tbuckley/cabot-search huggingface dataset:
CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T-cell product JCAR017 (TRANSCEND NHL 001).
Authors: Jeremy S. Abramson, Maria Lia Palomba, Leo I. Gordon, Matthew Alexander Lunning, Jon E. Arnason, Andres Forero-Torres, Michael Wang, Tina M. Albertson, Tara Allen, Claire Sutherland, Benhuai Xie, Jacob Garcia, Tanya Siddiqi
Journal: Journal of Clinical Oncology (2017)

7513 Background: JCAR017 is a second-generation, CD19-directed, 4-1BB CAR T cell product comprising CD8 and CD4 CAR T cells in a 1:1 ratio. A multicenter phase 1 trial of JCAR017 in R/R B-cell NHL (NCT02631044) is underway. Methods: Patients with R/R DLBCL, PMBCL, FL grade 3B, or MCL and adequate organ function are eligible. There was no minimum ALC requirement for apheresis; no test expansion was required. Treatment includes lymphodepletion with fludarabine and cyclophosphamide, followed by JCAR017. Multiple dose levels (DLs)/administration schedules of JCAR017 are being evaluated. Study objectives include safety, PK, and antitumor response. Results: As of November 23, 2016, 28 patients have been treated and are evaluable for safety and efficacy. Nineteen were male, 9 female; 25 DLBCL, 2 MCL, and 1 FL grade 3B. Median age was 63 years (range 37-79), median number of prior therapies was 4 (range 1-8), 23 (82%) were refractory to their last chemotherapy, and 16 (57%) had prior transplant. No severe cytokine release syndrome (sCRS) was observed; 10 patients had grade 1-2 CRS (1 received tocilizumab). Five patients developed neurotoxicity, including 4 grade 3-4; all events resolved in the 4 patients who had adequate follow up. Median onset of CRS and neurotoxicity were 5 and 11 days, respectively. Four deaths after disease progression occurred, none related to JCAR017. In 20 patients treated at DL1 (5×10 7 cells), the RR was 80% with 60% achieving CR. One patient with secondary CNS involvement achieved CR without neurotoxicity. JCAR017 was detected at 3 and 6 months in responding patients, including some who relapsed; higher mean peak levels were detected in patients with durable response at 3 months. Data on patients treated at DL2 (1×10 8 cells), alternative dose schedules, tumor biopsy, and additional biomarkers will be presented. Conclusions: Treatment with JCAR017 results in high CR rate in patients with heavily pretreated R/R DLBCL. Relapses can occur despite persistence of JCAR017, suggesting tumor immune evasion mechanisms may contribute to relapse. Observed toxicities are manageable and occurred at rates lower than those reported for other CD19-directed CAR T cell products. Clinical trial information: NCT02631044.
Abstract 19078: Adipose-derived Cell Treatment Improves Coronary Blood Flow Reserve in Aged Females and is Associated With Altered ROS Production in Coronary Arterioles
Authors: Christopher D Nevitt, Allison L Aird, Quang T Nguyen, James B Hoying, Stuart K Williams, Amanda LeBlanc
Journal: Circulation (2014)

Coronary blood flow reserve (CFR) is significantly decreased with advancing age and could contribute simultaneously to the increased risk for coronary heart disease (CHD). CFR is now considered a n...
Abstract 12554: Association of Left Ventricular Diffuse Fibrosis and Scar Assessed by Cardiac Magnetic Resonance Imaging With Depolarization and Repolarization on 12-Lead Electrocardiography: MESA (Multi-Ethnic Study of Atherosclerosis)
Authors: Yuko Y Inoue, Hiroshi Ashikaga, Bharath Ambale-Venkatesh, Gustavo J Volpe, Nathan Mewton, Yoshiaki Ohyama, Ravi K Sharma, Colin O Wu, Chia-Ying Liu, David A Bluemke, Elsayed Z Soliman, João A Lima
Journal: Circulation (2015)

Introduction: Left ventricular (LV) interstitial diffuse fibrosis and scar (replacement fibrosis) affect ventricular depolarization and repolarization parameters on an electrocardiogram (ECG) through local electrophysiology as well as LV global structure. The aim of this study is to examine the association between the two different types of fibrosis and ECG indices. Methods: A total of 1,669 participants (aged 54 to 94 years, 50% women) free of prior myocardial infarction or conduction delay underwent cardiac magnetic resonance with late gadolinium enhancement (LGE), and 1,136 participants without an LGE-defined scar were analyzed using T1 mapping. The associations of LV diffuse fibrosis or scar with ECG parameters [QRS Sokolow-Lyon and Cornell voltage, QRS duration, and corrected QT (QTcorr) interval] were evaluated using multivariable regression analyses adjusted for cardiovascular risk factors, LV end-diastolic volume, and LV mass. Results: Lower post-contrast T1 time at 12 min and 25 min, indicating greater diffuse fibrosis, was significantly associated with lower QRS Sokolow-Lyon voltage, lower QRS Cornell voltage, and shorter QRS duration (all P&lt;0.05). Greater extracellular volume fraction (ECV) was also significantly associated with lower QRS Sokolow-Lyon voltage (β=-38.9, P&lt;0.001) and Cornell voltage (β=-23.5, P&lt;0.001). By contrast, the presence of LV scar (n=106) was associated with longer QTcorr interval (β=4.2, P=0.034). Conclusions: In middle-aged multi-ethnic population, LV diffuse fibrosis assessed by T1 mapping was significantly associated with lower QRS voltage and shorter QRS duration, whereas LV scar was associated with longer QT interval; independent of cardiovascular risk factors and LV structure. Our results reveal the potential of 12-lead ECG of evaluating two different type of fibrosis.
Association of FBXW7 missense mutations (mt) with unfavorable prognosis in metastatic colorectal cancer (mCRC) patients (pts).
Authors: Krittiya Korphaisarn, Michael J. Overman, David R. Fogelman, Bryan K. Kee, Kanwal Pratap Singh Raghav, Imad Shureiqui, Robert A. Wolff, Keyur Patel, Kenna Rael Shaw, Cathy Eng, Dipen M. Maru, Mark Routbort, Funda Meric-Bernstam, Scott Kopetz, Van Karlyle Morris, Eduardo Vilar-Sanchez, Shanequa Manuel, A. Dasari
Journal: Journal of Clinical Oncology (2016)

3607 Background: FBXW7 functions as a ubiquitin ligase tagging dominant oncogenic proteins such as cyclin E, MYC, Jun and Notch for degradation by the proteasome system. FBXW7mt are noted throughout the gene and have been shown to have differential effects depending on location and type. Recent data suggests that missense mt lead to greater loss of FBXW7 function than nonsense or truncation mt but the clinicopathological factors associated with FBXW7 missense mt and clinical outcomes in mCRC have not been described. Methods: Data from pts with mCRC whose tumors were evaluated by next generation sequencing for hotspot mt through the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program at MD Anderson Cancer Center were obtained. Alterations in FBXW7 were identified and their implications on clinical, pathological features and overall survival (OS) were evaluated. Results: Of 854 mCRC pts in the ATTACC dataset, 574 had data on FBXW7 of which 45 pts (7.8%) had mt. Of these, 38 were missense mt while others were nonsense (5), insertions or deletions (1 each). R465H mt in exon9 and R497Q mt in exon10 were the most common missense mt (15.8% each). None of the clinicopathological features including age, gender, tumor site & grade, KRAS, BRAF, PIK3CA mt or microsatellite status were associated with FBXW7 missense mt. Pts with FBXW7 missense mt tumors had significantly inferior OS compared with pts with FBXW7 wild type tumors in both univariate (median OS 36.2 months, mos 95% confidence interval, CI 18.7-38.5 in mt vs median OS 47.5 mos 95% CI 44.2-50.9 mos; p = 0.003) and multivariate analyses after correcting for other known prognostic factors including KRAS, BRAF status and tumor grade (HR = 1.8, 95%CI: 1.14-2.86; p = 0.01). In contrast, other alterations in FBXW7 did not appear to impact prognosis (median OS 42.9 mos, 95% CI 21.1 – 64.8 mos). Conclusions: To date, this is the largest clinical dataset of FBXW7 missense mt which showed negative prognostic impact on survival in mCRC without any association with other known prognostic factors. Further studies on identification of downstream pathways underlying this worse prognosis and potential therapeutic targets are required.
Prevalence of MSI status in locally advanced rectal cancer and its correlation with response to neoadjuvant therapy and survival.
Authors: Nikhil Pande, Vikas S. Ostwal, Anant Ramaswamy, Mukta Ramadwar, Rohit Swami, Suprita Arya, Ashwin Desouza, Reena Engineer, Avanish Saklani, Shripad Dinanath Banavali
Journal: Journal of Clinical Oncology (2018)

e15668 Background: High microsatellite instability is associated with good overall prognosis. Adjuvant chemotherapy has not improved the survival in such patients. Emerging evidence suggests that dMMR can be predictive of significant response and survival gain from immune checkpoint inhibitors. Value of MSI has been studied less in rectal cancers. Methods: Consecutive patients registered between January 2014 and December 2015, who were histologically proven localized or locally advanced rectal cancer and received neoadjuvant long course radiotherapy with concurrent chemotherapy were included in the study. The samples of these patients were tested by IHC for the protein expressed by MMR genes. The responses of these patients to neoadjuvant NACT-RT along with the details of the type of therapy and the final outcome of these patients were noted and a correlation with the MSI status was analysed. Results: There was a total of 354 patients enrolled which 3 were dMMR. Median age of the cohort was 47 years and majority of them were males. 18% of patients had signet ring histology. 90% had nodal positivity and 55% had CRM positivity at baseline. Grade 3 or 4 toxicities with CTRT was seen in 12% of patients. 99 patients were planned for chemotherapy after CTRT with the reasons being either persistence of CRM positivity and bulky or unresectable disease. 240 patients (68%) underwent surgery. The median follow was of 32 months and the median OS was 47 months. On univariate analysis, the factors which were significant for survival were mucinous and signet ring histology, clinical T stage, presence of grade 3 or 4 toxicities, interruptions in Capecitabine and Radiotherapy for treatment related factors and presence or absence of pathological CR for post-surgery factors. On multivariate analysis only those who had toxicities and those with signet ring histology retained their impact on survival. Conclusions: 1% prevalence of dMMR in locally advanced rectal cancers preclude its testing to decide adjuvant chemotherapy in stage II/III rectal cancers, addition of Oxaliplatin along with Capecitabine in NACT setting and consideration of anti dMMR targeted immunotherapy in metastatic setting.
Impact of imaging based sarcopenia and modified advanced lung cancer inflammation index (mALI) on clinical outcomes in advanced NSCLC: A occult killer and a prognostic biomarker.
Authors: Abhishek Mahajan, Kumar Prabhash, Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Sujeet Agarwal, Devendra Goyal
Journal: Journal of Clinical Oncology (2018)

e24166 Background: Sarcopenia has been shown to be both predictive and prognostic marker in oncology. The objectives of the study was to evaluate the role of pre-treament sarcopenia/ Skeletal Muscle Index (SMI), skeletal muscle density (SMD) and Modified Advanced Lung Cancer Inflammation Index (mALI) in predicting clinical outcomes in advanced NSCLC. Methods: This retrospective study consisted of a total of 100 advanced NSCLC patients who had baseline CECT available for analysis. The morphometric parameters such as SMD, SMI, Fat mass (FM), fat-free mass (FFM), subcutaneous fat to muscle ratio (FMR) and visceral to subcutaneous adipose tissue ratio (VA/SA) were measured by CT at the L3 vertebra. ALI was defined as BMI x serum albumin/neutrophil-lymphocyte ratio (NLR) and mALI was defined as SMI x serum albumin/NLR.The Kaplan-Meier methods and a multivariable Cox proportional hazards model were used to evaluate the potential prognostic factors. Results: Prevalence of sarcopenia was 57% with male preponderance. The mean SMI was 49.9 cm2/m2. for males 51.8 cm2/ m2 and females 44.98 cm2/ m2 (p < .000). The mean SMD was 34.7 HU, SMI and SMD correlated. BMI was significantly lower in low SMI than high SMI (23.3 kg/m2 vs 28.0 kg/m2; p < 0.0001). Multivariate analyses revealed that pretreatment SMI, SMD and mALI were independently associated with inferior PFS and a higher likelihood of early progression. The mean PFS in patients with poor SMD was 17.83 months and in patients with good SMD was 21.58 months. Patients with low SMD and mALI had shorter OS than patients with high SMD and mALI (p < 0.001). Sarcopenic patients were also found to have poorer OS than nonsarcopenic patients, however, the survival difference was not statistically significant. OS of Sarcopenic patients was 21.0 and in nonsarcopenic patients was 25.5 (p: 0.09). Conclusions: The pretreatment SMI, SMD and mALI were found to be significant independent predictor of early progression and overall survival in patients with advanced NSCLC. These biomarkers could potentially help triage patients for chemotherapy according to their tolerability and active nutritional intervention for better outcomes.
An enhanced next-generation sequencing liquid biopsy assay for simultaneous detection of somatic variants, microsatellite instability and viral DNA.
Authors: Yukti Choudhury, Hao Chen, Farah Fadhlullah, Daniel Kian Hin Tan, Kim Tien Ng, Min-Han Tan
Journal: Journal of Clinical Oncology (2018)

e24107 Background: Liquid biopsy technology has demonstrated utility in non-invasive targeted detection of somatic cancer-associated variants in blood. Other actionable tumor alterations such as microsatellite instability (MSI) and cancer-derived viral DNA represent key circulating tumor DNA (ctDNA) targets, for which an optimized platform technology would help guide diagnosis and therapy. We developed an enhanced error-correction sequencing platform technology (AmpliMark) for this purpose. Methods: We developed a liquid biopsy panel on this platform covering 22 genes, 6 microsatellite loci and 2 viral targets, together with an optimized bioinformatics pipeline. AmpliMark is based on enumerating input DNA molecules for enhanced detection of variants (single nucleotide variants and short indels), microsatellite deletion and viral DNA. Analytical validation of the panel demonstrated lower limits of detection (LOD) for variant allele, MSI and viral DNA frequencies to be 0.1%, 5% and 100 IU/mL, respectively. Clinical quality validation in 80 anonymized lung, nasopharyngeal (NPC) and colorectal cancer plasma and tissue samples was conducted. Orthogonal analysis was done with PCR-based detection of EGFR mutation, EBV BamHI-W CpG DNA, and MSI fragment analysis in an ISO15189-accredited clinical laboratory. Results: The platform demonstrated high variant concordance (98%) with PCR detection for actionable EGFR mutations, including exon 19 deletions, L858R, T790M, G719X and C797X. Cancer-associated viral DNA detection showed 89% concordance in NPC, with additional detection of KIT, TP53 and MED12 variants. The technology demonstrated 92% concordance in FFPE tissue with fragment analysis, with MSI and somatic variant (APC, TP53 and KRAS) detection in matching plasma and tissue for samples with high ctDNA. Conclusions: We have developed a technology allowing improved detection of somatic cancer variants, microsatellite instability and cancer-associated viral sequences in liquid biopsies. Analytical and clinical validation demonstrates good concordance with conventional targeted assays in detecting actionable genetic alterations in blood.
Improved survival of stage 4 high grade ovarian cancer patients as staged by positron emission tomography (PETCT), who undergo chemotherapy (with a good PETCT response) and debulking surgery as seen in a prospective study in our cancer institution.
Authors: Chit Cheng Yeoh, Alisha Damani, Mark Collins, Chukwumobi Ihezue
Journal: Journal of Clinical Oncology (2016)

e17055 Background: Our institution has a large cohort of high grade ovarian cancer diagnosed at late stages. Conventionally all stage 4 ovarian cancer will not be considered for interval debulking surgery (IDS). They would be offered palliative chemotherapy (CT) alone. Our Institution is one of the first few large Cancer centres with a Positron emision tomography (PETCT) machine, with access as routine staging of all advanced cancers. We followed prospectively 19 patients, who are stage 4 by PETCT criteria, who are otherwise PS < 2, who embarked on primary CT, with good response, whom we performed interval IDS on. Methods: From 2013 -2016, we enrolled patients who have performance status < 2, into full PETCT staging. We choose the PETCT stage 4 disease patients to follow them into their treatment management. We performed an analysis of our patients, to see analyse their DFS, OS, and subsequent line treatments & quality of life. Results: Median follow up 35 months of PETCT-confirmed stage 4 ovarian cancer patients. Median overall survival at 3 years is 68%. Median disease free interval between 1st line and secondline is 7 months. Average of 54% have had 2 line chemotherapy (CT), 26% have 3rd line CT, and 20% had 4th line CT. To date 2 patients have died. 14/19 patients undergone IDS. 4 patients who did not have IDS; 1 had CR radiologically, 2 patients were not suitable as PD. All patients who underwent surgery were discharged by 5 days. 9/14 pateints who underwent IDS said they would consider secondline surgery again if it were clinically indicated. Two cases of remaining PETCT avid abdominal lymphnodes (LN) underwent surgery and excision of the LN. Incidentally these were found to have pathological CR. Both cases were a single-site-para-aortic LN. Both patients were not diabetics nor on any anti-glycemic drugs. Conclusions: PETCT upstaged 36% of baseline stage 3C disease on CT scans. PETCT confirmed stage 4 ovarian cancer can still benefit from primary CT followed by IDS as per stage 3C paradigm. Stage 4, fit patients do as well as stage 3C ovarian cancer patients, excluding the parachyma stage 4 disease.
Integration of ongoing quality assurance measures in colorectal cancer survivorship care plans.
Authors: Samantha S. Sigurdson, James Joseph Biagi, Hugh Langley, Kardi Kennedy, Aamer Mahmud
Journal: Journal of Clinical Oncology (2018)

e18858 Background: A follow up program for patients with stages II or III colorectal cancer (CRC) after treatment completion was initiated in 2014 at the Cancer Centre of South Eastern Ontario (CCSEO). Stable patients with no disease or treatment related issues and not participating in a clinical trial were discharged to their primary care providers (PCP). This study was conducted to assess if surveillance tests were completed according to guidelines. Methods: Research ethics board approval was obtained and 282 patients were identified as new referrals to CCSEO between April 1, 2014 and June 30, 2016 with stage II or III CRC. In a chart review 125 were excluded due to treatment elsewhere, repeat charts, patient’s refusal, or death. These 157 patients were identified as eligible for discharge to PCP. In addition, 64 patients were identified from the department quality assurance (QA) process. These patients completed treatment prior to April 2014 but were discharged according to the new protocol. In total 221 patients were included who were either eligible or were discharged to PCP. The dates of 1 year endoscopy, computed tomography (CT) scan, and Carcinoembryonic Antigen (CEA) tests were determined after a chart review. Results: Overall, 83.3% of eligible patients were discharged to PCP, and by December 31, 2017 99.0% had completed endoscopy, 84.1% CT scan, and 63.2% CEA tests. This study identified 59 patients discharged to PCP who were not included in the department QA process. There was some variation in practice as one oncologist preferred continuing follow up at CCSEO. While being followed at CCSEO 4 patients were lost to follow up. Fifteen patients developed recurrent or metastatic disease and were repatriated to CCSEO. Conclusions: A well follow up program for select CRC patients conducted by PCPs is feasible and has the benefit of decreasing wait times for new patients. However, a carefully designed QA component of this program is essential. About 32% of discharged patients were not identified in the department QA process. Earlier detection of oligometastatic disease or recurrence has curative potential. To identify issues related to process feedback from patients, PCPs, specialists, as well as a periodic review, is recommended.
A phase III trial (ZJBIO009): CMAB009 plus irinotecan versus irinotecan alone as second-line treatment after fluoropyrimidine and oxaliplatin failure in wild-type <i>K-ras</i> metastatic colorectal cancer patients.
Authors: Yuankai Shi, Jin Li, Jianming Xu, Ying Cheng, Wei Liu, Yigui Cheng, Li Bai, Yiping Zhang, Xiaohui He, Yi Luo, Yunpeng Liu, Qiang Yao, Yuhong Li, Shukui Qin, Xiaohua HU, Yajun Guo, Yan Sun
Journal: Journal of Clinical Oncology (2017)

3513 Background: More efficient second line treatment regimen for mCRC is urgently needed. CMAB009, a recombinant human/mouse chimeric monoclonal antibody, is specifically targeting human epidermal growth factor receptor. This study aimed to determine clinical efficacy and safety of CMAB009 plus irinotecan compared with irinotecan alone in wild-type K-ras mCRC patients (pts). Methods: This is a open-label, randomized, phase 3 trial. Patients had histologically confirmed wild-type K-ras mCRC, who previous failure of 5-fuorouracil plus oxaliplatin more than 1 month of the last-dose enrolled in study. Pts were randomly assigned on a 2:1 to receive CMAB009 (initial 400mg/m 2 on day 1, and then 250 mg/m 2 weekly) plus irinotecan (180mg/m 2 , every 2 weeks) (A arm) or irinotecan alone (B arm). B arm pts could switch to CMAB009 sequential treatment (C arm) on diseas progression. The primary end point was overall response rate (ORR). The secondary endpoints were PFS, OS, DCR, and DOR (NCT01550055). Results: From May 2009 to December 2012, 512 pts were assigned from 38 sites. Efficacy evaluation could be in 501 pts, ORR were 33.2% (112/337) and 12.8% (21/164) in A arm and B arm ( p &lt;0.0001). C arm had 115 pts, DCR was 63.5% (73/115). DOR in A arm and B arm were 210 days and 109 days ( p=0.001). In C arm, DOR was 148 days . Median PFS was significantly longer in A arm than B arm (169 days vs 95 days; p &lt; 0.0001). In C arm, median PFS was 84 days. Median OS was 425 days in A arm and 401 days in B arm ( p=0.94). 96.2% (484/503) pts experienced at least one adverse event (AE). 55.3%(187/338) and 37.6%(62/165) patients in A arm and B arm had at least one grade ≥3 AE respectively. The most common AE included diarrhea, emesis, leucopenia, neutropenia and fatigue. Adding CMAB009 to irinotecan increased the risk of rash (66.6% vs 5.5%, p &lt;0.001) and paronychia (9.8% vs 0,p &lt; 0.001). Conclusions: CMAB009 plus irinotecan significantly increased ORR and prolonged PFS compared with irinotecan alone. CMAB009 plus Irinotecan were efficient and well tolerated, which could be considered as a standard second-line treatment choice in wild-type K-ras mCRC pts. Clinical trial information: NCT01550055.