tbuckley/cabot-search huggingface dataset:
Using PIK3CB and connexin-43 inhibition to sensitize pediatric glioblastoma cells to temozolomide.
Authors: Farah Shah, Zhi Sheng
Journal: Journal of Clinical Oncology (2019)

e13572 Background: Glioblastoma (GBM) is one of the most common high grade gliomas in pediatric patients, accounting for 2.8% of central nervous system tumors. Standard of care for glioblastoma includes surgical resection, radiation, and temozolomide chemotherapy. However, many pediatric patients are not suitable candidates for surgery, and their tumors inevitably develop temozolomide resistance. Despite aggressive treatment, temozolomide (TMZ) resistance leads to tumor recurrence in 90% of patients. Thus, outcome for children with pediatric GBM remains poor with a 2-year survival rate ranging from 10-30%, highlighting the need for new therapeutic approaches. Connexin-43 (Cx43) and PIK3CB are proteins involved in conferring temozolomide resistance in glioblastoma. Combined inhibition of these proteins could improve temozolomide sensitivity and help develop a selective therapy that significantly improves quality of life and prognosis in pediatric glioblastoma patients. Methods: Primary GBM cells were plated in a 96-well plate and treated with vehicle (DMSO), TMZ (50 μmol/L), TGX-221 (20 μmol/L), αCT1 (30 μmol/L), or a combination of the latter three drugs. Cell viability was measured using the MTS assay. Primary pediatric GBM cell lines SJ-GBM2 and CHLA-200 were tested. These drug combinations were also tested in normal human astrocytes to make sure there were no off-target effects. Results: We found that targeting PIK3CB and Cx43 in primary pediatric GBM increases their sensitivity to TMZ. The triple combination of TMZ, TGX-221, and αCT1 significantly decreased cell viability than each drug alone while sparing normal human astrocytes. Conclusions: Our findings suggest that inhibiting PIK3CB and Cx43 enhances therapeutic response to TMZ and limits off-target effects in pediatric GBM. These findings closely mirror our results using the triple combination in adult glioblastoma as well, thus laying the groundwork for a novel combination therapeutic that can be used across age groups.
A novel EUS-guided liquid fiducial marker for image-guided radiotherapy in esophageal cancer: The safety and efficacy in vitro and vivo evaluations.
Authors: Liangchao Sun, Xue Meng
Journal: Journal of Clinical Oncology (2019)

e15573 Background: The true tumor extent of esophageal cancer is hard to visualize on current modalities during radiotherapy. In this study, we evaluated the safety and feasibility of the mixture of N-Butyl Cyanoacrylate and lipiodol to find the most optimal application as the fiducial marker to marking the true tumor extent in esophageal radiotherapy. Methods: Four types of injection matches (1:1-0.1ml, 1:1-0.15ml, 1:3-0.1ml, 1:30.15ml) were injected via syringes in subcutaneous tissue in rats model. Gross histopathological changes, weight, skin score, nodule volume, neutrophil counts and macrophage counts were observed to analyses the effect of different mixing ratios and injection volumes to find the best match. Evaluations following ISO standard criteria are further delivered to test the biocompatibility of the best applicable setting of this fiducial maker. Results: At 7th week, 42 markers (42/48, 87.5%) were still visualized on CT images. No serious adverse events or obvious artifacts were noted through the study. The overall review about the histopathological reaction of the NBCA/Lipiodol was considered to be a combination of acute inflammation, chronic inflammation, granulation tissue, foreign-body reaction and fibrous capsule formation in development. The quantitative analysis showed that when the density of NBCA was low (1:3), lower injection volume (0.1ml) brought the lower weights (p &lt; 0.001). When the injection volume is high (0.15ml), the high NBCA (1:1) caused the lower weight (p &lt; 0.001). At the most time points, the lower injection volume had the lower weights. High injection volume created a 0.079 cm 3 increase in nodule size than low volume and high NBCA density also increased the nodule size. As for the inflammatory cells counts, the 3rd week was a key time point, before which the neutrophils decreased sharply and the macrophages keep almost steady, but after that the neutrophils stayed a low level and the macrophages started a rapid growth. On the comparisons of different index (Table), it is showed that the 1:3-0.15ml had an excellent performance as the fiducial marker and final biocompatibility test proved its safety. Conclusions: Overall, our results show that the mixture of NBCA/Lip as the fiducial marker is safe and feasible and the setting of 1:3-0.15ml was most optimal.[Table: see text]
THU0032 DYNAMICS OF ADIPOCYTOKINES IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS IN DIFFERENT TREATMENT REGIMENS
Authors: Yulia Gorbunova, Tatiana Popkova, Evgeny Nasonov
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Adipose tissue is a highly active endocrine organ that produces a large number of various pro-inflammatory cytokines and adipocytokines (adiponectin, leptin, etc.) involved in the pathogenesis of rheumatoid arthritis (RA). The relationship of adipokines with activity markers and inflammation in RA and the effect of antirheumatic therapy on adipocytokine levels in patients with early RA is discussed. <h3>Objectives</h3> To assess the dynamics of adipocytokine levels (adiponectin, leptin) in patients with early RA (initial and after 24 weeks) using various treatment regimens: methotrexate monotherapy (MT) and combination therapy (MT + adalimumab (ADA). <h3>Methods</h3> The study included 47 patients with early RA (criteria ACR/EULAR, 2010.), 57 [46.5; 62.0] years, disease duration 6.0 [5.5;15.5] months, seropositive for IgM RF and anti-CCP, with highly active RA (DAS28 5,5 [5,1; 5,9]; SDAI 32,4 [22,4; 41,7], CDAI 29,0 [19,7; 39,5]). At study entry, all patients received methotrexate (MTX) (10 [10-15] mg/week), after 12 weeks, with inefficiency of MT, adalimumab (ADA) was administered 40 mg 1 time in 2 weeks. Serum concentration of adipokines (adiponectin, leptin) was measured with ELISA. <h3>Results</h3> By the 24th week of therapy, 23 (49%) patients with early RA received a combination therapy (adalimumab and methotrexate), 24 (51%) patients with RA received methotrexate monotherapy. In patients with RA, after 24 weeks, a significant decrease in adiponectin levels by 44 and 49% and an increase in the concentration of leptin by 39 and 43% were observed both against the background of MT monotherapy and with the use of combination therapy (p &lt;0.05 in all cases). By the end of the study, adiponectin levels were higher in the MT monotherapy group, and leptin in the combination therapy group. * -p &lt;0,05 reliability of differences in factors before treatment and after 6 months (Wilcoxon); ** -p &lt;0.05 difference in the indices between the groups by the 6th month of therapy; Δ,% -the difference between the indices between the groups by the 6th month of therapy. <h3>Conclusion</h3> After 24 weeks of therapy, the adipocytokine levels in the two groups changed: the adiponectin concentration decreased, and the leptin level increased. MT monotherapy and combination therapy (MT + ADA) acted on changes in adipocytokine levels unidirectionally, although the changes were more pronounced in patients on combination therapy. Disclosure of Interests: None declared
Determination of plasma EGFR mutations from non-small cell lung cancer patients at Bach Mai Hospital.
Authors: Cam Phuong Pham, Khoa Trong Mai, Nguyen Thuan Loi, NGO Thi Thu Hien, Quynh Thi Thuy Vo, Ha Dinh Tran
Journal: Journal of Clinical Oncology (2019)

e13121 Background: Lung cancer patients with mutations in the epidermal growth factor receptor (EGFR) are primary candidates for EGFR-targeted therapy. Reliable analyses of such mutations have previously been possible only in tumor tissue. Here, we demonstrate that mutations can be detected in plasma samples of non-small cell lung cancer patients at Bach Mai Hospital and relation of different variables to the frequency of EGFR mutations. Methods: 193 patients with non-small cell lung cancer were identified with EGFR mutation by cobas EGFR Mutation Test v2 kit (Roche Diagnostics, USA), evaluating the EGFR mutation status with different variables. Results: The EGFR mutation rate was 43%, common in patients with adenocarcinoma, female, non-smoking, late stage disease. The rate of EGFR T790M mutation was 36.1%. Among 78 patients who was previous treated TKIs, EGFR mutation rate was 73.1% and the rate of EGFR T790M mutation was 50.8% at the time of progression. The concordance of EGFR mutation from plasma sample with tissue sample was 81%. Conclusions: EGFR mutation in plasma sample results was not different from those in tissue samples and similar with result of studies in Vietnam and worldwide.
Development and validation of novel microenvironment-based immune molecular subtypes of breast cancer: Implications for immunotherapy.
Authors: Yunfang Yu, Wenda Zhang, Qiyun Ou, Anlin Li, Yongjian Chen, Ying Wang, Jianli Zhao, Yujie Tan, Herui Yao
Journal: Journal of Clinical Oncology (2019)

1094 Background: Breast cancer treatment with immunotherapy can improve clinical benefits, but the majority of patients did not respond to the treatment. To understand tumor–immune interactions in breast cancer, we identified novel microenvironment-based immune molecular subtypes. Methods: A training cohort of 1,394 breast cancer patients from the Molecular Taxonomy of Breast Cancer International Consortium profiled by RNA and DNA sequencing data were analyzed to calculate immune-related gene biomarkers and to assign prognostic categories using LASSO Cox regression model. Additionally, 969 patients from The Cancer Genome Atlas data set was used as an independent validation cohort. We further compared tumor mutation burden (TMB) and cytolytic activity (CYT) levels between different immune molecular subtypes. Results: Using the LASSO model, we established an immune molecular classifier based on following 5 features: IFN-γ signature, ICOSLG, TNFRSF14, Mast.cells.resting, and T.cells. CD4.memory.resting. Then we found that it contained two distinct microenvironment-based subtypes (immune class and non-immune class), characterized by significant differences in overall survival in the training cohort (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.61 to 0.81; P &lt; 0.001) and in the validation cohort (HR 0.34; 95% CI 0.22 to 0.54; P &lt; 0.001). We found an inverse association between immune gene expression and TMB levels (ρ = 0.096, P &lt; 0.001). Immune class subtype patients with good prognosis had significantly lower TMB and higher CYT than did non-immune class subtype patients with poor prognosis (all, P &lt; 0.05). The clinical use of the immune molecular subtypes showed a closer association with survival than did IFN-γ signature or PD-L1 expression (all, P &lt; 0.05). The robustness of the immune molecular subtypes was confirmed in the validation cohort. Conclusions: We revealed novel immune molecular subtypes, which represented better utility in predicting breast cancer patients’ survival compared with IFN-γ signature or PD-L1, and could be an important guide for precision immunotherapy.
Case discussion at cancer multidisciplinary meetings: What resourcing is required?
Authors: Paul Mitchell, Jennifer Soon, Joanne Kenny, Katherine Simons
Journal: Journal of Clinical Oncology (2019)

e18026 Background: Discussion of cancer cases at multi-disciplinary meetings (MDMs) is expected standard care in Australia. To our knowledge there are no local, and few international, data on the resourcing required for MDMs. Methods: Data covering 12 months of MDM activity at Austin Health, Victoria, were obtained retrospectively. Prospective data were also collected over 4 weeks focusing on time required for preparation and post-meeting activities. Capital, maintenance and general overhead costs were not included. Results: MDMs covered 15 tumour areas: 11 solid tumour, one lymphoma and 3 haematological. Over 12 months 452 MDMs were held, discussing 5943 patients with highest case volume for hepatoma (1243), breast (1084) and hepato-biliary (HPB, 679). On average 12 cases (range 3.5 – 38.3) were discussed per meeting, with average 3.8 minutes spent per case. An average of 3 imaging studies were reviewed per case and 60% of cases in the high volume MDMs required access to external imaging. Imaging consultants spent an average of 2.9 minutes preparation per imaging study, registrars 5.2 minutes and external imaging required 7.8 minutes per study. Pathologists spent an average of 6.8 minutes preparation per case, which rose to 9.4 minutes for external cases (making up between 3% - 30% of cases per MDM). Pathology administration time was 53 minutes per meeting. The mean cost of medical staff was AUD 1617 per meeting (range $532-$2860), and 78% of the cost was for consultant medical staff. The mean cost for diagnostic staff attendance was $216, and preparation $327. MDM and pathology administrative costs were $273. The MDMs with the highest annual total costs were breast, lung and HPB ($152,904 - $207,289). The overall mean cost for a meeting varied between $847 - $4080. The cost per case discussed varied from $106 - $422, with generally lower per-case costs for the high case volume MDMs. The average per case cost was $255. Conclusions: Data on staff time and costs associated with conducting cancer MDMs were able to be obtained. The average cost per case discussed was $255 (USD 184). These data may be useful in planning to extend MDM discussion to include a higher proportion of cancer cases and in seeking additional funding.
SWOG S1314: A randomized phase II study of co-expression extrapolation (COXEN) with neoadjuvant chemotherapy for localized, muscle-invasive bladder cancer.
Authors: Thomas W. Flaig, Catherine M. Tangen, Siamak Daneshmand, Ajjai Shivaram Alva, Seth P. Lerner, M. Scott Lucia, David James McConkey, Dan Theodorescu, Amir Goldkorn, Matthew I. Milowsky, Richard Carlton Bangs, Gary R. MacVicar, Bruno R. Bastos, Daniel Gustafson, Melissa Plets, Ian Murchie Thompson
Journal: Journal of Clinical Oncology (2019)

4506 Background: Both dose-dense Methotrexate-Vinblastine-Adriamycin/doxorubicin-Cisplatin (ddMVAC) and Gemcitabine-Cisplatin (GC) are accepted neoadjuvant regimens for muscle-invasive bladder cancer (BC). We investigated COXEN, a gene expression model, as a predictive biomarker. Methods: Eligibility included Stage cT2-T4a N0 M0, urothelial BC (mixed histology allowed), ≥ 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy. 237 patients were randomized between ddMVAC, given every 14 days for 4 cycles, and GC, given every 21 days for 4 cycles. The primary objective was to assess whether the pre-specified dichotomous treatment-specific COXEN gene expression profile is prognostic of pT0 rate or ≤ pT1 at surgery, and to assess whether COXEN score is a predictive factor between regimens and response. Logistic regression was used to model response, adjusting for stratification factors. Results: 167 patients were included; the ddMVAC/GC arms had a median age of 65/64, PS = 0 in 80%/75%, Male proportion of 88%/79% and T2 stage of 87%/92%. All had at least 3 cycles of chemo and surgery/progression within 100 days of last chemo. There were favorable COXEN ddMVAC scores in 32% and GC score in 26%. The pT0 rates for ddMVAC and GC were 32% and 35%; the rates of ≤ pT1 were 55% and 49%, respectively. Conclusion: The COXEN scores were not significantly prognostic for response in their individual arms; The COXEN GC score was significant predictor for downstaging in pooled arms. There was no evidence of an interaction between COXEN score and regimen in predicting response. The prospective data and samples from this study will allow for further development of COXEN and other predictive biomarkers. Clinical trial information: NCT02177695. [Table: see text]
Oral DNA vaccination targeting VEGFR-2 combined with anti-PD-L1 avelumab in patients with progressive glioblastoma, a phase I/II study: NCT03750071.
Authors: Wolfgang Wick, Antje Wick, Michael Platten, Olivier L. Chinot, Martin J. Van Den Bent, Frederic Dhermain, Marc Mansour, Lilli Podola, Heinz Lubenau
Journal: Journal of Clinical Oncology (2019)

TPS2076 Background: The vaccine (VXM01) is a VEGFR-2 coding DNA vaccine, using a Salmonella Ty21a carrier for oral application. VEGFR-2 is over-expressed in glioblastoma and serves as a promising target for VEGFR-2 primed T cells with the potential to alter tumor angiogenesis and/or eliminate VEGFR-2 expressing tumor cells. VXM01 was well tolerated in a previous phase I/II study involving 14 patients with progressive glioblastoma multiforme. Immunological correlates of vaccination and anti-tumor immunity in the blood and in the tumor were detected. At least one objective clinical response was attributed to vaccine monotherapy, with one more PR achieved in combination with nivolumab. Prolonged overall survival was associated with peripheral immune responses against VEGFR-2, J Clin Oncol 36, 2018 (suppl; abstr 2017). A combination study with the anti PD-L1 checkpoint inhibitor monoclonal antibody avelumab is currently underway. Methods: A multicentre, open-label phase I/II study ( EudraCT.gov no. 2017-003076-31), will enrol 30 patients with progressive glioblastoma, previously treated with temozolomide/radiotherapy. The primary objective is to evaluate safety and tolerability of the vaccine in combination with avelumab. In a 1+2 safety run in, two cohorts of non-reoperable patients will be vaccinated with one of 2 doses of the oral vaccine (10 6 or 10 7 CFU) with concurrent intravenous avelumab. After safety evaluation and recommendation of study continuation by the Data Safety Monitoring Board, 18 non-re-operable and 6 re-operable patients will be treated with 10 7 CFU of the vaccine + avelumab. Vaccinations for all patients will be on day 1, 3, 5, and 7, followed by 4-weekly boosts until progression. Avelumab 800 mg will be administered every two weeks until progression. The enrolment of cohort 1 started with inclusion of the 1st patient in November 2018. The end of study is week 60. Follow up visits will be on months 1, 3, 6, 12 and 24. Objective response rate (ORR), clinical response using iRano criteria, immunological correlates before and after treatment using ELISpot, FACS, TCR-sequencing, IF, and IHC laboratory methods. Clinical trial information: NCT03750071.
RAS-amplified colorectal cancers: Microsatellite stability status, RAS/BRAF mutations, and prediction of anti-EGFR resistance.
Authors: Alexa Betzig Schrock, Jaideep Singh Sandhu, Chongkai Wang, Ching Ouyang, Vincent A. Miller, Siraj Mahamed Ali, Marwan Fakih
Journal: Journal of Clinical Oncology (2019)

3533 Background: Pre-clinical models implicate RAS amplifications ( RAS a ) as a mechanism of resistance to anti-Epidermal Growth Factor Receptor (EGFR) therapies. Yet, there is little guidance on the impact of RAS a , as identified by next generation sequencing (NGS), on anti-EGFR response. Methods: We investigated the Foundation Medicine (FM) database for RAS a in CRC and characterized this population based on patient (pt) characteristics and other concurrent genomic alterations. We subsequently investigated City of Hope (COH) mCRC molecular data set (using FoundationOne) and described the RAS a population characteristics and response to anti-EGFR. Results: FM cohort included 21,315 CRC unique pt cases. 365 (1.5%) pts had RAS a , of which 123 (0.6%) had ≥ 20 copy number (CN) ( RAS a≥20 ). The incidence of MSI-H, RAS and BRAF short variant mutations in the overall, RAS a , and RAS a≥20 populations were (MSI-H: 5%, 0%, 0%), ( RAS: 54%, 32%, 2%), and ( BRAF: 6%, 1%, 0%), respectively. Copy number variation inversely correlated with likelihood of RAS mutation. COH cohort included 396 mCRC. 13 pts (3.3%) had RAS a . The median RAS CN was 25 (7 - 79); 8/13 pts had RAS a≥20 . All but 3 COH pts with RAS a had a RAS/BRAF-WT tumors. Pts with concurrent RAS mutations had relatively low RAS CN (7, 8, &amp;13). Tumors with RAS a were predominantly left-sided (12/13). 7/13 pts were treated with anti-EGFR therapy. All 7 pts were RAS/ BRAF wild-type: 6 left-sided; 3 pts 1 st /2 nd lines (1 pt oxaliplatin-based and 2 pts irinotecan-based) and 4 pts chemo-refractory (all irinotecan-based). All 4 chemo-refractory pts had RAS a≥20 and progressed on anti-EGFR on 1 st post-treatment CT (PFS in all pts ≤ 3 mo). One 1 st line pt had SD (PFS = 4 mo). One 2 nd line pt had SD (PFS = 7 mo) and one had PD as best response. Conclusions: NGS identifies RAS a and RAS a≥20 in 1.5% and 0.6% of CRC, respectively. RAS a≥20 tumors are MSS and, generally lack RAS/ BRAF mutations, and predict for resistance to anti-EGFR. This supports the potential relevance of 20-CN cut-point for the exclusion of pts from anti-EGFR. These findings would benefit from additional validation from retrospective analyses of completed prospective anti-EGFR clinical trials.
Abstract 17375: Anti-tachycardia Pacing Success for Fast Arrhythmias in the Settings of a Prolonged Detection. Data From the AdvanceIII Trial
Authors: Ahmad Hersi, Alessandro Proclemer, Angel Arenal, Axel Kloppe, Maurizio Lunati, José Bautista Martìnez Ferrer, Marcin Gulaj, Maurits C Wijfels, Elisabetta Santi, Lorenza Mangoni di S. Stefano, Maurizio Gasparini
Journal: Circulation (2013)

Purpose: ADVANCEIII trial demonstrated that a prolonged detection strategy combined with anti-tachycardia pacing (ATP) reduces significantly the overall Implantable Cardioverter Defibrillator (ICD)...
A MRI-based radiomics model for preoperative prediction of five-year survival status in hepatocellular carcinoma.
Authors: Xiao-Hang Wang, Liu-Hua Long, Yong Cui, Angela Y Jia, Xiang-Gao Zhu, Hong-Zhi Wang, Zhao-Hai Wang, Wei-Hu Wang
Journal: Journal of Clinical Oncology (2019)

e15596 Background: Recurrence is the major cause of mortality in resected hepatocellular carcinoma (HCC) patients. However, without a standard approach to evaluate prognosis, it is difficult to select potential candidates for additional therapy. We aim to develop and evaluate a magnetic resonance imaging (MRI)-based radiomics model to predict 5-year survival status of HCC patients in the preoperative setting. Methods: A total of 201 HCC patients who were followed up for at least 5 years (unless death occurred) after curative hepatectomy were enrolled in this retrospective multicenter study. 3144 radiomics features were extracted from four conventional sequences of preoperative MRI (T1WI, T2WI, DWI and dynamic contrast-enhanced MRI). The random forest method was used for feature selection and radiomics signature building. 5-fold cross validation was used for robust estimation. A radiomics model incorporating the radiomics signature and clinical risk factors was developed. The model performance was evaluated by its discrimination and calibration. Results: Patients were divided into survivor (n = 97) and non-survivor (n = 104) groups based on survival status at 5 years from surgery. The 30 most survival-related radiomics features were selected to develop the radiomics signature. The preoperative alpha-fetoprotein level was integrated into the model as an independent clinical risk factor in multivariable logistic regression analysis (OR = 3.764; 95% CI 1.997-7.096). The radiomics model demonstrated good calibration and satisfactory discrimination, with the mean area under the curve of 0.9340 (95% CI 0.9222-0.9458) in training set and 0.7383 (95% CI 0.6914-0.7852) in validation set. Conclusions: The MRI-based radiomics model represents a valid method to predict 5-year survival status in HCC patients in the preoperative setting, and may be used to guide neoadjuvant or adjuvant treatment decisions in high-risk patients.