate the feasibility and effectiveness of molecular-guided personalized therapy for cancer patients in a clinical routine setting showing a low but robust and durable disease control rate over time.
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http://dx.doi.org/10.3390/cancers13051151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962829PMC
March 2021

EPB41L5 controls podocyte extracellular matrix assembly by adhesome-dependent force transmission.

Cell Rep 2021 Mar;34(12):108883

Institute of Surgical Pathology, Faculty of Medicine, University Medical Center Freiburg, Freiburg 79106, Germany; Berta-Ottenstein Program, Medical Faculty, University Medical Center, Freiburg 79106, Germany. Electronic address:

The integrity of the kidney filtration barrier essentially relies on the balanced interplay of podocytes and the glomerular basement membrane (GBM). Here, we show by analysis of in vitro and in vivo models that a loss of the podocyte-specific FERM-domain protein EPB41L5 results in impaired extracellular matrix (ECM) assembly. By using quantitative proteomics analysis of the secretome and matrisome, we demonstrate a shift in ECM composition characterized by diminished deposition of core GBM components, such as LAMA5. Integrin adhesome proteomics reveals that EPB41L5 recruits PDLIM5 and ACTN4 to integrin adhesion complexes (IACs). Consecutively, EPB41L5 knockout podocytes show insufficient maturation of integrin adhesion sites, which translates into impaired force transmission and ECM assembly. These observations build the framework for a model in which EPB41L5 functions as a cell-type-specific regulator of the podocyte adhesome and controls a localized adaptive module in order to prevent podocyte detachment and thereby ensures GBM integrity.
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http://dx.doi.org/10.1016/j.celrep.2021.108883DOI Listing
March 2021

One Plus One Makes Three: Triangular Coupling of Correlated Amino Acid Mutations.

J Phys Chem Lett 2021 Apr 24;12(12):3195-3201. Epub 2021 Mar 24.

Computational Biomolecular Dynamics Group, Max-Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.

Correlated mutations have played a pivotal role in the recent success in protein fold prediction. Understanding nonadditive effects of mutations is crucial for altering protein structure, as mutations of multiple residues may change protein stability or binding affinity in a manner unforeseen by the investigation of single mutants. While the couplings between amino acids can be inferred from homologous protein sequences, the physical mechanisms underlying these correlations remain elusive. In this work we demonstrate that calculations based on the first-principles of statistical mechanics are capable of capturing the effects of nonadditivities in protein mutations. The identified thermodynamic couplings cover the short-range as well as previously unknown long-range correlations. We further explore a set of mutations in staphyloccocal nuclease to unravel an intricate interaction pathway underlying the correlations between amino acid mutations.
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http://dx.doi.org/10.1021/acs.jpclett.1c00380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041375PMC
April 2021

Immunohistochemistry-based hypoxia-immune prognostic classifier for head-and-neck cancer patients undergoing chemoradiation - Post-hoc analysis from a prospective imaging trial.

Radiother Oncol 2021 Mar 19;159:75-81. Epub 2021 Mar 19.

Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Purpose: As both tumor hypoxia and an immunosuppressing tumor microenvironment hamper the anti-tumor activity of radiotherapy in head-and-neck squamous cell carcinoma (HNSCC), we aimed to develop an immunohistochemistry-based hypoxia-immune classifier.

Methods: 39 patients receiving definitive chemoradiation for HNSCC within a prospective trial were included in this analysis. Baseline tumor samples were analyzed for the hypoxia marker carbonic anhydrase IX (CAIX) and tumor-infiltrating lymphocytes (TILs) and were correlated with [18F]-misonidazole ([18F]FMISO) PET measurements. The impact of the biomarkers on the locoregional control (LRC) was examined using Cox analyses and concordance index statistics.

Results: Low CAIX (HR = 0.352, 95%CI 0.124-1.001, p = 0.050) and high TIL levels (HR = 0.308, 95%CI 0.114-0.828, p = 0.020) were independent parameters for improved LRC and did not correlate with each other (Spearman's ρ = 0.034, p = 0.846). Harrell's C was 0.66 for CAIX and TIL levels alone and 0.71 for the combination. 2-year LRC was 73%, 62% and 11% for the prognostically good (CAIX/TIL), intermediate (CAIX/TIL or CAIX/TIL) and poor groups (CAIX/TIL), respectively (p = 0.001). Focusing on T lymphocytes, the hypoxia-immune classifier could still stratify between favorable (CAIX/CD3 + TIL), intermediate (CAIX/CD3 + TIL or CAIX/CD3 + TIL) and poor subgroups (CAIX/CD3 + TIL) with a 2-year LRC of 80%, 59% and 14%, respectively (p = 0.001). There was a positive correlation between baseline CAIX levels and [18F]FMISO SUV in week 2 of chemoradiation (ρ = 0.324, p = 0.050), indicating an association between higher baseline CAIX expression and tumor hypoxia persistence.

Conclusion: We developed a clinically feasible hypoxia-immune prognostic classifier for HNSCC patients based on pre-treatment immunohistochemistry. However, external validation is required to determine the prognostic value and the potential usage for personalized radiation oncology.
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http://dx.doi.org/10.1016/j.radonc.2021.03.014DOI Listing
March 2021

Tc-labelled PSMA ligand for radio-guided surgery in nodal metastatic prostate cancer: proof of principle.

EJNMMI Res 2021 Mar 4;11(1):22. Epub 2021 Mar 4.

Department of Urology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Purpose: Intraoperative identification of prostate cancer (PCa) lymph node (LN) metastases (LNM) detected by preoperative PSMA PET/CT may be facilitated by PSMA radio-guided surgery (RGS) with use of a γ-probe. Earlier we demonstrated excellent performance of the In-labelled PSMA ligand DKFZ-617 ([In]In-PSMA-617) in RGS for ex situ distinction of LN vs LNM at lymphadenectomy (LA) at a single LN level. In comparison with indium-111, technetium-99m has better physical properties for γ-probe measurements, better availability and lower radiation exposure for patients and medical personnel. Against this background, we evaluated the uptake of Tc-PSMA-I&S ligand at the level of single LN and its power to discriminate between unaffected LN and LNM.

Methods: Six patients with PCa with the suspicion of LNM on preoperative PSMA-PET/CT underwent [Tc]Tc-PSMA-I&S RGS (4 salvage LA, 2 primary LA) with intravenous injection of [Tc]Tc-PSMA-I&S 24 h prior to surgery. Resected samples were isolated manually aiming at the level of single LN. Uptake measurements were done ex situ with a high-purity germanium detector. Receiver operating characteristic (ROC) analysis was performed based on [Tc]Tc-PSMA-I&S uptake expressed as lean body mass standard uptake value (SUL).

Results: Separation of the tissue samples from 73 subregions resulted in 498 single samples. After final histopathology 356 LN, 160 LNM und 11 non-nodal PCa samples were identified. Median SUL of tumor-free samples (0.26) and samples with cancer (3.5) was significantly different (p < 0.0001). ROC analysis revealed an area under the curve (AUC) of 0.917 (95% CI 0.89-0.95). Using a SUL cutoff of 1.1, sensitivity, specificity, positive predictive value, and negative predictive values were 76.6%, 94.4%, 89.4% and 86.9%.

Conclusion: Ex situ analysis of [Tc]Tc-PSMA-I&S uptake at single LN level showed good diagnostic performance for the ex situ distinction of tumor-bearing vs tumor-free LN during RGS.
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http://dx.doi.org/10.1186/s13550-021-00762-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933311PMC
March 2021

SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance.

J Am Soc Nephrol 2021 Mar 29;32(3):563-579. Epub 2021 Jan 29.

Institute of Surgical Pathology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany

Background: Previous research demonstrated that small Rho GTPases, modulators of the actin cytoskeleton, are drivers of podocyte foot-process effacement in glomerular diseases, such as FSGS. However, a comprehensive understanding of the regulatory networks of small Rho GTPases in podocytes is lacking.

Methods: We conducted an analysis of podocyte transcriptome and proteome datasets for Rho GTPases; mapped , podocyte-specific Rho GTPase affinity networks; and examined conditional knockout mice and murine disease models targeting . To evaluate podocyte foot-process morphology, we used super-resolution microscopy and electron microscopy; proximity ligation assays were used to determine the subcellular localization of the small GTPase-activating protein SRGAP1. We performed functional analysis of CRISPR/Cas9-generated knockout podocytes in two-dimensional and three-dimensional cultures and quantitative interaction proteomics.

Results: We demonstrated SRGAP1 localization to podocyte foot processes and to cellular protrusions . but not knockout mice developed an FSGS-like phenotype at adulthood. Podocyte-specific deletion of by resulted in increased susceptibility to doxorubicin-induced nephropathy. Detailed analysis demonstrated significant effacement of podocyte foot processes. Furthermore, -knockout podocytes showed excessive protrusion formation and disinhibition of the small Rho GTPase machinery . Evaluation of a SRGAP1-dependent interactome revealed the involvement of SRGAP1 with protrusive and contractile actin networks. Analysis of glomerular biopsy specimens translated these findings toward human disease by displaying a pronounced redistribution of SRGAP1 in FSGS.

Conclusions: SRGAP1, a podocyte-specific RhoGAP, controls podocyte foot-process architecture by limiting the activity of protrusive, branched actin networks. Therefore, elucidating the complex regulatory small Rho GTPase affinity network points to novel targets for potentially precise intervention in glomerular diseases.
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http://dx.doi.org/10.1681/ASN.2020081126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920176PMC
March 2021

Delayed non-myeloablative irradiation to induce long-term allograft acceptance in a large animal lung transplantation model.

Transpl Immunol 2021 Apr 27;65:101350. Epub 2020 Oct 27.

Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Centre for Lung Research, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address:

We previously induced long-term allograft acceptance in an allogeneic lung transplantation (LTx) model in miniature swine using perioperative non-myeloablative irradiation (IRR) combined with infusion of donor specific alloantigen. In order to improve clinical applicability, we delayed induction with irradiation in this study. Left sided single LTx was performed in minipigs. Group 1 received non-myeloablative irradiation (7Gy thymus and 1.5Gy whole body IRR) before LTx and a perioperative donor specific splenocyte infusion (SpTx). Group 2 received perioperative SpTx but delayed IRR three days after LTx. Group 3 was exposed to delayed IRR without SpTx. Whereas 4 out of 7 animals from the non-delayed group never rejected their grafts and were electively sacrificed on postoperative day (POD) +500, all animals from group 2 rejected their grafts before POD 108. In group 3, 3 out of 8 animals developed long-term allograft acceptance. In all groups, donor leukocyte chimerism peaked up to 20% in peripheral blood one hour after reperfusion of the lung. Group 1 maintained prolonged chimerism beyond POD 7, whereas chimerism levels in groups 2 and 3 decreased continuously thereafter. Delayed irradiation has the potential to improve long-term graft survival, yet not as efficient as a perioperative conditioning protocol.
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http://dx.doi.org/10.1016/j.trim.2020.101350DOI Listing
April 2021

Prognostic impact of tumor budding and EMT in periampullary adenocarcinoma: a quantitative approach.

J Cancer 2020 17;11(22):6474-6483. Epub 2020 Sep 17.

Department of Surgery, UKSH Campus Lübeck, Germany.

The presence of invasive cell clusters known as tumor budding and the closely related epithelial mesenchymal transition (EMT) have a prognostic impact on cancer patients' overall survival. Interestingly, data quantitatively analyzing and correlating the amount of tumor buds and patient overall survival as well as the impact of expression of epithelial phenotype markers are missing. Periampullary carcinoma samples of 171 patients were immunohistochemically stained for E-Cadherin (ECad). Tumor cell clusters (TCC, defined from one to 50 cells) were manually quantified comprising tumor cell number and subcellular localization of ECad expression (membranous, cytoplasmic or mixed). Data analyses were performed using elastic net feature selection. Hereby, five distinct intervals of TCC sizes and corresponding fractions of cells with distinct ECad expression were identified. Prognostic features of the defined budding categories were entered into a subsequent Cox regression model together with standard clinicopathological parameters and, based on the model prediction, cases were categorized into "low and high budding" grades. Overall median TCC size was 16 cells (range: 2-36 cells). The median number of TCCs per tumor was 42 (range: 3-283). Elastic net feature selection identified TCCs of 6-10 and 31-35 cells as prognostically most relevant negative and positive features, respectively. Regarding ECad expression, cytoplasmic ECad expression in TCCs of 11-15 as well as of 26-30 cells revealed prognostic relevance. Combining TCC numbers and ECad expression, budding grade qualified as independent prognostic factor for patient overall survival (0.001) in a multivariable clinicopathologic Cox model. Applying an advanced modelling by machine learning on a cohort of periampullary cancers, we show that not the smallest TCCs (1-5 cells) but tumor cell nests containing 6-10 cells display the strongest negative prognostic relevance. Moreover, we demonstrate that larger TCCs might have a strong positive prognostic impact in periampullary adenocarcinomas, contributing to establishing an advanced grading system.
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http://dx.doi.org/10.7150/jca.46093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545681PMC
September 2020

Prevalence and characteristics of myeloproliferative neoplasms with concomitant monoclonal gammopathy.

Leuk Res 2020 11 15;98:106454. Epub 2020 Sep 15.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; German Cancer Consortium (DKTK) Partner Site, Freiburg, Germany. Electronic address:

Of BCR-ABL negative myeloproliferative neoplasm (MPN) patients, 3-14 % display a concomitant monoclonal gammopathy (MGUS). Nonetheless, literature on co-occurring MPN and MGUS is scarce, the molecular underpinnings are unknown and it is unclear whether patients require a specific management. Here, we compared the clinical and genetic features of MPN patients with and without concomitant MGUS. Of 114 MPN patients prospectively studied by serum immunofixation (median age, 67 years; 36.0 % essential thrombocythemia [ET], 24.6 % polycythemia vera [PV], 11.4 % secondary myelofibrosis [sMF], 28.1 % primary myelofibrois [PMF]; 73.7 % JAK2 V617F positive), 10 (9 %) harbored an M-protein. No relevant clinical differences existed between MPN patients with or without M-protein. Seven additional MPN/MGUS patients were retrospectively identified in our MPN registry, yielding a total of 17 patients (7 ET, 3 PV, 3 sMF, 4 PMF). One patient developed multiple myeloma (MM) and one smoldering MM. Seven of 12 patients analyzed carried mutations (e.g. in ASXL1 or TET2) in addition to those in JAK2 or CALR, and 4 of 10 patients showed aberrant cytogenetics. M-protein was mainly IgG (12/17), followed by IgM (4/17). In the two patients that underwent allogeneic stem cell transplantation mutant JAK2 and M-protein were no longer detectable post-transplant. In conclusion, MGUS prevalence in our cohort was in the range of previous reports and at most slightly higher than expected in the general population. MGUS presence did not correlate with a specific MPN entity, clinical features or genetic alterations. Our observations suggest that there is no strong clinical or biological relationship between the occurrence of MGUS and MPN.
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http://dx.doi.org/10.1016/j.leukres.2020.106454DOI Listing
November 2020

Immunohistochemistry and Radiomic Features for Survival Prediction in Small Cell Lung Cancer.

Front Oncol 2020 12;10:1161. Epub 2020 Aug 12.

Department of Pathology, Faculty of Medicine, Medical Center, Institute of Surgical Pathology, University Hospital Freiburg, Freiburg, Germany.

The aim of the study was to evaluate the role of different immunohistochemical and radiomics features in patients with small cell lung cancer (SCLC). Consecutive patients with histologically proven SCLC with limited ( = 47, 48%) or extensive disease ( = 51, 52%) treated with radiotherapy and chemotherapy at our department were included in the analysis. The expression of different immunohistochemical markers from the initial tissue biopsy, such as CD56, CD44, chromogranin A, synaptophysin, TTF-1, GLUT-1, Hif-1 a, PD-1, and PD-L1, and MIB-1/KI-67 as well as LDH und NSE from the initial blood sample were evaluated. H-scores were additionally generated for CD44, Hif-1a, and GLUT-1. A total of 72 computer tomography (CT) radiomics texture features from a homogenous subgroup ( = 31) of patients were correlated with the immunohistochemistry, the survival (OS), and the progression-free survival (PFS). The median OS, calculated from diagnosis, was 21 months for patients with limited disease and 13 months for patients with extensive disease. The expression of synaptophysin correlated with a better OS (HR 0.546 95% CI 0.308-0.966, = 0.03). The expression of TTF-1 (HR 0.286, 95% CI: 0.117-0.698, = 0.006) and a lower GLUT-1 H-score (median = 50, HR: 0.511, 95% CI: 0.260-1.003, = 0.05) correlated with a better PFS. Patients without chromogranin A expression had a higher risk for developing cerebral metastases ( = 0.02) and patients with PD 1 expression were at risk for developing metastases ( = 0.02). Our radiomics analysis did not reveal a single texture feature that correlated highly with OS or PFS. Correlation coefficients ranged between -0.48 and 0.39 for OS and between -0.46 and 0.38 for PFS. The role of synaptophysin should be further evaluated as synaptophysin-negative patients might profit from treatment intensification. We report an, at most, moderate correlation of radiomics features with overall and progression free survival and no correlation with the expression of different immunohistochemical markers.
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http://dx.doi.org/10.3389/fonc.2020.01161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438800PMC
August 2020

Lymphocyte Infiltration Determines the Hypoxia-Dependent Response to Definitive Chemoradiation in Head-and-Neck Cancer: Results from a Prospective Imaging Trial.

J Nucl Med 2021 Apr 28;62(4):471-478. Epub 2020 Aug 28.

Department of Radiation Oncology, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany.

Tumor hypoxia in head-and-neck squamous cell carcinoma (HNSCC) leads to an immunosuppressive microenvironment and reduces the response to radiotherapy. In this prospective imaging trial, we investigated potential interactions between functional hypoxia imaging and infiltrating lymphocyte levels as a potential predictor for treatment response in HNSCC patients. In total, 49 patients receiving definitive chemoradiation for locally advanced HNSCCs underwent pretherapeutic biopsies and peritherapeutic hypoxia imaging using F-misonidazole PET at weeks 0, 2, and 5 during chemoradiation. Hematoxylin-eosin and immunohistochemical stainings for tumor-infiltrating lymphocytes, tissue-based hypoxia, and microvascular markers were analyzed and correlated with the longitudinal hypoxia dynamics and patient outcomes. High levels of tumor-infiltrating total lymphocytes correlated with superior locoregional control (LRC) (hazard ratio [HR], 0.279; = 0.011) and progression-free survival (PFS) (HR, 0.276; = 0.006). Similarly, early resolution of F-misonidazole PET-detected tumor hypoxia quantified by F-misonidazole dynamics between weeks 0 and 2 of chemoradiation was associated with improved LRC (HR, 0.321; = 0.015) and PFS (HR, 0.402; = 0.043). Outcomes in the favorable early hypoxia resolution subgroup significantly depended on infiltrating lymphocyte counts, with patients who showed both an early hypoxia response and high lymphocyte infiltration levels exhibiting significantly improved LRC (HR, 0.259; = 0.036) and PFS (HR, 0.242; = 0.017) compared with patients with an early hypoxia response but low lymphocyte counts. These patients exhibited oncologic results comparable to those of patients with no hypoxia response within the first 2 wk of chemoradiation. This analysis established a clinical hypoxia-immune score that predicted treatment responses and outcomes in HNSCC patients undergoing chemoradiation and may help to devise novel concepts for biology-driven personalization of chemoradiation.
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http://dx.doi.org/10.2967/jnumed.120.248633DOI Listing
April 2021

High Numbers and Densities of PD1 T-Follicular Helper Cells in Triple-Negative Breast Cancer Draining Lymph Nodes Are Associated with Lower Survival.

Int J Mol Sci 2020 Aug 19;21(17). Epub 2020 Aug 19.

Institute of Surgical Pathology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany.

Breast cancer tumor draining lymph nodes (TDLNs) display distinct morphologic changes depending on the breast cancer subtype. For triple-negative breast cancers (TNBC), draining LNs display a higher amount of secondary lymphoid follicles, which can be regarded as a surrogate marker for an activated humoral immune response. In the present study, we focus on PD1 T-follicular helper cells (Tfh) in TDLNs of TNBC, since PD1 Tfh are drivers of the germinal center (GC) reaction. We quantified PD1 Tfh in 22 sentinel LNs with 853 GCs and interfollicular areas from 19 patients with TNBC by morphometry from digitalized immunostained tissue sections. Overall survival was significantly worse for patients with a higher number and area density of PD1 Tfh within GCs of TDLNs. Further, we performed T-cell receptor gamma chain (TRG) analysis from microdissected tissue in the primary tumor and TDLNs. Eleven patients showed the same TRG clones in the tumor and the LN. Five patients shared the same TRG clones in the tumor and the GCs. In two patients, those clones were highly enriched inside the GCs. Enrichment of identical TRG clones at the tumor site vs. the TDLN was associated with improved overall survival. TDLNs are important relays of cancer immunity and enable surrogate approaches to predict the outcome of TNBC itself.
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http://dx.doi.org/10.3390/ijms21175948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504397PMC
August 2020

Hypoxia dynamics on FMISO-PET in combination with PD-1/PD-L1 expression has an impact on the clinical outcome of patients with Head-and-neck Squamous Cell Carcinoma undergoing Chemoradiation.

Theranostics 2020 23;10(20):9395-9406. Epub 2020 Jul 23.

Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Tumor-associated hypoxia influences the radiation response of head-and-neck cancer (HNSCC) patients, and a lack of early hypoxia resolution during treatment considerably deteriorates outcomes. As the detrimental effects of hypoxia are partly related to the induction of an immunosuppressive microenvironment, we investigated the interaction between tumor hypoxia dynamics and the PD-1/PD-L1 axis in HNSCC patients undergoing chemoradiation and its relevance for patient outcomes in a prospective trial. 49 patients treated with definitive chemoradiation for locally advanced HNSCC were enrolled in this trial and received longitudinal hypoxia PET imaging using fluorine-18 misonidazole ([F]FMISO) at weeks 0, 2 and 5 during treatment. Pre-therapeutic tumor biopsies were immunohistochemically analyzed regarding the PD-1/PD-L1 expression both on immune cells and on tumor cells, and potential correlations between the PD-1/PD-L1 axis and tumor hypoxia dynamics during chemoradiation were assessed using Spearman's rank correlations. Hypoxia dynamics during treatment were quantified by subtracting the standardized uptake value (SUV) index at baseline from the SUV values at weeks 2 or 5, whereby SUV index was defined as ratio of maximum tumor [F]FMISO SUV to mean SUV in the contralateral sternocleidomastoid muscle ( tumor-to-muscle ratio). The impact of the PD-1/PD-L1 expression alone and in combination with persistent tumor hypoxia on locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) was examined using log-rank tests and Cox proportional hazards models. Neither PD-L1 nor PD-1 expression levels on tumor-infiltrating immune cells influenced LRC (HR = 0.734; = 0.480 for PD-L1, HR = 0.991; = 0.989 for PD-1), PFS (HR = 0.813; = 0.597 for PD-L1, HR = 0.796; = 0.713 for PD-1) or OS (HR = 0.698; = 0.405 for PD-L1, HR = 0.315; = 0.265 for PD-1). However, patients with no hypoxia resolution between weeks 0 and 2 and PD-L1 expression on tumor cells, quantified by a tumor proportional score (TPS) of at least 1%, showed significantly worse LRC (HR = 3.374, = 0.022) and a trend towards reduced PFS (HR = 2.752, = 0.052). In the multivariate Cox regression analysis, the combination of absent tumor hypoxia resolution and high tumoral PD-L1 expression remained a significant prognosticator for impaired LRC (HR = 3.374, = 0.022). On the other side, tumoral PD-L1 expression did not compromise the outcomes of patients whose tumor-associated hypoxia declined between week 0 and 2 during chemoradiation (LRC: HR = 1.186, = 0.772, PFS: HR = 0.846, = 0.766). In this exploratory analysis, we showed for the first time that patients with both persistent tumor-associated hypoxia during treatment and PD-L1 expression on tumor cells exhibited a worse outcome, while the tumor cells' PD-L1 expression did not influence the outcomes of patients with early tumor hypoxia resolution. While the results have to be validated in an independent cohort, these findings form a foundation to investigate the combination of hypoxic modification and immune checkpoint inhibitors for the unfavorable subgroup, moving forward towards personalized radiation oncology treatment.
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http://dx.doi.org/10.7150/thno.48392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415814PMC
July 2020

γδ T-cell Receptors Derived from Breast Cancer-Infiltrating T Lymphocytes Mediate Antitumor Reactivity.

Cancer Immunol Res 2020 04 4;8(4):530-543. Epub 2020 Feb 4.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

γδ T cells in human solid tumors remain poorly defined. Here, we describe molecular and functional analyses of T-cell receptors (TCR) from tumor-infiltrating γδ T lymphocytes (γδ TIL) that were in direct contact with tumor cells in breast cancer lesions from archival material. We observed that the majority of γδ TILs harbored a proinflammatory phenotype and only a minority associated with the expression of IL17. We characterized TCRγ or TCRδ chains of γδ TILs and observed a higher proportion of Vδ2 T cells compared with other tumor types. By reconstructing matched Vδ2 TCRγ and TCRδ pairs derived from single-cell sequencing, our data suggest that γδ TILs could be active against breast cancer and other tumor types. The reactivity pattern against tumor cells depended on both the TCRγ and TCRδ chains and was independent of additional costimulation through other innate immune receptors. We conclude that γδ TILs can mediate tumor reactivity through their individual γδ TCR pairs and that engineered T cells expressing TCRγ and δ chains derived from γδ TILs display potent antitumor reactivity against different cancer cell types and, thus, may be a valuable tool for engineering immune cells for adoptive cell therapies.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0513DOI Listing
April 2020

Sclerosing angiomatoid nodular transformation of the spleen, a rare cause for splenectomy: Two case reports.

World J Clin Cases 2020 Jan;8(1):103-109

Institute of Surgical Pathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.

Background: Sclerosing angiomatoid nodular transformation (SANT) is a rare benign disease of the spleen with unknown origin. Clinical symptoms are inhomogeneous, and suspicious splenic lesion often found incidentally, leading to splenectomy, as malignancy cannot securely be ruled out. Diagnosis is made histologically after resection.

Case Summary: Two cases of German, white, non-smoking, and non-drinking patients of normal weight are presented. The first one is a 26-year-old man without medical history who was exhibiting an undesired weight loss of 10 kg and recurring vomiting for about 18 mo. The second one is a 65-year-old woman with hypertension who had previously undergone gynecological surgery, suffering from a lasting feeling of abdominal fullness. Both showed radiologically an inhomogeneous splenic lesion leading to splenectomy approximately 6 and 9 wk after surgical presentation. Both diagnoses of SANT were made histologically. Follow-up went well, and both were treated according to the recommendation for asplenic patients.

Conclusion: SANT is a rare cause of splenectomy and an incidental histological finding. Further research should focus on clinical and radiological diagnosis of SANT as well as on treatment of patients with asymptomatic and small findings.
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http://dx.doi.org/10.12998/wjcc.v8.i1.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962071PMC
January 2020

Accessible and reproducible mass spectrometry imaging data analysis in Galaxy.

Gigascience 2019 12;8(12)

Institute of Surgical Pathology, Medical Center - University of Freiburg, Breisacher Straße 115a, 79106 Freiburg, Germany.

Background: Mass spectrometry imaging is increasingly used in biological and translational research because it has the ability to determine the spatial distribution of hundreds of analytes in a sample. Being at the interface of proteomics/metabolomics and imaging, the acquired datasets are large and complex and often analyzed with proprietary software or in-house scripts, which hinders reproducibility. Open source software solutions that enable reproducible data analysis often require programming skills and are therefore not accessible to many mass spectrometry imaging (MSI) researchers.

Findings: We have integrated 18 dedicated mass spectrometry imaging tools into the Galaxy framework to allow accessible, reproducible, and transparent data analysis. Our tools are based on Cardinal, MALDIquant, and scikit-image and enable all major MSI analysis steps such as quality control, visualization, preprocessing, statistical analysis, and image co-registration. Furthermore, we created hands-on training material for use cases in proteomics and metabolomics. To demonstrate the utility of our tools, we re-analyzed a publicly available N-linked glycan imaging dataset. By providing the entire analysis history online, we highlight how the Galaxy framework fosters transparent and reproducible research.

Conclusion: The Galaxy framework has emerged as a powerful analysis platform for the analysis of MSI data with ease of use and access, together with high levels of reproducibility and transparency.
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http://dx.doi.org/10.1093/gigascience/giz143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901077PMC
December 2019

Correlative analyses between tissue-based hypoxia biomarkers and hypoxia PET imaging in head and neck cancer patients during radiochemotherapy-results from a prospective trial.

Eur J Nucl Med Mol Imaging 2020 05 7;47(5):1046-1055. Epub 2019 Dec 7.

German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Purpose: Tumor hypoxia impairs the response of head-and-neck cancer (HNSCC) patients to radiotherapy and can be detected both by tissue biomarkers and PET imaging. However, the value of hypoxia biomarkers and imaging for predicting HNSCC patient outcomes are incompletely understood, and potential correlations between tissue and PET data remain to be elucidated. Here, we performed exploratory analyses of potential correlations between tissue-based hypoxia biomarkers and longitudinal hypoxia imaging in a prospective trial of HNSCC patients.

Methods: Forty-nine patients undergoing chemoradiation for locally advanced HNSCCs were enrolled in this prospective trial. They underwent baseline biopsies and [F]FDG PET imaging and [F]FMISO PET at weeks 0, 2, and 5 during treatment. Immunohistochemical analyses for p16, Ki67, CD34, HIF1α, CAIX, Ku80, and CD44 were performed, and HPV status was assessed. Biomarker expression was correlated with biological imaging information and patient outcome data.

Results: High HIF1α tumor levels significantly correlated with increased tumor hypoxia at week 2 as assessed by the difference in the [F]FMISO tumor-to-background ratios, and high HIF1α and CAIX expressions were both associated with a deferred decrease in hypoxia between weeks 2 and 5. Loco-regional recurrence rates after radiotherapy were significantly higher in patients with high CAIX expression and also increased for high levels of the DNA repair factor Ku80. HPV status did not correlate with any of the tested hypoxia biomarkers, and HPV-positive patients showed higher loco-regional control rates and progression-free survival independent of their hypoxia dynamics.

Conclusion: In this exploratory trial, high expression of the tissue-based hypoxia biomarkers HIF1α and CAIX correlated with adverse hypoxia dynamics in HNSCCs during chemoradiation as assessed by PET imaging, and high CAIX levels were associated with increased loco-regional recurrence rates. Hence, hypoxia biomarkers warrant further investigations as potential predictors of hypoxia dynamics and hypoxia-associated radiation resistance.
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http://dx.doi.org/10.1007/s00259-019-04598-9DOI Listing
May 2020

Treating Post-Angioplasty Dissection in the Femoropopliteal Arteries Using the Tack Endovascular System: 12-Month Results From the TOBA II Study.

JACC Cardiovasc Interv 2019 12;12(23):2375-2384

Yale Cardiovascular Research Group, New Haven, Connecticut.

Objectives: The aim of this study was to evaluate the Tack Endovascular System (Intact Vascular, Wayne, Pennsylvania) for treating dissections following angioplasty in the superficial femoral artery and/or proximal popliteal artery.

Background: Dissection after angioplasty of femoropopliteal arteries with either a plain balloon or a drug-coated balloon (DCB) can negatively affect both short- and long-term outcomes.

Methods: TOBA (Tack Optimized Balloon Angioplasty) II is a prospective, single-arm, multicenter study enrolling 213 patients, all with dissection following angioplasty. Eligibility included Rutherford classification 2 to 4 with a de novo or nonstented restenotic lesion in the superficial femoral artery or proximal popliteal artery undergoing plain balloon or DCB angioplasty. Following dilation, lesions with <30% residual stenosis and presence of ≥1 dissection were enrolled. The 12-month efficacy endpoint was primary patency (freedom from duplex-derived binary restenosis and clinically driven target lesion revascularization.

Results: Patients' mean age was 68 ± 9 years, and 43.2% had diabetes. Twenty-three percent of lesions were chronic total occlusions, and ∼60% had moderate to severe calcium. The mean lesion length was 74.3 ± 40.6 mm. Severe dissection (grade ≥C) was present in 69.4%. By operator choice, 57.7% of patients underwent DCB angioplasty. Most (92.1%) dissections resolved completely, and only 1 bailout stent was required. There were no 30-day major adverse events. The 12-month efficacy endpoint was met, with Kaplan-Meier primary patency and freedom from clinically driven target lesion revascularization of 79.3% and 86.5%, respectively. At 12 months, there were no device fractures or clinically significant migrations, and significant improvements were noted in Rutherford category, ankle-brachial index, and quality of life.

Conclusions: TOBA II demonstrated the safety and efficacy of the Tack Endovascular System for focal dissection repair following standard and DCB angioplasty.
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http://dx.doi.org/10.1016/j.jcin.2019.08.005DOI Listing
December 2019

Parallel Processing Strategies for Big Geospatial Data.

Authors:
Martin Werner

Front Big Data 2019 3;2:44. Epub 2019 Dec 3.

Institute for Applied Computer Science, Forschungsinstitut CODE, Bundeswehr University Munich, Munich, Germany.

This paper provides an abstract analysis of parallel processing strategies for spatial and spatio-temporal data. It isolates aspects such as data locality and computational locality as well as redundancy and locally sequential access as central elements of parallel algorithm design for spatial data. Furthermore, the paper gives some examples from simple and advanced GIS and spatial data analysis highlighting both that big data systems have been around long before the current hype of big data and that they follow some design principles which are inevitable for spatial data including distributed data structures and messaging, which are, however, incompatible with the popular MapReduce paradigm. Throughout this discussion, the need for a replacement or extension of the MapReduce paradigm for spatial data is derived. This paradigm should be able to deal with the imperfect data locality inherent to spatial data hindering full independence of non-trivial computational tasks. We conclude that more research is needed and that spatial big data systems should pick up more concepts like graphs, shortest paths, raster data, events, and streams at the same time instead of solving exactly the set of spatially separable problems such as line simplifications or range queries in manydifferent ways.
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http://dx.doi.org/10.3389/fdata.2019.00044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931969PMC
December 2019

Prospective Evaluation of the TIGRIS Vascular Stent Within a Modern Treatment Algorithm.

J Endovasc Ther 2019 10 14;26(5):637-642. Epub 2019 Jul 14.

Department of Radiology, Hanusch Krankenhaus, Vienna, Austria.

To prospectively evaluate the safety and efficacy of the TIGRIS Vascular Stent in the superficial femoral artery (SFA) and proximal popliteal artery within a treatment algorithm that reserved stent usage for more challenging patients. This prospective, single-center study enrolled 97 patients (mean age 68.7 years; 66 men) who were treated for 100 de novo or nonstented restenotic femoropopliteal lesions (≥70% stenosis) and had recoil or dissection after plain balloon predilation. The average lesion length was 5.6±2.3 cm (maximum 8 cm per protocol). The composite primary efficacy outcome was 12-month primary patency, defined as a peak systolic velocity ratio ≤2.5 at the stented target lesion on duplex ultrasound, and no clinically-driven reintervention within the stented segment. The primary safety outcome was freedom from device- and procedure-related target vessel revascularization, target limb major amputation (above the metatarsals), or death through 30 days. Secondary outcomes included secondary patency, clinically-driven target lesion revascularization (TLR), Rutherford category change relative to baseline, and binary restenosis of the target lesion. All devices were successfully implanted with no device-related complications at the time of implant or within the 30-day postimplant window. The average stented length was 7.0±2.5 cm; no stent elongation was observed during deployment. One patient was lost to follow-up before 12 months and another died of an unrelated cause, leaving 95 patients (98 lesions) available for 12-month follow-up and 77 patients/lesions for the 24-month preliminary analysis. The binary primary and secondary patency rates at 12 months were 92.9% and 100%. The binary freedom from TLR was 94.9%. At 24 months, the Kaplan-Meier estimate of primary patency was 90.0%. This prospective study demonstrated that the TIGRIS Vascular Stent is a safe and effective device in a modern treatment algorithm that reserved bare stent use for postangioplasty dissection or recoil in distal femoropopliteal arteries.
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http://dx.doi.org/10.1177/1526602819862778DOI Listing
October 2019

Global analysis reveals climatic controls on the oxygen isotope composition of cave drip water.

Nat Commun 2019 07 5;10(1):2984. Epub 2019 Jul 5.

Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research, Bremerhaven, 27570, Germany.

The oxygen isotope composition of speleothems is a widely used proxy for past climate change. Robust use of this proxy depends on understanding the relationship between precipitation and cave drip water δO. Here, we present the first global analysis, based on data from 163 drip sites, from 39 caves on five continents, showing that drip water δO is most similar to the amount-weighted precipitation δO where mean annual temperature (MAT) is < 10 °C. By contrast, for seasonal climates with MAT > 10 °C and < 16 °C, drip water δO records the recharge-weighted δO. This implies that the δO of speleothems (formed in near isotopic equilibrium) are most likely to directly reflect meteoric precipitation in cool climates only. In warmer and drier environments, speleothems will have a seasonal bias toward the precipitation δO of recharge periods and, in some cases, the extent of evaporative fractionation of stored karst water.
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http://dx.doi.org/10.1038/s41467-019-11027-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611902PMC
July 2019

Radiomic features from PSMA PET for non-invasive intraprostatic tumor discrimination and characterization in patients with intermediate- and high-risk prostate cancer - a comparison study with histology reference.

Theranostics 2019 13;9(9):2595-2605. Epub 2019 Apr 13.

Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine. University of Freiburg, Germany.

To evaluate the performance of radiomic features (RF) derived from PSMA PET for intraprostatic tumor discrimination and non-invasive characterization of Gleason score (GS) and pelvic lymph node status. Patients with prostate cancer (PCa) who underwent [Ga]-PSMA-11 PET/CT followed by radical prostatectomy and pelvic lymph node dissection were prospectively enrolled (n=20). Coregistered histopathological gross tumor volume (GTV-Histo) in the prostate served as reference. 133 RF were derived from GTV-Histo and from manually created segmentations of the intraprostatic tumor volume (GTV-Exp). Spearman´s correlation coefficients (ρ) were assessed between RF derived from the different GTVs. We additionally analyzed the differences in RF values for PCa and non-PCa tissues. Furthermore, areas under receiver-operating characteristics curves (AUC) were calculated and uni- and multivariate analyses were performed to evaluate the RF based discrimination of GS 7 and ≥8 disease and of patients with nodal spread (pN1) and non-nodal spread (pN0) in surgical specimen. The results found in the latter analyses were validated by a retrospective cohort of 40 patients. Most RF from GTV-Exp showed strong correlations with RF from GTV-Histo (86% with ρ>0.7). 81% and 76% of RF from GTV-Exp and GTV-Histo significantly discriminated between PCa and non-PCa tissue. The texture feature QSZHGE discriminated between GS 7 and ≥8 considering GTV-Histo (AUC=0.93) and GTV-Exp (prospective cohort: AUC=0.91 / validation cohort: AUC=0.84). QSZHGE also discriminated between pN1 and pN0 disease considering GTV-Histo (AUC=0.85) and GTV-Exp (prospective cohort: AUC=0.87 / validation cohort: AUC=0.85). In uni- and multivariate analyses including patients of both cohorts QSZHGE was a statistically significant (p<0.01) predictor for PCa patients with GS ≥8 tumors and pN1 status. RF derived from PSMA PET discriminated between PCa and non-PCa tissue within the prostate. Additionally, the texture feature QSZHGE discriminated between GS 7 and GS ≥8 tumors and between patients with pN1 and pN0 disease. Our results support the role of RF in PSMA PET as a new tool for non-invasive PCa discrimination and characterization of its biological properties.
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http://dx.doi.org/10.7150/thno.32376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525993PMC
May 2020

Variant classification in precision oncology.

Int J Cancer 2019 12 21;145(11):2996-3010. Epub 2019 May 21.

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Next-generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool in translational oncology. Its rapidly increasing use during the last decade has expanded the options for targeted tumor therapies, and molecular tumor boards have grown accordingly. However, with increasing detection of genetic alterations, their interpretation has become more complex and error-prone, potentially introducing biases and reducing benefits in clinical practice. To facilitate interdisciplinary discussions of genetic alterations for treatment stratification between pathologists, oncologists, bioinformaticians, genetic counselors and medical scientists in specialized molecular tumor boards, several systems for the classification of variants detected by large-scale sequencing have been proposed. We review three recent and commonly applied classifications and discuss their individual strengths and weaknesses. Comparison of the classifications underlines the need for a clinically useful and universally applicable variant reporting system, which will be instrumental for efficient decision making based on sequencing analysis in oncology. Integrating these data, we propose a generalizable classification concept featuring a conservative and a more progressive scheme, which can be readily applied in a clinical setting.
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http://dx.doi.org/10.1002/ijc.32358DOI Listing
December 2019

Resolving the controls of water vapour isotopes in the Atlantic sector.

Nat Commun 2019 04 9;10(1):1632. Epub 2019 Apr 9.

Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research, Bremerhaven, 27570, Germany.

Stable water isotopes are employed as hydrological tracers to quantify the diverse implications of atmospheric moisture for climate. They are widely used as proxies for studying past climate changes, e.g., in isotope records from ice cores and speleothems. Here, we present a new isotopic dataset of both near-surface vapour and ocean surface water from the North Pole to Antarctica, continuously measured from a research vessel throughout the Atlantic and Arctic Oceans during a period of two years. Our observations contribute to a better understanding and modelling of water isotopic composition. The observations reveal that the vapour deuterium excess within the atmospheric boundary layer is not modulated by wind speed, contrary to the commonly used theory, but controlled by relative humidity and sea surface temperature only. In sea ice covered regions, the sublimation of deposited snow on sea ice is a key process controlling the local water vapour isotopic composition.
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http://dx.doi.org/10.1038/s41467-019-09242-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456600PMC
April 2019

Sustainable Antirestenosis Effect With a Low-Dose Drug-Coated Balloon: The ILLUMENATE European Randomized Clinical Trial 2-Year Results.

JACC Cardiovasc Interv 2018 12;11(23):2357-2364

Center for Diagnostic Radiology & Minimally Invasive Therapy, The Jewish Hospital, Berlin, Germany.

Objectives: The aim of this study was to assess the safety and effectiveness of a next-generation low-dose drug-coated balloon (DCB) designed to optimize the amount of drug transferred into the vessel wall and to maximize the amount of time the drug resides in the vessel wall.

Background: Several randomized controlled studies evaluating various DCBs have demonstrated a significantly higher patency rate compared with noncoated percutaneous transluminal angioplasty balloons at 1 year. However, the data are limited and vary by DCB at longer follow-up time points. An earlier generation low-dose DCB failed to demonstrate significant treatment effect at 2 years, raising questions regarding the durability of low-dose DCBs.

Methods: In this prospective, multicenter trial, 294 patients were randomized (3:1) to treatment with a DCB or an uncoated percutaneous transluminal angioplasty balloon. Assessments at 2 years included primary patency with duplex ultrasonography, clinically driven target lesion revascularization, and functional outcomes.

Results: Primary patency at 2 years was significantly higher in the DCB cohort (75.9% vs. 61.0%; p = 0.025), and the rate of clinically driven target lesion revascularization was significantly lower (12.1% vs. 30.5%; p < 0.001). There were no major limb amputations in either group. The rates of all-cause (6.5% vs. 5.1%; p = 1.00) and cardiovascular-related (1.6% vs. 1.7%; p = 1.00) mortality were similar between groups. Functional improvements over baseline were sustained in both groups, with 60% fewer reinterventions in the DCB group.

Conclusions: A sustained treatment effect is achievable with a low-dose DCB with an optimized coating formulation. This trial demonstrated for the first time a statistically significantly higher primary patency rate for a low-dose DCB versus PTA at 2 years. (CVI Drug Coated Balloon European Randomized Clinical Trial; NCT01858363).
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http://dx.doi.org/10.1016/j.jcin.2018.08.034DOI Listing
December 2018

Image Quality Performance of Virtual Single-Source CT Using Dual-Source Computed Tomography.

Acad Radiol 2019 08 25;26(8):1095-1101. Epub 2018 Oct 25.

Institute for Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany.

Rationale And Objectives: The aim of this study is to analyze the image quality provided by a dual-source (DS) data set and a single-source (SS) data set at the same radiation exposure, in order to evaluate a dose splitting method for dual-source scanning protocols.

Materials And Methods: A 192-slice dual-source third generation CT (Somatom Force; Siemens Healthcare, Forchheim, Germany) was used to image a Catphan phantom (Catphan503; The Phantom Laboratory, Salem, New York) utilizing different X-ray tube voltages from 70 to 120 kVp with an organ-based tube-current modulation technique (X-CARE; Siemens Healthcare, Forchheim, Germany). In order to keep the radiation dose (given by volume computed tomography dose index) in a clinically relevant range, different X-ray tube time-current products ranging from 80 to 300 mAs were selected. The data sets by each X-ray tube voltage were collected using a single-source as well as a dual-source mode. The measurements in the dual-source mode were performed with five different tube currents of the X-ray tube A and B. Thereby, the tube current ratios were 50%|50% (DS 0.5), 60%|40% (DS 0.6), 70%|30% (DS 0.7), 80%|20% (DS 0.8), and 90%|10% (DS 0.9). The images were reconstructed by the use of a filter-back projection (Br40) and an advanced mode led iterative reconstruction algorithms (advanced modeled iterative reconstruction algorithms [ADMIRE]; Siemens Healthcare, Forchheim, Germany) with a strength range of 1-5. The image quality was evaluated in terms of noise, contrast-to-noise ratio (CNR), low-contrast detectability expressed as the structural similarity index (SSIM) and spatial resolution quantified by the full width at half maximum of the line-spread function.

Results: Image noise decreased by the use of the dual-source mode, which led to improvement of their CNR compared to the single-source mode. SSIM showed an almost constant behavior by both modes. The spatial resolution indicated a lower trend by the dual-source mode in comparison to the single-source mode. However, the loss of the spatial resolution performance was lower than 5% for the dual-source modes.

Conclusion: The presented phantom study demonstrated that SSIM and spatial resolution performance obtained by dual-source CT protocols showed a negligible variation to those by the single-source CT. However, the noise and CNR displayed an improvement for the dual-source CT. Therefore, the use of the dual-source CT enables to split the radiation dose between X-ray tubes and to compare the data sets with different radiation dose levels without loss in the image quality.
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http://dx.doi.org/10.1016/j.acra.2018.09.021DOI Listing
August 2019

Primary outcomes and mechanism of action of intravascular lithotripsy in calcified, femoropopliteal lesions: Results of Disrupt PAD II.

Catheter Cardiovasc Interv 2019 02 25;93(2):335-342. Epub 2018 Nov 25.

Universitäts- Herzzentrum Freiburg, Bad Krozingen, Germany.

Objective: DISRUPT PAD II was designed to evaluate the safety and performance of intravascular lithotripsy (IVL), a novel approach using pulsatile sonic pressure waves, to modify intimal and medial calcium in stenotic peripheral arteries.

Background: Vascular calcification restricts vessel expansion, increases the risk of vascular complications, and may impair the effect of anti-proliferative therapy.

Methods: Disrupt PAD II was a non-randomized, multi-center study that enrolled 60 subjects with complex, calcified peripheral arterial stenosis at eight sites. Patients were treated with IVL and followed to 12-months. The primary safety endpoint was major adverse events (MAE) through 30 days. The primary effectiveness endpoint was patency at 12 months as adjudicated by duplex ultrasonography (DUS). Key secondary endpoints included acute procedure success, freedom from re-intervention, and functional outcomes.

Results: Between June 2015 and December 2015, subjects with moderate or severe calcified arterial lesions were enrolled. The final residual stenosis was 24.2%, with an average acute gain of 3.0 mm. The 30-day MAE rate was 1.7% with one grade D dissection that resolved following stent placement. Primary patency at 12 months was 54.5%, and clinically driven TLR at 12 months was 20.7%. Optimal IVL technique defined by correct balloon sizing and avoiding therapeutic miss, improved 12-month primary patency and TLR outcomes to 62.9% and 8.6%, respectively.

Conclusions: IVL demonstrated compelling safety with minimal vessel injury, and minimal use of adjunctive stents in a complex, difficult to treat population.
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http://dx.doi.org/10.1002/ccd.27943DOI Listing
February 2019

A Five-MicroRNA Signature Predicts Survival and Disease Control of Patients with Head and Neck Cancer Negative for HPV Infection.

Clin Cancer Res 2019 03 31;25(5):1505-1516. Epub 2018 Aug 31.

Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer," Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.

Purpose: Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is associated with unfavorable prognosis, while independent prognostic markers remain to be defined.

Experimental Design: We retrospectively performed miRNA expression profiling. Patients were operated for locally advanced HPV-negative HNSCC and had received radiochemotherapy in eight different hospitals (DKTK-ROG; = 85). Selection fulfilled comparable demographic, treatment, and follow-up characteristics. Findings were validated in an independent single-center patient sample (LMU-KKG; = 77). A prognostic miRNA signature was developed for freedom from recurrence and tested for other endpoints. Recursive-partitioning analysis was performed on the miRNA signature, tumor and nodal stage, and extracapsular nodal spread. Technical validation used qRT-PCR. An miRNA-mRNA target network was generated and analyzed.

Results: For DKTK-ROG and LMU-KKG patients, the median follow-up was 5.1 and 5.3 years, and the 5-year freedom from recurrence rate was 63.5% and 75.3%, respectively. A five-miRNA signature (hsa-let-7g-3p, hsa-miR-6508-5p, hsa-miR-210-5p, hsa-miR-4306, and hsa-miR-7161-3p) predicted freedom from recurrence in DKTK-ROG [hazard ratio (HR) 4.42; 95% confidence interval (CI), 1.98-9.88, < 0.001], which was confirmed in LMU-KKG (HR 4.24; 95% CI, 1.40-12.81, = 0.005). The signature also predicted overall survival (HR 3.03; 95% CI, 1.50-6.12, = 0.001), recurrence-free survival (HR 3.16; 95% CI, 1.65-6.04, < 0.001), and disease-specific survival (HR 5.12; 95% CI, 1.88-13.92, < 0.001), all confirmed in LMU-KKG data. Adjustment for relevant covariates maintained the miRNA signature predicting all endpoints. Recursive-partitioning analysis of both samples combined classified patients into low ( = 17), low-intermediate ( = 80), high-intermediate ( = 48), or high risk ( = 17) for recurrence ( < 0.001).

Conclusions: The five-miRNA signature is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative HNSCC..
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0776DOI Listing
March 2019

Reconciling glacial Antarctic water stable isotopes with ice sheet topography and the isotopic paleothermometer.

Nat Commun 2018 08 30;9(1):3537. Epub 2018 Aug 30.

Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Sciences, Bussestr. 24, 27570, Bremerhaven, Germany.

Stable water isotope records from Antarctica are key for our understanding of Quaternary climate variations. However, the exact quantitative interpretation of these important climate proxy records in terms of surface temperature, ice sheet height and other climatic changes is still a matter of debate. Here we report results obtained with an atmospheric general circulation model equipped with water isotopes, run at a high-spatial horizontal resolution of one-by-one degree. Comparing different glacial maximum ice sheet reconstructions, a best model data match is achieved for the PMIP3 reconstruction. Reduced West Antarctic elevation changes between 400 and 800 m lead to further improved agreement with ice core data. Our modern and glacial climate simulations support the validity of the isotopic paleothermometer approach based on the use of present-day observations and reveal that a glacial ocean state as displayed in the GLAMAP reconstruction is suitable for capturing the observed glacial isotope changes in Antarctic ice cores.
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http://dx.doi.org/10.1038/s41467-018-05430-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117368PMC
August 2018