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Tumour budding (TB) has been associated with adverse clinicopathological factors and poor survival in a plethora of therapy-naive carcinoma entities including gastric adenocarcinoma (GC). As conventional histopathological grading is usually omitted in the post-neoadjuvant setting of GC, our study aimed to investigate the prognostic impact of TB in GCs resected after neoadjuvant therapy. We evaluated TB according to the criteria from the International Tumour Budding Consensus Conference (ITBCC) in 167 post-neoadjuvant resections of intestinaltype GC and correlated the results with overall survival (OS) and clinicopathological parameters. GCs were categorised into Bd1 (0-4 buds, low TB), Bd2 (5-9 buds, intermediate TB), and Bd3 (>= 10 buds, high TB). Carcinomas with intermediate and high TB were significantly enriched in higher ypTNM stages and strongly associated with reduced 5-year OS in univariable analyses (p < 0.001). In multivariable analyses including sex, age, resection status, UICC stage, and tumour regression grading, TB remained a stage-independent predictor of survival (p < 0.001, hazard ratio Bd2: 2.60, Bd3: 4.74). The assessment of TB according to the ITBCC criteria provides valuable prognostic information in the post-neoadjuvant setting of intestinal-type GC and may be a considerable substitute for the conventional grading system in GCs after neoadjuvant therapy.

We investigated the clinical impact of elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in the context of neoadjuvant chemotherapy (CTx) in gastric/gastro-oesophageal adenocarcinomas. We analysed 583 resected tumours (272 without and 311 after CTx) and 142 tumour biopsies before CTx. If at least two or three of the five tetranucleotide repeat markers tested showed instability, the tumours were defined as EMAST (2+) or EMAST (3+), respectively. Expression of mismatch repair proteins including MSH3 was analysed using immunohistochemistry. Microsatellite instability (MSI) and Epstein-Barr virus (EBV) positivity were determined using standard assays. EMAST (2+) and (3+) were detected in 17.8 and 11.5% of the tumours, respectively. The frequency of EMAST (2+) or (3+) in MSI-high (MSI-H) tumours was 96.2 or 92.5%, respectively, demonstrating a high overlap with this molecular subtype, and the association of EMAST and MSI status was significant (each overall p < 0.001). EMAST (2+ or 3+) alone in MSI-H and EBV-negative tumours demonstrated only a statistically significant association of EMAST (2+) positivity and negative lymph node status (42.3% in EMAST (2+) and 28.8% in EMAST negative, p = 0.045). EMAST alone by neither definition was significantly associated with overall survival (OS) of the patients. The median OS for EMAST (2+) patients was 40.0 months (95% confidence interval [CI] 16.4-63.6) compared with 38.7 months (95% CI 26.3-51.1) for the EMAST-negative group (p = 0.880). The median OS for EMAST (3+) patients was 46.7 months (95% CI 18.2-75.2) and 38.7 months (95% CI 26.2-51.2) for the negative group (p = 0.879). No statistically significant association with response to neoadjuvant CTx was observed (p = 0.992 and p = 0.433 for EMAST (2+) and (3+), respectively). In conclusion, our results demonstrate a nearly complete intersection between MSI-H and EMAST and they indicate that EMAST alone is not a distinct instability type associate

Hypothesis testing of random forest (RF) variable importance measures (VIMP) remains the subject of ongoing research. Among recent developments, heuristic approaches to parametric testing have been proposed whose distributional assumptions are based on empirical evidence. Other formal tests under regularity conditions were derived analytically. However, these approaches can be computationally expensive or even practically infeasible. This problem also occurs with non-parametric permutation tests, which are, however, distribution-free and can generically be applied to any type of RF and VIMP. Embracing this advantage, it is proposed here to use sequential permutation tests and sequential p-value estimation to reduce the high computational costs associated with conventional permutation tests. The popular and widely used permutation VIMP serves as a practical and relevant application example. The results of simulation studies confirm that the theoretical properties of the sequential tests apply, that is, the type-I error probability is controlled at a nominal level and a high power is maintained with considerably fewer permutations needed in comparison to conventional permutation testing. The numerical stability of the methods is investigated in two additional application studies. In summary, theoretically sound sequential permutation testing of VIMP is possible at greatly reduced computational costs. Recommendations for application are given. A respective implementation is provided through the accompanying R package $rfvimptest$. The approach can also be easily applied to any kind of prediction model.

Background The Cancer Genome Atlas (TCGA) consortium described EBV positivity(+), high microsatellite instability (MSI-H), genomic stability (GS) and chromosomal instability (CIN) as molecular subtypes in gastric carcinomas (GC). We investigated the predictive and prognostic value of these subtypes with emphasis on CIN in the context of neoadjuvant chemotherapy (CTx) in GC. Methods TCGA subgroups were determined for 612 resected adenocarcinomas of the stomach and gastro-oesophageal junction (291 without, 321 with CTx) and 143 biopsies before CTx. EBV and MSI-H were analysed by standard assays. CIN was detected by multiplex PCRs analysing 22 microsatellite markers. Besides the TCGA classification, CIN was divided into four CIN-subgroups: low, moderate, substantial, high. Mutation profiling was performed for 52 tumours by next-generation sequencing. Results EBV(+) (HR, 0.48; 95% CI, 0.23-1.02), MSI-H (HR, 0.56; 95% CI, 0.35-0.89) and GS (HR, 0.72; 95% CI, 0.45-1.13) were associated with increased survival compared to CIN in the resected tumours. Considering the extended CIN-classification, CIN-substantial was a negative prognostic factor in uni- and multivariable analysis in resected tumours with CTx (each p < 0.05). In biopsies before CTx, CIN-high predicted tumour regression (p = 0.026), but was not prognostically relevant. Conclusion A refined CIN classification reveals tumours with different biological characteristics and potential clinical implications.

Für diese Dissertation wurde eine Datenbank erstellt, die Patienten mit Lebermetastasenresektionen bei einem kolorektalen Adenokarzinom als Grundleiden am Klinikum rechts der Isar von 2007 bis 2016 einschloss. Anhand dieser wurden Risikofaktoren für die Entwicklung von Major-Morbidität analysiert und prognostische Faktoren für das Gesamtüberleben ermittelt. Zusätzlich wurde ein detaillierter Vergleich zwischen ein- und zweizeitigen Operationsvorgehen durchgeführt, bei dem sich beide Verfahren onkologisch äquivalent darstellten und einzeitige Eingriffe ebenfalls sicher erschienen., A database was created for this dissertation, that included patients who underwent a resection of liver metastasis from a colorectal adenocarcinoma as the primary tumor at the Klinikum rechts der Isar in Munich from 2007 to 2016. Based on that, risk factors for major morbidity were analyzed and prognostic factors that showed a negative impact on survival were identified. Furthermore, we performed a very detailed comparison between simultaneous and staged resections. Both surgical approaches showed to be equivalent from an oncological point of view and simultaneous resections proved equally safe.

Background The Cancer Genome Atlas (TCGA) consortium described EBV positivity(+), high microsatellite instability (MSI-H), genomic stability (GS) and chromosomal instability (CIN) as molecular subtypes in gastric carcinomas (GC). We investigated the predictive and prognostic value of these subtypes with emphasis on CIN in the context of neoadjuvant chemotherapy (CTx) in GC. Methods TCGA subgroups were determined for 612 resected adenocarcinomas of the stomach and gastro-oesophageal junction (291 without, 321 with CTx) and 143 biopsies before CTx. EBV and MSI-H were analysed by standard assays. CIN was detected by multiplex PCRs analysing 22 microsatellite markers. Besides the TCGA classification, CIN was divided into four CIN-subgroups: low, moderate, substantial, high. Mutation profiling was performed for 52 tumours by next-generation sequencing. Results EBV(+) (HR, 0.48; 95% CI, 0.23-1.02), MSI-H (HR, 0.56; 95% CI, 0.35-0.89) and GS (HR, 0.72; 95% CI, 0.45-1.13) were associated with increased survival compared to CIN in the resected tumours. Considering the extended CIN-classification, CIN-substantial was a negative prognostic factor in uni- and multivariable analysis in resected tumours with CTx (each p < 0.05). In biopsies before CTx, CIN-high predicted tumour regression (p = 0.026), but was not prognostically relevant. Conclusion A refined CIN classification reveals tumours with different biological characteristics and potential clinical implications.

Für diese Dissertation wurde eine Datenbank erstellt, die Patienten mit Lebermetastasenresektionen bei einem kolorektalen Adenokarzinom als Grundleiden am Klinikum rechts der Isar von 2007 bis 2016 einschloss. Anhand dieser wurden Risikofaktoren für die Entwicklung von Major-Morbidität analysiert und prognostische Faktoren für das Gesamtüberleben ermittelt. Zusätzlich wurde ein detaillierter Vergleich zwischen ein- und zweizeitigen Operationsvorgehen durchgeführt, bei dem sich beide Verfahren onkologisch äquivalent darstellten und einzeitige Eingriffe ebenfalls sicher erschienen., A database was created for this dissertation, that included patients who underwent a resection of liver metastasis from a colorectal adenocarcinoma as the primary tumor at the Klinikum rechts der Isar in Munich from 2007 to 2016. Based on that, risk factors for major morbidity were analyzed and prognostic factors that showed a negative impact on survival were identified. Furthermore, we performed a very detailed comparison between simultaneous and staged resections. Both surgical approaches showed to be equivalent from an oncological point of view and simultaneous resections proved equally safe.

Background and Purpose: To identify factors associated with prior stroke at presentation in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO). Methods: We studied cross-sectional data from the International PFO Consortium Study (NCT00859885). Patients with first-ever stroke and those with prior stroke at baseline were analyzed for an association with PFO-related (right-to-left shunt at rest, atrial septal aneurysm, deep venous thrombosis, pulmonary embolism, and Valsalva maneuver) and PFO-unrelated factors (age, gender, BMI, hypertension, diabetes mellitus, hypercholesterolemia, smoking, migraine, coronary artery disease, aortic plaque). A multivariable analysis was used to adjust effect estimation for confounding, e.g., owing to the age-dependent definition of study groups in this cross-sectional study design. Results: We identified 635 patients with first-ever and 53 patients with prior stroke. Age, BMI, hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and right-to-left shunt (RLS) at rest were significantly associated with prior stroke. Using a pre-specified multivariable logistic regression model, age (Odds Ratio 1.06), BMI (OR 1.06), hypercholesterolemia (OR 1.90) and RLS at rest (OR 1.88) were strongly associated with prior stroke.Based on these factors, we developed a nomogram to illustrate the strength of the relation of individual factors to prior stroke. Conclusion: In patients with CS and PFO, the likelihood of prior stroke is associated with both, PFO-related and PFO-unrelated factors.

Die Querschnittstudie untersuchte die Prävalenz von nichtmelanozytärem Hautkrebs (NMSC) bei außenberufstätigen (=UV-exponiert) Landwirten (LW) und Kontrollen (Innenberufstätige). Die Präkanzerose Aktinische Keratose wurde in unserer Studie als NMSC gewertet. In einem standardisierten Hautkrebsscreening lag die NMSC-Punktprävalenz in der Außenberufsgruppe bei 33% (n= 30/91) vs. 5% (n= 6/121) in der Kontrollgruppe, p<0.001. LW hatten eine 8-fach höhere Chance, an NMSC zu erkranken, OR=8.2 (3.1-21.6) p<0.001. Relevante Nebendiagnosen waren Handekzeme bei LW und Dermatomykosen in der Kontrollgruppe, insbesondere bei Kanalarbeitern, wobei in beiden Fällen eine berufliche Assoziation zu vermuten ist., In a cross-sectional study design, we investigated the prevalence of nonmelanoma skin cancer (NMSC) in outdoor working farmers (sun-exposed) and controls (indoor workers). In our study, NMSC also included the precancerous condition actinic keratosis. We performed standardized skin cancer screening examinations: NMSC was found in 33% (n=30/91) of farmers and in 5% (n=6/121) of controls (p<0.001). Thus, farmers had an eight times higher risk to develop NMSC, OR=8.2 (3.1-21.6) p<0.001. Other relevant diagnoses were hand eczema in farmers and mycosis pedis in controls, especially in sewer workers, both as possibly work-related effects.

In computational biology and other sciences, researchers are frequently faced with a choice between several computational methods for performing data analyses. Benchmarking studies aim to rigorously compare the performance of different methods using well-characterized benchmark datasets, to determine the strengths of each method or to provide recommendations regarding suitable choices of methods for an analysis. However, benchmarking studies must be carefully designed and implemented to provide accurate, unbiased, and informative results. Here, we summarize key practical guidelines and recommendations for performing high-quality benchmarking analyses, based on our experiences in computational biology.

Die Querschnittstudie untersuchte die Prävalenz von nichtmelanozytärem Hautkrebs (NMSC) bei außenberufstätigen (=UV-exponiert) Landwirten (LW) und Kontrollen (Innenberufstätige). Die Präkanzerose Aktinische Keratose wurde in unserer Studie als NMSC gewertet. In einem standardisierten Hautkrebsscreening lag die NMSC-Punktprävalenz in der Außenberufsgruppe bei 33% (n= 30/91) vs. 5% (n= 6/121) in der Kontrollgruppe, p<0.001. LW hatten eine 8-fach höhere Chance, an NMSC zu erkranken, OR=8.2 (3.1-21.6) p<0.001. Relevante Nebendiagnosen waren Handekzeme bei LW und Dermatomykosen in der Kontrollgruppe, insbesondere bei Kanalarbeitern, wobei in beiden Fällen eine berufliche Assoziation zu vermuten ist., In a cross-sectional study design, we investigated the prevalence of nonmelanoma skin cancer (NMSC) in outdoor working farmers (sun-exposed) and controls (indoor workers). In our study, NMSC also included the precancerous condition actinic keratosis. We performed standardized skin cancer screening examinations: NMSC was found in 33% (n=30/91) of farmers and in 5% (n=6/121) of controls (p<0.001). Thus, farmers had an eight times higher risk to develop NMSC, OR=8.2 (3.1-21.6) p<0.001. Other relevant diagnoses were hand eczema in farmers and mycosis pedis in controls, especially in sewer workers, both as possibly work-related effects.

Marion Ortner,1 Christine Hauser,2 Christoph Schmaderer,2 Claudia Muggenthaler,1 Alexander Hapfelmeier,3 Christian Sorg,1,4 Janine Diehl-Schmid,1 Alexander Kurz,1 Hans Förstl,1 Benno Ikenberg,5 Konstantin Kotliar,6 Holger Poppert,5,7,* Timo Grimmer1,* 1Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, Department of Psychiatry and Psychotherapy, Munich, Germany; 2Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, Department of Nephrology, Munich, Germany; 3Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, Institute for Medical Statistics and Epidemiology, Munich, Germany; 4Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, Department of Diagnostic and Interventional Neuroradiology, Munich, Germany; 5Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, Department of Neurology, Munich, Germany; 6Department of Medical Engineering and Technomathematics, FH Aachen, Jülich, Germany; 7Department of Neurology, Helios Dr. Horst Schmid Kliniken Wiesbaden, Wiesbaden, Germany*These authors contributed equally to this workCorrespondence: Marion OrtnerTechnical University of Munich, School of Medicine, Klinikum Rechts der Isar, Department of Psychiatry and Psychotherapy, Moehlstr. 26 81675, Muenchen, GermanyTel +49 89 4140 6463Fax +49 89 4140 4923Email marion.ortner@tum.dePurpose: Impaired paravascular drainage of β-Amyloid (Aβ) has been proposed as a contributing cause for sporadic Alzheimer’s disease (AD), as decreased cerebral blood vessel pulsatility and subsequently reduced propulsion in this pathway could lead to the accumulation and deposition of Aβ in the brain. Therefore, we hypothesized that there is an increased impairment in pulsatility across AD spectrum.Patients and Methods: Using transcranial color-coded duplex sonography (TCCS) the resistance and pulsatility index (RI; PI) of th

Low molecular weight heparin (LMWH) is routinely used to prevent thromboembolism in orthopaedic surgery, especially in the treatment of fractures or after joint-replacement. Impairment of fracture-healing due to increased bone-desorption, delayed remodelling and lower calcification caused by direct osteoclast stimulation is a well-known side effect of unfractioned heparin. However, the effect of LMWH is unclear and controversial. Recent studies strongly suggest impairment of bone-healing in-vitro and in animal models, characterized by a significant decrease in volume and quality of new-formed callus. Since October 2008, Rivaroxaban (Xarelto) is available for prophylactic use in elective knee- and hip-arthroplasty. Recently, some evidence has been found indicating an in vitro dose independent reduction of osteoblast function after Rivaroxaban treatment. In this study, the possible influence of Rivaroxaban and Enoxaparin on bone-healing in vivo was studied using a standardized, closed rodent fracture-model. 70 male Wistar-rats were randomized to Rivaroxaban, Enoxaparin or control groups. After pinning the right femur, a closed, transverse fracture was produced. 21 days later, the animals were sacrificed and both femora harvested. Analysis was done by biomechanical testing (three-point bending) and micro CT. Both investigated substances showed histomorphometric alterations of the newly formed callus assessed by micro CT analysis. In detail the bone (callus) volume was enhanced (sign. for Rivaroxaban) and the density reduced. The bone mineral content was enhanced accordingly (sign. for Rivaroxaban). Trabecular thickness was reduced (sign. for Rivaroxaban). Furthermore, both drugs showed significant enlarged bone (callus) surface and degree of anisotropy. In contrast, the biomechanical properties of the treated bones were equal to controls. To summarize, the morphological alterations of the fracture-callus did not result in functionally relevant deficits.

In an interesting and quite exhaustive review on Random Forests (RF) methodology in bioinformatics Touw et al. address-among other topics-the problem of the detection of interactions between variables based on RF methodology. We feel that some important statistical concepts, such as 'interaction', 'conditional dependence' or 'correlation', are sometimes employed inconsistently in the bioinformatics literature in general and in the literature on RF in particular. In this letter to the Editor, we aim to clarify some of the central statistical concepts and point out some confusing interpretations concerning RF given by Touw et al. and other authors.