Characterization of Metabolic, Diffusion, and Perfusion Properties in GBM: Contrast-Enhancing versus Non-Enhancing Tumor.

BackgroundAlthough the contrast-enhancing (CE) lesion on T1-weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T2-weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh-) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh- and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden.MethodsFifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy.ResultsThe Enh+ and Enh- tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data.ConclusionsThe similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh- tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM

Dominant Nuclear Outflow Driving Mechanisms in Powerful Radio Galaxies

In order to identify the dominant nuclear outflow mechanisms in Active Galactic Nuclei, we have undertaken deep, high resolution observations of two compact radio sources (PKS 1549-79 and PKS 1345+12) with the Advanced Camera for Surveys (ACS) aboard the Hubble Space Telescope. Not only are these targets known to have powerful emission line outflows, but they also contain all the potential drivers for the outflows: relativistic jets, quasar nuclei and starbursts. ACS allows the compact nature (<0.15") of these radio sources to be optically resolved for the first time. Through comparison with existing radio maps we have seen consistency in the nuclear position angles of both the optical emission line and radio data. There is no evidence for bi-conical emission line features on the large-scale and there is a divergance in the relative position angles of the optical and radio structure. This enables us to exclude starburst driven outflows. However, we are unable to clearly distinguish between radiative AGN wind driven outflows and outflows powered by relativistic radio jets. The small scale bi-conical features, indicative of such mechanisms could be below the resolution limit of ACS, especially if aligned close to the line of sight. In addition, there may be offsets between the radio and optical nuclei induced by heavy dust obscuration, nebular continuum or scattered light from the AGN.Comment: 9 pages, 8 figures, emulateapj, ApJ Accepte

Baseline Frailty Measured by the Risk Analysis Index and 30-Day Mortality After Surgery for Spinal Malignancy: Analysis of a Prospective Registry (2011–2020)

Objective To evaluate the prognostic utility of baseline frailty, measured by the Risk Analysis Index (RAI), for prediction of postoperative mortality among patients with spinal malignancy (SM) undergoing resection. Methods SM surgery cases were queried from the American College of Surgeons – National Surgical Quality Improvement Program database (2011–2020). The relationship between preoperative RAI frailty score and increasing rate of primary endpoint (mortality or discharge to hospice within 30 days, “mortality/hospice”) were assessed. Discriminatory accuracy was assessed by computation of C-statistics (with 95% confidence interval [CI]) in receiver operating characteristic (ROC) curve analysis. Results A total of 2,235 cases were stratified by RAI score: 0–20, 22.7%; 21–30, 11.9%; 31–40, 54.7%; and ≥ 41, 10.7%. The rate of mortality/hospice was 6.5%, which increased linearly with increasing RAI score (p < 0.001). RAI was also associated with increasing rates of major complication, extended length of stay, and nonhome discharge (all p < 0.05). The RAI demonstrated acceptable discriminatory accuracy for prediction of primary endpoint (C-statistic, 0.717; 95% CI, 0.697–0.735). In pairwise ROC comparison, RAI demonstrated superiority versus modified frailty index-5 and chronological age (p < 0.001). Conclusion Preoperative frailty, as measured by RAI, is a robust predictor of mortality/hospice after SM surgery. The frailty score may be applied in clinical settings using a user-friendly calculator, deployed here: https://nsgyfrailtyoutcomeslab.shinyapps.io/spinalMalignancyRAI/

A Predictive Model of Failure to Rescue After Thoracolumbar Fusion

Objective Although failure to rescue (FTR) has been utilized as a quality-improvement metric in several surgical specialties, its current utilization in spine surgery is limited. Our study aims to identify the patient characteristics that are independent predictors of FTR among thoracolumbar fusion (TLF) patients. Methods Patients who underwent TLF were identified using relevant diagnostic and procedural codes from the National Surgical Quality Improvement Program (NSQIP) database from 2011–2020. Frailty was assessed using the risk analysis index (RAI). FTR was defined as death, within 30 days, following a major complication. Univariate and multivariable analyses were used to compare baseline characteristics and early postoperative sequelae across FTR and non-FTR cohorts. Receiver operating characteristic (ROC) curve analysis was used to assess the discriminatory accuracy of the frailty-driven predictive model for FTR. Results The study cohort (N = 15,749) had a median age of 66 years (interquartile range, 15 years). Increasing frailty, as measured by the RAI, was associated with an increased likelihood of FTR: odds ratio (95% confidence interval [CI]) is RAI 21–25, 1.3 [0.8–2.2]; RAI 26–30, 4.0 [2.4–6.6]; RAI 31–35, 7.0 [3.8–12.7]; RAI 36–40, 10.0 [4.9–20.2]; RAI 41– 45, 21.5 [9.1–50.6]; RAI ≥ 46, 45.8 [14.8–141.5]. The frailty-driven predictive model for FTR demonstrated outstanding discriminatory accuracy (C-statistic = 0.92; CI, 0.89–0.95). Conclusion Baseline frailty, as stratified by type of postoperative complication, predicts FTR with outstanding discriminatory accuracy in TLF patients. This frailty-driven model may inform patients and clinicians of FTR risk following TLF and help guide postoperative care after a major complication

USP48 restrains resection by site-specific cleavage of the BRCA1 ubiquitin mark from H2A

BRCA1 ligase activity is tightly regulated to maintain genome stability and confer DNA double strand repair. Here the authors identify USP48 as a H2A deubiquitinating enzyme that acts as a BRCA1 E3 ligase antagonist and characterize its role during DNA repair

White matter hyperintensities at critical crossroads for executive function and verbal abilities in small vessel disease

© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC. The presence of white matter lesions in patients with cerebral small vessel disease (SVD) is among the main causes of cognitive decline. We investigated the relation between white matter hyperintensity (WMH) locations and executive and language abilities in 442 SVD patients without dementia with varying burden of WMH. We used Stroop Word Reading, Stroop Color Naming, Stroop Color-Word Naming, and Category Fluency as language measures with varying degrees of executive demands. The Symbol Digit Modalities Test (SDMT) was used as a control task, as it measures processing speed without requiring language use or verbal output. A voxel-based lesion–symptom mapping (VLSM) approach was used, corrected for age, sex, education, and lesion volume. VLSM analyses revealed statistically significant clusters for tests requiring language use, but not for SDMT. Worse scores on all tests were associated with WMH in forceps minor, thalamic radiations and caudate nuclei. In conclusion, an association was found between WMH in a core frontostriatal network and executive-verbal abilities in SVD, independent of lesion volume and processing speed. This circuitry underlying executive-language functioning might be of potential clinical importance for elderly with SVD. More detailed language testing is required in future research to elucidate the nature of language production difficulties in SVD

Cytoreductive surgery followed by chemotherapy versus chemotherapy alone for recurrent platinum- sensitive epithelial ovarian cancer (SOCceR trial):a multicenter randomised controlled study

BACKGROUND: Improvement in treatment for patients with recurrent ovarian cancer is needed. Standard therapy in patients with platinum-sensitive recurrent ovarian cancer consists of platinum-based chemotherapy. Median overall survival is reported between 18 and 35 months. Currently, the role of surgery in recurrent ovarian cancer is not clear. In selective patients a survival benefit up to 62 months is reported for patients undergoing complete secondary cytoreductive surgery. Whether cytoreductive surgery in recurrent platinum-sensitive ovarian cancer is beneficial remains questionable due to the lack of level I-II evidence. METHODS/DESIGN: Multicentre randomized controlled trial, including all nine gynecologic oncologic centres in the Netherlands and their affiliated hospitals. Eligible patients are women, with first recurrence of FIGO stage Ic-IV platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, who meet the inclusion criteria. Participants are randomized between the standard treatment consisting of at least six cycles of intravenous platinum based chemotherapy and the experimental treatment which consists of secondary cytoreductive surgery followed by at least six cycles of intravenous platinum based chemotherapy. Primary outcome measure is progression free survival. In total 230 patients will be randomized. Data will be analysed according to intention to treat. DISCUSSION: Where the role of cytoreductive surgery is widely accepted in the initial treatment of ovarian cancer, its value in recurrent platinum-sensitive epithelial ovarian cancer has not been established so far. A better understanding of the benefits and patients selection criteria for secondary cytoreductive surgery has to be obtained. Therefore the 4(th) ovarian cancer consensus conference in 2010 stated that randomized controlled phase 3 trials evaluating the role of surgery in platinum-sensitive recurrent epithelial ovarian cancer are urgently needed. We present a recently started multicentre randomized controlled trial that will investigate the role of secondary cytoreductive surgery followed by chemotherapy will improve progression free survival in selected patients with first recurrence of platinum-sensitive epithelial ovarian cancer. TRIAL REGISTRATION: Netherlands Trial Register number: NTR3337

In vivo tumor growth of high-grade serous ovarian cancer cell lines

OBJECTIVE: Genomic studies of ovarian cancer (OC) cell lines frequently used in research revealed that these cells do not fully represent high-grade serous ovarian cancer (HGSOC), the most common OC histologic type. However, OC lines that appear to genomically resemble HGSOC have not been extensively used and their growth characteristics in murine xenografts are essentially unknown. METHODS: To better understand growth patterns and characteristics of HGSOC cell lines in vivo, CAOV3, COV362, KURAMOCHI, NIH-OVCAR3, OVCAR4, OVCAR5, OVCAR8, OVSAHO, OVKATE, SNU119 and UWB1.289 cells were assessed for tumor formation in nude mice. Cells were injected intraperitoneally (i.p.) or subcutaneously (s.c.) in female athymic nude mice and allowed to grow (maximum of 90 days) and tumor formation was analyzed. All tumors were sectioned and assessed using H&E staining and immunohistochemistry for p53, PAX8 and WT1 expression. RESULTS: Six lines (OVCAR3, OVCAR4, OVCAR5, OVCAR8, CAOV3, and OVSAHO) formed i.p xenografts with HGSOC histology. OVKATE and COV362 formed s.c. tumors only. Rapid tumor formation was observed for OVCAR3, OVCAR5 and OVCAR8, but only OVCAR8 reliably formed ascites. Tumors derived from OVCAR3, OVCAR4, and OVKATE displayed papillary features. Of the 11 lines examined, three (Kuramochi, SNU119 and UWB1.289) were non-tumorigenic. CONCLUSIONS: Our findings help further define which HGSOC cell models reliably generate tumors and/or ascites, critical information for preclinical drug development, validating in vitro findings, imaging and prevention studies by the OC research community

Sentence Repetition in Deaf Children with Specific Language Impairment in British Sign Language

Children with specific language impairment (SLI) perform poorly on sentence repetition tasks across different spoken languages, but until now, this methodology has not been investigated in children who have SLI in a signed language. Users of a natural sign language encode different sentence meanings through their choice of signs and by altering the sequence and inflections of these signs. Grammatical information is expressed through movement and configurational changes of the hands and face. The visual modality thus influences how grammatical morphology and syntax are instantiated. How would language impairment impact on the acquisition of these types of linguistic devices in child signers? We investigated sentence repetition skills in a group of 11 deaf children who display SLI in British Sign Language (BSL) and 11 deaf controls with no language impairment who were matched for age and years of BSL exposure. The SLI group was significantly less accurate on an overall accuracy score, and they repeated lexical items, overall sentence meaning, sign order, facial expressions, and verb morphological structures significantly less accurately than controls. This pattern of language deficits is consistent with the characterization of SLI in spoken languages even though expression is in a different modality. We conclude that explanations of SLI, and of poor sentence repetition by children with this disorder, must be able to account for both the spoken and signed modalities