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Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Methods: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles. Results: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR. Conclusion: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.
To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification.
Background: While ICF-CY-based models of care are promising avenues for improving participation of children with chronic health conditions, feasible and valid instruments to assess participation as an outcome in routine are still needed. We aimed to validate a German parent-report version of the Child and Adolescent Scale of Participation (CASP) in children with chronic health conditions of different severity.
Methods: Cross-sectional data were collected in 327 children (mean age 7.8 years, 55% boys) from two paediatric centres (n = 112) and one population-based sample (n = 215). Cronbach’s alpha, factor analyses, face validity assessments, correlation analyses, receiver operating characteristics (ROC) curves, and parent-reported health-related quality of life (HRQoL: KINDL) were used to examine internal consistency, test-retest reliability, and capacity to differentiate between disease severity groups. Disease severity was operationalized according to ICD-diagnosis groups and/or parent-reports on health problems, medical and educational support, and medication. A newly developed item "overall perceived participation" was added to the CASP and evaluated.
Results: We found good to excellent content validity, excellent internal consistency, and good-to-excellent test-retest reliability of the instrument. While children with mild disease had a significantly greater extent of participation (higher CASP scores) than children with severe disease, they did not differ from healthy children. Children with mild compared to severe disease much more differed in participation as measured by the CASP compared to the KINDL (area under the ROC curve: 0.92 vs. 0.75). In addition, the item "overall perceived participation" was highly correlated (r = 0.86) with the CASP total score, indicating the potential value of this specific single item. Finally, we provided preliminary reference values for the CASP obtained in a population-based sample of children without chronic health conditions.
Conclusions: The German version of the CASP and the new item are efficient, valid and reliable measures of social participation in childhood. The CASP-measured participation focuses more on attendance than on involvement into social circumstances of everyday life. To detect children with a high burden of disease on everyday life, the CASP may be more accurate than HRQoL instruments such as the KINDL. As outcome measurement, the CASP may facilitate the implementation of patient-centred paediatric health care.
Background: Neonatal manifestation of life-threatening hyperammonemic encephalopathy in urea cycle disorders (UCD) is often misdiagnosed as neonatal sepsis, resulting in significantly delayed start of specific treatment and poor outcome. The major aim of this study was to identify specific initial symptoms or signs to clinically distinguish hyperammonemic encephalopathy in neonates from neonatal sepsis in order to identify affected individuals with UCD and to start metabolic therapy without delay. Furthermore, we evaluated the impact of diagnostic delay, peak plasma ammonium (NH4+) concentration, mode of emergency treatment and transfer to a tertiary referral center on the outcome.
Methods: Detailed information of 17 patients (born between 1994 and 2012) with confirmed diagnosis of UCD and neonatal hyperammonemic encephalopathy were collected from the original medical records.
Results: The initially suspected diagnosis was neonatal sepsis in all patients, but was not confirmed in any of them. Unlike neonatal sepsis and not previously reported blood pressure increased above the 95th percentile in 13 (81%) of UCD patients before emergency treatment was started. Respiratory alkalosis was found in 11 (65%) of UCD patients, and in 14 (81%) plasma NH4+concentrations further increased despite initiation of metabolic therapy.
Conclusion: Detection of high blood pressure could be a valuable parameter for distinguishing neonatal sepsis from neonatal manifestation of UCD. Since high blood pressure is not typical for neonatal sepsis, other reasons such as encephalopathy and especially hyperammonemic encephalopathy (caused by e.g. UCD) should be searched for immediately. However, our result that the majority of newborns with UCD initially present with high blood pressure has to be evaluated in larger patient cohorts.
kurz und kn@pp news : Nr. 46
(2019)
kurz und kn@pp news : Nr. 47
(2019)
Toll-like Rezeptoren (TLRs) spielen als Pathogen-Erkennungsrezeptoren eine wichtige Rolle und vermitteln die angeborene Immunität. Nach Erkennung spezifischer Pathogene lösen sie in der Rezeptor tragenden Zelle eine Entzündungsreaktion aus und es kommt unter anderem zur Aktivierung von Proteinkinasen, des Transkriptionsfaktors NF-κB und zur Sekretion von Zytokinen. Während der TLR4 für die Erkennung von Lipopolysacchariden (LPS) verantwortlich ist, dient der TLR2 unter anderem als Rezeptor für Peptidoglycan, Lipoteichonsäure und Lipoproteine von gram-positiven Bakterien. In dieser Dissertation wurde das Vorkommen der TLR2 und TLR4 in den circumventriculären Organen (CVO), speziell im Subcommissuralorgan (SCO), untersucht. Im Hinblick darauf, dass die circumventriculären Organe durch das Fehlen einer Blut-Hirn-Schranke gekennzeichnet sind, ist das Vorkommen einer Abwehr durch das angeborene Immunsystem im Sinne von TLR2 und TLR4 von besonderem Interesse gewesen. Zur Darstellung der Verteilung der beiden Rezeptoren wurden immunhistochemische Färbungen an Gewebeschnitten von Wistar-Ratten durchgeführt.
Es konnte ein Vorkommen beider Rezeptor-Typen in den circumventriculären Organen und dem Plexus choroideus nachgewiesen werden. Vor allem zeigt sich ein verstärktes Vorkommen von TLRs an Gefäßen und dem fenestrierten Endothel der circumventriculären Organe sowie den umgebenden perivaskulären Räumen. Das SCO zeigte vor allem dort eine starke Tingierung, wo es in Kontakt zu den Ependymzellen des dritten Ventrikels steht. Die Rezeptoren scheinen auf Eventualitäten an prädisponierten Stellen entwickelt zu sein. Dies ermöglicht eine sofortige Abwehrreaktion auch bei raschem Eindringen von Pathogenen. Es wurden kaum immunreaktive Neurone oder Perikaryen gefunden, was auf eine Auseinandersetzung der Pathogene im zentralen Nervensystem (ZNS) mit den Epithelbarrieren spricht. Die frühzeitige Inhibition der Schadenskaskade durch die TLRs bereits an den Gefäßen der CVOs könnte neuroprotektive Bedeutung haben.
Objective: Biologics have an important role in the treatment of juvenile idiopathic arthritis (JIA). Long‐term safety data are limited. Direct comparison of different agents regarding occurrence of adverse events (AEs), especially of rare events, requires large quantities of patient years. In this analysis, long‐term safety with regard to AE of special interest (AESI) was compared between different biologics.
Methods: Patients with nonsystemic JIA were selected from the German BIKER registry. Safety assessments were based on AE reports. Number of AEs, serious AEs, and 25 predefined AESIs, including medically important infection, uveitis, inflammatory bowel disease, cytopenia, hepatic events, anaphylaxis, depression, pregnancy, malignancy, and death, were analyzed. Event rates and relative risks were calculated using AEs reported after first dose through 70 days after last dose.
Results: A total of 3873 patients entered the analysis with 7467 years of exposure to biologics. The most common AESIs were uveitis (n = 231) and medically important infections (n = 101). Cytopenia and elevation of transaminases were more frequent with tocilizumab (risk ratio [RR] 8.0, 95% confidence interval [CI] 4.2‐15, and RR 4.7, 95% CI 1.8‐12.2, respectively). Anaphylactic events were associated with intravenous route of administration. In patients ever exposed to biologics, eight malignancies were reported. Six pregnancies have been documented in patients with tumor necrosis factor inhibitors. No death occurred in this patient cohort during observation.
Conclusion: Surveillance of pharmacotherapy as provided by the BIKER registry is an import approach, especially for long‐term treatment of children. Overall, tolerance was acceptable. Differences between biologics were noted and should be considered in daily patient care.
The quest for new and improved therapies for glioblastoma (GB) has been mostly unsuccessful in more than a decade despite significant efforts. The few exceptions include the optimization of classical alkylating chemotherapy by including lomustine in the first line regimen for GB with a methylated MGMT promoter and tumor treating fields. The GB signaling network has been well-characterized and genetic alterations resulting in activation of receptor tyrosine kinases and especially epidermal growth factor receptor (EGFR) and downstream mammalian target of rapamycin complex 1 (mTORC1) signaling were found in the majority of GBs. ...
Glioblastomas (GBs) frequently display activation of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR). mTOR exists as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). In GBs, mTORC1 inhibitors such as rapamycin have performed poorly in clinical trials, and in vitro protect GB cells from nutrient and oxygen deprivation. Next generation ATP-competitive mTOR inhibitors with affinity for both mTOR complexes have been developed, but data exploring their effects on GB metabolism are scarce. In this study, we compared the ATP-competitive mTORC1/2 inhibitors torin2, INK-128 and NVP-Bez235 to the allosteric mTORC1 inhibitor rapamycin under conditions that mimic the glioma microenvironment. In addition to inhibiting mTORC2 signaling, INK-128 and NVP-Bez235 more effectively blocked mTORC1 signaling and prompted a stronger cell growth inhibition, partly by inducing cell cycle arrest. However, under hypoxic and nutrient-poor conditions mTORC1/2 inhibitors displayed even stronger cytoprotective effects than rapamycin by reducing oxygen and glucose consumption. Thus, therapies that arrest proliferation and inhibit anabolic metabolism must be expected to improve energy homeostasis of tumor cells. These results mandate caution when treating physiologically or therapeutically induced hypoxic GBs with mTOR inhibitors.
The goal of this study was to identify a novel target for antibody-drug conjugate (ADC) development in triple negative breast cancer (TNBC), which has limited treatment options, using gene expression datasets and in vitro siRNA/CRISPR and in vivo functional assays. We analyzed 4467 breast cancers and identified GABRP as top expressed gene in TNBC with low expression in most normal tissues. GABRP protein was localized to cell membrane with broad range of receptors/cell (815–53,714) and expressed by nearly half of breast cancers tissues. GABRP gene knockdown inhibited TNBC cell growth and colony formation in vitro and growth of MDA-MB-468 xenografts in nude mice. Commercially available anti-GABRP antibody (5–100 μg/ml) or de novo generated Fabs (20 μg/ml) inhibited TNBC cell growth in vitro. The same antibody conjugated to mertansine (DM1) also showed significant anticancer activity at nanomolar concentrations. Our results indicate that GABRP is a potential novel therapeutic target for ADC development.
Background and objectives: Preoperative anaemia is an independent risk factor for a higher morbidity and mortality, a longer hospitalization and increased perioperative transfusion rates. Managing preoperative anaemia is the first of three pillars of Patient Blood Management (PBM), a multidisciplinary concept to improve patient safety. While various studies provide medical information on (successful) anaemia treatment pathways, knowledge of organizational details of diagnosis and management of preoperative anaemia across Europe is scarce.
Materials and methods: To gain information on various aspects of preoperative anaemia management including organization, financing, diagnostics and treatment, we conducted a survey (74 questions) in ten hospitals from seven European nations within the PaBloE (Patient Blood Management in Europe) working group covering the year 2016.
Results: Organization and activity in the field of preoperative anaemia management were heterogeneous in the participating hospitals. Almost all hospitals had pathways for managing preoperative anaemia in place, however, only two nations had national guidelines. In six of the ten participating hospitals, preoperative anaemia management was organized by anaesthetists. Diagnostics and treatment focused on iron deficiency anaemia which, in most hospitals, was corrected with intravenous iron.
Conclusion: Implementation and approaches of preoperative anaemia management vary across Europe with a primary focus on treating iron deficiency anaemia. Findings of this survey motivated the hospitals involved to critically evaluate their practice and may also help other hospitals interested in PBM to develop action plans for diagnosis and management of preoperative anaemia.
Einleitung: Ataxia telangiectasia (A-T) ist eine lebenslimitierende autosomal-rezessiv vererbte Systemerkrankung, die durch eine Mutation im ATM Gen hervorgerufen wird. Symptome wie Neurodegeneration, Immundefizienz, Teleangiektasien, Wachstums- und Gedeihstörungen, endokrine Dysfunktionen, erhöhte Strahlensensitivität, sowie Malignomprädisposition sind charakterisierend für die Erkrankung. Des Weiteren zeigen viele Patienten eine progrediente Lebererkrankung, die bis jetzt nur unzureichend untersucht wurde.
Zielsetzung: Untersuchung der laborchemischen und strukturellen Veränderungen im Rahmen der Hepatopathie bei A-T Patienten. Des Weiteren soll der Zusammenhang der Körperzusammensetzung, der Muskelkraft und der Lebensqualität mit der Lebererkrankung analysiert werden.
Methoden: Von November 2016 bis Mai 2018, wurden 31 A-T Patienten in die Studie eingeschlossen. Die Patienten wurden zur Auswertung in zwei Gruppen eingeteilt (21 Patienten ≤ zwölf Jahre, zehn Patienten > zwölf Jahre). Neben der Bestimmung der Laborparameter wurden die Veränderungen der Leber anhand der transienten Elastographie und des FibroMax® erhoben. Die Körperzusammensetzung wurde mit Hilfe der bioelektrischen Impedanzanalyse (BIA) ermittelt, die Muskelkraft anhand des Five-Times-Sit-to-Stand-Tests (FTSST). Zur Erfassung der Lebensqualität wurde der EuroQol-Fragebogen 5Q-5D-5L durchgeführt.
Ergebnisse: Bei der transienten Elastographie zeigte sich bei zwei (10%) jüngeren im Vergleich zu neun (90%) älteren Patienten eine Steatose. Eine Fibrose lag bei fünf (50%) älteren Patienten vor. Die Leberenzyme (AST (37.8 ± 7.9 U/l vs. 49.8 ± 15.2 U/l, p<0,05), ALT (25.1 ± 9.6 U/l vs. 71.6 ± 25.8 U/l, p<0,001), GGT (13.2 ± 4,5 U/l vs. 123.7 ± 99.6 U/l, p<0,0001)), das Alpha-Fetoprotein (AFP) (313.4 ± 267,2 ng/ml vs. 540.8 ± 275.8 ng/ml, p<0,05), der HbA1c (4,8 ± 0,4 % vs. 5,7 ± 0,6 %, p<0,0001) sowie die Triglyceride (66.5 ± 34.3 mg/dl vs. 200.4 ± 98.8 mg/dl, p<0,0001) waren signifikant in der älteren Patientengruppe erhöht. Zusätzlich zeigte sich eine signifikante Korrelation der Steatose und Fibrose mit dem Alter (r=0,82, p<0,0001; r=0,59, p<0,001), der AST (r=0,39, p<0,05; r=0,42, p<0,05), der ALT (r=0,77, p<0,0001; r=0,53, p<0,01), der
GGT (r=0,83, p<0,0001; r=0,67, p<0,0001), dem HbA1c (r=0,59, p<0,01; r=0,63, p<0,001) und den Triglyceriden (r=0,74, p<0,0001; r=0,62, p<0,001). Die transiente Elastographie und der SteatoTest des FibroMax zeigten übereinstimmende Ergebnisse.
Eine Magermasse unterhalb der zehnten Perzentile wiesen elf (52%) jüngere im Gegensatz zu neun (90%) älteren Patienten auf. Auch der Phasenwinkel lag bei neun (43%) jüngeren und acht (80%) älteren Patienten unterhalb der zehnten Perzentile. Die jüngeren Patienten waren beim FTSST signifikant schneller (10,8 ± 6,1s vs. 19,4 ± 5,6s, p < 0,01). Die Auswertung des EuroQol-Fragebogen 5Q-5D-5L zeigte einen signifikanten Unterschied der Einschätzung der Beweglichkeit / Mobilität der Patienten (3 (1-4) vs. 4 (2-5), p<0,05).
Schlussfolgerung: Eine Hepatopathie im Sinne einer nicht-alkoholische Fettlebererkrankung (NAFLD) bzw. nicht-alkoholische Steatohepatitis (NASH) tritt bei fast allen älteren A-T Patienten auf. Charakteristisch hierfür sind erhöhte Leberenzyme und eine Fettleber bis hin zur Leberfibrose und Zirrhose. Oxidativer Stress, Inflammation und ein partielles metabolisches Syndrom in Form einer Dyslipidämie und Dysglykämie tragen zu diesem Prozess bei. Die Lebererkrankung im Rahmen der A-T sollte regelmäßig qualifiziert erfasst werden, um Langzeitfolgen, wie beispielsweise die Entwicklung eines hepatozellulären Karzinoms rechtzeitig zu detektieren. Die transiente Elastographie stellt hierfür eine gut reproduzierbare, nicht invasive Methode dar, mit der bereits frühe Stadien der Lebererkrankung erkannt werden können.
Der VEGF-neutralisierende Antikörper Bevacizumab ist ein wichtiger Bestandteil der modernen Tumortherapie. Auch in der Glioblastom Therapie wird Bevacizumab eingesetzt, da in klinischen Studien eine Verlängerung des progressionsfreien Überlebens beobachtet wurde. Leider entwickeln sich schnell Resistenzen und das Gesamtüberleben konnte durch Bevacizumab in der Erstlinientherapie von Glioblastomen nicht verlängert werden.
Die genaue Wirkungsweise von Bevacizumab und somit auch die Resistenzentwicklung sind nur teilweise bekannt. Es wird vermutet, dass es durch Gefäßveränderungen zu einer Mangelsituation und zu Hypoxie kommt. Einige Studien deuten darauf hin, dass es neben der Wiedererlangung einer VEGF-unabhängigen Gefäßversorgung auch zu Resistenz gegen das durch Bevacizumab hervorgerufene, von Sauerstoffmangel gekennzeichnete Mikromilieu kommt. So konnte gezeigt werden, dass Bevacizumab-resistente Tumoren einen stark glykolytischen, sauerstoff-unabhängigen Zellmetabolismus aufweisen und vermehrt Laktat produzieren. Darüber hinaus wurde in Folge der Bevacizumab-Behandlung eine Fehlfunktion von Mitochondrien beobachtet. Unklar ist noch, ob die beschriebenen metabolischen Veränderungen ein Epiphänomen der Nährstoffmangelsituation sind oder ob sie kausal mit der Resistenzentwicklung in Zusammenhang stehen.
In der vorliegenden Arbeit sollte deshalb geprüft werden, ob die metabolische Umstellung hin zu einem glykolytischen, anaeroben Phänotyp eine hinreichende Bedingung zur Entwicklung einer Hypoxie- und Bevacizumabresistenz darstellt.
Hierzu wurden Glioblastomzellen (LNT229) derart verändert, dass sie keine oxidative Phosphorylierung durchführen konnten und rein auf die glykolytische Energiegewinnung angewiesen waren (rho0-Zellen). Diese Veränderung führte in-vitro zu einer Hypoxieresistenz der Zellen. Außerdem waren rho0-Zellen empfindlicher gegenüber Glukoseentzug und einer Behandlung mit dem Glykolyse-Inhibitor 2-Deoxyglucose (2DG). Des Weiteren waren im Mausmodell intrakranielle rho0-Tumorxenografts resistent gegenüber Bevacizumab. Diese Resistenz konnte durch zusätzliche Therapie mit 2DG wieder aufgehoben werden.
Somit konnte in der vorliegenden Arbeit gezeigt werden, dass die Hemmung der oxidativen Phosphorylierung zu einem glykolytischen Phänotyp führt, der hinreichend ist, um eine Hypoxieresistenz und in Folge dessen eine Bevacizumabresistenz in Glioblastomzellen zu verursachen. Dies lässt einen kausalen Zusammenhang zwischen bereits in anderen Studien beschriebenen metabolischen Veränderungen und einer Bevacizumabresistenz in Tumoren vermuten. Der zelluläre Glukosestoffwechsel ist damit ein vielversprechender therapeutischer Angriffspunkt zur Vermeidung und Überwindung einer Bevacizumabresistenz.
Ziel: Das Ziel dieser Studie war es, den Einfluss der Erfahrung von Radiologen auf die Qualität der radiologischen Diagnostik von Speicheldrüsentumoren mittels MRT- und CT-Aufnahmen zu analysieren.
Material und Methoden: Drei Radiologen mit unterschiedlicher Erfahrung (R1 > 20, R2 > 11 und R3 > 7 Jahre) diagnostizierten retrospektiv 128 Fälle (116 MRT-, 12 CT-Studien) mit Verdacht auf Speicheldrüsentumoren hinsichtlich der Dignität und Entität mit Histopathologie als Referenzstandard. Um die diagnostische Leistung zu vergleichen, wurden die Sensitivität, die Spezifität, der positive/negative Vorhersagewert und die Inter-Observer-Übereinstimmung unter Verwendung von Cohens Kappa (κ) berechnet.
Ergebnisse: In 87 Fällen waren die Tumoren gutartig und in 23 Fällen bösartig, 18 Fälle waren ohne Neoplasien (davon 15 Fälle mit sonstigen Erkrankungen and 3 Fälle ohne pathologischen Befund). Bei CT-Aufnahmen wurde bei der Dignitätsbestimmung die höchste Inter-Observer-Reliabilität zwischen R1 und R2 (κ = 0,74, p <0,001) erreicht und die niedrigste zwischen R2 und R3 (κ = 0,28, p <0,001). Bei MRT-Aufnahmen war die Sensitivität/Spezifität bei der Klassifizierung von pleomorphen Adenomen wie folgt: R1 (100 % / 100 %), R2 (76,92 % / 87,01 %), R3 (43,53 % / 67,53 %) und für CT: R1 (100 % / 100 %), R2 (100 % / 88,89 %), R3 (66,67 % / 88,89 %); für Warthin-Tumor mit MRT: R1 (100 % / 97,44 %), R2 (68,42 % / 83,33 %), R3 (50,00 % / 67,95 %) und unter Verwendung von CT: R1 (100 % / 100 %), R2 (50,00 % / 100 %), R3 (100 % / 100 %); für Plattenepithelkarzinome mittels MRT: R1 (100 % / 100 %), R2 (75,00 % / 97,12 %), R3 (75,00 % / 99,04 %) und unter Verwendung von CT: R1 (100 % / 100 %), R2 (66,67 % / 88,89 %), R3 (66,67 % / 66,67 %). Bei MRT bestand die größte Übereinstimmung zwischen R1 und R2 (κ = 0,62, p <0,001) und die niedrigste zwischen R1 und R3 (κ = 0,28, p <0,001).
Schlussfolgerung: Die diagnostische Qualität bei der Bewertung von Speicheldrüsentumoren ist von der Erfahrung des Radiologen abhängig und die Diagnostikgüte steigt mit zunehmender Berufserfahrung.
Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group’s cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The “ex-novo” occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies’ positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition.
Introduction: The Retro-IDEAL (ILUVIEN Implant for chronic DiabEtic MAcuLar edema) study is a retrospective study designed to assess real-world outcomes achieved with the ILUVIEN® (0.19 mg fluocinolone acetonide (FAc)) in patients with chronic diabetic macular edema (DME) in clinical practices in Germany.
Methods: This study was conducted across 16 sites in Germany and involved 81 eyes (63 patients) with persistent or recurrent DME and a prior suboptimal response to a first-line intravitreal therapy (primarily anti-VEGF intravitreal therapies).
Results: Patients were followed-up for 30.8 ± 11.3 months (mean ± standard deviation) and had a mean age of 68.0 ± 10.4 years. Best-recorded visual acuity (BRVA) improved by +5.5 letters at month 9 (P ⩽ 0.005, n=56; from a baseline of 49 letters) and this was maintained through to month 30 (P ⩽ 0.05, n = 42). There was a concurrent improvement in central macular thickness with a reduction from 502 µm at baseline to 338 µm at year 1 (P ⩽ 0.0001, n = 43). This effect was sustained to year 3 (i.e. 318 µm; P ⩽ 0.0001, n = 29). Mean intraocular pressure (IOP) remained constant between baseline and year 3 with a peak change of 1.9 mm Hg occurring at year 1. Elevated IOP was observed in a similar percentage of patients prior to (22.2% of cases) and following (27.2%) treatment with the FAc implant. In the majority of cases, these elevations were managed effectively with IOP medications.
Conclusions: Despite substantial amounts of prior intravitreal treatments – primarily with anti–vascular endothelial growth factor (VEGF) drugs – this real-world study showed that sustained structural and functional improvements can last for up to 3 years with a single FAc implant.
Immunosuppressive compounds affect the fungal growth and viability of defined aspergillus species
(2019)
Immunosuppressive drugs are administered to a number of patients; e.g., to allogeneic hematopoietic stem cell transplant recipients. Immunosuppressive drugs impair the immune system and thus increase the risk of invasive fungal disease, but may exhibit antifungal activity at the same time. We investigated the impact of various concentrations of three commonly used immunosuppressive compounds—cyclosporin A (CsA), methylprednisolone (mPRED), and mycophenolic acid (MPA)—on the growth and viability of five clinically important Aspergillus species. Methods included disc diffusion, optical density of mycelium, and viability assays such as XTT. MPA and CsA had a species-specific and dose-dependent inhibitory effect on the growth of all Aspergillus spp. tested, although growth inhibition by MPA was highest in A. niger, A. flavus and A. brasiliensis. Both agents exhibited species-specific hyphal damage, which was higher when the immunosuppressants were added to growing conidia than to mycelium. In contrast, mPRED increased the growth of A. niger, but had no major impact on the growth and viability of any of the other Aspergillus species tested. Our findings may help to better understand the interaction of drugs with Aspergillus species and ultimately may have an impact on individualizing immunosuppressive therapy.
Ceritinib-induced regression of an insulin-like growth factor-driven neuroepithelial brain tumor
(2019)
The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood–brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.
Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers.
Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics.
Adults with autism spectrum disorder (ASD) are frequently prescribed selective serotonin reuptake inhibitors (SSRIs). However, there is limited evidence to support this practice. Therefore, it is crucial to understand the impact of SSRIs on brain function abnormalities in ASD. It has been suggested that some core symptoms in ASD are underpinned by deficits in executive functioning (EF). Hence, we investigated the role of the SSRI citalopram on EF networks in 19 right-handed adult males with ASD and 19 controls who did not differ in gender, age, IQ or handedness. We performed pharmacological functional magnetic resonance imaging to compare brain activity during two EF tasks (of response inhibition and sustained attention) after an acute dose of 20 mg citalopram or placebo using a randomised, double-blind, crossover design. Under placebo condition, individuals with ASD had abnormal brain activation in response inhibition regions, including inferior frontal, precentral and postcentral cortices and cerebellum. During sustained attention, individuals with ASD had abnormal brain activation in middle temporal cortex and (pre)cuneus. After citalopram administration, abnormal brain activation in inferior frontal cortex was ‘normalised’ and most of the other brain functional differences were ‘abolished’. Also, within ASD, the degree of responsivity in inferior frontal and postcentral cortices to SSRI challenge was related to plasma serotonin levels. These findings suggest that citalopram can ‘normalise’ atypical brain activation during EF in ASD. Future trials should investigate whether this shift in the biology of ASD is maintained after prolonged citalopram treatment, and if peripheral measures of serotonin predict treatment response.
Background: Disease progression and delayed neurological complications are common after aneurysmal subarachnoid hemorrhage (aSAH). We explored the potential of quantitative blood-brain barrier (BBB) imaging to predict disease progression and neurological outcome.
Methods: Data were collected as part of the Co-Operative Studies of Brain Injury Depolarizations (COSBID). We analyzed retrospectively, blinded and semi-automatically magnetic resonance images from 124 aSAH patients scanned at 4 time points (24–48 h, 6–8 days, 12–15 days and 6–12 months) after the initial hemorrhage. Volume of brain with apparent pathology and/or BBB dysfunction (BBBD), subarachnoid space and lateral ventricles were measured. Neurological status on admission was assessed using the World Federation of Neurosurgical Societies and Rosen-Macdonald scores. Outcome at ≥6 months was assessed using the extended Glasgow outcome scale and disease course (progressive or non-progressive based on imaging-detected loss of normal brain tissue in consecutive scans). Logistic regression was used to define biomarkers that best predict outcomes. Receiver operating characteristic analysis was performed to assess accuracy of outcome prediction models.
Findings: In the present cohort, 63% of patients had progressive and 37% non-progressive disease course. Progressive course was associated with worse outcome at ≥6 months (sensitivity of 98% and specificity of 97%). Brain volume with BBBD was significantly larger in patients with progressive course already 24–48 h after admission (2.23 (1.23–3.17) folds, median with 95%CI), and persisted at all time points. The highest probability of a BBB-disrupted voxel to become pathological was found at a distance of ≤1 cm from the brain with apparent pathology (0·284 (0·122–0·594), p < 0·001, median with 95%CI). A multivariate logistic regression model revealed power for BBBD in combination with RMS at 24-48 h in predicting outcome (ROC area under the curve = 0·829, p < 0·001).
Interpretation: We suggest that early identification of BBBD may serve as a key predictive biomarker for neurological outcome in aSAH.
Fund: Dr. Dreier was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (DFG DR 323/5-1 and DFG DR 323/10–1), the Bundesministerium für Bildung und Forschung (BMBF) Center for Stroke Research Berlin 01 EO 0801 and FP7 no 602150 CENTER-TBI.
Dr. Friedman was supported by grants from Israel Science Foundation and Canada Institute for Health Research (CIHR). Dr. Friedman was supported by grants from European Union's Seventh Framework Program (FP7/2007–2013; grant #602102).
Prescribing practice of pregabalin/gabapentin in pain therapy : an evaluation of German claim data
(2019)
Objectives: To analyse the prevalence and incidence of pregabalin and gabapentin (P/G) prescriptions, typical therapeutic uses of P/G with special attention to pain-related diagnoses and discontinuation rates.
Design: Secondary data analysis.
Setting: Primary and secondary care in Germany.
Participants: Four million patients in the years 2009–2015 (anonymous health insurance data).
Intervention: None.
Primary and secondary outcome measures: P/G prescribing rates, P/G prescribing rates associated with pain therapy, analysis of pain-related diagnoses leading to new P/G prescriptions and the discontinuation rate of P/G.
Results: In 2015, 1.6% of insured persons received P/G prescriptions. Among the patients with pain first treated with P/G, as few as 25.7% were diagnosed with a typical neuropathic pain disorder. The remaining 74.3% had either not received a diagnosis of neuropathic pain or showed a neuropathic component that was pathophysiologically conceivable but did not support the prescription of P/G. High discontinuation rates were observed (85%). Among the patients who had discontinued the drug, 61.1% did not receive follow-up prescriptions within 2 years.
Conclusion: The results show that P/G is widely prescribed in cases of chronic pain irrespective of neuropathic pain diagnoses. The high discontinuation rate indicates a lack of therapeutic benefits and/or the occurrence of adverse effects.
Background: The number of Mesenchymal Stem/Stromal Cells (MSCs) in the human bone marrow (BM) is small compared to other cell types. BM aspirate concentration (BMAC) may be used to increase numbers of MSCs, but the composition of MSC subpopulations and growth factors after processing are unknown. The purpose of this study was to assess the enrichment of stem/progenitor cells and growth factors in BM aspirate by two different commercial concentration devices versus standard BM aspiration.
Methods: 120 mL of BM was aspirated from the iliac crest of 10 male donors. Each sample was processed simultaneously by either Emcyte GenesisCS® (Emcyte) or Harvest SmartPReP2 BMAC (Harvest) devices and compared to untreated BM aspirate. Samples were analyzed with multicolor flow cytometry for cellular viability and expression of stem/progenitor cells markers. Stem/progenitor cell content was verified by quantification of colony forming unit-fibroblasts (CFU-F). Platelet, red blood cell and total nucleated cell (TNC) content were determined using an automated hematology analyzer. Growth factors contents were analyzed with protein quantification assays. Statistical analyses were performed by ANOVA analysis of variance followed by Tukey’s multiple comparison test or Wilcoxon matched-pairs signed rank test with p < 0.05 for significance.
Results: Cell viability after processing was approximately 90% in all groups. Compared to control, both devices significantly enriched TNCs and platelets, as well as the CD45−CD73+ and CD45−CD73+CD90+ cell populations. Further, Harvest significantly concentrated CD45−CD10+, CD45−CD29+, CD45−CD90+, CD45−CD105+, CD45−CD119+ cells, and CD45dimCD90+CD271+ MSCs, whereas Emcyte significantly enriched CD45dimCD44+CD271+ MSCs. BM concentration also increased the numbers of CFU-F, platelet-derived growth factor, vascular endothelial growth factor, macrophage colony-stimulating factor, interleukin-1b, VCAM-1 and total protein. Neither system concentrated red blood cells, hematopoietic stem cells or bone morphogenetic proteins.
Conclusion: This data could contribute to the development of BMAC quality control assays as both BMAC systems concentrated platelets, growth factors and non-hematopoietic stem cell subpopulations with distinct phenotypes without loss of cell viability when compared to unprocessed BM.
During the past 15 years there have been dramatic changes in the medical landscape, particularly in oncology and regenerative medicine. Cell therapies have played a substantial part in this progress. Cellular immunotherapies can use immune cells, such as T cells or natural killer cells that, after functional modification ex vivo, exert powerful anti-cancer effects when given to the patient. Innovative technologies, such as re-programming terminally differentiated cells into pluripotent stem cells or into other cell types and applying specific enzymes to more precisely edit the human genome, are paving the way towards more potent cell and gene therapies.
Mesenchymal stromal cells are promising cellular immunotherapeutics, which also have potential for use in tissue engineering strategies and other regenerative medicine applications. However, substantial gaps in our knowledge of their biology and therapeutic efficacy present major challenges to their sustainable implementation in the clinical routine.
In this article, progress in the field of cell therapeutics during the past 15 years will be briefly discussed, with a focus on mesenchymal stromal cells, highlighting the impact of this field on patient care.
Memory impairments are a major characteristic of schizophrenia (SZ). In the current study, we used an associative memory task to test the hypothesis that SZ patients and first-degree relatives have altered functional patterns in comparison to healthy controls. We analyzed the fMRI activation pattern during the presentation of a face-name task in 27 SZ patients, 23 first-degree relatives, and 27 healthy controls. In addition, we performed correlation analyses between individual psychopathology, accuracy and reaction time of the task and the beta scores of the functional brain activations. We observed a lower response accuracy and increased reaction time during the retrieval of face-name pairs in SZ patients compared with controls. Deficient performance was accompanied by abnormal functional activation patterns predominantly in DMN regions during encoding and retrieval. No significant correlation between individual psychopathology and neuronal activation during encoding or retrieval of face-name pairs was observed. Findings of first-degree relatives indicated slightly different functional pattern within brain networks in contrast to controls without significant differences in the behavioral task. Both the accuracy of memory performance as well as the functional activation pattern during retrieval revealed alterations in SZ patients, and, to a lesser degree, in relatives. The results are of potential relevance for integration within a comprehensive model of memory function in SZ. The development of a neurophysiological model of cognition in psychosis may help to clarify and improve therapeutic options to improve memory and functioning in the illness.
Objectives: To compare efficacy and safety of ixekizumab (IXE) to adalimumab (ADA) in biological disease-modifying antirheumatic drug-naïve patients with both active psoriatic arthritis (PsA) and skin disease and inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARDs).
Methods: Patients with active PsA were randomised (1:1) to approved dosing of IXE or ADA in an open-label, head-to-head, blinded assessor clinical trial. The primary objective was to evaluate whether IXE was superior to ADA at week 24 for simultaneous achievement of a ≥50% improvement from baseline in the American College of Rheumatology criteria (ACR50) and a 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI100). Major secondary objectives, also at week 24, were to evaluate whether IXE was: (1) non-inferior to ADA for achievement of ACR50 and (2) superior to ADA for PASI100 response. Additional PsA, skin, treat-to-target and quality-of-life outcome measures were assessed at week 24.
Results: The primary efficacy endpoint was met (IXE: 36%, ADA: 28%; p=0.036). IXE was non-inferior for ACR50 response (IXE: 51%, ADA: 47%; treatment difference: 3.9%) and superior for PASI100 response (IXE: 60%, ADA: 47%; p=0.001). IXE had greater response versus ADA in additional PsA, skin, nail, treat-to-target and quality-of-life outcomes. Serious adverse events were reported in 8.5% (ADA) and 3.5% (IXE) of patients.
Conclusions: IXE was superior to ADA in achievement of simultaneous improvement of joint and skin disease (ACR50 and PASI100) in patients with PsA and inadequate response to csDMARDs. Safety and tolerability for both biologicals were aligned with established safety profiles.
Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2) with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-Knockin (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin, and gangliosides GM1a/GD1b despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide–sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage and not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals; thus, our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode, and mouse orthologs as mTORC1 inhibitors and autophagy promoters.
Background: Although mechanistic target of rapamycin (mTOR) inhibitors, such as temsirolimus, show promise in treating bladder cancer, acquired resistance often hampers efficacy. This study evaluates mechanisms leading to resistance. Methods: Cell growth, proliferation, cell cycle phases, and cell cycle regulating proteins were compared in temsirolimus resistant (res) and sensitive (parental—par) RT112 and UMUC3 bladder cancer cells. To evaluate invasive behavior, adhesion to vascular endothelium or to immobilized extracellular matrix proteins and chemotactic activity were examined. Integrin α and β subtypes were analyzed and blocking was done to evaluate physiologic integrin relevance. Results: Growth of RT112res could no longer be restrained by temsirolimus and was even enhanced in UMUC3res, accompanied by accumulation in the S- and G2/M-phase. Proteins of the cdk-cyclin and Akt-mTOR axis increased, whereas p19, p27, p53, and p73 decreased in resistant cells treated with low-dosed temsirolimus. Chemotactic activity of RT112res/UMUC3res was elevated following temsirolimus re-exposure, along with significant integrin α2, α3, and β1 alterations. Blocking revealed a functional switch of the integrins, driving the resistant cells from being adhesive to being highly motile. Conclusion: Temsirolimus resistance is associated with reactivation of bladder cancer growth and invasive behavior. The α2, α3, and β1 integrins could be attractive treatment targets to hinder temsirolimus resistance.
Nonerythroid spectrin αII (SPTAN1) is an important cytoskeletal protein that ensures vital cellular properties including polarity and cell stabilization. In addition, it is involved in cell adhesion, cell-cell contact, and apoptosis. The detection of altered expression of SPTAN1 in tumors indicates that SPTAN1 might be involved in the development and progression of cancer. SPTAN1 has been described in cancer and therapy response and proposed as a potential marker protein for neoplasia, tumor aggressiveness, and therapeutic efficiency. On one hand, the existing data suggest that overexpression of SPTAN1 in tumor cells reflects neoplastic and tumor promoting activity. On the other hand, nuclear SPTAN1 can have tumor suppressing effects by enabling DNA repair through interaction with DNA repair proteins. Moreover, SPTAN1 cleavage products occur during apoptosis and could serve as markers for the efficacy of cancer therapy. Due to SPTAN1’s multifaceted functions and its role in adhesion and migration, SPTAN1 can influence tumor growth and progression in both positive and negative directions depending on its specific regulation. This review summarizes the current knowledge on SPTAN1 in cancer and depicts several mechanisms by which SPTAN1 could impact tumor development and aggressiveness.
Die Prognose eines malignen Glioms ist trotz verschiedener Therapiemöglichkeiten noch immer sehr schlecht. Zwar hat sich für die Primärsituation seit 2005 eine Standardtherapie etabliert, doch im Rezidivfall fehlt es weiterhin an einer einheitlichen Behandlung. Das Ziel dieser retrospektiven Datenerfassung war es, den prognostischen Stellenwert klinisch- pathologischer Parameter zu vergleichen und eine Konsensempfehlung zu erarbeiten. Zusätzlich wurde ein Teil dieser Daten im Rahmen einer multizentrischen retrospektiven Analyse des DKTKs zur Validierung des im Zuge dessen entwickelten prognostischen RRRSs erhoben und verwendet.
Grundlage dafür bildeten die in der internen Datenbank „Orbis“ und in archivierten Patientenakten gespeicherten Daten von Patienten, die zwischen 07/2009 und 02/2017 in der Klinik für Strahlentherapie am Universitätsklinikum Frankfurt am Main therapiert wurden. Hierbei handelte es sich um Patienten mit einem histologisch gesicherten Glioblastomen WHO Grad IV zum Zeitpunkt der ReRT. Die mediane Gesamtdosis betrug 28 Gy (20-60 Gy), die mediane Einzeldosis 3,5 Gy/Tag (1,8-4 Gy).
Es wurden 102 Patienten eingeschlossen, wobei zwei Patienten als primäre Diagnose ein niedriggradiges Gliom WHO Grad I/II, sechs ein Astrozytom WHO Grad III und 96 ein Glioblastomen WHO Grad IV aufwiesen. Das durchschnittliche Alter betrug 55 Jahre und die mittlere Zeit zwischen initialer und erneuter RT 21,07 Monate. Im Rezidivfall unterzogen sich 40 Patienten einer chirurgischen Intervention, bei welcher es sich in 32 der Fälle um eine totale und acht Mal um eine subtotale Resektion handelte. Des Weiteren erhielten 52 der Patienten eine Chemotherapie mit Temozolomid, 20 eine mit CCNU, 17 mit Avastin und fünf bzw. acht ein anderes oder kein Chemotherapeutikum.
Das mOS nach initialer Diagnosestellung eines malignen Glioms ergab 42,64 Monaten, das progressionsfreie Überleben 14,77 Monate. Das mOS nach der ReRT lag bei 11,8 Monaten und der mediane Zeitraum bis zu einem erneuten Progress betrug 4,25 Monate.
Bezüglich der Primärdiagnose konnten die initiale Histologie (p = 0,002), das Alter (p = 0,016) und der MGMT-Promotor-Status (p = 0,001) als statistisch signifikante Einflussfaktoren identifiziert werden. Demnach wiesen jüngere Patienten mit einer niedriggradigeren Histologie sowie einer Hypermethylierung des MGMT-Promotors eine bessere Prognose auf. Der KPS (p < 0,001), die Zeit zwischen erster und zweiter Bestrahlung (p = 0,003), der MGMT-Promotor-Status (p = 0,025) und das Tumorwachstum (p = 0,024) waren determinante Faktoren hinsichtlich des Outcomes nach der ReRT. Außerdem zeigte sich, dass eine Gesamtstrahlendosis von mehr als 28,90 Gy auf statistisch signifikante Art und Weise (p = 0,042) mit einem längeren OS nach erneuter RT assoziiert war, sowie eine Parietal- bzw. Temporallappenlokalisation (p = 0,009) mit einem längeren progressionsfreien Überleben. Was die Therapiemodalitäten angeht, zeigte sich keine der anderen überlegen.
Die erneute Validierung dieser Daten mit dem RRRS ergab ebenfalls ein statistisch signifikantes Ergebnis bezogen auf die durchschnittliche Überlebenszeit zwischen den einzelnen prognostischen Gruppen ab dem Zeitpunkt der ReRT.
Die Ergebnisse dieser Arbeit legen dar, dass noch immer keine optimale Therapie für Patienten mit rezidivierendem Glioblastomen existiert und weiterhin Forschungsbedarf in der Modifizierung bestehender Behandlungsoptionen sowie in der Entwicklung neuer Therapiemöglichkeiten besteht. Des Weiteren unterstreichen sie die Wichtigkeit und den Wert spezifischer Einflussfaktoren zur Prognoseabschätzung und die Notwendigkeit des Einschlusses bedeutender neuer molekularer Marker anhand der WHO- Klassifikation von 2016 für zukünftige Studien.
Ziel: Es erfolgte eine Untersuchung der Langzeitergebnisse der mikrochirurgischen Dekompression bei lumbaler Spinalkanalstenose (LSS) in Bezug auf die Lebensqualität.
Material und Methoden: Zwischen 10/2010 – 12/2015 wurden 272 Patienten in der Klinik für Neurochirurgie des Universitätsklinikums Frankfurt am Main aufgrund einer LSS mikrochirurgisch dekomprimiert. Von ihnen wurden retrospektive Daten bezüglich demographischer und klinischer Kriterien erhoben. Ihre Lebensqualität wurde mithilfe des 36-Item Short Form Health Survey (SF-36) und den dazugehörigen Summenskalen bei einem Follow-Up von 3-8 Jahren beurteilt. 250 Patienten erfüllten die Einschlusskriterien, von denen 103 den Fragebogen vollständig ausfüllten.
Ergebnisse: Das präoperative Vorliegen einer Spondylolisthese °I, was signifikant mit dem weiblichen Geschlecht assoziiert ist, beeinflusste nicht das Outcome. Die relative Häufigkeit postoperativer Instabilität war bei präoperativem Vorliegen einer Spondylolisthese höher (2,4% vs. 1,3%). Die stationäre Liegedauer hängt signifikant mit der OP-Dauer zusammen, was mit einem niedrigen BMI signifikant mit einer niedrigeren Summenskala für körperliche Gesundheit (SKKÖ) zusammenhängt. Frauen erzielten insgesamt eine niedrigere psychische Summenskala als Männer.
Schlussfolgerung: Ein niedriger BMI, eine möglichst kurze OP-Zeit und eine kurze Liegedauer sind positive Prädiktoren, um langfristig eine gute körperliche Gesundheit zu erhalten. Frauen neigen eher dazu, eine Spondylolisthese zu entwickeln, während dies mit einer postoperativen Instabilität und der Notwendigkeit einer Fusion einhergehen kann. Das Outcome ist nicht vom präoperativen Vorliegen einer Spondylolisthese abhängig; De Novo-Listhesen traten nur zu 1,3% auf. Insgesamt ist das Outcome der Patienten bezüglich ihrer körperlichen Gesundheit im Follow-Up altersentsprechend und zufriedenstellend.
Background: Hepatitis C virus (HCV) is currently classified into 8 genotypes and 86 subtypes. The objective of this study was to characterize novel HCV subtypes and to investigate the impact of subtypes on treatment outcome.
Methods: Full-genome sequencing was performed on HCV plasma samples with <85% sequence homology of NS3, NS5A, and/or NS5B to HCV genotype (GT) 1–8 reference strains.
Results: A total of 14 653 patients with GT1–6 HCV infection were enrolled in clinical studies of sofosbuvir-based regimens. For the majority of the patients, a specific subtype could be assigned based on a close genetic relationship to previously described subtypes. However, for 19 patients, novel subtypes were identified with <85% homology compared with previously described subtypes. These novel subtypes had the following genotypes: 9 in GT2, 5 in GT4, 2 in GT6, and 1 each in GT1, GT3, and GT5. Despite the presence of polymorphisms at resistance-associated substitution positions, 18 of the 19 patients treated with sofosbuvir-containing therapy achieved SVR12.
Conclusions: Nineteen novel HCV subtypes were identified, suggesting an even greater genetic diversity of HCV subtypes than previously recognized.
Hintergrund: Die Therapie des elektrischen Sturms (ES), d.h. ≥3 ICD-Therapieabgaben wegen ventrikulärer Tachyarrhythmien (VT) innerhalb von 24 Stunden, besteht in der Beseitigung potenzieller reversibler Ursachen, der Gabe von Antiarrhythmika oder der Katheterablation (CA).
Ziel der Untersuchung war es, die unterschiedlichen Therapien des ES in Bezug auf Erfolg und Sicherheit zu analysieren.
Methoden: Alle ICD-Patienten, die zwischen 2000 und 2015 mit ES am Cardioangiologischen Centrum Bethanien behandelt wurden, wurden in die retrospektive Analyse eingeschlossen. Mittels elektronischer Datenbanksuche wurden potenzielle Patienten identifiziert und anhand der Krankenakte und der ICD-Auslesungen selektiert.
Neben demographischen Parametern wurden die prozeduralen Variablen der Ablationen analysiert. Alle CA wurden mit Hilfe eines 3D-Mappingsystems durchgeführt. Der Erfolg der CA wurde definiert als Nicht-Induzierbarkeit von VT durch programmierte Elektrostimulation von RVA und RVOT mit 2 Basiszykluslängen (510/440ms) und Ankopplung von bis zu 3 Extrastimuli bis zur jeweiligen Refraktärzeit.
Die Patienten wurden alle 6 Monate untersucht und der ICD-Speicher ausgelesen.
Der primäre Endpunkt war das ereignisfreie Überleben ohne adäquate ICD-Interventionen oder ES in einem Zeitraum von 12 Monaten nach Therapie des ES.
Ergebnisse: Insgesamt wurden 87 Patienten (mittleres Alter 71±9,6 Jahre; 89% männlich; LVEF 34,1%±13,3%) eingeschlossen, davon 58 konservativ und 29 per CA behandelt.
Die ICD-Implantation der Patienten in der CA-Gruppe lag länger zurück als die in der konservativen Gruppe (1868 Tage vs. 905 Tage; p = 0,0009).
Die CA war bei 26 Patienten (3 Therapieversager der kons. Gruppe einbezogen) erfolgreich. Dabei wurden im Mittel 2,6±1,8 VT abladiert. Hierzu war in 16,2% ein epikardiales Vorgehen notwendig. Die Prozeduren dauerten 153±47,5 min.
In der konservativen Gruppe hatten 15 (25,9%) Patienten eine reversible Ursache für den ES (Ischämie, Elektrolytstörung), außerdem wurden 34 (58,6%) mit Antiarrhythmika behandelt, davon 28 (48,3%) mit Amiodaron.
Der primäre Endpunkt wurde von 19 (32,8%) Patienten der konservativen und 13 (44,8%) der CA Gruppe erreicht (p = 0,35).
Es ergaben sich ebenfalls keine Unterschiede bzgl. der einzelnen Endpunkte Tod, VT-, ES- oder ICD-Schockrezidiv.
Im Falle einer erfolgreichen CA wurde der primäre Endpunkt signifikant häufiger erreicht (46,2% vs. 16,7%; p = 0,01; HR = 0,29; CI 0,11-0,75). Die Wahrscheinlichkeit das erste Jahr nach CA zu überleben war um 84% höher (88,5% vs. 50%; p = 0,01; HR = 0,16; CI 0,04-0,65).
Im Falle einer erfolgreichen CA ist die Wahrscheinlichkeit für das Überleben gegenüber einer Amiodarontherapie um 70% höher (88,5% vs. 64,3%; p= 0,07; HR = 0,30; CI 0,09-1,04).
Schlussfolgerung: Patienten mit einem ES können primär zu 81,3% mit einer CA erfolgreich behandelt werden. Wenn alle VT durch die CA eliminiert werden können, ist die CA einer konservativen Therapie mit Amiodaron in Hinblick auf das Überleben um 70% überlegen.
Infektionen durch multiresistente Erreger führen jährlich zum Tod von ca. 33.000 Menschen in Europa.192 Insbesondere ist eine weltweite Zunahme von multiresistenten Gram-negativen Bakterien zu verzeichnen.193 Im Rahmen dieser Arbeit wurden zwei Projekte bezüglich der Resistenzmechanismen gegenüber Beta-Laktam-Antibiotika bei Gram-negativen Bakterien bearbeitet.
Das Gammaproteobakterium Psychrobacter sanguinis PS2578 wurde im März 2015 von einem Neonaten isoliert und verursachte eine early onset Neugeboreneninfektion. Aufgrund der insuffizienten Datenlage bezüglich Diagnostik, Antibiotikaresistenz und Pathogenität von Psychrobacter spp. wurden diese Aspekte weiter evaluiert. P. sanguinis zeigte geringes Wachstum auf Blutagar und keinerlei Wachstum in Standardnährmedien. Als optimales Nährmedium erwies sich das Spezialmedium BHI mit 10% Fetalem Kälberserum, wobei eine Abhängigkeit des Wachstums von FCS beobachtet wurde. Die Virulenz des klinischen Isolats sowie des Referenzstamms P. sanguinis DSM 23635 war in einem in vivo Infektionsmodell vergleichbar mit klinischen Escherichia coli und Klebsiella pneumoniae Isolaten sowie dem phylogenetisch nahe verwandten Acinetobacter calcoaceticus DSM 30006. Demnach ist die Spezies P. sanguinis moderat virulent und als humanpathogen anzusehen. Als molekulares Äquivalent der phänotypischen Penicillinresistenz wurde die Carbenicillinase CARB-8 (RTG-3) identifiziert, wodurch die These gestützt wird, dass der Genus Psychrobacter spp. ein mögliches Genreservoir von Carbenicillinasen darstellt.3 Im Rahmen dieser Arbeit konnte das Genom der Spezies erstmals komplett sequenziert werden. Es beinhaltete ein Chromosom von 2.946.289 bp, ein größeres Plasmid von 49.981 bp und ein kleineres Plasmid von 11.576 bp, welches blaCARB-8 kodierte.
Der Nachweis von Carbapenem-resistenten Gammaproteobacteria hat sich von 2010 zu 2017 in Deutschland mehr als verzehnfacht. Dabei ist OXA-48 die häufigste Carbapenemase in Europa und tritt vor allem bei den Spezies K. pneumoniae und E. coli auf.75 In dieser Arbeit wurden 62 klinische Stämme hinsichtlich ihres Plasmidtyps und ihres Verwandtschaftsgrads untersucht.
In der Klonalitätsanalyse gehörten 25 (n=44) K. pneumoniae derselben klonalen Linie an. Hiervon wurden 22 (n=25) Isolate in den Jahren 2010 und 2011 isoliert, was einen klonalen Ausbruch vermuten lässt.158 Bei der Spezies E. coli (n=8) waren lediglich zwei Stämme klonal verwandt. Insgesamt indizierten diese Ergebnisse eine hohe Diversität der klinischen Isolate. Die Plasmidtypisierung hingegen zeigte, dass 95% der Stämme (n=62) ein IncL Plasmid aufwiesen. Basierend auf den Selektionskriterien Klonalität und Plasmidtyp wurden 21 Stämme für weitere Analysen mittels Multilocus-Sequenz-Typisierung und Transkonjugation ausgewählt. Es konnten sehr hohe Konjugationsfrequenzen von 7,51 x 10-1 im Intraspezies- und von 8,15 x 10-1 im Intergenus- HGT für das blaOXA-48 IncL Plasmid in vitro ermittelt werden. Unter Verwendung von Galleria mellonella Larven als in vivo Transkonjugationsmodell wurde eine Transkonjugationsfrequenz von nahezu 100% detektiert. Daher lässt sich vermuten, dass der HGT von Antibiotikaresistenzgenen im Darm eines Patienten eine sehr viel höhere Effizienz aufweisen könnte, als bisher basierend auf in vitro generierten Daten angenommen. Dies impliziert, dass die globale Verbreitung von OXA-48 auf dem effizienten horizontalen Gentransfers eines einzigen IncL Plasmids beruht und nicht auf der Expansion einer bestimmten klonalen Linie.
Background: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia.
Methods: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7–28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL.
Results: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects’ underlying diseases.
Conclusion: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation.
Trial registration: ClinicalTrials.gov identifier: NCT01716234
Diagnosing and treating acute severe and recurrent antivenom-related anaphylaxis (ARA) is challenging and reported experience is limited. Herein, we describe our experience of severe ARA in patients with neurotoxic snakebite envenoming in Nepal. Patients were enrolled in a randomised, double-blind trial of high vs. low dose antivenom, given by intravenous (IV) push, followed by infusion. Training in ARA management emphasised stopping antivenom and giving intramuscular (IM) adrenaline, IV hydrocortisone, and IV chlorphenamine at the first sign/s of ARA. Later, IV adrenaline infusion (IVAI) was introduced for patients with antecedent ARA requiring additional antivenom infusions. Preantivenom subcutaneous adrenaline (SCAd) was introduced in the second study year (2012). Of 155 envenomed patients who received ≥ 1 antivenom dose, 13 (8.4%), three children (aged 5−11 years) and 10 adults (18−52 years), developed clinical features consistent with severe ARA, including six with overlapping signs of severe envenoming. Four and nine patients received low and high dose antivenom, respectively, and six had received SCAd. Principal signs of severe ARA were dyspnoea alone (n=5 patients), dyspnoea with wheezing (n=3), hypotension (n=3), shock (n=3), restlessness (n=3), respiratory/cardiorespiratory arrest (n=7), and early (n=1) and late laryngeal oedema (n=1); rash was associated with severe ARA in 10 patients. Four patients were given IVAI. Of the 8 (5.1%) deaths, three occurred in transit to hospital. Severe ARA was common and recurrent and had overlapping signs with severe neurotoxic envenoming. Optimising the management of ARA at different healthy system levels needs more research. This trial is registered with NCT01284855.
Background: To evaluate the diagnostic performance of radiomic signatures extracted from contrast-enhanced magnetic resonance imaging (CE-MRI) for the assessment of breast cancer receptor status and molecular subtypes.
Methods: One hundred and forty-three patients with biopsy-proven breast cancer who underwent CE-MRI at 3 T were included in this IRB-approved HIPAA-compliant retrospective study. The training dataset comprised 91 patients (luminal A, n = 49; luminal B, n = 8; HER2-enriched, n = 11; triple negative, n = 23), while the validation dataset comprised 52 patients from a second institution (luminal A, n = 17; luminal B, n = 17; triple negative, n = 18). Radiomic analysis of manually segmented tumors included calculation of features derived from the first-order histogram (HIS), co-occurrence matrix (COM), run-length matrix (RLM), absolute gradient (GRA), autoregressive model (ARM), discrete Haar wavelet transform (WAV), and lesion geometry (GEO). Fisher, probability of error and average correlation (POE + ACC), and mutual information coefficients were used for feature selection. Linear discriminant analysis followed by k-nearest neighbor classification (with leave-one-out cross-validation) was used for pairwise radiomic-based separation of receptor status and molecular subtypes. Histopathology served as the standard of reference.
Results: In the training dataset, radiomic signatures yielded the following accuracies > 80%: luminal B vs. luminal A, 84.2% (mainly based on COM features); luminal B vs. triple negative, 83.9% (mainly based on GEO features); luminal B vs. all others, 89% (mainly based on COM features); and HER2-enriched vs. all others, 81.3% (mainly based on COM features). Radiomic signatures were successfully validated in the separate validation dataset for luminal A vs. luminal B (79.4%) and luminal B vs. triple negative (77.1%).
Conclusions: In this preliminary study, radiomic signatures with CE-MRI enable the assessment of breast cancer receptor status and molecular subtypes with high diagnostic accuracy. These results need to be confirmed in future larger studies.
Spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato (s.l.) complex differ in their ability to establish infection and to survive in diverse vertebrate hosts. Association with and adaption to various hosts most likely correlates with the spirochetes' ability to acquire complement regulator factor H (FH) to overcome the host's innate immune response. Here we assessed binding of serum FH from human and various animals including bovine, cat, chicken, dog, horse, mouse, rabbit, and rat to viable B. burgdorferi sensu stricto (s.s.), B. afzelii, B. garinii, B. spielmanii, B. valaisiana, and B. lusitaniae. Spirochetes ectopically producing CspA orthologs of B. burgdorferi s.s., B. afzelii, and B. spielmanii, CspZ, ErpC, and ErpP, respectively, were also investigated. Our comparative analysis using viable bacterial cells revealed a striking heterogeneity among Lyme disease spirochetes regarding their FH-binding patterns that almost mirrors the serum susceptibility of the respective borrelial genospecies. Moreover, native CspA from B. burgdorferi s.s., B. afzelii, and B. spielmanii as well as CspZ were identified as key ligands of FH from human, horse, and rat origin while ErpP appears to bind dog and mouse FH and to a lesser extent human FH. By contrast, ErpC did not bind FH from human as well as from animal origin. These findings indicate a strong restriction of distinct borrelial proteins toward binding of polymorphic FH of various vertebrate hosts.
Background: Understanding the location and cell-type specific binding of Transcription Factors (TFs) is important in the study of gene regulation. Computational prediction of TF binding sites is challenging, because TFs often bind only to short DNA motifs and cell-type specific co-factors may work together with the same TF to determine binding. Here, we consider the problem of learning a general model for the prediction of TF binding using DNase1-seq data and TF motif description in form of position specific energy matrices (PSEMs).
Methods: We use TF ChIP-seq data as a gold-standard for model training and evaluation. Our contribution is a novel ensemble learning approach using random forest classifiers. In the context of the ENCODE-DREAM in vivo TF binding site prediction challenge we consider different learning setups.
Results: Our results indicate that the ensemble learning approach is able to better generalize across tissues and cell-types compared to individual tissue-specific classifiers or a classifier built based upon data aggregated across tissues. Furthermore, we show that incorporating DNase1-seq peaks is essential to reduce the false positive rate of TF binding predictions compared to considering the raw DNase1 signal.
Conclusions: Analysis of important features reveals that the models preferentially select motifs of other TFs that are close interaction partners in existing protein protein-interaction networks. Code generated in the scope of this project is available on GitHub: https://github.com/SchulzLab/TFAnalysis (DOI: 10.5281/zenodo.1409697).
Objectives: Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness.
Methods: We set up a web-based registry on www.ClinicalSurveys.net for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively.
Results: Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 – 03/2016 were observed. Median age was 58 years (range: 19 – 77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 μg/L (IQR 573–1,498 μg/L) and 904 μg/L (IQR 728–1,550 μg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86%. The median overall duration of POS therapy was 18 days (IQR: 7 – 23 days). Fourteen patients (48%) had progressive IFD under POS therapy, of these five patients (36%) died related to or likely related to IFD.
Conclusions: Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species.
Strategies to interfere with tumor metabolism through the interplay of innate and adaptive immunity
(2019)
The inflammatory tumor microenvironment is an important regulator of carcinogenesis. Tumor-infiltrating immune cells promote each step of tumor development, exerting crucial functions from initiation, early neovascularization, to metastasis. During tumor outgrowth, tumor-associated immune cells, including myeloid cells and lymphocytes, acquire a tumor-supportive, anti-inflammatory phenotype due to their interaction with tumor cells. Microenvironmental cues such as inflammation and hypoxia are mainly responsible for creating a tumor-supportive niche. Moreover, it is becoming apparent that the availability of iron within the tumor not only affects tumor growth and survival, but also the polarization of infiltrating immune cells. The interaction of tumor cells and infiltrating immune cells is multifaceted and complex, finally leading to different activation phenotypes of infiltrating immune cells regarding their functional heterogeneity and plasticity. In recent years, it was discovered that these phenotypes are mainly implicated in defining tumor outcome. Here, we discuss the role of the metabolic activation of both tumor cells and infiltrating immune cells in order to adapt their metabolism during tumor growth. Additionally, we address the role of iron availability and the hypoxic conditioning of the tumor with regard to tumor growth and we describe the relevance of therapeutic strategies to target such metabolic characteristics.