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Cancer stem cells (CSCs) are nowadays one of the major focuses in tumor research since this subpopulation was revealed to be a great obstacle for successful treatment. The identification of CSCs in pediatric solid tumors harbors major challenges because of the immature character of these tumors. Here, we present CD34, CD90, OV-6 and cell-surface vimentin (csVimentin) as reliable markers to identify CSCs in hepatoblastoma cell lines. We were able to identify CSC characteristics for the subset of CD34+CD90+OV-6+csVimentin+-co-expressing cells, such as pluripotency, self-renewal, increased expression of EMT markers and migration. Treatment with Cisplatin as the standard chemotherapeutic drug in hepatoblastoma therapy further revealed the chemo-resistance of this subset, which is a main characteristic of CSCs. When we treated the cells with the Hsp90 inhibitor 17-AAG, we observed a significant reduction in the CSC subset. With our study, we identified CSCs of hepatoblastoma using CD34, CD90, OV-6 and csVimentin. This set of markers could be helpful to estimate the success of novel therapeutic approaches, as resistant CSCs are responsible for tumor relapses.
Background: Dual-source dual-energy computed tomography (DECT) offers the potential for opportunistic osteoporosis screening by enabling phantomless bone mineral density (BMD) quantification. This study sought to assess the accuracy and precision of volumetric BMD measurement using dual-source DECT in comparison to quantitative CT (QCT). Methods: A validated spine phantom consisting of three lumbar vertebra equivalents with 50 (L1), 100 (L2), and 200 mg/cm3 (L3) calcium hydroxyapatite (HA) concentrations was scanned employing third-generation dual-source DECT and QCT. While BMD assessment based on QCT required an additional standardised bone density calibration phantom, the DECT technique operated by using a dedicated postprocessing software based on material decomposition without requiring calibration phantoms. Accuracy and precision of both modalities were compared by calculating measurement errors. In addition, correlation and agreement analyses were performed using Pearson correlation, linear regression, and Bland-Altman plots. Results: DECT-derived BMD values differed significantly from those obtained by QCT (p < 0.001) and were found to be closer to true HA concentrations. Relative measurement errors were significantly smaller for DECT in comparison to QCT (L1, 0.94% versus 9.68%; L2, 0.28% versus 5.74%; L3, 0.24% versus 3.67%, respectively). DECT demonstrated better BMD measurement repeatability compared to QCT (coefficient of variance < 4.29% for DECT, < 6.74% for QCT). Both methods correlated well to each other (r = 0.9993; 95% confidence interval 0.9984–0.9997; p < 0.001) and revealed substantial agreement in Bland-Altman plots. Conclusions: Phantomless dual-source DECT-based BMD assessment of lumbar vertebra equivalents using material decomposition showed higher diagnostic accuracy compared to QCT.
We investigated the effects of sexual arousal induced by olfactory stimuli on the expression of neuromodulators, neurotransmitters and sexual steroid receptors in the suprachiasmatic nucleus (SCN, the circadian pacemaker of mammals) and other cerebral entities of Syrian hamsters (Mesocricetus auratus) compared to manual sleep deprivation and immobilization stress. The hamsters kept under a 12:12 hours (h) light:dark cycle were deprived of sleep by sexual stimulation, gentle manual handling or immobilization stress for 1 h at the beginning of the light phase and subsequently sacrificed at zeitgeber time 01:00, respectively; for comparison, hamsters were manually sleep deprived for 6 or 20 h or sacrificed after completing a full sleep phase. As demonstrated by immunohistochemistry, apart from various alterations after manual sleep deprivation, sexual stimulation caused down-regulation of arginine-vasopressin (AVP), vasointestinal peptide (VIP), serotonin (5-HT), substance P (SP), and met-enkephalin (ME) in the SCN. Somatostatin (SOM) was diminished in the medial periventricular nucleus (MPVN). In contrast, an increase in AVP was observed in the PVN, that of oxytocin (OXY) in the supraoptic nucleus (SON), of tyrosine-hydroxylase (TH) in the infundibular nucleus (IN), and dopamine beta-hydroxylase (DBH) in the A7 neuron population of the brain stem (A7), respectively. Testosterone in plasma was increased. The results indicate that sexual arousal extensively influences the neuropeptide systems of the SCN, suggesting an involvement of the SCN in reproductive behavior.
Rodent models of Parkinson’s disease are based on transgenic expression of mutant synuclein, deletion of PD genes, injections of MPTP or rotenone, or seeding of synuclein fibrils. The models show histopathologic features of PD such as Lewi bodies but mostly only subtle in vivo manifestations or systemic toxicity. The models only partly mimic a predominant loss of dopaminergic neurons in the substantia nigra. We therefore generated mice that express the transgenic diphtheria toxin receptor (DTR) specifically in DA neurons by crossing DAT-Cre mice with Rosa26 loxP-STOP-loxP DTR mice. After defining a well-tolerated DTx dose, DAT-DTR and DTR-flfl controls were subjected to non-toxic DTx treatment (5 × 100 pg/g) and subsequent histology and behavioral tests. DAT protein levels were reduced in the midbrain, and tyrosine hydroxylase-positive neurons were reduced in the substantia nigra, whereas the pan-neuronal marker NeuN was not affected. Despite the promising histologic results, there was no difference in motor function tests or open field behavior. These are tests in which double mutant Pink1−/−SNCAA53T Parkinson mice show behavioral abnormalities. Higher doses of DTx were toxic in both groups. The data suggest that DTx treatment in mice with Cre/loxP-driven DAT-DTR expression leads to partial ablation of DA-neurons but without PD-reminiscent behavioral correlates.
Peptide receptor radionuclide therapy (PRRT) of metastatic neuroendocrine tumors (NET) can be successfully repeated but may eventually be dose-limited. Since 177Lu-DOTATATE dose limitation may come from hematological rather than renal function, hematological peripheral blood stem cell backup might be desirable. Here, we report our initial experience of peripheral blood stem-cell collection (PBSC) in patients with treatment-related cytopenia and therefore high risk of bone-marrow failure. Five patients with diffuse bone-marrow infiltration of NET and relevant myelosuppression (≥grade 2) received PBSC before one PRRT cycle with 177Lu-DOTATATE (7.6 ± 0.8 GBq/cycle). Standard stem-cell mobilization with Granulocyte-colony stimulating factor (G-CSF) was applied, and successful PBSC was defined as a collection of >2 × 106/kg CD34+ cells. In case of initial failure, Plerixafor was administered in addition to G-CSF prior to apheresis. PBSC was successfully performed in all patients with no adverse events. Median cumulative activity was 44.8 GBq (range, 21.3–62.4). Three patients had been previously treated with PRRT, two of which needed the addition of Plerixafor for stem-cell mobilization. Only one of five patients required autologous peripheral blood stem-cell transplantation during the median follow up time of 28 months. PBSC collection seems to be feasible in NET with bone-marrow involvement and might be worth considering as a backup strategy prior to PRRT, in order to overcome dose-limiting bone-marrow toxicity.
Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders.
The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Most SARS-CoV-2 infections are mild or even asymptomatic. However, a small fraction of infected individuals develops severe, life-threatening disease, which is caused by an uncontrolled immune response resulting in hyperinflammation. However, the factors predisposing individuals to severe disease remain poorly understood. Here, we show that levels of CD47, which is known to mediate immune escape in cancer and virus-infected cells, are elevated in SARS-CoV-2-infected Caco-2 cells, Calu-3 cells, and air−liquid interface cultures of primary human bronchial epithelial cells. Moreover, SARS-CoV-2 infection increases SIRPalpha levels, the binding partner of CD47, on primary human monocytes. Systematic literature searches further indicated that known risk factors such as older age and diabetes are associated with increased CD47 levels. High CD47 levels contribute to vascular disease, vasoconstriction, and hypertension, conditions that may predispose SARS-CoV-2-infected individuals to COVID-19-related complications such as pulmonary hypertension, lung fibrosis, myocardial injury, stroke, and acute kidney injury. Hence, age-related and virus-induced CD47 expression is a candidate mechanism potentially contributing to severe COVID-19, as well as a therapeutic target, which may be addressed by antibodies and small molecules. Further research will be needed to investigate the potential involvement of CD47 and SIRPalpha in COVID-19 pathology. Our data should encourage other research groups to consider the potential relevance of the CD47/ SIRPalpha axis in their COVID-19 research.
A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0–3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-β signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.
Background: To test the effect of urological primary cancers (bladder, kidney, testis, upper tract, penile, urethral) on overall mortality (OM) after secondary prostate cancer (PCa). Methods: Within the Surveillance, Epidemiology and End Results (SEER) database, patients with urological primary cancers and concomitant secondary PCa (diagnosed 2004-2016) were identified and were matched in 1:4 fashion with primary PCa controls. OM was compared between secondary and primary PCa patients and stratified according to primary urological cancer type, as well as to time interval between primary urological cancer versus secondary PCa diagnoses. Results: We identified 5,987 patients with primary urological and secondary PCa (bladder, n = 3,287; kidney, n = 2,127; testis, n = 391; upper tract, n = 125; penile, n = 47; urethral, n = 10) versus 531,732 primary PCa patients. Except for small proportions of Gleason grade group and age at diagnosis, PCa characteristics between secondary and primary PCa were comparable. Conversely, proportions of secondary PCa patients which received radical prostatectomy were smaller (29.0 vs. 33.5%), while no local treatment rates were higher (34.2 vs. 26.3%). After 1:4 matching, secondary PCa patients exhibited worse OM than primary PCa patients, except for primary testis cancer. Here, no OM differences were recorded. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis. Conclusions: After detailed matching for PCa characteristics, secondary PCa patients exhibit worse survival, except for testis cancer patients. The survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary urological cancer diagnosis.
Objective: To evaluate the prognostic impact of gastrointestinal involvement on the survival of children with Langerhans cell histiocytosis (GI-LCH) registered with the international clinical trials of the Histiocyte Society. Study design: This was a retrospective analysis of 2414 pediatric patients registered onto the consecutive trials DAL-HX 83, DAL-HX 90, LCH-I, LCH-II, and LCH-III. Results: Among the 1289 patients with single-system LCH, there was no single case confined to the GI tract; 114 of 1125 (10%) patients with multisystem LCH (MS-LCH) had GI-LCH at initial presentation. GI-LCH was significantly more common in children aged <2 years at diagnosis (13% vs 6% in those aged >2 years; P < .001) and in those with risk organ involvement (15% vs 6% in those without risk organ involvement; P < .001). The 5-year overall survival (OS) in patients without risk organ involvement was excellent irrespective of GI disease (98% vs 97% in patients with GI-LCH; P = .789). In patients with risk organ involvement, the 5-year OS was 51% in 70 patients with GI-LCH vs 72% in 394 patients without GI-LCH (P < .001). Conclusions: GI-LCH has an additive unfavorable prognostic impact in children with MS-LCH and risk organ involvement. The emerding need for more intensive or alternative treatments mandates prospective evaluation.
Objective: The term ‘precision medicine’ describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy. Methods: A systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management. Results: We included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, >50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%). Significance: Our survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.
Abstract: Neurophysiological measures of preparation and attention are often atypical in ADHD. Still, replicated findings that these measures predict which patients improve after Neurofeedback (NF), reveal neurophysiological specificity, and reflect ADHD-severity are limited. Methods: We analyzed children’s preparatory (CNV) and attentional (Cue-P3) brain activity and behavioral performance during a cued Continuous Performance Task (CPT) before and after slow cortical potential (SCP)-NF or semi-active control treatment (electromyogram biofeedback). Mixed-effects models were performed with 103 participants at baseline and 77 were assessed for pre-post comparisons focusing on clinical outcome prediction, specific neurophysiological effects of NF, and associations with ADHD-severity. Results: Attentional and preparatory brain activity and performance were non-specifically reduced after treatment. Preparatory activity in the SCP-NF group increased with clinical improvement. Several performance and brain activity measures predicted non-specific treatment outcome. Conclusion: Specific neurophysiological effects after SCP-NF were limited to increased neural preparation associated with improvement on ADHD-subscales, but several performance and neurophysiological measures of attention predicted treatment outcome and reflected symptom severity in ADHD. The results may help to optimize treatment.
Selfish genetic elements that act as post-segregation distorters cause lethality in non-carrier individuals after fertilization. Two post-segregation distorters have been previously identified in Caenorhabditis elegans, the peel-1/zeel-1 and the sup-35/pha-1 elements. These elements seem to act as modification-rescue systems, also called toxin/antidote pairs. Here we show that the maternal-effect toxin/zygotic antidote pair sup-35/pha-1 is required for proper expression of apical junction (AJ) components in epithelia and that sup-35 toxicity increases when pathways that establish and maintain basal epithelial characteristics, die-1, elt-1, lin-26, and vab-10, are compromised. We demonstrate that pha-1(e2123) embryos, which lack the antidote, are defective in epidermal morphogenesis and frequently fail to elongate. Moreover, seam cells are frequently misshaped and mispositioned and cell bond tension is reduced in pha-1(e2123) embryos, suggesting altered tissue material properties in the epidermis. Several aspects of this phenotype can also be induced in wild-type embryos by exerting mechanical stress through uniaxial loading. Seam cell shape, tissue mechanics, and elongation can be restored in pha-1(e2123) embryos if expression of the AJ molecule DLG-1/Discs large is reduced. Thus, our experiments suggest that maternal-effect toxicity disrupts proper development of the epidermis which involves distinct transcriptional regulators and AJ components.
Background: This study aims to test the effect of the 10 most common nonurological primary cancers (skin, rectal, colon, lymphoma, leukemia, pancreas, stomach, esophagus, liver, lung) on overall mortality (OM) after secondary prostate cancer (PCa). Material and Methods: Within the Surveillance, Epidemiology, and End Results (SEER) database, patients with 10 most common primary cancers and concomitant secondary PCa (diagnosed 2004–2016) were identified and were matched in 1:4 fashion (age, year at diagnosis, race/ethnicity, treatment type, TNM stage) with primary PCa controls. OM was compared between secondary and primary PCa patients and was stratified according to primary cancer type, as well as according to time interval between primary cancer vs. secondary PCa diagnoses. Results: We identified 24,848 secondary PCa patients (skin, n = 3,871; rectal, n = 798; colon, n = 3,665; lymphoma, n = 2,583; leukemia, n = 1,102; pancreatic, n = 118; stomach, n = 361; esophagus, n = 219; liver, n = 160; lung, n = 1,328) vs. 531,732 primary PCa patients. Secondary PCa characteristics were less favorable than those of primary PCa patients (PSA and grade), and smaller proportions of secondary PCa patients received active treatment. After 1:4 matching, all secondary PCa exhibited worse OM than primary PCa patients. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis and subsequent secondary PCa. Conclusion: Patients with secondary PCa are diagnosed with less favorable PSA and grade. Even after matching for PCa characteristics, secondary PCa patients still exhibit worse survival. However, the survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary cancer diagnosis.
1. Zusammenfassung
1.1. Zielsetzung
Die hier beschriebene Studie vergleicht die effektive Linsenposition (ELP), die Vorderkammertiefenveränderung und den korrigierten Fernvisus nach einer Kataraktoperation bei Patienten mit und ohne Pseudoexfoliationssyndrom (PEX-Syndrom). Bei Patienten mit einem koexistierenden PEX-Syndrom wird während der Kataraktoperation eine Zonulaschwächen bedingte Verlagerung und tiefere Positionierung der eingesetzten Intraokular-linse erwartet.
1.2. Design
Prospektiv, randomisiert.
1.3. Methoden
In dieser prospektiven Studie wurden 56 Augen von 56 konsekutiven Patienten mit PEX-Syndrom (n = 28) oder ohne PEX-Syndrom (n = 28) und klinisch signifikanter Katarakt eingeschlossen. Sämtlichen Patienten beider Gruppen wurde mittels Phakoemulsifikation eine einteilige Acryl-Hinterkammer-Intraokularlinse implantiert. Als primäre Zielparameter der Studie dienten die Vorderkammertiefe als Indikator für die postoperative axiale Position der IOL benannt als die effektive Linsenposition sowie der korrigierte Fernvisus.
1.4. Ergebnisse
Vor der Operation betrug die Vorderkammertiefe (VKT) 2,54 ± 0,42 mm in der PEX-Gruppe und 2,53 ± 0,38 mm in der Kontrollgruppe (p = 0,941). Postoperativ betrug die VKT 4,29 ± 0,71 mm in der PEX-Gruppe bzw. 4,33 ± 0,72 mm in der Normalgruppe (p = 0,533). Es gab keinen signifikanten Unterschied in Bezug auf die Veränderungen der VKT zwischen den Gruppen (PEX-Gruppe: 1,75 ± 0,74 mm, Kontrollgruppe: 1,81 ± 0,61 mm, p = 0,806) und dem korrigierten Fernvisus (DCVA) prä- (p = 0,469) sowie postoperativ (PEX-Gruppe: 0,11 ± 0,13 logMAR, Kontrollgruppe: 0,09 ± 0,17 logMAR, p = 0,245).
1.5. Schlussfolgerung
Die Kataraktoperation induzierten Veränderungen waren bei Patienten, die an einem PEX-Syndrom erkrankt waren, die gleichen, die auch bei Patienten ohne PEX-Syndrom zu beobachten waren. Die präoperative und postoperative Vorderkammertiefe, als Indikator für die ELP, zeigte zwischen PEX-Augen und gesunden Augen nach der Kataraktoperation keine signifikanten Unterschiede. Des Weiteren waren keine Unterschiede in Bezug auf den korrigierten Fernvisus zwischen beiden Gruppen zu beobachten. Demnach ist zu erwarten, dass eine Erkrankung am PEX-Syndrom bei einer durch einen erfahrenen Chirurgen durchgeführten Kataraktoperation nicht zu einer Verschlechterung des Visus oder einer tieferen Positionierung der eingesetzten Intraokularlinse führt.
Background: Patients with colorectal carcinoma and high-grade microsatellite instability (MSI-H) or deficiency in mismatch repair (dMMR) exceptionally respond to immune checkpoint inhibitors (ICIs). ICIs are more active in treatment-naïve patients than in patients with refractory MSI-H/dMMR metastatic colorectal cancer and even more active in patients with locally advanced tumors. Material and Methods: A 33-year-old male patient with Lynch syndrome was diagnosed with a locally advanced rectal cancer and refused standard neoadjuvant chemoradiation because of the potential harm of sexual dysfunction. MMR and microsatellite instability status were analyzed by immunohistochemistry and fragment length polymerase chain reaction followed by capillary electrophoresis. Results: After MSI-H/dMMR was confirmed, the patient was treated with ICIs (1 mg/kg ipilimumab at day 1 and 3 mg/kg nivolumab at day 1 and 15). A complete clinical response was documented at day 21 after start of treatment. The patient underwent a total mesorectal excision at day 30. In the extirpated tissue, a complete pathological response was confirmed. Conclusion: In MSI-H/dMMR locally advanced rectal cancer short-course ICI treatment is highly effective and may be discussed in patients with dMMR locally advanced rectal cancer.
Background: To analyze postoperative, in-hospital, complication rates in patients with organ transplantation before radical prostatectomy (RP). Methods: From National Inpatient Sample (NIS) database (2000–2015) prostate cancer patients treated with RP were abstracted and stratified according to prior organ transplant versus nontransplant. Multivariable logistic regression models predicted in-hospital complications. Results: Of all eligible 202,419 RP patients, 216 (0.1%) underwent RP after prior organ transplantation. Transplant RP patients exhibited higher proportions of Charlson comorbidity index ≥2 (13.0% vs. 3.0%), obesity (9.3% vs. 5.6%, both p < 0.05), versus to nontransplant RP. Of transplant RP patients, 96 underwent kidney (44.4%), 44 heart (20.4%), 40 liver (18.5%), 30 (13.9%) bone marrow, <11 lung (<5%), and <11 pancreatic (<5%) transplantation before RP. Within transplant RP patients, rates of lymph node dissection ranged from 37.5% (kidney transplant) to 60.0% (bone marrow transplant, p < 0.01) versus 51% in nontransplant patients. Regarding in-hospital complications, transplant patients more frequently exhibited, diabetic (31.5% vs. 11.6%, p < 0.001), major (7.9% vs. 2.9%) cardiac complications (3.2% vs. 1.2%, p = 0.01), and acute kidney failure (5.1% vs. 0.9%, p < 0.001), versus nontransplant RP. In multivariable logistic regression models, transplant RP patients were at higher risk of acute kidney failure (odds ratio [OR]: 4.83), diabetic (OR: 2.81), major (OR: 2.39), intraoperative (OR: 2.38), cardiac (OR: 2.16), transfusion (OR: 1.37), and overall complications (1.36, all p < 0.001). No in-hospital mortalities were recorded in transplant patients after RP. Conclusions: Of all transplants before RP, kidney ranks first. RP patients with prior transplantation have an increased risk of in-hospital complications. The highest risk, relative to nontransplant RP patients appears to acute kidney failure.
The majority of excitatory synapses terminating on cortical neurons are found on dendritic spines. The geometry of spines, in particular the size of the spine head, tightly correlates with the strength of the excitatory synapse formed with the spine. Under conditions of synaptic plasticity, spine geometry may change, reflecting functional adaptations. Since the cytokine tumor necrosis factor (TNF) has been shown to influence synaptic transmission as well as Hebbian and homeostatic forms of synaptic plasticity, we speculated that TNF-deficiency may cause concomitant structural changes at the level of dendritic spines. To address this question, we analyzed spine density and spine head area of Alexa568-filled granule cells in the dentate gyrus of adult C57BL/6J and TNF-deficient (TNF-KO) mice. Tissue sections were double-stained for the actin-modulating and plasticity-related protein synaptopodin (SP), a molecular marker for strong and stable spines. Dendritic segments of TNF-deficient granule cells exhibited ∼20% fewer spines in the outer molecular layer of the dentate gyrus compared to controls, indicating a reduced afferent innervation. Of note, these segments also had larger spines containing larger SP-clusters. This pattern of changes is strikingly similar to the one seen after denervation-associated spine loss following experimental entorhinal denervation of granule cells: Denervated granule cells increase the SP-content and strength of their remaining spines to homeostatically compensate for those that were lost. Our data suggest a similar compensatory mechanism in TNF-deficient granule cells in response to a reduction in their afferent innervation.
Aim: It can be challenging to distinguish COVID-19 in children from other common infections. We set out to determine the rate at which children consulting a primary care paediatrician with an acute infection are infected with SARS-CoV-2 and to compare distinct findings. Method: In seven out-patient clinics, children aged 0–13 years with any new respiratory or gastrointestinal symptoms and presumed infection were invited to be tested for SARS-CoV-2. Factors that were correlated with testing positive were determined. Samples were collected from 25 January 2021 to 01 April 2021. Results: Seven hundred and eighty-three children participated in the study (median age 3 years and 0 months, range 1 month to 12 years and 11 months). Three hundred and fifty-eight were female (45.7%). SARS-CoV-2 RNA was detected in 19 (2.4%). The most common symptoms in children with as well as without detectable SARS-CoV-2 RNA were rhinitis, fever and cough. Known recent exposure to a case of COVID-19 was significantly correlated with testing positive, but symptoms or clinical findings were not. Conclusion: COVID-19 among the children with symptoms of an acute infection was uncommon, and the clinical presentation did not differ significantly between children with and without evidence of an infection with SARS-CoV-2.
Introduction: Adeno-associated virus (AAV)-based gene therapy for haemophilia presents a challenge to the existing structure of haemophilia centres and requires a rethink of current collaboration and information exchange with the aim of ensuring a system that is fit-for-purpose for advanced therapies to maximise benefits and minimise risks. In Europe, a certification process based on the number of patients and facilities is offered to the haemophilia centres by European Haemophilia Network (EUHANET). Aim and methods: This joint European Association for Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) publication describes criteria for centres participating in gene therapy care that require a reassessment of the infrastructure of comprehensive care and provides an outlook on how these criteria can be implemented in the future work of haemophilia centres. Results: The core definition of a haemophilia treatment centre remains, but additional roles could be implemented. A modifiable ‘hub-and-spoke’ model addresses all aspects associated with gene therapy, including preparation and administration of the gene therapy product, determination of coagulation and immunological parameters, joint.
Introduction: Over the last decade, multiple clinical trials demonstrated improved survival after chemotherapy for metastatic prostate cancer (mPCa). However, real-world data validating this effect within large-scale epidemiological data sets are scarce. We addressed this void. Materials and Methods: Men with de novo mPCa were identified and systemic chemotherapy status was ascertained within the Surveillance, Epidemiology, and End Results database (2004–2016). Patients were divided between historical (2004–2013) versus contemporary (2014–2016). Chemotherapy rates were plotted over time. Kaplan–Meier plots and Cox regression models with additional multivariable adjustments addressed overall and cancer-specific mortality. All tests were repeated in propensity-matched analyses. Results: Overall, 19,913 patients had de novo mPCa between 2004 and 2016. Of those, 1838 patients received chemotherapy. Of 1838 chemotherapy-exposed patients, 903 were historical, whereas 905 were contemporary. Chemotherapy rates increased from 5% to 25% over time. Median overall survival was not reached in contemporary patients versus was 24 months in historical patients (hazard ratio [HR]: 0.55, p < 0.001). After propensity score matching and additional multivariable adjustment (age, prostate-specific antigen, GGG, cT-stage, cN-stage, cM-stage, and local treatment) a HR of 0.55 (p < 0.001) was recorded. Analyses were repeated for cancer-specific mortality after adjustment for other cause mortality in competing risks regression models and recorded virtually the same findings before and after propensity score matching (HR: 0.55, p < 0.001). Conclusions: In mPCa patients, chemotherapy rates increased over time. A concomitant increase in survival was also recorded.
Purpose: To evaluate the impact of testing asymptomatic cancer patients, we analyzed all tests for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) before and during radiotherapy at a tertiary cancer center throughout the second wave of the pandemic in Germany. Methods: Results of all real-time polymerase chain reaction (RT-PCR) tests for SARS-CoV 2 performed at our radio-oncology department between 13 October 2020 and 11 March 2021 were included. Clinical data and anamnestic information at the time of testing were documented and examined for (i) the presence of COVID-19-related symptoms and (ii) virus-related anamnesis (high-risk [prior positive test or contact to a positive tested person within the last 14 days] or low-risk [inconspicuous anamnesis within the last 14 days]). Results: A total of 1056 SARS-CoV 2 tests in 543 patients were analyzed. Of those, 1015 tests were performed in asymptomatic patients and 41 tests in patients with COVID-19-associated symptoms. Two of 940 (0.2%) tests in asymptomatic patients with low-risk anamnesis and three of 75 (4.0%) tests in asymptomatic patients with high-risk anamnesis showed a positive result. For symptomatic patients, SARS-CoV 2 was detected in three of 36 (8.3%) low-risk and three of five (60.0%) high-risk tests. Conclusion: To the best of our knowledge, this is the first study evaluating the correlation between individual risk factors and positivity rates of SARS-CoV 2 tests in cancer patients. The data demonstrate that clinical and anamnestic assessment is a simple and effective measure to distinctly increase SARS-CoV 2 test efficiency. This might enable cancer centers to adjust test strategies in asymptomatic patients, especially when test resources are scarce.
Interpretation bias and dysfunctional social assumptions are proposed to play a pivotal role in the development and maintenance of social phobia (SP), especially in youth. In this study, we aimed to investigate disorder-specific implicit assumptions of rejection and implicit interpretation bias in youth with severe, chronic SP and healthy controls (CG). Twenty-seven youth with SP in inpatient/day-care treatment (M age = 15.6 years, 74% female) and 24 healthy controls (M age = 15.7 years, 54% female) were included. The Implicit Association Test (IAT) and the Affect Misattribution Procedure (AMP) were completed to assess implicit assumptions and interpretation bias related to the processing of social and affective stimuli. No group differences were observed for the IAT controlling for depressive symptoms in the analyses. However, group differences were found regarding interpretation bias (p = .017, η2p = .137). Correlations between implicit scores and explicit questionnaire results were medium to large in the SP group (r =|.28| to |.54|, pall ≤ .05), but lower in the control group (r =|.04| to |.46|, pall ≤ .05). Our results confirm the finding of an interpretation bias in youth SP, especially regarding the implicit processing of faces, whereas implicit dysfunctional social assumptions of being rejected do not seem to be specific for SP. Future research should investigate the causal relationship of assumptions/interpretation bias and SP.
Estimating the age of the developmental stages of the blow fly Calliphora vicina (Diptera: Calliphoridae) is of forensic relevance for the determination of the minimum post-mortem interval (PMImin). Fly eggs and larvae can be aged using anatomical and morphological characters and their modification during development. However, such methods can only hardly be applied for aging fly pupae. Previous study described age estimation of C. vicina pupae using gene expression, but just when reared at constant temperatures, but fluctuating temperatures represent a more realistic scenario at a crime scene. Therefore, age-dependent gene expression of C. vicina pupae were compared at 3 fluctuating and 3 constant temperatures, the latter representing the mean values of the fluctuating profiles. The chosen marker genes showed uniform expression patterns during metamorphosis of C. vicina pupae bred at different temperature conditions (constant or fluctuating) but the same mean temperature (e.g. constant 10 °C vs. fluctuating 5–15 °C). We present an R-based statistical tool, which enables estimation of the age of the examined pupa based on the analysed gene expression data.
Sprach- und Sprechstörungen kommen bei zahlreichen Kindern vor und werden in der ICD-11 analog zur ICD-10 als Entwicklungsstörungen im Kapitel 6 (Psychische, Verhaltens- und Entwicklungsstörungen) klassifiziert. International sind bislang die ICD-10-Kriterien nicht von allen Professionen, die sich mit Sprach- und Sprechstörungen klinisch oder im Rahmen der Forschung beschäftigen, akzeptiert. Sie werden einerseits als zu wenig differenziert hinsichtlich der unterschiedlichen Sprachkomponenten vonseiten der Linguistik, Sprachtherapie oder Logopädie erlebt. Zum anderen wird die unklare Abgrenzung organisch bedingter Sprach- und Sprechprobleme von der Sprachentwicklungsstörung vonseiten der Medizin teilweise kritisch bewertet. In dem vorliegenden Artikel wird deshalb einerseits die Klassifikation von Sprach- und Sprechproblemen und -störungen in der ICD-11 im Vergleich zur ICD-10 vorgenommen. Wesentlich erscheint hier die in der ICD-11 neu eingeführte Differenzierung in „primäre“ und „sekundäre“ Neuroentwicklungsstörungen. Zum anderen erfolgt aber auch eine Auseinandersetzung mit dem DSM-5 sowie anderen Klassifikationsvorschlägen vonseiten der englischsprachigen Sprachtherapie (CATALISE-2) und der deutschsprachigen Pädaudiologie („phonologische Wahrnehmungsstörung“) sowie der Vorschlag einer Ergänzung der aktuellen ICD-11-Klassifikation hinsichtlich konkreter sprachlicher Einschränkungen bei einem Kind mit Sprachentwicklungsstörung, basierend auf einer ausführlichen Diagnostik. Wir hoffen, mit dem Artikel so den Weg für eine berufsübergreifende Klassifikation von Sprach- und Sprechstörungen nach ICD-11 zu bahnen, damit perspektivisch alle Berufsgruppen, die Diagnostik und Therapie der betroffenen Personen anbieten, eine vergleichbare Terminologie verwenden. Diese vergleichbare Terminologie soll sowohl die klinische Versorgung verbessern als auch die unterschiedlichen Forschungsansätze und -richtungen vergleichbarer machen.
Der Einfluss von Chemotherapie bei malignen pädiatrischen Erkrankungen auf kindliche Impftiter
(2021)
Hintergrund: Chemotherapie hat nicht nur einen Einfluss auf die Krebszellen, sondern auch auf das Immunsystem der Behandelten. In unserer Studie untersuchten wir den Impftiterverlust impfpräventablen Erkrankungen (Masern, Mumps, Röteln und Varizella zoster) bei Kindern und Jugendlichen, welche eine chemotherapeutische Behandlung wegen einer malignen Erkrankung erhielten.
Methoden: Eingeschlossen in die retrospektive Studie wurden Kinder, Jugendliche und junge Erwachsene im Alter bis zum 21. Lebensjahr, welche zwischen 2001 und 2010 an der Kinderklinik für Hämatologie und Onkologie der Universitätsklinik Frankfurt am Main therapiert wurden. Es erfolgte die Analyse von Antikörper-Titer für Masern, Mumps, Röteln und Varizella zoster zum Diagnosezeitpunkt und erneut bis zu 12 Monate nach Therapieende.
Ergebnis: Insgesamt konnten 195 Kinder und Jugendliche in die Studie eingeschlossen werden. 122 Probanden waren männlich, 73 weiblich. Die größte Patientengruppe war an ALL erkrankt (80 Patienten). Die übrigen Patienten verteilten sich auf 15 Patienten mit AML, 18 Patienten mit NHL, 22 Patienten mit Hodgkin Lymphom. 60 Patienten waren an soliden Tumoren erkrankt. Insgesamt haben 27%, 47%, 19% und 17% der Kinder und Jugendlichen ihren Impfschutz gegen Masern, Mumps, Röteln und Varizella zoster verloren. Hierbei zeigte sich eine Altersabhängigkeit. In der Auswertung zeigte sich bei jüngeren Kindern unter 7 Jahren häufiger ein Titerverlust als bei den älteren Kindern und Jugendlichen. Auch an ALL-erkrankte und behandelte Kinder und Jugendliche verloren häufiger ihren Impfschutz als die Patienten mit anderen untersuchten Krebserkrankungen (AML, NHL, M. Hodgkin, solide Tumore).
Fazit: Die Daten unserer retrospektiven Studie zeigen, dass eine signifikante Anzahl von Kindern und Jugendlichen durch eine chemotherapeutischen Behandlung ihre vorbestehenden Impftiter gegen impfpräventable Erkrankungen wie Masern, Mumps, Röteln und Varizella zoster verlieren. Dieser Verlust zeigt sich häufiger bei jüngeren Patienten und ALL-Patienten. Unsere Daten unterstreichen daher, wie wichtig es ist, Kinder und Jugendliche nach Beendigung der Chemotherapie erneut zu impfen, um einen neuen ausreichenden Impfschutz gegen Masern, Mumps, Röteln und Varizella zoster zu erhalten.
The locus coeruleus (LC) contains the majority of central noradrenergic neurons sending wide projections throughout the entire CNS. The LC is considered to be essential for multiple key brain functions including arousal, attention and adaptive stress responses as well as higher cognitive functions and memory. Electrophysiological studies of LC neurons have identified several characteristic functional features such as low-frequency pacemaker activity with broad action potentials, transient high-frequency burst discharges in response to salient stimuli and an apparently homogeneous inhibition of firing by activation of somatodendritic α2 autoreceptors (α2AR). While stress-mediated plasticity of the α2AR response has been described, it is currently unclear whether different LC neurons projecting to distinct axonal targets display differences in α2AR function. Using fluorescent beads-mediated retrograde tracing in adult C57Bl6/N mice, we compared the anatomical distributions and functional in vitro properties of identified LC neurons projecting either to medial prefrontal cortex, hippocampus or cerebellum. The functional in vitro analysis of LC neurons confirmed their mostly uniform functional properties regarding action potential generation and pacemaker firing. However, we identified significant differences in tonic and evoked α2AR-mediated responses. While hippocampal-projecting LC neurons were partially inhibited by endogenous levels of norepinephrine and almost completely silenced by application of saturating concentrations of the α2 agonist clonidine, prefrontal-projecting LC neurons were not affected by endogenous levels of norepinephrine and only partially inhibited by saturating concentrations of clonidine. Thus, we identified a limited α2AR control of electrical activity for prefrontal-projecting LC neurons indicative of functional heterogeneity in the LC-noradrenergic system.
The precise understanding of the dopaminergic (DA) system and its pharmacological modifications is crucial for diagnosis and treatment of neuropsychiatric disorders, as well as for understanding basic processes, such as motivation and reward. We probed the functional connectivity (FC) of subcortical nuclei related to the DA system according to seed regions defined according to an atlas of subcortical nuclei. We conducted a large pharmaco-fMRI study using a double-blind, placebo-controlled design, where we examined the effect of l -DOPA, a dopamine precursor, and amisulpride, a D2/D3-receptor antagonist on resting-state FC in 45 healthy young adults using a cross-over design. We examined the FC of subcortical nuclei with connection to the reward system and their reaction to opposing pharmacological probing. Amisulpride increased FC from the putamen to the precuneus and from ventral striatum to precentral gyrus. l -DOPA increased FC from the ventral tegmental area (VTA) to the insula/operculum and between ventral striatum and ventrolateral prefrontal cortex and it disrupted ventral striatal and dorsal caudate FC with the medial prefrontal cortex. In an exploratory analysis, we demonstrated that higher self-rated impulsivity goes together with a significant increase in VTA-mid-cingulate gyrus FC during l -DOPA-challenge. Therefore, our DA challenge modulated distinct large-scale subcortical connectivity networks. A dopamine-boost can increase midbrain DA nuclei connectivity to the cortex. The involvement of the VTA-cingulum connectivity in dependence of impulsivity has implications for diagnosis and therapy in disorders like ADHD.
The physiotherapist plays an essential role for people with haemophilia, an inherited bleeding disease responsible for musculoskeletal complications. Yet, with the advent of new and advanced therapies, the medical landscape is changing, and physiotherapy must adapt alongside. This paper considers whether there will still be a need for physiotherapy in the era of advanced therapies, and discusses ways in which services should evolve to complement emerging treatment paradigms for haemostasis in people with haemophilia. Ultimately, physiotherapy will remain an important element of care, even for people with little joint damage and low risks in the era of the new mild phenotype. However, competencies will need to evolve, and physiotherapists in both primary care and specialist treatment centres should work with haematology colleagues to develop more sensitive tools for detecting early joint changes. Physiotherapists will also play a crucial role in counselling and physically coaching, monitoring the musculoskeletal status of people with haemophilia who have transitioned to new treatments.
Unter dem vielseitigen Symptomkomplex der autosomal-rezessiv vererbten Erkrankung Ataxia-teleangiectasia (A-T) nimmt die Lungenschädigung eine herausragende Rolle ein. Sie beeinflusst die Morbidität und Mortalität der Erkrankung durch rezidivierende Infekte, Bronchiektasien sowie akutes oder chronisches Lungenversagen nachhaltig. Als pathophysiologische Grundlage gilt oxidativer Stress mit einer erhöhten Sensitivität für reaktive Sauerstoffspezies (ROS) und DNA-schädigende Reagenzien. Das aus dem gleichnamigen Gen resultierende Protein ATM wird durch das Vorkommen von DNADoppelstrangbrüchen (DSB) und ROS auf verschiedene Arten aktiviert und reguliert anschließend diverse Prozesse wie der DNA-Reparatur und den zellulären Stressantwortmechanismen. Ziel dieser Arbeit war es die Sensitivität von ATM-defizienten Lungenzellen im Hinblick auf oxidativen Stress näher zu untersuchen. Hierfür wurden Atm-defiziente murine Lungenzellen spontan und nach Stimulation mit Bleomycin (BLM) auf ihre prozentuale Verteilung in der Lunge, auf den Level von ROS, ihre Viabilität und ROS-induzierte DNA-Schäden hin untersucht. Spontan zeigte sich ein signifikant erhöhtes Vorkommen von Alveolarepithelzellen vom Typ 2 (AT2-Zellen) in Atm-defizienten Mauslungen im Vergleich zu Wildtyp-Lungen, welches sich durch die Stimulation mit BLM noch verstärkte und auf erhöhte Regenerations- und Reparaturvorgänge in der Lunge hindeutet. Zudem ist der intrazelluläre Level an ROS in den Lungenzellen und AT2-Zellen signifikant erhöht. Mit steigenden Konzentrationen an BLM sank die Zellviabilität pulmonaler Atm-defizienter Zellen deutlich und die Resolution von DNA-Schäden ist im Vergleich zu Wildtyp-Zellen verzögert. Die Ergebnisse der Arbeit deuten auf eine Beteiligung von oxidativem Stress und DNA-Schäden als pathophysiologische Komponente bei der Entstehung der Lungenmanifestation bei A-T hin.
Given the ongoing global SARS-CoV-2-vaccination efforts, clinical awareness needs to be raised regarding the possibility of an increased incidence of SARS-CoV-2-vaccine-related immune-mediated thrombocytopenia in patients with intracerebral hemorrhage (ICH) secondary to cerebral sinus and vein thrombosis (CVT) requiring (emergency) neurosurgical treatment in the context of vaccine-induced immune thrombotic thrombocytopenia (VITT). Only recently, an association of vaccinations and cerebral sinus and vein thrombosis has been described. In a number of cases, neurosurgical treatment is warranted for these patients and special considerations are warranted when addressing the perioperative coagulation. We, herein, describe the past management of patients with VITT and established a literature-guided algorithm for the treatment of patients when addressing the impaired coagulation in these patients. Increasing insights addressing the pathophysiology of SARS-CoV-2-vaccine-related immune-mediated thrombocytopenia guide physicians in developing an interdisciplinary algorithm taking into account the special considerations of this disease.
Background: Both selective mutism (SM) and social anxiety disorder (SAD) are severe pediatric anxiety disorders with the common trait of behavioral inhibition (BI). The underlying pathophysiology of these disorders remains poorly understood, however converging evidence suggests that alterations in several peripheral molecular pathways might be involved. In a pilot study, we investigated alterations in plasma molecular markers (dipeptidyl peptidase-4 [DPPIV], interleukin-6 [IL-6], tumor necrosis factor-β [TNF-β] and neuropeptide-Y [NPY]) in children with SM, SAD, and healthy controls, as well as the correlation of these markers to symptom severity. Methods: We included 51 children and adolescents (aged 5–18 years; n = 29 girls): n = 20 children in the SM-, n = 16 in the SAD- and n = 15 in the control-group (CG). Peripheral blood samples were analyzed for DPPIV, IL-6, TNF-β, and NPY concentrations. Diverse psychometric measures were used for BI, anxiety, and mutism symptoms. Results: Lower DPPIV-levels were correlated with more anxiety symptoms. However, we could not find a difference in any molecular marker between the patients with SAD and SM in comparison to the CG. Conclusion: DPPIV is proposed as relevant marker for child and adolescent anxiety. Investigating the pathophysiology of SM and SAD focusing on state and trait variables as anxiety or BI might help better understanding the underlying mechanisms of these disorders. Further studies with especially larger cohorts are needed to validate the current pilot-findings.
Since the survival rates of pediatric patients undergoing cancer treatment or hematopoietic stem cell transplantation (HSCT) have increased rapidly in recent decades, the late effects of treatment are now an important focus of patient care. Access to fertility preservation (FP) procedures as well as their financing differs considerably across Europe. However, some countries in Europe have recently changed the legal basis for financing FP procedures; therefore, the implementation of structures is mandatory to give patients access to FP. In this prospective cohort study, we characterized the process for establishing pediatric fertility counseling, including the development of an in-house standard procedure for recommendations regarding FP with potentially gonadotoxic treatment and valuating data from all FP counseling sessions. All data concerning patient characteristics (pubertal status, disease group) and recommendation of FP measures were prospectively collected and adoption of FP measures analyzed. Prior to the establishment of a structured process for FP in our pediatric oncology and stem cell transplantation center, there was no standardized FP counseling. We demonstrate that with the establishment of an inhouse standard procedure, it is possible to give consistent yet individualized FP counseling to approximately 90% of our patients facing gonadotoxic treatment, counseling over 200 patients between 2017 and 2019. This pilot study could potentially be adapted in other pediatric hematology, oncology, and stem cell transplantation centers to allow a more standardized handling of FP counseling for all patients facing gonadotoxic treatment.
Purpose: To investigate short-term (3 months follow-up) changes in visual quality following Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy (FED). Methods: In this prospective institutional case series, 51 patients that underwent DMEK for FED were included. Assessment included the Quality of Vision (QoV) questionnaire preoperatively, at 1 month, and 3 months after surgery. Secondary outcome measures were anterior segment parameters acquired by Scheimpflug imaging, corrected distance visual acuity (CDVA), and endothelial cell density (ECD). Results: Glare, hazy vision, blurred vision, and daily fluctuation in vision were the symptoms mostly reported preoperatively. All symptoms demonstrated a significant reduction of item scores for severity, frequency, and bothersome in the course after DMEK (P < 0.01). Glare and fluctuation in vision remained to some extent during the follow-up period (median score = 1). Preoperatively, corneal densitometry correlated moderately to weakly with severity of hazy vision (rs = 0.39; P = 0.03) and frequency (rs = 0.26; P = 0.02) as well as severity (rs = 0.27; P = 0.03) of blurry vision. CDVA and central corneal thickness (CCT) did not correlate with visual complains. Conclusions: Following DMEK for FED, patient-reported visual symptoms assessed by the QoV questionnaire represent a useful tool providing valuable information on the impact of DMEK on visual quality that cannot be directly estimated by morphological parameters and visual acuity only.
Background: SAMHD1 mediates resistance to anti-cancer nucleoside analogues, including cytarabine, decitabine, and nelarabine that are commonly used for the treatment of leukaemia, through cleavage of their triphosphorylated forms. Hence, SAMHD1 inhibitors are promising candidates for the sensitisation of leukaemia cells to nucleoside analogue-based therapy. Here, we investigated the effects of the cytosine analogue CNDAC, which has been proposed to be a SAMHD1 inhibitor, in the context of SAMHD1. Methods: CNDAC was tested in 13 acute myeloid leukaemia (AML) cell lines, in 26 acute lymphoblastic leukaemia (ALL) cell lines, ten AML sublines adapted to various antileukaemic drugs, 24 single cell-derived clonal AML sublines, and primary leukaemic blasts from 24 AML patients. Moreover, 24 CNDAC-resistant sublines of the AML cell lines HL-60 and PL-21 were established. The SAMHD1 gene was disrupted using CRISPR/Cas9 and SAMHD1 depleted using RNAi, and the viral Vpx protein. Forced DCK expression was achieved by lentiviral transduction. SAMHD1 promoter methylation was determined by PCR after treatment of genomic DNA with the methylation-sensitive HpaII endonuclease. Nucleoside (analogue) triphosphate levels were determined by LC-MS/MS. CNDAC interaction with SAMHD1 was analysed by an enzymatic assay and by crystallisation. Results: Although the cytosine analogue CNDAC was anticipated to inhibit SAMHD1, SAMHD1 mediated intrinsic CNDAC resistance in leukaemia cells. Accordingly, SAMHD1 depletion increased CNDAC triphosphate (CNDAC-TP) levels and CNDAC toxicity. Enzymatic assays and crystallisation studies confirmed CNDAC-TP to be a SAMHD1 substrate. In 24 CNDAC-adapted acute myeloid leukaemia (AML) sublines, resistance was driven by DCK (catalyses initial nucleoside phosphorylation) loss. CNDAC-adapted sublines displayed cross-resistance only to other DCK substrates (e.g. cytarabine, decitabine). Cell lines adapted to drugs not affected by DCK or SAMHD1 remained CNDAC sensitive. In cytarabine-adapted AML cells, increased SAMHD1 and reduced DCK levels contributed to cytarabine and CNDAC resistance. Conclusion: Intrinsic and acquired resistance to CNDAC and related nucleoside analogues are driven by different mechanisms. The lack of cross-resistance between SAMHD1/ DCK substrates and non-substrates provides scope for next-line therapies after treatment failure.
Cancer therapies have experienced significant advances in recent years. While conventional cytotoxic chemotherapy has long been the cornerstone for the treatment of many tumor entities, uprising immunotherapies have revolutionized the therapeutic landscape. Among them, immune checkpoint inhibitors (ICIs) with their demonstrated increased overall survival rates and response rates in cancer patients are now FDA-approved for metastatic melanoma and multiple other malignancies. Despite their clinical benefit in cancer therapies, ICIs can induce unique autoimmune-like toxicities known as immune-related adverse events (irAEs), which can involve any organ system including the nervous system. Although neurotoxicities are rare complications of ICI therapy they are often severe and can lead to long-term disability or even death if left untreated.
Neurological irAEs exhibit a broad spectrum of clinical presentations affecting the entire nervous system. Diagnosing neurological irAEs is often challenging as symptoms and laboratory findings can be uncharacteristic for common neurological disorders and clinical experience with ICI-mediated toxicities is still limited. In light of expanding clinical indications for ICIs, physicians will encounter ICI-mediated neurotoxicities more frequently. Thus, thorough characterizations of the diverse set of neurological irAEs are essential for optimal patient care, the prevention of severe ICI-mediated complications, and the development of diagnostic and therapeutic algorithms. This work portrays the clinical presentation, management and outcome of neurological irAEs following ICI therapies.
Patients with neurotoxicities related to ICIs who presented at the Yale New Haven Hospital between January 2014 and June 2018 were retrospectively identified from the quality control database. A comprehensive chart review was performed and data regarding patient demographics, medical history, ICI regimen and neurotoxicity were recorded. In total, 18 patients with neurological irAEs following ICI therapy for melanoma, small cell lung cancer, non-small cell lung cancer, and Merkel-cell carcinoma were identified. Neurotoxicities included central nervous system disorders comprising central demyelinating disorder,autoimmune encephalitis predominantly affecting the grey matter, and aseptic meningitis. Peripheral nervous system toxicities included sensorimotor polyneuropathy and myasthenia gravis. Cases of hypophysitis were also recorded. Time to onset of neurological irAEs ranged from 1 to72 weeks with a median of five weeks. In all patients ICIs were held and steroids initiated. Additional immunomodulatory therapies were required in nine patients. Sixteen of 18 patients showed neurological improvement. Fourteen patients had highgrade neurotoxicity (grade 3-4), six of whom deceased due to cancer progression, while none of the low-grade neurotoxicity patients (grade 1-2) died. High-grade neurotoxicity was identified as a negative prognostic marker for overall survival (p = 0.046).
This work shows that neurotoxicities present early-onset, rapidly progressive complications of ICIs with a broad spectrum of clinical phenotypes affecting the central nervous system, peripheral nervous system, and neuroendocrine system. A high index of caution for neurological irAEs is warranted throughout ICI therapy as timely diagnosis and management can reduce morbidity and mortality. Randomized clinical trials are needed to develop standardized diagnostic and therapeutic algorithms of ICI-induced neurotoxicities.
Eines der übergeordneten Ziele neurowissenschaftlicher Grundlagenforschung ist es, die Pathomechanismen neuropsychiatrischer Erkrankungsbilder besser zu verstehen. Als Erklärungsmodell für einige dieser Erkrankungen dient unter anderem ein gestörtes Verhältnis zwischen Exzitation und Inhibition im Gehirn. Synaptische Strukturproteine sind wichtige Modulatoren dieses Verhältnisses. Für eine unbeeinträchtigte inhibitorische synaptische Transmission spielt das postsynaptische Zelladhäsionsprotein Neuroligin 2 eine maßgebliche Rolle, um das Gleichgewicht zwischen Exzitation und Inhibition aufrechtzuerhalten. Neuroligin 2 ist an der inhibitorischen Synapse lokalisiert und beeinflusst die Entwicklung, Reifung und Funktion dieser Synapse. Die klinische Relevanz von Neuroligin 2 wurde bereits bei zahlreichen Erkrankungsbildern wie Schizophrenie, Depression oder Epilepsie im Rahmen von Studien nachgewiesen. Um das Verhältnis zwischen Exzitation und Inhibition in vivo sowie Mechanismen der synaptischen Übertragung und Plastizität zu untersuchen, hat sich die Ableitung von Feldpotentialen im Gyrus Dentatus des Hippocampus etabliert. Im Neuroligin 2 Knockout Mausmodell konnte bereits gezeigt werden, dass eine pränatale Deletion dieses Proteins eine stark erhöhte Erregbarkeit der Körnerzellen und eine verminderte GABAerge Netzwerkinhibition im Gyrus Dentatus in vivo zur Folge hat.
Unklar blieb bisher, ob diese durch den konventionellen Neuroligin 2 Knockout (pränatal) hervorgerufenen Netzwerkveränderungen alleine auf das Fehlen dieses Proteins zurückzuführen sind oder durch eine zusätzliche Beeinträchtigung der Hirnentwicklung hervorgerufen werden. Ziel dieser Dissertation ist es deshalb, die Rolle von Neuroligin 2 im Gyrus Dentatus durch einen induzierten Knockout in adulten Mäusen (postnatal) unabhängig von einem möglichen Entwicklungseffekt zu klären.
Dazu wurde im ersten methodischen Schritt dieser Dissertation durch orale Tamoxifen-Gabe eine zeitspezifische konditionale Eliminierung von Neuroligin 2 in genetisch modifizierten, adulten Mäusen erzielt. Im Anschluss an diese konditionale Eliminierung wurde die synaptische Transmission, Plastizität sowie neuronale Erregbarkeit von Körnerzellen im Gyrus Dentatus mittels elektrophysiologischer Experimente untersucht. Hierzu wurde zunächst der Tractus Perforans und die Körnerzellschicht durch stereotaktische Chirurgie in anästhesierten Mäusen lokalisiert. Anschließend wurde eine Stimulation des Tractus Perforans sowie eine Ableitung von Feldpotentialen im Gyrus Dentatus durchgeführt. Um die Erregbarkeit der Körnerzellen, die synaptische Transmission, Kurz- und Langzeitplastizität sowie Netzwerkinhibition im Gyrus Dentatus zu analysieren, wurden unterschiedliche Stimulationsprotokolle verwendet. Im Anschluss an die elektrophysiologischen Experimente wurden die Hippocampi beidseitig entnommen, konserviert und später einer Proteinquantifizierung von Neuroligin 2 mittels Western-Blotting unterzogen.
Die Ergebnisse zeigten ein signifikant verringertes Proteinlevel von Neuroligin 2 auf 41,07% im Hippocampus von konditionalen Neuroligin 2 Knockout Mäusen. Unter dieser Reduktion von Neuroligin 2 in adulten Mäusen war die in vivo Erregbarkeit der Körnerzellen des Gyrus Dentatus sowie GABAerge Netzwerkinhibition weitgehend unbeeinträchtigt und die signifikanten Beobachtungen des konventionellen Knockout Modells ließen sich nicht reproduzieren. Aufgrund der unvollständigen Proteinreduktion lässt sich jedoch nicht abschließend beurteilen, ob die Restmenge den elektrophysiologischen Effekt kompensiert oder ob die im konventionellen Neuroligin 2 Knockout Modell beobachteten Effekte auf eine ausschließliche Rolle von Neuroligin 2 in der Hirnentwicklungsperiode zurückzuführen sind. Kürzlich veröffentlichte Daten zeigten allerdings, dass die postnatale Deletion von Neuroligin 2 in anderen Hirnregionen zu einer verminderten Netzwerkinhibition führt.
Neben der hier verwendeten in vivo Methodik ist eine Ergänzung von Untersuchungen in nicht-anästhesierten Tieren sowie Messungen einzelner Zellen durch whole-cell patch-clamp Untersuchungen in vitro oder in vivo zu erwägen. Es sollte dabei auf eine konditionale Proteineliminierung geachtet werden, damit mögliche Kompensationsmechanismen weitgehend ausgeschlossen werden können. Eine weiterführende immunhistochemische Bildgebung der Hippocampuspräparate, wie sie im konventionellen Knockout durchgeführt wurde, könnte sich hierbei ebenso als aufschlussreich für die Funktion von Neuroligin 2 im Hippocampus des adulten Tieres erweisen.
Transcatheter left atrial appendage occlusion (LAAO) is non-inferior to vitamin K antagonists (VKAs) in preventing thromboembolic events in atrial fibrillation (AF). Non-vitamin K antagonists (NOACs) have an improved safety profile over VKAs; however, evidence regarding their effect on cardiovascular and neurological outcomes relative to LAAO is limited. Up-to-date randomized trials or propensity-score-matched data comparing LAAO vs. NOACs in high-risk patients with AF were pooled in our study. A total of 2849 AF patients (LAAO: 1368, NOACs: 1481, mean age: 75 ± 7.5 yrs, 63.5% male) were enrolled. The mean CHA2DS2-VASc score was 4.3 ± 1.7, and the mean HAS-BLED score was 3.4 ± 1.2. The baseline characteristics were comparable between the two groups. In the LAAO group, the success rate of device implantation was 98.8%. During a mean follow-up of 2 years, as compared with NOACs, LAAO was associated with a significant reduction of ISTH major bleeding (p = 0.0002). There were no significant differences in terms of ischemic stroke (p = 0.61), ischemic stroke/thromboembolism (p = 0.63), ISTH major and clinically relevant minor bleeding (p = 0.73), cardiovascular death (p = 0.63), and all-cause mortality (p = 0.71). There was a trend toward reduction of combined major cardiovascular and neurological endpoints in the LAAO group (OR: 0.84, 95% CI: 0.64–1.11, p = 0.12). In conclusion, for high-risk AF patients, LAAO is associated with a significant reduction of ISTH major bleeding without increased ischemic events, as compared to “contemporary NOACs”. The present data show the superior role of LAAO over NOACs among high-risk AF patients in terms of reduction of major bleeding; however, more randomized controlled trials are warranted.
Simple Summary: The role of transcriptionally deregulated miRNAs (microRNAs) in classical Hodgkin lymphoma (cHL) is still not fully understood. To address this issue, we have performed global miRNA expression profiling of commonly used cHL cell lines and we present a complete cHL miRNome (microRNome). Within this group, we identify miRNAs recurrently deregulated in cHL cell lines, and compare them to non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells. Moreover, we show that several of the recurrently overexpressed miRNAs in cHL cell lines, and also primary microdissected HRS (Hodgkin and Reed-Sternberg) cells, target known B-cell-related transcription factors and NF-κB inhibitors. These findings provide evidence that deregulated miRNAs contribute to the loss of B-cell phenotype and NF-κB activation observed in this lymphoma.
Abstract: A hallmark of classical Hodgkin lymphoma (cHL) is the attenuation of B-cell transcription factors leading to global transcriptional reprogramming. The role of miRNAs (microRNAs) involved in this process is poorly studied. Therefore, we performed global miRNA expression profiling using RNA-seq on commonly used cHL cell lines, non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells as controls and characterized the cHL miRNome (microRNome). Among the 298 miRNAs expressed in cHL, 56 were significantly overexpressed and 23 downregulated (p < 0.05) compared to the controls. Moreover, we identified five miRNAs (hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-196a-5p, hsa-miR-21-5p, hsa-miR-155-5p) as especially important in the pathogenesis of this lymphoma. Target genes of the overexpressed miRNAs in cHL were significantly enriched (p < 0.05) in gene ontologies related to transcription factor activity. Therefore, we further focused on selected interactions with the SPI1 and ELF1 transcription factors attenuated in cHL and the NF-ĸB inhibitor TNFAIP3. We confirmed the interactions between hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1, hsa-miR-450b-5p:ELF-1 and hsa-miR-23a-3p:TNFAIP3, which suggest that overexpression of these miRNAs contributes to silencing of the respective genes. Moreover, by analyzing microdissected HRS cells, we demonstrated that these miRNAs are also overexpressed in primary tumor cells. Therefore, these miRNAs play a role in silencing the B-cell phenotype in cHL.
Introduction: Cancer patients tend to prefer oral instead of parenteral chemotherapy. To date, there is little evidence on the medication adherence in cancer patients. We investigated medication adherence to tyrosine kinase inhibitors in patients suffering from non-small cell lung cancer. Methods: Tyrosine kinase inhibitor adherence was measured electronically by MEMS® (medication event monitoring system) over at least six months. Adherence rates were calculated in terms of Dosing Compliance, Timing Compliance, Taking Compliance, and Drug Holidays. Patients were dichotomized as adherent when Dosing Compliance and Timing Compliance were ≥80%, Taking Compliance ranged between 90 and 110%, and <1 Drug Holiday was registered. Quality of life was assessed by two questionnaires (EORTC QLQ-C30 version 3.0, EORTC QLQ-LC13) at three time points. Adverse drug events were reported via patient diaries. Results: Out of 32 patients enrolled, data from 23 patients were evaluable. Median Dosing Compliance, Taking Compliance, and Timing Compliance adherence rates of tyrosine kinase inhibitor intake amounted to 100%, 98%, and 99%, respectively; Drug Holidays were observed in three patients. Four patients were dichotomized as non-adherent. Three of them had a twice-daily tyrosine kinase inhibitor regimen. Median quality of life scores amounted to 67 (max. 100) and remained unchanged over the study period. Fatigue and rash were the most frequently reported adverse drug events. Conclusion: Medication adherence of non-small cell lung cancer patients treated with tyrosine kinase inhibitors was extraordinarily high and is likely to support the effectiveness of tyrosine kinase inhibitor treatment and a good quality of life over a long period of time. Adherence facilitating information and education is especially relevant for patients taking tyrosine kinase inhibitors in a twice-daily regimen.
Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (β-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.
Although anti-cancer properties of the natural compound curcumin have been reported, low absorption and rapid metabolisation limit clinical use. The present study investigated whether irradiation with visible light may enhance the inhibitory effects of low-dosed curcumin on prostate cancer cell growth, proliferation, and metastasis in vitro. DU145 and PC3 cells were incubated with low-dosed curcumin (0.1–0.4 µg/mL) and subsequently irradiated with 1.65 J/cm2 visible light for 5 min. Controls remained untreated and/or non-irradiated. Cell growth, proliferation, apoptosis, adhesion, and chemotaxis were evaluated, as was cell cycle regulating protein expression (CDK, Cyclins), and integrins of the α- and β-family. Curcumin or light alone did not cause any significant effects on tumor growth, proliferation, or metastasis. However, curcumin combined with light irradiation significantly suppressed tumor growth, adhesion, and migration. Phosphorylation of CDK1 decreased and expression of the counter-receptors cyclin A and B was diminished. Integrin α and β subtypes were also reduced, compared to controls. Irradiation distinctly enhances the anti-tumor potential of curcumin in vitro and may hold promise in treating prostate cancer.
The aim of this study was to evaluate whether recurrent carpal tunnel syndrome (CTS) after complete and sufficient division of the transverse ligament really exists. Another goal was to analyze the underlying reasons for recurrent CTS operated on in our department. Over an observation period of eleven years, 156 patients underwent surgical intervention due to CTS. The records of each patient were analyzed with respect to baseline data (age, gender, affected hand), as were clinical signs and symptoms pre- and postoperatively. To assess long-term results, standardized telephone interviews were performed using a structured questionnaire in which the patients were questioned about persisting symptoms, if any. Of the 156 patients, 128 underwent first surgical intervention due to CTS in our department. In long-term follow-up, two-thirds of these patients had no symptoms at all; one-third of the patients described mild persisting numbness. None of the patients experienced a recurrence of CTS. The 28 patients who received their first operation outside of our department were operated on for recurrent CTS. The cause of recurrence was incomplete division of the distal part of the transverse carpal ligament in all cases. The results suggest that recurrent CTS after complete and sufficient division of the transverse ligament is very unlikely.
Background: Dentists (Ds) and dental assistants (DAs) have a high lifetime prevalence of musculoskeletal disorders (MSDs). In this context, it is assumed that they have an increased intake of substances such as pain medication. Currently, there exist no data on the use of medication among Ds and DAs with MSDs in Germany. Methods: The online questionnaire (i.e., the Nordic Questionnaire) analysed the medical therapies used by 389 Ds (240 f/149 m) and 406 DAs (401 f/5 m) to treat their MSDs. Results: Ds (28.3–11.5%) and DAs (29.4–10.3%) with MSDs took medication depending on the affected body region. A trend between the Ds and DAs in the intake of drug therapy and the frequency was found for the neck region (Ds: 21.1%, DAs: 28.7%). A single medication was taken most frequently (Ds: 60.0–33.3%, DAs: 71.4–27.3%). The frequency of use varied greatly for both occupational groups depending on the region affected. Conclusion: Ds and DAs perceived the need for medical therapies because of their MSDs. Painkillers such as ibuprofen and systemic diclofenac were the medications most frequently taken by both occupational groups. The intake of pain killers, most notably for the neck, should prevent sick leave.
Sphingosine 1 phosphate (S1P) lyase (Sgpl1) catalyses the irreversible cleavage of S1P and thereby the last step of sphingolipid degradation. Loss of Sgpl1 in humans and mice leads to accumulation of sphingolipids and multiple organ injuries. Here, we addressed the role of hepatocyte Sgpl1 for regulation of sphingolipid homoeostasis by generating mice with hepatocyte-specific deletion of Sgpl1 (Sgpl1HepKO mice). Sgpl1HepKO mice had normal body weight, liver weight, liver structure and liver enzymes both at the age of 8 weeks and 8 months. S1P, sphingosine and ceramides, but not glucosylceramides or sphingomyelin, were elevated by ~1.5–2-fold in liver, and this phenotype did not progress with age. Several ceramides were elevated in plasma, while plasma S1P was normal. Interestingly, S1P and glucosylceramides, but not ceramides, were elevated in bile of Sgpl1HepKO mice. Furthermore, liver cholesterol was elevated, while LDL cholesterol decreased in 8-month-old mice. In agreement, the LDL receptor was upregulated, suggesting enhanced uptake of LDL cholesterol. Expression of peroxisome proliferator-activated receptor-γ, liver X receptor and fatty acid synthase was unaltered. These data show that mouse hepatocytes largely compensate the loss of Sgpl1 by secretion of accumulating sphingolipids in a specific manner into blood and bile, so that they can be excreted or degraded elsewhere.
Objective: Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). Methods: We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between .13 and .7 mg/kg/day Results: Overall, 78 patients with DS (median age = 8.0 years, range = 2.1–46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5 days (range = 31–572). Responder rates (a ≥50% reduction; n = 78) and seizure-freedom rates at 3 months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic–clonic seizures. Responder rates were consistent at 6 and 12 months (n = 66 and n = 43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5–30) to 3.0 (range = 0–30) in the 3-month period before and after FFA treatment (p < .001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p = .005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. Significance: In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.
Objective: Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). Methods: We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between .13 and .7 mg/kg/day. Results: Overall, 78 patients with DS (median age = 8.0 years, range = 2.1–46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5 days (range = 31–572). Responder rates (a ≥50% reduction; n = 78) and seizure-freedom rates at 3 months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic–clonic seizures. Responder rates were consistent at 6 and 12 months (n = 66 and n = 43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5–30) to 3.0 (range = 0–30) in the 3-month period before and after FFA treatment (p < .001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p = .005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. Significance: In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.
Key Points: Seventy-eight patients with Dravet syndrome were treated with FFA at multiple centers within the CUP in Germany; FFA had a good retention rate over a sustained period; 85% of patients remained on treatment with FFA for a median duration of 255.5 days; FFA was associated with clinically meaningful reductions in total and convulsive seizures, seizure days per month, and episodes of status epilepticus; FFA was associated with reductions in the number or dose of concomitant antiseizure medications in 68% of patients; FFA was well tolerated, with the main adverse events being somnolence (36%), decreased appetite (22%), and ataxia (8%).
Background: To test the effect of urological primary cancers (bladder, kidney, testis, upper tract, penile, urethral) on overall mortality (OM) after secondary prostate cancer (PCa). Methods: Within the Surveillance, Epidemiology and End Results (SEER) database, patients with urological primary cancers and concomitant secondary PCa (diagnosed 2004-2016) were identified and were matched in 1:4 fashion with primary PCa controls. OM was compared between secondary and primary PCa patients and stratified according to primary urological cancer type, as well as to time interval between primary urological cancer versus secondary PCa diagnoses. Results: We identified 5,987 patients with primary urological and secondary PCa (bladder, n = 3,287; kidney, n = 2,127; testis, n = 391; upper tract, n = 125; penile, n = 47; urethral, n = 10) versus 531,732 primary PCa patients. Except for small proportions of Gleason grade group and age at diagnosis, PCa characteristics between secondary and primary PCa were comparable. Conversely, proportions of secondary PCa patients which received radical prostatectomy were smaller (29.0 vs. 33.5%), while no local treatment rates were higher (34.2 vs. 26.3%). After 1:4 matching, secondary PCa patients exhibited worse OM than primary PCa patients, except for primary testis cancer. Here, no OM differences were recorded. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis. Conclusions: After detailed matching for PCa characteristics, secondary PCa patients exhibit worse survival, except for testis cancer patients. The survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary urological cancer diagnosis.