tbuckley/cabot-search huggingface dataset:
Abstract 20152: Human Neural Stem Cell Transplantation Ameliorates Hemorrhagic Transformation Caused by Delayed Antithrombotic Treatment in Aged Stroke Brains
Authors: Auston D Eckert, Jean-Pyo Lee
Journal: Circulation (2016)

Background: Despite aging being a strong risk factor, most preclinical stroke studies employ young animals instead of aged animals. tPA dissolves clots and restores blood flow. Yet, while tPA’s role within blood vessels can be beneficial, reports of harmful effects within the CNS have been reported. Issues surrounding tPA are two-fold: (1) Treatment requires the patient receive recombinant tPA quickly (<4.5 hours) after stroke onset, and (2) there is the probability of ischemic reperfusion (IR) damage, a destabilization of the blood-brain barrier (BBB) that leads to bleeding into the brain (hemorrhagic transformation, HT). While age alone is not a barrier for tPA treatment (within 4.5 h), the effect of delayed tPA treatment (e.g., 6h) on aged stroke brains has not been well studied. In this study, we explore the effect of aging as it affects the BBB and HT in a delayed tPA-treated stroke mice. Methods and Results: One day post-stroke, we injected human neural stem cells (hNSCs) into the ipsilesional hippo...
Colorectal cancer: Impact of primary tumor location on genetic alterations.
Authors: Mohamed E. Salem, Heinz-Josef Lenz, Joanne Xiu, Jimmy J. Hwang, Philip Agop Philip, Anthony Frank Shields, John Marshall
Journal: Journal of Clinical Oncology (2017)

3578 Background: Recent data show that patients with left sided colon tumors (LT) have better survival and respond differently to biologics compared to patients with right-sided tumors (RT), likely due to molecular differences. We sought to examine these differences. Methods: Primary colorectal tumors (n = 1730) with origins clearly defined as RT (cecum to hepatic flexure; n = 273), LT (splenic flexure to sigmoid colon; n = 585), or rectal (RC; n = 872) were examined by NextGen sequencing, protein expression and gene amplification. Tumor mutational load (TML) was calculated in 1001 of these tumors using only somatic nonsynonymous missense mutations. Chi-square was used for comparison. Results: When compared to LT, RT carried a significantly higher rate of BRAF (25% vs 7%; p &lt; 0.0001), PTEN (5.4% vs 1.3%; p = 0.008), and ATM (4% vs 1%; p = 0.04) mutations. RT were likely to have more MSI-high tumors (22% vs 5%; p &lt; 0.0001) and PD-1 overexpression (58% vs 44%; p = 0.01). There were no differences in the rate of KRAS (50% vs 42%; p = 0.07) or NRAS mutations (2.2% vs 3.4%; p = 0.4). When compared to RC, RT had a higher rate of BRAF (25% vs 3%; p = 7E -07 ), PIK3CA (22% vs 11%; p = 0.001), CTNNB1 (3% vs 0.3%; p = 0.02); ATM (3% vs 1%; p = 0.04), PTEN (5% vs 1%; p = 0.004), and BRCA1 mutations (4% vs 0%; p = 0.02), and a lower rate of TP53 (56% vs 71%; p = 0.001) and APC (53% vs 66%; p = 0.003) mutations. When compared to RC, LT showed higher rates of BRAF (6.7% vs 3.2%; p = 0.04) and CTNNB1 (2.1% vs 0.3%; p = 0.04) mutations, and a higher rate of MSI-high tumors (4.6% vs 0.7%; p = 0.04), whereas RC had a higher rate of KRAS mutation (50% vs 42%; p = 0.04). There were no differences between RT, LT, and RC for the frequency of PD-L1 (2%, 2%, and 1%) or Her-2 (1%, 2%, and 3%) overexpression, although Her-2 amplification was significantly different (1%, 3%, and 5%, RT vs RC; p = 0.03). Mean TML was 12, 11, and 8 mutations/megabase for RT, LT, and RC, respectively (RT vs RC; p = 0.01). There was a correlation between TML and PD-L1 (p = 0.04) and PD-1 (p = 0.01). Conclusions: Tumors arising in the right colon carry genetic alterations that are different from LT as well as RC. However, it appears that CRCs carry a continuum of molecular alterations from the right to the left side, rather than displaying sharp, clear-cut differences.
Count me in: A patient-driven research initiative to accelerate cancer research.
Authors: Nikhil Wagle, Corrie Painter, Eliezer Mendel Van Allen, Adam Joel Bass, Elana Anastasio, Michael Dunphy, Mary McGillicuddy, Rachel Stoddard, Sara Balch, Beena Thomas, Brett N. Tomson, Colleen Nguyen, Esha Jain, Stephanie Wankowicz, Jim Palma, Simone Maiwald, Esme O. Baker, Andrew Zimmer, Todd Golub, Eric Lander
Journal: Journal of Clinical Oncology (2018)

e13501 Background: A challenge in cancer research is the availability of tumor samples linked to clinical information. To address this, we worked with patients (pts) to develop patient-driven studies which empower pts to share samples and clinical data. These studies aim to generate a public database of clinical, genomic, and pt-reported data to accelerate discoveries and the development of new treatment strategies Methods: Pts register through a website and are sent an online consent form that asks permission to obtain and analyze medical records and samples. Pts mail in a saliva sample, used to extract germline DNA (gDNA), and a blood sample, used to extract cell free DNA (cfDNA). We contact pts' medical providers and obtain medical records and a portion of their stored tumor biopsies. Whole exome sequencing (WES) is performed on tumor DNA, gDNA, and cfNDA; RNA-seq is performed on tumor RNA. Clinically annotated genomic data are used to study specific pt cohorts and identify mechanisms of response/resistance. De-identified data are shared via public databases. Study updates are shared with pts regularly. Results: To date, we have launched the Metastatic Breast Cancer Project (mbcproject.org), the Angiosarcoma Project (ascproject.org), and the Metastatic Prostate Cancer Project (mpcproject.org). The Gastro-Esophageal Cancer Project is expected to launch in 2018. Enrollment statistics are shown in the Table. All project data are publicly released every 6 months on a pre-publication basis. Conclusions: A patient-driven approach enabled rapid identification of pts willing to share samples and clinical data. Remote acquisition and analysis of medical records, saliva, blood, and tumors from pts across the U.S. is feasible. These shared clinico-genomic databases should enable research and may serve as a model for patient-driven research in other cancers. Date Launched Pts Enrolled Pts Consented (%) Saliva received / requested Blood samples received / requested Medical records received Tumor samples received Initial Public Data Release MBCproject 10/2015 4372 2557 (58%) 1632 / 2226 342 / 569 360 293 10/2017 ASCproject 3/2017 279 242 (87%) 136 / 185 29 / 70 94 36 2/2018 MPCproject 1/2018 218 179 (82%) 85 / 158 9 / 12 18 1 TBD GECproject Mid-2018
Tumor mutational burden (TMB), intratumoral genetic heterogeneity (ITGH) and BCG responsiveness in high-risk non-muscle invasive bladder cancer (NMIBC).
Authors: Diogo Assed Bastos, Mariana Lima, Romulo Loss Mattedi, Carlos Dzik, Leopoldo Ribeiro-Filho, Mauricio Cordeiro, William Carlos Nahas, Jussara Michaloski Souza, Mariane Amano, Fabiana Bettoni, Vanessa Buzatto, Filipe Ferreira dos Santos, Rodrigo Barreiro, Pedro Alexandre Favoretto Galante, Anamaria Aranha Camargo
Journal: Journal of Clinical Oncology (2018)

e16516 Background: Despite optimal management of NMIBC with transurethral resection of bladder tumor (TURBT) and intravesical BCG therapy, a significant proportion of patients (pts) will eventually present with disease recurrence or progression. To date, there is no validated predictive biomarker to guide patient selection for the most appropriate therapy in this setting. Methods: We retrospectively identified pts with high-risk NMIBC treated with TURBT and intravesical BCG (≥ 6 instillations) from 2009 to 2016. Patients were classified as BCG-responsive (BCG-R) and BCG-unresponsive (BCG-UR) based on the International Bladder Cancer Group criteria. Whole-exome sequencing (WES) was conducted to assess TMB and ITGH. Immunohistochemistry (IHC) was used to evaluate PD-L1 expression and the presence of tumor infiltrating lymphocytes (TILs - CD8+, CD56, CD68, CD83 and FOXP3). Association with BCG responsiveness was evaluated using Mann-Whitney test. Results: Thirty-six patients were identified (BCG-R n = 17, BCG-UR n = 19). Median follow-up was 44 months for BCG-R and 49 months for BCG-UR pts. The majority of pts was male (92.1%), former smoker (68.4%), and presented with high-grade urothelial carcinoma (92.1%) and/or T1 staging (71%). Median time for relapse or progression was 11 months in the BCG-UR group. In this cohort, TMB was not significantly different in BCG-R and BCG-UR groups, with a median TMB of 7.63 and 7.89 mutations/Mb, respectively (P= 0.85). ITGH assessed by mutant-allele tumor heterogeneity (MATH) score was also similar between the groups, with a median MATH score of 21.6 and 22.8 for BCG-R and BCG-UR, respectively. Exploratory analyses of neoantigen load, DNA damage repair (DDR) gene alterations, PDL-1 expression and TIL subpopulations will be presented at the meeting. Conclusions: In this exploratory biomarker study, TMB and ITGH were not able to identify NMIBC pts more likely to benefit from immunotherapy with intravesical BCG. The identification of predictive biomarkers in this setting is an important unmet need and integrative analysis of TMB, ITGH with other potential predictive biomarkers should be assessed in larger datasets.
HBV Pre-S deletion mutation analysis: A high resolution diagnosis method.
Authors: Wu-Chi Hsu, Yuan-Chil Liu, Lin-Kang Hsu, Yen-Ting Lin, Yu-Ming Yeh
Journal: Journal of Clinical Oncology (2016)

e15612 Background: The Pre-S region(nucleotides 2854-155) locates at the S gene(encodeing the surface protein) of HBV DNA genome and consists of the Pre-S1 and Pre-S2 domains. A meta-analysis with more than 10,000 cases and dozens reports all indicate that infection of HBV with Pre-S mutant is associated with 3.77-fold increased risk of HCC. Methods: To evaluate the performance of the Pre-S deletion mutation detection system, several HBV infected serum samples with different viral titer were collected. And viral DNA was extracted with 300 uL serum. A set of Pre-S primers, which is applicable for all HBV genotypes, was used to amplify the target region with highly fidelity PCR polymerase. Results: Results with high resolution came out via a technology called capillary electrophoresis (CE). This analytic method was accomplished by Qsep100TM machine from BiOptic Inc. This Pre-S PCR system has been successfully verified with many clinical samples, and it could be applied to samples with different HBV genotypes. Traditional method often use agarose gel system to bring out results. However, it may be not applicable when it comes to samples with low viral titer. Now, this problem can be solved with the capillary electrophoresis platform. Capillary electrophoresis not only can detect the pre-S signal at E+03 viral titer grade but also provide a system with analyzing consistency. Conclusions: To sum up, the capillary electrophoresis platform is a high resolution and sensitive method for detection of Pre-S deletion, especially for low viral titer samples.
Genomic profiling of circulating tumor DNA in small cell lung cancer: comparison of relapsed disease to initial tumor biopsies.
Authors: Priyanka Bhateja, Gary Wildey, Mary Beth Lipka, Neelesh Sharma, Afshin Dowlati
Journal: Journal of Clinical Oncology (2017)

e20017 Background: Genomic studies in small cell lung cancer (SCLC) are hampered by the small amounts of biopsy tissue typically available. The emergence of ‘liquid biopsy’ to identify tumor DNA mutations in plasma (circulating tumor DNA or ctDNA) has the potential to overcome this restriction and also facilitates multiple sampling during disease treatment. Here we use ctDNA to compare mutation profiles in SCLC and non-small cell lung cancer (NSCLC)patients and to identify changes that occur post-relapse in SCLC. Methods: Targeted exome sequencing of 73 genes in plasma from 13 SCLC and 17 NSCLC patients was obtained along with matched patient targeted exome sequencingof 315 genes for 6 SCLC and 8 NSCLC tumor biopsies. Only the 70 genes analyzed by both assays were studied. Results: 3 SCLC and 8 NSCLC ctDNA specimens were collected pre-treatment, with the remainder post-relapse. In SCLC, 46 total gene mutations were detected in ctDNA with a mean allelic fraction (mAF) of 16.0%. TP53 (mAF 30.8%, N= 15) and ARID1A (mAF 16.0%, N= 6) were the most frequently mutated SCLC genes. In NSCLC, 53 gene mutations were detected with a mAF of 2.5%. TP53 (mAF 5.9%, N= 13), EGFR (mAF 2.3%, N= 10) and KRAS (mAF 4.4%, N= 5) were frequently mutated NSCLC genes. 44 and 10 gene amplifications were detected in SCLC and NSCLC ctDNA, respectively. 5 SCLC patients with tumor DNA profiles obtained pre-treatment had matching ctDNA profiles obtained post-relapse. TP53 mutation status agreed in 4 of the matched specimens. 6 new gene mutations occurred post-relapse in ctDNA, notably a TSC1 mutation (AF 8.4%) in one patient. 7 tumor gene mutations were lost post-relapse, notably ARID1A and NTRK1 mutations were lost in two patients each. Remarkably, 23 new gene amplifications were detected post-relapse in ctDNA, including PIK3CA ( N= 5) and CCNE1 ( N= 5), whereas only 1 was detected in pre-treatment tumors. Conclusions: SCLC exhibits much greater ctDNA mAF values than NSCLC, although their overall mutation profiles agree with published tumor DNA mutation profiles. Interestingly, the predominant change observed in SCLC ctDNA profiles in relapsed specimens is increased gene amplification.
TCT-731 Potential Benefits of Modified Short Axis View and Long Axis View Use in Ultrasound-guided Radial Artery Catheterization: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Homam Moussa Pacha, Mohamad Soud, Yasser Al-khadra, Fahed Darmoch, Fares Alahdab, Zaher Fanari, Amir Kaki, M Chadi Alraies
Journal: Journal of the American College of Cardiology (2018)
Safety and efficacy of GVD and anti-PD-1 (SHR-1210) regimen with or without low-dose decitabine priming for refractory bulky and aggressive primary mediastinal large B-cell lymphoma.
Authors: Wenying Zhang, Yang Liu, Qian Mei, Lianjun Shen, Qingming Yang, WeiDong Han
Journal: Journal of Clinical Oncology (2018)

7556 Background: Relapsed/refractory PMBCL (rrPMBCL) generally has limited treatment options and dismal prognosis. Recently, monotherapy of anti-PD-1 was reported to induce an effective and durable clinical response in nearly half PMBCL patients. However, the use of anti-PD-1 alone is notably unpractical for those with bulky aggressive lesions or life-threatening tumor mass given that anti-PD-1 alone always induce delayed tumor degradation. This ongoing, phase I/II study was aimed to evaluate the safety and efficacy of GVD chemo-regimen plus anti-PD-1 (SHR-1210) with or without low-dose decitabine priming in rrPMBCL patients with bulky aggressive lesions. Methods: This trial is enrolling patients with rrPMBCL who have bulky disease (minimum measurement must be > 75 mm in the longest diameter) with aggressive phenotype, rapid progression and fatal prediction. Enrolled patients were randomizedly assigned into 2 salvage treatment cohorts: GVD (Gemcitabine 0.8 g/m2,Vinorelbine 30 mg/d, Doxorubicin 20 mg/m2 , day 1, per 3 weeks) plus SHR-1210 (4 mg/kg, day 2, per 3 weeks) with (cohort 1) or without (cohort 2) low-dose decitabine priming (10mg/d, day -1 to -5, per 3 weeks). Safety was assessed by CTCAEv4.0, and clinical response by International Working Group (IWG) Response Criteria. Results: The prominent adverse event is ≤Grade 3 hematotoxicity in cohort 1. All enrolled 18 heavily-pretreated PMBCL patients had an effective control of disease progression after 1-cycle treatment and no death incident occurred so far. 11 patients had completed 4- to 8-cycle treatment, among them, 7 from cohort 1 were 2 CR, 4 PR, and 1 SD; 4 from cohort 2 were 3 CR and 1 PR. 6 patients who finished 8-cycle treatment had a 6- to 10-month ongoing progression-free survival so far. Conclusions: Both 2 regimens had comparably life-saving and durable clinical efficacy. Although all observed adverse events were tolerable in both groups, patients enrolled in the future will by treated by regimen without decitabine in view of the relatively lower treatment-associated toxicities. Clinical trial information: NCT03346642.
Safety of trifluridine/tipiracil for metastatic colorectal cancer in African American patients participating in an expanded access program.
Authors: Philip Agop Philip, Brandon George Smaglo, Bassel F. El-Rayes, Christian Lesuisse, Lukas Makris
Journal: Journal of Clinical Oncology (2017)

e15039 Background: A Phase 3 clinical trial (RECOURSE) showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (mCRC) (Mayer et al. NEJM 2015;372:1909-19). An expanded-access program (EAP) for patients with refractory mCRC assessed FTD/TPI safety in a real-world setting. One limitation of RECOURSE was the small number of African-American (AA) patients enrolled in the study (n=8). The EAP enrolled 45 AA patients, enabling assessment of FTD/TPI safety in this population. Methods: Patients aged ≥18 years with refractory mCRC resistant to ≥2 regimens of standard chemotherapy and an ECOG performance status of 0 or 1 were enrolled in this open-label EAP. Patients received FTD/TPI 35 mg/m 2 twice daily for 5 days followed by 2 days’ rest repeated twice followed by 14 days’ rest over a 28-day treatment cycle until drug discontinuation. We investigated duration of exposure to FTD/TPI and associated adverse events (AEs) in AA patients to compare them with non-AA and US patients from RECOURSE. Results: Median duration of FTD/TPI therapy for AA patients in the EAP was 9.7 weeks, similar to non-AA patients in the EAP (9.7 weeks) and US patients in RECOURSE (8.9 weeks) (differences not statistically significant). 73.3% of AA patients (n=33) in the EAP discontinued treatment due to disease progression and 8.9% (n=4) discontinued due to AEs. AEs related to FTD/TPI are summarized in the table. Conclusions: Lung cancer patients in Eastern North Carolina possess a strikingly poor inflammatory signature with significant implications for quality of life and survival. Clinical trial information: NCT02286492. [Table: see text]
Prognostic value of a 12-gene signature in platinum-based chemotherapy treated SCLC.
Authors: Jie Zhang, Chen Tian, Henghui Zhang, Xiaoling Chen, Jindi Han, Jun Nie, Ling Dai, Weiheng Hu, Guangming Tian, Xiangjuan Ma, Di Wu, Jian Fang
Journal: Journal of Clinical Oncology (2017)

e20011 Background: Small cell lung cancer (SCLC), which accounts for 15-20% of lung cancer, is a highly aggressive neoplasm. Different from non-small cell lung cancer, SCLC is characterized by a high proliferation rate and early metastasis. Only about 25% of patients with limited stage disease will be cured after first-line standard treatment and majority of the patients will relapse after initial sensitivity to the chemotherapy and radiotherapy. The highly complex genetic landscape of SCLC may be the reason for its resistance to conventional therapy but the details are still unclear. Methods: Nine patients with SCLC received platinum-based chemotherapy and/or radiotherapy were included in this study. According to the prognosis, patients were classified into two groups: poor prognosis group (PP group, PFS &lt; 6 months, n = 5) and better prognosis group (BP group, PFS &gt; 24 months, n = 4). Tumor DNA was isolated from pre-treatment paraffin-embedded tumor tissue and subjected to enrichment for a 1.15M size panel cover exon regions from 1,086 genes. Followed by next generation sequencing on an Illumina X10 platform, the captured sequencing data was further processed using bioinformatics analysis to identify somatic mutations, including single nucleotide variants (SNV), short insertions/deletions (indels) and copy number variation (CNV). Changes in tumor DNA were compared with clinical efficiency. Results: We show that the tumor mutation burden in PP group is higher than the BP group (p = 0.06). Using the mutation burden of 12 genes (PTEN, TP53, JAK2, BCL2, CCNE1, EGFR, ROS1, NTRK3, MYC, FGFR1, RANBP2, and CREBBP) as a factor, the PP group can be distinguished from BP group. In addition, TP53 loss is more frequently appeared in the PP group. Conclusions: Our results suggest that high mutation burden status of 12 genes (PTEN, TP53, JAK2, BCL2, CCNE1, EGFR, ROS1, NTRK3, MYC, FGFR1, RANBP2, and CREBBP) might correlate with poor prognosis of small cell lung cancer.
Abstract 18750: Systemic Lupus Erythematosus is Associated With Higher In-hospital Mortality Among Patients Hospitalized With Heart Failure: Findings From a United States National Study
Authors: Nabila K Mazumder, Marjan Mujib, Wilbert S Aronow, Tanush Gupta, Neha Paul, Dhaval Kolte, Sahil Khera, Prakash Harikrishnan, Chandrasekar Palaniswamy, Sachin Sule, Ali Ahmed, William H Frishman, Diwakar Jain, Howard A Cooper, Gregg C Fonarow, Julio A Panza
Journal: Circulation (2015)

Background: The association between systemic lupus erythematosus (SLE) and heart failure (HF) has been primarily described in case reports and case series. However, the relationship between SLE and clinical outcomes among patients hospitalized for HF has not been systemically evaluated in real-world setting. Hypothesis: SLE diagnosis is associated with higher in-hospital mortality among patients hospitalized for acute HF. Methods: We used the Nationwide Inpatient Sample (NIS) database to evaluate adult patients who were primarily hospitalized for HF (ICD 9 code 428.xx). Discharge weights were used to enable national estimates. Of 11,992,861 patients hospitalized for HF between 2002-2012, 50,878 (0.4%) had SLE. Logistic regression was used to evaluate the association between SLE and in-hospital mortality among these patients. Results: Patients hospitalized for HF had a mean age of 73 (±14) years, 52% were women and 68% were whites. Compared with hospitalized HF patients without SLE, those with SLE were younger (60 years vs. 73 years, P&lt;0.001), more likely to be female and of black race. In-hospital mortality occurred in 2.9% and 3.5% of hospitalized HF patients with and without SLE respectively (unadjusted OR for in-hospital mortality, when HF patients with SLE was compared with HF patients without SLE, 0.81; 95% CI, 0.77-0.85; P &lt;0.001). After adjusting only for age, SLE independently increased risk of in-hospital mortality among HF patients (age adj. OR, 1.22; 95% CI, 1.16-1.28; P &lt;0.001). The association remained statistically significant after adjusting for other patient demographics, risk factors and hospital characteristics (adjusted OR, 1.08; 95% CI, 1.01-1.15; P = 0.019). When compared with HF patients without SLE, those with SLE had a higher mean length of stay (5.68 vs 5.34 days) and higher hospitalization charges ($ 33,330 vs $ 31,098) (all p-values &lt;0.001). Conclusions: In this nation-wide study, prevalence of SLE was low among hospitalized HF patients. SLE was independently associated with increased risk of in-hospital mortality, prolonged hospital stay and increased total hospital charge. Further prospective studies are needed to better understand the relationship in this high-risk population.