PET/MRI of Hepatic 90Y Microsphere Deposition Determines Individual Tumor Response.

PurposeThe purpose of our study is to determine if there is a relationship between dose deposition measured by PET/MRI and individual lesion response to yttrium-90 ((90)Y) microsphere radioembolization.Materials and methods26 patients undergoing lobar treatment with (90)Y microspheres underwent PET/MRI within 66 h of treatment and had follow-up imaging available. Adequate visualization of tumor was available in 24 patients, and contours were drawn on simultaneously acquired PET/MRI data. Dose volume histograms (DVHs) were extracted from dose maps, which were generated using a voxelized dose kernel. Similar contours to capture dimensional and volumetric change of tumors were drawn on follow-up imaging. Response was analyzed using both RECIST and volumetric RECIST (vRECIST) criteria.ResultsA total of 8 hepatocellular carcinoma (HCC), 4 neuroendocrine tumor (NET), 9 colorectal metastases (CRC) patients, and 3 patients with other metastatic disease met inclusion criteria. Average dose was useful in predicting response between responders and non-responders for all lesion types and for CRC lesions alone using both response criteria (p < 0.05). D70 (minimum dose to 70 % of volume) was also useful in predicting response when using vRECIST. No significant trend was seen in the other tumor types. For CRC lesions, an average dose of 29.8 Gy offered 76.9 % sensitivity and 75.9 % specificity for response.ConclusionsPET/MRI of (90)Y microsphere distribution showed significantly higher DVH values for responders than non-responders in patients with CRC. DVH analysis of (90)Y microsphere distribution following treatment may be an important predictor of response and could be used to guide future adaptive therapy trials

Separating the BL Lac and Cluster X-ray Emissions in Abell 689 with Chandra

We present the results of a Chandra observation of the galaxy cluster Abell 689 (z=0.279). Abell 689 is one of the most luminous clusters detected in the ROSAT All Sky Survey (RASS), but was flagged as possibly including significant point source contamination. The small PSF of the Chandra telescope allows us to confirm this and separate the point source from the extended cluster X-ray emission. For the cluster we determine a bolometric luminosity of L_{bol}=(3.3+/-0.3)x10^{44} erg s-1 and a temperature of kT=5.1^{+2.2}_{-1.3} keV when including a physically motivated background model. We compare our measured luminosity for A689 to that quoted in the Rosat All Sky Survey (RASS) and find L_{0.1-2.4,keV}=2.8x10^{44} erg s-1, a value \sim10 times lower than the ROSAT measurement. Our analysis of the point source shows evidence for significant pileup, with a pile-up fraction of ~60%. SDSS spectra and HST images lead us to the conclusion that the point source within Abell 689 is a BL Lac object. Using radio and optical observations from the VLA and HST archives, we determine {\alpha}_{ro}=0.50, {\alpha}_{ox}=0.77 and {\alpha}_{rx}=0.58 for the BL Lac, which would classify it as being of 'High-energy peak BL Lac' (HBL) type. Spectra extracted of A689 show a hard X-ray excess at energies above 6 keV that we interpret as inverse Compton emission from aged electrons that may have been transported into the cluster from the BL Lac.Comment: 11 pages, 15 figures, MNRAS in pres

X-MAS2: Study Systematics on the ICM Metallicity Measurements

(Abridged)The X-ray measurements of the ICM metallicity are becoming more frequent due to the availability of powerful X-ray telescope with excellent spatial and spectral resolutions. The information which can be extracted from the measurements of the alpha-elements, like Oxygen, Magnesium and Silicon with respect to the Iron abundance is extremely important to better understand the stellar formation and its evolutionary history. In this paper we investigate possible source of bias connected to the plasma physics when recovering metal abundances from X-ray spectra. To do this we analyze 6 simulated galaxy clusters processed through the new version of our X-ray MAp Simulator, which allows to create mock XMM-Newton EPIC MOS1 and MOS2 observations. By comparing the spectroscopic results to the input values we find that: i) Fe is recovered with high accuracy for both hot (T>3 keV) and cold (T<2 keV) systems; at intermediate temperatures, however, we find a systematic overestimate which depends on the number counts; ii) O is well recovered in cold clusters, while in hot systems its measure may overestimate by a factor up to 2-3; iii) Being a weak line, the measurement of Mg is always difficult; despite of this, for cold systems (T<2 keV) we do not find any systematic behavior, while for very hot systems (T>5 keV) the spectroscopic measurement may be strongly overestimated up to a factor of 4; iv) Si is well recovered for all the clusters in our sample. We investigate in detail the nature of the systematic effects and biases found. We conclude that they are mainly connected with the multi-temperature nature of the projected observed spectra and to the intrinsic limitation of the XMM-Newton EPIC spectral resolution that does not always allow to disentangle among the emission lines produced by different elements.Comment: (e.g.: 17 pages, 8 figures, accepted for publication in the Astrophysical Journal, updated discussion to match published version-new section:6.3

A phase II study of capecitabine and oxalplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gall bladder or biliary tract

Background: Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. Methods: This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Com mittee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecit abine (1000 mg/m2 po, twice daily, days 1–14) and oxaliplatin (130 mg/m2 i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. Results: Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8 % (95 % CI 12.05–39.5 %). Stable disease was observed in a further 13 patients (31 %) and progressive disease observed in 12 (28.6 %) of patients. The median progression-free survival was 4.6 months (95 % CI 2.8–6.4 months; Fig. 1) and the median overall survival 7.9 months (95 % CI 5.3–10.4 months; Fig. 2). Conclusion: Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. How ever, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated

The impact of schizophrenia and mood disorder risk alleles on emotional problems: investigating change from childhood to middle age

Previous studies find that both schizophrenia and mood disorder risk alleles contribute to adult depression and anxiety. Emotional problems (depression or anxiety) begin in childhood and show strong continuities into adult life; this suggests that symptoms are the manifestation of the same underlying liability across different ages. However, other findings suggest that there are developmental differences in the etiology of emotional problems at different ages. To our knowledge, no study has prospectively examined the impact of psychiatric risk alleles on emotional problems at different ages in the same individuals. Data were analyzed using regression-based analyses in a prospective, population-based UK cohort (the National Child Development Study). Schizophrenia and major depressive disorder (MDD) polygenic risk scores (PRS) were derived from published Psychiatric Genomics Consortium genome-wide association studies. Emotional problems were assessed prospectively at six time points from age 7 to 42 years. Schizophrenia PRS were associated with emotional problems from childhood [age 7, OR 1.09 (1.03–1.15), p = 0.003] to mid-life [age 42, OR 1.10 (1.05–1.17), p < 0.001], while MDD PRS were associated with emotional problems only in adulthood [age 42, OR 1.06 (1.00–1.11), p = 0.034; age 7, OR 1.03 (0.98–1.09), p = 0.228]. Our prospective investigation suggests that early (childhood) emotional problems in the general population share genetic risk with schizophrenia, while later (adult) emotional problems also share genetic risk with MDD. The results suggest that the genetic architecture of depression/anxiety is not static across development

On the Self-Similar Appearance of Galaxy Clusters in X-rays

The largest uncertainty for cosmological studies using clusters of galaxies is introduced by our limited knowledge of the statistics of galaxy cluster structure, and of the scaling relations between observables and cluster mass. A large effort is therefore undertaken to compile global galaxy cluster properties in particular obtained through X-ray observations and to study their scaling relations. However, the scaling schemes used in the literature differ. The present paper aims to clarify this situation by providing a thorough review of the scaling laws within the standard model of large-scale structure growth and to discus various steps of practical approximations. We derive the scaling laws for X-ray observables and cluster mass within the pure gravitational structure growth scenario. Using N-body simulations we test the recent formation approximation used in earlier analytic approaches which involves a redshift dependent overdensity parameter.We find this approximation less precise than the use of a fiducial radius based on a fixed overdensity with respect to critical density. Inspired by the comparison of the predicted scaling relations with observations we propose a first order modification of the scaling scheme to include the observed effects of hydrodynamics in structure formation. This modification involves a cluster mass dependent gas mass fraction. We also discuss the observational results of the reshift evolution of the most important scaling relations and find that also a redshift dependence of the gas mass to total mass relation has to be invoked within our modification scheme. We find that the current observational data are within their uncertainties consistent with the proposed modified scaling laws.Comment: Astronomy and Astrophysics (in press) 14 pages, 6 figure

Childhood maltreatment and adult medical morbidity in mood disorders: comparison of unipolar depression with bipolar disorder.

BACKGROUND: The medical burden in mood disorders is high; various factors are thought to drive this pattern. Little research has examined the role of childhood maltreatment and its effects on medical morbidity in adulthood among people with unipolar depression and bipolar disorder.AimsThis is the first study to explore the association between childhood maltreatment and medical morbidity in bipolar disorder and in unipolar depression, and examine whether the impact of abuse and neglect are distinct or combined. METHOD: The participants consisted of 354 psychiatrically healthy controls, 248 participants with recurrent unipolar depression and 72 with bipolar disorder. Participants completed the Childhood Trauma Questionnaire and received a validated medical history interview. RESULTS: Any type of childhood maltreatment, child abuse and child neglect were significantly associated with the medical burden in bipolar disorder, but not unipolar depression or for controls. These associations worked in a dose-response fashion where participants with bipolar disorder with a history of two or more types of childhood maltreatment had the highest odds of having a medical illness relative to those without such history or those who reported one form. No such significant dose-response patterns were detected for participants with unipolar depression or controls. CONCLUSIONS: These findings suggest that childhood maltreatment may play a stronger role in the development of medical illnesses in individuals with bipolar disorder relative to those with unipolar depression. Individuals who had been maltreated with a mood disorder, especially bipolar disorder may benefit most from prevention and intervention efforts surrounding physical health.Declaration of interestNone.GlaxoSmithKline Research and Development funded BaCCs. The UK Medical Research Council (MRC; G0701420) funded DeCC. The BADGE study was supported by an Interdisciplinary PhD studentship from the UK Economic Social Research Council and MRC to G.M.H. H.L.F. is supported by an MQ Fellows Award (MQ14F40). K.H. is supported by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The sources of funding had no involvement in the study design, data collection or decision to submit for publication

A phase 1 trial of the safety, tolerability and biological effects of intravenous Enadenotucirev, a novel oncolytic virus, in combination with chemoradiotherapy in locally advanced rectal cancer (CEDAR)

BACKGROUND: Chemoradiotherapy remains the standard of care for locally advanced rectal cancer. Efforts to intensify treatment and increase response rates have yet to yield practice changing results due to increased toxicity and/or absence of increased radiosensitization. Enadenotucirev (EnAd) is a tumour selective, oncolytic adenovirus which can be given intravenously. Pre-clinical evidence of synergy with radiation warrants further clinical testing and assessment of safety with radiation. METHODS: Eligibility include histology confirmed locally advanced rectal cancer that require chemoradiation. The trial will use a Time-to-Event Continual Reassessment Model-based (TiTE-CRM) approach using toxicity and efficacy as co-primary endpoints to recommend the optimal dose and treatment schedule 30 patients will be recruited. Secondary endpoints include pathological complete response the neoadjuvant rectal score. A translational program will be based on a mandatory biopsy during the second week of treatment for 'proof-of-concept' and exploration of mechanism. The trial opened to recruitment in July 2019, at an expected rate of 1 per month for up to 4 years. DISCUSSION: Chemoradiation with Enadenotucirev as a radiosensitiser in locally Advanced Rectal cancer (CEDAR) is a prospective multicentre study testing a new paradigm in radiosensitization in rectal cancer. The unique ability of EnAd to selectively infect tumour cells following intravenous delivery is an exciting opportunity with a clear translational goal. The novel statistical design will make efficient use of both toxicity and efficacy data to inform subsequent studies. TRIAL REGISTRATION: ClinicalTrial.gov, NCT03916510. Registered 16th April 2019