Publications by authors named "Markus Loeffler"

249 Publications

Renal function and lipid metabolism are major predictors of circumpapillary retinal nerve fiber layer thickness-the LIFE-Adult Study.

BMC Med 2021 Sep 7;19(1):202. Epub 2021 Sep 7.

Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.

Background: Circumpapillary retinal nerve fiber layer thickness (cpRNFLT) as assessed by spectral domain optical coherence tomography (SD-OCT) is a new technique used for the detection and evaluation of glaucoma and other optic neuropathies. Before translating cpRNFLT into clinics, it is crucially important to investigate anthropometric, biochemical, and clinical parameters potentially affecting cpRNFLT in a large population-based dataset.

Methods: The population-based LIFE-Adult Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. All participants underwent standardized systemic assessment of various cardiometabolic risk markers and ocular imaging, including cpRNFLT measurement using SD-OCT (Spectralis, Heidelberg Engineering). After employing strict SD-OCT quality criteria, 8952 individuals were analyzed. Multivariable linear regression analyses were used to evaluate the independent associations of various cardiometabolic risk markers with sector-specific cpRNFLT. For significant markers, the relative strength of the observed associations was compared to each other to identify the most relevant factors influencing cpRNFLT. In all analyses, the false discovery rate method for multiple comparisons was applied.

Results: In the entire cohort, female subjects had significantly thicker global and also sectoral cpRNFLT compared to male subjects (p < 0.05). Multivariable linear regression analyses revealed a significant and independent association between global and sectoral cpRNFLT with biomarkers of renal function and lipid profile. Thus, thinner cpRNFLT was associated with worse renal function as assessed by cystatin C and estimated glomerular filtration rate. Furthermore, an adverse lipid profile (i.e., low high-density lipoprotein (HDL) cholesterol, as well as high total, high non-HDL, high low-density lipoprotein cholesterol, and high apolipoprotein B) was independently and statistically significantly related to thicker cpRNFLT. In contrast, we do not observe a significant association between cpRNFLT and markers of inflammation, glucose homeostasis, liver function, blood pressure, or obesity in our sector-specific analysis and globally.

Conclusions: Markers of renal function and lipid metabolism are predictors of sectoral cpRNFLT in a large and deeply phenotyped population-based study independently of previously established covariates. Future studies on cpRNFLT should include these biomarkers and need to investigate whether incorporation will improve the diagnosis of early eye diseases based on cpRNFLT.
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http://dx.doi.org/10.1186/s12916-021-02064-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422631PMC
September 2021

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.

Nat Genet 2021 Sep 2;53(9):1300-1310. Epub 2021 Sep 2.

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
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http://dx.doi.org/10.1038/s41588-021-00913-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432599PMC
September 2021

Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X.

Int J Cancer 2021 Sep 1. Epub 2021 Sep 1.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX.
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http://dx.doi.org/10.1002/ijc.33790DOI Listing
September 2021

Chemotherapy for adult patients with spinal cord gliomas.

Neurooncol Pract 2021 Aug 8;8(4):475-484. Epub 2021 Mar 8.

Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.

Background: The incidence of spinal cord gliomas, particularly in adults is low, and the role of chemotherapy has remained unclear.

Methods: We performed a multicenter, retrospective study of 21 patients diagnosed with spinal cord glioma who received chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by magnetic resonance imaging. Data on radiotherapy were taken into consideration.

Results: Thirteen patients were diagnosed with astrocytic gliomas World Health Organization (WHO) grades 1-4, the remaining eight patients with ependymomas WHO grades 1 or 3. Most patients had more than one neurosurgical intervention. Median age at time of first chemotherapy was 33 years (range 21-67 years). Seven patients had chemotherapy combined with radiotherapy as first-line treatment. Two patients had chemoradiotherapy at recurrence, without prior tumor-specific treatment beyond surgery. One patient received chemotherapy alone as first-line treatment and 2 patients had chemotherapy alone at recurrence, without prior treatment. Nine patients had received radiation therapy at an earlier time and chemotherapy was given at time of further recurrences. Best responses in astrocytomas were as follows: chemotherapy alone-2 stable disease (SD) and 3 progressive disease (PD); chemoradiotherapy-1 complete response, 3 SD, and 4 PD. Best responses in ependymomas were as follows: chemotherapy alone-1 partial response, 5 SD, and 1 PD; chemoradiotherapy-1 SD.

Conclusions: Spinal cord gliomas represent a heterogeneous group of tumors. Survival outcomes in response to chemotherapy in adult spinal cord glioma patients vary substantially, but individual patients appear to derive benefit from chemotherapy.
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http://dx.doi.org/10.1093/nop/npab017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278344PMC
August 2021

High-Resolution Cartography of the Transcriptome and Methylome Landscapes of Diffuse Gliomas.

Cancers (Basel) 2021 Jun 26;13(13). Epub 2021 Jun 26.

IZBI, Interdisciplinary Centre for Bioinformatics, Universität Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany.

Molecular mechanisms of lower-grade (II-III) diffuse gliomas (LGG) are still poorly understood, mainly because of their heterogeneity. They split into astrocytoma- (IDH-A) and oligodendroglioma-like (IDH-O) tumors both carrying mutations(s) at the isocitrate dehydrogenase (IDH) gene and into IDH wild type (IDH-wt) gliomas of glioblastoma resemblance. We generated detailed maps of the transcriptomes and DNA methylomes, revealing that cell functions divided into three major archetypic hallmarks: (i) increased proliferation in IDH-wt and, to a lesser degree, IDH-O; (ii) increased inflammation in IDH-A and IDH-wt; and (iii) the loss of synaptic transmission in all subtypes. Immunogenic properties of IDH-A are diverse, partly resembling signatures observed in grade IV mesenchymal glioblastomas or in grade I pilocytic astrocytomas. We analyzed details of coregulation between gene expression and DNA methylation and of the immunogenic micro-environment presumably driving tumor development and treatment resistance. Our transcriptome and methylome maps support personalized, case-by-case views to decipher the heterogeneity of glioma states in terms of data portraits. Thereby, molecular cartography provides a graphical coordinate system that links gene-level information with glioma subtypes, their phenotypes, and clinical context.
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http://dx.doi.org/10.3390/cancers13133198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268631PMC
June 2021

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in and : A Prospective Lynch Syndrome Database Study.

J Clin Med 2021 Jun 28;10(13). Epub 2021 Jun 28.

Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, 4031 Basel, Switzerland.

Background: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown.

Objective: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the and genes.

Methods: Carriers of pathogenic variants of () and () genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity.

Results: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately.

Conclusion: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of and .
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http://dx.doi.org/10.3390/jcm10132856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269121PMC
June 2021

Theranostic AGuIX nanoparticles as radiosensitizer: A phase I, dose-escalation study in patients with multiple brain metastases (NANO-RAD trial).

Radiother Oncol 2021 07 5;160:159-165. Epub 2021 May 5.

Radiotherapy Department, Grenoble Alps University Hospital, Grenoble, France.

Background And Purpose: Brain metastasis impacts greatly on patients' quality of life and survival. The phase I NANO-RAD trial assessed the safety and maximum tolerated dose of systemic administration of a novel gadolinium-based nanoparticle, AGuIX, in combination with whole brain radiotherapy in patients with multiple brain metastases not suitable for stereotactic radiotherapy.

Materials And Methods: Patients with measurable brain metastases received escalating doses of AGuIX nanoparticles (15, 30, 50, 75, or 100 mg/kg intravenously) on the day of initiation of WBRT (30 Gy in 10 fractions) in 5 cohorts of 3 patients each. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events v4.03.

Results: Fifteen patients with 354 metastases were included. No dose-limiting toxic effects were observed up to AGuIX 100 mg/kg. Plasma elimination half-life of AGuIX was similar for all groups (mean 1.3 h; range 0.8-3 h). Efficient targeting of metastases (T MRI enhancement, tumor selectivity) and persistence of AGuIX contrast enhancement were observed in metastases from patients with primary melanoma, lung, breast, and colon cancers. The concentration of AGuIX in metastases after administration was proportional to the injected dose. Thirteen of 14 evaluable patients had a clinical benefit, with either stabilization or reduction of tumor volume. MRI analysis showed significant correlation between contrast enhancement and tumor response, thus supporting a radiosensitizing effect.

Conclusion: Combining AGuIX with radiotherapy for patients with brain metastases is safe and feasible. AGuIX specifically targets brain metastases and is retained within tumors for up to 1 week; ongoing phase II studies will more definitively assess efficacy.
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http://dx.doi.org/10.1016/j.radonc.2021.04.021DOI Listing
July 2021

Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas.

Leukemia 2021 07 5;35(7):2002-2016. Epub 2021 May 5.

University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Düsseldorf, Germany.

B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but the mutational processes are poorly understood. By performing whole genome and transcriptome sequencing of 181 germinal center derived B-cell lymphomas (gcBCL) we identified distinct mutational signatures linked to SHM and CSR. We show that not only SHM, but presumably also CSR causes off-target mutations in non-IG genes. Kataegis clusters with high mutational density mainly affected early replicating regions and were enriched for SHM- and CSR-mediated off-target mutations. Moreover, they often co-occurred in loci physically interacting in the nucleus, suggesting that mutation hotspots promote increased mutation targeting of spatially co-localized loci (termed hypermutation by proxy). Only around 1% of somatic small variants were in protein coding sequences, but in about half of the driver genes, a contribution of B-cell specific mutational processes to their mutations was found. The B-cell-specific mutational processes contribute to both lymphoma initiation and intratumoral heterogeneity. Overall, we demonstrate that mutational processes involved in the development of gcBCL are more complex than previously appreciated, and that B cell-specific mutational processes contribute via diverse mechanisms to lymphomagenesis.
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http://dx.doi.org/10.1038/s41375-021-01251-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257491PMC
July 2021

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Eur J Cancer 2021 May 17;148:124-133. Epub 2021 Mar 17.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; MGZ- Medical Genetics Center, Munich, Germany; The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark's Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK; European Hereditary Tumour Group (EHTG), C/o Lindsays, Caledonian Exchange, 19A Canning Street, Edinburgh, EH3 8HE, United Kingdom.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.

Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.

Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.
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http://dx.doi.org/10.1016/j.ejca.2021.02.022DOI Listing
May 2021

The Human Blood Transcriptome in a Large Population Cohort and Its Relation to Aging and Health.

Front Big Data 2020 30;3:548873. Epub 2020 Oct 30.

IZBI, Interdisciplinary Centre for Bioinformatics, Universität Leipzig, Leipzig, Germany.

The blood transcriptome is expected to provide a detailed picture of an organism's physiological state with potential outcomes for applications in medical diagnostics and molecular and epidemiological research. We here present the analysis of blood specimens of 3,388 adult individuals, together with phenotype characteristics such as disease history, medication status, lifestyle factors, and body mass index (BMI). The size and heterogeneity of this data challenges analytics in terms of dimension reduction, knowledge mining, feature extraction, and data integration. Self-organizing maps (SOM)-machine learning was applied to study transcriptional states on a population-wide scale. This method permits a detailed description and visualization of the molecular heterogeneity of transcriptomes and of their association with different phenotypic features. The diversity of transcriptomes is described by personalized SOM-portraits, which specify the samples in terms of modules of co-expressed genes of different functional context. We identified two major blood transcriptome types where type 1 was found more in men, the elderly, and overweight people and it upregulated genes associated with inflammation and increased heme metabolism, while type 2 was predominantly found in women, younger, and normal weight participants and it was associated with activated immune responses, transcriptional, ribosomal, mitochondrial, and telomere-maintenance cell-functions. We find a striking overlap of signatures shared by multiple diseases, aging, and obesity driven by an underlying common pattern, which was associated with the immune response and the increase of inflammatory processes. Machine learning applications for large and heterogeneous omics data provide a holistic view on the diversity of the human blood transcriptome. It provides a tool for comparative analyses of transcriptional signatures and of associated phenotypes in population studies and medical applications.
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http://dx.doi.org/10.3389/fdata.2020.548873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931910PMC
October 2020

Rituximab plus high-dose chemotherapy (MegaCHOEP) or conventional chemotherapy (CHOEP-14) in young, high-risk patients with aggressive B-cell lymphoma: 10-year follow-up of a randomised, open-label, phase 3 trial.

Lancet Haematol 2021 Apr 2;8(4):e267-e277. Epub 2021 Mar 2.

Department of Medicine A, Haematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany. Electronic address:

Background: R-MegaCHOEP was the first phase 3 study comparing high-dose chemotherapy plus rituximab followed by autologous haematopoietic stem-cell transplantation (HSCT) with conventional chemotherapy plus rituximab in first-line therapy for patients aged 60 years or younger with high-risk aggressive B-cell lymphoma. Little is known about the long-term outcomes of these patients. We aimed to evaluate the long-term efficacy and safety of conventional chemotherapy versus high-dose chemotherapy after 10 years of follow-up in the R-MegaCHOEP trial.

Methods: In this open-label, randomised, phase 3 trial done across 61 centres in Germany, patients aged 18-60 years with newly diagnosed, high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) aggressive B-cell lymphoma were randomly assigned (1:1, using Pocock minimisation) to eight cycles of conventional chemotherapy (cyclosphosphamide, doxorubicin, vincristine, etoposide, and prednisolone) plus rituximab (R-CHOEP-14) or four cycles of high-dose chemotherapy plus rituximab followed by autologous HSCT (R-MegaCHOEP). The trial was unmasked. Patients were stratified by age-adjusted IPI factors, presence of bulky disease (tumour mass ≥7·5 cm diameter), and treatment centre. The primary endpoint was event-free survival, analysed here 10 years after randomisation. 10-year overall survival, progression-free survival, conditional survival, relapse patterns, secondary malignancies, and molecular characteristics were also analysed. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00129090.

Findings: Between March 3, 2003, and April 7, 2009, 275 patients were randomly assigned to R-CHOEP-14 (n=136) or R-MegaCHOEP (n=139). 130 patients in the R-CHOEP-14 group and 132 patients in the R-MegaCHOEP group were included in the intention-to-treat population. After a median follow-up of 9·3 years (IQR 5·1-11·1), 10-year event-free survival was 51% (95% CI 42-61) in the R-MegaCHOEP group and 57% (47-67) in the R-CHOEP-14 group (adjusted hazard ratio [HR] 1·3 [95% CI 0·9-1·8], p=0·23). 10-year progression-free survival was 59% (50-68) in the R-MegaCHOEP group and 60% (51-70) in the R-CHOEP-14 group (adjusted HR 1·1 [0·7-1·7], p=0·64). 10-year overall survival was 66% (57-76) in the R-MegaCHOEP group and 72% (63-81) in the R-CHOEP-14 group (adjusted HR 1·3 [0·8-2·1], p=0·26). Relapse occurred in 30 (16% [95% CI 11-22]) of 190 patients who had complete remission or unconfirmed complete remission; 17 (17%) of 100 patients in the R-CHOEP-14 group and 13 (14%) of 90 patients in the R-MegaCHOEP group. Seven (23%) of 30 patients had low-grade histology at relapse and had better outcomes compared with patients who relapsed with aggressive histologies. Lymphoma affected the CNS in 18 (28%) of 64 patients with treatment failure. 22 secondary malignancies were reported in the intention-to-treat population; in 12 (9%) of 127 patients in the R-CHOEP-14 group and ten (8%) of 126 patients in the R-MegaCHOEP group.

Interpretation: Event-free survival and overall survival were similar between groups after 10 years of follow-up; outcomes were not improved in the R-MegaCHOEP group by high-dose chemotherapy and autologous HSCT. Patients who relapsed with aggressive histology showed a high incidence of CNS involvement and poor prognosis. For these patients, novel therapies are greatly warranted.

Funding: Deutsche Krebshilfe (German Cancer Aid).
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http://dx.doi.org/10.1016/S2352-3026(21)00022-3DOI Listing
April 2021

Telomerase reverse transcriptase promoter mutation- and O-methylguanine DNA methyltransferase promoter methylation-mediated sensitivity to temozolomide in isocitrate dehydrogenase-wild-type glioblastoma: is there a link?

Eur J Cancer 2021 Apr 22;147:84-94. Epub 2021 Feb 22.

Institute of Neuropathology, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany; German Cancer Consortium, Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Aim Of The Study: Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wild-type glioblastoma is essentially limited to patients with O-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma.

Methods: MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH-wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302).

Results: In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter-unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07-2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter-methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes.

Conclusions: Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH-wild-type glioblastoma.
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http://dx.doi.org/10.1016/j.ejca.2021.01.014DOI Listing
April 2021

Heart failure is independently associated with white matter lesions: insights from the population-based LIFE-Adult Study.

ESC Heart Fail 2021 02 15;8(1):697-704. Epub 2020 Dec 15.

Clinic and Policlinic for Cardiology, University Hospital Leipzig, Leipzig, Germany.

Aims: White matter lesions (WML) are common structural alterations in the white matter of the brain and their prevalence increases with age. They are associated with cerebral ischaemia and cognitive dysfunction. Patients with heart failure (HF) are at risk for cognitive decline. We hypothesized that the presence and duration of HF are associated with WML.

Methods And Results: The LIFE-Adult Study is a population-based study of 10 000 residents of Leipzig, Germany. WML were quantitated in 2490 participants who additionally underwent cerebral MRI using the Fazekas score. Mean age was 64 years, and 46% were female; 2156 (86.6%) subjects had Fazekas score of 0-1, and 334 (13.4%) had Fazekas score of 2-3. Thirty participants had a medical history of HF, 1019 had hypertension, and 51 had a history of stroke. Median left ventricular ejection fraction of the participants with HF was 57% (interquartile ranges 54-62). Age, troponin T, NT-proBNP, body mass index, history of acute myocardial infarction, stroke, HF, and diabetes were positively associated with WML in univariate analysis. On multivariate analysis, age, hypertension, stroke, and HF were independently associated with WML. The odd's ratio for the association of WML (Fazekas 2-3) with HF was 2.8 (95% CI 1.2-6.5; P = 0.019). WML increased with longer duration of HF (P = 0.036 for trend).

Conclusions: In addition to age, hypertension, and stroke, the prevalence and duration of HF are independently associated with WML. This observation sets the stage to investigate the prognostic value of WML in HF and the impact of HF therapies on WML.
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http://dx.doi.org/10.1002/ehf2.13166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835595PMC
February 2021

A biomathematical model of immune response and barrier function in mice with pneumococcal lung infection.

PLoS One 2020 3;15(12):e0243147. Epub 2020 Dec 3.

Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.

Pneumonia is one of the leading causes of death worldwide. The course of the disease is often highly dynamic with unforeseen critical deterioration within hours in a relevant proportion of patients. Besides antibiotic treatment, novel adjunctive therapies are under development. Their additive value needs to be explored in preclinical and clinical studies and corresponding therapy schedules require optimization prior to introduction into clinical practice. Biomathematical modeling of the underlying disease and therapy processes might be a useful aid to support these processes. We here propose a biomathematical model of murine immune response during infection with Streptococcus pneumoniae aiming at predicting the outcome of different treatment schedules. The model consists of a number of non-linear ordinary differential equations describing the dynamics and interactions of the pulmonal pneumococcal population and relevant cells of the innate immune response, namely alveolar- and inflammatory macrophages and neutrophils. The cytokines IL-6 and IL-10 and the chemokines CCL2, CXCL1 and CXCL5 are considered as major mediators of the immune response. We also model the invasion of peripheral blood monocytes, their differentiation into macrophages and bacterial penetration through the epithelial barrier causing blood stream infections. We impose therapy effects on this system by modelling antibiotic therapy and treatment with the novel C5a-inactivator NOX-D19. All equations are derived by translating known biological mechanisms into equations and assuming appropriate response kinetics. Unknown model parameters were determined by fitting the predictions of the model to time series data derived from mice experiments with close-meshed time series of state parameters. Parameter fittings resulted in a good agreement of model and data for the experimental scenarios. The model can be used to predict the performance of alternative schedules of combined antibiotic and NOX-D19 treatment. We conclude that we established a comprehensive biomathematical model of pneumococcal lung infection, immune response and barrier function in mice allowing simulations of new treatment schedules. We aim to validate the model on the basis of further experimental data. We also plan the inclusion of further novel therapy principles and the translation of the model to the human situation in the near future.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243147PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714238PMC
January 2021

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Genet Med 2021 04 1;23(4):705-712. Epub 2020 Dec 1.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.

Purpose: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages.

Results: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively.

Conclusion: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.
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http://dx.doi.org/10.1038/s41436-020-01029-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026395PMC
April 2021

Age-dependent increase of treatment-related mortality in older patients with aggressive B cell lymphoma: analysis of outcome, treatment feasibility, and toxicity in 1171 elderly patients with aggressive B cell lymphoma-data from phase II and III trials of the DSHNHL (German High-Grade Non-Hodgkin's Lymphoma Study Group).

Ann Hematol 2021 Apr 26;100(4):1031-1038. Epub 2020 Nov 26.

Department of Hematology and Medical Oncology, Georg August University Göttingen, Göttingen, Germany.

In elderly patients (pts) with aggressive B cell lymphoma (aNHL), curative treatment often cannot be administered because of comorbidities and tolerability. We analyzed the influence of age in pts > 60 years receiving the R-CHOP-14 regimen within different prospective DSHNHL trials. Of the RICOVER-60 trial and CHOP-R-ESC trials, 1171 aNHL pts were included in this retrospective analysis of age-dependent event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All patients received prophylactic G-CSF, and anti-infective prophylaxis with amphotericin B mouth wash and oral fluorchinolone was optional. In the CHOP-R-ESC trials, prophylaxis was augmented to include mandatory continuous orally administered aciclovir and a pneumocystis prophylaxis with cotrimoxazole as well as oral fluorchinolones during neutropenia. The patient population was separated into 4 age groups (61-65 years, 66-70 years, 71-75 years, and 76-80 years). The results from the RICOVER-60 trial were subsequently confirmed in the following CHOP-R-ESC trials by a multivariate analysis adjusted for IPI factors and gender. Significant differences (p < 0.001) in EFS, PFS, and OS were seen between age groups (RICOVER-60). Hematotoxicity, infections, and TRM increased with age. TRM was significantly elevated in the age group 76-80 years. Therefore, this analysis shows that an age above 75 years defines an especially vulnerable patient population when being treated with chemoimmunotherapy for aNHL. Prophylactic anti-infective drugs are essential and clinically effective in reducing morbidity when treating elderly aNHL pts.
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http://dx.doi.org/10.1007/s00277-020-04345-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960591PMC
April 2021

Depressive Symptomatology in Early Retirees Associated With Reason for Retirement-Results From the Population-Based LIFE-Adult-Study.

Front Psychiatry 2020 18;11:565442. Epub 2020 Sep 18.

Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, Germany.

Background: Transition from employment to retirement is regarded a crucial event. However, there is mixed evidence on associations between retirement and mental health, especially regarding early retirement. In Germany, cases of early retirement due to ill health-particularly, mental ill health-are increasing. Therefore, we investigated the association between early retirement and depressive symptoms, including information on different types of early retirement.

Methods: We analyzed data from 4,808 participants of the population-based LIFE-Adult-Study (age: 40-65 years, 654 retired, 4,154 employed), controlling for sociodemographic information, social network, pre-existing health conditions, and duration of retirement. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Regression analysis using entropy balancing was applied to achieve covariate balance between retired and employed subjects.

Results: We found no overall-differences in depressive symptoms between employed and retired persons (men: b = -.52; p = 0.431; women: b = .05; p = .950). When looking at different types of early retirement, ill-health retirement was linked to increased depressive symptoms in women (b = 4.68, 95% CI = 1.71; 7.65), while voluntary retirement was associated with reduced depressive symptoms in men (b= -1.83, 95% CI = -3.22; -.43) even after controlling for covariates. For women, statutory retirement was linked to lower depressive symptomatology (b = -2.00, 95% CI = -3.99; -.02).

Conclusion: Depressive symptomatology among early retirees depends on reason for retirement: For women, ill-health retirement is linked to higher levels of depressive symptoms. Women who retire early due to ill-health constitute a risk group for depressive symptoms that needs specific attention in the health care and social security system.
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http://dx.doi.org/10.3389/fpsyt.2020.565442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530286PMC
September 2020

Reactive oligodendrocyte progenitor cells (re-)myelinate the regenerating zebrafish spinal cord.

Development 2020 12 16;147(24). Epub 2020 Dec 16.

Center for Regenerative Therapies Dresden TU Dresden (CRTD) and Cluster of Excellence, Physics of Life (PoL), TU Dresden, Dresden 01307, Germany.

Spinal cord injury (SCI) results in loss of neurons, oligodendrocytes and myelin sheaths, all of which are not efficiently restored. The scarcity of oligodendrocytes in the lesion site impairs re-myelination of spared fibres, which leaves axons denuded, impedes signal transduction and contributes to permanent functional deficits. In contrast to mammals, zebrafish can functionally regenerate the spinal cord. Yet, little is known about oligodendroglial lineage biology and re-myelination capacity after SCI in a regeneration-permissive context. Here, we report that, in adult zebrafish, SCI results in axonal, oligodendrocyte and myelin sheath loss. We find that OPCs, the oligodendrocyte progenitor cells, survive the injury, enter a reactive state, proliferate and differentiate into oligodendrocytes. Concomitantly, the oligodendrocyte population is re-established to pre-injury levels within 2 weeks. Transcriptional profiling revealed that reactive OPCs upregulate the expression of several myelination-related genes. Interestingly, global reduction of axonal tracts and partial re-myelination, relative to pre-injury levels, persist at later stages of regeneration, yet are sufficient for functional recovery. Taken together, these findings imply that, in the zebrafish spinal cord, OPCs replace lost oligodendrocytes and, thus, re-establish myelination during regeneration.
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http://dx.doi.org/10.1242/dev.193946DOI Listing
December 2020

Higher BMI, but not obesity-related genetic polymorphisms, correlates with lower structural connectivity of the reward network in a population-based study.

Int J Obes (Lond) 2021 03 25;45(3):491-501. Epub 2020 Oct 25.

Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103, Leipzig, Germany.

Background: Obesity is of complex origin, involving genetic and neurobehavioral factors. Genetic polymorphisms may increase the risk for developing obesity by modulating dopamine-dependent behaviors, such as reward processing. Yet, few studies have investigated the association of obesity, related genetic variants, and structural connectivity of the dopaminergic reward network.

Methods: We analyzed 347 participants (age range: 20-59 years, BMI range: 17-38 kg/m) of the LIFE-Adult Study. Genotyping for the single nucleotid polymorphisms rs1558902 (FTO) and rs1800497 (near dopamine D2 receptor) was performed on a microarray. Structural connectivity of the reward network was derived from diffusion-weighted magnetic resonance imaging at 3 T using deterministic tractography of Freesurfer-derived regions of interest. Using graph metrics, we extracted summary measures of clustering coefficient and connectivity strength between frontal and striatal brain regions. We used linear models to test the association of BMI, risk alleles of both variants, and reward network connectivity.

Results: Higher BMI was significantly associated with lower connectivity strength for number of streamlines (β = -0.0025, 95%-C.I.: [-0.004, -0.0008], p = 0.0042), and, to lesser degree, fractional anisotropy (β = -0.0009, 95%-C.I. [-0.0016, -0.00008], p = 0.031), but not clustering coefficient. Strongest associations were found for left putamen, right accumbens, and right lateral orbitofrontal cortex. As expected, the polymorphism rs1558902 in FTO was associated with higher BMI (F = 6.9, p < 0.001). None of the genetic variants was associated with reward network structural connectivity.

Conclusions: Here, we provide evidence that higher BMI correlates with lower reward network structural connectivity. This result is in line with previous findings of obesity-related decline in white matter microstructure. We did not observe an association of variants in FTO or near DRD2 receptor with reward network structural connectivity in this population-based cohort with a wide range of BMI and age. Future research should further investigate the link between genetics, obesity and fronto-striatal structural connectivity.
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http://dx.doi.org/10.1038/s41366-020-00702-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906899PMC
March 2021

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

Soft Tissue Injury Considerations in the Treatment of Tibial Plateau Fractures.

Orthop Clin North Am 2020 Oct 12;51(4):471-479. Epub 2020 Aug 12.

Department of Orthopedic Surgery, Prisma Health, Greenville Memorial Medical Hospital, 701 Grove Road, 2nd Floor Support Tower, Greenville, SC 29605, USA.

Tibial plateau fractures represent a highly variable spectrum of injury that requires a multifaceted diagnostic and therapeutic approach in order to adequately treat. Constant vigilance is required to consider all the injured structures and avoid focusing only on the bony aspect of the injury. Management of the soft tissue envelope and repair/reconstruction of critical stabilizing structures of the knee should be at the forefront of the thought process when approaching these complex injuries. This article aims to emphasize the high incidence of injury to associated soft tissue structures and provide general approach considerations to these complex injuries.
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http://dx.doi.org/10.1016/j.ocl.2020.06.003DOI Listing
October 2020

Value of upper gastrointestinal endoscopy for gastric cancer surveillance in patients with Lynch syndrome.

Int J Cancer 2021 01 13;148(1):106-114. Epub 2020 Oct 13.

Department of Hematology and Oncology, Klinikum Hochsauerland, Meschede, Germany.

In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from the registry of the German Consortium for Familial Intestinal Cancer. In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty-nine GC events were observed in 47 patients. MLH1 (n = 21) and MSH2 (n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early-stage disease (UICC I) than GCs detected through symptoms (83% vs 25%; P = .0231). Thirty-two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28-66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30.
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http://dx.doi.org/10.1002/ijc.33294DOI Listing
January 2021

Dynamics of cytokines, immune cell counts and disease severity in patients with community-acquired pneumonia - Unravelling potential causal relationships.

Cytokine 2020 12 4;136:155263. Epub 2020 Sep 4.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

Background: Community acquired pneumonia (CAP) is a severe and often rapidly deteriorating disease. To better understand its dynamics and potential causal relationships, we analyzed time series data of cytokines, blood and clinical parameters in hospitalized CAP patients.

Methods: Time series data of 10 circulating cytokines, blood counts and clinical parameters were related to baseline characteristics of 403 CAP patients using univariate mixed models. Bivariate mixed models were applied to analyze correlations between the time series. To identify potential causal relationships, we inferred cross-lagged relationships between pairs of parameters using latent curve models with structured residuals.

Results: IL-6 levels decreased faster over time in younger patients (P = 0.06). IL-8, VCAM-1, and IL-6 correlated strongly with disease severity as assessed by the sequential organ failure assessment (SOFA) score (r = 0.49, 0.48, 0.46, respectively; all P < 0.001). IL-6 and bilirubin correlated with respect to their mean levels and slopes over time (r = 0.36 and r = 0.46, respectively; P < 0.001). A number of potential causal relationships were identified, e.g., a negative effect of ICAM-1 on MCP-1, or a positive effect of the level of creatinine on the subsequent VCAM-1 concentration (P < 0.001).

Conclusions: These results suggest that IL-6 trajectories of CAP patients are associated with age and run parallel to bilirubin levels. The time series analysis also unraveled directed, potentially causal relationships between cytokines, blood parameters and clinical outcomes. This will facilitate the development of mechanistic models of CAP, and with it, improvements in treatment or surveillance strategies for this disease.

Trial Registration: clinicaltrials.gov NCT02782013, May 25, 2016, retrospectively registered.
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http://dx.doi.org/10.1016/j.cyto.2020.155263DOI Listing
December 2020

Norms of Interocular Circumpapillary Retinal Nerve Fiber Layer Thickness Differences at 768 Retinal Locations.

Transl Vis Sci Technol 2020 08 12;9(9):23. Epub 2020 Aug 12.

Leipzig Research Centre for Civilization Diseases (LIFE), Leipzig University, Leipzig, Germany.

Purpose: The onset and progression of optic neuropathies like glaucoma often occurs asymmetrically between the two eyes of a patient. Interocular circumpapillary retinal nerve fiber layer thickness (cpRNFLT) differences could detect disease earlier. To apply such differences diagnostically, detailed location specific norms are necessary.

Methods: Spectral-domain optical coherence tomography cpRNFLT circle scans from the population-based Leipzig Research Centre for Civilization Diseases-Adult study were selected. At each of the 768 radial scanning locations, normative interocular cpRNFLT difference distributions were calculated based on age and interocular radius difference.

Results: A total of 8966 cpRNFLT scans of healthy eyes (4483 patients; 55% female; age range, 20-79 years) were selected. Global cpRNFLT average was 1.53 µm thicker in right eyes ( < 2.2 × 10). On 96% of the 768 locations, left minus right eye differences were significant ( < 0.05), varying between +11.6 µm (superonasal location) and -11.8 µm (nasal location). Increased age and difference in interocular scanning radii were associated with an increased mean and variance of interocular cpRNFLT difference at most retinal locations, apart from the area temporal to the inferior RNF bundle where cpRNFLT becomes more similar between eyes with age.

Conclusions: We provide pointwise normative distributions of interocular cpRNFLT differences at an unprecedentedly high spatial resolution of 768 A-scans and reveal considerable location specific asymmetries as well as their associations with age and scanning radius differences between eyes.

Translational Relevance: To facilitate clinical application, we implement these age- and radius-specific norms across all 768 locations in an open-source software to generate patient-specific normative color plots.
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http://dx.doi.org/10.1167/tvst.9.9.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442876PMC
August 2020

Genome-wide association analysis of pulse wave velocity traits provide new insights into the causal relationship between arterial stiffness and blood pressure.

PLoS One 2020 13;15(8):e0237237. Epub 2020 Aug 13.

Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.

Background: The pathophysiology of arterial stiffness is not completely understood. Pulse wave velocity (PWV) is an established marker for arterial stiffness. We compare genetics of three PWV modes, namely carotid-femoral PWV (cfPWV), brachial-ankle (baPWV) and brachial-femoral (bfPWV), reflecting different vascular segments to analyse association with genetic variants, heritability and genetic correlation with other biological traits. Furthermore we searched for shared genetic architecture concerning PWV, blood pressure (BP) and coronary artery disease (CAD) and examined the causal relationship between PWV and BP.

Methods And Results: We performed a genome-wide association study (GWAS) for cfPWV, baPWV and bfPWV in LIFE-Adult (N = 3,643-6,734). We analysed the overlap of detected genetic loci with those of BP and CAD and performed genetic correlation analyses. By bidirectional Mendelian Randomization, we assessed the causal relationships between PWV and BP. For cfPWV we identified a new locus with genome-wide significance near SLC4A7 on cytoband 3p24.1 (lead SNP rs939834: p = 2.05x10-8). We replicated a known PWV locus on cytoband 14q32.2 near RP11-61O1.1 (lead SNPs: rs17773233, p = 1.38x10-4; rs1381289, p = 1.91x10-4) For baPWV we estimated a heritability of 28% and significant genetic correlation with hypertension (rg = 0.27, p = 6.65x10-8). We showed a positive causal effect of systolic blood pressure on PWV modes (cfPWV: p = 1.51x10-4; bfPWV: p = 1.45x10-3; baPWV: p = 6.82x10-15).

Conclusions: We identified a new locus for arterial stiffness and successfully replicated an earlier proposed locus. PWV shares common genetic architecture with BP and CAD. BP causally affects PWV. Larger studies are required to further unravel the genetic determinants and effects of PWV.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237237PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425880PMC
October 2020

ProstaTrend-A Multivariable Prognostic RNA Expression Score for Aggressive Prostate Cancer.

Eur Urol 2020 09 4;78(3):452-459. Epub 2020 Jul 4.

Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; Institute of Clinical Immunology, Faculty of Medicine, University of Leipzig, Leipzig, Germany.

Background: Prostate cancer (PCa) is the most prevalent solid cancer among men in Western Countries. The clinical behavior of localized PCa is highly variable. Some cancers are aggressive leading to death, while others can even be monitored safely. Hence, there is a high clinical need for precise biomarkers for identification of aggressive disease in addition to established clinical parameters.

Objective: To develop an RNA expression-based score for the prediction of PCa prognosis that facilitates clinical decision making.

Design, Setting, And Participants: We assessed 233 tissue specimens of PCa patients with long-term follow-up data from fresh-frozen radical prostatectomies (RPs), from formalin-fixed and paraffin-embedded RP specimens and biopsies by transcriptome-wide next-generation sequencing and customized expression microarrays.

Outcome Measurements And Statistical Analysis: We applied Cox proportional hazard models to the cohorts from different platforms and specimen types. Evidence from these models was combined by fixed-effect meta-analysis to identify genes predictive of the time to death of disease (DoD). Genes were combined by a weighted median approach into a prognostic score called ProstaTrend and transferred for the prediction of biochemical recurrence (BCR) after RP in an independent cohort of The Cancer Genome Atlas (TCGA).

Results And Limitations: ProstaTrend comprising ∼1400 genes was significantly associated with DoD in the training cohort of PCa patients treated by RP (leave-one-out cross-validation, Cox regression: p=2e-09) and with BCR in the TCGA validation cohort (Cox regression: p=3e-06). The prognostic impact persisted after multivariable Cox regression analysis adjusting for Gleason grading group (GG) ≥3 and resection status (p=0.001; DoD, training cohort) and for GG≥3, pathological stage ≥T3, and resection state (p=0.037; BCR, validation cohort).

Conclusions: ProstaTrend is a transcriptome-based score that predicts DoD and BCR in cohorts of PCa patients treated with RP.

Patient Summary: ProstaTrend provides molecular patient risk stratification after radical prostatectomy.
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http://dx.doi.org/10.1016/j.eururo.2020.06.001DOI Listing
September 2020

Genome-wide analysis of carotid plaque burden suggests a role of IL5 in men.

PLoS One 2020 29;15(5):e0233728. Epub 2020 May 29.

Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.

Background: Carotid artery plaque is an established marker of subclinical atherosclerosis with pronounced sex-dimorphism. Here, we aimed to identify genetic variants associated with carotid plaque burden (CPB) and to examine potential sex-specific genetic effects on plaque sizes.

Methods And Results: We defined six operationalizations of CPB considering plaques in common carotid arteries, carotid bulb, and internal carotid arteries. We performed sex-specific genome-wide association analyses for all traits in the LIFE-Adult cohort (n = 727 men and n = 550 women) and tested significantly associated loci for sex-specific effects. In order to identify causal genes, we analyzed candidate gene expression data for correlation with CPB traits and corresponding sex-specific effects. Further, we tested if previously reported SNP associations with CAD and plaque prevalence are also associated with CBP. We found seven loci with suggestive significance for CPB (p<3.33x10-7), explaining together between 6 and 13% of the CPB variance. Sex-specific analysis showed a genome-wide significant hit for men at 5q31.1 (rs201629990, β = -0.401, p = 5.22x10-9), which was not associated in women (β = -0.127, p = 0.093) with a significant difference in effect size (p = 0.008). Analyses of gene expression data suggested IL5 as the most plausible candidate, as it reflected the same sex-specific association with CPBs (p = 0.037). Known plaque prevalence or CAD loci showed no enrichment in the association with CPB.

Conclusions: We showed that CPB is a complementary trait in analyzing genetics of subclinical atherosclerosis. We detected a novel locus for plaque size in men only suggesting a role of IL5. Several estrogen response elements in this locus point towards a functional explanation of the observed sex-specific effect.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233728PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259763PMC
September 2020

Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study.

BMC Cancer 2020 May 24;20(1):460. Epub 2020 May 24.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

Background: Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population.

Methods: Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX.

Results: The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX.

Conclusions: The characterisation of cancer risks in patients with LLS and FCCX is important to develop appropriate surveillance programmes for these specific intermediate risk groups. Larger prospective studies are needed to obtain more precise risk estimates.
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http://dx.doi.org/10.1186/s12885-020-06926-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245918PMC
May 2020

Standardization and Feasibility of Voice Range Profile Measurements in Epidemiological Studies.

J Voice 2020 May 10. Epub 2020 May 10.

Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany; LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.

Objectives: The voice range profile (VRP) is composed of the speaking VRP (spVRP) and the singing VRP (siVRP). Different examination methods of VRP and effects of interobserver variability were evaluated to define a standard operating procedure (SOP) suitable for the specific use in epidemiological studies. Subsequently the feasibility of the SOP was investigated in a larger number of participants.

Study Design: Cross-sectional study.

Methods: In a first phase both the spVRP and the siVRP of 51 female students were measured by four differently experienced examiners. Using a cross-over study design the effects of two different recording methods (manual vs automatic) and three different types of instructions given by the examiner (none vs before vs during recording) were investigated. In a second phase, the SOP for VRP recording was tested in the framework of a feasibility study in 110 (55 female and 55 male) participants.

Results: The average total investigation time was significantly (P = 0.001) higher for the manual recording method (6.1 minutes ± 1.0) in comparison to the automated (5.5 minutes ± 0.7) recording method. The manual recording method led to significantly lower values of minimum frequency (F0min) (P = 0.013) and minimum intensity (SPLmin) (P < 0.001) and higher values of the maximum frequency (F0max) (P = 0.005) of the siVRP. The maximum phonation time, F0max, SPLmax of the siVRP and the frequency and intensity of the shouting voice (Level IV) of the spVRP showed significantly (P < 0.001) higher values when the examiner was allowed to give instructions and advise during the recording. Voice parameters of the siVRP did not show significant associations with the experience of the examiner.

Conclusions: Standardization of VRP measurements is important to obtain correct and reproducible data in a reasonable examination time. The SOP proposed here proved to be feasible in the setting of an epidemiological study.
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http://dx.doi.org/10.1016/j.jvoice.2020.04.014DOI Listing
May 2020
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