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Supplemental material, sj-docx-1-eso-10.1177_23969873231161381 for Acute triage of childhood stroke in Denmark by Julie Brix Bindslev, Klaus Hansen, Nicolaj Groenbaek Laugesen, Goetz Benndorf, Christina Engel Hoei-Hansen and Thomas Truelsen in European Stroke Journal

The estimation of growth rate of lytic bone tumors based on conventional radiography has been extensively studied. While benign tumors exhibit slow growth, malignant tumors are more likely to show fast growth. The most frequently used algorithm for grading of growth rate on conventional radiography was published by Gwilym Lodwick. Based on the evaluation of the four descriptors (1) type of bone destruction (including the subdescriptor “margin” for geographic lesions), (2) penetration of cortex, (3) presence of a sclerotic rim, and (4) expanded shell, an overall growth grade (IA, IB, IC, II, III) can be assigned, with higher grade representing faster tumor growth. In this article, we provide an easy-to-use decision tree of Lodwick’s original grading algorithm, suitable for teaching of students and residents. Subtleties of the grading algorithm and potential pitfalls in clinical practice are explained and illustrated. Exemplary conventional radiographs provided for each descriptor in the decision tree may be used as a guide and atlas for assisting in evaluation of individual features in daily clinical practice.

Background The Prostate Imaging Reporting and Data System, version 2.1 (PI-RADSv2.1) standardizes reporting of multiparametric MRI of the prostate. Assigned assessment categories are a risk stratification algorithm, higher categories indicate a higher probability of clinically significant cancer compared to lower categories. PI-RADSv2.1 does not define these probabilities numerically. We conduct a systematic review and meta-analysis to determine the cancer detection rates (CDR) of the PI-RADSv2.1 assessment categories on lesion level and patient level. Methods Two independent reviewers screen a systematic PubMed and Cochrane CENTRAL search for relevant articles (primary outcome: clinically significant cancer, index test: prostate MRI reading according to PI-RADSv2.1, reference standard: histopathology). We perform meta-analyses of proportions with random-effects models for the CDR of the PI-RADSv2.1 assessment categories for clinically significant cancer. We perform subgroup analysis according to lesion localization to test for differences of CDR between peripheral zone lesions and transition zone lesions. Results A total of 17 articles meet the inclusion criteria and data is independently extracted by two reviewers. Lesion level analysis includes 1946 lesions, patient level analysis includes 1268 patients. On lesion level analysis, CDR are 2% (95% confidence interval: 0–8%) for PI-RADS 1, 4% (1–9%) for PI-RADS 2, 20% (13–27%) for PI-RADS 3, 52% (43–61%) for PI-RADS 4, 89% (76–97%) for PI-RADS 5. On patient level analysis, CDR are 6% (0–20%) for PI-RADS 1, 9% (5–13%) for PI-RADS 2, 16% (7–27%) for PI-RADS 3, 59% (39–78%) for PI-RADS 4, 85% (73–94%) for PI-RADS 5. Higher categories are significantly associated with higher CDR (P Conclusions Our estimates of CDR demonstrate that PI-RADSv2.1 stratifies lesions and patients as intended. Our results might serve as an initial evidence base to discuss management strategies linked to assessment categories.

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies of men in the world. Due to a variety of treatment options in different risk groups, proper diagnostic and risk stratification is pivotal in treatment of PCa. The development of precise medical imaging procedures simultaneously to improvements in big data analysis has led to the establishment of radiomics - a computer-based method of extracting and analyzing image features quantitatively. This approach bears the potential to assess and improve PCa detection, tissue characterization and clinical outcome prediction. This article gives an overview on the current aspects of methodology and systematically reviews available literature on radiomics in PCa patients, showing its potential for personalized therapy approaches. The qualitative synthesis includes all imaging modalities and focuses on validated studies, putting forward future directions.

Background The impact of body compositions on surgical results is controversially discussed. This study examined whether visceral obesity, sarcopenia or sarcopenic obesity influence the outcome after hepatic resections of synchronous colorectal liver metastases. Methods Ninety-four consecutive patients with primary hepatic resections of synchronous colorectal metastases were identified from a single center database between January 2013 and August 2018. Patient characteristics and 30-day morbidity were retrospectively analyzed. Body fat and skeletal muscle were calculated by planimetry from single-slice CT images at the level of L3. Results Fifty-nine patients (62.8%) underwent minor hepatectomies, and 35 patients underwent major resections (37.2%). Postoperative complications occurred in 60 patients (62.8%) including 35 patients with major complications (Clavien–Dindo grade III–V). The mortality was nil at 30 days and 2.1% at 90 days. The body mass index showed no influence on postoperative outcomes (p = 1.0). Visceral obesity was found in 66 patients (70.2%) and was significantly associated with overall and major complication rates (p = .002, p = .012, respectively). Sarcopenia was observed in 34 patients (36.2%) without a significant impact on morbidity (p = .461), however, with longer hospital stay. Sarcopenic obesity was found in 18 patients (19.1%) and was significantly associated with postoperative complications (p = .014). Visceral obesity, sarcopenia and sarcopenic obesity were all identified as significant risk factors for overall postoperative complications. Conclusion Visceral obesity, sarcopenic obesity and sarcopenia are independent risk factors for overall complications after resections of CRLM. Early recognition of extremes in body compositions could prompt to perioperative interventions and thus improve postoperative outcomes.

Comparison studies using histopathology as standard of reference enable a validation of the diagnostic performance of imaging methods. This study analysed (1) the impact of different image-histopathology co-registration pathways, (2) the impact of the applied data analysis method and (3) intraindividually compared multiparametric magnet resonance tomography (mpMRI) and prostate specific membrane antigen positron emission tomography (PSMA-PET) by using the different approaches. Ten patients with primary PCa who underwent mpMRI and [18F]PSMA-1007 PET/CT followed by prostatectomy were prospectively enrolled. We demonstrate that the choice of the intermediate registration step [(1) via ex-vivo CT or (2) mpMRI] does not significantly affect the performance of the registration framework. Comparison of analysis methods revealed that methods using high spatial resolutions e.g. quadrant-based slice-by-slice analysis are beneficial for a differentiated analysis of performance, compared to methods with a lower resolution (segment-based analysis with 6 or 18 segments and lesions-based analysis). Furthermore, PSMA-PET outperformed mpMRI for intraprostatic PCa detection in terms of sensitivity (median %: 83–85 vs. 60–69, p

Introduction Primary prostate cancer (PCa) can be visualized on prostate-specific membrane antigen positron emission tomography (PSMA-PET) with high accuracy. However, intraprostatic lesions may be missed by visual PSMA-PET interpretation. In this work, we quantified and characterized the intraprostatic lesions which have been missed by visual PSMA-PET image interpretation. In addition, we investigated whether PSMA-PET-derived radiomics features (RFs) could detect these lesions. Methodology This study consists of two cohorts of primary PCa patients: a prospective training cohort (n = 20) and an external validation cohort (n = 52). All patients underwent 68Ga-PSMA-11 PET/CT and histology sections were obtained after surgery. PCa lesions missed by visual PET image interpretation were counted and their International Society of Urological Pathology score (ISUP) was obtained. Finally, 154 RFs were derived from the PET images and the discriminative power to differentiate between prostates with or without visually undetectable lesions was assessed and areas under the receiver-operating curve (ROC-AUC) as well as sensitivities/specificities were calculated. Results In the training cohort, visual PET image interpretation missed 134 tumor lesions in 60% (12/20) of the patients, and of these patients, 75% had clinically significant (ISUP > 1) PCa. The median diameter of the missed lesions was 2.2 mm (range: 1–6). Standard clinical parameters like the NCCN risk group were equally distributed between patients with and without visually missed lesions (p U: p Conclusion Visual PSMA-PET image interpretation may miss small but clinically significant PCa in a relevant number of patients and RFs can be implemented to uncover them. This could be used for guiding personalized treatments.

Chondrogenic tumors are the most frequent primary bone tumors. Malignant chondrogenic tumors represent about one quarter of malignant bone tumors. Benign chondrogenic bone tumors are frequent incidental findings at imaging. Radiological parameters may be helpful for identification, characterization, and differential diagnosis. Systematic PubMed literature research. Identification and review of studies analyzing and describing imaging characteristics of chondrogenic bone tumors. The 2020 World Health Organization (WHO) classification system differentiates between benign, intermediate (locally aggressive or rarely metastasizing), and malignant chondrogenic tumors. On imaging, typical findings of differentiated chondrogenic tumors are lobulated patterns with a high signal on T2-weighted magnetic resonance imaging (MRI) and ring- and arc-like calcifications on conventional radiography and computed tomography (CT). Depending on the entity, the prevalence of this chondrogenic pattern differs. While high grade tumors may be identified due to aggressive imaging patterns, the differentiation between benign and intermediate grade chondrogenic tumors is challenging, even in an interdisciplinary approach. · The WHO defines benign, intermediate, and malignant chondrogenic bone tumors. · Frequent benign tumors: osteochondroma and enchondroma; Frequent malignant tumor: conventional chondrosarcoma. · Differentiation between enchondroma versus low-grade chondrosarcoma is challenging for radiologists and pathologists. · Pain, deep scalloping, cortical destruction, bone expansion, soft tissue component: favor chondrosarcoma. · Potential malignant transformation of osteochondroma: progression after skeletal maturity, cartilage cap thickness ( 2 cm adult; 3 cm child). · Potentially helpful advanced imaging methods: Dynamic MRI, texture analysis, FDG-PET/CT.· Engel H, Herget GW, Füllgraf H et al. Chondrogenic Bone Tumors: The Importance of Imaging Characteristics. Fortschr Röntgenstr 2021; 193: 262 - 274. Chondrogene Tumoren sind die häufigsten primären Knochentumoren. Maligne chondrogene Tumoren repräsentieren etwa ein Viertel der malignen Knochentumoren. Benigne chondrogene Knochentumoren sind häufige radiologische Zufallsbefunde. Radiologische Parameter können hilfreich sein zur Identifikation, Charakterisierung und Differenzialdiagnostik. Systematische Literaturrecherche mittels PubMed. Identifikation und kritische Beurteilung von Studien, welche die Bildgebung chondrogener Knochentumoren analysieren oder beschreiben. Nach der World-Health-Organization (WHO)-Klassifikation von 2020 werden benigne, intermediäre (lokal aggressiv oder selten metastasierend) und maligne chondrogene Tumoren unterschieden. Das typische radiologische Bild chondrogen differenzierter Tumoren ist gekennzeichnet durch ein lobuliertes Wachstumsmuster mit einem hohen Signal in T2-gewichteten Sequenzen in der Magnetresonanztomografie (MRT) und durch ein meist ring- und bogenförmiges Verkalkungsmuster in der Projektionsradiografie und der Computertomografie (CT). In Abhängigkeit der Entität ist dieses typische Muster unterschiedlich ausgeprägt. Während hochmaligne Tumoren häufig ein eindeutig malignes Wachstumsmuster zeigen, ist die Differenzierung zwischen benignen und intermediären chondrogenen Tumoren auch interdisziplinär schwierig. · Die WHO unterscheidet gutartige, intermediäre und bösartige chondrogene Knochentumoren.. · Häufige gutartige Tumoren: Osteochondrom und Enchondrom; häufiger bösartiger Tumor: konventionelles Chondrosarkom.. · Differenzierung Enchondrom versus Low-grade-Chondrosarkom ist für Radiologen und Pathologen gleichermaßen schwierig.. · Schmerzen, tiefes Scalloping, Kortikalisdestruktion, Knochenexpansion und Weichteilanteil sprechen für ein Chondrosarkom (versus Enchondrom).. · Transformationshinweise beim Osteochondrom: Größenprogredienz nach Wachstumsabschluss, Knorpelkappendicke 2 cm (Erwachsene) bzw. 3 cm (Kinder).. · Neuere, potenziell hilfreiche Bildgebungsmethoden: dynamisches MRT, Texturanalysen und FDG-PET/CT..· Engel H, Herget GW, Füllgraf H et al. Chondrogenic Bone Tumors: The Importance of Imaging Characteristics. Fortschr Röntgenstr 2021; 193: 262 – 275.

Purpose Accurate delineation of intraprostatic gross tumor volume (GTV) is mandatory for successful fusion biopsy guidance and focal therapy planning of prostate cancer (PCa). Multiparametric magnetic resonance imaging (mpMRI) is the current gold standard for GTV delineation; however, prostate-specific membrane antigen positron emission tomography (PSMA-PET) is emerging as a promising alternative. This study compares GTV delineation between mpMRI and 68Ga-PSMA-PET in a large number of patients using validated contouring approaches. Methods One hundred one patients with biopsy-proven primary PCa who underwent mpMRI and 68Ga-PSMA-PET within 3 months before primary treatment were retrospectively enrolled. Clinical parameters (age, PSA, Gleason score in biopsy) were documented. GTV based on MRI and PET images were delineated; volumes measured and laterality determined. Additionally, biopsy data from 77 patients was analyzed. Univariate and multivariate binary logistic regression analyses were performed using concordance in laterality as the endpoint. Results In total mpMRI and 68Ga-PSMA-PET detected 151 and 159 lesions, respectively. Median GTV-MRI (2.8 ml, 95% CI 2.31–3.38 ml) was significantly (p 68Ga-PSMA-PET detected significantly more bilateral lesions than mpMRI (71 vs 57, p = 0.03). Analysis of patients with bilateral lesions in biopsy showed a significant higher concordance of laterality in 68Ga-PSMA-PET (p = 0.03). In univariate analysis, PSA level and volume of GTV-MRI had an impact on concordance in laterality (p = 0.02 and p = 0.01), whereas in multivariate analysis, only GTV-MRI volume remained significant (p = 0.04). Conclusion MpMRI and 68Ga-PSMA-PET detect a similar amount of PCa lesions. However, GTV-PET had approximately twice the volume (median 4.9 ml vs 2.8 ml) and detected significantly more bilateral lesions than mpMRI. Thus, 68Ga-PSMA-PET gives highly important complementary information. Since we could not find any strong evidence for parameters to guide when 68Ga-PSMA-PET is dispensable, it should be performed additionally to MRI in patients with intermediate and high-risk PCa according to D’Amico classification to improve GTV delineation.

Context Men suspected of harboring prostate cancer (PCa) increasingly undergo multiparametric magnetic resonance imaging (mpMRI) and mpMRI-guided biopsy. The potential of mpMRI coupled to artificial intelligence (AI) methods to detect and classify PCa before decision-making requires investigation. Objective To review the literature for studies addressing the diagnostic performance of combined mpMRI and AI approaches to detect and classify PCa, and to provide selection criteria for relevant articles having clinical significance. Evidence acquisition We performed a nonsystematic search of the English language literature using the PubMed-MEDLINE database up to October 30, 2020. We included all original studies addressing the diagnostic accuracy of mpMRI and AI to detect and classify PCa with histopathological analysis as a reference standard. Evidence synthesis Eleven studies assessed AI and mpMRI approaches for PCa detection and classification based on a ground truth that referred to the entire prostate either with radical prostatectomy specimens (RPS) or relocalization of positive systematic and/or targeted biopsy. Seven studies retrospectively annotated cancerous lesions onto mpMRI identified in whole-mount sections from RPS, three studies used a backward projection of histological prostate biopsy information, and one study used a combined cohort of both approaches. All studies cross-validated their data sets; only four used a test set and one a multisite validation scheme. Performance metrics for lesion detection ranged from 87.9% to 92% at a threshold specificity of 50%. The lesion classification accuracy of the algorithms was comparable to that of the Prostate Imaging-Reporting and Data System. Conclusions For an algorithm to be implemented into radiological workflows and to be clinically applicable, it must be trained with a ground truth labeling that reflects histopathological information for the entire prostate and it must be externally validated. Lesion detection and classification performance metrics are promising but require prospective implementation and external validation for clinical significance. Patient summary We reviewed the literature for studies on prostate cancer detection and classification using magnetic resonance imaging (MRI) and artificial intelligence algorithms. The main application is in supporting radiologists in interpreting MRI scans and improving the diagnostic performance, so that fewer unnecessary biopsies are carried out.

Ionotropic purinergic receptors (P2X receptors) are non-specific cation channels that are activated by the binding of ATP at their extracellular side. P2X receptors contribute to multiple functions, including the generation of pain, inflammation, or synaptic transmission. The channels are trimers and structural information on several of their isoforms is available. In contrast, the cooperation of the subunits in the activation process is poorly understood. We synthesized a novel fluorescent ATP derivative, 2-[DY-547P1]-AET-ATP (fATP) to unravel the complex activation process in P2X2 and mutated P2X2 H319K channels with enhanced apparent affinity by characterizing the relation between ligand binding and activation gating. fATP is a full agonist with respect to ATP that reports the degree of binding by bright fluorescence. For quantifying the binding, a fast automated algorithm was employed on human embryonic kidney cell culture images. The concentrations of half maximum occupancy and activation as well as the respective Hill coefficients were determined. All Hill coefficients exceeded unity, even at an occupancy

Background and purpose Focal therapies are a promising approach to treat prostate cancer (PCa) more precisely instead of conventional whole gland treatment. Nowadays, multiparametric MRI (mpMRI) is routinely used for gross tumor volume (GTV) delineation. The aim of our study was to compare PSMA-PET/CT and mpMRI for the delineation of intraprostatic tumor burden by using whole mount histopathology as a reference standard. Material and methods 17 prospectively enrolled patients with primary PCa underwent [68Ga-]PSMA-11 PET/CT and mpMRI before radical prostatectomy. PSMA-PET/CT, mpMRI and histopathology of the resected specimens were co-registered. Two teams of experts generated GTV contours for mpMRI and PET, respectively. The imaging was validated on a lesion level and slice by slice in quadrants based on the distribution of PCa in histopathology. Overall, 772 quadrants were analyzed with 414 being true positive for tumor (53.6%). Results Median tumor volumes were 10.4 ml for GTV-histo, 10.8 ml for PSMA-PET and 4.5 ml for mpMRI. Median tumor volume in mpMRI was significant (p Conclusion Our investigation demonstrates an increased consensus of PSMA-PET with histopathology compared to mpMRI for intraprostatic GTV delineation, especially with a higher sensitivity. Additionally mpMRI contours underestimate tumor volume significantly. Thus PSMA-PET may be a complementary augmentation for GTV delineation in focal therapies.

Cerebral polymer coating embolism from intravascular devices represents a potentially serious complication to endovascular therapy (EVT). We report two cases of neuroendovascular treatment where filamentous polymer fragments were noted possibly due to damage of the surface coating during manipulation and backloading of microguidewires. As the exact origin of the debris was initially not known, microguidewires and fragments were examined with light microscopy, stereomicroscopy, scanning electron microscopy and attenuated-total-reflection Fourier transform infrared spectroscopy. Fragments consisted of polytetrafluoroethylene and silicone oil stemming from the proximal shaft of a standard microguidewire. To our knowledge, this is the first report of polytetrafluoroethylene coating fragments created during EVT. Future studies should assess the mechanism of polymer coating delamination and its potential consequences during EVT including inadvertent fragment migration into the cerebral circulation.

PurposeMultiparametric magnetic resonance tomography (mpMRI) and prostate specific membrane antigen positron emission tomography (PSMA-PET/CT) are used to guide focal radiotherapy (RT) dose escalation concepts. Besides improvements of treatment effectiveness, maintenance of a good quality of life is essential. Therefore, this planning study investigates whether urethral sparing in moderately hypofractionated RT with focal RT dose escalation influences tumour control probability (TCP) and normal tissue complication probability (NTCP).Patients and Methods10 patients with primary prostate cancer (PCa), who underwent 68Ga PSMA-PET/CT and mpMRI followed by radical prostatectomy were enrolled. Intraprostatic tumour volumes (gross tumor volume, GTV) based on both imaging techniques (GTV-MRI and -PET) were contoured manually using validated contouring techniques and GTV-Union was created by summing both. For each patient three IMRT plans were generated with 60 Gy to the whole prostate and a simultaneous integrated boost up to 70 Gy to GTV-Union in 20 fractions by (Plan 1) not respecting and (Plan 2) respecting dose constraints for urethra as well as (Plan 3) respecting dose constraints for planning organ at risk volume for urethra (PRV = urethra + 2mm expansion). NTCP for urethra was calculated applying a Lyman-Kutcher-Burman model. TCP-Histo was calculated based on PCa distribution in co-registered histology (GTV-Histo). Complication free tumour control probability (P+) was calculated. Furthermore, the intrafractional movement was considered.ResultsMedian overlap of GTV-Union and PRV-Urethra was 1.6% (IQR 0-7%). Median minimum distance of GTV-Histo to urethra was 3.6 mm (IQR 2 – 7 mm) and of GTV-Union to urethra was 1.8 mm (IQR 0.0 – 5.0 mm). The respective prescription doses and dose constraints were reached in all plans. Urethra-sparing in Plans 2 and 3 reached significantly lower NTCP-Urethra (p = 0.002) without significantly affecting TCP-GTV-Histo (p = p > 0.28), NTCP-Bladder (p > 0.85) or NTCP-Rectum (p = 0.85), resulting in better P+ (p = 0.006). Simulation of intrafractional movement yielded even higher P+ values for Plans 2 and 3 compared to Plan 1.ConclusionUrethral sparing may increase the therapeutic ratio and should be implemented in focal RT dose escalation concepts.

Gut microbiota-mediated inflammation promotes obesity-associated low-grade inflammation, which represents a hallmark of metabolic syndrome. To investigate if lifestyle-induced weight loss (WL) may modulate the gut microbiome composition and its interaction with the host on a functional level, we analyzed the fecal metaproteome of 33 individuals with metabolic syndrome in a longitudinal study before and after lifestyle-induced WL in a well-defined cohort. The 6-month WL intervention resulted in reduced BMI (−13.7%), improved insulin sensitivity (HOMA-IR, −46.1%), and reduced levels of circulating hsCRP (−39.9%), indicating metabolic syndrome reversal. The metaprotein spectra revealed a decrease of human proteins associated with gut inflammation. Taxonomic analysis revealed only minor changes in the bacterial composition with an increase of the families Desulfovibrionaceae, Leptospiraceae, Syntrophomonadaceae, Thermotogaceae and Verrucomicrobiaceae. Yet we detected an increased abundance of microbial metaprotein spectra that suggest an enhanced hydrolysis of complex carbohydrates. Hence, lifestyle-induced WL was associated with reduced gut inflammation and functional changes of human and microbial enzymes for carbohydrate hydrolysis while the taxonomic composition of the gut microbiome remained almost stable. The metaproteomics workflow has proven to be a suitable method for monitoring inflammatory changes in the fecal metaproteome.

Glucocorticoid (GC) resistance complicates the treatment of ~10–20% of children with nephrotic syndrome (NS), yet the molecular basis for resistance remains unclear. We used RNAseq analysis and in silico algorithm-based approaches on peripheral blood leukocytes from 12 children both at initial NS presentation and after ~7 weeks of GC therapy to identify a 12-gene panel able to differentiate steroid resistant NS (SRNS) from steroid-sensitive NS (SSNS). Among this panel, subsequent validation and analyses of one biologically relevant candidate, sulfatase 2 (SULF2), in up to a total of 66 children, revealed that both SULF2 leukocyte expression and plasma arylsulfatase activity Post/Pre therapy ratios were greater in SSNS vs. SRNS. However, neither plasma SULF2 endosulfatase activity (measured by VEGF binding activity) nor plasma VEGF levels, distinguished SSNS from SRNS, despite VEGF’s reported role as a downstream mediator of SULF2’s effects in glomeruli. Experimental studies of NS-related injury in both rat glomeruli and cultured podocytes also revealed decreased SULF2 expression, which were partially reversible by GC treatment of podocytes. These findings together suggest that SULF2 levels and activity are associated with GC resistance in NS, and that SULF2 may play a protective role in NS via the modulation of downstream mediators distinct from VEGF.

Abstract Adaptations of animal cells to growth in suspension culture concern in particular viral vaccine production, where very specific aspects of virus-host cell interaction need to be taken into account to achieve high cell specific yields and overall process productivity. So far, the complexity of alterations on the metabolism, enzyme, and proteome level required for adaptation is only poorly understood. In this study, for the first time, we combined several complex analytical approaches with the aim to track cellular changes on different levels and to unravel interconnections and correlations. Therefore, a Madin-Darby canine kidney (MDCK) suspension cell line, adapted earlier to growth in suspension, was cultivated in a 1-L bioreactor. Cell concentrations and cell volumes, extracellular metabolite concentrations, and intracellular enzyme activities were determined. The experimental data set was used as the input for a segregated growth model that was already applied to describe the growth dynamics of the parental adherent cell line. In addition, the cellular proteome was analyzed by liquid chromatography coupled to tandem mass spectrometry using a label-free protein quantification method to unravel altered cellular processes for the suspension and the adherent cell line. Four regulatory mechanisms were identified as a response of the adaptation of adherent MDCK cells to growth in suspension. These regulatory mechanisms were linked to the proteins caveolin, cadherin-1, and pirin. Combining cell, metabolite, enzyme, and protein measurements with mathematical modeling generated a more holistic view on cellular processes involved in the adaptation of an adherent cell line to suspension growth. Key points • Less and more efficient glucose utilization for suspension cell growth • Concerted alteration of metabolic enzyme activity and protein expression • Protein candidates to interfere glycolytic activity in MDCK cells

BackgroundWide necked bifurcation aneurysms (WNBA) are among the most difficult aneurysms to treat. Very low dome-to-neck (DTN) and aspect ratios provide an even greater challenge in the management of WNBAs. We present the safety and efficacy profile for endovascular clip system (eCLIPs) device in the treatment of this subset of WNBAs with very unfavorable morphologies.MethodsIn our case series, 24 patients treated at 12 international centers were taken from a larger prospective voluntary post-marketing registry of 65 patients treated with the eCLIPs device and coiling. Those who had WNBAs at either the carotid or basilar terminus with a DTN ratio ResultsThe eCLIPs device was successfully deployed in 23 cases (96%). One patient (4.2%) died due to guidewire perforation distal to the implant site. No other complications were documented. After a mean follow-up of 15.8 months (range 3–40 months), good radiologic outcomes (modified Raymond–Roy classification (MRRC) scores of 1 or 2) were documented in 20 of 21 patients (95%) with follow-up data. The lone patient with an MRRC score of 3 showed coiled compaction after incomplete neck coverage with the device.ConclusionOur series of patients with aneurysms having adverse DTN and aspect ratios demonstrated that the eCLIPs device has a safety and efficacy profile comparable with currently available devices in the treatment of WNBAs.

IntroductionAn accurate delineation of the intraprostatic gross tumor volume (GTV) is of importance for focal treatment in patients with primary prostate cancer (PCa). Multiparametric MRI (mpMRI) is the standard of care for lesion detection but has been shown to underestimate GTV. This study investigated how far the GTV has to be expanded in MRI in order to reach concordance with the histopathological reference and whether this strategy is practicable in clinical routine.Patients and MethodsTwenty-two patients with planned prostatectomy and preceded 3 Tesla mpMRI were prospectively examined. After surgery, PCa contours delineated on histopathological slides (GTV-Histo) were superimposed on MRI using ex-vivo imaging as support for co-registration. According to the PI-RADSv2 classification, GTV was manually delineated in MRI (GTV-MRI) by two experts in consensus. For volumetric analysis, we compared GTV-MRI and GTV-Histo. Subsequently, we isotropically enlarged GTV-MRI in 1 mm increments within the prostate and also compared those with GTV-Histo regarding the absolute volumes. For evaluating the spatial accuracy, we considered the coverage ratio of GTV-Histo, the Sørensen–Dice coefficient (DSC), as well as the contact with the urethra.ResultsIn 19 of 22 patients MRI underestimated the intraprostatic tumor volume compared to histopathological reference: median GTV-Histo (4.7 cm3, IQR: 2.5–18.8) was significantly (p3, IQR: 1.2–6.9). A median expansion of 1 mm (range: 0–4 mm) adjusted the initial GTV-MRI to at least the volume of GTV-Histo (GTVexp-MRI). Original GTV-MRI and expansion with 1, 2, 3, and 4 mm covered in median 39% (IQR: 2%–78%), 62% (10%–91%), 70% (15%–95%), 80% (21–100), 87% (25%–100%) of GTV-Histo, respectively. Best DSC (median: 0.54) between GTV-Histo and GTV-MRI was achieved by median expansion of 2 mm. The urethra was covered by initial GTVs-MRI in eight patients (36%). After applying an expansion with 2 mm the urethra was covered in one more patient by GTV-MRI. ConclusionUsing histopathology as reference, we demonstrated that MRI underestimates intraprostatic tumor volume. A 2 mm–expansion may improve accurate GTV-delineation while respecting the balance between histological tumor coverage and overtreatment.

Hypoglossal canal dural arteriovenous fistulas (HC-DAVF) involve the anterior condylar vein (ACV) and anterior condylar confluence (ACC). They often present with tinnitus, bruit, and hypoglossal nerve palsy. The most common treatment in HC-DAVFs is transvenous embolization using coils and the most direct transvenous route is the trans-internal jugular vein access. When this approach is not feasible, a treatment attempt is possible through alternative routes. We report 2 patients with DAVFs involving the anterior condylar confluence. The first patient presented with pulsatile tinnitus and hypoglossal nerve palsy, and was treated by a standard transjugular approach. The second patient presented with pulse-synchronous bruit. Following an unsuccessful attempt of the transjugular approach, the fistulous point was reached via the deep cervical vein and complete occlusion was achieved by coil deployment. Both patients had complete regression of symptoms. Endovascular therapy is the elective treatment for HC-DAVFs and the transjugular approach is the most commonly used. The deep cervical vein (DCV) can be an alternative transvenous route when the transjugular approach fails.

Abstract The novel influenza A virus (IAV) defective interfering particle “OP7” inhibits IAV replication in a co-infection and was previously suggested as a promising antiviral agent. Here, we report a batch-mode cell culture-based production process for OP7. In the present study, a seed virus containing standard virus (STV) and OP7 was used. The yield of OP7 strongly depended on the production multiplicity of infection. To inactivate infectious STV in the OP7 material, which may cause harm in a potential application, UV irradiation was used. The efficacy of OP7 in this material was preserved, as shown by an in vitro interference assay. Next, steric exclusion chromatography was used to purify and to concentrate (~ 13-fold) the UV-treated material. Finally, administration of produced OP7 material in mice did not show any toxic effects. Furthermore, all mice infected with a lethal dose of IAV survived the infection upon OP7 co-treatment. Thus, the feasibility of a production workflow for OP7 and its potential for antiviral treatment was demonstrated. Key points • OP7 efficacy strongly depended on the multiplicity of infection used for production • Purification by steric exclusion chromatography increased OP7 efficacy • OP7-treated mice were protected against a lethal infection with IAV

Background: The aim of the study was to evaluate the role of different immunohistochemical and radiomics features in patients with small cell lung cancer (SCLC). Methods: Consecutive patients with histologically proven SCLC with limited (n = 47, 48%) or extensive disease (n = 51, 52%) treated with radiotherapy and chemotherapy at our department were included in the analysis. The expression of different immunohistochemical markers from the initial tissue biopsy, such as CD56, CD44, chromogranin A, synaptophysin, TTF-1, GLUT-1, Hif-1 a, PD-1, and PD-L1, and MIB-1/KI-67 as well as LDH und NSE from the initial blood sample were evaluated. H-scores were additionally generated for CD44, Hif-1a, and GLUT-1. A total of 72 computer tomography (CT) radiomics texture features from a homogenous subgroup (n = 31) of patients were correlated with the immunohistochemistry, the survival (OS), and the progression-free survival (PFS). Results: The median OS, calculated from diagnosis, was 21 months for patients with limited disease and 13 months for patients with extensive disease. The expression of synaptophysin correlated with a better OS (HR 0.546 95% CI 0.308–0.966, p = 0.03). The expression of TTF-1 (HR 0.286, 95% CI: 0.117–0.698, p = 0.006) and a lower GLUT-1 H-score (median = 50, HR: 0.511, 95% CI: 0.260–1.003, p = 0.05) correlated with a better PFS. Patients without chromogranin A expression had a higher risk for developing cerebral metastases (p = 0.02) and patients with PD 1 expression were at risk for developing metastases (p = 0.02). Our radiomics analysis did not reveal a single texture feature that correlated highly with OS or PFS. Correlation coefficients ranged between −0.48 and 0.39 for OS and between −0.46 and 0.38 for PFS. Conclusions: The role of synaptophysin should be further evaluated as synaptophysin-negative patients might profit from treatment intensification. We report an, at most, moderate correlation of radiomics features with overall and progression free survival and no correlation with the expression of different immunohistochemical markers.

Background/Aim: We examined the prognostic value of intraprostatic gross tumour volume (GTV) as measured by multiparametric MRI (mpMRI) in patients with prostate cancer following (primary) external beam radiation therapy (EBRT). Patients and Methods: In a retrospective monocentric study, we analysed patients with prostate cancer (PCa) after EBRT. GTV was delineated in pre-treatment mpMRI (GTV-MRI) using T2-weighted images. Cox-regression analyses were performed considering biochemical failure recurrence-free survival (BRFS) as outcome variable. Results: Among 131 patients, after a median follow-up of 57 months, biochemical failure occurred in 27 (21%). GTV-MRI was not correlated with % of positive biopsy cores, Gleason score and initial PSA (all r

BACKGROUND: Arteriovenous fistulas (AVFs) involving the cavernous sinus usually become clinically apparent due to eye symptoms. Although rare, the same symptoms can be associated with AVFs located remote from the cavernous sinus when the shunt drains into its tributaries. We report the unusual case of a dural AVF in which such communication was not immediately obvious from the diagnostic angiogram.CASE DESCRIPTION: A 61-year-old male presented with increasing lid swelling, proptosis, and redness of the right eye for 1 month. Digital subtraction angiography showed no evidence of a cavernous sinus fistula but revealed a dural AVF between the right middle meningeal artery and the vein of Trolard. The fistula had a minor drainage through a small superficial middle cerebral vein toward the middle cranial fossa. Late venous-phase images eventually revealed faint opacification of the right cavernous sinus and superior ophthalmic vein. Endovascular treatment was performed by transarterial embolization with complete occlusion of the AVF obtained after 2 sessions.CONCLUSIONS: Dural AVFs involving cortical veins may cause atypical symptoms suggesting a cavernous sinus fistula due to remote venous drainage. Understanding venous anatomy helps to correlate vascular pathology and clinical symptoms and thus allows efficient and safe treatment.

Background Microcatheter entrapment during embolization of brain arteriovenous malformations (AVMs) represents a potentially harmful technical complication. Although several techniques have been reported for endovascular catheter retrieval from an Onyx cast, such methods have never been demonstrated with acrylic glues. We report a case of removal of a glued microcatheter from an N-butyl cyanoacrylate (NBCA) cast using a microsnare. Methods and Results A 26-year-old woman presented with an intracranial hemorrhage resulting from a ruptured right choroidal AVM. A microcatheter used for transarterial embolization was unintentionally glued into the NBCA cast. Because attempts to remove the catheter by simple traction failed, a microsnare was used and allowed withdrawal of the entrapped microcatheter without causing damage to the cerebral vasculature. The patient woke up without clinical sequelae. Conclusions Although it is not recommended as routine practice, snaring a glued microcatheter is feasible and can be used in selected cases as a last resort if thromboembolic complications are feared.

Zusammenfassung Anamnese und klinischer Befund In dieser Kasuistik berichten wir über einen 60-jährigen Patienten, der in unserer Ambulanz für Spezielle Schmerztherapie aufgrund einer „Mixed-Pain“-Schmerzsymptomatik bei Zustand nach operativer Entfernung eines Plattenepithelkarzinoms des Mundbodens analgetisch behandelt wurde. Nebenbefundlich war bei dem Patienten ein Zustand nach Alkoholabusus bekannt. Untersuchungen und Diagnose Der Patient war in reduziertem Allgemeinzustand und kachektischem Ernährungszustand. Es bestanden progrediente Schmerzen im Mund mit Ausstrahlung in beide Ohren sowie Appetitlosigkeit, so dass die Diagnose eines tumorbedingten Schmerzes (Mixed-Pain) und einer tumorbedingten Kachexie bei Zustand nach kurativer Behandlung eines Plattenepithelkarzinoms des Mundbodens gestellt wurde. Therapie und Verlauf Aufgrund des zunehmend kachektischen Ernährungszustandes und andauernder Appetitlosigkeit des Patienten wurde nach Abstimmung mit dem Versicherungsträger eine Therapie mit dem Cannabis-Spray Sativex® (enthält u. a. delta-9-Tetrahydrocannabinol und Cannabidiol) eingeleitet. Trotz anfänglich guter Verträglichkeit musste die Therapie aufgrund eines Alkoholrückfalls des Patienten abgebrochen werden. Nach Beendigung der Therapie konnte der Alkoholkonsum wieder beherrscht werden. Folgerung Dieser Fall bestätigt aus unserer Sicht, dass Medizinisches Cannabis bei Patienten mit anamnestisch bekannten Suchterkrankungen nur äußerst zurückhaltend eingesetzt werden sollte.

To validate the risk stratification algorithm of the Prostate Imaging Reporting and Data System (PI-RADSv2) for intermediary risk lesions (PI-RADSv2 category 3) in the peripheral zone based on focal contrast enhancement and to compare cancer rates in category 3, upgraded category 4 and category 4 based on markedly low ADC value.We retrospectively analyze 172 consecutive patients undergoing prostate MRI with 315 histopathologically verified lesions. We select all lesions either assigned category 3 or category 4 in the peripheral zone for further analysis. We compare cancer rates with the two-sided chi-squared test. To determine inter-observer agreement about contrast enhancement two blinded radiologists evaluate the subset of category 3 lesions based on the diffusion weighted sequence.The frequency of peripheral PI-RADS 3, upgraded PI-RADS 4 and PI-RADS 4 lesions based on markedly low ADC value is 10.8%, 10.8% and 20.3%, respectively. Cancer rates (significant cancer only) in these subgroups are 8.8% (3/34), 23.5% (8/34) and 40.6% (26/64), P 0.01. Inter-observer agreement is moderate for evaluation of contrast enhancement with kappa values between 0.46 and 0.5.We demonstrate a trend of increasing cancer rate from PI-RADSv2 category 3 to upgraded category 4 to category 4 based on markedly low ADC value. Peripheral lesions of intermediary risk in the diffusion weighted sequence account for 21.6% of all prostate lesions encountered. Since it is likely that patient management recommendations will be linked to assessment categories in future versions of PI-RADS, cancer rates in upgraded category 4 and category 4 based on markedly low ADC values should be in a similar range. We conclude that in future studies of PI-RADSv2 upgraded category 4 and category 4 based on markedly low ADC value should be reported separately to generate a database for meta-analysis of cancer rates.

Simple Summary Prostate cancer (PCa) is the most diagnosed malignancy of men worldwide, and radiotherapy (RT) is a main treatment option for patients in all disease stages. Modern diagnostic imaging and RT techniques enable an effective and safe delivery of high RT doses and a reduction of treatment time. We present a study protocol of a phase III trial implementing most modern imaging techniques and RT approaches. We compare the standard RT treatment with an RT concept of reduced treatment time and focal dose escalation based on the patient’s individual tumor morphology. This HypoFocal-SBRT trial aims to individualize treatment of PCa patients. Abstract Technical advances in radiotherapy (RT) treatment planning and delivery have substantially changed RT concepts for primary prostate cancer (PCa) by (i) enabling a reduction of treatment time, and by (ii) enabling safe delivery of high RT doses. Several studies proposed a dose–response relationship for patients with primary PCa and especially in patients with high-risk features, as dose escalation leads to improved tumor control. In parallel to the improvements in RT techniques, diagnostic imaging techniques like multiparametric magnetic resonance imaging (mpMRI) and positron-emission tomography targeting prostate-specific-membrane antigen (PSMA-PET) evolved and enable an accurate depiction of the intraprostatic tumor mass for the first time. The HypoFocal-SBRT study combines ultra-hypofractionated RT/stereotactic body RT, with focal RT dose escalation on intraprostatic tumor sides by applying state of the art diagnostic imaging and most modern RT concepts. This novel strategy will be compared with moderate hypofractionated RT (MHRT), one option for the curative primary treatment of PCa, which has been proven by several prospective trials and is recommended and carried out worldwide. We suspect an increase in relapse-free survival (RFS), and we will assess quality of life in order to detect potential changes.

The AT1 receptor, a major effector of the renin-angiotensin system, has been extensively studied in the context of cardiovascular and renal disease. Moreover, angiotensin receptor blockers, sartans, are among the most frequently prescribed drugs for the treatment of hypertension, chronic heart failure and chronic kidney disease. However, precise molecular insights into the structure of this important drug target have not been available until recently. In this context, seminal studies have now revealed exciting new insights into the structure and biased signaling of the receptor and may thus foster the development of novel therapeutic approaches to enhance the efficacy of pharmacological angiotensin receptor antagonism or to enable therapeutic induction of biased receptor activity. In this review, we will therefore highlight these and other seminal publications to summarize the current understanding of the tertiary structure, ligand binding properties and downstream signal transduction of the AT1 receptor.

Acetate is a characteristic by-product of Escherichia coli K-12 growing in batch cultures with glucose, both under aerobic as well as anaerobic conditions. While the reason underlying aerobic acetate production is still under discussion, during anaerobic growth acetate production is important for ATP generation by substrate level phosphorylation. Under both conditions, acetate is produced by a pathway consisting of the enzyme phosphate acetyltransferase (Pta) producing acetyl-phosphate from acetyl-coenzyme A, and of the enzyme acetate kinase (AckA) producing acetate from acetyl-phosphate, a reaction that is coupled to the production of ATP. Mutants in the AckA-Pta pathway differ from each other in the potential to produce and accumulate acetyl-phosphate. In the publication at hand, we investigated different mutants in the acetate pathway, both under aerobic as well as anaerobic conditions. While under aerobic conditions only small changes in growth rate were observed, all acetate mutants showed severe reduction in growth rate and changes in the by-product pattern during anaerobic growth. The AckA– mutant showed the most severe growth defect. The glucose uptake rate and the ATP concentration were strongly reduced in this strain. This mutant exhibited also changes in gene expression. In this strain, the atoDAEB operon was significantly upregulated under anaerobic conditions hinting to the production of acetoacetate. During anaerobic growth, protein acetylation increased significantly in the ackA mutant. Acetylation of several enzymes of glycolysis and central metabolism, of aspartate carbamoyl transferase, methionine synthase, catalase and of proteins involved in translation was increased. Supplementation of methionine and uracil eliminated the additional growth defect of the ackA mutant. The data show that anaerobic, fermentative growth of mutants in the AckA-Pta pathway is reduced but still possible. Growth reduction can be explained by the lack of an important ATP generating pathway of mixed acid fermentation. An ackA deletion mutant is more severely impaired than pta or ackA-pta deletion mutants. This is most probably due to the production of acetyl-P in the ackA mutant, leading to increased protein acetylation.