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Purpose: In this study, we examined distress levels and quality of life (QoL) of patients with hematologic malignancies under treatment in an acute setting. We used external- and self-assessment instruments for distress. Additionally, we investigated the relation between distress and QoL as well as whether highly distressed patients differed from less distressed patients concerning their QoL.
Methods: A cross-sectional study with patients of the Medical Clinic II of the University Hospital Frankfurt was conducted. One hundred and nine patients were assessed with an expert rating scale and completed self-report questionnaires. Data were exploratively analyzed and group comparisons between patients who scored above the cut-off of the respective screening instruments and those who did not were conducted.
Results: Patients with hematologic malignancies experience high levels of distress and low QoL. Especially, role and social functioning are affected. Patients suffer most from fatigue, appetite loss, and insomnia. Using established cut-offs, all screening instruments were able to differentiate between patients regarding distress and QoL. Patients scoring above the cut-off were significantly more distressed and had a lower QoL. There was a medium-to-strong correlation between distress and QoL indicators.
Conclusion: Cancer-specific screening instruments seem to be able to identify treatment needs more specifically. They also allowed a better differentiation concerning QoL. The close link between distress and QoL needs to be recognized to enable a holistic approach to treatment and thereby optimize the quality of treatment.
Purpose: The coronavirus disease 2019 (COVID-19) poses major challenges to health-care systems worldwide. This pandemic demonstrates the importance of timely access to intensive care and, therefore, this study aims to explore the accessibility of intensive care beds in 14 European countries and its impact on the COVID-19 case fatality ratio (CFR).
Methods: We examined access to intensive care beds by deriving (1) a regional ratio of intensive care beds to 100,000 population capita (accessibility index, AI) and (2) the distance to the closest intensive care unit. The cross-sectional analysis was performed at a 5-by-5 km spatial resolution and results were summarized nationally for 14 European countries. The relationship between AI and CFR was analyzed at the regional level.
Results: We found national-level differences in the levels of access to intensive care beds. The AI was highest in Germany (AI = 35.3), followed by Estonia (AI = 33.5) and Austria (AI = 26.4), and lowest in Sweden (AI = 5) and Denmark (AI = 6.4). The average travel distance to the closest hospital was highest in Croatia (25.3 min by car) and lowest in Luxembourg (9.1 min). Subnational results illustrate that capacity was associated with population density and national-level inventories. The correlation analysis revealed a negative correlation of ICU accessibility and COVID-19 CFR (r = − 0.57; p < 0.001).
Conclusion: Geographical access to intensive care beds varies significantly across European countries and low ICU accessibility was associated with a higher proportion of COVID-19 deaths to cases (CFR). Important differences in access are due to the sizes of national resource inventories and the distribution of health-care facilities relative to the human population. Our findings provide a resource for officials planning public health responses beyond the current COVID-19 pandemic, such as identifying potential locations suitable for temporary facilities or establishing logistical plans for moving severely ill patients to facilities with available beds.
Improving spatial accessibility to hospitals is a major task for health care systems which can be facilitated using recent methodological improvements of spatial accessibility measures. We used the integrated floating catchment area (iFCA) method to analyze spatial accessibility of general inpatient care (internal medicine, surgery and neurology) on national level in Germany determining an accessibility index (AI) by integrating distances, hospital beds and morbidity data. The analysis of 358 million distances between hospitals and population locations revealed clusters of lower accessibility indices in areas in north east Germany. There was a correlation of urbanity and accessibility up to r = 0.31 (p < 0.001). Furthermore, 10% of the population lived in areas with significant clusters of low spatial accessibility for internal medicine and surgery (neurology: 20%). The analysis revealed the highest accessibility for heart failure (AI = 7.33) and the lowest accessibility for stroke (AI = 0.69). The method applied proofed to reveal important aspects of spatial accessibility i.e. geographic variations that need to be addressed. However, for the majority of the German population, accessibility of general inpatient care was either high or at least not significantly low, which suggests rather adequate allocation of hospital resources for most parts of Germany.
Hintergrund: Parkinson-Syndrome führen im Krankheitsverlauf zur Pflegebedürftigkeit bei den Betroffenen. Zur Prävalenz der Bewohner*innen mit einem Parkinson-Syndrom in Pflegeeinrichtungen, zu ihrer Versorgungssituation und zur vorhandenen Expertise der Pflegefachpersonen in den Einrichtungen ist wenig bekannt.
Ziel der Arbeit: Die vorliegende Studie untersucht die Prävalenzrate der Bewohner*innen mit einem Parkinson-Syndrom in stationären Pflegeeinrichtungen in Deutschland. Die Arbeit exploriert die Zusammenarbeit verschiedener Akteure, deren Koordination sowie Information und Wissen des Pflegepersonals. Ziel ist es, einen möglichen Bedarf an spezialisierter Pflege in Pflegeeinrichtungen aufzuzeigen.
Methode: Die schriftliche Querschnittsbefragung der Wohnbereichsleitungen von 500 zufällig ausgewählten Pflegeeinrichtungen in Deutschland erfolgte von Januar bis Juni 2020. Der eingesetzte Fragebogen wurde vorab literaturbasiert entwickelt. Die Daten wurden deskriptiv analysiert.
Ergebnisse: Aus 57 Einrichtungen wurden Fragebogen von 85 Wohnbereichen analysiert (Rücklaufquote 11,4 %). Die Prävalenzrate von Bewohner*innen mit einem Parkinson-Syndrom in der stationären Altenhilfe beträgt 13,9 %. Mehr als die Hälfte haben zusätzlich eine Demenzdiagnose (52,8 %). In 26 % der Fälle erfolgen Krankenhausaufenthalte infolge von Sturzereignissen. Eine eindeutige Koordination der Versorgung durch ärztliche oder pflegerische Spezialisten gibt es nicht.
Diskussion: Bewohner*innen mit einem Parkinson-Syndrom in der stationären Altenhilfe sind häufig, und sie zeigen komplexe motorische und nichtmotorische Symptome – auch durch die Komorbidität Demenz. Die Häufigkeit von Sturzereignissen mit Krankenhausaufenthalten und die geringe Anzahl Parkinson-Syndrom-spezifischer Hilfsmittel zeigen, dass das Wissen der Pflege vor Ort gesteigert werden kann. Eine zentrale Koordination und Unterstützung hierzu sollten in der stationären Langzeitpflege etabliert werden.
Bloodstream infections (BSI) are a frequent complication in patients with hematological and oncological diseases. However, the impact of different bacterial species causing BSI and of multiple BSI remains incompletely understood. We performed a retrospective study profiling 637 bacterial BSI episodes in hematological and oncological patients. Based on the 30-day (30d) overall survival (OS), we analyzed different types of multiple BSI and grouped BSI-associated bacteria into clusters followed by further assessment of clinical and infection-related characteristics. We discovered that polymicrobial BSI (different organisms on the first day of a BSI episode) and sequential BSI (another BSI before the respective BSI episode) were associated with a worse 30d OS. Different bacterial groups could be classified into three BSI outcome clusters based on 30d OS: favorable (FAV) including mainly common skin contaminants, Escherichia spp. and Streptococcus spp.; intermediate (INT) including mainly Enterococcus spp., vancomycin-resistant Enterococcus spp., and multidrug-resistant gram-negative bacteria (MDRGN); and adverse (ADV) including MDRGN with an additional carbapenem-resistance (MDRGN+CR). A polymicrobial or sequential BSI especially influenced the outcome in the combination of two INT cluster BSI. The presence of a polymicrobial BSI and the assignment into the BSI outcome clusters were identified as independent risk factors for 30d mortality in a Cox multivariate regression analysis. The assignment to a BSI outcome cluster and the differentiated perspective of multiple BSI open new insights into the prognosis of patients with BSI and should be further validated in other patient cohorts.
Purpose: Perfusion-weighted MRI (PWI) and O-(2-[18F]fluoroethyl-)-l-tyrosine ([18F]FET) PET are both applied to discriminate tumor progression (TP) from treatment-related changes (TRC) in patients with suspected recurrent glioma. While the combination of both methods has been reported to improve the diagnostic accuracy, the performance of a sequential implementation has not been further investigated. Therefore, we retrospectively analyzed the diagnostic value of consecutive PWI and [18F]FET PET.
Methods: We evaluated 104 patients with WHO grade II–IV glioma and suspected TP on conventional MRI using PWI and dynamic [18F]FET PET. Leakage corrected maximum relative cerebral blood volumes (rCBVmax) were obtained from dynamic susceptibility contrast PWI. Furthermore, we calculated static (i.e., maximum tumor to brain ratios; TBRmax) and dynamic [18F]FET PET parameters (i.e., Slope). Definitive diagnoses were based on histopathology (n = 42) or clinico-radiological follow-up (n = 62). The diagnostic performance of PWI and [18F]FET PET parameters to differentiate TP from TRC was evaluated by analyzing receiver operating characteristic and area under the curve (AUC).
Results: Across all patients, the differentiation of TP from TRC using rCBVmax or [18F]FET PET parameters was moderate (AUC = 0.69–0.75; p < 0.01). A rCBVmax cutoff > 2.85 had a positive predictive value for TP of 100%, enabling a correct TP diagnosis in 44 patients. In the remaining 60 patients, combined static and dynamic [18F]FET PET parameters (TBRmax, Slope) correctly discriminated TP and TRC in a significant 78% of patients, increasing the overall accuracy to 87%. A subgroup analysis of isocitrate dehydrogenase (IDH) mutant tumors indicated a superior performance of PWI to [18F]FET PET (AUC = 0.8/< 0.62, p < 0.01/≥ 0.3).
Conclusion: While marked hyperperfusion on PWI indicated TP, [18F]FET PET proved beneficial to discriminate TP from TRC when PWI remained inconclusive. Thus, our results highlight the clinical value of sequential use of PWI and [18F]FET PET, allowing an economical use of diagnostic methods. The impact of an IDH mutation needs further investigation.
This focus issue of the European Journal of Trauma and Emergency Surgery compiles a collection of outstanding clinical research using the immense dataset of the German TraumaRegister DGU® (TR-DGU). The TR-DGU of the German Trauma Society (Deutsche Gesellschaft für Unfallchirurgie, DGU) was founded in 1993. Currently, approximately 40,000 cases from more than 600 hospitals are entered into the database every year. The selected articles of this focus on issue highlight the immense value the TR-DGU constitutes for the current, but also for the future trauma research.
Zielsetzung: Die Daten für das Jahr 2019 des Registers „Abdominelles Aortenaneurysma“ (AAA) des Deutschen Instituts für Gefäßmedizinische Gesundheitsforschung (DIGG) der Deutschen Gesellschaft für Gefäßchirurgie und Gefäßmedizin werden vorgestellt.
Methodik: Im Jahr 2019 beteiligten sich an dem Register insgesamt 109 Kliniken. Für die offene Versorgung (OR) des intakten AAA (iAAA) gaben 78 (71,6 %) Kliniken, für die endovaskuläre Versorgung (EVAR) des iAAA 102 (93,6 %) Kliniken Daten ein. Für das rupturierte AAA (rAAA) wurden von 36 Kliniken (33,0 %) (EVAR) bzw. 50 (45,9 %) Kliniken (OR) Patienten gemeldet. Ausgewertet wurden die Daten von 1967 stationär behandelten Patienten. Von den insgesamt 1793 iAAA waren 1501 infrarenal (83,7 %) und 292 (16,3 %) juxtarenal gelegen.
Ergebnisse: 1429 iAAA (79,7 %) wurden endovaskulär und 364 (20,3 %) offen versorgt. Bei den endovaskulär versorgten Patienten mit iAAA verlief der Eingriff in 86,3 % der Fälle komplikationslos. Es verstarben insgesamt 15 Patienten (1,0 %) bis zur Entlassung. Bei den offen versorgten Patienten wiesen 67,0 % der Patienten keine Komplikationen auf. Verstorben sind insgesamt 20 Patienten (5,5 %). Bei EVAR war die Klinikletalität bei Versorgung juxtarenaler AAA mit 3,7 % signifikant höher als bei Versorgung infrarenaler AAA mit 0,6 % (p = 0,002), bei OR konnten hingegen keine signifikanten Unterschiede hinsichtlich der Klinikletalität aufgezeigt werden (juxtarenal 4,8 %, infrarenal 5,8 %; p = 0,470). Von den 174 Patienten mit rAAA wurden 80 (46,0 %) endovaskulär und 94 (54,0 %) offen versorgt. Bei EVAR sind 20,0 % der Patienten während des stationären Aufenthalts verstorben, bei OR 36,2 %.
Schlussfolgerung: Die Ergebnisse des Jahres 2019 zu Klinikletalität und Morbidität bei endovaskulärer und offener Versorgung des iAAA bestätigen weitgehend die publizierten Ergebnisse für die Jahre 2013 bis 2018. Beim rAAA sind die Ergebnisse der einzelnen Jahresberichte hingegen widersprüchlich, die kleinen berichteten jährlichen Fallzahlen erlauben nur Aussagen über größere Zeiträume.
Introduction: The induced membrane technique for the treatment of large bone defects is a two-step procedure. In the first operation, a foreign body membrane is induced around a spacer, then, in the second step, several weeks or months later, the spacer is removed and the Membrane pocket is filled with autologous bone material. Induction of a functional biological membrane might be avoided by initially using a biological membrane. In this study, the effect of a human acellular dermis (hADM, Epiflex, DIZG gGmbH) was evaluated for the treatment of a large (5 mm), plate-stabilised femoral bone defect.
Material and Methods: In an established rat model, hADM was compared to the two-stage induced membrane technique and a bone defect without membrane cover. Syngeneous spongiosa from donor animals was used for defect filling in all groups. The group size in each case was n = 5, the induction time of the membrane was 3–4 weeks and the healing time after filling of the defect was 8 weeks.
Results: The ultimate loads were increased to levels comparable with native bone in both membrane groups (hADM: 63.2% ± 29.6% of the reference bone, p < 0.05 vs. no membrane, induced membrane: 52.1% ± 25.8% of the reference bone, p < 0.05 vs. no membrane) and were significantly higher than the control group without membrane (21.5%). The membrane groups were radiologically and histologically almost completely bridged by new bone formation, in contrast to the control Group where no closed osseous bridging could be observed.
Conclusion: The use of the human acellular dermis leads to equivalent healing results in comparison to the two-stage induced membrane technique. This could lead to a shortened therapy duration of large bone defects.
Aims: SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications.
Subject and method: SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the ClinicalTrials.gov webpage listed n=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, “SARS-CoV-2,” “COVID-19,” “antivirals,” “therapy”), of which n=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19.
Results: Lopinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir.
Discussion: This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds.
Background: The prevalence of multimorbidity is increasing in recent years, and patients with multimorbidity often have a decrease in quality of life and require more health care. The aim of this study was to explore the evolution of multimorbidity taking the sequence of diseases into consideration.
Methods: We used a Belgian database collected by extracting coded parameters and more than 100 chronic conditions from the Electronic Health Records of general practitioners to study patients older than 40 years with multiple diagnoses between 1991 and 2015 (N = 65 939). We applied Markov chains to estimate the probability of developing another condition in the next state after a diagnosis. The results of Weighted Association Rule Mining (WARM) allow us to show strong associations among multiple conditions.
Results: About 66.9% of the selected patients had multimorbidity. Conditions with high prevalence, such as hypertension and depressive disorder, were likely to occur after the diagnosis of most conditions. Patterns in several disease groups were apparent based on the results of both Markov chain and WARM, such as musculoskeletal diseases and psychological diseases. Psychological diseases were frequently followed by irritable bowel syndrome.
Conclusions: Our study used Markov chains and WARM for the first time to provide a comprehensive view of the relations among 103 chronic conditions, taking sequential chronology into consideration. Some strong associations among specific conditions were detected and the results were consistent with current knowledge in literature, meaning the approaches were valid to be used on larger data sets, such as National Health care Systems or private insurers.
Das Corona-Update Frankfurt
(2022)
Seit Beginn der Coronapandemie haben die vier Arbeitsgruppen am Institut für Medizinische Virologie ihre Forschungsschwerpunkte innerhalb kürzester Zeit verlagert. Sie haben wichtige Erkenntnisse zu Teststrategien, Impfschutz und Therapieansätzen gewonnen. Dieser Weg wird durch Förderung des Landes Hessen weiter ausgebaut. Eine Bestandsaufnahme.
Aqueous solutions of a nonionic surfactant (either Tween20 or BrijL23) and an anionic surfactant (sodium dodecyl sulfate, SDS) are investigated, using small-angle neutron scattering (SANS). SANS spectra are analysed by using a core-shell model to describe the form factor of self-assembled surfactant micelles; the intermicellar interactions are modelled by using a hard-sphere Percus–Yevick (HS-PY) or a rescaled mean spherical approximation (RMSA) structure factor. Choosing these specific nonionic surfactants allows for comparison of the effect of branched (Tween20) and linear (BrijL23) surfactant headgroups, both constituted of poly-ethylene oxide (PEO) groups. The nonionic–anionic surfactant mixtures are studied at various concentrations up to highly concentrated samples (ϕ ≲ 0.45) and various mixing ratios, from pure nonionic to pure anionic surfactant solutions. The scattering data reveal the formation of mixed micelles already at concentrations below the critical micelle concentration of SDS. At higher volume fractions, excluded volume effects dominate the intermicellar structuring, even for charged micelles. In consequence, at high volume fractions, the intermicellar structuring is the same for charged and uncharged micelles. At all mixing ratios, almost spherical mixed micelles form. This offers the opportunity to create a system of colloidal particles with a variable surface charge. This excludes only roughly equimolar mixing ratios (X≈ 0.4–0.6) at which the micelles significantly increase in size and ellipticity due to specific sulfate–EO interactions.
While B-cell acute lymphoblastic leukaemia (B-ALL) can be described as the leukaemia of childhood, chronic myeloid leukaemia (CML) mostly develops in elderly individuals. Understanding and utilising mechanisms involved in the development and persistence of these leukaemias as possible targets for treatment strategies has received particular interest. Processes that happen in the vicinity of the cancerous cells themselves could influence cancer growth and behaviour and hence can serve as novel targets, leading to the development of two-pronged therapies that act both on leukaemic cells directly as well as their niche. The niche in the case of leukaemia is the bone marrow microenvironment (BMM) where these cells are not only generated but also instructed and protected. As the BMM is situated inside bones that undergo drastic changes and growth processes during the ageing process, the BMM itself is also being altered throughout life. These alterations and the very process of expansion itself may therefore also provide distinct regulatory influences on the cells (healthy or malignant) that are generated inside this niche, leading to the question: Does the age of the bone marrow microenvironment differentially influence the development of (“childhood”) B-ALL versus (“adult”) CML by the release of cytokines?
In previous studies by the host-laboratory the age distribution of B-ALL versus CML in a murine transduction/ transplantation model could be recapitulated; young mice which received the same number of leukaemia-initiating cells as their old counterparts died significantly earlier of B-ALL while showing a significantly delayed clinical course, when they were suffering from CML. The tumour load and other leukaemia-associated parameters also showed a clear disposition towards preferential induction of CML in elderly and B-ALL in younger mice.
In this project we could support the hypothesis that the age of the BMM differentially influences the proliferation of leukaemic cells and thereby the development and persistence of different types of leukaemias by utilising different in vitro culture experiments. Specifically, we could show that young (compared to old) bone marrow
11 stroma cells (BMSC) support the growth of (BCR-ABL1+) B-ALL cells both in a direct, cell on cell co-culture setting, as well as in young BMSC-derived conditioned medium. This supports the hypothesis that varying factors are differentially released from a young versus an old BMM and influence the growth of the leukaemia cells. The opposite might be true for CML cells (BCR-ABL1+ 32D cells); BMSC obtained from old animals showed a tendency to support their growth more profoundly than cells acquired from young animals.
Possible proteins responsible for the distinct regulation of myeloid versus lymphatic leukaemic cells by young versus old BMM have also been studied. We investigated C-X-C motif chemokine 13 (CXCL13) and growth differentiation factor 11 (GDF11) in their effect on leukaemia cells, as both proteins having previously been described to have tumour-modelling properties and age-dependent levels (see below).
We identified an increased secretion of CXCL13, a B-cell chemotactic factor, into conditioned medium from young versus old BMSC. In accordance with this we found migration of B-ALL cells towards BMSC from young compared to old mice to be improved, while adhesion of both B-ALL and CML cells to young versus old BMSC did not show any differences. By blocking CXCL13 the proliferation-supporting effect of young BMSC on B-ALL cells could be diminished. Similar effects could be demonstrated by blocking GDF11.
In the case of CML cells we could observe the opposite effect; blocking CXCL13 and GDF11 increased their proliferation in a co-culture with BMSC. This supported our hypothesis that both cytokines differentially regulate B-ALL and CML behaviour. After the completion of this thesis, another member of the host-laboratory convincingly demonstrated the role of BMM age in the regulation of B-ALL via CXCL13 signalling (see discussion).
Objective In rheumatoid arthritis (RA), chronic inflammation can enhance the development of sarcopenia with a depletion of muscle mass, strength and performance. Currently, a consensus definition for sarcopenia and solid results for the prevalence of sarcopenia in patients with RA are lacking.
Methods In this cross-sectional study, 289 patients ≥18 years with RA were recruited. Dual X-ray absorptiometry was performed to measure appendicular lean mass. Assessment of muscle function included grip strength, gait speed and chair rise time. Prevalence of sarcopenia was defined using the updated European Working Group on Sarcopenia in Older People (EWGSOP2) and the Foundation for the National Institutes of Health (FNIH) definition. In addition, the RA study population was compared with existing data of healthy controls (n=280).
Results 4.5% of patients (59.4±11.3 years) and 0.4% of controls (62.9±11.9 years) were affected by sarcopenia according to the EWGSOP2 definition. Body weight (OR 0.92, 95% CI 0.86 to 0.97), body mass index (BMI) (OR 0.70, 95% CI 0.57 to 0.87), C reactive protein (CRP) (OR 1.05, 95% CI 1.01 to 1.10), disease duration (OR 1.08, 95% CI 1.02 to 1.36), current medication with glucocorticoids (OR 5.25, 95% CI 2.14 to 24.18), cumulative dose of prednisone equivalent (OR 1.04, 95% CI 1.02 to 1.05) and Health Assessment Questionnaire (HAQ) (OR 2.50, 95% CI 1.27 to 4.86) were associated with sarcopenia in patients with RA. In contrast, the prevalence was 2.8% in patients compared with 0.7% in controls when applying the FNIH definition, and body height (OR 0.75, 95% CI 0.64 to 0.88), BMI (OR 1.20, 95% CI 1.02 to 1.41), CRP (OR 1.06, 95% CI 1.01 to 1.11) and HAQ (OR 2.77, 95% CI 1.17 to 6.59) were associated with sarcopenia.
Conclusion Sarcopenia is significantly more common in patients with RA compared with controls using the EWGSOP2 criteria. The FNIH definition revealed sarcopenia in individuals with high BMI and fat mass, regardless of the presence of RA.
Trial registration number It was registered at the German Clinical Trials Registry (DRKS) as well as WHO Clinical Trials Registry (ICTRP) (DRKS00011873, registered on 16 March 2017).
Hidradenitis suppurativa/Acne inversa (HS/AI) ist eine chronisch-entzündliche Hauterkrankung, deren Behandlung sowohl konservative als auch chirurgische Behandlungsmöglichkeiten umfasst. In den Hurley-Stadien II und III ist die chirurgische Resektion irreversibel zerstörten Gewebes anzustreben. Hierzu existieren verschiedene Resektionstechniken, die sich vor allem in ihrer Invasivität und Rezidivneigung unterscheiden. Bis heute gibt es keinen allgemein akzeptierten Konsens hinsichtlich verschiedener Resektions- und Rekonstruktionstechniken sowie der Einbeziehung medikamentöser Therapien in das therapeutische Gesamtkonzept.
Omicron is the evolutionarily most distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 VOCs but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding memory B (BMEM) cells against epitopes shared broadly among variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted BMEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. Whereas selective amplification of BMEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.
The current SARS-CoV-2 outbreak leads to a growing need of point-of-care thoracic imaging that is compatible with isolation settings and infection prevention precautions. We retrospectively reviewed 17 COVID-19 patients who received point-of-care lung ultrasound imaging in our isolation unit. Lung ultrasound was able to detect interstitial lung disease effectively; severe cases showed bilaterally distributed B-Lines with or without consolidations; one case showed bilateral pleural plaques. Corresponding to CT scans, interstitial involvement is accurately depicted as B-Lines on lung ultrasound. Lung ultrasound might be suitable for detecting interstitial involvement in a bedside setting under high security isolation precautions.
Objectives: Immune checkpoint inhibitors have become the standard of care for metastatic non–small-cell lung cancer (NSCLC) progressing during or after platinum-based chemotherapy. Real-world clinical practice tends to represent more diverse patient characteristics than randomized clinical trials. We sought to evaluate overall survival (OS) outcomes in the total study population and in key subsets of patients who received nivolumab for previously treated advanced NSCLC in real-world settings in France, Germany, or Canada.
Materials and methods: Data were pooled from two prospective observational cohort studies, EVIDENS and ENLARGE, and a retrospective registry in Canada. Patients included in this analysis were aged ≥18 years, had stage IIIB/IV NSCLC, and received nivolumab after at least one prior line of systemic therapy. OS was estimated in the pooled population and in various subgroups using the Kaplan-Meier method. Timing of data collection varied across cohorts (2015–2019).
Results: Of the 2585 patients included in this analyses, 1235 (47.8 %) were treated in France, 881 (34.1 %) in Germany, and 469 (18.1 %) in Canada. Median OS for the total study population was 11.3 months (95 % CI: 10.5–12.2); this was similar across France, Germany, and Canada. The OS rate was 49 % at 1 year and 28 % at 2 years for the total study population. In univariable Cox analyses, the presence of epidermal growth factor receptor mutations in nonsquamous disease, liver, or bone metastases were associated with significantly shorter OS, whereas tumor programmed death ligand 1 expression and Eastern Cooperative Oncology Group performance status 0–1 were associated with significantly prolonged OS. Similar OS was noted across subgroups of age and prior lines of therapy.
Conclusion: OS rates in patients receiving nivolumab for previously treated advanced NSCLC in real-world clinical practice closely mirrored those in phase 3 studies, suggesting similar effectiveness of nivolumab in clinical trials and clinical practice.
Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2−/− mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2−/− mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2−/− mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2−/− mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2−/− were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2−/− phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions.
Background: Rare Diseases (RDs) are difficult to diagnose. Clinical Decision Support Systems (CDSS) could support the diagnosis for RDs. The Medical Informatics in Research and Medicine (MIRACUM) consortium developed a CDSS for RDs based on distributed clinical data from eight German university hospitals. To support the diagnosis for difficult patient cases, the CDSS uses data from the different hospitals to perform a patient similarity analysis to obtain an indication of a diagnosis. To optimize our CDSS, we conducted a qualitative study to investigate usability and functionality of our designed CDSS. Methods: We performed a Thinking Aloud Test (TA-Test) with RDs experts working in Rare Diseases Centers (RDCs) at MIRACUM locations which are specialized in diagnosis and treatment of RDs. An instruction sheet with tasks was prepared that the participants should perform with the CDSS during the study. The TA-Test was recorded on audio and video, whereas the resulting transcripts were analysed with a qualitative content analysis, as a ruled-guided fixed procedure to analyse text-based data. Furthermore, a questionnaire was handed out at the end of the study including the System Usability Scale (SUS). Results: A total of eight experts from eight MIRACUM locations with an established RDC were included in the study. Results indicate that more detailed information about patients, such as descriptive attributes or findings, can help the system perform better. The system was rated positively in terms of functionality, such as functions that enable the user to obtain an overview of similar patients or medical history of a patient. However, there is a lack of transparency in the results of the CDSS patient similarity analysis. The study participants often stated that the system should present the user with an overview of exact symptoms, diagnosis, and other characteristics that define two patients as similar. In the usability section, the CDSS received a score of 73.21 points, which is ranked as good usability. Conclusions: This qualitative study investigated the usability and functionality of a CDSS of RDs. Despite positive feedback about functionality of system, the CDSS still requires some revisions and improvement in transparency of the patient similarity analysis.
Durch körperliche Aktivität oder auch im Rahmen einer Ergometrie (Laufband oder Fahrrad) wird die Muskulatur derart belastet, dass sich die Herz-Kreislauf-Funktion verändert. Hierdurch ist ca. 2 h nach der Belastung der Anstieg der Kreatininkinase (CK) und der Laktatdehydrogenase (LDH) im Blut als Indikator für die Muskelbeanspruchung messbar. Auch der Wert des prostataspezifischen Antigens (PSA), insbesondere bei Männern, ist ein diagnostischer Parameter zur Beurteilung der Prostatafunktion, der bei Belastung der Prostataregion, wie z. B. Rennradfahren, beeinträchtigt werden kann. CK samt Isoenzyme, LDH und PSA können gezielt als Indikatoren für körperliche Belastung eingesetzt werden, insofern eine Aussage zur Vitalität des Patienten formuliert werden soll.
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.
Endokrin inaktives Hypophysenadenom und sekundäre Nebennierenrindeninsuffizienz : ein Fallbericht
(2021)
Das Hypophysenadenom als Ursache einer sekundären Nebennierenrindeninsuffizienz, nur mit isoliertem ACTH-Defizit, ist außergewöhnlich. Ein ACTH-Mangel tritt in der Regel nicht isoliert, sondern zusammen mit dem Ausfall anderer Hypophysenfunktionen auf. Besonders bei Patienten mit Kinderwunsch sollte den Erkrankungen der Hypophyse und der Nebennieren große Aufmerksamkeit geschenkt werden.
Caspase-8 is an aspartate-specific cysteine protease, which is best known for its apoptotic functions. Caspase-8 is placed at central nodes of multiple signal pathways, regulating not only the cell cycle but also the invasive and metastatic cell behavior, the immune cell homeostasis and cytokine production, which are the two major components of the tumor microenvironment (TME). Ovarian cancer often has dysregulated caspase-8 expression, leading to imbalance between its apoptotic and non-apoptotic functions within the tumor and the surrounding milieu. The downregulation of caspase-8 in ovarian cancer seems to be linked to high aggressiveness with chronic inflammation, immunoediting, and immune resistance. Caspase-8 plays therefore an essential role not only in the primary tumor cells but also in the TME by regulating the immune response, B and T lymphocyte activation, and macrophage differentiation and polarization. The switch between M1 and M2 macrophages is possibly associated with changes in the caspase-8 expression. In this review, we are discussing the non-apoptotic functions of caspase-8, highlighting this protein as a modulator of the immune response and the cytokine composition in the TME. Considering the low survival rate among ovarian cancer patients, it is urgently necessary to develop new therapeutic strategies to optimize the response to the standard treatment. The TME is highly heterogenous and provides a variety of opportunities for new drug targets. Given the variety of roles of caspase-8 in the TME, we should focus on this protein in the development of new therapeutic strategies against the TME of ovarian cancer.
Background: Cerebral radiation injury, including subacute radiation reactions and later stage radiation necrosis, is a severe side effect of brain tumor radiotherapy. A protocol of four infusions of the monoclonal antibody bevacizumab has been shown to be a highly effective treatment. However, bevacizumab is costly and can cause severe complications including thrombosis, bleeding and gastrointestinal perforations.
Methods: We performed a retrospective analysis of patients treated in our clinic for cerebral radiation injury who received only a singular treatment with bevacizumab. Single-shot was defined as a singular administration of bevacizumab without a second administration during an interval of at least 6 weeks.
Results: We identified 11 patients who had received a singular administration of bevacizumab to treat cerebral radiation injury. Prior radiation had been administered to treat gliomas (ten patients) or breast cancer brain metastases (one patient). 9 of 10 patients with available MRIs showed a marked reduction of edema at first follow-up. Discontinuation of Dexamethasone was possible in 6 patients and a significant dose reduction could be achieved in all other patients. One patient developed pulmonary artery embolism 2 months after bevacizumab administration. The median time to treatment failure of any cause was 3 months.
Conclusions: Single-shot bevacizumab therefore has meaningful activity in cerebral radiation injury, but durable control is rarely achieved. In patients where a complete protocol of four infusions with bevacizumab is not feasible due to medical contraindications or lack of reimbursement, single-shot bevacizumab treatment may be considered.
Die Multiple Sklerose (MS) ist die häufigste nicht-traumatische, autoimmun-vermittelte Erkrankung des zentralen Nervensystems (ZNS), welche vor allem bei jüngeren Patienten mit Invalidisierung und anhaltenden neurologischen Defiziten einhergehen kann.
Im Rahmen eines optimalen Therapiekonzepts wurden deshalb immer neuere und potentere Medikamente eingeführt. Mit den Sphingosin-1-Phosphat-Rezeptor-1 (S1P1) -Agonisten Fingolimod und Siponimod sind seit mehreren Jahren Medikamente auf dem Markt deren Wirksamkeit bewiesen, jedoch die genauen Wirkprinzipien noch nicht vollends verstanden sind. Angenommen wurde bisher eine Lymphozytendepletion aufgrund einer Hemmung der Lymphozyteninfiltation ins ZNS über den ubiquitär exprimierten, G-protein gekoppelten S1P1-Rezeptor. Neben Wirksamkeiten im Bereich des Immunsystems spielt der S1P1-Rezeptor und sein natürliches Substrat, das S1P, in vielen essenziellen Bereichen eine entscheidende Rolle, unter anderem in der Ausbildung und Reifung des vaskulären Systems in der Embryogenese.
Die genaue Untersuchung des S1P1-Signalwegs in-vivo gestaltete sich deshalb erschwert, da S1P1-Knock-Out-Mäuse einen letalen Phänotyp ausbilden. Jedoch deuten immer mehr Untersuchungen auch auf eine direkte S1P1-Rezeptor-vermittelte Wirksamkeit von Fingolimod auf Zellen des ZNS hin, somit eine Wirkung über die bisher bekannte Lymphozytenaffektion hinaus. Eine genaue Darstellung der im ZNS-beteiligten Zellen und ihrer S1P1-Aktivität gelang bisher auf zellulärer Ebene nicht.
Mit dem in dieser Arbeit genutzten Mausmodell der genmodifizierten S1P1-Signaling-Maus sollte erstmals eine lokoregionale und zelluläre Untersuchung der am S1P1-Signalweg beteiligten Zellen im Rahmen von physiologischen und experimentellen autoimmunen Enzephalomyelitis (EAE)-Bedingungen im ZNS erfolgen. Hierbei entspricht die EAE weitgehend einem tierexperimentellen Korrelat der menschlichen MS. Bei Aktivierung eines S1P1-Rezeptors bei der S1P1-Signaling-Maus erfolgt durch eine gekoppelte Signalkaskade eine konsekutive Expression eines Histonproteins, welches an ein grün-fluoreszierendes Protein gekoppelt ist. Es resultiert eine grüne Fluoreszenz des Zellkerns der betroffenen Zelle. Bei der Kontroll-Maus findet sich keine Kopplung zwischen Rezeptor und im Zellkern befindlicher Proteine.
Hierbei konnte mit Hilfe von Immunhistochemie sowie der quantitativen Methode der Durchflusszytometrie ein S1P1-Signaling in peripheren Organen wie beispielweise der im Rahmen der MS bedeutsamen Milz nachgewiesen werden. Dadurch eröffnen sich Einblicke in Migrationsverhalten und Zusammensetzung der Lymphozyten-Subtypen und deren S1P1-Signaling im Rahmen von physiologischen Bedingungen und unter EAE-Bedingungen.
Die Darstellung des S1P1-Signalings im ZNS, als Hauptmanifestationsort der MS, gelang unter Zuhilfenahme der EAE mit dem genmodifizierten Mausmodell jedoch nicht. Da sich keine Unterschiede in der GFP-Expression zwischen der Signaling-Maus und der heterozygoten Kontroll-Maus zeigen, sind keinerlei Rückschlüsse auf ein echtes S1P1-Signaling möglich. Es zeigen sich zwar deutliche Expressionsunterschiede des GFP im Vergleich erkrankter und gesunder Versuchstiere, Rückschlüsse auf eine echte S1P1-Aktivität konnten jedoch nicht getroffen werden.
Zusammenfassend eignet sich das hier genutzte Mausmodell der genmodifizierten S1P1-Maus zur Untersuchung peripherer Organe und ihrem S1P1-Signaling, z.B. zur Untersuchung kardiovaskulärer Fragestellungen oder zur dezidierteren Veranschaulichung peripher lymphatischer Prozesse.
Zur Untersuchung ZNS-eigener Zellen sowie zur Beantwortung der Frage, ob und wie sie über den S1P1-Rezeptor agieren, bedarf es jedoch noch der Entwicklung eines geeigneteren Tiermodells.
Die bereits erprobte Möglichkeit der Biolumineszenz zeigte in vorherigen Untersuchungen zwar eine S1P1-Aktivität in-vivo, jedoch sind hier keinerlei Untersuchungen auf zellulärer Basis möglich, sodass mit dem aktuellen Stand der Forschung ein direkter Nachweis der S1P1-Aktivität auf zellulärer Ebene im ZNS nicht möglich ist.
Ziel: Obwohl es eine Fülle an Literatur zur Messung der Jodaufnahme mittels Dual-Energy-CT bei unterschiedlichen Pathologien gibt, wurden bisher noch keine zuverlässigen physiologischen Referenzwerte für diese Messtechnik bestimmt. Aus diesem Grund wurde die Jodaufnahme von morphologisch gesunden abdominellen Organen sowie Organen des Beckens in einer großen Studienkohorte untersucht.
Material und Methoden: Aufeinanderfolgende portalvenöse abdominelle DECT-Aufnahmen wurden überprüft und morphologisch gesunde Untersuchungsunterlagen wurden eingeschlossen (n=599; weiß/asiatisch=574, durchschnittliches Alter=58 ± 16,6Jahre; 263w/ 336m). ROI-Messungen wurden in den folgenden anatomischen Regionen durchgeführt (Anzahl der ROIs): Leber (9), Pankreas (3), Milz (3), Nebenniere (2), Nieren (6), Prostata (4), Uterus (2), Blasenwand (1) und Lymphknoten (3). Die Jodaufnahme wurde zwischen unterschiedlichen Organen verglichen und eine Subgruppenanalyse fand statt (jung vs alt/ männlich vs weiblich/niedriger BMI vs. hoher BMI).
Ergebnisse: Die gesamte Jodaufnahme war wie folgt (mg/ml): Leber=1,96 ± 0,59, Pankreas=2,07 ± 0,58, Milz=2,45 ± 0,66, Nebenniere=1,61 ± 0,43, Nieren=6,1 ± 1,32, Prostata=1,1 ± 0,53, Uterus=1,01 ± 0,68, Blasenwand=0,69 ± 0,26 und Lymphknoten=0,71 ± 0,28.
Bei Frauen kommt es zu einer höheren Jodaufnahme in der Leber (2,12 ± 0,54 vs 1,84 ± 0,43 mg/ml), Pankreas (2,27 ± 0,54 vs 1,91±0,46 mg/ml), Milz (2,7 ± 0,64 vs 2,3 ± 0,51 mg/ml), Nebenniere (1,72 ± 0,47 vs 1,52 ± 0,39 mg/ml) und Niere (6,6 ± 1,31 vs 5,65 ± 1,1 mg/ml) als bei Männern (P < 0,001). In älteren Patienten nimmt die Jodaufnahme in der Leber (1,80 ± 0,45 vs 2,04 ± 0,52 mg/ml), im Pankreas (1,87 ± 0,46 vs. 2,21 ± 0,52 mg/ml) und der Milz (2,21 ± 0,46 vs 2,64 ± 0,65 mg/ml) verglichen mit jüngeren Studienteilnehmern zu (P ≤ 0.040). Einzig im Uterus präsentierten sich niedrigere Werte in älteren Frauen (01,31 ± 0,72 vs 0,75 ± 0,46 mg/ml, P < 0,001). Bei Patienten mit einem hohen BMI kommt es in der Leber (2,32 ± 0,54 vs. 1,84 ± 0,45 mg/ml), im Pankreas (2,54 ± 0,67 vs. 1,95 ± 0,48 mg/ml), in der Milz (2,85 ± 0,66 vs. 2,32 ± 0,55 mg/ml) und in den Nebennieren (1,79 ± 0,38 vs. 1,56 ±0,44 mg/ml) zu einer signifikanten Abnahme der Jodaufnahme (P < 0,001).
Fazit: Die physiologische Jodaufnahme zeigt alters-, geschlechts- und BMI-abhängige Unterschiede für Leber, Pankreas und Milz. Pankreas und Nebennieren zeigen einen höheren Jod Durchfluss in Frauen. Während die Perfusion des Prostataparenchyms sich unverändert über die gesamte Altersspanne zeigt, nimmt die Jodaufnahme des Uterus bei Frauen im Laufe des Lebens ab. Lymphknoten als auch die Blase zeigen sich unbeeinflusst von demographischen Faktoren sowie von der Veränderung des BMI.
Klinische Relevanz: Wir definierten physiologische Referenzwerte für den statischen Durchfluss der abdominellen Organe wie angegeben mittels DECT-Jodaufnahme-Messungen in einer großen Studienkohorte und beschrieben die zusammenhängenden Unterschiede in Bezug auf Alter und Geschlecht. Dies soll die zuverlässige klinische Anwendung erleichtern und zu einer potentiellen Implementierung in zukünftige Richtlinien führen.
Trotz vielfältiger Ansätze, das Trauma der empfindlichen Innenohrstrukturen während des Einsetzens der Elektrode eines Cochlea-Implantats (CI) zu reduzieren, wird das postoperative Auftreten von Schwindel immer noch als eine der häufigsten Komplikationen in der aktuellen Literatur beschrieben.
Ziel der vorliegenden prospektiven Studie war es, die Häufigkeit sowie die Ursache von postoperativem Schwindel im Zusammenhang mit einer CI-Operation zu ermitteln. Darüber hinaus wurden der zeitliche Verlauf des postoperativen Schwindels, sowie der Einfluss des Elektrodendesigns und des Einführungswinkels auf das Auftreten von Schwindel untersucht. Die Auswahl der Patienten und die Untersuchung erfolgte an der Klinik für Hals-Nasen-Ohrenheilkunde der Johann Wolfgang Goethe-Universität Frankfurt am Main.
29 Erwachsene wurden rekrutiert und erhielten ein unilaterales CI unter Verwendung eines von sechs verschiedenen Elektrodenträgern, die in folgende Kategorien eingeteilt wurden: "strukturerhaltend" (I), "potentiell strukturerhaltend" (II) und "nicht strukturerhaltend" (III).
Der subjektive Schwindel wurde anhand von Fragebögen, die im Anhang zu finden sind, zu fünf verschiedenen Zeitpunkten vor bis zu sechs Monaten nach der Operation beurteilt. Die Teilnehmer wurden in vier Gruppen eingeteilt, abhängig vom Zeitpunkt des Auftretens von Schwindel vor und nach der Operation. Präoperativ und sechs Monate postoperativ wurde eine umfassende Schwindeldiagnostik, bestehend aus Romberg-Test, Unterberger-Test, Test der subjektiven visuellen Vertikalen, optokinetischem Test, Video-Kopf-Impuls-Test (vHIT) und kalorischem Spültest durchgeführt. Zusätzlich wurde der Insertionswinkel (IA) bestimmt und die Patienten wurden in zwei Gruppen (<430°; ≥430°) eingeteilt.
Ergebnis der Studie war, dass 45,8% der Teilnehmer neuen Schwindel nach der Implantation erlebten. Basierend auf den Fragebogendaten wurde bei 72,7% ein vestibulärer Ursprung vermutet. Es zeigte sich keine signifikante Korrelation von auffälligen Ergebnissen der durchgeführten Tests mit dem Auftreten von subjektivem Schwindel.
In der Gruppe 1 (ohne präoperativen Schwindel und mit postoperativem Schwindel) zeigten 18% der Patienten auffällige Ergebnisse in der quantitativen Analyse des kalorischen Spültests, obwohl in dieser Gruppe Elektroden der Kategorie I oder II implantiert wurden, die zur Strukturerhaltung der Cochlea geeignet sind. Der durchschnittliche IA betrug 404° für die Gesamtgruppe und 409° für Gruppe 1. Es gab keine statistisch signifikante Korrelation zwischen IA und wahrgenommenem Schwindel.
Obwohl Schwindel nach CI-Operation eine häufige Komplikation zu sein scheint, konnte die hier verwendete Testbatterie die Symptome nicht objektivieren. Ebenso wurde keine Korrelation zwischen Elektrodendesign, Einführungswinkel oder vestibulären Testergebnissen und selbstberichtetem Schwindel gefunden. Weitere Studien sollten klären, ob dies an einer multifaktoriellen Ursache des Schwindels oder an der mangelnden Sensitivität der derzeit verwendeten Tests liegt. Der Nachweis einer verringerten Schwindelwahrscheinlichkeit bei Verwendung wenig traumatischer Elektrodenträger gelang nicht, ebenso wenig der Nachweis eines Einflusses der verwendeten Einstecktiefe.
Insgesamt reiht sich dieses Manuskript in eine überschaubare Anzahl von Arbeiten ein, die die Schwierigkeit für Kliniker beschreiben, eine nachweisbare Ursache für Schwindelsymptome nach Cochlea-Implantation sicher zu definieren.
Hintergrund: Die ASA-Klassifikation wurde 1941 von den Anästhesisten Saklad, Rovenstine und Taylor gegründet und seither mehrfach überarbeitet, zuletzt 2014 und 2020 durch Hinzunahme von Beispieldiagnosen durch die ASA. Sie bietet eine prägnante Zusammenfassung des präoperativen Gesundheitsstatus des Patienten anhand von sechs Klassen. Je schwerer die Vorerkrankungen eines Patienten sind, desto höher die Klasse und desto mehr anästhesiologische Aufmerksamkeit sollte dem Patienten prä-, intra- und postoperativ gewidmet werden. Ziel der Untersuchung war es, die Reproduzierbarkeit jenes Klassifizierungssystems anhand der Interrater-Reliabilität zu bestimmen sowie ihre prädiktive Validität zu überprüfen.
Methoden: In die vorliegende Studie wurden 684 allgemeinchirurgische Patienten >18 Jahre (Frauen 43%) eingeschlossen. Es erfolgte die Klassifizierung sämtlicher Patienten durch drei Gruppen: Chirurgen, Anästhesisten sowie ein Board bestehend aus einer Oberärztin der Chirurgie und einem Oberarzt der Anästhesie. Die Interrater-Reliabilität zwischen allen drei Rater-Gruppen sowie zwischen je zwei der Gruppen wurde mittels Kappa-Statistik (Fleiss‘ Kappa) berechnet. Weiterhin wurde in einer Subgruppenanalyse die Interrater-Reliabilität bei Bewertung onkologischer Patienten und Patienten ohne Malignom, bei multimorbiden sowie bei geriatrischen Patienten untersucht. Ferner wurde der Einfluss der Arbeitserfahrung (Assistenzarzt vs. Facharzt) auf den Grad der Übereinstimmung untersucht. Zur Überprüfung der prädiktiven Validität der Klassifikation wurde eine Korrelationsanalyse nach Spearman zwischen ASA-Status und Komplikationsklassifikation nach Clavien-Dindo (CDC) durchgeführt.
Ergebnisse und Beurteilung: Die Interrater-Reliabilität zwischen allen Ratern (κ = 0,28, CI 0,21-0,34, p < 0,0001) und zwischen jeweils zwei der Rater-Gruppen ergab eine ausreichende Übereinstimmung (Chirurgen vs. Anästhesisten: κ = 0,25, CI 0,19-0,30, Chirurgen vs. ASA-Board: κ = 0,21, CI 0,15-0,27 und Anästhesisten vs. ASA-Board: κ = 0,36, CI 0,30-0,43, jeweils mit p < 0,0001). Der höchste Grad an Übereinstimmung war zwischen den Anästhesisten und dem ASA-Board zu verzeichnen.
Die Subgruppenanalyse im Vergleich onkologischer und nicht-onkologischer Patienten erbrachte einen niedrigeren Grad an Übereinstimmung in der Gruppe der Patienten mit Malignom (κ = 0,18, CI 0,10-0,26 vs. κ = 0,38, CI 0,29-0,47, jeweils mit p<0,0001). Der Faktor Multimorbidität (κ = 0,19, CI 0,1-0,28, p = 0,00004) sowie ein hohes Patientenalter ≥ 75 Jahre (κ = 0,19, CI 0,03-0,34, p = 0,02) gingen ebenfalls mit einer geringeren Übereinstimmung einher.
Mit steigender Berufserfahrung zeigte sich in der Gruppe der Chirurgen eine höhere Übereinstimmung zwischen den Ratern und dem ASA-Board (Assistenzärzte κ = 0,20, CI 0,13-0,26, p < 0,0001, Fachärzte κ = 0,32, CI 0,12-0,51, p = 0,002), in der Gruppe der Anästhesisten zeigte sich kein nennenswerter Unterschied zwischen jungen und erfahrenen Ärzten (Assistenzärzte κ = 0,37, CI 0,29-0,44, Fachärzte κ = 0,35, CI 0,24-0,46, jeweils p < 0,0001). Es zeigte sich in der hiesigen Arbeit eine Korrelation zwischen ASA-Status und CDC (ϱ = 0,11, CI 0,04-0,19, p = 0,003).
Schlussfolgerung: Vorteil der ASA-Klassifikation ist ihre einfache Erhebung ohne die Notwendigkeit aufwändiger Diagnostik. Sie erweist sich als valides Tool zur Erhebung des präoperativen Gesundheitsstatus der Patienten und korreliert mit den postoperativen Komplikationen. Ein wesentlicher Nachteil ist ihre schwache Reproduzierbarkeit aufgrund ihrer Subjektivität und Untersucherabhängigkeit. Faktoren wie onkologische Begleiterkrankungen, Multimorbidität sowie ein hohes Patientenalter sind schwierig zu kategorisieren und führen zur Verunsicherung der Bewerter. Sie sollten im Beispielkatalog der ASA aufgeführt werden, was die Reproduzierbarkeit erleichtern könnte. Wie auch bereits durch einschlägige Vorstudien aufgezeigt wurde, wäre grundsätzlich eine Überarbeitung der ASA-Klassifikation wünschenswert.
In haploidentical stem cell transplantation (SCT), achieving a balance between graft versus host disease (GvHD), graft versus leukemia effect (GvL) and bridging the vulnerable phase of aplasia against viral infections is still a challenge. Graft preparation strategies attempt to achieve this balance by removing and retaining harmful and helpful cells. At this point it is known that T cell subpopulations hold different properties concerning GvHD promotion and immunocompetence towards pathogens. CD45RA+ naïve T cells show the greatest, while CD45RO+ memory T cells show less alloreactive potential but provide immunocompetence. CD45RA depletion is a promising new approach to graft processing that potentially combines GvHD prevention, GvL promotion and transfer of immunological competence by removing potentially harmful CD45RA+ naïve T cells and retaining CD45RO+ memory cells. This work focused on manufacturing CD45RA-depleted grafts within a one- or two-step approach, as well as a feasibility assessment of the process and the establishment of a 10-color fluorescence activated cell sorting (FACS) measurement panel for clinical-scale graft generation. CD45RA depletions were conducted from granulocyte-colony stimulated factor (G-CSF) mobilized peripheral blood stem cells (PBSC) applying two different strategies, direct depletion of CD45RA+ cells (one-step approach), or depletion following preceding CD34 selection. A 10-color FACS measurement panel was established ensuring quality control and enabling preliminary data acquisition on CD45RA co-expression for cell loss estimations. Residual virus-specific T cells after depletion were measured using MHC multimers. It was observed that the depletion antibody occupied the cell binding sites, resulting in insufficient binding of the fluorescent dye for subsequent FACS measurement. Therefore, three FACS antibodies were tested and compared, and CD45RA-PE (clone:2H4) was found to be the best choice for reliable cell detection. To further characterize residual T cells, two homing markers, CD62L and CCR7, were compared, with particular attention paid to the expression of the surface markers after cooling. Both markers were complementary to each other, resulting in the decision to include an additional FACS measuring tube whenever samples are cooled or further T cell characterization is needed. With a median log depletion of -3.9 (one-step) and -3.8 (two-step) data showed equally efficient removal of CD45RA+CD3+ T cells for both approaches. Close to complete B cell removal was obtained without additional reagent use. However, also close to complete NK cell loss occurred due to high CD45RA co-expression. Stem cells recovered at a median of 52% (range: 49.7 - 67.2%) after one-step CD45RA depletion. CD45RO+ memory T cells recovery was statistically not differing between both approaches. Virus-specific T cells were detectable after depletion, suggesting that virus-specific immunocompetence is transferable. In conclusion, CD45RA depletions are equally feasible for both approaches when performed from fresh, non-cryopreserved starting products, show reliable reduction of CD45RA and B cells, but also result in co-depletion of NK cells. Stem cell recovery and NK cell losses must be considered carefully especially regarding overcoming HLA barriers, pathogen protection during aplasia, early engraftment an GvL. Therefore, a combination of CD45RA-depleted products with already established other processing methods to ensure sufficient stem and NK cells is desirable to allow high clinical flexibility.
GATA2 deficiency is a heterogeneous multi-system disorder characterized by a high risk of developing myelodysplastic syndrome (MDS) and myeloid leukemia. We analyzed the outcome of 65 patients reported to the registry of the European Working Group (EWOG) of MDS in childhood carrying a germline GATA2 mutation (GATA2mut) who had undergone hematopoietic stem cell transplantation (HSCT). At 5 years the probability of overall survival and disease-free survival (DFS) was 75% and 70%, respectively. Non-relapse mortality and relapse equally contributed to treatment failure. There was no evidence of increased incidence of graft-versus-host-disease or excessive rates of infections or organ toxicities. Advanced disease and monosomy 7 (−7) were associated with worse outcome. Patients with refractory cytopenia of childhood (RCC) and normal karyotype showed an excellent outcome (DFS 90%) compared to RCC and −7 (DFS 67%). Comparing outcome of GATA2mut with GATA2wt patients, there was no difference in DFS in patients with RCC and normal karyotype. The same was true for patients with −7 across morphological subtypes. We demonstrate that HSCT outcome is independent of GATA2 germline mutations in pediatric MDS suggesting the application of standard MDS algorithms and protocols. Our data support considering HSCT early in the course of GATA2 deficiency in young individuals.
Purpose: Colorectal cancer (CRC) is the second most common cancer in Germany. Around 60,000 people were diagnosed CRC in 2016 in Germany. Since 2019, screening colonoscopies are offered in Germany for men by the age of 50 and for women by the age of 55. It is recently discussed if women should also undergo a screening colonoscopy by the age of 50 and if there are any predictors for getting CRC.
Methods: Colonoscopies of 1553 symptomatic patients younger than 55 years were compared with colonoscopies of 1075 symptomatic patients older than 55 years. We analyzed if there are any significant differences between those two groups in the prevalence of CRC and its precursor lesions or between symptomatic men and women. We evaluated if there is a correlation between abdominal symptoms and the prevalence of CRC.
Results: In 164/1553 symptomatic patients, 194 (12.5%) polyps were detected. In total, six colorectal carcinomas (0.4%) were detected. There were no significant differences between men and women. In symptomatic patients ≥ 55 years, significantly more polyps were found (p<0.0001; 26.6% vs. 12.5%). Totally, 286 polyps (26.6%) were removed in 1075 symptomatic patients older than 55 years. Anorectal bleeding was the only abdominal symptom being a significant indicator for the prevalence of the occurrence of colon and rectum cancer in both groups (p=0.03, OR=2.73 95%-CI [1.11;6.70]), but with only low sensitivity (44%).
Conclusion: Due to no significant differences in men and women, we recommend screening colonoscopies also for women by the age of 50.
Background: Autism spectrum disorder (ASD) is characterized by impaired social communication and interaction, and stereotyped, repetitive behaviour and sensory interests. To date, there is no effective medication that can improve social communication and interaction in ASD, and effect sizes of behaviour-based psychotherapy remain in the low to medium range. Consequently, there is a clear need for new treatment options. ASD is associated with altered activation and connectivity patterns in brain areas which process social information. Transcranial direct current stimulation (tDCS) is a technique that applies a weak electrical current to the brain in order to modulate neural excitability and alter connectivity. Combined with specific cognitive tasks, it allows to facilitate and consolidate the respective training effects. Therefore, application of tDCS in brain areas relevant to social cognition in combination with a specific cognitive training is a promising treatment approach for ASD. Methods: A phase-IIa pilot randomized, double-blind, sham-controlled, parallel-group clinical study is presented, which aims at investigating if 10 days of 20-min multi-channel tDCS stimulation of the bilateral tempo-parietal junction (TPJ) at 2.0 mA in combination with a computer-based cognitive training on perspective taking, intention and emotion understanding, can improve social cognitive abilities in children and adolescents with ASD. The main objectives are to describe the change in parent-rated social responsiveness from baseline (within 1 week before first stimulation) to post-intervention (within 7 days after last stimulation) and to monitor safety and tolerability of the intervention. Secondary objectives include the evaluation of change in parent-rated social responsiveness at follow-up (4 weeks after end of intervention), change in other ASD core symptoms and psychopathology, social cognitive abilities and neural functioning post-intervention and at follow-up in order to explore underlying neural and cognitive mechanisms. Discussion: If shown, positive results regarding change in parent-rated social cognition and favourable safety and tolerability of the intervention will confirm tDCS as a promising treatment for ASD core-symptoms. This may be a first step in establishing a new and cost-efficient intervention for individuals with ASD.
Individual patient data (IPD) from the CELESTIAL trial (cabozantinib) and population-level data from the REACH-2 trial (ramucirumab) were used. To align with REACH-2, the CELESTIAL population was limited to patients who received first-line sorafenib only and had baseline serum AFP ≥ 400 ng/mL. The IPD from CELESTIAL were weighted to balance the distribution of 11 effect-modifying baseline characteristics with those of REACH-2. Overall survival (OS; primary endpoint) and progression-free survival (PFS) were compared for the CELESTIAL (matching-adjusted) and REACH-2 populations using weighted Kaplan-Meier (KM) curves and parametric (OS, Weibull; PFS, log-logistic) modeling. Rates of treatment-related adverse events (TRAEs) and TRAE-related discontinuations were also compared.
Pathogenic genetic variants in the ATP7B gene cause Wilson disease, a recessive disorder of copper metabolism showing a significant variability in clinical phenotype. Promoter mutations have been rarely reported, and controversial data exist on the site of transcription initiation (the core promoter). We quantitatively investigated transcription initiation and found it to be located in immediate proximity of the translational start. The effects human single-nucleotide alterations of conserved bases in the core promoter on transcriptional activity were moderate, explaining why clearly pathogenic mutations within the core promoter have not been reported. Furthermore, the core promoter contains two frequent polymorphisms (rs148013251 and rs2277448) that could contribute to phenotypical variability in Wilson disease patients with incompletely inactivating mutations. However, neither polymorphism significantly modulated ATP7B expression in vitro, nor were copper household parameters in healthy probands affected. In summary, the investigations allowed to determine the biologically relevant site of ATP7B transcription initiation and demonstrated that genetic variations in this site, although being the focus of transcriptional activity, do not contribute significantly to Wilson disease pathogenesis.
'Skelettfund' im Keller
(2021)
Bei der Identifizierung einer unbekannten, stark verwesten Leiche oder eines Skelettes ohne Hinweise auf die Identität durch die Auffindesituation spielt die Erstellung des sog. biologischen Profils eine entscheidende Rolle. Vorgestellt wird ein Leichenfund in einem mehr oder weniger frei zugänglichen Kellerabteil eines Mehrfamilienhauses. Der Leichnam war weitgehend skelettiert, das Skelett jedoch durch mumifizierte Weichteilreste noch nahezu vollständig zusammengehalten. Bei den Hinweisen auf die Identität ergaben sich insbesondere in der Altersschätzung scheinbare Widersprüche, die jedoch zufällig eine relativ genau zutreffende Schätzung lieferten. Die Überreste konnten mittels forensischer DNA-Analyse einer seit 4 Jahren vermissten 49-Jährigen zugeordnet werden. Als Todesursache wurde ein Kältetod diskutiert.
Der Fall wies eine außergewöhnliche Auffindesituation auf, die an Bilder von „Skelettfunden“ in Kriminalverfilmungen erinnerte. Derartige Befunde dürften jedoch in der Realität wohl nur sehr selten vorkommen. Darüber hinaus werden die Wichtigkeit und die Probleme der forensisch-osteologischen Untersuchungen bei der Identifizierung eines stark verwesten, unbekannten Leichnams demonstriert.
Die Bestimmung von Procalcitonin im Serum stellt einen wesentlichen Bestandteil der Diagnostik, Verlaufskontrolle und Therapieüberwachung septischer Infektionen dar. Das Procalcitonin ist ein Marker, der in der Diagnostik von Infektionen, schweren Entzündungen und Sepsis wertvolle und therapieentscheidende Aussagen ermöglicht. Er sollte allerdings nicht zum Screening asymptomatischer Personen im Rahmen arbeitsmedizinischer Vorsorgen oder sog. Manager-Untersuchungen genutzt werden, sondern lediglich beim klinischen Verdacht einer vorliegenden systemischen Infektion bei entsprechenden Symptomen.
More than 97 percent of the transcribed RNA in mammalian cells is not coding for proteins. Among these are micro RNAs (miRs), transfer RNAs (tRNA) as well as ribosomal RNAs (rRNA) but also long non-coding RNAs (lncRNAs). This RNA class is only defined by its sequence length of more than 200 nucleotides and its lack of protein coding potential. The human genome encodes for more than 18.000 lncRNAs which contribute to gene expression control. Here, we discuss the function of these lncRNAs and how they modulate the angiogenic process of vessel growth.
Retrospektive Analyse der RSV Bronchiolitis bei hospitalisierten Kindern im ersten Lebensjahr
(2021)
Einleitung: RSV ist der häufigste Erreger einer Bronchiolitis bei Säuglingen und Kleinkindern. Besonders oft betroffen sind Säuglinge in den ersten vier Lebensmonaten. RSV-Infektionen führen saisonal gehäuft weltweit zu zahlreichen Hospitalisierungen. Dennoch gibt es in Deutschland keine aktuellen Daten über die Krankheitslast.
Methoden: Es erfolgte eine retrospektive Analyse der elektronischen Krankenakten an der Klinik für Kinder- und Jugendmedizin des Universitätsklinikums Frankfurt am Main. Erfasst wurden alle von 2007 bis 2017 stationär aufgenommenen Patienten mit positivem RSV-Nachweis. Die Daten wurden aus dem elektronischen Patientenverwaltungsprogramm ORBIS in Exceltabellen übertragen.
Ergebnisse: Insgesamt wurden in den letzten zehn Jahren 800 Kinder mit RSV-Infektion stationär aufgenommen. Die Mehrzahl der Kinder befand sich in den ersten 12 Lebensmonaten, n = 564 (70,5 %) und der Hauptteil bestand aus Patienten in den ersten vier Lebensmonaten, n = 341 (60,4 %). In diesem Patientenkollektiv stand bei 289 Kindern eine elektronische Krankenakte zur Datenauswertung zur Verfügung. Von den 289 Patienten handelte es sich bei 35 (12,1 %) um FG und 25 Patienten mussten intensivmedizinisch betreut werden. Von den intensivmedizinisch betreuten Kindern waren 15 Patienten (60 %) FG. Klassischerweise unterschied sich das Gewicht der FG von dem der RG (Frühgeborene: Median 3,43 kg vs Reifgeborene: 5 kg). Unter den FG zeigte sich folgende Verteilung nach Schwangerschaftswochen bei insgesamt 289 analysierten Patienten: < 28. SSW (extremely preterm): n = 4 (1,38 %) der Patienten; < 32. SSW (very preterm): n = 8 (2,76 %) der Patienten und 32 + 1 bis 36 + 6 SSW (late preterms): n = 23 (7,95 %) der Patienten. Die geringe Anzahl an RSV-Infektionen bei FG < 28. SSW hängt vermutlich mit einer erfolgreichen Palivizumab Prophylaxe zusammen. Dafür spricht auch, dass sich der Anteil der späten FG (late 43 preterms), die keine Prophylaxe erhielten, in unserer Untersuchung ähnlich wie in frühere Studien darstellte.
Von den 254 RG mussten 10 (3,9 %) Kinder auf Intensivstation (Schwergrad 3 der WHO-Klassifikation), während 102 (40,2 %) Patienten eine Bronchiolitis (Grad 2 der WHO-Klassifikation) aufwiesen und 142 (55,9 %) Patienten hatten eine RSV-Infektion mit Sättigungswerten > 95 %.
Schlussfolgerung: Die Krankheitslast der RSV-Bronchiolitis in Deutschland ist sehr hoch, vor allem in den ersten vier Lebensmonaten. Typischerweise ging die RSV-Saison von Dezember bis März, sodass eine Immunprophylaxe bei Risikokindern in dieser Zeit verabreicht werden sollte.
Objective: Trauma is the most common cause of death among young adults. Alcohol intoxication plays a significant role as a cause of accidents and as a potent immunomodulator of the post-traumatic response to tissue injury. Polytraumatized patients are frequently at risk to developing infectious complications, which may be aggravated by alcohol-induced immunosuppression. Systemic levels of integral proteins of the gastrointestinal tract such as syndecan-1 or intestinal fatty acid binding proteins (FABP-I) reflect the intestinal barrier function. The exact impact of acute alcohol intoxication on the barrier function and endotoxin bioactivity have not been clarified yet. Methods: 22 healthy volunteers received a precisely defined amount of alcohol (whiskey–cola) every 20 min over a period of 4 h to reach the calculated blood alcohol concentration (BAC) of 1‰. Blood samples were taken before alcohol drinking as a control, and after 2, 4, 6, 24 and 48 h after beginning with alcohol consumption. In addition, urine samples were collected. Intestinal permeability was determined by serum and urine values of FABP-I, syndecan-1, and soluble (s)CD14 as a marker for the endotoxin translocation via the intestinal barrier by ELISA. BAC was determined. Results: Systemic FABP-I was significantly reduced 2 h after the onset of alcohol drinking, and remained decreased after 4 h. However, at 6 h, FABP-I significantly elevated compared to previous measurements as well as to controls (p < 0.05). Systemic sCD14 was significantly elevated after 6, 24 and 48 h after the onset of alcohol consumption (p < 0.05). Systemic FABP-I at 2 h after drinking significantly correlated with the sCD14 concentration after 24 h indicating an enhanced systemic LPS bioactivity. Women showed significantly lower levels of syndecan-1 in serum and urine and urine for all time points until 6 h and lower FABP-I in the serum after 2 h. Conclusions: Even relative low amounts of alcohol affect the immune system of healthy volunteers, although these changes appear minor in women. A potential damage to the intestinal barrier and presumed enhanced systemic endotoxin bioactivity after acute alcohol consumption is proposed, which represents a continuous immunological challenge for the organism and should be considered for the following days after drinking.
Depletion of the enzyme cofactor, tetrahydrobiopterin (BH4), in T-cells was shown to prevent their proliferation upon receptor stimulation in models of allergic inflammation in mice, suggesting that BH4 drives autoimmunity. Hence, the clinically available BH4 drug (sapropterin) might increase the risk of autoimmune diseases. The present study assessed the implications for multiple sclerosis (MS) as an exemplary CNS autoimmune disease. Plasma levels of biopterin were persistently low in MS patients and tended to be lower with high Expanded Disability Status Scale (EDSS). Instead, the bypass product, neopterin, was increased. The deregulation suggested that BH4 replenishment might further drive the immune response or beneficially restore the BH4 balances. To answer this question, mice were treated with sapropterin in immunization-evoked autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Sapropterin-treated mice had higher EAE disease scores associated with higher numbers of T-cells infiltrating the spinal cord, but normal T-cell subpopulations in spleen and blood. Mechanistically, sapropterin treatment was associated with increased plasma levels of long-chain ceramides and low levels of the poly-unsaturated fatty acid, linolenic acid (FA18:3). These lipid changes are known to contribute to disruptions of the blood–brain barrier in EAE mice. Indeed, RNA data analyses revealed upregulations of genes involved in ceramide synthesis in brain endothelial cells of EAE mice (LASS6/CERS6, LASS3/CERS3, UGCG, ELOVL6, and ELOVL4). The results support the view that BH4 fortifies autoimmune CNS disease, mechanistically involving lipid deregulations that are known to contribute to the EAE pathology.
Background: This prospective randomized trial is designed to compare the performance of conventional transarterial chemoembolization (cTACE) using Lipiodol-only with additional use of degradable starch microspheres (DSM) for hepatocellular carcinoma (HCC) in BCLC-stage-B based on metric tumor response. Methods: Sixty-one patients (44 men; 17 women; range 44–85) with HCC were evaluated in this IRB-approved HIPPA compliant study. The treatment protocol included three TACE-sessions in 4-week intervals, in all cases with Mitomycin C as a chemotherapeutic agent. Multiparametric magnetic resonance imaging (MRI) was performed prior to the first and 4 weeks after the last TACE. Two treatment groups were determined using a randomization sheet: In 30 patients, TACE was performed using Lipiodol only (group 1). In 31 cases Lipiodol was combined with DSMs (group 2). Response according to tumor volume, diameter, mRECIST criteria, and the development of necrotic areas were analyzed and compared using the Mann–Whitney-U, Kruskal–Wallis-H-test, and Spearman-Rho. Survival data were analyzed using the Kaplan–Meier estimator. Results: A mean overall tumor volume reduction of 21.45% (± 62.34%) was observed with an average tumor volume reduction of 19.95% in group 1 vs. 22.95% in group 2 (p = 0.653). Mean diameter reduction was measured with 6.26% (± 34.75%), for group 1 with 11.86% vs. 4.06% in group 2 (p = 0.678). Regarding mRECIST criteria, group 1 versus group 2 showed complete response in 0 versus 3 cases, partial response in 2 versus 7 cases, stable disease in 21 versus 17 cases, and progressive disease in 3 versus 1 cases (p = 0.010). Estimated overall survival was in mean 33.4 months (95% CI 25.5–41.4) for cTACE with Lipiosol plus DSM, and 32.5 months (95% CI 26.6–38.4), for cTACE with Lipiodol-only (p = 0.844), respectively. Conclusions: The additional application of DSM during cTACE showed a significant benefit in tumor response according to mRECIST compared to cTACE with Lipiodol-only. No benefit in survival time was observed.
Hintergrund
In Anbetracht ihres bedeutenden Potenzials zur Verbesserung der medizinischen Versorgung wird Telemedizin weiterhin zu wenig genutzt. Trotz einiger erfolgreicher Pilotprojekte in den vergangenen Jahren ist insbesondere über die Hindernisse der Etablierung und Verstetigung von Telemedizin wenig bekannt. Diese Studie hatte das Ziel, die Einstellung niedergelassener Neurologen hinsichtlich der Nutzung von Telemedizin in der Epileptologie und resultierende Hinderungsgründe zu verstehen. Gleichzeitig werden mögliche Lösungsansätze präsentiert.
Methoden
Mithilfe eines individuell erstellten 14-Item-Fragebogens befragten wir prospektiv alle Neurologen, die zuvor die Teilnahme an einem transregionalen Telemedizinpilotprojekt im Bereich der Epileptologie abgelehnt oder keine Rückmeldung gegeben hatten, zu Gründen für und gegen den generellen Einsatz von bzw. die Teilnahme an Telemedizin.
Ergebnisse
Von 58 kontaktierten Neurologen antworteten 33 (57 %). Die häufigsten Gründe für die fehlende Nutzung der Telemedizin waren ein vermuteter Zeitmangel oder ein vermuteter zu großer organisatorischer Aufwand (49 %). Zudem wurden Bedenken bezüglich der technischen Ausstattung (30 %) und eine Präferenz für alternative Wege der intersektoralen Kommunikation (30 %) angegeben. Befürchtete Probleme in Bezug auf die Kostenerstattung für telemedizinische Leistungen waren für 27 % ein Hindernis. Neurologen in ländlichen Gebieten waren signifikant häufiger bereit, zunächst eine telemedizinische Konsultation anzufordern, bevor sie eine Überweisung ausstellen (p = 0,006).
Schlussfolgerungen
Die flächendeckende Etablierung von Telemedizinstrukturen ist immer noch durch Hindernisse erschwert, die meist im organisatorischen Bereich liegen. Die bestehenden Herausforderungen im Gesundheitswesen in ländlichen Gebieten sind eine besondere Chance für die Implementierung von Telemedizin. Die meisten Probleme der Telemedizin können gelöst werden, sollten aber bereits bei der Konzeptionierung von Projekten mitbedacht werden, um ihre Verstetigung zu erleichtern.
Despite major improvements of the therapy, many B-cell Non-Hodgkin’s lymphoma (B-NHL) entities still have a poor prognosis. New therapeutic options are urgently needed. Therefore this study sets out to investigate oncogenic signalling pathways in the two B-NHL entities mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) in order to define new potential therapeutic targets.
MCL cells overexpress the anti-apoptotic protein BCL-2, thereby they evade apoptosis. With venetoclax, the first-in-class BCL-2 specific inhibitor was approved and achieved good response rates in MCL. However, some cases display intrinsic or acquired resistance to venetoclax. In order to improve the therapy, this study aimed to identify genes which confer sensitivity or resistance towards venetoclax upon their respective knockout. To this end, a genome-wide CRISPR/Cas9-based loss-of-function screen was conducted in the MCL cell line Maver-1. The E3 ubiquitin
ligase MARCH5 was identified as one of the top hits conferring sensitivity
towards venetoclax upon its knockout. This finding was validated in a competitive growth assay including two more MCL cell lines, Jeko-1 and Mino. MARCH5 knockout also sensitised Jeko-1 cells towards venetoclax even though this cell line was insensitive towards venetoclax in its wild-type form. Using BH3 profiling, an increased dependency on BCL-2 of MARCH5-depleted cells confirmed this finding. The sensitisation was found to be based on induction of apoptosis upon MARCH5 knockout and to an even higher extent upon additional treatment of MARCH5-depleted cells with venetoclax. As already described for epithelial cancer entities, the BCL-2 family members MCL-1 and NOXA were upregulated in MCL cell lines upon MARCH5 knockout. This led to the hypothesis that MARCH5 is a potential
regulator of intrinsic apoptosis with NOXA as a key component. A competitive growth assay with MARCH5 and NOXA co-depleted cells revealed a partial reversion of the BCL-2 sensitisation compared to MARCH5 knockout alone. Furthermore, mass spectrometry-based methods were used to gain more insight into other cellular pathways and networks which might be regulated in a MARCH5-dependent manner. In an interactome analysis, proteins which regulate mitochondrial morphology, such as Drp-1 were identified as MARCH5 interactors. Besides this expected finding, interaction between MARCH5 and several members of the BCL-2 family as well as a potential connection between MARCH5 and vesicular trafficking was discovered. As expected, an ubiquitinome analysis of MARCH5-depleted cells revealed decreased levels of MCL-1 and NOXA ubiquitination. Additionally, a potential role of MARCH5 in the ubiquitination of several members of the cell cycle regulatory
pathway was discovered. Based on the broad spectrum of cellular pathways which seem to be regulated in a MARCH5-dependent manner, it was hypothesised that MARCH5 primarily regulates BCL-2 family members which in turn regulate intrinsic apoptosis on the one hand and additionally are involved in the regulation of various other pathways on the other hand.
In summary, this study provides insight into a MARCH5-dependent MCL1-1/NOXA axis in MCL cells and potential implications into related cellular processes.
In addition to the anti-apoptotic pathways described above, B-cell receptor (BCR) signalling is known to provide a pro-survival signal to both normal and malignant B-cells. Targeting the BCR signalling pathway therefore is a promising therapeutic target for B-cell malignancies. In order to gain more insight into the differential modes of BCR signalling of ABC- and GCB-DLBCL cells, genes/proteins which displayed differential essentiality in ABC- and GCB-DLBCL cells were aimed to be defined. Consequently, data sets from a CRISPR/Cas9-based loss-of-function screen
were re-analysed. SASH3 was identified as a gene which was essential for GCB- but not for ABC-DLBCL cells. Since this protein is known to be involved in T-cell receptor (TCR)-signalling, SASH3 was assumed to play a potential role in BCR signalling as well and was therefore investigated in more detail. A competitive growth assay confirmed that SASH3 knockout was toxic exclusively for GCB-DLBCL cell lines. An interactome analysis in ABC- and GCB-DLBCL cells revealed interaction between SASH3 and many components of the proximal BCR signalling pathway as well as several downstream signalling pathways such as the PI3K or the NF-ΚB pathway.
An integration of the interactome with data from the CRISPR/Cas9-based loss-offunction screen revealed differential essentiality of the SASH3-interacting proteins in ABC- and GCB-DLBCL cells. It was hypothesised that SASH3 might regulate PI3K signalling on which GCB- but not ABC-DLBCL cells are known to dependent. Discontinuation of the regulation of PI3K signalling could therefore be exclusively toxic to GCB-DLBCL cells.
Taken together, this study describes a subtype-specific dependency of GCB-DLBCL cells on SASH3. Furthermore, the SASH3 interactome has been investigated in B-cells for the first time, thereby highlighting a potential role in proximal BCR signalling and involvement in specific BCR-related downstream signalling pathways.