tbuckley/cabot-search huggingface dataset:
Antigen (Ag) spread after sipuleucel-T and correlation with overall survival (OS): A real-world experience.
Authors: William R. Berry, Christopher Michael Pieczonka, Nicholas J. Vogelzang, Lawrence Ivan Karsh, James L. Bailen, Krista Van Velzen, Harini Kandadi, Nadeem Anwar Sheikh, Shaker R. Dakhil
Journal: Journal of Clinical Oncology (2019)

e16504 Background: Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In IMPACT (NCT00065442), a phase 3 trial, sipuleucel-T-induced immune responses against target Ag prostatic acid phosphatase (PAP) or PA2024, a recombinant protein consisting of PAP and granulocyte macrophage colony stimulating factor, correlated with OS (Sheikh 2013). Additionally, sipuleucel-T-induced immunoglobulin G (IgG) responses against secondary, non-target Ag (i.e. Ag spread) and the breadth of Ag spread also correlated with improved OS (GuhaThakurta 2015). Here we assessed Ag spread and OS in real-world patients from PRIME (NCT01727154), an immune monitoring sub-study of sipuleucel-T trials Methods: IgG levels in pre and wk 6 (2 wk post sipuleucel-T completion) sera from PRIME (n = 100) were quantified using Luminex xMAP. IgG responses to secondary Ag (LGALS3, PSA, KLK2, LGALS8, K-Ras, E-Ras) were defined as ≥ 1.5-fold increase over baseline. OS associations with individual Ag responses and total number of Ag per patient were assessed using the Kaplan-Meier method. Hazard ratios (HR) were estimated using a Cox Proportional Hazard Model. Results: IgG responses to ≥1 secondary Ag were observed in ≥72% of patients. Individual IgG responses to LGALS3, K-Ras, and LGALS8 at wk 6 were significantly associated with OS. Furthermore, breadth of Ag spread positively correlated with OS (Table); as the total number of Ag responses per patient increased, OS improved compared to patients with no secondary IgG responses. Conclusions: The results presented are consistent with findings from the prior phase 3 trial IMPACT. Secondary Ag responses were generated in real-world patients treated with sipuleucel-T, and these responses correlated with OS. Furthermore, breadth of Ag spread also correlated with improved OS. Clinical trial information: NCT01727154. [Table: see text]
Urokinase secretion by gastrointestinal adenocarcinoma.
Authors: Larisa S. Kozlova, Oleg I. Kit, Elena M. Frantsiyants, Yuriy A. Gevorkyan, Andrey A. Maslov, Elena A. Dzhenkova, Nikolay S. Samoylenko, V. I. Aleynov, Maksim N. Duritskiy
Journal: Journal of Clinical Oncology (2019)

e15529 Background: The serine protease urokinase plasminogen activator (uPA) plays an important role in growth and invasion of malignant tumors. The purpose of the study was a comparative analysis of uPA activity (uPA-act) and its antigen (uPA-Ag) content in adenocarcinoma (A) of the esophagus (EA), stomach (SA), pancreatic head (PHA), sigmoid colon (SCA) and rectum (RA). Methods: Tissues of A, perifocal tissues (PT) and resection line tissues were studied by ELISA in 144 patients (39-73 years) with EA (n = 12, G2, T 2-3 N 0-1 M 0 ), SA (n = 28, G2, T 2-3 N 0-1 M 0 ), PHA (n = 46, G2, Т 2-4 N 0 M 0 ), SCA (n = 31, G2, T 2-3 N 0-1 M 0 ) and RA (n = 26, G2,T 2-3 N 0-1 M 0 ). Statistical analysis was performed using the Statistica 10 program. Results: The levels of uPA-Ag in gastrointestinal A decreased from SA to PHA: SA˃RA˃SCA˃EA˃PHA (p &lt; 0.01). The uPA-Ag levels in A were higher than in the resection line in all cases (p &lt; 0.01). PT levels of uPA-Ag decreased from SA to PHA: SA˃SCA˃RA˃EA˃PHA (p &lt; 0.01). In EA and PHA, PT levels of uPA-Ag were lower than in resection line tissues (p &lt; 0.01), while in SA, SCA and RA they were higher (p &lt; 0.01). Levels of uPA-act were similar in SA and SCA, while in EA and RA they were 1.2 (p = 0.4324) and 1.3 (p = 0.4012) times lower, and in PHA – 40.0-52.5 times lower (p &lt; 0.01) compared to all A samples. The uPA-act in PT was the highest in SCA; 1.4 times lower in SA and RA; 1.7 times lower in EA; 30.9 times lower in PHA. The levels in PT were higher than in the resection line in all cases (p &lt; 0.01). The resection line tissues in EA showed the maximal uPA-Ag content, while their uPA-act was similar to that in other tumors. Levels of uPA-Ag and uPA-act in resection line tissues in other tumors varied but were comparable. Estimated uPA-Ag/uPA-act coefficients in the resection line in SCA and RA were 20.4 and 29.5, respectively; in EA and PHA – 102.0 and 34.8, respectively. Conclusions: Adenocarcinomas of the esophagus, stomach, pancreatic head, sigmoid colon and rectum secrete uPA-Ag and uPA-act into surrounding tissues. The rate of uPA-Ag secretion by the tumor and its activation into uPA-act in pancreatic head cancer differ from that in other tumors.
MDNA55: A locally administered IL4 guided toxin as a targeted treatment for recurrent glioblastoma.
Authors: Dina Randazzo, Achal Achrol, Manish K. Aghi, Martin Bexon, Steven Brem, Andrew Jacob Brenner, Nicholas A. Butowski, Chandtip Chandhasin, Sajeel A. Chowdhary, Melissa Coello, John Floyd, Santosh Kesari, Fahar Merchant, Nina Merchant, Michael A. Vogelbaum, Frank D Vrionis, Miroslaw Zabek, John H. Sampson
Journal: Journal of Clinical Oncology (2019)

2039 Background: IL4 receptor (IL4R) is frequently and intensely expressed on a variety of human cancers and is associated with poor survival outcomes. Determining the role of the IL4R biomarker in glioblastoma (GBM) will be important for treatment with targeted therapies such as the IL4 fusion toxin MDNA55. Methods: A classification for IL4Rα expression in GBM tissues by H-Score was developed using a validated immunohistochemistry-based approach. MDNA55-05 is an open-label study of MDNA55 administered intratumorally via convection enhanced delivery in recurrent GBM. Levels of IL4Rα expression were assessed retrospectively in 24 subjects in the clinical trial and were correlated with GBM history, imaging responses and survival outcomes following treatment with MDNA55 to explore clinical validation. Results: Range, linearity, specificity and sensitivity testing using a rabbit polyclonal antibody to IL4Rα were performed using normal cortex (negative control) and a panel of normal human tissues and GBM cases from tissue banks. A total of 41 GBM samples were screened and grouped by reactivity thresholds: H-Scores ≥50 were observed in 95% of cases (39/41), H-Scores ≥200 were observed in 51% of cases (21/41), and H-Scores ≥250 were observed in 24% of cases (10/41). GBM tissues obtained at initial diagnosis from subjects enrolled in the trial show that moderate/high IL4R expression (H-Score &gt; 75) was associated with shorter time to first relapse when compared to subjects with low IL4R expression (H-Score ≤ 75) (10.3 mos vs. 16.7 mos, respectively) after upfront standard-of-care treatment, consistent with published findings that IL4R expression is associated with more aggressive disease. Remarkable decreases in tumor size seen in some subjects following MDNA55 treatment were associated only with moderate/high IL4R expression and survival rate at 12 months in this group was also improved (OS12 = 55%) compared to subjects with low IL4R expression (OS12 = 30%). Conclusions: Treatment options for patients with recurrent GBM are very limited and positive outcomes remain rare. Targeting therapies such as MDNA55 by IL4R status may improve patient outcomes and help guide patient selection strategies for future clinical studies. Clinical trial information: NCT02858895.
Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab.
Authors: Ken Masuda, Hirokazu Shoji, Kengo Nagashima, Shun Yamamoto, Masashi Ishikawa, Hiroshi Imazeki, Masahiko Aoki, Takahiro Miyamoto, Hidekazu Hirano, Yoshitaka Honma, Satoru Iwasa, Natsuko Okita, Atsuo Takashima, Ken Kato, Narikazu Boku
Journal: Journal of Clinical Oncology (2019)

4049 Background: Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with clinical benefit in patients with melanoma or lung cancer. In advanced gastric cancer (AGC) patients, there have been few reports about the correlation between irAEs and efficacy of immune checkpoint inhibitors. Therefore, in this study, we retrospectively investigated the correlation between irAEs and efficacy in AGC patients treated with nivolumab. Methods: The subjects of this study were AGC patients that had received nivolumab monotherapy between January 2015 and August 2018. IrAEs were defined as those AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy and/or endocrine therapy. We divided the patients who received nivolumab into two groups based on occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group). We assessed the efficacy in both groups. Results: Of the 65 AGC patients that received nivolumab monotherapy, 14 developed irAEs. The median time to onset of irAEs was 30.5 days (range 3–407 days). Median follow-up period for survivors was 32 months (95% CI, 10.8 to 34.5). The median progression-free survival was 7.5 months (95% CI, 3.6 to 11.5) in the irAE group and 1.4 months (95% CI, 1.2 to 1.6) in the non-irAE group (HR = 0.11, p &lt; 0.001). The median overall survival was 16.8 months (95% CI, 4.4 to not reached) in the irAE group and 3.2 months (95% CI, 2.2 to 4.1) in the non-irAE group (HR = 0.17, p &lt; 0.001). Multivariate analysis demonstrated that high ALP level (HR = 2.88; 95% CI, 1.51 to 5.51) and absence of irAEs (HR = 3.06, 95% CI, 3.06 to 23.46 for yes vs. no) were associated with a poor prognosis. The most frequent irAEs was diarrhea/colitis (n = 5). Grade 3 adverse events were observed in 6 patients; hyperglycemia (n = 2), diarrhea/colitis (n = 1), adrenal insufficiency (n = 1), increased aspartate aminotransferase increased (n = 1), peripheral motor neuropathy (n = 1). One of the 14 patients experienced the irAE after discontinuation of nivolumab due to progression of disease. There were no grade 4 or 5 adverse events related to nivolumab. Conclusions: Development of irAEs was associated with clinical benefit for AGC patients receiving nivolumab monotherapy.
Imaging biomarker phenotyping system (iBiopsy) to accelerate hepatocellular carcinoma (HCC) drug development.
Authors: Yan Liu, Corinne Ramos, Pierre Baudot, Johan Brag, Olivier Lucidarme
Journal: Journal of Clinical Oncology (2019)

e15671 Background: Current drug therapies in HCC remain limited because of substantial genomic, cellular and molecular heterogeneity of the liver tumor microenvironment (TME). This heterogeneity has implications for tumor development, immune response and cellular invasion and is compounded by multiple molecular pathways related to the various HCC etiologies. In this context, it is challenging to find biomarkers that are predictive of therapeutic response or outcome. A systems biology approach leveraging the iBiopsy phenotyping platform to automatically detect HCC and TME subtypes using non-invasive medical imaging could help identify specific disease pathways and accelerate HCC drug development. Methods: In this retrospective study, 50 patients with primary HCC were used to extract voxel level image signatures from the segmented livers on CT scans. The automatic classification of liver signatures was obtained by Log Linear Local density peak clustering computed using Wasserstein’s optimal transport distance between Gray Level Co-occurrence matrices of local luminance tiles of the Liver. Through this hypothesis-free clustering, phenotypes representative of tumor and tumor environment were identified and further correlated with clinical data. Results: Nine classes of statistically significantly distant clusters were identified on the 50 patients. Preliminary correlation analysis on individual patient showed that up to 3 clusters were specific to the tumor and characterized phenotype heterogeneity within the tumor. Notably, specific clusters at the tumor front-line and surrounding adjacent non-tumoral tissue were also identified. Conclusions: Preliminary results show that a multiplicity of phenotypes representative of a complex heterogeneous lesion and tissue microenvironment that might have prognostic and predictive value can be identified. This support the use of a non-invasive phenotypic approach for the subtyping of HCC that can be used for the identification of a multiplicity of important biological pathways that can be specifically targeted to treat HCC.
AB1046 PHYSICAL ACTIVITY ASSESSMENT IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS COMPARED TO CONTROLS
Authors: Alia Fazaa, Meriem Sellami, Saousen Miladi, Kmar Ouenniche, Leila Souabni, Selma Kassab, Selma Chekili, Leith Zakraoui, Kawther Ben Abdelghani, Ahmed Laatar
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Physical activity (PA), known to maintain optimal metabolic function and normal development could be impaired during Juvenile Idiopathic Arthritis (JIA). <h3>Objectives</h3> The aim of our study was to assess PA in children and adolescents with JIA compared to healthy peers using the physical activity questionnaire for children (cPAQ) and adolescents (aPAQ). <h3>Methods</h3> This is a cross-sectional study of measured level of PA in children and adolescents with JIA, compared to age and gender-matched healthy Tunisian schoolchildren. PA was estimated by cPAQ and aPAQ filled by the patient group and the reference group. If the child is unable or unsure to answer the questions we have helped with the parents' response. The PAQ scores 2 as "low activity," &gt;2 and ≤ 3 as "moderate activity," and &gt;3 as "high to vigorous activity". <h3>Results</h3> A total of 55 patients (38 boys and 17 girls) with JIA and 60 healthy control schoolchildren were included. No significant difference in demographic background was found between the two groups. The mean age was 8.5 ± 4.12 years in the JIA group and 9.2 ± 3.51 years in the control group. Thirty-one patients (53%) had persistant oligoarticular JIA, 15 (27%) had polyarticular JIA, 5 patients (9%) had systemic JIA, and 4 (7%) had enthesitis-related arthritis. The median disease duration was 3.2 ± 2.8 years. The mean cPAQ was 2.101 ± 0.722 in the JIA group and 4.112 ± 0.644 in the control group (p=0.0001). Children and adolescents with JIA had a significantly lower levels of PA compared with their healthy peers as assessed by cPAQ/aPAQ (p=0.012). The time spent in each cPAQ/aPAQ item was significantly lower in the JIA group compared to the healthy group: sports activities (3.4 ± 0.5 versus 4.7 ± 1.4 hours/week, p=0.002), leisure time activities (2.2 ± 0.3 versus 6.2 ±1.3 hours/week, p=0.001), activities at school (1.1 ± 0.3 versus 2.1 ± 0.5 hours/week, p=0.001), and after school activities (0.5 ± 0.5 versus 2.5 ± 0.8 hours/week, p=0.001). Seventy six percent of the JIA group spent the day on the two lowest PA categories: sleeping and sitting, which was significantly higher compared with the reference group (p=0.001 and p=0.055, respectively). <h3>Conclusion</h3> In our study, children and adolescents with JIA were less physically active than the healthy peers as assessed by the PAQ. More objective methods are needed to better evaluate and quantify the PA. <h3>Disclosure of Interests</h3> None declared
Real-world practice patterns and impact of PD-L1 expression testing in patients with advanced non-small cell lung cancer.
Authors: Michael Leapman, Carolyn J Presley, Weiwei Zhu, Pamela R. Soulos, Kerin B. Adelson, Daniel J. Boffa, Cary Philip Gross
Journal: Journal of Clinical Oncology (2019)

9059 Background: Several tests measuring programmed cell death ligand 1 (PD-L1) expression are available to select patients with advanced non-small cell lung cancer (aNSCLC) for PD-1 axis therapy including FDA approved companion diagnostics (CoDx), as well as complementary (CyDx) and laboratory developed tests (LDTs). However, it is unknown how rapidly PD-L1 expression testing has become adopted, which type of tests are used, or whether testing affects first-line therapy. Methods: We retrospectively reviewed the Flatiron Health electronic health record-derived database, reflecting real-world care at community oncology practices in the U.S. We evaluated trends in the use of PD-L1 expression testing within 12 months of diagnosis. Among patients diagnosed after FDA approval of PD-L1 testing prior to first-line therapy (Oct 2016), and without other identifiable driver mutations, we used multivariable logistic regression to examine the association between PD-L1 testing and receipt of first-line PD-1 axis therapy. We further examined the association between PD-L1 expression result (using overall reported status or % staining) and choice of first-line therapy. Results: We identified 49,546 patients with aNSCLC from 2011 through the third quarter of 2018. The use of PD-L1 expression testing increased from 7.0% in 2015 to 70.6% in 2017 (p &lt; 0.01). Among those receiving testing, the proportion of patients receiving CoDx increased from 29.9% in 2015 to 73.0% in 2017 with corresponding reductions in CyDx and LDTs. PD-L1 expression testing was associated with use of PD1-axis therapy in the first-line (OR = 2.92, 95% CI 2.59-3.30). Among 4,942 treated patients diagnosed after Oct 2016, those with ≥50% staining more frequently received first line PD-1 axis therapy (82.9%) than those with intermediate (35.5%) or low (25.8%) positive staining; conversely, patients with ≥50% were less likely to receive chemotherapy alone or combination with PD-1 axis therapy. Conclusions: PD-L1 expression testing was rapidly adopted following FDA approval of companion diagnostic testing for aNSCLC. Although the results of PD-L1 expression testing inform the choice of first-line therapy, a substantial proportion of patients are not tested prior to first line treatment.
Clinical and prognostic implications of sarcopenia in patients affected by locally advanced NSCLC.
Authors: Sabrina Rossi, Luca Disconzi, Luca Toschi, Giovanna Finocchiaro, Laura Giordano, Ezio Lanza, Romano Fabio Lutman, Armando Santoro
Journal: Journal of Clinical Oncology (2019)

e20046 Background: Sarcopenia is a loss of skeletal muscle mass that has been studied as prognostic factor in several cancers. Retrospective studies have suggested that sarcopenia is associated with poorer survival outcomes and with an increase of major chemotherapy toxicities resulting in dose reduction and delay. This study examined the value of sarcopenia in patients with stage III non-small cell lung cancer (NSCLC). Methods: This retrospective analysis includes 68 patients affected by stage III NSCLC treated with induction chemotherapy followed by surgery or radical radiation therapy in our cancer center. Weight and height were obtained from medical records at diagnosis. Skeletal muscle index (SMI) was measured by the analysis of electronically stored computed tomography images obtained before the start of chemotherapy; sarcopenia was defined by international consensus as a SMI≤39 cm2/m2 for women and ≤55 cm2/m2 for men. Kaplan-Meier method and Log-Rank test were used to determine the impact of sarcopenia on overall survival (OS) and progression-free survival (PFS). Exact Fisher test and Chi-squared test were used to establish the association between the presence of sarcopenia and other variables. Results: A total of 68 patients (stage 3A = 39; stage 3B = 29) with performance status 0-1 and median age 67 yrs were analyzed. Forty-five patients (66%) were sarcopenic: 100% of underweight patients (BMI ≤18.5), 83% of patients with normal weight (BMI 18.5-24.9), 56% of overweight patients (BMI 25-29.9) and 30% of obese (BMI≥30). Sarcopenia was not associated with age≥70 yrs (p = 0.67), Charlson Comorbidity Index (p = 1.00), stage (p = 0.53), response rate to chemotherapy (p = 0.78) or toxicities of grade≥3 (p = 0.83). Median OS in sarcopenic patients was 18.2 months compared with 33.2 months in nonsarcopenic patients (p = 0.03); the difference in terms of PFS was not statistically significant (10.7 vs 14.9 months; p = 0.19). Conclusions: Sarcopenia is associated with shorter OS in patients with locally advanced NSCLC but it seems not related with worse response to induction chemotherapy or higher toxicities. These data should be validated in larger prospective clinical studies.
Immunotherapy predictive biomarkers in metastatic breast cancer (MBC).
Authors: Jeffrey S. Ross, Ethan Sokol, Lee A. Albacker, Garrett M. Frampton, Dean Pavlick, Julia Andrea Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Nhu Ngo, Douglas I. Lin, Shakti Ramkissoon, Eric Allan Severson, Siraj Mahamed Ali, Alexa Betzig Schrock, Jon Chung, Prasanth Reddy, Kimberly McGregor, Brian Alexander, Abirami Sivapiragasam, Vincent A. Miller
Journal: Journal of Clinical Oncology (2019)

1023 Background: We queried whether comprehensive genomic profiling (CGP) of mBC subtypes could identify biomarkers that have been linked to responsiveness to immunotherapy (IO) treatments. Methods: DNA was extracted from 3,871mBC: 1,388 ER+/HER2-, 1,969 HER2 amplified (amp) and 643 TNBC. CGP was performed using a hybrid-capture assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci in 564 cases. PD-L1 was determined by IHC (Dako 22C3). Results: Patient ages were similar. Genomic alterations (GA)/tumor were similar ranging from 5.9 to 7.3. MTOR pathway targets were common; lowest in TNBC. CDH1 and ESR1 GA most frequent in ER+/HER2- cases. ERBB2 short variant (SV) mut were most frequent in ER+/HER2- and HER2 amp and not seen in TNBC. Other kinase targets were uncommon except for FGFR1 GA in ER+/HER2-. BRCA1/ 2 GA least frequent in HER2 amp. AR was amplified in 1% of all mBC. Markers of potential IO benefit: CD274 ( PD-L1) amp (1-3%), BRAF GA (1-4%), TMB of ≥10 mut/Mb (8-12%), TMB of ≥20 mut/Mb (2-3%), MSI-High (0.1-0.4%), PBRM1 GA (1%) and low (1-10%) or high (0-3%) PD-L1 staining. Potential markers of resistance: inactivating GA in STK11 (1-2%) and MDM2 amplification (3-6%). Examples of mBC patients responding to IO therapies will be presented. Conclusions: In addition to guiding targeted therapy selection, CGP shows potential to identify GA linked to response and resistance to IO in mBC. The demonstrations of clinical benefit of immunotherapy in mBC supports the need for the development of biomarkers used to guide the use of ICPI drugs for these patients. [Table: see text]