tbuckley/cabot-search huggingface dataset:
Plasma cell-free circulating tumor DNA (ctDNA) detection in longitudinally followed glioblastoma patients using <i>TERT</i> promoter mutation-specific droplet digital PCR assays.
Authors: Christine Cordova, Mahrukh M. Syeda, Broderick Corless, Jennifer M. Wiggins, Amie Patel, Sylvia Christine Kurz, Malcolm Delara, Zacharia Sawaged, Minerva Utate, Dimitris Placantonakis, John Golfinos, Jessica Schafrick, Joshua Seth Silverman, Rajan Jain, Matija Snuderl, David Zagzag, Yongzhao Shao, George Alan Karlin-Neumann, David Polsky, Andrew S. Chi
Journal: Journal of Clinical Oncology (2019)

2026 Background: There is a critical need for more specific and less invasive diagnostic and pharmacodynamic biomarkers in glioblastoma (GBM) patients (pts). Previously, we detected TERT promoter hotspot mutations (C228T and C250T) in the ctDNA of IDH wildtype ( IDHwt) TERT promoter mutant GBM pts with 100% specificity using mutation-specific droplet digital PCR (ddPCR) assays. Here, we explored the dynamics and clinical associations of mutant TERT ctDNA levels in GBM pts undergoing therapy. Methods: We examined 14 pts with suspected IDHwt GBM based on preoperative MRI. Plasma was isolated and frozen from ~15 mL whole blood samples collected pre- and post-op, at end of radiation (RT), and 1, 3, and 6 m after end of RT. TERT promoter mutations were identified in FFPE tumor samples using ddPCR assays for C228T/C250T. Plasma samples were analyzed using ddPCR assays specific for the corresponding tumor mutation. The validated thresholds for positive detection were 1.5 (C228T) and 1.7 copies/mL (C250T). Results: 13/14 (92.9%) IDHwt tumors had TERT mutations (7 C228T and 6 C250T). Six of these 13 (46%) pts had positive plasma TERT ctDNA preop (4 C228T, 2 C250T). The mean cross sectional area of enhancing disease at presentation for positive or negative preop mutant ctDNA was similar. All 4 pts with multiple contrast enhancing lesions had positive preop mutant ctDNA. 2 pts who were negative initially developed detectable mutant ctDNA preceding progression. 3/4 pts with equivocal radiographic pseudoprogression had ctDNA dynamics that correlated with eventual clinical outcome. One patient with unresectable GBM had declining mutant ctDNA in later collections during clinical stability. Conclusions: We detected plasma TERT ctDNA in 46% of TERT mutant GBM pts before surgery, and in 100% of pts with multiple contrast enhancing lesions. TERT mutant ctDNA levels correlated with pseudoprogression or true disease progression and predicted progression before MRI. These data suggest that larger studies to test circulating cell-free TERT mutation as a diagnostic and pharmacodynamic biomarker in GBM are warranted.
AB0230B STUDY OF CELIAC DISEASE ANTIBODIES IN PATIENTS WITH JUVENILE ONSET RHEUMATOLOGICAL DISORDERS
Authors: Eman Hassan, Nermen Magdy
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Preclinical autoimmunity can be detected in the form of circulating autoantibodies in the peripheral blood many years preceding the onset of the clinical disease. Celiac disease (CD) is an immunological response to gluten in genetically susceptible people. The clinical presentation of CD includes abdominal pain, diarrhea and nutritional deficiencies. However; clinical symptoms could be misleading in most of the patients presenting subclinical forms with only minor gastroenterological symptoms. Celiac disease will present in older children by atypical presentation. Most celiac disease patients show atypical symptoms and may remain undiagnosed; which makes screening is mandatory in high-risk patients with autoimmune diseases. This collectively highlights the need to check for clinical evidence of celiac disease among patients diagnosed as juvenile onset rheumatic diseases <h3>Objectives</h3> The aim of the work is to screen for celiac disease antibodies (anti-tissue transglutaminase IgA and IgG auto-antibodies) in the serum of juvenile onset rheumatic diseases patients in comparison with normal subjects <h3>Methods</h3> Serum tTG (both IgA and IgG) level was detected in 60 juvenile onset rheumatic patients and 20 age and sex matched healthy controls. We also assessed different clinical and laboratory markers of disease parameters; 31 juvenile onset systemic lupus erythematosus (SLE), 21 juvenile onset idiopathic arthritis (JIA), 4 juvenile onset systemic sclerosis and 2 juvenile onset behcet’s disease and each disease activity score. We also correlated serum transglutaminase auto-antibodies with each disease activity. Endoscopic examination and histopathologic examination, for the patients with a least one positive anti-tTG Ab was done <h3>Results</h3> Serum anti-tTG Abs was no statistical significant differences in the patients group than in the control group, and there was no correlation between anti-tTG Abs with positive disease activity score <h3>Conclusion</h3> The presence of concomitant CD and another rheumatic disorder in the same patient is unlikely <h3>References</h3> [1] Roth B. Transglutaminase and peptidylarginine deiminase in the pathogenesis of autoimmune diseases. Doctorial Dissertation series. Sweden, Lund: Media-Tryck2008. [2] Vojdani A. Antibodies as predictors of complex autoimmune diseases and cancer. International Journal of Immunopathology and Pharmacology. 2008; 21(3):553–566. <h3>Disclosure of Interests</h3> None declared
Effect of right censoring bias on survival analysis.
Authors: Enrique Barrajon, Laura Barrajon
Journal: Journal of Clinical Oncology (2019)

e18188 Background: Survival Kaplan-Meier analysis represents the most objective measure of treatment efficacy in oncology, though subjected to potential bias which is worrisome in an era of precision medicine. Independent of the bias inherent to the design of clinical trials, bias may be the result of patient censoring, or incomplete observation. Unlike disease/progression free survival, overall survival is based on a well defined time point and thus avoids interval censoring, but it is our claim that right censoring, due to incomplete follow-up, may still be a source of bias. Methods: The R version 3.5.1 language and the integrated development environment RStudio were used for simulations and survival analysis with the survival package and their available datasets . Survival time was simulated according to a Weibull model with 2 parameters, shape and scale, that determine the event time for every case. Three types of right censoring mechanisms are considered and analyzed independently: 1) case censoring, in which a random number of cases are censored, and the resulting survival time is shortened by a random amount, 2) time censoring, in which a random censoring time variable is applied if and only if it is shorter than the event time, and 3) interim censoring, where a random time variable determines the case inclusion time since the start of trial, and a fixed cutt-off time determines if every case is censored (if the cutt-off time is shorter the the inclusion time plus the event time) or not. For every censoring mechanism, 100 trials was simulated with a 1000 uncensored cases arm and 1000 censored cases arm, in such a way that a censoring Cox hazard ratio (cHR) may be estimated for every trial. An interactive app showing the right censoring effect is presented. Results: A bias index (BI) was buit based on the survival time of event and censored cases. Case censoring was associated with higher BI (mean = 1.75, SD = 0.29) than time censoring (mean = 1.15, SD = 0.19, p = 2.02e-30) and interim censoring (mean = 0.72, SD = 0.21, p = 3.46e-34). It was found an inverse relationship between the censoring proportion and the cHR in case censoring (r = -0.86). Of all the available datasets, the Veterans' Administration Lung Cancer study showed a bias of 1.83, suggesting case censoring bias in both treatment arms. Conclusions: Based in the results of this study it is suggested that: 1) Final results should include all the events in the defined period of interest, 2) a bias index may help in detecting potential bias and correct estimated survival. Censoring bias analysis is planned in recent clinical trials.
Landscape of innate and adaptive immunity targets in oesophagogastric adenocarcinoma (OGA).
Authors: Elizabeth Catherine Smyth, Constanza Linossi, Sriganesh Jammula, Ginny Devonshire, Rebecca C. Fitzgerald
Journal: Journal of Clinical Oncology (2019)

4063 Background: Anti-PD-1 therapy modestly improves survival in chemorefractory OGA. Combining PD-1 blockade with novel checkpoint inhibitors, T-cell co-stimulatory molecules, or myeloid suppressors could enhance PD-1 inhibition. Herein, we explore the landscape of known targetable immune markers in non-Asian OGA. Methods: OGA patient biopsies were prospectively collected and clinically annotated from 19 UK cancer centres (Oesophageal Cancer Clinical and Molecular Stratification – OCCAMs network). Genomic (WGS) and transcriptomic (bulk-RNA seq) data were generated using Illumina and processed using a validated in-house pipeline (Frankell, Nat Genetics 2019). Gene expression was computed in transcripts per kilobase. Using unsupervised clustering patient clusters were selected according to the expression of gene targets for immune therapy - PD-L1, LAG3, TIM3, TIGIT, ICOS, CCR2, CCR5, CXCR4, and CSF1R. Immune cell infiltration was extrapolated using GSVA gene set enrichment analysis. Results: RNAseq data were available for 251 patients; 96% had operable tumours (Stage I: 6%, II: 63%, III: 22%, IV: 4%). In untreated patients (n = 156) 3 subgroups were identified: immune low (83, 53%) with low level expression of all 9 markers, immune high (14, 9%) with high expression of all or majority of markers and intermediate (59, 38%) with heterogenous marker expression. Clinicopathological variables (sex, age, smoking, tumour location (gastric/GEJ/esophagus) and tumour regression grade) were similarly distributed across subgroups. In a cohort of 114 patients with matched WGS and RNAseq data tumour mutation burden was not different between subgroups. In post-chemotherapy biopsies (n = 95) a similar co-expression pattern was observed. Gene enrichment analysis supported infiltration by cells of innate and adaptive immune system in immune high patients. Neoantigen results, phenotypic immunohistochemistry and optimised survival outcomes according to lymphoid and myeloid target expression will be presented. Conclusions: High level co-expression of immune regulatory targets in OGA patients may limit the efficacy of anti-PD-1 monotherapy. Combination immune directed therapies may be required in this patient group.
IRX-2 therapy with PD-L1 blockade in immunocompetent animal model.
Authors: Lu Wen, Gregory T. Wolf, Monil Shah, David B. Page, Lynn Sadowski-Mason, Mark Prince, Jeffrey Moyer, Alfred E. Chang, Qiao Li
Journal: Journal of Clinical Oncology (2019)

e14149 Background: Multiple therapeutic components in IRX-2 including IL-2, IL-1, IFN-γ, TNFα, IL-6, GM-CSF, and IL-8 work synergistically to activate various immune cells including T cells, dendritic cells, and natural killer cells to recognize and kill tumors. Previous Phase 1 and Phase 2a clinical trials in head and neck cancer with IRX-2 have shown a benign safety profile. Immunologically stimulating host immunity using IRX-2, while simultaneously blocking PD-1/PD-L1-mediated immune suppression, may have the potential to enhance the outcome of current immunotherapy using IRX-2 alone. Methods: Healthy C3H mice were inoculated with SCC7 murine head and neck cancer cells. Fourteen days after inoculation, the tumor-bearing mice were treated with subcutaneous injection of IRX-2 once a week for 3 weeks, followed with anti-mPD-L1(i.p.) injection after each IRX-2 administration. Tumor size and survival were monitored for the therapeutic efficacy evaluation. Two weeks after the last IRX-2 administration, all mice were sacrificed and spleen, blood and residual tumor samples were harvested for immune function assays. Results: High levels of PD-L1 were expressed on SCC7 cell line and fresh tumors. The FCM data suggested that PD-L1 was preferentially expressed on the ALDH high SCC7 cancer stem cells. IRX-2 alone significantly inhibited SCC7 tumor growth, and the anti-tumor efficacy of IRX-2 was significantly enhanced by anti-mPD-L1 injection in a dose dependent manner in the immunocompetent hosts. Serum IgG from animals subjected to IRX-2 plus anti-mPD-L1 treatment mediated significantly (p &lt; 0.05) higher cytotoxicity on SCC7 cells via ADCC than the IgG from animals treated with IRX-2 alone. CD8 + lymphocytes isolated from purified, activated and expanded CD3 + splenic T cells harvested from the animals subjected to IRX-2+anti-mPD-L1 treatment mediated significantly (p &lt; 0.05) higher cytotoxicity than those subjected to IRX-2 or anti-PD-L1 mono-therapy against SCC7 tumor cells. Conclusions: Co-administration of IRX-2 and anti-PD-L1 promoted more powerful antitumor immunity with both B cell and T cell modulation. The combination treatment increased the specific IgG production that could kill tumor cells via ADCC, and enhanced the T cell CTL activity. Therefore, IRX-2 therapy plus anti-PD-L1 administration may represent a promising novel strategy to treat cancer patients.
<sup>18</sup>F-alfatide PET may predict anti-angiogenic drugs toxicity.
Authors: Jie Liu, Xue Meng, Jinming Yu
Journal: Journal of Clinical Oncology (2019)

e14608 Background: Identifying predictive markers for toxicity could decrease the number of patients experiencing dose-limiting toxicity. The study aims to investigate whether 18 F-Alfatide positron emission tomography (PET) can predict the antiangiogenic drugs toxicity. Methods: A549 xenografted mice underwent 18 F-Alfatide PET at baseline when tumor volume reached 100-200 mm 3 and after treatment with apatinib (100mg/kg once daily), bevacizumab (20mg/kg every four days), endostar (20mg/kg once daily) or vehicle. Tumor growth and body weight were monitored every two days. The changed rate of tumor volume (TV) and organ uptake (OU) after therapy were calculated using the formula: [mean value(negative control) – each value(experimental)]/mean value(negative control)×100%, and [each value(experimental) – mean value(negative control)]/mean value(negative control)×100% for pathological injury degree of organs (PID) after therapy. We compared the antiangiogenic response and organs PID among three groups. Then, linear correlation was analyzed between mean OU and mean TV or mean PID, and between organ uptakes before treatment and PIDs in all model group. Results: TVs treated by endostar was lower than that of bevacizumab, both of which were lower than that of apatinib (mean IR±SD: endostar (13.56±11.78)%, bevacizumab (37.19±12.50)% and apatinib (48.43±8.71)%, respectively, P &gt; 0.05 for the three groups, but P &lt; 0.05 for the comparison of endastar and apatinib groups). The same is true for the PIDs (mean PID±SD for livers: endostar (32.58±11.81) %, bevacizumab (36.12±11.01)% and apatinib (41.12±9.99)%, P &gt; 0.05; mean PID±SD for kidneys: endostar (39.54±4.80)%, bevacizumab (43.24±5.46)% and apatinib (52.90±8.75)%, P &gt; 0.05). There was an excellent linear relationship between mean OU and mean PID (Liver: R 2 = 0.93, P &gt; 0.05 for OU SUVmean ; R 2 = 0.80, P &gt; 0.05 for OU SUVmax ; Kidney: R 2 = 0.85, P &gt; 0.05 for OU SUVmean ; R 2 = 0.97, P &gt; 0.05 for OU SUVmax ) and an excellent linear relationship between mean OU and mean IR (Liver: R 2 = 0.99, P &lt; 0.05 for OU SUVmean ; R2 = 0.97, P &gt; 0.05 for OU SUVmax ; Kidney: R 2 = 0.99, P &lt; 0.05 for OU SUVmean ; R 2 = 0.93, P &gt; 0.05 for OU SUVmax ). There was a significantly moderate linear association between the uptakes of organs prior to treatment and the PIDs (Liver: R 2 = 0.49, P &lt; 0.001 for OU SUVmean ; R 2 = 0.45, P &lt; 0.001 for OU SUVmax ; Kidney: R 2 = 0.57, P &lt; 0.0001 for OU SUVmean ; R 2 = 0.53, P &lt; 0.001 for OU SUVmax ). Conclusions: 18 F-Alfatide PET may be a useful molecular imaging tool for individual selection with toxicity before antiangiogenic therapy.
FDA analysis of outcomes in Asian patients (pts) with metastatic non-small cell lung cancer (mNSCLC) receiving immune checkpoint inhibitors (ICI).
Authors: Elaine Chang, Yutao Gong, Jonathon Joseph Vallejo, QI LIU, Luckson Noe Mathieu, Brian Booth, Rajeshwari Sridhara, Julia A. Beaver, Richard Pazdur, Gideon Michael Blumenthal
Journal: Journal of Clinical Oncology (2019)

e20690 Background: Asian pts tend to be well-represented in mNSCLC clinical trials, and drug development in Asia is growing. We sought to investigate outcomes of Asian pts enrolled in clinical trials testing ICI in mNSCLC. Methods: We identified 11 ICI mNSCLC randomized trials submitted to FDA 2014-2018. We divided the trials into 3 groups: 1 st -line monotherapy (1L-M), 1 st -line combination with chemotherapy [chemo] (1L-C), and 2 nd -line monotherapy (2L-M). Overall survival (OS) and progression-free survival (PFS) were evaluated with Kaplan-Meier methodology. We performed meta-analyses to assess if treatment effect is consistent across Asian and non-Asian populations. Results: There were 3399 patients enrolled in five 2L-M trials, 1579 in two 1L-M trials, and 2500 in four 1L-C trials. Most Asian pts were located geographically in Asia (90%). Asians comprised 15% of patients enrolled in 2L-M trials, 27% in 1L-M, and 11% in 1L-C. Compared to non-Asians, a higher proportion of Asians were never-smokers (32% vs. 13%) and EGFR-mutated (13% vs. 4%). Asian pts had better unadjusted and adjusted OS than non-Asian pts for each treatment in each line of therapy. The 3 covariates with greatest prognostic impact on OS in 2L-M were race, performance status, and histology. The magnitude of ICI treatment effect relative to chemo was similar for Asian and non-Asian pts. Conclusions: Asians appear to have better prognosis than non-Asians; no uniquely better or worse benefit was observed from ICI when compared to chemotherapy. [Table: see text]
A framework for building a clinically relevant risk model.
Authors: Robert Michael Daly, Dmitriy Gorenshteyn, Lior Gazit, Stefania Sokolowski, Kevin Nicholas, Claire Perry, Lynn Adams, Abigail Baldwin, Jessie C. Holland, Alice Zervoudakis, Han Xiao, Rori Salvaggio, Yeneat O. Chiu, Lauren L. Katzen, Margarita Rozenshteyn, Diane Lauren Reidy, Brett A Simon, Wendy Perchick, Isaac Wagner
Journal: Journal of Clinical Oncology (2019)

6554 Background: Acute care accounts for half of cancer expenditures and is a measure of poor quality care. Identifying patients at high risk for emergency department (ED) visits enables institutions to target resources to those most likely to benefit. Risk stratification models developed to date have not been meaningfully employed in oncology, and there is a need for clinically relevant models to improve patient care. Methods: We established and applied a predictive framework for clinical use with attention to modeling technique, clinician feedback, and application metrics. The model employs electronic health record data from initial visit to first antineoplastic administration for patients at our institution from January 2014 to June 2017. The binary dependent variable is occurrence of an ED visit within the first 6 months of treatment. The final regularized multivariable logistic regression model was chosen based on clinical and statistical significance. In order to accommodate for the needs to the program, parameter selection and model calibration were optimized to suit the positive predictive value of the top 25% of observations as ranked by model-determined risk. Results: There are 5,752 antineoplastic administration starts in our training set, and 1,457 in our test set. The positive predictive value of this model for the top 25% riskiest new start antineoplastic patients is 0.53. From over 1,400 data features, the model was refined to include 400 clinically relevant ones spanning demographics, pathology, clinician notes, labs, medications, and psychosocial information. At the patient level, specific features determining risk are surfaced in a web application, RiskExplorer, to enable clinician review of individual patient risk. This physician facing application provides the individual risk score for the patient as well as their quartile of risk when compared to the population of new start antineoplastic patients. For the top quartile of patients, the risk for an ED visit within the first 6 months of treatment is greater than or equal to 49%. Conclusions: We have constructed a framework to build a clinically relevant risk model. We are now piloting it to identify those likely to benefit from a home-based, digital symptom management intervention.
Gender differences in relative survival among patients with primary peritoneal carcinoma.
Authors: Aneesha Ananthula, Rangaswamy Govindarajan, Rohan Sharma
Journal: Journal of Clinical Oncology (2019)

e13092 Background: Primary peritoneal cancer(PPC) is a very rare aggressive cancer and is usually diagnosed late due to which it is generally portrays a poor prognosis. There are very few retrospective studies with limited knowledge about PPC. NCCN treatment guidelines for PPC is the same as that of ovarian cancer. Methods: We used 18 registries from Surveillance, Epidemiology, and End Results database to identify 6570 patients with Primary peritoneal carcinoma from 2000 to 2012 with follow up period upto 2015. Actuarial method was used to calculate 1 and 3 year Relative Survival (RS). Covariates included age, sex, race and grade. Results: PPC occurs more commonly in women with about 93% of the cases documented in women and about 88% of those documented in white women as per this database. The 1-year and 3-year RS for white women was 77.7% and 46% versus 69.6% and 54.1% for white males respectively. Males with grade I and grade II cancers had a better 3-year RS of 88.1% and 64.6%, in comparison with females with 77.3% and 55% respectively. Females with grade III and Grade IV cancers had a better 3 -year survival of 47.9% and 49% versus males who has a RS of only 35.3% and 39%. RS was significantly better in patients &lt; 60 years with 3-year RS rate of 60.9% versus 36.4% for patients &gt; 70 years. 3-year RS rates at during 2000-04, 2005-09 and 2010-14 were similar with 43.8%, 48.7% and 48.5% respectively. Conclusions: PPC is treated in a similar manner to epithelial ovarian carcinoma given some of its similarities in biological and pathological behavior. The cause of primary peritoneal cancer in unknown and there are only few studies done due to paucity of cases. Over the years survival seems to have not changed significantly and we need more clinical trials to identify the best course of treatment. [Table: see text][Table: see text][Table: see text][Table: see text]