Delayed engraftment remains a major hurdle after cord blood (CB) transplantation. It may be due, at least in part, to low fucosylation of cell surface molecules important for homing to the bone ...marrow microenvironment. Because fucosylation of specific cell surface ligands is required before effective interaction with selectins expressed by the bone marrow microvasculature can occur, a simple 30-minute ex vivo incubation of CB hematopoietic progenitor cells with fucosyltransferase-VI and its substrate (GDP-fucose) was performed to increase levels of fucosylation. The physiologic impact of CB hematopoietic progenitor cell hypofucosylation was investigated in vivo in NOD-SCID interleukin (IL)-2Rγ(null) (NSG) mice. By isolating fucosylated and nonfucosylated CD34(+) cells from CB, we showed that only fucosylated CD34(+) cells are responsible for engraftment in NSG mice. In addition, because the proportion of CD34(+) cells that are fucosylated in CB is significantly less than in bone marrow and peripheral blood, we hypothesize that these combined observations might explain, at least in part, the delayed engraftment observed after CB transplantation. Because engraftment appears to be correlated with the fucosylation of CD34(+) cells, we hypothesized that increasing the proportion of CD34(+) cells that are fucosylated would improve CB engraftment. Ex vivo treatment with fucosyltransferase-VI significantly increases the levels of CD34(+) fucosylation and, as hypothesized, this was associated with improved engraftment. Ex vivo fucosylation did not alter the biodistribution of engrafting cells or pattern of long-term, multilineage, multi-tissue engraftment. We propose that ex vivo fucosylation will similarly improve the rate and magnitude of engraftment for CB transplant recipients in a clinical setting.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
During the European Commission's Framework Six Programme, HERMES, we investigated three main areas along the European margin, each characterized by the presence of seep-related structures exhibiting ...different intensity of activity and biological diversity. These areas are: (1) the Nordic margin with the Håkon Mosby mud volcano and many pockmarks, (2) the Gulf of Cádiz, and (3) the eastern Mediterranean with its hundreds of mud volcanoes and brine pool structures. One of the main goals of the HERMES project was to unravel the biodiversity associated with these seep-associated ecosystems, and to understand their driving forces and functions, using an integrated approach. Several multidisciplinary research cruises to these three areas provided evidence of high variability in ecosystem processes and associated biodiversity at different spatial scales, illustrating the "hotspot" nature of these deep water systems.
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BFBNIB, NUK, PNG, UL, UM, UPUK
3550 Background: Doublet chemotherapy plus bevacizumab is a well-established standard of care in the first-line treatment of RAS-mutant (RASmut) metastatic colorectal cancer (mCRC). The FIRE-3 trial ...was the first randomized study to compare FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in mCRC. Since this trial initially included patients irrespective of RAS mutation status, the present analysis performs an updated evaluation of therapeutic efficacy of targeted therapy with bevacizumab versus cetuximab in RASmut mCRC. Methods: FIRE-3 trial included 752 patients. Initially, pyrosequencing (PSeq) was used to identify RAS mutations. In a subsequent investigation next-generation sequencing (NGS) was applied in 373 available tumors. A 5% mutant allele cutoff was used for both PSeq and NGS both of which were done centrally. Results: Of the 224 RASmut and BRAF wild-type patients, 187 were identified by polymerase chain reaction (PCR) and PSeq, 122 by NGS. 86 tumors were PCR positive and NGS positive (PCR+/NGS+), 36 tumors PCR negative and NGS positive (PCR-/NGS+). In the overall RASmut cohort of 224 patients, no overall survival (OS) benefit was observed when cetuximab was compared to bevacizumab (20.3 months vs 21.1 months; HR 1.028; 95% CI, 0.547-1.583; P=.842). This effect was observed independent of sidedness of primary tumors (PT) for left-sided (21.5 months vs 22.1 months; HR 1.054; 95% CI, 0.763-1.456) and right-sided PT (19.2 months vs 19.5 months; HR 0.931; 95% CI, 0.547-1.583). Conclusions: While cetuximab notably is not effective in RASmut mCRC, this randomized comparison does not provide an indication for superior efficacy of bevacizumab in the first-line treatment of this patient group. Trial identification number: NCT00433927 clinicaltrials.gov
3529 Background: CMS were associated with prognostic relevance in RAS WT mCRC, while their role as predictive biomarker is debatable. We aimed to assess the predictive impact of CMS on treatment with ...anti-EGFR vs. anti-VEGF antibodies vs. cytotoxic treatment alone in a pooled analysis. Methods: Available CMS data (called by predictedCMS method) of the randomized controlled trials FIRE-1 (FUFIRI vs. mIrOx); FIRE-3 (FOLFIRI+ cetuximab vs. bevacizumab), XELAVIRI (sequential vs. initially combined FOLFIRI+bevacizumab) and PanaMa (FOLFOX+panitumumab followed by FU/FA +/- panitumumab) of RAS WT mCRC were included. Non-evaluable CMS were excluded. Kaplan-Meier estimated overall survival (OS) and progression-free survival (PFS). Uni- and multivariate Cox regression analysis (including all baseline characteristics) was used to calculate hazard ratio (HR) and 95% confidence interval (95% CI). Results: 1147 tumors had available CMS data and 746 (65.0%) were RAS wild-type (WT): CMS1, n=89; CMS2, n=346; CMS3, n=71; CMS4, n=240. CMS were significant prognostic biomarkers in terms of PFS (median months, CMS1, 6.7; CMS2, 11.1; CMS3, 8.1; CMS4, 10.0, P<0.001) and OS (median months: CMS1, 14.8; CMS2, 28.7; CMS3, 19.5; CMS4, 26.5; P<0.001). CMS remained significant in a multivariate backward elimination Cox regression analysis including all baseline characteristic variables and BRAF status with regard to PFS ( P=0.03) and OS ( P=0.04) Interaction of CMS and treatment was significant regarding OS ( P<0.001) and PFS ( P=0.001). The longest OS was observed using anti-VEGF antibodies in CMS1 and anti-EGFR antibodies in CMS2 or CMS4 RAS WT tumors (Table). Conclusions: CMS were confirmed as prognostic biomarkers and might contain predictive information for the choice of anti-EGFR or anti-VEGF antibodies in RAS WT mCRC. Prospective validation remains mandatory. Table: see text
Abstract
Introduction Tumefactive multiple sclerosis (MS) and glioblastoma (GBM) can be difficult to differentiate. Clinical presentations are nonspecific and may occur in patients with both ...diseases. Magnetic resonance imaging (MRI) scans are routinely used to generate an initial differential diagnosis. Although imaging features can help distinguish these entities, there are no pathognomonic signs, neither on traditional nor advanced MRI. Moreover, the ability to differentiate these entities depends on the radiologists’ experience. Ensuring the correct diagnosis has important therapeutic and prognostic implications, as the management of these diseases is very different. To date, a brain biopsy often represents the only option to obtain a diagnosis, but it may be inconclusive and could add unnecessary morbidity. We hypothesize that a machine-learning tool based on routinely performed MRI scans could guarantee a more reliable, fast, and reproducible diagnosis. Methods Only patients with a histological diagnosis were included in the study. Patients that underwent any form of radiation therapy before the surgery were excluded to avoid confounding factors due to treatment-related effects. A total of 99 MS and 257 GBMs were included, and preoperative T2-weighted images were collected. For each patient, the lesions' segmentation was performed, including both the contrast-enhancing and non-enhancing areas of the lesions. The segmentation masks were used to extract radiomic features from the T2-weighted sequences. All MRI images were standardized to the same mean and standard deviation before feature extraction and resampled to a voxel size of 1.0 × 1.0 × 1.0 mm. Features extraction was performed using Pyradiomics (v. 3.0.1) and included first order, shape, and texture features, totaling 100 features. The classifier consisted of a support vector machine (SVM) model. Patients were randomly assigned to the training and test sets with an 80-20% proportion for each class. To select the best hyperparameters for the SVM classifier, a grid-search analysis was performed on the training set using a nested cross-validation scheme (k=5). All experiments were performed using Python (v. 3.5) and the Scikit-learn library (v. 0.23.1). Results The mean accuracy and area under the ROC curve for the best set of hyperparameters on the validation set were 0.83 and 0.86, respectively. The weighted-average precision, recall, and F1 scores on the test set were 0.78, 0.76, and 0.77, respectively. Conclusions Radiomic features extracted from a routinely acquired MRI sequence showed promising results in differentiating tumefactive multiple sclerosis from glioblastoma, opening the possibility to obtain a reliable diagnosis without the need for a brain biopsy. Future experiments Future experiments will focus on using post-contrast T1-weighted images for the radiomic features extractions, testing multiple machine learning models and features selection algorithms, and including more diagnostic classes (i.e., metastasis, lymphomas).
Citation Format: Gian Marco Conte, Jeanette E. Eckel-Passow, W. Oliver Tobin, Paul Decker, Daniel H. Lachance, Robert B. Jenkins, Bradley J. Erickson. Differentiation of tumefactive multiple sclerosis and glioblastoma using radiomics features extracted from magnetic resonance imaging and machine learning abstract. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-023.
Recent evidence has suggested a relationship between the baseline quality of life (QOL) self-reported by patients with cancer and genetic disposition. We report an analysis exploring relationships ...among baseline QOL assessments and candidate genetic variations in a large cohort of patients with lung cancer.
QOL data were provided by 1,299 patients with non-small-cell lung cancer observed at the Mayo Clinic between 1997 and 2007. Overall QOL and subdomains were assessed by either Lung Cancer Symptom Scale or Linear Analog Self Assessment measures; scores were transformed to a scale of 0 to 10, with higher scores representing better status. Baseline QOL scores assessed within 1 year of diagnosis were dichotomized as clinically deficient (CD) or not. A total of 470 single nucleotide polymorphisms (SNPs) in 56 genes of three biologic pathways were assessed for association with QOL measures. Logistic regression with training/validation samples was used to test the association of SNPs with CD QOL.
Six SNPs on four genes were replicated using our split schemes. Three SNPs in the MGMT gene (adjusted analysis, rs3858300; unadjusted analysis, rs10741191 and rs3852507) from DNA repair pathway were associated with overall QOL. Two SNPs (rs2287396 GSTZ1 and rs9524885 ABCC4) from glutathione metabolic pathway were associated with fatigue in unadjusted analysis. In adjusted analysis, two SNPs (rs2756109 ABCC2 and rs9524885 ABCC4) from glutathione metabolic pathway were associated with pain.
We identified three SNPs in three glutathione metabolic pathway genes and three SNPs in two DNA repair pathway genes associated with QOL measures in patients with non-small-cell lung cancer.
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Background: Optimal patient selection for first-line treatment targeting epithelial growth factor receptor (EGFR) in RAS-WT mCRC is based on primary tumor sidedness (PTS) with anti-EGFR being the ...preferred option for patients with left-sided mCRC (LC). Right-sided mCRCs (RC) are preferentially treated in combination with bevacizumab targeting vascular endothelial growth factor (VEGF). Here, improvement in patient selection was evaluated by combining clinical biomarkers beyond PTS using the randomized phase III trial FIRE-3. Methods: FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC. Besides PTS, further clinical biomarkers were evaluated in pairwise combinations using Cox regression models and model-based recursive partitioning with Weibull models to predict treatment benefit of either treatment arm regarding overall survival (OS): age, sex, liver-limited disease status (LLD) and baseline carcinoembryonic antigen serum level (CEA). The resulting P-values of second-order interactions were adjusted using Holm-Bonferroni correction. The model with the best test statistics and P-value was chosen for further evaluations. Results: In 400 patients with RAS-WT mCRC, a model combining PTS and LLD status best predicted treatment outcome of either treatment arm (c-index = 0.603, p=0.005). Here, a significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was evident in patients with LC/non-LLD (HR 0.62, p=0.02) compared to LC/LLD (HR 0.83, p=0.40). In patients with RC, FOLFIRI/Bev was significantly associated with increased OS compared to FOLFIRI/Cet when patients suffered from non-LLD (HR 2.09, p=0.010). However, patients with RC/LLD rather had a benefit from FOLFIRI/Cet compared to FOLFIRI/Bev (HR 0.59, p=0.218). Conclusions: Combining clinical biomarkers PTS and LLD status might improve optimal patient selection for targeted first-line treatment in RAS-WT mCRC. Validation in further data sets is warranted. Clinical trial information: NCT00433927 .
The heterogeneous group of B3 lesions in the breast harbors lesions with different malignant potential and progression risk. As several studies about B3 lesions have been published since the last ...Consensus in 2018, the 3rd International Consensus Conference discussed the six most relevant B3 lesions (atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), classical lobular neoplasia (LN), radial scar (RS), papillary lesions (PL) without atypia, and phyllodes tumors (PT)) and made recommendations for diagnostic and therapeutic approaches. Following a presentation of current data of each B3 lesion, the international and interdisciplinary panel of 33 specialists and key opinion leaders voted on the recommendations for further management after core-needle biopsy (CNB) and vacuum-assisted biopsy (VAB). In case of B3 lesion diagnosis on CNB, OE was recommended in ADH and PT, whereas in the other B3 lesions, vacuum-assisted excision was considered an equivalent alternative to OE. In ADH, most panelists (76%) recommended an open excision (OE) after diagnosis on VAB, whereas observation after a complete VAB-removal on imaging was accepted by 34%. In LN, the majority of the panel (90%) preferred observation following complete VAB-removal. Results were similar in RS (82%), PL (100%), and FEA (100%). In benign PT, a slim majority (55%) also recommended an observation after a complete VAB-removal. VAB with subsequent active surveillance can replace an open surgical intervention for most B3 lesions (RS, FEA, PL, PT, and LN). Compared to previous recommendations, there is an increasing trend to a de-escalating strategy in classical LN. Due to the higher risk of upgrade into malignancy, OE remains the preferred approach after the diagnosis of ADH.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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