Publications by authors named "Raphael Koch"

58 Publications

Predicting the Effect of Variants of Unknown Significance in Molecular Tumor Boards with the VUS-Predict Pipeline.

Stud Health Technol Inform 2021 Sep;283:209-216

Dept. of Medical Bioinformatics, University Medical Center Göttingen, Germany.

Precision oncology utilizing molecular biomarkers for targeted therapies is one of the hopes to treat cancer. The availability of patient specific molecular profiling through next-generation sequencing, though, increases the amount of available data per patient to an extent that computational support is required to identify potential driver alterations for targeted therapies and rational decision-making in molecular tumor boards (MTBs). For some genetic variants evidence-based drug recommendations are available in public databases, but for the majority, the variants of unknown significance (VUS), this clinical information is missing. Additionally, for most of these variants no information about the functional impact on the protein is accessible. To acquire maximal functional evidence for VUS, the VUS-Predict pipeline collects estimations about the effect of a VUS by integrating multiple pre-existing tools. Pre-existing tools implement different approaches for their predictions, which are summarized by our newly developed tool with a common score and classification in neutral or deleterious variants. The primary tools are chosen based on their sensitivity and specificity on well-known variants of the transcription factor TP53. Resulting negative and positive predictive values are used to calibrate the VUS-Predict pipeline. Further, the pipeline is evaluated using data from public cancer databases and cases of the MTB in Göttingen, both also in comparison with the ensemble method REVEL. The results show that VUS-Predict has clear advantages in a clinical setting due to clear and traceable predictions. In particular, VUS outperforms REVEL in the real-life setting of a MTB. Likewise, an evaluation on variants of public cancer databases confirms the good results of VUS-Predict and shows the need for a reliable gold standard and unambiguous results of the tools under test.
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http://dx.doi.org/10.3233/SHTI210562DOI Listing
September 2021

Increased renal function decline in fast metabolizers using extended-release tacrolimus after kidney transplantation.

Sci Rep 2021 08 2;11(1):15606. Epub 2021 Aug 2.

Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.

Fast metabolism of immediate-release tacrolimus (IR-Tac) is associated with decreased kidney function after renal transplantation (RTx) compared to slow metabolizers. We hypothesized, by analogy, that fast metabolism of extended-release tacrolimus (ER-Tac) is associated with worse renal function. We analyzed data from patients who underwent RTx at three different transplant centers between 2007 and 2016 and received an initial immunosuppressive regimen with ER-Tac, mycophenolate, and a corticosteroid. Three months after RTx, a Tac concentration to dose ratio (C/D ratio) < 1.0 ng/ml · 1/mL defined fast ER-Tac metabolism and ≥ 1.0 ng/ml · 1/mL slow metabolism. Renal function (estimated glomerular filtration rate, eGFR), first acute rejection (AR), conversion from ER-Tac, graft and patient survival were observed up to 60-months. 610 RTx patients were divided into 192 fast and 418 slow ER-Tac metabolizers. Fast metabolizers showed a decreased eGFR at all time points compared to slow metabolizers. The fast metabolizer group included more patients who were switched from ER-Tac (p < 0.001). First AR occurred more frequently (p = 0.008) in fast metabolizers, while graft and patient survival rates did not differ between groups (p = 0.529 and p = 0.366, respectively). Calculation of the ER-Tac C/D ratio early after RTx may facilitate individualization of immunosuppression and help identify patients at risk for an unfavorable outcome.
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http://dx.doi.org/10.1038/s41598-021-95201-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329201PMC
August 2021

Diagnostic, Clinical and Post-SARS-CoV-2 Scenarios in Cancer Patients with SARS-CoV-2: Retrospective Analysis in Three German Cancer Centers.

Cancers (Basel) 2021 Jun 11;13(12). Epub 2021 Jun 11.

Medical Clinic A, Haematology, Haemostasiology, Oncology and Pulmonology, University Hospital Münster, 48149 Münster, Germany.

Oncologists face challenges in the management of SARS-CoV-2 infections and post-SARS-CoV-2 cancer treatment. We analyzed diagnostic, clinical and post-SARS-CoV-2 scenarios in patients from three German cancer centers with RT-PCR confirmed SARS-CoV-2 infection. Sixty-three patients with SARS-CoV-2 and hematologic or solid neoplasms were included. Thirty patients were initially asymptomatic, 10 of whom developed COVID-19 symptoms subsequently. Altogether 20 (32%) patients were asymptomatic, 18 (29%) had mild, 12 (19%) severe and 13 (20%) critical courses. Lymphocytopenia increased risk of severe/critical COVID-19 three-fold ( = 0.015). Asymptomatic course was not associated with age, remission status, therapies or co-morbidities. Secondary bacterial infection accompanied more than one third of critical COVID-19 cases. Treatment was delayed post-SARS-CoV-2 in 46 patients, 9 of whom developed progressive disease (PD). Cancer therapy was modified in 8 SARS-CoV-2 survivors because of deteriorating performance or PD. At the last follow-up, 17 patients had died from COVID-19 ( = 8) or PD ( = 9) giving an estimated 73% four-month overall survival rate. SARS-CoV-2 infection has a heterogenous course in cancer patients. Lymphocytopenia carries a significant risk of severe/critical COVID-19. SARS-CoV-2 disruption of therapy is as serious as SARS-CoV-2 infection itself. Careful surveillance will allow early restart of the anti-cancer treatment.
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http://dx.doi.org/10.3390/cancers13122917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230714PMC
June 2021

Correlation of first-trimester thymus size with chromosomal anomalies.

J Perinat Med 2021 Jun 10;49(5):604-613. Epub 2021 Feb 10.

Department of Obstetrics and Gynecology, University Hospital of Muenster, Muenster, Germany.

Objectives: The aim of this study was to investigate the correlation between fetal thymus size measured during first-trimester screening and chromosomal anomalies.

Methods: This study is a retrospective evaluation, in which the anterior-posterior diameter of the thymus in a midsagittal plane was measured in first-trimester ultrasound between 11 and 13 weeks of gestation in 168 fetuses with chromosomal anomalies (study group) and 593 healthy fetuses (control group). The included cases were subdivided into six groups: (1) trisomy 21, (2) trisomy 18, (3) trisomy 13, (4) Turner syndrome, (5) triploidy and (6) normal controls. Thymus size measurements were adjusted to the week of gestation, which was determined by ultrasound using crown-rump-length (CRL), by calculating a ratio between CRL and thymus size (CRL-thymus-ratio). Each study group was compared with the control group separately.

Results: Thymus size in fetuses affected by trisomy 18 or trisomy 13 was noticeably smaller compared to the control group (1.4 mm [1.3, 1.5] and 1.3 mm [1.2, 1.4] vs. 1.8 mm [1.6, 2.1]; all p<0.001; respectively). The thymus size of fetuses with trisomy 21 and Turner syndrome did not differ from healthy fetuses. Between the CRL-thymus-ratios of the separate study groups no statistically noticeable differences could be found.

Conclusions: Fetal thymus size appeared to be smaller in pregnancies affected by trisomy 18 and trisomy 13. The predictive value of fetal thymus size in first-trimester screening should be evaluated prospectively.
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http://dx.doi.org/10.1515/jpm-2020-0599DOI Listing
June 2021

Retrospective analysis of the long-term effect of subgingival air polishing in supportive periodontal therapy.

J Clin Periodontol 2021 02 9;48(2):263-271. Epub 2020 Nov 9.

Clinic for Periodontology and Conservative Dentistry, University of Muenster, Münster, Germany.

Aim: Glycine powder air polishing (GPAP) procedure has become popular. Aim of the analysis was to compare the clinical outcomes during supportive periodontal therapy (SPT) of subgingival application of GPAP with those using sole conventional mechanical debridement (SC).

Material And Methods: Over a median SPT period of 5.3 years (re-evaluation through last observation), the GPAP cohort (n = 263) received supra- and subgingival biofilm removal with GPAP. Supragingival calculus was removed using curets and sonic scalers here. Patients in the SC cohort (n = 264) were treated with sonic scalers, curets and rubber cup polishing only. Changes in, that is pocket probing depth (PPD) and furcation involvement were assessed retrospectively. A bootstrapping equivalence testing method in line with the principle of the two one-sided tests (TOST) procedure was used to compare clinical outcomes.

Results: The GPAP procedure was statistically equivalent to SC regarding the number of sites with stable PPDs (83.3%; IQR 68.8%, 91.0% vs. 84.0%; IQR 77.8%, 90.0%). However, in the GPAP cohort, a trend towards deterioration in furcation status (no equivalence) was noted.

Conclusions: In periodontal maintenance, the use of GPAP instead of mechanical plaque removal does not improve the clinical outcome. It seems to be contraindicated to treat furcation defects with GPAP only.
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http://dx.doi.org/10.1111/jcpe.13392DOI Listing
February 2021

Controversies in the Treatment of Peripheral T-cell Lymphoma.

Hemasphere 2020 Oct 1;4(5):e461. Epub 2020 Sep 1.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

Peripheral T-cell lymphomas are a heterogeneous group of rare diseases with an aggressive behavior and dismal prognosis. Their classification is complex and still evolving, and several biomolecular markers now help refine the prognosis of specific disease entities, although still have limited impact in tailoring the treatment. First-line treatment strategies can cure only a minority of patients and relapsed-refractory disease still represents the major cause of failure. Frontline autologous transplantation may have an impact in the consolidation of response; however, its role is still questioned as far as complete responses obtained after induction chemotherapy are concerned. Newer drugs are now being evaluated in clinical trials, but effective salvage strategies for those who experience treatment failures are lacking. Here we review and discuss the most controversial aspects of diagnosis and treatment of peripheral T-cell lymphomas.
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http://dx.doi.org/10.1097/HS9.0000000000000461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469987PMC
October 2020

DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas.

J Hematol Oncol 2020 07 16;13(1):95. Epub 2020 Jul 16.

Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Background: Patients with advanced T cell lymphomas (TCLs) have limited therapeutic options and poor outcomes in part because their TCLs evade apoptosis through upregulation of anti-apoptotic Bcl-2 proteins. Subsets of TCL cell lines, patient-derived xenografts (PDXs), and primary patient samples depend on Bcl-xL for survival. However, small molecule Bcl-xL inhibitors such as ABT263 have failed during clinical development due to on-target and dose-limiting thrombocytopenia.

Methods: We have developed DT2216, a proteolysis targeting chimera (PROTAC) targeting Bcl-xL for degradation via Von Hippel-Lindau (VHL) E3 ligase, and shown that it has better anti-tumor activity but is less toxic to platelets compared to ABT263. Here, we examined the therapeutic potential of DT2216 for TCLs via testing its anti-TCL activity in vitro using MTS assay, immunoblotting, and flow cytometry and anti-TCL activity in vivo using TCL cell xenograft and PDX model in mice.

Results: The results showed that DT2216 selectively killed various Bcl-xL-dependent TCL cells including MyLa cells in vitro. In vivo, DT2216 alone was highly effective against MyLa TCL xenografts in mice without causing significant thrombocytopenia or other toxicity. Furthermore, DT2216 combined with ABT199 (a selective Bcl-2 inhibitor) synergistically reduced disease burden and improved survival in a TCL PDX mouse model dependent on both Bcl-2 and Bcl-xL.

Conclusions: These findings support the clinical testing of DT2216 in patients with Bcl-xL-dependent TCLs, both as a single agent and in rational combinations.
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http://dx.doi.org/10.1186/s13045-020-00928-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364785PMC
July 2020

Patterns of Late Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with T-Cell Prolymphocytic Leukemia.

Acta Haematol 2021 7;144(1):105-110. Epub 2020 Apr 7.

Department of Hematology and Medical Oncology, University Medicine Göttingen (UMG), Göttingen, Germany.

Initial treatment with the monoclonal anti-CD52 antibody alemtuzumab induces responses in the majority of patients with T-cell prolymphocytic leukemia (T-PLL). In eligible patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an option to consolidate hematological remissions. Here, we report our experience with 10 patients who received allo-HSCT against T-PLL. Notably, 3 patients with complete remission at transplantation and durable full-donor chimerism relapsed at months 12, 59, and 84 after transplantation, respectively. This relapse was associated with rapid progressive leukemia in 1 patient and extralymphatic lymphoma growth in the other 2. Despite CD52 positivity at relapse, alemtuzumab retreatment, donor lymphocyte infusions, and/or chemotherapy including salvage therapy, allo-HSCT yielded a transient partial response, only. Alemtuzumab induction and consolidative allo-HSCT enabled prolonged disease-free survival in these patients but failed to procure cure.
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http://dx.doi.org/10.1159/000506302DOI Listing
March 2021

Effect of periodontal therapy on adipokine biomarkers in overweight.

J Clin Periodontol 2020 07 11;47(7):842-850. Epub 2020 May 11.

Department of Periodontology and Operative Dentistry, University Hospital Münster, Münster, Germany.

Aim: The aim of this study was to evaluate the effect of non-surgical periodontal therapy on circulating levels of the systemic inflammation-associated biomarkers orosomucoid (ORM), high-sensitivity C-reactive protein (hsCRP), chemerin, and retinol-binding protein 4 (RBP4) in overweight or normal-weight patients with periodontitis at 27.5 months after therapy.

Materials And Methods: This exploratory subanalysis includes patients from the ABPARO-trial (ClinicalTrials.gov NCT00707369). The per-protocol collective provided untreated periodontitis patients with high (≥28 kg/m ) or moderate (21-24 kg/m ) BMI. Out of the per-protocol collective, 80 patients were randomly selected and stratified for BMI group, sex, and treatment group (antibiotics/placebo), resulting in 40 overweight and normal-weight patients. Patients received non-surgical periodontal therapy and maintenance at 3-month intervals. Plasma samples from baseline and 27.5 months following initial treatment were used to measure the concentrations of ORM, hsCRP, chemerin, and RBP4.

Results: At the 27.5-month examination, ORM and hsCRP decreased noticeably in the overweight group (ORM: p = .001, hsCRP: p = .004) and normal-weight patients (ORM: p = .007, hsCRP: p < .001). Chemerin decreased in the overweight group (p = .048), and RBP4 concentrations remained stable.

Conclusion: Non-surgical periodontal therapy reduced systemically elevated inflammation-associated biomarkers in periodontitis patients. These improvements were more pronounced in overweight patients than in normal-weight patients.
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http://dx.doi.org/10.1111/jcpe.13288DOI Listing
July 2020

Proposal of a Clinical Endpoint for Periodontal Trials: The Treat-to-Target Approach.

J Int Acad Periodontol 2020 04 1;22(2):41-53. Epub 2020 Apr 1.

Department of Periodontology, Dental Research Division, Guarulhos University, Guarulhos, São Paulo, Brazil.

Objective: The selection of proper outcome measures is a critical step in clinical research. Most randomized clinical trials (RCTs) assessing the effects of initial anti-infective periodontal therapies use surrogate outcomes as primary outcome variables, such as mean changes in probing depth (PD) or in clinical attachment. However, these parameters do not reflect disease remission/control at patient level, which has led to subjective interpretations of the data from RCTs and Systematic Reviews. Based on a comprehensive analysis of 724 patients from USA, Germany and Brazil treated for periodontitis, this paper suggests that the clinical endpoint of "≤4 sites with PD≥5mm" is effective in determining disease remission/control after active periodontal treatment and therefore, may represent a pertinent endpoint for applying the treat-to-target concept in RCTs. Furthermore, regression models showed that the presence of >10% and >20% sites with bleeding on probing in the mouth post-treatment increases the risk of a patient leaving the endpoint from 1-2 years (OR=3.5 and 8.7, respectively). Researchers are encouraged to present results on this outcome when reporting their trials, as this will allow for an objective comparison across studies and facilitate systematic reviews, and consequently, the extrapolation of data from research to clinical practice.
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April 2020

Destruction of a Microtubule-Bound MYC Reservoir during Mitosis Contributes to Vincristine's Anticancer Activity.

Mol Cancer Res 2020 06 11;18(6):859-872. Epub 2020 Mar 11.

Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany.

Tightly regulated activity of the transcription factor MYC is essential for orderly cell proliferation. Upon deregulation, MYC elicits and promotes cancer progression. Proteasomal degradation is an essential element of MYC regulation, initiated by phosphorylation at Serine62 (Ser62) of the MB1 region. Here, we found that Ser62 phosphorylation peaks in mitosis, but that a fraction of nonphosphorylated MYC binds to the microtubules of the mitotic spindle. Consequently, the microtubule-destabilizing drug vincristine decreases wild-type MYC stability, whereas phosphorylation-deficient MYC is more stable, contributing to vincristine resistance and induction of polyploidy. PI3K inhibition attenuates postmitotic MYC formation and augments the cytotoxic effect of vincristine. IMPLICATIONS: The spindle's function as a docking site for MYC during mitosis may constitute a window of specific vulnerability to be exploited for cancer treatment.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1203DOI Listing
June 2020

Conversion to Everolimus was Beneficial and Safe for Fast and Slow Tacrolimus Metabolizers After Renal Transplantation.

J Clin Med 2020 Jan 23;9(2). Epub 2020 Jan 23.

Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, 48149 Münster, Germany.

Fast tacrolimus (TAC) metabolism (concentration/dose (C/D) ratio < 1.05 ng/ml/mg) is a risk factor for inferior outcomes after renal transplantation (RTx) as it fosters, e.g., TAC-related nephrotoxicity. TAC minimization or conversion to calcineurin-inhibitor free immunosuppression are strategies to improve graft function. Hence, we hypothesized that especially patients with a low C/D ratio profit from a switch to everolimus (EVR). We analyzed data of 34 RTx recipients (17 patients with a C/D ratio < 1.05 ng/ml/mg vs. 17 patients with a C/D ratio ≥ 1.05 ng/ml/mg) who were converted to EVR within 24 months after RTx. The initial immunosuppression consisted of TAC, mycophenolate, prednisolone, and basiliximab induction. During an observation time of 36 months after changing immunosuppression from TAC to EVR, renal function, laboratory values, and adverse effects were compared between the groups. Fast TAC metabolizers were switched to EVR 4.6 (1.5-21.9) months and slow metabolizers 3.3 (1.8-23.0) months after RTx (p = 0.838). Estimated glomerular filtration rate (eGFR) did not differ between the groups at the time of conversion (baseline). Thereafter, the eGFR in all patients increased noticeably (fast metabolizers eGFR 36 months: + 11.0 ± 11.7 (p = 0.005); and slow metabolizers eGFR 36 months: + 9.4 ± 15.9 mL/min/1.73m² ( = 0.049)) vs. baseline. Adverse events were not different between the groups. After the switch, eGFR values of all patients increased statistically noticeably with a tendency towards a higher increase in fast TAC metabolizers. Since conversion to EVR was safe in a three-year follow-up for slow and fast TAC metabolizers, this could be an option to protect fast metabolizers from TAC-related issues.
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http://dx.doi.org/10.3390/jcm9020328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074544PMC
January 2020

AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells.

Clin Cancer Res 2020 02 7;26(4):922-934. Epub 2019 Nov 7.

Bioscience, Oncology R&D, AstraZeneca, Boston, Massachusetts.

Purpose: Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and potential therapeutic target for many cancers. Multiple nonselective CDK9 inhibitors have progressed clinically but were limited by a narrow therapeutic window. This work describes a novel, potent, and highly selective CDK9 inhibitor, AZD4573.

Experimental Design: The antitumor activity of AZD4573 was determined across broad cancer cell line panels as well as cell line- and patient-derived xenograft models . Multiple approaches, including integrated transcriptomic and proteomic analyses, loss-of-function pathway interrogation, and pharmacologic comparisons, were employed to further understand the major mechanism driving AZD4573 activity and to establish an exposure/effect relationship.

Results: AZD4573 is a highly selective and potent CDK9 inhibitor. It demonstrated rapid induction of apoptosis and subsequent cell death broadly across hematologic cancer models , and MCL-1 depletion in a dose- and time-dependent manner was identified as a major mechanism through which AZD4573 induces cell death in tumor cells. This pharmacodynamic (PD) response was also observed , which led to regressions in both subcutaneous tumor xenografts and disseminated models at tolerated doses both as monotherapy or in combination with venetoclax. This understanding of the mechanism, exposure, and antitumor activity of AZD4573 facilitated development of a robust pharmacokinetic/PD/efficacy model used to inform the clinical trial design.

Conclusions: Selective targeting of CDK9 enables the indirect inhibition of MCL-1, providing a therapeutic option for MCL-1-dependent diseases. Accordingly, AZD4573 is currently being evaluated in a phase I clinical trial for patients with hematologic malignancies (clinicaltrials.gov identifier: NCT03263637)..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1853DOI Listing
February 2020

Impaired Isometric Force Matching in Upper and Lower Limbs Revealed by Quantitative Motor Assessments in Huntington's Disease.

J Huntingtons Dis 2019 ;8(4):483-492

George-Huntington-Institute, Deilmann-Building IV, Technology-Park, Muenster, Germany.

Background: Assessment of motor symptoms in Huntington's disease (HD) is based on the Unified-HD-Rating-Scale-Total-Motor-Score (UHDRS-TMS). Its categorical and rater-dependent nature reduces the ability to detect subtle changes and often placebo effects have been observed in trials. We have previously shown that impairments in isometric force matching can be detected by quantitative motor (Q-Motor) assessments of tongue protrusion forces (glossomotography) in HD.

Objective: We aimed to investigate whether similar impairments in isometric force matching can be detected in tasks assessing hand and foot force coordination and whether correlations with clinical measures and the disease burden score can be found.

Methods: Using a pre-calibrated force transducer, the ability of subjects to generate and maintain isometric forces at different target levels displayed on a monitor was assessed. Target forces applied in the hand were 1.5 and 5 Newton [N] and in feet 1, 5, and 10 N. Subjects with HD (n = 31) and age-matched controls (n = 22) were recruited from the HD out-patient clinic.

Results: All paradigms distinguished controls from HD. The static coefficient of variability (%) was the most robust measure across all matching tasks. Correlations with clinical measures, such as the UHDRS-TMS, TFC, and the DBS were found.

Conclusions: Assessment of hand and foot force matching tasks was feasible and provided quantitative objective measures for severity of motor phenotype in HD. Since both upper and lower extremity motor function are relevant for everyday activities, these measures should be further assessed as candidates for developing functionally meaningful quantitative motor tasks.
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http://dx.doi.org/10.3233/JHD-190354DOI Listing
July 2020

Intraoperative fluorescence diagnosis in the brain: a systematic review and suggestions for future standards on reporting diagnostic accuracy and clinical utility.

Acta Neurochir (Wien) 2019 10 30;161(10):2083-2098. Epub 2019 Jul 30.

Department of Neurosurgery, University Hospital of Münster, Albert-Schweitzer-Campus 1, A1, 48149, Münster, Germany.

Background: Surgery for gliomas is often confounded by difficulties in distinguishing tumor from surrounding normal brain. For better discrimination, intraoperative optical imaging methods using fluorescent dyes are currently being explored. Understandably, such methods require the demonstration of a high degree of diagnostic accuracy and clinical benefit. Currently, clinical utility is determined by tissue biopsies which are correlated to optical signals, and quantified using measures such as sensitivity, specificity, positive predictive values, and negative predictive values. In addition, surgical outcomes, such as extent of resection rates and/or survival (progression-free survival (PFS) and overall survival (OS)) have been measured. These assessments, however, potentially involve multiple biases and confounders, which have to be minimized to ensure reproducibility, generalizability and comparability of test results. Test should aim at having a high internal and external validity. The objective of this article is to analyze how diagnostic accuracy and outcomes are utilized in available studies describing intraoperative imaging and furthermore, to derive recommendations for reliable and reproducible evaluations.

Methods: A review of the literature was performed for assessing the use of measures of diagnostic accuracy and outcomes of intraoperative optical imaging methods. From these data, we derive recommendations for designing and reporting future studies.

Results: Available literature indicates that potential confounders and biases for reporting the diagnostic accuracy and usefulness of intraoperative optical imaging methods are seldom accounted for. Furthermore, methods for bias reduction are rarely used nor reported.

Conclusions: Detailed, transparent, and uniform reporting on diagnostic accuracy of intraoperative imaging methods is necessary. In the absence of such reporting, studies will not be comparable or reproducible. Future studies should consider some of the recommendations given here.
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http://dx.doi.org/10.1007/s00701-019-04007-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739423PMC
October 2019

5-Aminolevulinic Acid Fluorescence-Guided Resection of 18F-FET-PET Positive Tumor Beyond Gadolinium Enhancing Tumor Improves Survival in Glioblastoma.

Neurosurgery 2019 12;85(6):E1020-E1029

Department of Neurosurgery, University Hospital Münster, Münster, Germany.

Background: The value of early postoperative 18F-FET-PET in patients with glioblastoma (GBM) is unclear. Five-aminolevulinic acid (5-ALA) is used for fluorescence-guided resections in these patients and previous data suggest that fluorescence and 18F-FET-PET both demarcate larger tumor volumes than gadolinium enhanced magnet resonance imaging (MRI).

Objective: To correlate fluorescence with enhancing volumes on postoperative MRI and 18F-FET-PET tumor volumes, and determine the value of postoperative 18F-FET-PET for predicting survival through observational study.

Methods: GBM patients underwent fluorescence-guided resection after administration of 5-ALA followed by early postoperative MRI and 18F-FET-PET for determination of residual tissue volumes. All patients were treated with standard temozolomide radiochemotherapy and monitored for progression-free and overall survival (PFS, OS).

Results: A total of 31 patients were included. For functional reasons, residual 5-ALA derived fluorescent tissue was left unresected in 18 patients with a median 18F-FET-PET volume of 17.82 cm3 (interquartile range 6.50-29.19). In patients without residual fluorescence, median 18F-FET-PET volume was 1.20 cm3 (interquartile range 0.87-5.50) and complete resection of gadolinium enhancing tumor was observed in 100% of patients. A 18F-FET-PET volume of above 4.3 cm3 was associated with worse OS (logrank P-value ≤ .05), also in patients with no residual contrast enhancing tumor on MRI. More patients in whom fluorescencing tissue had been removed completely had postoperative 18F-FET-PET tumor volumes below 4.3 cm3.

Conclusion: Postoperative 18F-FET-PET volumes predict OS and PFS. Resection of 5-ALA derived fluorescence beyond gadolinium enhancing tumor tissue leads to lower postoperative 18F-FET-PET tumor volumes and improved OS and PFS without additional deficits.
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http://dx.doi.org/10.1093/neuros/nyz199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855932PMC
December 2019

Expanding the donor pool in kidney transplantation: Should organs with acute kidney injury be accepted?-A retrospective study.

PLoS One 2019 13;14(3):e0213608. Epub 2019 Mar 13.

Department of Internal Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital Münster, Münster, Germany.

Background: Given the gap between patients in need of a renal transplantation (RTx) and organs available, transplantation centers increasingly accept organs of suboptimal quality, e.g. from donors with acute kidney injury (AKI).

Methods: To determine the outcome of kidney transplants from deceased donors with AKI (defined as ≥ AKIN stage 1), all 107 patients who received a RTx from donors with AKI between August 2004 and July 2014 at our center were compared to their respective consecutively transplanted patients receiving kidneys from donors without AKI. 5-year patient and graft survival, frequencies of delayed graft function (DGF), acute rejections and glomerular filtration rate (eGFR, CKD-EPI) were assessed.

Results: Patient survival was similar in both groups, whereas death-censored and overall graft survival were decreased in AKI kidney recipients. AKI kidney recipients showed higher frequencies of DGF and had a reduced eGFR at 7 days, three months and one and three years after RTx. However, mortality was noticeably lower compared to waiting list candidates. Rejection-free survival was similar between groups.

Conclusions: In our cohort, both short-term and long-term renal function was inferior in recipients of AKI kidneys, while patient survival was similar. Our data indicates that recipients of donor AKI kidneys should be carefully selected and additional factors impairing short- and long-term outcome should be minimized to prevent further deterioration of graft function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213608PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415810PMC
December 2019

Clinical benefits of systemic amoxicillin/metronidazole may depend on periodontitis severity and patients' age: An exploratory sub-analysis of the ABPARO trial.

J Clin Periodontol 2019 04 12;46(4):491-501. Epub 2019 Apr 12.

Department of Periodontology, University Hospital Münster, Münster, Germany.

Aim: The aim was to identify benefit thresholds for clinical variables. We hypothesize, if variables fall below or exceed these threshold levels, systemic amoxicillin/metronidazole may contribute to reducing progression of periodontitis.

Material & Methods: This is an explorative per-protocol collective analysis (n = 345) conducted on the placebo-controlled, multi-centre ABPARO trial (ClinicalTrials.gov NCT00707369). Patients received debridement with systemic amoxicillin 500 mg/metronidazole 400 mg (3×/day, 7 days, n = 170) or placebo (n = 175) and maintenance therapy every three months. To identify thresholds, each of the following baseline characteristics was classified into two groups (≥threshold value/
Results: Adjunctive antimicrobials reduced median new attachment loss in patients < 55 years (5.2%), or with ≥ 35% PPD ≥ 5 mm (4.5%) or with a mean attachment level > 5 mm (5.2%) at baseline compared to the placebo (9.0%, 11.6%, and 12.5%, respectively; p < 0.005).

Conclusions: The clinical benefits of systemic amoxicillin/metronidazole may depend on periodontitis severity and patients' age.
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http://dx.doi.org/10.1111/jcpe.13096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594242PMC
April 2019

Biomarker-driven strategy for MCL1 inhibition in T-cell lymphomas.

Blood 2019 02 29;133(6):566-575. Epub 2018 Nov 29.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

There is a pressing need for more effective therapies to treat patients with T-cell lymphomas (TCLs), including first-line approaches that increase the response rate to cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) chemotherapy. We characterized the mitochondrial apoptosis pathway in cell lines and patient-derived xenograft (PDX) models of TCL and assessed the in vitro efficacy of BH3 mimetics, including the BCL2 inhibitor venetoclax, the BCL2/BCL-xL inhibitor navitoclax, and the novel MCL1 inhibitor AZD5991. The abundance of antiapoptotic BCL2 family members based on immunoblotting or RNA transcript levels correlated poorly with the activity of BH3 mimetics. In contrast, the functional approach BH3 profiling reliably predicted sensitivity to BH3 mimetics in vitro and in vivo. We used BH3 profiling to select TCL PDX that were dependent on MCL1. Mice xenografted with these PDX and treated with AZD5991 had markedly improved survival. The combination of AZD5991 and CHOP achieved synergy based on survival improvement beyond a mathematical "sum of benefits" model. Thus, MCL1 inhibition is a promising strategy as both a single agent and in combination with chemotherapy for patients with TCL and functional dependence on MCL1.
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http://dx.doi.org/10.1182/blood-2018-07-865527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367646PMC
February 2019

Comparison of Longitudinal and Apical Foetal Speckle Tracking Echocardiography Using Tissue Motion Annular Displacement and Segmental Longitudinal Strain.

Ultrasound Med Biol 2019 01 25;45(1):233-245. Epub 2018 Oct 25.

Department of Obstetrics and Gynecology, University Hospital Münster, Münster, Germany.

The aim of our prospective pilot study with exploratory analysis was to compare longitudinal and apical foetal speckle tracking echocardiography (STE) using tissue motion annular displacement (TMAD) and segmental longitudinal strain (SLS). We compared two different STE quantification tools in a longitudinal and apical four-chamber view in 57 normal foetuses between 20 and 40 wk of gestation. Myocardial mechanical dyssynchrony and strain were assessed using offline quantification software (QLab Version 10.3, Philips Medical Systems, Andover, MA, USA). We compared the dyssynchrony measurements with TMAD and SLS in longitudinal and apical four-chamber views. Furthermore, we examined the segmental strain values of both ventricles with SLS and compared the differences between longitudinal and apical measurements. Dyssynchrony measurements with TMAD and SLS and strain measurements with SLS were feasible in all cases. In the apical view, the dyssynchrony measurements with TMAD were systematically greater than those achieved with SLS (p < 0.001). For the longitudinal view, no differences were observed between tools (p = 0.153). The application of SLS provided similar results for dyssynchrony in both views (intra-class correlation coefficient [ICC] = 0.281, p = 0.623), but the strain measurements in the left and right ventricles differed significantly between views (ICC = -0.082, p = 0.011, and ICC = -0.061, p = 0.024, respectively). For TMAD, we found large differences in the dyssynchrony values between longitudinal and apical assessment (ICC = -0.060, p = 0.03). Furthermore, TMAD exhibited reduced accuracy in the system's automatic tracking algorithm, limiting the data quality. The dyssynchrony assessment is affected less by the foetal position in SLS than in TMAD. The strain readings in SLS varied depending on the view in which they were assessed. The application of TMAD cannot be recommended for foetal STE.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2018.09.013DOI Listing
January 2019

Sequential high-dose cytarabine and mitoxantrone (S-HAM) versus standard double induction in acute myeloid leukemia-a phase 3 study.

Leukemia 2018 12 1;32(12):2558-2571. Epub 2018 Oct 1.

Insitute for Biostatistics and Clinical Research, University Hospital, Münster, Germany.

Dose-dense induction with the S-HAM regimen was compared to standard double induction therapy in adult patients with newly diagnosed acute myeloid leukemia. Patients were centrally randomized (1:1) between S-HAM (2nd chemotherapy cycle starting on day 8 = "dose-dense") and double induction with TAD-HAM or HAM(-HAM) (2nd cycle starting on day 21 = "standard"). 387 evaluable patients were randomly assigned to S-HAM (N = 203) and to standard double induction (N = 184). The primary endpoint overall response rate (ORR) consisting of complete remission (CR) and incomplete remission (CR) was not significantly different (P = 0.202) between S-HAM (77%) and double induction (72%). The median overall survival was 35 months after S-HAM and 25 months after double induction (P = 0.323). Duration of critical leukopenia was significantly reduced after S-HAM (median 29 days) versus double induction (median 44 days)-P < 0.001. This translated into a significantly shortened duration of hospitalization after S-HAM (median 37 days) as compared to standard induction (median 49 days)-P < 0.001. In conclusion, dose-dense induction therapy with the S-HAM regimen shows favorable trends but no significant differences in ORR and OS compared to standard double induction. S-HAM significantly shortens critical leukopenia and the duration of hospitalization by 2 weeks.
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http://dx.doi.org/10.1038/s41375-018-0268-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286323PMC
December 2018

Evaluation of an ex vivo porcine model to investigate the effect of low abrasive airpolishing.

Clin Oral Investig 2018 Sep 29;22(7):2669-2673. Epub 2018 Jun 29.

Clinic of Periodontology, Philipps University Marburg, Georg-Voigt-Str. 3, 35039, Marburg, Germany.

Objectives: Evaluation of an ex vivo porcine model to investigate the influence of periodontal instrumentation on soft tissue.

Material And Methods: In each of 120 pig mandibles, one molar tooth was chosen at random and instrumented. For subgingival debridement, two different low abrasive airpolishing powders (glycine d = 25 μm, erythritol d = 14 μm, n = 30 teeth each), curets, and a piezoelectric ultrasonic scaler were used (n = 30 teeth each). Thirty teeth in 30 other mandibles served as the untreated control. Gingival biopsies were histologically assessed for destruction using a four-graded scale.

Results: The porcine model was deemed suitable for the planned investigation. Hand instrumentation and ultrasonic scaling caused higher tissue damage than both low abrasive airpolishing modes (Fisher's exact test, p = 0.0025). Glycine powder led to less, yet non-statistical noticeable gingival changes compared to erythritol-based powder (Fisher's exact test, p = 0.39).

Conclusion: An animal model using pig jaws may be used as a preliminary model to analyze histological effects of periodontal instrumentation in advance of studies performed in human tissues. Among the techniques assessed, low abrasive airpolishing (LAA) caused the smallest tissue damage.

Clinical Relevance: To avoid gingival damage using LAA, histological observations of gingival tissue are needed. Since numerous powders for LAA have been developed and it may be expected that additional products will follow, it appears to be useful to establish ex vivo animal models to prove the powders safety.
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http://dx.doi.org/10.1007/s00784-018-2536-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097043PMC
September 2018

Idiopathic Hypersomnia Patients Revealed Longer Circadian Period Length in Peripheral Skin Fibroblasts.

Front Neurol 2018 7;9:424. Epub 2018 Jun 7.

Division of Sleep Medicine and Neuromuscular Disorders, Department of Neurology, University Hospital Muenster, Muenster, Germany.

The vast majority of living organisms have evolved a circadian rhythm of roughly 24 h in adaptation to ever-changing environmental conditions, such as the cycle of light and darkness. In some sleep disorders like idiopathic hypersomnia (IH) this adaptation is defective. As the etiology of this disease is largely unknown, we examined the circadian period length of patients suffering from IH. The patients were diagnosed according to the ICSD3-criteria by clinical history, polysomnography (PSG), and multiple sleep latency testing (MSLT). In order to gain insight into the molecular mechanism of this sleep disorder we collected fibroblasts from skin biopsies of IH patients and healthy subjects. We determined the circadian period length of the primary fibroblast cells by lentiviral infection with a construct expressing a luciferase gene under the control of a promoter. The group of IH patients revealed on average a prolonged circadian period length. In comparison to the group of healthy controls (HC) the mean period length was estimated to be 0.82 h (95%-CI 0.44-1.20 h) longer in the patient group. This finding further stresses a disturbed regulation of the circadian rhythm in IH patients as part of the pathophysiology of this complex and poorly understood primary sleep disorder.
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http://dx.doi.org/10.3389/fneur.2018.00424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999733PMC
June 2018

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models.

Nat Commun 2018 05 22;9(1):2024. Epub 2018 May 22.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.
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http://dx.doi.org/10.1038/s41467-018-04356-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964252PMC
May 2018

Do we treat our patients or rather periodontal microbes with adjunctive antibiotics in periodontal therapy? A 16S rDNA microbial community analysis.

PLoS One 2018 18;13(4):e0195534. Epub 2018 Apr 18.

Department of Periodontology and Restaurative Dentistry, Münster University Hospital, Münster, Germany.

Empiric antibiotics are often used in combination with mechanical debridement to treat patients suffering from periodontitis and to eliminate disease-associated pathogens. Until now, only a few next generation sequencing 16S rDNA amplicon based publications with rather small sample sizes studied the effect of those interventions on the subgingival microbiome. Therefore, we studied subgingival samples of 89 patients with chronic periodontitis (solely non-smokers) before and two months after therapy. Forty-seven patients received mechanical periodontal therapy only, whereas 42 patients additionally received oral administered amoxicillin plus metronidazole (500 and 400 mg, respectively; 3x/day for 7 days). Samples were sequenced with Illumina MiSeq 300 base pairs paired end technology (V3 and V4 hypervariable regions of the 16S rDNA). Inter-group differences before and after therapy of clinical variables (percentage of sites with pocket depth ≥ 5mm, percentage of sites with bleeding on probing) and microbiome variables (diversity, richness, evenness, and dissimilarity) were calculated, a principal coordinate analysis (PCoA) was conducted, and differential abundance of agglomerated ribosomal sequence variants (aRSVs) classified on genus level was calculated using a negative binomial regression model. We found statistically noticeable decreased richness, and increased dissimilarity in the antibiotic, but not in the placebo group after therapy. The PCoA revealed a clear compositional separation of microbiomes after therapy in the antibiotic group, which could not be seen in the group receiving mechanical therapy only. This difference was even more pronounced on aRSV level. Here, adjunctive antibiotics were able to induce a microbiome shift by statistically noticeably reducing aRSVs belonging to genera containing disease-associated species, e.g., Porphyromonas, Tannerella, Treponema, and Aggregatibacter, and by noticeably increasing genera containing health-associated species. Mechanical therapy alone did not statistically noticeably affect any disease-associated taxa. Despite the difference in microbiome modulation both therapies improved the tested clinical parameters after two months. These results cast doubt on the relevance of the elimination and/or reduction of disease-associated taxa as a main goal of periodontal therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195534PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906003PMC
July 2018

Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma.

Blood 2018 02 12;131(8):888-898. Epub 2017 Dec 12.

Dana-Farber Cancer Institute, Boston, MA.

Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a phase 1, open-label study of duvelisib in patients with relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and in vivo models of TCL. The overall response rates in patients with PTCL and CTCL were 50.0% and 31.6%, respectively ( = .32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes. The most frequently observed grade 3 and 4 adverse events were transaminase increases (40% alanine aminotransferase, 17% aspartate aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders and nonresponders had markedly different changes in serum cytokine profiles induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT ( = .024) and exceeded cell killing by the PI3K-δ-specific inhibitor idelalisib. Administration of duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In summary, duvelisib demonstrated promising clinical activity and an acceptable safety profile in relapsed/refractory TCL, as well as preclinical evidence of both tumor cell-autonomous and immune-mediated effects. This trial was registered at www.clinicaltrials.gov as #NCT01476657.
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http://dx.doi.org/10.1182/blood-2017-08-802470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824337PMC
February 2018

Male kidney allograft recipients at risk for urinary tract infection?

PLoS One 2017 16;12(11):e0188262. Epub 2017 Nov 16.

Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital Münster, Münster, Germany.

Background: Urinary tract infection (UTI) is the most common infection after renal transplantation (RTx). Although female sex is a well-known risk factor for the development of UTI after RTx, the role of the donor sex in this context remains unclear.

Methods: In this case control study 6,763 RTx cases were screened for UTI when presenting at our transplant outpatient clinics. 102 different RTx patients fulfilled the inclusion criteria and were compared to 102 controls. Data on renal function was prospectively followed for 12 months. Results were compared to a previous RTx cohort from our transplant center. Additionally, we assessed the immunological response of leukocytes from 58 kidney recipients and 16 controls to lipopolysaccharide stimulation.

Result: After identification by univariate analysis, multivariate logistic regression analysis indicated female sex, minor height, advanced age and male kidney allograft sex to be associated with the occurrence of UTI after RTx. Female recipients who received male grafts had the best renal function 12 months after presentation. However, leukocyte response of recipients to lipopolysaccharide was impaired irrespective of donor and recipient sex to the same extend.

Conclusions: We conclude from our data that male kidney allografts are associated with the occurrence of UTI after RTx but did not influence the response of leukocytes to lipopolysaccharide. Further prospective studies are needed to identify the underlying mechanisms of higher male kidney donor dependent UTI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188262PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690643PMC
December 2017

Lung toxicity after radiation in childhood: Results of the International Project on Prospective Analysis of Radiotoxicity in Childhood and Adolescence.

Radiother Oncol 2017 11 16;125(2):286-292. Epub 2017 Oct 16.

Department of Radiotherapy, Medical School Hannover, Germany. Electronic address:

Background And Purpose: This study presents the evaluation of acute and late toxicities of the lung in children and adolescents after irradiation in terms of dose-volume effects.

Materials And Methods: Irradiated children and adolescents in Germany have prospectively been documented since 2001 in the "Registry for the Evaluation of Side-Effects after Radiotherapy in Childhood and Adolescence (RiSK)"; in Sweden since 2008 in the RADTOX registry.

Results: Up to April 2012, 1,392 children were recruited from RiSK, and up to June 2013, 485 from the RADTOX-registry. Of these patients, 295 were irradiated to the lung. Information about acute toxicity was available for 228 patients. 179 patients have been documented concerning late toxicity (≥grade 1: n = 28). The acute toxicity rate was noticeably higher in children irradiated with 5-20Gy (p < 0.05). In the univariate analysis, a shorter time until late toxicity was noticeably associated with irradiation with 5-15Gy (p < 0.05).

Conclusion: Acute and late toxicities appear to be correlated with higher irradiation volumes and low doses. Our data indicate that similar to the situation in adult patients, V5, V10, V15 and V20 should be kept as low as possible (e.g., at least V5 < 50%, V10 and V15 < 35% and V20 < 30%) in children and adolescents to lower the risk of toxicity.
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http://dx.doi.org/10.1016/j.radonc.2017.09.026DOI Listing
November 2017

Response Evaluation of Malignant Liver Lesions After TACE/SIRT: Comparison of Manual and Semi-Automatic Measurement of Different Response Criteria in Multislice CT.

Rofo 2017 Nov 23;189(11):1067-1075. Epub 2017 Aug 23.

Department of Clinical Radiology, University Hospital Münster (UKM), Münster, Germany.

 To compare measurement precision and interobserver variability in the evaluation of hepatocellular carcinoma (HCC) and liver metastases in MSCT before and after transarterial local ablative therapies.  Retrospective study of 72 patients with malignant liver lesions (42 metastases; 30 HCCs) before and after therapy (43 SIRT procedures; 29 TACE procedures). Established (LAD; SAD; WHO) and vitality-based parameters (mRECIST; mLAD; mSAD; EASL) were assessed manually and semi-automatically by two readers. The relative interobserver difference (RID) and intraclass correlation coefficient (ICC) were calculated.  The median RID for vitality-based parameters was lower from semi-automatic than from manual measurement of mLAD (manual 12.5 %; semi-automatic 3.4 %), mSAD (manual 12.7 %; semi-automatic 5.7 %) and EASL (manual 10.4 %; semi-automatic 1.8 %). The difference in established parameters was not statistically noticeable (p > 0.05). The ICCs of LAD (manual 0.984; semi-automatic 0.982), SAD (manual 0.975; semi-automatic 0.958) and WHO (manual 0.984; semi-automatic 0.978) are high, both in manual and semi-automatic measurements. The ICCs of manual measurements of mLAD (0.897), mSAD (0.844) and EASL (0.875) are lower. This decrease cannot be found in semi-automatic measurements of mLAD (0.997), mSAD (0.992) and EASL (0.998).  Vitality-based tumor measurements of HCC and metastases after transarterial local therapies should be performed semi-automatically due to greater measurement precision, thus increasing the reproducibility and in turn the reliability of therapeutic decisions.   · Liver lesion measurements according to EASL and mRECIST are more precise when performed semi-automatically.. · The higher reproducibility may facilitate a more reliable classification of therapy response.. · Measurements according to RECIST and WHO offer equivalent precision semi-automatically and manually.. · Höink AJ, Schülke C, Koch R et al. Response Evaluation of Malignant Liver Lesions After TACE/SIRT: Comparison of Manual and Semi-Automatic Measurement of Different Response Criteria in Multislice CT. Fortschr Röntgenstr 2017; 189: 1067 - 1075.
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http://dx.doi.org/10.1055/s-0043-116220DOI Listing
November 2017

Hyaluronan-mediated mononuclear leukocyte binding to gingival fibroblasts.

Clin Oral Investig 2018 Mar 12;22(2):1063-1070. Epub 2017 Aug 12.

Hylitis, Rudolf-Harbig-Straße 5, 48301, Nottuln, Germany.

Objectives: Binding of mononuclear leukocytes to hyaluronan cable structures is a well-known pathomechanism in several chronic inflammatory diseases, but has not yet described for chronic oral inflammations. The aim of this study was to evaluate if and how binding of mononuclear leukocytes to pathologic hyaluronan cable structures can be induced in human gingival fibroblasts.

Material And Methods: Experiments were performed with human gingival fibroblasts and peripheral blood mononuclear cells (PBMCs) from three healthy blood donors. Gingival fibroblasts were stimulated with (1) tunicamycin, (2) polyinosinic/polycytidylic acid (Poly:IC), and (3) lipopolysaccharides (LPS) to simulate (1) ER stress and (2) viral and (3) bacterial infections, respectively. Fibroblasts were then co-incubated with PBMCs, and the number of bound and fluorescently labeled PBMCs was assessed using a fluorescence reader and microscopy. For data analysis, a linear mixed model was used.

Results: Hyaluronan-mediated binding of PBMCs to gingival fibroblasts was increased by tunicamycin and Poly(I:C) but not by LPS. Hyaluronidase treatment and co-incubation with hyaluronan transport inhibitors reduced this binding.

Conclusions: Results suggest that hyaluronan-mediated binding of blood cells might play a role in oral inflammations. A potential superior role of viruses needs to be confirmed in further clinical studies.

Clinical Relevance: The linkage between pathological hyaluronan matrices and oral infections opens up potential applications of hyaluronan transport inhibitors in the treatment of chronic oral inflammations.
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http://dx.doi.org/10.1007/s00784-017-2188-xDOI Listing
March 2018
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