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Mosquitoes and other arthropods may transmit medically important pathogens, in particular viruses such as West Nile virus. The presence of suitable hosts and competent vectors for those zoonotic viruses is essential for an enzootic transmission, which is a prerequisite for epidemics. To establish reliable risk projections, it is an urgent need for an exact identification of mosquito species, which is especially challenging in the case of sibling species, such as Culex. pipiens pipiens biotypes pipiens and molestus. To facilitate detection of different Culex pipiens forms and their hybrids we established a multiplex real-time PCR. Culex pipiens samples were obtained by egg raft collection and rearing until imago stage or adult sampling using CO2 baited traps and gravid traps. In total, we tested more than 16,500 samples collected all over Germany in the years 2011 and 2012. The predominant species in Germany are Culex pipiens pipiens biotype pipiens and Culex. torrentium, but we also detected Culex pipiens pipiens biotype molestus and hybrids of the two pipiens biotypes at sites where both species occur sympatrically. This report of a potentially important bridge vector for West Nile virus might have major impact in the risk projections for West Nile virus in Germany.
This report provides a brief review of the 20th annual meeting of the German Language Branch of the Society of Environmental Toxicology and Chemistry (SETAC GLB) held from September 7th to 10th 2015 at ETH (Swiss Technical University) in Zurich, Switzerland. The event was chaired by Inge Werner, Director of the Swiss Centre for Applied Ecotoxicology (Ecotox Centre) Eawag-EPFL, and organized by a team from Ecotox Centre, Eawag, Federal Office of the Environment, Federal Office of Agriculture, and Mesocosm GmbH (Germany). Over 200 delegates from academia, public agencies and private industry of Germany, Switzerland and Austria attended and discussed the current state of science and its application presented in 75 talks and 83 posters. In addition, three invited keynote speakers provided new insights into scientific knowledge ‘brokering’, and—as it was the International Year of Soil—the important role of healthy soil ecosystems. Awards were presented to young scientists for best oral and poster presentations, and for best 2014 master and doctoral theses. Program and abstracts of the meeting (mostly in German) are provided as Additional file 1.
Background: Available data on the incidence and outcome of invasive fungal diseases (IFD) in children with hematological malignancies or after allogeneic hematopoietic stem cell transplantation (HSCT) are mostly based on monocenter, retrospective studies or on studies performed prior to the availability of newer triazoles or echinocandins.
Procedure: We prospectively collected clinical data on incidence, diagnostic procedures, management and outcome of IFD in children treated for hematological malignancies or undergoing HSCT in three major European pediatric cancer centers.
Results: A total of 304 children (median age 6.0 years) who underwent 360 therapies (211 chemotherapy treatments, 138 allogeneic HSCTs and/or 11 investigational chemotherapeutic treatments) were included in the analysis. Nineteen children developed proven/probable IFD, mostly due to Aspergillus (n = 10) and Candida spp. (n = 5), respectively. In patients receiving chemotherapy, 11 IFDs occurred, all during induction or re-induction therapy. None of these patients died due to IFD, whereas IFD was lethal in 3 of the 8 HSCT recipients with IFD. Significant differences among centers were observed with regard to the use of imaging diagnostics and the choice, initiation and duration of antifungal prophylaxis.
Conclusion: This prospective multicenter study provides information on the current incidence and outcome of IFD in the real life setting. Practice variation between the centers may help to ultimately improve antifungal management in children at highest risk for IFDs.
Background: Simultaneous pancreas kidney transplantation (SPK), pancreas transplantation alone (PTA) or pancreas transplantation after kidney (PAK) are the only curative treatment options for patients with type 1 (juvenile) diabetes mellitus with or without impaired renal function. Unfortunately, transplant waiting lists for this indication are increasing because the current organ acceptability criteria are restrictive; morbidity and mortality significantly increase with time on the waitlist. Currently, only pancreas organs from donors younger than 50 years of age and with a body mass index (BMI) less than 30 are allocated for transplantation in the Eurotransplant (ET) area. To address this issue we designed a study to increase the available donor pool for these patients.
Methods/Design: This study is a prospective, multicenter (20 German centers), single blinded, non-randomized, two armed trial comparing outcome after SPK, PTA or PAK between organs with the currently allowed donor criteria versus selected organs from donors with extended criteria. Extended donor criteria are defined as organs procured from donors with a BMI of 30 to 34 or a donor age between 50 and 60 years. Immunosuppression is generally standardized using induction therapy with Myfortic, tacrolimus and low dose steroids. In principle, all patients on the waitlist for primary SPK, PTA or PAK are eligible for the clinical trial when they consent to possibly receiving an extended donor criteria organ. Patients receiving an organ meeting the current standard criteria for pancreas allocation (control arm) are compared to those receiving extended criteria organ (study arm); patients are blinded for a follow-up period of one year. The combined primary endpoint is survival of the pancreas allograft and pancreas allograft function after three months, as an early relevant outcome parameter for pancreas transplantation.
Discussion: The EXPAND Study has been initiated to investigate the hypothesis that locally allocated extended criteria organs can be transplanted with similar results compared to the currently allowed standard ET organ allocation. If our study shows a favorable comparison to standard organ allocation criteria, the morbidity and mortality for patients waiting for transplantation could be reduced in the future.
Trial registered at: NCT01384006
Aims: We investigated N471D WASH complex subunit strumpellin (Washc5) knock-in and Washc5 knock-out mice as models for hereditary spastic paraplegia type 8 (SPG8). Methods: We generated heterozygous and homozygous N471D Washc5 knock-in mice and subjected them to a comprehensive clinical, morphological and laboratory parameter screen, and gait analyses. Brain tissue was used for proteomic analysis. Furthermore, we generated heterozygous Washc5 knock-out mice. WASH complex subunit strumpellin expression was determined by qPCR and immunoblotting. Results: Homozygous N471D Washc5 knock-in mice showed mild dilated cardiomyopathy, decreased acoustic startle reactivity, thinner eye lenses, increased alkaline phosphatase and potassium levels and increased white blood cell counts. Gait analyses revealed multiple aberrations indicative of locomotor instability. Similarly, the clinical chemistry, haematology and gait parameters of heterozygous mice also deviated from the values expected for healthy animals, albeit to a lesser extent. Proteomic analysis of brain tissue depicted consistent upregulation of BPTF and downregulation of KLHL11 in heterozygous and homozygous knock-in mice. WASHC5-related protein interaction partners and complexes showed no change in abundancies. Heterozygous Washc5 knock-out mice showing normal WASHC5 levels could not be bred to homozygosity. Conclusions: While biallelic ablation of Washc5 was prenatally lethal, expression of N471D mutated WASHC5 led to several mild clinical and laboratory parameter abnormalities, but not to a typical SPG8 phenotype. The consistent upregulation of BPTF and downregulation of KLHL11 suggest mechanistic links between the expression of N471D mutated WASHC5 and the roles of both proteins in neurodegeneration and protein quality control, respectively.
We developed three bathochromic, green-light activatable, photolabile protecting groups based on a nitrodibenzofuran (NDBF) core with D-π-A push–pull structures. Variation of donor substituents (D) at the favored ring position enabled us to observe their impact on the photolysis quantum yields. Comparing our new azetidinyl-NDBF (Az-NDBF) photolabile protecting group with our earlier published DMA-NDBF, we obtained insight into its excitation-specific photochemistry. While the “two-photon-only” cage DMA-NDBF was inert against one-photon excitation (1PE) in the visible spectral range, we were able to efficiently release glutamic acid from azetidinyl-NDBF with irradiation at 420 and 530 nm. Thus, a minimal change (a cyclization adding only one carbon atom) resulted in a drastically changed photochemical behavior, which enables photolysis in the green part of the spectrum.
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
Activation of hypoxia inducible factor 1 is a general phenomenon in infections with human pathogens
(2010)
Background: Hypoxia inducible factor (HIF)-1 is the key transcriptional factor involved in the adaptation process of cells and organisms to hypoxia. Recent findings suggest that HIF-1 plays also a crucial role in inflammatory and infectious diseases. Methodology/Principal Findings: Using patient skin biopsies, cell culture and murine infection models, HIF-1 activation was determined by immunohistochemistry, immunoblotting and reporter gene assays and was linked to cellular oxygen consumption. The course of a S. aureus peritonitis was determined upon pharmacological HIF-1 inhibition. Activation of HIF-1 was detectable (i) in all ex vivo in biopsies of patients suffering from skin infections, (ii) in vitro using cell culture infection models and (iii) in vivo using murine intravenous and peritoneal S. aureus infection models. HIF-1 activation by human pathogens was induced by oxygen-dependent mechanisms. Small colony variants (SCVs) of S. aureus known to cause chronic infections did not result in cellular hypoxia nor in HIF-1 activation. Pharmaceutical inhibition of HIF-1 activation resulted in increased survival rates of mice suffering from a S. aureus peritonitis. Conclusions/Significance: Activation of HIF-1 is a general phenomenon in infections with human pathogenic bacteria, viruses, fungi and protozoa. HIF-1-regulated pathways might be an attractive target to modulate the course of life-threatening infections.
Meeting Abstract : Deutscher Kongress für Orthopädie und Unfallchirurgie ; 73. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie ; 95. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie ; 50. Tagung des Berufsverbandes der Fachärzte für Orthopädie und Unfallchirurgie ; 21. - 24.10.2009, Berlin Fragestellung: Ziel war die Evaluierung der funktionellen und radiologischen Ergebnisse nach osteosynthestischer Versorgung von Olecranonfrakturen mit einer zur Hakenplatte modifizierten Drittelrohrplatte. Methodik: In einem Zeitraum von 12 Monaten wurden 29 Patienten mit Olecranonfrakturen prospektiv erfasst und eine Osteosynthese mit einer zur Hakenplatte modifizierten Kleinfragment-Drittelrohrplatte durchgeführt. Eine additive Verschraubung von zusätzlichen Fragmenten erfolgte bei 6 Patienten (20%). Das mittlere Patientenalter zum Unfallzeitpunkt betrug 50 Jahre (Min 29/ Max 83). Unter Verwendung der Frakturklassifikation nach Schatzker stellte sich in 8 Fällen (28%) eine Querfraktur vom Typ A, in 6 Fällen (20%) eine Querfraktur mit Impaktion vom Typ B und in 15 Fällen (52%) eine Mehrfragmentfraktur vom Typ D dar. Bei 4 Patienten (14%) lag eine offene Fraktursituation vor. Nach im Mittel 7,2 Monaten (Min 6/ Max 8) wurde das funktionelle Outcome anhand des Mayo Elbow Performence Scores (MEPS), der visuellen Analogskala (VAS) und des Disabilities of the Arm, Shoulder and Hand Scores (DASH) bewertet sowie die radiologischen Befunde erhoben. Ergebnisse und Schlussfolgerungen: Das Ziel einer primär übungsstabilen Osteosynthese konnte bei allen Patienten erreicht werden. Unter Verwendung des MEPS wurden annähernd ausschließlich sehr gute (12 Fälle/41%) und gute (16 Fälle/55%) Ergebnisse erzielt. Lediglich bei einem Patienten ergab sich ein nur befriedigendes Ergebnis. Der mittlere Punktwert für den MEPS betrug 91,4 (Min 65/Max 100). In der VAS konnte ein Mittelwert von 8,2 Punkten (Min 7/Max 10) erzielt werden (0=keine Zufriedenheit, 10=volle Zufriedenheit). Der mittlere DASH-Wert betrug 16,2 Punkte (Min 0/Max 39). Der mittlere Bewegungsumfang betrug für Extension/Flexion bei einem durchschnittlichen Streckdefizit von 8° (Min 0°/Max 25°) und einer Beugung von 135° (Min 105°/Max 155°) 125° (Min 90°/Max 155°). Die Unterarmumwendbewegungen waren mit 175° (Min 165°/Max 180°) kaum eingeschränkt. Bei keinem Patienten gab es postoperative Komplikationen. Eine zur Hakenplatte modifizierte Drittelrohrplatte stellt im Gegensatz zu präformierten, winkelstabilen Implantaten eine kostengünstige Alternative zur Osteosynthese bei Olecranonfrakturen dar. Auch bei komplexen mehrfragmentären Frakturtypen und osteoporotischer Knochenqualität konnte so im nachuntersuchten Kollektiv eine sichere Frakturretention erzielt werden. Hinsichtlich des funktionellen Ergebnisses profitieren die Patienten von einer dadurch unmittelbar postoperativ möglichen, physiotherapeutischen Nachbehandlung. Das für die Hakenplatte benötigte Osteosynthesematerial (Kleinfragment-Drittelrohrplatte) ist nahezu überall verfügbar und lässt sich in kurzer Zeit der individuellen Anatomie und Frakturmorphologie anpassen. Eine Drahtmigration, wie bei der weit verbreiteten Zuggurtungsosteosynthese häufig beobachtet, ist ausgeschlossen.
Introduction and Objectives: Surgical techniques such as preservation of the full functional-length of the urethral sphincter (FFLU) have a positive impact on postoperative continence rates. Thereby, data on very early continence rates after radical prostatectomy (RP) are scarce. The aim of the present study was to analyze very early continence rates in patients undergoing FFLU during RP.
Materials and Methods: Very early-continence was assessed by using the PAD-test within 24 h after removal of the transurethral catheter. The PAD-test is a validated test that measures the amount of involuntary urine loss while performing predefined physical activities within 1 h (e.g., coughing, walking, climbing stairs). Full continence was defined as a urine loss below 1 g. Mild, moderate, and severe incontinence was defined as urine loss of 1–10 g, 11–50 g, and >50 g, respectively.
Results: 90 patients were prospectively analyzed. Removal of the catheter was performed on the 6th postoperative day. Proportions for no, mild, moderate and severe incontinence were 18.9, 45.5, 20.0, and 15.6%, respectively. In logistic regression younger age was associated with significant better continence (HR 2.52, p = 0.04), while bilateral nerve-sparing (HR 2.56, p = 0.057) and organ-confined tumor (HR 2.22, p = 0.078) showed lower urine loss, although the effect was statistically not significant. In MVA, similar results were recorded.
Conclusion: Overall, 64.4% of patients were continent or suffered only from mild incontinence at 24 h after catheter removal. In general, reduced urine loss was recorded in younger patients, patients with organ-confined tumor and in patients with bilateral nerve sparing. Severe incontinence rates were remarkably low with 15.6%.
Objective: To investigate the value of standard [digital rectal examination (DRE), PSA] and advanced (mpMRI, prostate biopsy) clinical evaluation for prostate cancer (PCa) detection in contemporary patients with clinical bladder outlet obstruction (BOO) scheduled for Holmium laser enucleation of the prostate (HoLEP).
Material and Methods: We retrospectively analyzed 397 patients, who were referred to our tertiary care laser center for HoLEP due to BOO between 11/2017 and 07/2020. Of those, 83 (20.7%) underwent further advanced clinical PCa evaluation with mpMRI and/or prostate biopsy due to elevated PSA and/or lowered PSA ratio and/or suspicious DRE. Logistic regression and binary regression tree models were applied to identify PCa in BOO patients.
Results: An mpMRI was conducted in 56 (66%) of 83 patients and revealed PIRADS 4/5 lesions in 14 (25%) patients. Subsequently, a combined systematic randomized and MRI-fusion biopsy was performed in 19 (23%) patients and revealed in PCa detection in four patients (5%). A randomized prostate biopsy was performed in 31 (37%) patients and revealed in PCa detection in three patients (4%). All seven patients (9%) with PCa detection underwent radical prostatectomy with 29% exhibiting non-organ confined disease. Incidental PCa after HoLEP (n = 76) was found in nine patients (12%) with advanced clinical PCa evaluation preoperatively. In univariable logistic regression analyses, PSA, fPSA ratio, and PSA density failed to identify patients with PCa detection. Conversely, patients with a lower International Prostate Symptom Score (IPSS) and PIRADs 4/5 lesion in mpMRI were at higher risk for PCa detection. In multivariable adjusted analyses, PIRADS 4/5 lesions were confirmed as an independent risk factor (OR 9.91, p = 0.04), while IPSS did not reach significance (p = 0.052).
Conclusion: In advanced clinical PCa evaluation mpMRI should be considered in patients with elevated total PSA or low fPSA ratio scheduled for BOO treatment with HoLEP. Patients with low IPSS or PIRADS 4/5 lesions in mpMRI are at highest risk for PCa detection. In patients with a history of two or more sets of negative prostate biopsies, advanced clinical PCa evaluation might be omitted.
Background: Since January 2018 performance of urethroplasties is done on regular basis at the University Hospital Frankfurt (UKF). We aimed to implement and transfer an institutional standardized perioperative algorithm for urethral surgery (established at the University Hospital Hamburg-Eppendorf—UKE) using a validated Urethral Stricture Surgery Patient-Reported Outcome Measure (USS-PROM) in patients undergoing urethroplasty at UKF. Materials and Methods: We retrospectively analyzed all patients who underwent urethroplasty for urethral stricture disease between January 2018 and January 2020 at UKF. All patients were offered to revisit for clinical follow-up (FU) and completion of USS-PROM. Primary end point was stricture recurrence-free survival (RFS). Secondary endpoints were functional outcomes, quality of life (QoL), and patient satisfaction. Results: In total, 50 patients underwent urethroplasty and 74 and 24% had a history of previous urethrotomy or urethroplasty, respectively. A buccal mucosal graft urethroplasty was performed in 86% (n = 43). After patient's exclusion due to lost of FU, FU <3 months, and/or a pending second stage procedure, 40 patients were eligible for final analysis. At median FU of 10 months (interquartile-range 5.0–18.0), RFS was 83%. After successful voiding trial, the postoperative median Qmax significantly improved (24.0 vs. 7.0 mL/s; p < 0.01). Conversely, median residual urine decreased significantly (78 vs. 10 mL; p < 0.01). Overall, 95% of patients stated that QoL improved and 90% were satisfied by the surgical outcome. Conclusions: We demonstrated a successful implementation and transfer of an institutional standardized perioperative algorithm for urethral surgery from one location (UKE) to another (UKF). In our short-term FU, urethroplasty showed excellent RFS, low complication rates, good functional results, improvement of QoL and high patient satisfaction. PROMs allow an objective comparison between different centers.
Objective: To investigate temporal trends in prostate cancer (PCa) radical prostatectomy (RP) candidates.
Materials and Methods: Patients who underwent RP for PCa between January 2014 and December 2019 were identified form our institutional database. Trend analysis and logistic regression models assessed RP trends after stratification of PCa patients according to D'Amico classification and Gleason score. Patients with neoadjuvant androgen deprivation or radiotherapy prior to RP were excluded from the analysis.
Results: Overall, 528 PCa patients that underwent RP were identified. Temporal trend analysis revealed a significant decrease in low-risk PCa patients from 17 to 9% (EAPC: −14.6%, p < 0.05) and GS6 PCa patients from 30 to 14% (EAPC: −17.6%, p < 0.01). This remained significant even after multivariable adjustment [low-risk PCa: (OR): 0.85, p < 0.05 and GS6 PCa: (OR): 0.79, p < 0.001]. Furthermore, a trend toward a higher proportion of intermediate-risk PCa undergoing RP was recorded.
Conclusion: Our results confirm that inverse stage migration represents an ongoing phenomenon in a contemporary RP cohort in a European tertiary care PCa center. Our results demonstrate a significant decrease in the proportion of low-risk and GS6 PCa undergoing RP and a trend toward a higher proportion of intermediate-risk PCa patients undergoing RP. This indicates a more precise patient selection when it comes to selecting suitable candidates for definite surgical treatment with RP.
Neurological diseases associated with neuronal death are also accompanied by axonal denervation of connected brain regions. In these areas, denervation leads to a decrease in afferent drive, which may in turn trigger active central nervous system (CNS) circuitry rearrangement. This rewiring process is important therapeutically, since it can partially recover functions and can be further enhanced using modern rehabilitation strategies. Nevertheless, the cellular mechanisms of brain rewiring are not fully understood. We recently reported a mechanism by which neurons remodel their local connectivity under conditions of network-perturbance: hippocampal pyramidal cells can extend spine head protrusions (SHPs), which reach out toward neighboring terminals and form new synapses. Since this form of activity-dependent rewiring is observed only on some spines, we investigated the required conditions. We speculated, that the actin-associated protein synaptopodin, which is involved in several synaptic plasticity mechanisms, could play a role in the formation and/or stabilization of SHPs. Using hippocampal slice cultures, we found that ~70 % of spines with protrusions in CA1 pyramidal neurons contained synaptopodin. Analysis of synaptopodin-deficient neurons revealed that synaptopodin is required for the stability but not the formation of SHPs. The effects of synaptopodin could be linked to its role in Ca(2+) homeostasis, since spines with protrusions often contained ryanodine receptors and synaptopodin. Furthermore, disrupting Ca(2+) signaling shortened protrusion lifetime. By transgenically reintroducing synaptopodin on a synaptopodin-deficient background, SHP stability could be rescued. Overall, we show that synaptopodin increases the stability of SHPs, and could potentially modulate the rewiring of microcircuitries by making synaptic reorganization more efficient.
Objective: We aimed to assess the correlation between serum prostate-specific antigen (PSA) and tumor burden in prostate cancer (PCa) patients undergoing radical prostatectomy (RP), because estimation of tumor burden is of high value, e.g., in men undergoing RP or with biochemical recurrence after RP. Patients and Methods: From January 2019 to June 2020, 179 consecutive PCa patients after RP with information on tumor and prostate weight were retrospectively identified from our prospective institutional RP database. Patients with preoperative systemic therapy (n=19), metastases (cM1, n=5), and locally progressed PCa (pT4 or pN1, n=50) were excluded from analyses. Histopathological features, including total weight of the prostate and specific tumor weight, were recorded by specialized uro-pathologists. Linear regression models were performed to evaluate the effect of PSA on tumor burden, measured by tumor weight after adjustment for patient and tumor characteristics. Results: Overall, median preoperative PSA was 7.0 ng/ml (interquartile range [IQR]: 5.41–10) and median age at surgery was 66 years (IQR: 61-71). Median prostate weight was 34 g (IQR: 26–46) and median tumor weight was 3.7 g (IQR: 1.8–7.1), respectively. In multivariable linear regression analysis after adjustment for patients and tumor characteristics, a significant, positive correlation could be detected between preoperative PSA and tumor weight (coefficient [coef.]: 0.37, CI: 0.15–0.6, p=0.001), indicating a robust increase in PSA of almost 0.4 ng/ml per 1g tumor weight. Conclusion: Preoperative PSA was significantly correlated with tumor weight in PCa patients undergoing RP, with an increase in PSA of almost 0.4 ng/ml per 1 g tumor weight. This might help to estimate both tumor burden before undergoing RP and in case of biochemical recurrence.
Neurons which lose part of their input respond with a compensatory increase in excitatory synaptic strength. This observation is of particular interest in the context of neurological diseases, which are accompanied by the loss of neurons and subsequent denervation of connected brain regions. However, while the cellular and molecular mechanisms of pharmacologically induced homeostatic synaptic plasticity have been identified to a certain degree, denervation-induced homeostatic synaptic plasticity remains not well understood. Here, we employed the entorhinal denervation in vitro model to study the role of tumor necrosis factor alpha (TNFα) on changes in excitatory synaptic strength of mouse dentate granule cells following partial deafferentation. Our experiments disclose that TNFα is required for the maintenance of a compensatory increase in excitatory synaptic strength at 3–4 days post lesion (dpl), but not for the induction of synaptic scaling at 1–2 dpl. Furthermore, laser capture microdissection combined with quantitative PCR demonstrates an increase in TNFα-mRNA levels in the denervated zone, which is consistent with our previous finding on a local, i.e., layer-specific increase in excitatory synaptic strength at 3–4 dpl. Immunostainings for the glial fibrillary acidic protein and TNFα suggest that astrocytes are a source of TNFα in our experimental setting. We conclude that TNFα-signaling is a major regulatory system that aims at maintaining the homeostatic synaptic response of denervated neurons.
Objective: Many patients with localized prostate cancer (PCa) do not immediately undergo radical prostatectomy (RP) after biopsy confirmation. The aim of this study was to investigate the influence of “time-from-biopsy-to- prostatectomy” on adverse pathological outcomes.
Materials and Methods: Between January 2014 and December 2019, 437 patients with intermediate- and high risk PCa who underwent RP were retrospectively identified within our prospective institutional database. For the aim of our study, we focused on patients with intermediate- (n = 285) and high-risk (n = 151) PCa using D'Amico risk stratification. Endpoints were adverse pathological outcomes and proportion of nerve-sparing procedures after RP stratified by “time-from-biopsy-to-prostatectomy”: ≤3 months vs. >3 and < 6 months. Medians and interquartile ranges (IQR) were reported for continuously coded variables. The chi-square test examined the statistical significance of the differences in proportions while the Kruskal-Wallis test was used to examine differences in medians. Multivariable (ordered) logistic regressions, analyzing the impact of time between diagnosis and prostatectomy, were separately run for all relevant outcome variables (ISUP specimen, margin status, pathological stage, pathological nodal status, LVI, perineural invasion, nerve-sparing).
Results: We observed no difference between patients undergoing RP ≤3 months vs. >3 and <6 months after diagnosis for the following oncological endpoints: pT-stage, ISUP grading, probability of a positive surgical margin, probability of lymph node invasion (LNI), lymphovascular invasion (LVI), and perineural invasion (pn) in patients with intermediate- and high-risk PCa. Likewise, the rates of nerve sparing procedures were 84.3 vs. 87.4% (p = 0.778) and 61.0% vs. 78.8% (p = 0.211), for intermediate- and high-risk PCa patients undergoing surgery after ≤3 months vs. >3 and <6 months, respectively. In multivariable adjusted analyses, a time to surgery >3 months did not significantly worsen any of the outcome variables in patients with intermediate- or high-risk PCa (all p > 0.05).
Conclusion: A “time-from-biopsy-to-prostatectomy” of >3 and <6 months is neither associated with adverse pathological outcomes nor poorer chances of nerve sparing RP in intermediate- and high-risk PCa patients.
Purpose: To test for differences in cancer-specific mortality (CSM) rates in Hispanic/Latino prostate cancer patients according to treatment type, radical prostatectomy (RP) vs external beam radiotherapy (EBRT).
Methods: Within the Surveillance, Epidemiology, and End Results database (2010–2016), we identified 2290 NCCN (National Comprehensive Cancer Network) high-risk (HR) Hispanic/Latino prostate cancer patients. Of those, 893 (39.0%) were treated with RP vs 1397 (61.0%) with EBRT. First, cumulative incidence plots and competing risks regression models tested for CSM differences after adjustment for other cause mortality (OCM). Second, cumulative incidence plots and competing risks regression models were refitted after 1:1 propensity score matching (according to age, PSA, biopsy Gleason score, cT-stage, cN-stage).
Results: In NCCN HR patients, 5-year CSM rates for RP vs EBRT were 2.4 vs 4.7%, yielding a multivariable hazard ratio of 0.37 (95% CI 0.19–0.73, p = 0.004) favoring RP. However, after propensity score matching, the hazard ratio of 0.54 was no longer statistically significant (95% CI 0.21–1.39, p = 0.2).
Conclusion: Without the use of strictest adjustment for population differences, NCCN high-risk Hispanic/Latino prostate cancer patients appear to benefit more of RP than EBRT. However, after strictest adjustment for baseline patient and tumor characteristics between RP and EBRT cohorts, the apparent CSM benefit of RP is no longer statistically significant. In consequence, in Hispanic/Latino NCCN high-risk patients, either treatment modality results in similar CSM outcome.
During postnatal development hippocampal dentate granule cells (GCs) often extend dendrites from the basal pole of their cell bodies into the hilar region. These so-called hilar basal dendrites (hBD) usually regress with maturation. However, hBDs may persist in a subset of mature GCs under certain conditions (both physiological and pathological). The functional role of these hBD-GCs remains not well understood. Here, we have studied hBD-GCs in mature (≥18 days in vitro) mouse entorhino-hippocampal slice cultures under control conditions and have compared their basic functional properties (basic intrinsic and synaptic properties) and structural properties (dendritic arborisation and spine densities) to those of neighboring GCs without hBDs in the same set of cultures. Except for the presence of hBDs, we did not detect major differences between the two GC populations. Furthermore, paired recordings of neighboring GCs with and without hBDs did not reveal evidence for a heavy aberrant GC-to-GC connectivity. Taken together, our data suggest that in control cultures the presence of hBDs on GCs is neither sufficient to predict alterations in the basic functional and structural properties of these GCs nor indicative of a heavy GC-to-GC connectivity between neighboring GCs.
Introduction: MRI-targeted biopsy (TB) increases overall prostate-cancer (PCa) detection-rates and decreases the risk of insignificant PCa detection. However, the impact of these findings on the definite pathology after radical prostatectomy (RP) is under debate.
Materials and Methods: Between 01/2014 and 12/2018, 366 patients undergoing prostate biopsy and RP were retrospectively analyzed. The correlation between biopsy Gleason-score (highest Gleason-score in a core) and the RP Gleason-score in patients undergoing systematic biopsy (SB-group) (n = 221) or TB+SB (TB-group, n = 145) was tested using the ISUP Gleason-group grading (GGG, scale 1–5). Sub analyses focused on biopsy GGG 1 and GGG ≥ 2.
Results: Proportions of biopsy GGG 1–5 in the SB-group and TB-group were 24.4, 37.6, 19, 10.9, 8.1% and 13.8, 43.4, 24.2, 13.8, 4.8%, respectively (p = 0.07). Biopsy and pathologic GGG were concordant in 108 of 221 (48.9%) in SB- and 74 of 145 (51.1%) in TB-group (p = 0.8). Gleason upgrading was recorded in 33.5 and 31.7% in SB- vs. TB-group (p = 0.8). Patients with biopsy GGG 1 undergoing RP showed an upgrading in 68.5%(37/54) in SB- and 75%(15/20) in TB-group (p = 0.8). In patients with biopsy GGG ≥ 2 concordance increased for both biopsy approaches (54.5 vs. 55.2% for SB- vs. TB-group, p = 0.9).
Discussion: Irrespective of differences in PCa detection-rates between TB- and SB-groups, no significant differences in GGG concordance and upgrading between patients of both groups undergoing biopsy, followed by RP, were recorded. Concordance rates increased in men with biopsy GGG ≥ 2. TB seems to detect more patients with PCa without a difference in concordance with final pathology.
Electroencephalography (EEG) represents a widely established method for assessing altered and typically developing brain function. However, systematic studies on EEG data quality, its correlates, and consequences are scarce. To address this research gap, the current study focused on the percentage of artifact-free segments after standard EEG pre-processing as a data quality index. We analyzed participant-related and methodological influences, and validity by replicating landmark EEG effects. Further, effects of data quality on spectral power analyses beyond participant-related characteristics were explored. EEG data from a multicenter ADHD-cohort (age range 6 to 45 years), and a non-ADHD school-age control group were analyzed (ntotal = 305). Resting-state data during eyes open, and eyes closed conditions, and task-related data during a cued Continuous Performance Task (CPT) were collected. After pre-processing, general linear models, and stepwise regression models were fitted to the data. We found that EEG data quality was strongly related to demographic characteristics, but not to methodological factors. We were able to replicate maturational, task, and ADHD effects reported in the EEG literature, establishing a link with EEG-landmark effects. Furthermore, we showed that poor data quality significantly increases spectral power beyond effects of maturation and symptom severity. Taken together, the current results indicate that with a careful design and systematic quality control, informative large-scale multicenter trials characterizing neurophysiological mechanisms in neurodevelopmental disorders across the lifespan are feasible. Nevertheless, results are restricted to the limitations reported. Future work will clarify predictive value.
hintergrund: Männer in Deutschland sterben früher als Frauen und nehmen weniger häufig Krebsvorsorgeuntersuchungen wahr.
Fragestellung: Ziel war die prospektive Evaluation einer „Movember-Gesundheitsinitiative“ am Universitätsklinikum Frankfurt (UKF) im November 2019.
Methoden: Im Rahmen der „Movember-Gesundheitsinitiative“ wurde allen männlichen Mitarbeitern des UKF ab dem 45. Lebensjahr und bei erstgradiger familiärer Vorbelastung eines Prostatakarzinoms ab dem 40. Lebensjahr im November 2019 gemäß S3-Leitlinien der Deutschen Gesellschaft für Urologie (DGU) eine Prostatakarzinom-Vorsorgeuntersuchung angeboten.
Ergebnisse: Insgesamt nahmen 14,4 % der Mitarbeiter teil. Eine familiäre Vorbelastung gaben insgesamt 14,0 % Teilnehmer an. Das mediane Alter betrug 54 Jahre. Der mediane PSA(prostataspezifisches Antigen)-Wert lag bei 0,9 ng/ml, der mediane PSA-Quotient bei 30 %. Bei 5 % (n = 6) zeigte sich ein suspekter Tastbefund in der DRU (digital-rektale Untersuchung). Nach Altersstratifizierung (≤ 50 vs. > 50 Lebensjahre) zeigten sich signifikante Unterschiede im medianen PSA-Wert (0,7 ng/ml vs. 1,0 ng/ml, p < 0,01) und der bereits zuvor durchgeführten urologischen Vorsorge (12,1 vs. 42,0 %, p < 0,01). Vier Teilnehmer (3,3 %) zeigten erhöhte Gesamt-PSA-Werte. Bei 32,2 % der Teilnehmer zeigte sich mindestens ein kontrollbedürftiger Befund. Insgesamt wurden 6 Prostatabiopsien durchgeführt. Hierbei zeigte sich in einem Fall ein intermediate-risk Prostatakarzinom (Gleason 3 + 4, pT3a, pPn1, pNx, R0).
Schlussfolgerungung: Im Rahmen der UKF-Movember-Gesundheitsinitiative 2019 konnten durch ein Vorsorgeangebot 121 Männer für eine Prostatakrebs-Vorsorge inklusive PSA-Testung gewonnen werden. Auffällige/kontrollbedürftige Befunde zeigten sich bei 32,2 %. Bei einem Mitarbeiter wurde ein therapiebedürftiges Prostatakarzinom entdeckt und therapiert.
Background: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. Methods: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 3-year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. (trial registered at www.clinicaltrials.gov: NCT00355862) (EudraCT Number: 2005-005362-36)
Severe traumatic injury induces phenotypic and functional changes of neutrophils and monocytes
(2021)
Background: Severe traumatic injury has been associated with high susceptibility for the development of secondary complications caused by dysbalanced immune response. As the first line of the cellular immune response, neutrophils and monocytes recruited to the site of tissue damage and/or infection, are divided into three different subsets according to their CD16/CD62L and CD16/CD14 expression, respectively. Their differential functions have not yet been clearly understood. Thus, we evaluated the phenotypic changes of neutrophil and monocyte subsets among their functionality regarding oxidative burst and the phagocytic capacity in severely traumatized patients. Methods: Peripheral blood was withdrawn from severely injured trauma patients (TP; n = 15, ISS ≥ 16) within the first 12 h post-trauma and from healthy volunteers (HV; n = 15) and stimulated with fMLP and PMA. CD16dimCD62Lbright (immature), CD16brightCD62Lbright (mature) and CD16brightCD62Ldim (CD62Llow) neutrophil subsets and CD14brightCD16− (classical), CD14brightCD16+ (intermediate) and CD14dimCD16+ (non-classical) monocyte subsets of HV and TP were either directly analyzed by flow cytometry or the examined subsets of HV were sorted first by fluorescence-activated cell sorting and subsequently analyzed. Subset-specific generation of reactive oxygen species (ROS) and of E. coli bioparticle phagocytosis were evaluated. Results: In TP, the counts of immature neutrophils were significantly increased vs. HV. The numbers of mature and CD62Ldim neutrophils remained unchanged but the production of ROS was significantly enhanced in TP vs. HV and the stimulation with fMLP significantly increased the generation of ROS in the mature and CD62Ldim neutrophils of HV. The counts of phagocyting neutrophils did not change but the mean phagocytic capacity showed an increasing trend in TP. In TP, the monocytes shifted toward the intermediate phenotype, whereas the classical and non-classical monocytes became less abundant. ROS generation was significantly increased in all monocyte subsets in TP vs. HV and PMA stimulation significantly increased those level in both, HV and TP. However, the PMA-induced mean ROS generation was significantly lower in intermediate monocytes of TP vs. HV. Sorting of monocyte and neutrophil subsets revealed a significant increase of ROS and decrease of phagocytic capacity vs. whole blood analysis. Conclusions: Neutrophils and monocytes display a phenotypic shift following severe injury. The increased functional abnormalities of certain subsets may contribute to the dysbalanced immune response and attenuate the antimicrobial function and thus, may represent a potential therapeutic target. Further studies on isolated subsets are necessary for evaluation of their physiological role after severe traumatic injury.
[Nachruf] Burkhardt Lindner
(2015)
MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy
(2014)
Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1) were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients.
UNDERSTANDING HOW HOUSEHOLDS REACT TO THE ARRIVAL OF PERMANENT AND TRANSITORY INCOME IS OF INTEREST FOR RESEARCHERS AND REGULATORS. PREVIOUS STUDIES HAD TO USE IMPRECISE SURVEY DATA TO MEASURE CONSUMPTION AND THUS CONCLUSIONS OFTEN DIVERGED. WE LEVERAGE GRANULAR PERSONAL FINANCE MANAGEMENT FINTECH DATA TO TEST FRIEDMAN'S PERMANENT INCOME HYPOTHESIS AND TO ASSESS HOUSEHOLD SPENDING ELASTICITY AND MARGINAL PROPENSITY TO CONSUME FOR VARIOUS SPENDING CATEGORIES IN RESPONSE TO DIFFERENT INCOME TYPES.
Background: To test the effect of variant histology relative to urothelial histology on stage at presentation, cancer specific mortality (CSM) and overall mortality (OM) after chemotherapy use, in urethral cancer.
Materials and Methods: Within the Surveillance, Epidemiology and End Results (2004–2016) database, we identified 1,907 primary variant histology urethral cancer patients. Kaplan-Meier plots, Cox regression analyses, cumulative incidence-plots, multivariable competing-risks regression models and propensity score matching for patient and tumor characteristics were used.
Results:Of 1,907 eligible urethral cancer patients, urothelial histology affected 1,009 (52.9%) vs. squamous cell carcinoma (SCC) 455 (23.6%) vs. adenocarcinoma 278 (14.6%) vs. other histology 165 (8.7%) patients. Urothelial histological patients exhibited lower stages at presentation than SCC, adenocarcinoma or other histology patients. In urothelial histology patients, five-year CSM was 23.5% vs. 34.4% in SCC (Hazard Ratio (HR) 1.57) vs. 40.7% in adenocarcinoma (HR 1.69) vs. 43.4% in other histology (HR 1.99, p<0.001). After matching in multivariate competing-risks regression models, variant histology exhibited 1.35-fold higher CSM than urothelial. Finally, in metastatic urethral cancer, lower OM was recorded after chemotherapy in general, including metastatic adenocarcinoma and other variant histology subtypes, except metastatic SCC.
Conclusion: Adenocarcinoma, SCC and other histology subtypes affect fewer patients than urothelial histology. Presence of variant histology results in higher CSM. Finally, chemotherapy for metastatic urethral cancer improves survival in adenocarcinoma and other variant histology subtypes, but not in SCC.
Rezensionen [2017]
(2017)
156 Ansari, Christine (Hrsg.): Adoleszenz in Medienkontexten. Literaturrezeption, Medienwirkung und Jugendmedienschutz (judith mathez)
158 Bachmann, Christian A. / Emans, Laura / Schmitz-Emans, Monika (Hrsg.): Bewegungsbücher. Spielformen, Poetiken, Konstellationen (gundel mattenklott)
160 Ballis, Anja /Schlachter, Birgit (Hrsg.): Schätze der Kinder- und Jugendliteratur wiederentdeckt. Frühe Lektüreerfahrung und Kanonbildung im akademischen Kontext (ernst seibert)
162 Benner, Julia: Federkrieg. Kinder- und Jugendliteratur gegen den Nationalsozialismus 1933 – 1945 (linde storm)
164 Born, Stefan: Allgemeinliterarische Adoleszenzromane. Untersuchungen zu Herrndorf, Regener, Strunk, Kehlmann und anderen (lena hoffmann)
166 Börnchen, Stefan: Poetik der Linie. Wilhelm Busch, Max und Moritz und die Tradition (lukas sarvari)
168 Burwitz-Melzer, Eva /O’Sullivan, Emer (Hrsg.): Einfachheit in der Kinder- und Jugendliteratur. Ein Gewinn für den Fremdsprachenunterricht (roland alexander issler)
169 Emde, Oliver /Möller, Lukas /Wicke, Andreas (Hrsg.): Von »Bibi Blocksberg« bis »TKKG«. Kinderhörspiele aus gesellschafts- und kulturwissenschaftlicher Perspektive (anika ullmann)
171 Ferstl, Paul /Walach, Thomas / Zahlmann, Stefan (Hrsg.): Fantasy Studies (maren bonacker)
173 Giesa, Felix: Graphisches Erzählen von Adoleszenz. Deutschsprachige Autorencomics nach 2000 (michael staiger)
175 Hahn, Heidi / Laudenberg, Beate / Rösch, Heidi (Hrsg.): »Wörter raus!?« Zur Debatte um eine diskriminierungsfreie Sprache im Kinderbuch (julia benner)
177 Haug, Christine / Frimmel, Johannes (Hrsg.): Schulbücher um 1800. Ein Spezialmarkt zwischen staatlichem, volksaufklärerischem und konfessionellem Auftrag (ortwin beisbart)
179 Hollerweger, Elisabeth /Stemmann, Anna (Hrsg.): Narrative Delikatessen. Kulturelle Dimensionen von Ernährung (sonja loidl)
180 Hopp, Margarete: Sterben, Tod und Trauer im Bilderbuch seit 1945 (iris schäfer)
182 Huemer, Georg: Mira Lobe. Doyenne der österreichischen Kinder- und Jugendliteratur (andreas schumann)
183 Josting, Petra (Hrsg.): Andreas Steinhöfel, Bielefelder Poet in Residence 2014 (heinke kilian)
185 Josting, Petra /Roeder, Caroline /Dettmar, Ute (Hrsg.): Immer Trouble mit Gender. Genderperspektiven in Kinder- und Jugendliteraturforschung und -medien (jana mikota)
187 Kurwinkel, Tobias /Schmerheim, Philipp /Sevi, Annika (Hrsg.): Michael Ende intermedial. Von Lokomotivführern, Glücksdrachen und dem (phantastischen) Spiel mit Mediengrenzen (michael stierstorfer)
188 Mikota, Jana / Pecher, Claudia Maria / von Glasenapp, Gabriele (Hrsg.): Literarisch-kulturelle Begegnungen mit dem Judentum. Beiträge zur kinderliterarischen Fachöffentlichkeit (susanne blumesberger)
190 Müller, Karla / Decker, Jan-Oliver / Krah, Hans / Schilcher, Anita (Hrsg.): Genderkompetenz mit Kinder- und Jugendliteratur entwickeln: Grundlagen – Analysen – Modelle (annette kliewer)
192 Nikolajeva, Maria: Reading for Learning. Cognitive Approaches to Children’s Literature (sabine fuchs)
194 Paul, Lissa / Johnston, Rosemary R. / Short, Emma (Hrsg.):Children’s Literature and Culture of the First World War.(julia benner)
195 Payrhuber, Franz-Josef / Meier, Bernhard(Hrsg.): Franz, Kurt: Kinderlyrik. Geschichte, Formen, Rezeption(ludger scherer)
197 Payrhuber, Franz-Josef:Gedichte entdecken. Wege zu Gedichten in der ersten bis sechsten Klasse (andreas schumann)
198 Pohlmann, Carola (Hrsg): Kinder- und Jugendliteratur. Sammeln und Erwerben (wolfgang wangerin)
200 Pompe, Anja (Hrsg): Kind und Gedicht. Wie wir lesen lernen (heinz-jürgen kliewer)
202 Preindl, Nadia:Russische Kinderliteratur im europäischen Exil der Zwischenkriegszeit (verena rutschmann)
204 Richter, Karin: Die Kinder- und Jugend-literatur der DDR. Entwicklungslinien – Themen und Genres. Autorenporträts und Textanalysen (maria becker)
206 Riemhofer, Andra:Interkulturelle Kinder- und Jugendliteratur in Deutschland. Lesen auf eigene Gefahr (roger meyer)
208Roeder, Caroline (Hrsg.): Himmel und Hölle. Raumerkundungen – interdisziplinär & in schulischer Praxis (claudia blei-hoch)
210 Ruzicka Kenfel, Vejka (Hrsg.): New Trends in Children’s Literature Research. Twenty-first Century Approaches (2000–2012) from the University of Vigo (Spain) (susanne blumesberger)
212 Schäfer, Iris:Von der Hysterie zur Magersucht. Adoleszenz und Krankheit in Romanen und Erzählungen der Jahrhundert- und der Jahrtausendwende (philipp schmerheim)
214 Scherer, Gabriela / Volz, Steffen (Hrsg.): Im Bildungsfokus: Bilderbuchrezeptions-forschung (margarete hopp)
216 Schmitt, Susann Sophie:Nachwuchs für die Literatur. Kinder- und Jugendprogramme ausgewählter Literaturhäuser Deutschlands, Österreichs und der Schweiz (renate grubert)
217 Seelinger Trites, Roberta:Literary Conceptu-alizations of Growth. Metaphors and Cogni-tion in Adolescent Literature (iris schäfer)
219 Seifert, Martina:Die Bilderfalle. Kanada in der deutschsprachigen Kinder- und Jugend-literatur: Produktion und Rezeption (sabine planka)
222 Stein, Daniel / Thon, Jan-Noël (Hrsg.): From Comic Strips to Graphic Novels. Contributions to the Theory and History of Graphic Narrative (anna stemmann)
223 Tomberg, Markus (Hrsg.): Alle wichtigen Bücher handeln von Gott. Religiöse Spuren in aktueller Kinder- und Jugendliteratur (martin anker)
Purpose: We evaluated efficacy and safety profile of patients with anticoagulation therapy (AT) undergoing holmium laser enucleation of the prostate (HoLEP).
Methods: Within our prospective institutional database (11/2017 to 11/2019), we analyzed functional outcomes and 30-day complication rates of HoLEP patients according to Clavien–Dindo classification (CLD), stratified according to specific AT vs. no AT. Further analyses consisted of uni- and multivariate logistic regression models (LRM) predicting complications.
Results: Of 268 patients undergoing HoLEP, 104 (38.8%) received AT: 25.7% were treated with platelet aggregation inhibitors (PAI), 8.2% with new oral anticoagulants (NOAC) and 4.9% with AT-combinations or coumarins bridged with low molecular weight heparins (LMWH/combination). Patients receiving AT were significantly more comorbid (p < 0.01). Pre- and postoperative maximal flow rates, residual void urine and IPSS at 3 months after surgery were invariably improved after HoLEP for patients with/ without AT. Overall complication rate was 19.5% in patients with no AT vs. 26.1% vs. 27.3 vs. 46.2%, respectively, in patients with PAI, NOAC and LMWH/combination (p < 0.01). Major complications (CLD ≥ 3b) occurred in 6.1% of no AT patients vs. 4.3% vs. 4.5 vs. 0% in patients with PAI, NOAC and LMWH/combination, respectively (p < 0.01). In multivariate LRM, AT was not significantly associated with higher complication rates, whereas high ASA status (OR 2.2, p = 0.04), age (OR 1.04, p = 0.02) and bioptical or incidental prostate cancer (OR 2.5, p = 0.01) represented independent risk factors.
Conclusion: Despite higher overall complication rates in AT patients, major complications were not more frequent in AT patients. HoLEP is safe and effective in anticoagulated patients.
The aim of this study is to investigate the incidental prostate cancer (iPCa) detection rates of different embedding methods in a large, contemporary cohort of patients with bladder outlet obstruction (BOO) treated with transurethral surgery. We relied on an institutional tertiary-care database to identify BOO patients who underwent either transurethral loop resection or laser (Holmium:yttrium–aluminium garnet) enucleation of the prostate (HoLEP) between 01/2012 and 12/2019. Embedding methods differed with regard to the extent of the additional prostate tissue submitted following the first ten cassettes of primary embedding (cohort A: one [additional] cassette/10 g residual tissue vs. cohort B: complete embedding of the residual tissue). Detection rates of iPCa among the different embedding methods were compared. Subsequently, subgroup analyses by embedding protocol were repeated in HoLEP-treated patients only. In the overall cohort, the iPCa detection rate was 11% (46/420). In cohort A (n = 299), tissue embedding resulted in a median of 8 cassettes/patient (range 1–38) vs. a median of 15 (range 2–74) in cohort B (n = 121) (p < .001). The iPCa detection rate was 8% (23/299) and 19% (23/121) in cohort A vs. cohort B, respectively (p < .001). Virtual reduction of the number of tissue cassettes to ten cassettes resulted in a iPCa detection rate of 96% in both cohorts, missing one stage T1a/ISUP grade 1 carcinoma. Increasing the number of cassettes by two and eight cassettes, respectively, resulted in a detection rate of 100% in both cohorts without revealing high-grade carcinomas. Subgroup analyses in HoLEP patients confirmed these findings, demonstrated by a 100 vs. 96% iPCa detection rate following examination of the first ten cassettes, missing one case of T1a/ISUP 1. Examination of 8 additional cassettes resulted in a 100% detection rate. The extent of embedding of material obtained from transurethral prostate resection correlates with the iPCa detection rate. However, the submission of 10 cassettes appears to be a reasonable threshold to reduce resource utilization while maintaining secure cancer detection.
Background: To test the value of immunohistochemistry (IHC) staining in prostate biopsies for changes in biopsy results and its impact on treatment decision-making. Methods: Between January 2017–June 2020, all patients undergoing prostate biopsies were identified and evaluated regarding additional IHC staining for diagnostic purpose. Final pathologic results after radical prostatectomy (RP) were analyzed regarding the effect of IHC at biopsy. Results: Of 606 biopsies, 350 (58.7%) received additional IHC staining. Of those, prostate cancer (PCa) was found in 208 patients (59.4%); while in 142 patients (40.6%), PCa could be ruled out through IHC. IHC patients harbored significantly more often Gleason 6 in biopsy (p < 0.01) and less suspicious baseline characteristics than patients without IHC. Of 185 patients with positive IHC and PCa detection, IHC led to a change in biopsy results in 81 (43.8%) patients. Of these patients with changes in biopsy results due to IHC, 42 (51.9%) underwent RP with 59.5% harboring ≥pT3 and/or Gleason 7–10. Conclusions: Patients with IHC stains had less suspicious characteristics than patients without IHC. Moreover, in patients with positive IHC and PCa detection, a change in biopsy results was observed in >40%. Patients with changes in biopsy results partly underwent RP, in which 60% harbored significant PCa.
Background: The impact of MRI-lesion targeted (TB) and systematic biopsy (SB) Gleason score (GS) as a predictor for final pathological GS still remains unclear. Methods: All patients with TB + SB, and subsequent radical prostatectomy (RP) between 01/2014-12/2020 were analyzed. Rank correlation coefficient predicted concordance with pathological GS for patients’ TB and SB GS, as well as for the combined effect of SB + TB. Results: Of 159 eligible patients, 77% were biopsy naïve. For SB taken in addition to TB, a Spearman’s correlation of +0.33 was observed regarding final GS. Rates of concordance, upgrading, and downgrading were 37.1, 37.1 and 25.8%, respectively. For TB, a +0.52 correlation was computed regarding final GS. Rates of concordance, upgrading and downgrading for TB biopsy GS were 45.9, 33.3, and 20.8%, respectively. For the combination of SB + TB, a correlation of +0.59 was observed. Rates of concordance, upgrading and downgrading were 49.7, 15.1 and 35.2%, respectively. The combined effect of SB + TB resulted in a lower upgrading rate, relative to TB and SB (both p < 0.001), but a higher downgrading rate, relative to TB (p < 0.01). Conclusions: GS obtained from TB provided higher concordance and lower upgrading and downgrading rates, relative to SB GS with regard to final pathology. The combined effect of SB + TB led to the highest concordance rate and the lowest upgrading rate.
Introduction: There is still an ongoing debate whether a transrectal ultrasound (TRUS) approach for prostate biopsies is associated with higher (infectious) complications rates compared to transperineal biopsies. This is especially of great interests in settings with elevated frequencies of multidrug resistant organisms (MDRO).
Materials and Methods: Between 01/2018 and 05/2019 230 patients underwent a TRUS-guided prostate biopsy at the department of Urology at University Hospital Frankfurt. Patients were followed up within the clinical routine that was not conducted earlier than 6 weeks after the biopsy. Among 230 biopsies, 180 patients took part in the follow-up. No patients were excluded. Patients were analyzed retrospectively regarding complications, infections and underlying infectious agents or needed interventions.
Results: Of all patients with follow up, 84 patients underwent a systematic biopsy (SB) and 96 a targeted biopsy (TB) after MRI of the prostate with additional SB. 74.8% of the patients were biopsy-naïve. The most frequent objective complications (classified by Clavien-Dindo) lasting longer than one day after biopsy were hematuria (17.9%, n = 32), hematospermia (13.9%, n = 25), rectal bleeding (2.8%, n = 5), and pain (2.2%, n = 4). Besides a known high MDRO prevalence in the Rhine-Main region, only one patient (0.6%) developed fever after biopsy. One patient each (0.6%) consulted a physician due to urinary retention, rectal bleeding or gross hematuria. There were no significant differences in complications seen between SB and SB + TB patients. The rate of patients who consulted a physician was significantly higher for patients with one or more prior biopsies compared to biopsy-naïve patients.
Conclusion: Complications after transrectal prostate biopsies are rare and often self-limiting. Infections were seen in <1% of all patients, regardless of an elevated local prevalence of MDROs. Severe complications (Clavien-Dindo ≥ IIIa) were only seen in 3 (1.7%) of the patients. Repeated biopsy is associated with higher complication rates in general.
Objective: To analyze the effect of adverse preoperative patient and tumor characteristics on perioperative outcomes of open (ORP) and robot-assisted radical prostatectomy (RARP).
Material and Methods: We retrospectively analyzed 656 patients who underwent ORP or RARP according to intraoperative blood loss (BL), operation time (OR time), neurovascular bundle preservation (NVBP) and positive surgical margins (PSM). Univariable and multivariable logistic regression models were used to identify risk factors for impaired perioperative outcomes.
Results: Of all included 619 patients, median age was 66 years. BMI (<25 vs. 25-30 vs. ≥30) had no influence on blood loss. Prostate size >40cc recorded increased BL compared to prostate size ≤ 40cc in patients undergoing ORP (800 vs. 1200 ml, p < 0.001), but not in patients undergoing RARP (300 vs. 300 ml, p = 0.2). Similarly, longer OR time was observed for ORP in prostates >40cc, but not for RARP. Overweight (BMI 25-30) and obese ORP patients (BMI ≥30) showed longer OR time compared to normal weight (BMI <25). Only obese patients, who underwent RARP showed longer OR time compared to normal weight. NVBP was less frequent in obese patients, who underwent ORP, relative to normal weight (25.8% vs. 14.0%, p < 0.01). BMI did not affect NVPB at RARP. No differences in PSM were recorded according to prostate volume or BMI in ORP or RARP. In multivariable analyses, patient characteristics such as prostate volume and BMI was an independent predictor for prolonged OR time. Moreover, tumor characteristics (stage and grade) predicted worse perioperative outcome.
Conclusion: Patients with larger prostates and obese patients undergoing ORP are at risk of higher BL, OR time or non-nervesparing procedure. Conversely, in patients undergoing RARP only obesity is associated with increased OR time. Patients with larger prostates or increased BMI might benefit most from RARP compared to ORP.
Global response of diacylglycerol kinase towards substrate binding observed by 2D and 3D MAS NMR
(2019)
Escherichia coli diacylglycerol kinase (DGK) is an integral membrane protein, which catalyses the ATP-dependent phosphorylation of diacylglycerol (DAG) to phosphatic acid (PA). It is a unique trimeric enzyme, which does not share sequence homology with typical kinases. It exhibits a notable complexity in structure and function despite of its small size. Here, chemical shift assignment of wild-type DGK within lipid bilayers was carried out based on 3D MAS NMR, utilizing manual and automatic analysis protocols. Upon nucleotide binding, extensive chemical shift perturbations could be observed. These data provide evidence for a symmetric DGK trimer with all of its three active sites concurrently occupied. Additionally, we could detect that the nucleotide substrate induces a substantial conformational change, most likely directing DGK into its catalytic active form. Furthermore, functionally relevant interprotomer interactions are identified by DNP-enhanced MAS NMR in combination with site-directed mutagenesis and functional assays.
Light‐induced activation of biomolecules by uncaging of photolabile protection groups has found many applications for triggering biochemical reactions with minimal perturbations directly within cells. Such an approach might also offer unique advantages for solid‐state NMR experiments on membrane proteins for initiating reactions within or at the membrane directly within the closed MAS rotor. Herein, we demonstrate that the integral membrane protein E. coli diacylglycerol kinase (DgkA), which catalyzes the phosphorylation of diacylglycerol, can be controlled by light under MAS‐NMR conditions. Uncaging of NPE‐ATP or of lipid substrate NPE‐DOG by in situ illumination triggers its enzymatic activity, which can be monitored by real‐time 31P‐MAS NMR. This proof‐of‐concept illustrates that combining MAS‐NMR with uncaging strategies and illumination methods offers new possibilities for controlling biochemical reactions at or within lipid bilayers.
Background: This study aims to test the effect of the 10 most common nonurological primary cancers (skin, rectal, colon, lymphoma, leukemia, pancreas, stomach, esophagus, liver, lung) on overall mortality (OM) after secondary prostate cancer (PCa). Material and Methods: Within the Surveillance, Epidemiology, and End Results (SEER) database, patients with 10 most common primary cancers and concomitant secondary PCa (diagnosed 2004–2016) were identified and were matched in 1:4 fashion (age, year at diagnosis, race/ethnicity, treatment type, TNM stage) with primary PCa controls. OM was compared between secondary and primary PCa patients and was stratified according to primary cancer type, as well as according to time interval between primary cancer vs. secondary PCa diagnoses. Results: We identified 24,848 secondary PCa patients (skin, n = 3,871; rectal, n = 798; colon, n = 3,665; lymphoma, n = 2,583; leukemia, n = 1,102; pancreatic, n = 118; stomach, n = 361; esophagus, n = 219; liver, n = 160; lung, n = 1,328) vs. 531,732 primary PCa patients. Secondary PCa characteristics were less favorable than those of primary PCa patients (PSA and grade), and smaller proportions of secondary PCa patients received active treatment. After 1:4 matching, all secondary PCa exhibited worse OM than primary PCa patients. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis and subsequent secondary PCa. Conclusion: Patients with secondary PCa are diagnosed with less favorable PSA and grade. Even after matching for PCa characteristics, secondary PCa patients still exhibit worse survival. However, the survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary cancer diagnosis.
Purpose: To test the value of preoperative and postoperative cystatin C (CysC) as a predictor on kidney function after partial (PN) or radical nephrectomy (RN) in renal cell carcinoma (RCC) patients with normal preoperative renal function.
Methods: From 01/2011 to 12/2014, 195 consecutive RCC patients with a preoperative estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73m2 underwent surgical RCC treatment with either PN or RN. Logistic and linear regression models tested for the effect of CysC as a predictor of new-onset chronic kidney disease in follow-up (eGFR < 60 ml/min/1.73m2). Moreover, postoperative CysC and creatinine values were compared for kidney function estimation.
Results: Of 195 patients, 129 (66.2%) underwent PN. In postoperative and in follow-up setting (median 14 months, IQR 10–20), rates of eGFR < 60 ml/min/1.73m2 were 55.9 and 30.2%. In multivariable logistic regression models, preoperative CysC [odds ratio (OR): 18.3] and RN (OR: 13.5) were independent predictors for a reduced eGFR < 60 ml/min/1.73m2 in follow-up (both p < 0.01), while creatinine was not. In multivariable linear regression models, a difference of the preoperative CysC level of 0.1 mg/dl estimated an eGFR decline in follow-up of about 5.8 ml/min/1.73m2. Finally, we observed a plateau of postoperative creatinine values in the range of 1.2–1.3 mg/dl, when graphically depicted vs. postoperative CysC values (‘creatinine blind area’).
Conclusion: Preoperative CysC predicts renal function impairment following RCC surgery. Furthermore, CysC might be superior to creatinine for renal function monitoring in the early postoperative setting.
Purpose: To test the effect of anatomic variants of the prostatic apex overlapping the membranous urethra (Lee type classification), as well as median urethral sphincter length (USL) in preoperative multiparametric magnetic resonance imaging (mpMRI) on the very early continence in open (ORP) and robotic-assisted radical prostatectomy (RARP) patients. Methods: In 128 consecutive patients (01/2018–12/2019), USL and the prostatic apex classified according to Lee types A–D in mpMRI prior to ORP or RARP were retrospectively analyzed. Uni- and multivariable logistic regression models were used to identify anatomic characteristics for very early continence rates, defined as urine loss of ≤ 1 g in the PAD-test. Results: Of 128 patients with mpMRI prior to surgery, 76 (59.4%) underwent RARP vs. 52 (40.6%) ORP. In total, median USL was 15, 15 and 10 mm in the sagittal, coronal and axial dimensions. After stratification according to very early continence in the PAD-test (≤ 1 g vs. > 1 g), continent patients had significantly more frequently Lee type D (71.4 vs. 54.4%) and C (14.3 vs. 7.6%, p = 0.03). In multivariable logistic regression models, the sagittal median USL (odds ratio [OR] 1.03) and Lee type C (OR: 7.0) and D (OR: 4.9) were independent predictors for achieving very early continence in the PAD-test. Conclusion: Patients’ individual anatomical characteristics in mpMRI prior to radical prostatectomy can be used to predict very early continence. Lee type C and D suggest being the most favorable anatomical characteristics. Moreover, longer sagittal median USL in mpMRI seems to improve very early continence rates.
Background: To evaluate the impact of time to castration resistance (TTCR) in metastatic hormone-sensitive prostate cancer (mHSPC) patients on overall survival (OS) in the era of combination therapies for mHSPC.
Material and Methods: Of 213 mHSPC patients diagnosed between 01/2013-12/2020 who subsequently developed metastatic castration resistant prostate cancer (mCRPC), 204 eligible patients were analyzed after having applied exclusion criteria. mHSPC patients were classified into TTCR <12, 12-18, 18-24, and >24 months and analyzed regarding OS. Moreover, further OS analyses were performed after having developed mCRPC status according to TTCR. Logistic regression models predicted the value of TTCR on OS.
Results: Median follow-up was 34 months. Among 204 mHSPC patients, 41.2% harbored TTCR <12 months, 18.1% for 12-18 months, 15.2% for 18-24 months, and 25.5% for >24 months. Median age was 67 years and median PSA at prostate cancer diagnosis was 61 ng/ml. No differences in patient characteristics were observed (all p>0.05). According to OS, TTCR <12 months patients had the worst OS, followed by TTCR 12-18 months, 18-24 months, and >24 months, in that order (p<0.001). After multivariable adjustment, a 4.07-, 3.31-, and 6.40-fold higher mortality was observed for TTCR 18-24 months, 12-18 months, and <12 months patients, relative to TTCR >24 months (all p<0.05). Conversely, OS after development of mCRPC was not influenced by TTCR stratification (all p>0.05).
Conclusion: Patients with TTCR <12 months are at the highest OS disadvantage in mHSPC. This OS disadvantage persisted even after multivariable adjustment. Interestingly, TTCR stratified analyses did not influence OS in mCRPC patients.
The objective of the study was to test the impact of implementing standard full functional-length urethral sphincter (FFLU) and neurovascular bundle preservation (NVBP) with intraoperative frozen section technique (IFT) on long-term urinary continence in patients undergoing robotic-assisted radical prostatectomy (RARP). We relied on an institutional tertiary-care database to identify patients who underwent RARP between 01/2014 and 09/2019. Until 10/2017, FFLU was not performed and decision for NVBP was taken without IFT. From 11/2017, FFLU and IFT-guided NVBP was routinely performed in all patients undergoing RARP. Long-term continence (≥ 12 months) was defined as the usage of no or one safety- pad. Uni- and multivariable logistic regression models tested the correlation between surgical approach (standard vs FFLU + NVBP) and long-term continence. Covariates consisted of age, body mass index, prostate volume and extraprostatic extension of tumor. The study cohort consisted of 142 patients, with equally sized groups for standard vs FFLU + NVBP RARP (68 vs 74 patients). Routine FFLU + NVBP implementation resulted in a long-term continence rate of 91%, compared to 63% in standard RARP (p < 0.001). Following FFLU + NVBP RARP, 5% needed 1–2, 4% 3–5 pads/24 h and no patient (0%) suffered severe long-term incontinence (> 5 pads/24 h). No significant differences in patient or tumor characteristics were recorded between both groups. In multivariable logistic regression models, FFLU + NVBP was a robust predictor for continence (Odds ratio [OR]: 7.62; 95% CI 2.51–27.36; p < 0.001). Implementation of FFLU and NVBP in patients undergoing RARP results in improved long-term continence rates of 91%.
Aims: To analyze the relationship between exposure to chlorinated and aromatic organic solvents and malignant lymphoma in a multi-centre, population-based case-control study.
Methods: Male and female patients with malignant lymphoma (n=710) between 18 and 80 years of age were prospectively recruited in six study regions in Germany (Ludwigshafen /Upper Palatinate, Heidelberg/ Rhine-Neckar-County, Wurzburg/ Lower Frankonia, Hamburg, Bielefeld/ Gutersloh, and Munich). For each newly recruited lymphoma case, a gender, region and age-matched (+/- 1 year of birth) population control was drawn from the population registers. In a structured personal interview, we elicited a complete occupational history, including every occupational period that lasted at least one year. On the basis of job task-specific supplementary questionnaires, a trained occupational physician assessed the exposure to chlorinated hydrocarbons (trichloroethylene, tetrachloroethylene, dichloromethane, carbon tetrachloride) and aromatic hydrocarbons (benzene, toluene, xylene, styrene). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression analysis, adjusted for smoking (in pack years) and alcohol consumption. To increase the statistical power, patients with specific lymphoma subentities were additionally compared with the entire control group using unconditional logistic regression analysis.
Results: We observed a statistically significant association between high exposure to chlorinated hydrocarbons and malignant lymphoma (Odds ratio = 2.1; 95% confidence interval 1.1-4.3). In the analysis of lymphoma subentities, a pronounced risk elevation was found for follicular lymphoma and marginal zone lymphoma. When specific substances were considered, the association between trichloroethylene and malignant lymphoma was of borderline statistical significance. Aromatic hydrocarbons were not significantly associated with the lymphoma diagnosis.
Conclusions: In accordance with the literature, this data point to a potential etiologic role of chlorinated hydrocarbons (particularly trichloroethylene) and malignant lymphoma. Chlorinated hydrocarbons might affect specific lymphoma subentities differentially. Our study does not support a strong association between aromatic hydrocarbons (benzene, toluene, xylene, or styrene) and the diagnosis of a malignant lymphoma.
Background: Survival data regarding cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) patients according to the type and extent of tumor-associated vascular thrombus are scarce.
Objective: To test for survival differences in mRCC patients treated with CN according to the type and extent of tumor-associated vascular thrombus.
Design, setting, and participants: Within Surveillance, Epidemiology, and End Results Research Plus (2004–2017), we identified CN mRCC patients with renal vein (pT3a-TT) versus infradiaphragmatic inferior vena cava (IVC; pT3b) versus supradiaphragmatic IVC tumor thrombus/IVC invasion (pT3c).
Outcome measurements and statistical analysis: Overall survival (OS) was addressed in Kaplan-Meier and Cox regression analyses, in addition to 3-mo landmark analyses.
Results and limitations: Of 2170 mRCC patients, 1880 (87%), 204 (9%), and 86 (4%) harbored pT3a-TT, pT3b, and pT3c, respectively. The respective median OS periods were 21, 23, and 12 mo (p < 0.001). In multivariable Cox regression models, pT3c stage, but not pT3b stage, was an independent predictor of higher overall mortality (hazard ratio [HR]: 1.37; 95% confidence interval [CI]: 1.09–1.73; p = 0.007), as well as in 6-mo landmark analyses (HR: 1.36; 95% CI: 1.02–1.80; p = 0.04). In the sensitivity analysis, relying on all pT3a patients, the predictor status of pT3c stage remained unchanged (HR: 1.37; 95% CI: 1.09–1.71; p = 0.007). Limitations have to be addressed regarding the sample size and the retrospective design of the current study.
Conclusions: Although overall mortality is significantly higher in pT3c mRCC patients than in their pT3b and pT3a-TT counterparts, these individuals may still expect 12-mo or better OS after CN versus virtually 2-yr OS in their pT3a and pT3b counterparts.
Patient summary: In this study, we looked at the survival outcomes of metastatic renal cell carcinoma patients who presented with tumor thrombus at cytoreductive nephrectomy. Even though these patients with most advanced tumor thrombus stage demonstrated lower survival rates, the median overall survival was still 1 yr.
Objective: To analyze the influence of biopsy Gleason score on the risk for lymph node invasion (LNI) during pelvic lymph node dissection (PLND) in patients undergoing radical prostatectomy (RP) for intermediate-risk prostate cancer (PCa).
Materials and Methods: We retrospectively analyzed 684 patients, who underwent RP between 2014 and June 2020 due to PCa. Univariable and multivariable logistic regression, as well as binary regression tree models were used to assess the risk of positive LNI and evaluate the need of PLND in men with intermediate-risk PCa.
Results: Of the 672 eligible patients with RP, 80 (11.9%) men harbored low-risk, 32 (4.8%) intermediate-risk with international society of urologic pathologists grade (ISUP) 1 (IR-ISUP1), 215 (32.0%) intermediate-risk with ISUP 2 (IR-ISUP2), 99 (14.7%) intermediate-risk with ISUP 3 (IR-ISUP3), and 246 (36.6%) high-risk PCa. Proportions of LNI were 0, 3.1, 3.7, 5.1, and 24.0% for low-risk, IR-ISUP1, IR-ISUP 2, IR-ISUP-3, and high-risk PCa, respectively (p < 0.001). In multivariable analyses, after adjustment for patient and surgical characteristics, IR-ISUP1 [hazard ratio (HR) 0.10, p = 0.03], IR-ISUP2 (HR 0.09, p < 0.001), and IR-ISUP3 (HR 0.18, p < 0.001) were independent predictors for lower risk of LNI, compared with men with high-risk PCa disease.
Conclusions: The international society of urologic pathologists grade significantly influence the risk of LNI in patients with intermediate- risk PCa. The risk of LNI only exceeds 5% in men with IR-ISUP3 PCa. In consequence, the need for PLND in selected patients with IR-ISUP 1 or IR-ISUP2 PCa should be critically discussed.
The effect of race/ethnicity on cancer-specific mortality after salvage radical prostatectomy
(2022)
Background: To test the effect of race/ethnicity on cancer-specific mortality (CSM) after salvage radical prostatectomy (SRP).
Material and methods: We relied on the Surveillance, Epidemiology and End Results database (SEER, 2004–2016) to identify SRP patients of all race/ethnicity background. Univariate and multivariate Cox regression models addressed CSM according to race/ethnicity.
Results: Of 426 assessable SRP patients, Caucasians accounted for 299 (69.9%) vs. 68 (15.9%) African-Americans vs. 39 (9.1%) Hispanics vs. 20 (4.7%) Asians. At diagnosis, African-Americans (64 years) were younger than Caucasians (66 years), but not younger than Hispanics (66 years) and Asians (67 years). PSA at diagnosis was significantly higher in African-Americans (13.2 ng/ml), Hispanics (13.0 ng/ml), and Asians (12.2 ng/ml) than in Caucasians (7.8 ng/ml, p = 0.01). Moreover, the distribution of African-Americans (10.3%–36.6%) and Hispanics (0%–15.8%) varied according to SEER region. The 10-year CSM was 46.5% in African-Americans vs. 22.4% in Caucasians vs. 15.4% in Hispanics vs. 15.0% in Asians. After multivariate adjustment (for age, clinical T stage, lymph node dissection status), African-American race/ethnicity was an independent predictor of higher CSM (HR: 2.2, p < 0.01), but not Hispanic or Asian race/ethnicity. The independent effect of African-American race/ethnicity did not persist after further adjustment for PSA.
Conclusion: African-Americans treated with SRP are at higher risk of CSM than other racial/ethnic groups and also exhibited the highest baseline PSA. The independent effect of African-American race/ethnicity on higher CSM no longer applies after PSA adjustment since higher PSA represents a distinguishing feature in African-American patients.
Background: Does the dogma of nephron sparing surgery (NSS) still stand for large renal masses? Available studies dealing with that issue are considerably biased often mixing imperative with elective indications for NSS and also including less malignant variants or even benign renal tumors. Here, we analyzed the oncological long-term outcomes of patients undergoing elective NSS or radical tumor nephrectomy (RN) for non-endophytic, large (≥7cm) clear cell renal carcinoma (ccRCC).
Methods: Prospectively acquired, clinical databases from two academic high-volume centers were screened for patients from 1980 to 2010. The query was strictly limited to patients with elective indications. Surgical complications were retrospectively assessed and classified using the Clavien-Dindo-classification system (CDS). Overall survival (OS) and cancer specific survival (CSS) were analyzed using the Kaplan-Meier-method and the log-rank test.
Results: Out of in total 8664 patients in the databases, 123 patients were identified (elective NSS (n = 18) or elective RN (n = 105)) for ≥7cm ccRCC. The median follow-up over all was 102 months (range 3–367 months). Compared to the RN group, the NSS group had a significantly longer median OS (p = 0.014) and median CSS (p = 0.04).
Conclusions: In large renal masses, NSS can be performed safely with acceptable complication rates. In terms of long-term OS and CSS, NSS was at least not inferior to RN. Our findings suggest that NSS should also be performed in patients presenting with renal tumors ≥7cm whenever technically feasible. Limitations include its retrospective nature and the limited availability of data concerning long-term development of renal function in the two groups.
Objective: Relative to urban populations, rural patients may have more limited access to care, which may undermine timely bladder cancer (BCa) diagnosis and even survival.
Methods: We tested the effect of residency status (rural areas [RA < 2500 inhabitants] vs. urban clusters [UC ≥ 2500 inhabitants] vs. urbanized areas [UA, ≥50,000 inhabitants]) on BCa stage at presentation, as well as on cancer-specific mortality (CSM) and other cause mortality (OCM), according to the US Census Bureau definition. Multivariate competing risks regression (CRR) models were fitted after matching of RA or UC with UA in stage-stratified analyses.
Results: Of 222,330 patients, 3496 (1.6%) resided in RA, 25,462 (11.5%) in UC and 193,372 (87%) in UA. Age, tumor stage, radical cystectomy rates or chemotherapy use were comparable between RA, UC and UA (all p > 0.05). At 10 years, RA was associated with highest OCM followed by UC and UA (30.9% vs. 27.7% vs. 25.6%, p < 0.01). Similarly, CSM was also marginally higher in RA or UC vs. UA (20.0% vs. 20.1% vs. 18.8%, p = 0.01). In stage-stratified, fully matched CRR analyses, increased OCM and CSM only applied to stage T1 BCa patients.
Conclusion: We did not observe meaningful differences in access to treatment or stage distribution, according to residency status. However, RA and to a lesser extent UC residency status, were associated with higher OCM and marginally higher CSM in T1N0M0 patients. This observation should be further validated or refuted in additional epidemiological investigations.
Highlights
• TAM polarization induces CP RNA.
• CP RNA expression is regulated by HIF-2 and STAT1.
• CP RNA is transferred from TAMs to HT1080 cells.
• CP RNA is translated by HT1080 cells and protects from ferroptosis.
• Co-cultured HT1080 cells decrease iron and lipid peroxidation.
Abstract
Solid tumors are characterized by hypoxic areas, which are prone for macrophage infiltration. Once infiltrated, macrophages polarize to tumor associated macrophages (TAM) to support tumor progression. Therefore, the crosstalk between TAMs and tumor cells is of current interest for the development of novel therapeutic strategies. These may comprise induction of an iron- and lipid peroxidation-dependent form of cell death, known as ferroptosis. To study the macrophage - tumor cell crosstalk we polarized primary human macrophages towards a TAM-like phenotype, co-cultured them with HT1080 fibrosarcoma cells, and analyzed the tumor cell response to ferroptosis induction. In TAMs the expression of ceruloplasmin mRNA increased, which was driven by hypoxia inducible factor 2 and signal transducer and activator of transcription 1. Subsequently, ceruloplasmin mRNA was transferred from TAMs to HT1080 cells via extracellular vesicles. In tumor cells, mRNA was translated into protein to protect HT1080 cells from RSL3-induced ferroptosis. Mechanistically this was based on reduced iron abundance and lipid peroxidation. Interestingly, in naïve macrophages also hypoxia induced ceruloplasmin under hypoxia and a co-culture of HT1080 cells with hypoxic macrophages recapitulated the protective effect observed in TAM co-cultures. In conclusion, TAMs provoke tumor cells to release iron and thereby protect them from lipid peroxidation/ferroptosis.
Background: To test the impact of urethral sphincter length (USL) and anatomic variants of prostatic apex (Lee-type classification) in preoperative multiparametric magnet resonance imaging (mpMRI) on mid-term continence in prostate cancer patients treated with radical prostatectomy (RP). Methods: We relied on an institutional tertiary-care database to identify patients who underwent RP between 03/2018 and 12/2019 with preoperative mpMRI and data available on mid-term (>6 months post-surgery) urinary continence, defined as usage 0/1 (-safety) pad/24 h. Univariable and multivariable logistic regression models were fitted to test for predictor status of USL and prostatic apex variants, defined in mpMRI measurements. Results: Of 68 eligible patients, rate of mid-term urinary continence was 81% (n = 55). Median coronal (15.1 vs. 12.5 mm) and sagittal (15.4 vs. 11.1 mm) USL were longer in patients reporting urinary continence in mid-term follow-up (both p < 0.01). No difference was recorded for prostatic apex variants distribution (Lee-type) between continent vs. incontinent patients (p = 0.4). In separate multivariable logistic regression models, coronal (odds ratio (OR): 1.35) and sagittal (OR: 1.67) USL, but not Lee-type, were independent predictors for mid-term continence. Conclusion: USL, but not apex anatomy, in preoperative mpMRI was associated with higher rates of urinary continence at mid-term follow-up.
Background: To determine the correlation between urine loss in PAD-test after catheter removal, and early urinary continence (UC) in RP treated patients. Methods: Urine loss was measured by using a standardized, validated PAD-test within 24 h after removal of the transurethral catheter, and was grouped as a loss of <1, 1–10, 11–50, and >50 g of urine, respectively. Early UC (median: 3 months) was defined as the usage of no or one safety-pad. Uni- and multivariable logistic regression models tested the correlation between PAD-test results and early UC. Covariates consisted of age, BMI, nerve-sparing approach, prostate volume, and extraprostatic extension of tumor. Results: From 01/2018 to 03/2021, 100 patients undergoing RP with data available for a PAD-test and early UC were retrospectively identified. Ultimately, 24%, 47%, 15%, and 14% of patients had a loss of urine <1 g, 1–10 g, 11–50 g, and >50 g in PAD-test, respectively. Additionally, 59% of patients reported to be continent. In multivariable logistic regression models, urine loss in PAD-test predicted early UC (OR: 0.21 vs. 0.09 vs. 0.03; for urine loss 1–10 g vs. 11–50 g vs. >50 g, Ref: <1 g; all p < 0.05). Conclusions: Urine loss after catheter removal strongly correlated with early continence as well as a severity in urinary incontinence.
Background: We aimed to determine the concordance between the radiologic stage (rT), using multiparametric magnetic resonance imaging (mpMRI), and pathologic stage (pT) in patients with high-risk prostate cancer and its influence on nerve-sparing surgery compared to the use of the intraoperative frozen section technique (IFST). Methods: The concordance between rT and pT and the rates of nerve-sparing surgery and positive surgical margin were assessed for patients with high-risk prostate cancer who underwent radical prostatectomy. Results: The concordance between the rT and pT stages was shown in 66.4% (n = 77) of patients with clinical high-risk prostate cancer. The detection of patients with extraprostatic disease (≥pT3) by preoperative mpMRI showed a sensitivity, negative predictive value and accuracy of 65.1%, 51.7% and 67.5%. In addition to the suspicion of extraprostatic disease in mpMRI (≥rT3), 84.5% (n = 56) of patients with ≥rT3 underwent primary nerve-sparing surgery with IFST, resulting in 94.7% (n = 54) of men with at least unilateral nerve-sparing surgery after secondary resection with a positive surgical margin rate related to an IFST of 1.8% (n = 1). Conclusion: Patients with rT3 should not be immediately excluded from nerve-sparing surgery, as by using IFST some of these patients can safely undergo nerve-sparing surgery.
Purpose: We assessed contemporary incidence rates and trends of primary urethral cancer.
Methods: We identified urethral cancer patients within Surveillance, Epidemiology and End Results registry (SEER, 2004–2016). Age-standardized incidence rates per 1,000,000 (ASR) were calculated. Log linear regression analyses were used to compute average annual percent change (AAPC).
Results: From 2004 to 2016, 1907 patients with urethral cancer were diagnosed (ASR 1.69; AAPC: -0.98%, p = 0.3). ASR rates were higher in males than in females (2.70 vs. 0.55), respectively and did not change over the time (both p = 0.3). Highest incidence rates were recorded in respectively ≥75 (0.77), 55–74 (0.71) and ≤54 (0.19) years of age categories, in that order. African Americans exhibited highest incidence rate (3.33) followed by Caucasians (1.72), other race groups (1.57) and Hispanics (1.57), in that order. A significant decrease occurred over time in Hispanics, but not in other race groups. In African Americans, male and female sex-stratified incidence rates were higher than in any other race group. Urothelial histological subtype exhibited highest incidence rate (0.92), followed by squamous cell carcinoma (0.41), adenocarcinoma (0.29) and other histologies (0.20). In stage stratified analyses, T1N0M0 stage exhibited highest incidence rate. However, it decreased over time (−3.00%, p = 0.02) in favor of T1-4N1-2M0 stage (+ 2.11%, p = 0.02).
Conclusion: Urethral cancer is rare. Its incidence rates are highest in males, elderly patients, African Americans and in urothelial histological subtype. Most urethral cancer cases are T1N0M0, but over time, the incidence of T1N0M0 decreased in favor of T1-4N1-2M0.
The inclusive charged particle transverse momentum distribution is measured in proton–proton collisions at s=900 GeV at the LHC using the ALICE detector. The measurement is performed in the central pseudorapidity region (|η|<0.8) over the transverse momentum range 0.15<pT<10 GeV/c. The correlation between transverse momentum and particle multiplicity is also studied. Results are presented for inelastic (INEL) and non-single-diffractive (NSD) events. The average transverse momentum for |η|<0.8 is 〈pT〉INEL=0.483±0.001 (stat.)±0.007 (syst.) GeV/c and 〈pT〉NSD=0.489±0.001 (stat.)±0.007 (syst.) GeV/c, respectively. The data exhibit a slightly larger 〈pT〉 than measurements in wider pseudorapidity intervals. The results are compared to simulations with the Monte Carlo event generators PYTHIA and PHOJET.
Background and Objectives: To test for differences in perioperative outcomes and total hospital costs (THC) in nonmetastatic bladder cancer patients undergoing open (ORC) versus robotic-assisted radical cystectomy (RARC).
Methods: We relied on the National Inpatient Sample database (2016–2019). Statistics consisted of trend analyses, multivariable logistic, Poisson, and linear regression models.
Results: Of 5280 patients, 1876 (36%) versus 3200 (60%) underwent RARC versus ORC. RARC increased from 32% to 41% (estimated annual percentage change [EAPC]: + 8.6%; p = 0.02). Rates of transfusion (8% vs. 16%), intraoperative (2% vs. 3%), wound (6% vs. 10%), and pulmonary (6% vs. 10%) complications were lower in RARC patients (all p < 0.05). Moreover, median length of stay (LOS) was shorter in RARC (6 vs. 7days; p < 0.001). Conversely, median THC (31,486 vs. 27,162$; p < 0.001) were higher in RARC. Multivariable logistic regression-derived odds ratios addressing transfusion (0.49), intraoperative (0.53), wound (0.68), and pulmonary (0.71) complications favored RARC (all p < 0.01). In multivariable Poisson and linear regression models, RARC was associated with shorter LOS (Rate ratio:0.86; p < 0.001), yet higher THC (Coef.:5,859$; p < 0.001). RARC in-hospital mortality was lower (1% vs. 2%; p = 0.04).
Conclusions: RARC complications, LOS, and mortality appear more favorable than ORC, but result in higher THC. The favorable RARC profile contributes to its increasing popularity throughout the United States.
Non-organ confined stage and upgrading rates in exclusive PSA high-risk prostate cancer patients
(2022)
Background: The pathological stage of prostate cancer with high-risk prostate-specific antigen (PSA) levels, but otherwise favorable and/or intermediate risk characteristics (clinical T-stage, Gleason Grade group at biopsy [B-GGG]) is unknown. We hypothesized that a considerable proportion of such patients will exhibit clinically meaningful GGG upgrading or non-organ confined (NOC) stage at radical prostatectomy (RP).
Materials and methods: Within the Surveillance, Epidemiology, and End Results database (2010–2015) we identified RP-patients with cT1c-stage and B-GGG1, B-GGG2, or B-GGG3 and PSA 20–50 ng/ml. Rates of GGG4 or GGG5 and/or rates of NOC stage (≥ pT3 and/or pN1) were analyzed. Subsequently, separate univariable and multivariable logistic regression models tested for predictors of NOC stage and upgrading at RP.
Results: Of 486 assessable patients, 134 (28%) exhibited B-GGG1, 209 (43%) B-GGG2, and 143 (29%) B-GGG3, respectively. The overall upgrading and NOC rates were 11% and 51% for a combined rate of upgrading and/or NOC stage of 53%. In multivariable logistic regression models predicting upgrading, only B-GGG3 was an independent predictor (odds ratio [OR]: 5.29; 95% confidence interval [CI]: 2.21–14.19; p < 0.001). Conversely, 33%–66% (OR: 2.36; 95% CI: 1.42–3.95; p = 0.001) and >66% of positive biopsy cores (OR: 4.85; 95% CI: 2.84–8.42; p < 0.001), as well as B-GGG2 and B-GGG3 were independent predictors for NOC stage (all p ≤ 0.001).
Conclusions: In cT1c-stage patients with high-risk PSA baseline, but low- to intermediate risk B-GGG, the rate of upgrading to GGG4 or GGG5 is low (11%). However, NOC stage is found in the majority (51%) and can be independently predicted with percentage of positive cores at biopsy and B-GGG.
Background: The survival benefit of primary external beam radiation therapy (EBRT) has never been formally tested in elderly men who were newly diagnosed with metastatic prostate cancer (mPCa). We hypothesized that elderly patients may not benefit of EBRT to the extent as younger newly diagnosed mPCa patients, due to shorter life expectancy.
Methods: We relied on Surveillance, Epidemiology and End Results (2004–2016) to identify elderly newly diagnosed mPCa patients, aged >75 years. Kaplan–Meier, univariable and multivariable Cox regression models, as well as Competing Risks Regression models tested the effect of EBRT versus no EBRT on overall mortality (OM) and cancer-specific mortality (CSM).
Results: Of 6556 patients, 1105 received EBRT (16.9%). M1b stage was predominant in both EBRT (n = 823; 74.5%) and no EBRT (n = 3908; 71.7%, p = 0.06) groups, followed by M1c (n = 211; 19.1% vs. n = 1042; 19.1%, p = 1) and M1a (n = 29; 2.6% vs. n = 268; 4.9%, p < 0.01). Median overall survival (OS) was 23 months for EBRT and 23 months for no EBRT (hazard ratio [HR]: 0.97, p = 0.6). Similarly, median cancer-specific survival (CSS) was 29 months for EBRT versus 30 months for no EBRT (HR: 1.04, p = 0.4). After additional multivariable adjustment, EBRT was not associated with lower OM or lower CSM in the entire cohort, as well as after stratification for M1b and M1c substages.
Conclusions: In elderly men who were newly diagnosed with mPCa, EBRT does not affect OS or CSS. In consequence, our findings question the added value of local EBRT in elderly newly diagnosed mPCa patients.
Background Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Methodology/Principal Findings Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Conclusion Thus, aging Pink1 -/- mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.
Denervation-induced changes in excitatory synaptic strength were studied following entorhinal deafferentation of hippocampal granule cells in mature (≥3 weeks old) mouse organotypic entorhino-hippocampal slice cultures. Whole-cell patch-clamp recordings revealed an increase in excitatory synaptic strength in response to denervation during the first week after denervation. By the end of the second week synaptic strength had returned to baseline. Because these adaptations occurred in response to the loss of excitatory afferents, they appeared to be in line with a homeostatic adjustment of excitatory synaptic strength. To test whether denervation-induced changes in synaptic strength exploit similar mechanisms as homeostatic synaptic scaling following pharmacological activity blockade, we treated denervated cultures at 2 days post lesion for 2 days with tetrodotoxin. In these cultures, the effects of denervation and activity blockade were not additive, suggesting that similar mechanisms are involved. Finally, we investigated whether entorhinal denervation, which removes afferents from the distal dendrites of granule cells while leaving the associational afferents to the proximal dendrites of granule cells intact, results in a global or a local up-scaling of granule cell synapses. By using computational modeling and local electrical stimulations in Strontium (Sr2+)-containing bath solution, we found evidence for a lamina-specific increase in excitatory synaptic strength in the denervated outer molecular layer at 3–4 days post lesion. Taken together, our data show that entorhinal denervation results in homeostatic functional changes of excitatory postsynapses of denervated dentate granule cells in vitro.
Background: Only one previously published study by Nocera et al. addressed the risk of upstaging to ≥pT3 in cT1 clear cell renal cell carcinoma (ccRCC) by using characteristics of the R.E.N.A.L and PADUA score (age, tumor size, rim location, exophytic rate, polar involvement) developing an accurate nomogram. However, this nomogram has never been externally validated yet.
Material and methods: The study cohort consisted of 288 patients with cT1a-b ccRCC, diagnosed between 2008-2021 at the University Hospital Frankfurt, Germany. Analyses addressed clinical, tumor and radiographic characteristics. The external validation of the nomogram relied on accuracy calculations derived from the area under the curve of the receiver operator characteristic analysis.
Results: Overall, 11.8% (n=34) patients harbored ≥pT3 ccRCC. Median radiographic tumor size (3.6 vs. 5.3cm), R.E.N.A.L. (8 vs. 9 points) and PADUA score (9 vs. 11 points), as well as proportions of renal sinus involvement (82.4% vs. 51.6%), renal hilus involvement (44.1 vs. 13.0%), and medial rim location significantly differed between the pT1-2 and ≥pT3 group (all p ≤ 0.01). In subgroup analyses of small renal mass ccRCC patients (<4cm, cT1a), only 3.8% (n=6) patients had ≥pT3 pathology. Upstaged patients were significantly older and more frequently had endophytic tumor than pT1-2 counterparts (p<0.05). The external validation of the Nocera nomogram showed a good accuracy of 76.6%. Using the suggested cut-off of 21%, 26.5% of patients exhibited ≥pT3 ccRCC. Conversely, within patients below cut-off, 5.9% patients exhibited ≥pT3 ccRCC.
Conclusion: We reported the first external validation of the nomogram addressing the risk of ≥pT3 in cT1 ccRCC patients, demonstrating a good accuracy, with a low false-negative rate. Therefore, the nomogram can accurately be used for patients’ counselling and treatment decision making.