tbuckley/cabot-search huggingface dataset:
Mutation profiling of BRAF gene in Chinese patients with early or advanced colorectal cancer using comprehensive NGS panel.
Authors: Canfeng Lin, Wanqiu Jia, Wang Sheng, Lijiao Zhang, Feiran Zhang, Yanhong Gu, Lingjun Zhu, Rongrong Chen, Xuefeng Xia
Journal: Journal of Clinical Oncology (2019)

e15124 Background: It has been reported that BRAF gene mutation occurs in approximately 10% of metastatic colorectal cancer (mCRC), and is associated with resistance to EGFR inhibitors. Moreover, patients with non-V600E BRAF mutations with a better prognosis than patients with V600E BRAF mutations in advanced colorectal cancer. However, little is known about mutation profiling of BRAF in early stage colorectal cancer. Methods: We reviewed mutation profiling of 1429 colorectal cancer samples in our institute from 2016 to 2018. Tissue biopsy and/or ctDNA samples were analyzed using hybridization capture-based NGS ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations at least 59 genes (range 59-1021 genes). Results: A total of 1429 samples from 1120 patients with CRC, included 86 early stage (Ⅰ-Ⅱ ), 966 advanced stage (Ⅲ -Ⅳ), and 377 samples with unknown stage. We identified 109 samples from 94 patients with BRAF gene mutation in the cohort (109/1429=7.63%), of which V600E and non-V600E were 62(4.34%) and 47 (3.29%), respectively. Among the 109 samples, there were 15 of early stage, 84 of advanced stage and 10 of unknown stages. BRAF mutation were more common in early CRC samples (15/86=17.44%) than in advanced CRC samples (84/966=8.7%, p = 0.007). Furthermore, 10 of the 15 early CRC samples yet 32 of the 84 mCRC samples had non-V600E were detected (66.67% vs 38.1%, p=0.039). In contrast to V600E mutation, some of the non-V600E variants were variants of unknown clinical significance (VUS) in this study (see Table). Conclusions: BRAF mutation is more common in early stage CRC, the higher prevalence of non-V600E BRAF mutations in early CRC may account for the better prognosis of early stage CRC. non-V600E BRAF mutation subtype. [Table: see text]
Germline analysis of DNA-damage repair genes in men with advanced prostate cancer in comparison to women with breast cancer.
Authors: Amy Kunz, Natalie Tri, Arash Samiei, Shifeng Mao
Journal: Journal of Clinical Oncology (2019)

e13147 Background: Women with breast cancer have traditionally been the population for genetic counseling. The association of hereditary cancer syndromes and the development of advanced prostate cancer have been established only since recent years. There has been increased utilization of germline analysis in men with prostate cancer since NCCN updated its guideline on genetic testing for DNA damage repair (DDR) genes in the homologous recombination (HR) pathway in this population. In this study, we analyzed the prevalence of genetic alterations in DDR genes in men with advanced prostate cancer in relevance to women with breast cancer in our institution. Methods: Patients who were referred to genetic counseling in 2018 and met NCCN criteria underwent genetic testing following pretest genetic counseling. Samples obtained from buccal mucosa or peripheral blood were analyzed for germline variants using commercially available multi-gene panels which included DDR genes in the HR pathway. Results: In 2018, 54 men with prostate cancer with relapsed disease following local therapy, or de novo metastasis, and 305 women with breast cancer were included. At least one pathogenic or likely pathogenic variant was identified in 9 men (16.7%), most frequently in BRCA2, ATM, and CHEK2, as compared to those in 30 women (9.8%), p = 0.137. 17 men (31.5%) had at least one variant of uncertain clinical significance (VUS) detected in a DDR gene as compared to those in 74 (24.3%) women with breast cancer, p = 0.261. Conclusions: Men with advanced prostate cancer have a statistically comparable but numerically trending higher frequency of pathogenic variants and VUS in DDR genes detected on germline testing in comparison to women with breast cancer. The high prevalence of VUS in prostate cancer is an intriguing finding. VUS represent a genetic alteration with undefined clinical outcome. With increasing genetic testing in prostate cancer, further correlation between VUS of DDR genes and clinical risk features from a larger population is warranted.
Abstract 20144: Increasing Preload Permits Maintenance of Cardiac Output During Rapid Atrial Pacing in Infant Piglets but is Associated With Possible Right Heart Diastolic Impairment in Neonatal Piglets
Authors: Etienne Fortin-Pellerin, Lisa K Hornberger, James Y Coe, Lindsay Mills, Jesus Serrano-Lomelin, Po-Yin Cheung, Nee S Khoo
Journal: Circulation (2016)

Introduction: Rapid LV maturation in the neonatal period influences response to hemodynamic challenges. We recently demonstrated in a piglet model, that the neonatal heart tolerates atrial tachycar...
Venous thromboembolism related hospitalizations among patients with genitourinary malignancy in the United States: A nationwide analysis.
Authors: Sara Albagoush, Kamelah Abushalha, Sarah J Aurit, Janani Baskaran, Maryam Gbadamosi-Akindele
Journal: Journal of Clinical Oncology (2019)

e16126 Background: Cancer Patients are at high risk of developing venous thromboembolism (VTE), pulmonary embolism (PE), and deep venous thrombosis (DVT). In this study, we aim to get an estimate of the incidence of VTE as a primary admission diagnosis among patients with genitourinary malignancies. Methods: We utilized ICD-9-CM and ICD-10-CM codes to identify patients with malignant neoplasms of the prostate, bladder, kidney, and testis who are older than 18 years and admitted with a primary diagnosis of DVT, PE within the NIS database during 2007-2016. Unadjusted incidence of DVT and PE was analyzed for each cancer site with the Rao-Scott chi-square test; multivariable logistic regression was employed to adjust for age, biological sex ( not for prostate/ testicular cancer), race, insurance, year of admission, and use of chemotherapy to further examine incidence. Results: We identified 3,339,985 admissions affiliated with genitourinary malignancies of whom 0.59% experienced DVT and 0.13% experienced PE with bladder cancer patients have the highest risk of hospitalization for VTE ( 79/1000). Within bladder cancer population; insurance ( p &lt; 0.001) and hospital location and teaching status ( p &lt; 0.001) were associated with DVT incidence; and biological sex ( p = 0.040) and race and ethnicity ( p = 0.026) with PE incidence. For all sites combined and after adjusting for all else, it was found that every year increase in age was associated with 1.2% increased odds of DVT or PE incidence (OR 95% CI: 1.01-1.02; p &lt; 0.001). Further, rural vs. urban teaching hospitals had 41.2% increased odds (95% CI: 1.26-1.58; p &lt; 0.001), and urban non teaching vs. urban teaching hospitals had 35.1% increased odds (95% CI: 1.26-1.45) of DVT or PE incidence. African Americans vs. whites had 46.8% increased odds of DVT or PE incidence (95% CI: 1.35-1.60; p &lt; 0.001). Conclusions: Within the population of genitourinary malignancies who admitted with a primary diagnosis of VTE; the incidence was higher with older age, African Americans, uninsured population, in rural and urban non teaching facilities, bladder cancer population.
The SUNEVO (GETNE-1408) trial to evaluate the activity and safety of thecombination of sunitinib with evofosfamide (TH-302) in patients with G1/G2 metastatic pancreatic neuroendocrine tumours (pNETs) naïve forsystemic treatment: A phase II study of the Spanish Task Force Group for Neuroendocrine and Endocrine Tumors (GETNE).
Authors: Enrique Grande, Carlos Lopez, Teresa Alonso-Gordoa, Marta Benavent, Jaume Capdevila, Alex Teule, Ana Custodio, Isabel Sevilla, Pablo Gajate, Javier Molina-Cerrillo, Jorge Hernando-Cubero, Rocio Garcia-Carbonero
Journal: Journal of Clinical Oncology (2019)

4105 Background: Angiogenesis plays an important role in tumorigenesis and progression of pNETs. Evofosfamide (EVO) is a DNA alkylator prodrug that selectively activates under hypoxia. Sunitinib as monotherapy shows a wide range of responses (9-24%) in similar populations. We hypothesized that sunitinib-induced hypoxia might increase the cytotoxic activity of EVO in patients with metastatic pNETS and naïve for systemic treatment other than somatostatin analogues (SSA). Methods: This is a phase-II, single-arm, and multicenter trial of EVO (340mg/m2 on days 8, 15 and 22 every 4 weeks) and sunitinib (37.5mg/day continuously). Primary endpoint was Objective Response Rate (ORR) by RECIST v1.1 assessed every 8 weeks. A Simon two-stage optimal design was used, considering a minimum of 3 responses in the first 18 pts in order to start with the second stage (power = 0.80, alpha = 0.05). Results: Between May/2015 and May/2018, 17 pts were included (median age was 62.4 y.o). Prior SSA was reported in 7 (41.2%) pts and 8 (47.1%) had a Ki-67 &gt; 10%. There were 2 responders (11.8%; n = 1 complete and n = 1 partial response); stable disease was observed in 76.5%. Median (range) PFS and duration of response were 10.4 months (m) (2.9-17.9m) and, respectively 24.4m (13.7-35.2m), respectively. Grade 3 or 4 adverse events occurred in 11 (64.7%) pts, being neutropenia (33.3%), fatigue (16.7%), thrombocytopenia (11.1%), hand-foot syndrome (5.6%), and pancreatitis (5.6%) the most frequent. Toxicity led to treatment discontinuation in 5 (38.5%) pts. Dose reductions were reported in 20% (sunitinib) and 100 % (EVO) of pts. Conclusions: Combination of sunitinib and EVO failed to demonstrate activity in terms of tumor shrinkage as only two patients achieved response, therefore, second stage was not proceeded. While cross trial comparisons are difficult, response rate of 12% with the combination was disappointing. Concerns over toxicity arose; translational analysis are undergoing. Clinical trial information: NCT02402062.
Results from a first-in-man, open label, safety and tolerability trial of CAN04 (nidanilimab), a fully humanized monoclonal antibody against the novel antitumor target, IL1RAP, in patients with solid tumor malignancies.
Authors: Ahmad Awada, Ferry Eskens, Debbie Robbrecht, Ulrik Niels Lassen, Morten Mau Soerensen, Neeltje Steeghs, Christiane Jungels, Philippe Georges Aftimos, Signe Øien Fretland, Lars Thorsson, Tormod Kyrre Guren
Journal: Journal of Clinical Oncology (2019)

2504 Background: Interleukin 1 receptor Accessory protein, IL1RAP, is expressed in several solid tumors, both on cancer cells and tumor-associated inflammatory cells. CAN04 is a first-in-class fully humanized monoclonal antibody targeting IL1RAP blocking IL-1 alpha and beta signaling and triggering antibody dependent cellular cytotoxicity. Methods: The primary objective was to assess safety and tolerability of weekly CAN04 in order to define the Recommended Phase 2 Dose (RP2D). Patients (pts) with relapsed or refractory non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), breast or colorectal cancer were included using a 3+3 dose escalation design. Key eligibility criteria were ECOG ≤1, normal organ function and no bleeding disorder/coagulopathy. Tumor responses were evaluated according to irRC every 8 weeks. PK and biomarkers were analyzed in serum. Results: 22 pts were enrolled across 5 cohorts (1-10 mg/kg). Demography: mean age 62 yrs (39-81); gender 14 M and 8 F; median number of prior lines of therapy 3 (range 1-11). AEs occurred mainly following the first dose and the most common AEs were: infusion related reaction (IRR) (41%), pyrexia (27%), fatigue (23%), chills (23%) and nausea (23%). AE grade 3 or 4: one IRR, one neutropenia/leukopenia and one hypokalemia, all of them grade 3. Serum CRP and IL-6 were reduced after two weeks of treatment. There were linear increases of AUC and Cmax (1-10 mg/kg) and CAN04 exposure at 10mg/kg was above levels associated with signs of efficacy in preclinical models. In pts receiving at least one dose of CAN04, 9/20 (45%) had SD by irRC (7/20 had SD by RECIST 1.1) at 8 weeks follow up. Two pts, one with NSCLC and one with PDAC, had SD for 6 and 4 months (latter still on therapy). Conclusions: CAN04 demonstrated a manageable safety profile and a RP2D of 10 mg/kg has been established. The dose expansion phase of the trial will evaluate CAN04 as monotherapy as well as in combination with relevant chemotherapy regimens in NSCLC and PDAC in separate arms. Clinical trial information: NCT03267316.
Deep learning hybrid 3D/2D convolutional neural network for prostate MRI recognition.
Authors: Jasper Van, Choongheon Yoon, Justin Glavis-Bloom, Michelle Bardis, Alexander Ushinsky, Daniel S. Chow, Peter Chang, Roozbeh Houshyar, Chanon Chantaduly, William A. Grant, Dylann Fujimoto
Journal: Journal of Clinical Oncology (2019)

e16600 Background: Prostate cancer is the most common cancer of men in the United States, with over 200,000 new cases diagnosed in 2018. Multiparametric MRI of the prostate (mpMRI) has emerged as valuable adjunct for the detection and characterization of prostate cancer as well as for guidance of prostate biopsy. As mpMRI progresses towards widespread clinical use, major challenges have been identified, arising from the need to increase accuracy of mpMRI localization of prostate lesions, improve in lesion categorization, and decrease the time and technical complexity of mpMRI evaluation by radiologists or urologists. Deep learning convolutional neural networks (CNN) for image recognition are becoming a more common method of machine learning and show promise in evaluation of complex medical imaging. In this study we describe a deep learning approach for automatic localization and segmentation of prostates organ on clinically acquired mpMRIs. Methods: This IRB approved retrospective review included patients who had a prostate MRI between September 2014 and August 2018 and an MR-guided transrectal biopsy. For each mpMRI the prostate was manually segmented by a board-certified abdominal radiologist on T2 weighted sequence. A hybrid 3D/2D CNN based on U-Net architecture was developed and trained using these manually segmented images to perform automated organ segmentation. After training, the CNN was used to produce prostate segmentations autonomously on clinical mpMRI. Accuracy of the CNN was assessed by Sørensen–Dice coefficient and Pearson coefficient. Five-fold validation was performed. Results: The CNN was successfully trained and five-fold validation performed on 411 prostate mpMRIs. The Sørensen–Dice coefficient from the five-fold cross validation was 0.87 and the Pearson correlation coefficient for segmented volume was 0.99. Conclusions: These results demonstrate that a CNN can be developed and trained to automatically localize and volumetrically segment the prostate on clinical mpMRI with high accuracy. This study supports the potential for developing an automated deep learning CNN for organ segmentation to replace clinical manual segmentation. Future studies will look towards prostate lesion localization and categorization on mpMRI.
Does the time to initiate adjuvant chemotherapy effect outcome in patients with breast cancer? A National Cancer Database-based retrospective analysis.
Authors: Prashanth Ashok Kumar, Dongliang Wang, Shreya Sinha, Abirami Sivapiragasam
Journal: Journal of Clinical Oncology (2019)

e12054 Background: The Early Breast Cancer Trialists Collaborative Group showed that adjuvant therapy for breast cancer (BC) significantly reduces the 5-year recurrence and 15-year mortality rates. After surgery, it usually takes around 4-6 weeks to begin adjuvant chemotherapy and delay in initiating the same is believed to lead to poorer outcomes. A number of studies have sought to evaluate the role of delayed initiation of chemotherapy on survival but results have remained controversial and an optimal time has not been defined. Methods: Our aim was to determine the effect of delay in starting chemotherapy from the date of surgery on survival of patients with early BC using the National Cancer Database (NCDB) data. From the database, we selected patients aged &gt;18 years with stage 1-3 BC who received adjuvant chemotherapy. We included all ER/PR statuses. A total of 544,005 patients were divided into 3 groups based on the time of initiating chemotherapy from the date of surgery i.e., 0-60 days, 60-90 days and &gt;90 days and had a distribution of 38.07%, 35.90% and 26.03 % respectively. Results: Estimates from cox models showed the following adjusted Hazard Ratios(HR): 0-60 days vs &gt;90 days (HR 0.976, CI 0.955-0.998), 60-90 days vs &gt;90 days (HR 0.899, CI 0.879-0.920). Kaplan Meier Survival estimates revealed that the 0-60 days and the 60-90 days groups had a better 10 year survival estimate than the &gt; 90 days group with a p&lt;0.0001. The factors that correlate with delay in initiating adjuvant chemotherapy are African American race, poor Charlson Deyo Score, uninsured or government insurance holders, well differentiated tumors and ER/PR positive status. Conclusions: Based on our analysis from a large national database, we hypothesize that delaying adjuvant therapy for more than 90 days may have worse outcomes due to reasons like rapid growth of micro metastasis following removal of the primary tumor. Thus for stage 1-3 BC, the ideal time to start adjuvant chemotherapy from the date of surgery is before 90 days. Survival estimates from Kaplan-Meier analysis. [Table: see text]
Impact of cardiovascular comorbidities on mortality in patients admitted for neutropenic fever in 2016.
Authors: Suheil Albert Atallah-Yunes, Faris Haddadin, Anis Kadado, Syed S. Ali
Journal: Journal of Clinical Oncology (2019)

6586 Background: Neutropenic fever (NF) remains one of the most common causes for hospitalization and mortality in oncology patients. Concomitant cardiovascular disease in patients with cancer is not uncommon. There is limited data on the impact of cardiovascular (CVS) comorbidities on mortality in cancer patients with NF. Methods: This is a retrospective cohort study using the 2016 National Inpatient Sample database (NIS) of adults ( &gt; 18 years) admitted for NF based on the ICD-10 code. Mortality was the primary outcome. Multivariate linear regression adjusted for potential confounder of age, sex, race, Charlson comorbidity index and all the CVS comorbidities of the study including atrial fibrillation (AF), heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), coronary artery disease (CAD), peripheral vascular disease (PVD), hypertension (HTN), history of smoking, history of cerebrovascular accident (CVA) or TIA and dyslipidemia. STATA 15 was used for analysis. Results: We identified 31,310 patients (mean age 44.6) (49.6% females) admitted with NF, among which 250 died during same admission. On multivariate linear regression there was a significant increase in adjusted all-cause mortality in patients with AF (OR: 2.39; 95%-CI 1.06- 5.40, P = 0.035) and HFpEF (OR: 4.30; 95%-CI 1.08- 17.17, P = 0.039). There was no significant increase in mortality in patients with HFrEF, dyslipidemia, HTN, PVD, CAD, history of CVA/TIA and smoking. Conclusions: Patients with NF and concomitant history of AF or HFpEF have an increased risk of mortality during hospitalization. Inflammation is emerging as a key player in AF pathogenesis. This may explain why AF appears to correlate with mortality, as those with more severe presentations are more likely to have a heightened state of inflammation. Patients with NF are more likely to receive fluids in the setting of infectious complications which could explain the increased mortality in CHF patients with NF. Identifying risk factors for increased mortality in patients with NF is important for risk stratification and in guiding clinicians in the management of this delicate population. [Table: see text]
Genetic identification and characterization of Lynch syndrome in a multi-ethnic biobank.
Authors: Rachel Rosenblum, Sabrina A. Suckiel, Gillian M. Belbin, Sinead Cullina, Judy H. Cho, Eimear E. Kenny, Aimee L. Lucas, Celina Ang, Noura S. Abul-Husn
Journal: Journal of Clinical Oncology (2019)

1520 Background: Lynch syndrome (LS), caused by germline pathogenic variants in mismatch repair (MMR) genes, results in increased risk of colorectal, endometrial, and other cancers. LS has a prevalence of ~1 in 440 in European ancestry populations; prevalence data in other populations are limited. We identified and characterized carriers of pathogenic MMR gene variants in the multi-ethnic Bio Me Biobank in New York City. Methods: Exome sequence data from ~31,000 Bio Me participants were evaluated for known (per ClinVar) and predicted (loss-of-function) pathogenic variants in MMR genes. Population groups were defined by genetic ancestry. Participant questionnaires and electronic health records (EHRs) of carriers were reviewed for personal or family history of malignancy. Results: We identified 48 carriers of 33 distinct pathogenic variants in PMS2 (48%), MLH1 (27%), MSH6 (15%), and MSH2 (10%), for an estimated prevalence of ~1/640 in the Bio Me Biobank. Prevalence was higher among individuals of Non-Jewish European (N = 14; 1/400) and African (N = 14; 1/490) ancestries, compared to Puerto Rican (N = 8; 1/640), Ashkenazi Jewish (N = 6; 1/690), and other/mixed (N = 6) ancestries. Carriers had a median age of 56 (range 27 to 77) years and were 50% female. Overall rate of malignancy among carriers was 38%, with the lowest rate in PMS2 (26%) and the highest rate in MSH6 (57%) variant carriers. We found a high prevalence of endometrial cancer (21% of female carriers) and a lower prevalence of colorectal cancer (4% of all carriers). Only 2 carriers (4%) had a diagnosis of LS in their EHRs, and only 1 carrier met Amsterdam diagnostic criteria for LS. Conclusions: These data show that ~0.15% of participants in a multi-ethnic biobank are carriers of pathogenic MMR gene variants and suggest that the prevalence is higher in European and lower in non-European ancestry populations. Notably, most carriers do not have a clinical diagnosis of LS and do not meet diagnostic criteria for LS. Carriers demonstrate variable rates of cancer, which may contribute to under-diagnosis of LS. Genomic screening for pathogenic MMR variants may lead to earlier diagnosis of LS and improved outcomes.