Hepatocellular carcinoma tumor thrombus entering the right atrium treated with combining percutaneous and intravenous high-dose-rate brachytherapy: a case report

The presented report describes a case of a Hepatocellular carcinoma (HCC) tumor thrombus (TT) infiltrating the inferior vena cava (IVC) and the right atrium (RA) in a 66-year old male patient who initially presented with TT related symptoms. CT-guided high-dose-rate brachytherapy (HDRBT) was performed for both, the intraparenchymal primary and the TT. A marked improvement of the tumor-related symptoms and shrinkage of the tumor mass were achieved six months after treatment initiation. The combination of intravascular and percutaneous HDRBT demonstrating a promising approach to palliate tumor-related symptoms in advanced HCC with macrovascular invasion

Elastin-specific MRI of extracellular matrix-remodelling following hepatic radiofrequency-ablation in a VX2 liver tumor model

Hepatic radiofrequency ablation (RFA) induces a drastic alteration of the biomechanical environment in the peritumoral liver tissue. The resulting increase in matrix stiffness has been shown to significantly influence carcinogenesis and cancer progression after focal RF ablation. To investigate the potential of an elastin-specific MR agent (ESMA) for the assessment of extracellular matrix (ECM) remodeling in the periablational rim following RFA in a VX2 rabbit liver tumor-model, twelve New-Zealand-White-rabbits were implanted in the left liver lobe with VX2 tumor chunks from donor animals. RFA of tumors was performed using a perfused RF needle-applicator with a mean tip temperature of 70 degrees C. Animals were randomized into four groups for MR imaging and scanned at four different time points following RFA (week 0 [baseline], week 1, week 2 and week 3 after RFA), followed by sacrifice and histopathological analysis. ESMA-enhanced MR imaging was used to assess ECM remodeling. Gadobutrol was used as a third-space control agent. Molecular MR imaging using an elastin-specific probe demonstrated a progressive increase in contrast-to-noise ratio (CNR) (week 3: ESMA: 28.1 +/- 6.0; gadobutrol: 3.5 +/- 2.0), enabling non-invasive imaging of the peritumoral zone with high spatial-resolution, and accurate assessment of elastin deposition in the periablational rim. In vivo CNR correlated with ex vivo histomorphometry (ElasticaVanGiesson-stain, y=1.2x - 1.8, R-2=0.89, p<0.05) and gadolinium concentrations at inductively coupled mass spectroscopy (ICP-MS, y=0.04x+1.2, R-2=0.95, p<0.05). Laser-ICP-MS confirmed colocalization of elastin-specific probe with elastic fibers. Following thermal ablation, molecular imaging using an elastin-specific MR probe is feasible and provides a quantifiable biomarker for the assessment of the ablation-induced remodeling of the ECM in the periablational rim

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

The use and evaluation of image-based techniques for the assessment of tumor response to loco-regional and systemic therapies

Zielsetzung: In den vorliegenden Studien wurden bildgestützte Verfahren zur Erfassung des Tumoransprechens auf lokale und systemische Therapien eingesetzt, modifiziert und als Indikatoren für einen Therapieerfolg evaluiert. Material und Methoden: Kontrastmittel (KM)-verstärkte Magnetresonanztomographie (MRT)-Bildgebung wurde zur Erfassung der therapeutischen Effekte loko-regionärer Interventionen verwendet. Eingeschlossen wurden Patientinnen mit Uterusmyomen (uterine fibroids [UF]) nach MRT-gestützter hochintensiver fokussierter Ultraschallablation (MRgHIFU, n=24) oder bilateraler Embolisation der Aa. uterinae (UAE, n=25) sowie Patienten/innen mit Leber-metastasen bei kolorektalem Karzinom (colorectal liver metastases [CLM]) nach intraarterieller Tumortherapie (IAT, n=29). Im Vergleich zu manuellen Messungen wurde eine neue semi-automatische dreidimensionale (3D) Segmentierungstechnik eingesetzt, um das Gesamtvolumen (Total Lesion Volume [TLV], cm3) und die KM-Aufnahme (Enhancing Lesion Volume [ELV], % und cm3) der Tumoren auf den MRT-Bildgebungen prä- und posttherapeutisch zu quantifizieren. Durch Korrelationsanalysen mit dem klinischen Tumoransprechen wurde der Vorhersagewert der Bildgebungsparameter untersucht. Für die CLM wurde der prädiktive Wert etablierter bildgestützter Kriterien des Tumoransprechens für das Gesamtüberleben vergleichend für die Verwendung von 1D, 2D und 3D ermittelten Markern analysiert. Die statistische Auswertung beinhaltete lineare Regressionsanalysen, den Wilcoxon t-Test, den Mann-Whitney-Test sowie eine Kaplan-Meier-Analyse des Gesamtüberlebens. In einem translationalen Tierexperiment wurden die Effekte des anti-glykolytisch wirksamen 3-Bromopyruvat (3-BrPA) in der systemischen Therapie des duktalen Pankreas-adenokarzinoms untersucht. Die Wirksamkeit von 3-BrPA in einer mikro- enkapsulierten Applikationsform wurde in vitro sowie in einem orthotopischen Maustumormodell erforscht und durch Lumineszenz-basierte Bildgebungen (ATP- Assay, Biolumineszenzbildgebung) dargestellt. Ergebnisse: Für UF nach MRgHIFU ergab sich eine statistisch signifikante Abnahme des TLV nach sechs Monaten, welche über einen Beobachtungszeitraum von 24 Monaten relativ stabil blieb. In der Verlaufskontrolle nach UAE waren sowohl TLV als auch ELV in cm3 bei allen Patientinnen reduziert, was mit der klinischen Besserung übereinstimmte. Für das Ansprechen von CLM nach IAT konnte eine positive Korrelation der quantitativen European Association for the Study of the Liver (qEASL)-Kriterien unter Verwendung der 3D ermittelten Parameter mit dem Gesamtüberleben gezeigt werden. In vitro und in vivo waren für den Einschlusskomplex von 3-BrPA zytotoxische und anti-invasive Effekte nachweisbar. Ein reduziertes Signal in der Biolumineszenzbildgebung diente als Indikator für den Therapieerfolg im Tiermodell und konnte in histopathologischen Analysen der Tumoren bestätigt werden. Schlussfolgerung: In drei Studien konnte die semi-automatische 3D Quantifizierung des Tumor- ansprechens angewendet und als akkurat und reproduzierbar validiert werden. Die Bildgebungs-marker waren in Abhängigkeit von der Interventionsmethode repräsentativ für das klinische Therapieansprechen. Im translationalen Tumormodell konnte durch die Mikro-Enkapsulierung von 3-BrPA die Möglichkeit zur systemischen anti-glykolytischen Tumortherapie gezeigt und die Tumorantwort durch Biolumineszenz-basierte Methoden visualisiert werden.Purpose: The present studies investigated image-based analyses for the assessment of tumor response to loco-regional or systemic therapies and evaluated the predictive role of imaging parameters for the clinical outcome. Materials and Methods: The therapeutic efficacy of loco-regional treatments was assessed on contrast-enhanced magnetic resonance imaging (ceMRI) scans. Patients with uterine fibroids (UF) after MRI-guided high-intensity focused ultrasound ablation (MRgHIFU, n=24) or bilateral uterine artery embolization (UAE, n=25) and colorectal liver metastases (CLM) after intra-arterial therapies (IAT, n=29) were included in the analysis. A novel semi-automatic three-dimensional (3D) segmentation technique was used to quantify the total (TLV) and enhancing lesion volume (ELV) on ceMRI scans before and after treatment. The volumetric imaging markers were compared to subjective manual measurements. Their predictive value for the clinical outcome was calculated by correlation analyses. For CLM, imaging-based response to treatment was determined using established evaluation criteria with 1D, 2D and 3D assessed markers. The statistical analysis included a linear regression model, the Wilcoxon t-Test, the Mann-Whitney-Test and a Kaplan-Meier analysis of the overall survival (OS). A translational study evaluated the effects of the anti-glycolytic drug 3-bromopyruvate (3-BrPA) in a microencapsulated formula for the systemic therapy of pancreatic ductal adenocarcinoma. Anti-cancer efficacy was investigated in vitro and in a mouse xenograft tumor model and monitored using luminescence-based imaging (ATP-Assay, bioluminescence imaging [BLI]). Results: A reduction of the TLV in UF became apparent six months after MRgHIFU and remained relatively stable for the follow-up period of 24 months. After UAE, 3D measurements revealed a reduction of TLV and ELV in cm3 in all patients, which correlated well with an improvement of symptoms. Regarding CLM after IAT, quantitative European Association for the Study of the Liver (qEASL) criteria deploying the 3D assessed parameters were identified as predictors of the OS. Microencapsulated 3-BrPA exhibited strong cytotoxic and anti-invasive efficacy in vitro and in vivo. Reduced BLI signal intensity after treatment indicated tumor response in the animal experiments and was confirmed by histopathological ex vivo analyses. Conclusion: For three different settings, the semi-automatic 3D assessment has proven feasible, accurate and reproducible in the quantification of tumor response to treatment. Imaging markers appeared to be predictive of the clinical outcome depending on the therapeutic rationale of the treatment. The microencapsulation of 3-BrPA represents a pioneering approach for the systemic delivery of anti-glycolytic drugs and bioluminescence-based imaging was successfully used to visualize tumor response in a translational setting