tbuckley/cabot-search huggingface dataset:
Immune checkpoint inhibitors (ICIs) in gastrointestinal (GI) cancer: Immune-related adverse events (IRAEs) and efficacy.
Authors: Satya Das, Kristen Keon Ciombor, Sigurdis Haraldsdottir, Yoanna S Pumpalova, Ibrahim Halil Sahin, Yu Shyr, Shih-Kai Chu, Emily Pei-Ying Lin, Chih-Yuan Hsu, Laura Williams Goff, Dana Backlund Cardin, Mehmet Asim Bilen, Jordan Berlin, Christina Wu
Journal: Journal of Clinical Oncology (2019)

4116 Background: Despite the therapeutic promise of ICIs for patients (pts) with some advanced malignancies, they are FDA-approved for only a few GI cancer pts. In NSCLC, melanoma and urothelial carcinoma, there is emerging data that pts who experience IRAEs while on ICIs have improved outcomes compared with pts who do not. This association in GI cancer pts has not been reported. Methods: We retrospectively analyzed outcomes for metastatic GI cancer pts receiving ICIs for FDA-approved indications (later-line MSI-H tumors, 2 nd line hepatocellular carcinoma (HCC), 3 rd line PD-L1+ gastric (GA)/gastroesophageal junction (GEJ) adenocarcinoma), at Vanderbilt Ingram Cancer Center, Winship Cancer Institute and Stanford Cancer Institute. Our primary aim was to compare progression-free survival (PFS) and overall survival (OS) between pts who did and did not experience IRAEs. Secondary aims were comparison of these outcomes within pts who experienced IRAEs, by initial IRAE severity (Grade (G)3/G4 vs G1/G2) (CTCAE v5.0), time-to-onset (TTO) (≤ 6 weeks (w) vs &gt; 6 w) and management (steroids vs drug cessation vs observation). PFS and OS were determined by Kaplan-Meier (KM) analysis; KM comparisons were done by the logrank test. Results: Between 1/2015-12/2018 61 GI cancer pts with HCC (28), colorectal cancer (27) and GA/GEJ cancer (6) were treated with ICIs; median age was 63 years. The majority (59) received single-agent nivolumab or pembrolizumab while minority (2) received nivolumab and ipilimumab; median time on ICIs was 5.9 months (mos). Twenty-four pts experienced initial IRAEs (6 G3/G4, 18 G1/G2); median TTO was 3.8 mos. Pts who experienced any IRAE had improvements in PFS and OS compared to those who did not (PFS: 32.4 mos (95% confidence interval (CI), 32.4-not reached (NR)) vs 4.8 mos (95% CI, 2.9-8.7), p = 0.0001; OS: 32.4 mos (95% CI, 32.4-NR) vs 8.5 mos (95% CI, 6-NR), p = 0.0036). Among pts who experienced IRAEs, PFS and OS differences between above-specified subgroups did not meet statistical significance. Conclusions: GI cancer pts who experienced IRAEs while on ICIs had marked improvements in PFS and OS compared to those who did not, suggesting the predictive potential for IRAEs as a clinical biomarker in this population.
Abstract 11181: Effects of Rosuvastatin and Atorvastatin on Macrophage Reverse Cholesterol Transport in Vivo
Authors: Tomohiko Shimizu, Hiroyuki Tanigawa, Shin-ichiro Miura, Yoshinari Uehara, Bo Zhang, Keijiro Saku
Journal: Circulation (2011)

Clinical trials have consistently shown that statin reduces the incidence of cardiovascular events. While statins significantly decrease LDL-C, it is controversial whether they increase HDL-C and i...
Dabrafenib and trametinib in patients with tumors with BRAF V600E/K mutations: Results from the molecular analysis for therapy choice (MATCH) Arm H.
Authors: April K.S. Salama, Shuli Li, Erin Renee Macrae, Jong-In Park, Edith P. Mitchell, James A. Zwiebel, Helen X. Chen, Robert James Gray, Lisa McShane, Lawrence Rubinstein, David Patton, Paul M. Williams, Stanley R. Hamilton, Deborah Kay Armstrong, Barbara A. Conley, Carlos L. Arteaga, Lyndsay Harris, Peter J. O'Dwyer, Alice P. Chen, Keith Flaherty
Journal: Journal of Clinical Oncology (2019)

3002 Background: The NCI-MATCH precision medicine trial assigns patients (pts) with solid tumors, lymphomas, or multiple myeloma with progression on prior treatment to a targeted therapy based on genetic alterations identified in pre-treatment biopsies. Arm H (EAY131-H) evaluated the combination of the BRAF inhibitor (inh) dabrafenib (DAB), and the MEK inh, trametinib (TRM), in pts with BRAF V600E/K mutations. Methods: Pts with melanoma, thyroid, or colorectal cancer were excluded. Pts with NSCLC were excluded after the U.S. Food and Drug Administration (FDA) approved DAB/TRM for this indication. Pts received DAB 150 mg po BID and TRM 2 mg PO daily on 28 day cycles until disease progression or intolerable toxicity; restaging was performed every 2 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Results: A total of 35 pts were enrolled from 1/2016-2/2018; 2 were ineligible (CrCl below criteria; labs out of window). Over 17 distinct tumor histologies were represented. 58% of pts were female, median age was 63 (range 21-85), 94% were Caucasian, and 48% of pts had received at least 3 prior therapies (range 1- 8). The confirmed ORR was 33.3% (90% CI 19.9%, 49.1%), with a median duration of response (DoR) of 12 months (mon). Varied histologies had a DoR of &gt; 12 mon: histiocytic sarcoma, cholangiocarcinoma and mixed adenoneuroendocrine carcinoma of unknown primary, among others. Median PFS was 9.4 mon; the 6 mon PFS rate was 70.6% (90% CI 58.2%-85.5%), and an additional 10 pts had a PFS &gt; 5.5 mon. Median OS has not been reached. At the time of data cutoff (12/2018) 11 pts continue on treatment. Adverse events (AE) were comparable to previously reported profiles of DAB/TRM; no new AEs were identified. The most frequent grade 3 AEs were fatigue, neutropenia, hyponatremia, hypophosphatemia, and urinary tract infection; there was 1 grade 4 sepsis; no grade 5 AEs. Conclusions: In this pre-treated, mixed histology cohort, DAB and TRM showed promising activity outside of currently approved FDA indications warranting further investigations. Correlative analyses are planned. Clinical trial information: NCT02465060.
Biomarkers of resistance to cetuximab in head and neck squamous cell carcinoma (HNSCC).
Authors: Ekaterina I. Surikova, Oleg I. Kit, Irina V. Neskubina, Elena M. Frantsiyants, Liubov Yu Vladimirova, Aza A. Lyanova, Marina A. Engibaryan, Elena V. Shalashnaya, Irina V. Aedinova, Yulia V. Ulianova, Viktoriya L. Volkova, Irina Viktorovna Pustovaya, Maria Ezhova
Journal: Journal of Clinical Oncology (2019)

e17523 Background: Treatment of advanced HNSCC (T3 and T4) involves the use of anti-EGFR monoclonal antibodies targeting the EGF-EGFR and VEGF-VEGFR cascades responsible for the cell proliferation, differentiation, invasion, metastasis, angiogenesis and apoptosis. The purpose of the study was the search for biomarkers of resistance to cetuximab in HNSCC patients. Methods: Tumor biopsy was performed in patients with HNSCC (n = 40) (Т3-4N0-1M0) before and after two cycles of chemotherapy with cetuximab - 400 mg/m2 administered on day 1 and 250 mg/m2 per week, cisplatin 100 mg/m2 on day 1, fluorouracil 1000 mg/m2 - 96-hour continuous infusion. Patients were divided into group 1 (progression, n = 11) and group 2 (stabilization and partial remission, n = 29). Levels of VEGF-A (pg/mL) (BenderMedSystem, Austria) and TGF-β (pg/mL) (eBioscience, USA) were determined in biopsy samples by ELISA, and the VEGF-A/TGF-β ratio was calculated. Statistical analysis of the results was performed using the Statistica 10.0 program with M±m determination. Differences were considered significant at p &lt; 0.05. Results: Before treatment, levels of VEGF-A in biopsy samples were 634.8±37.2, TGF-β – 1092.5±71.9, and VEGF-A/TGF-β – 0.58±0.03. After 2 cycles of chemotherapy with cetuximab, results in group 1 for VEGF-A were 680.3±41.2, TGF-β – 1773.7±111.4, and VEGF-A/TGF-β – 0.384±0.021; in group 2: VEGF-A – 487.7±26.1, TGF-β – 572.3±34.7, and VEGF-A/TGF-β – 0.85±0.043. Thus, after 2 cycles of chemotherapy with cetuximab, TGF-β in group 1 increased by 1.6 times and VEGF-A/TGF-β – by 1.5 times (p &lt; 0.05). In group 2, VEGF-A decreased by 1.3 times, TGF-β by 1.9 times, and VEGF-A/TGF-β increased by 1.46 times (p &lt; 0.05). Conclusions: Decreased levels of markers and increased VEGF-A/TGF-β can predict cetuximab efficacy. Increased TGF-β and reduced VEGF-A/TGF-β allow predicting resistance to chemotherapy with cetuximab.
Risk assessment of hepatocellular carcinoma development for indeterminate hepatic nodules in patients with chronic hepatitis B
Authors: Haneulsaem Shin, Yeon Woo Jung, Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han, Yeun-Yoon Kim, Jin-Young Choi, Seung Up Kim
Journal: Clinical and Molecular Hepatology (2019)

A risk prediction model for the development of hepatocellular carcinoma (HCC) from indeterminate nodules detected on computed tomography (CT) (RadCT score) in patients with chronic hepatitis B (CHB)-related cirrhosis was proposed. We validated this model for indeterminate nodules on magnetic resonance imaging (MRI).Between 2013 and 2016, Liver Imaging Reporting and Data System (LI-RADS) 2/3 nodules on MRI were detected in 99 patients with CHB. The RadCT score was calculated.The median age of the 72 male and 27 female subjects was 58 years. HCC history and liver cirrhosis were found in 47 (47.5%) and 44 (44.4%) patients, respectively. The median RadCT score was 112. The patients with HCC (n=41, 41.4%) showed significantly higher RadCT scores than those without (median, 119 vs. 107; P=0.013); the Chinese university-HCC and risk estimation for HCC in CHB (REACH-B) scores were similar (both P>0.05). Arterial enhancement, T2 hyperintensity, and diffusion restriction on MRI were not significantly different in the univariate analysis (all P>0.05); only the RadCT score significantly predicted HCC (hazard ratio [HR]=1.018; P=0.007). Multivariate analysis showed HCC history was the only independent HCC predictor (HR=2.374; P=0.012). When the subjects were stratified into three risk groups based on the RadCT score (<60, 60-105, and >105), the cumulative HCC incidence was not significantly different among them (all P>0.05, log-rank test).HCC history, but not RadCT score, predicted CHB-related HCC development from LI-RADS 2/3 nodules. New risk models optimized for MRI-defined indeterminate nodules are required.
Object Vision in a Structured World
Authors: Daniel Kaiser, Genevieve L. Quek, Radoslaw M. Cichy, Marius V. Peelen
Journal: Trends in Cognitive Sciences (2019)

In natural vision, objects appear at typical locations, both with respect to visual space (e.g., an airplane in the upper part of a scene) and other objects (e.g., a lamp above a table). Recent studies have shown that object vision is strongly adapted to such positional regularities. In this review we synthesize these developments, highlighting that adaptations to positional regularities facilitate object detection and recognition, and sharpen the representations of objects in visual cortex. These effects are pervasive across various types of high-level content. We posit that adaptations to real-world structure collectively support optimal usage of limited cortical processing resources. Taking positional regularities into account will thus be essential for understanding efficient object vision in the real world.
Development and analytical validation of a 523-gene clinical assay for cell-free DNA.
Authors: Robin Harrington, Biswajit Das, Tingting Jiang, Jennifer S. LoCoco, Rajesh Patidar, Amanda Peach, Chen Zhao, Corinne Camalier, Ting-Chia Chang, Alice P. Chen, Li Chen, Thomas Forbes, Sigrid Katz, Nikitha Nair, David J. Sims, Geraldine Helen O'Sullivan Coyne, Naoko Takebe, Paul M. Williams, Chris Alan Karlovich, James H. Doroshow
Journal: Journal of Clinical Oncology (2019)

3039 Background: Liquid biopsies are emerging as a powerful complement to tumor biopsies for the clinical management of cancer patients. A large gene panel with robust analytical performance that accurately assesses variants, tumor mutational burden (TMB), and microsatellite instability in plasma would be of high value for immunotherapy studies, monitoring minimal residual disease and early cancer detection. To this end, we have completed the initial validation for the cell-free DNA (cfDNA) assay, TruSight Oncology 500 (TSO500), which interrogates the full coding region of 523 genes plus selected intronic regions for fusion detection in 23 driver genes. Methods: Cell-free DNA was extracted from plasma collected from Streck or EDTA blood tubes and quantitated to achieve an assay input of ≥10 ng. Libraries were constructed using unique molecular identifiers (UMIs) and duplex barcodes for error correction, then enriched by target capture and sequenced on a NovaSeq 6000. Healthy donor (HD) specificity assessment used matched white blood cell results to filter germline and clonal hematopoiesis variants. Contrived specimens were used to evaluate sensitivity. Single nucleotide variants (SNVs) (n = 36), insertion/deletions (indels) (n = 19), copy number variants (CNVs) (n = 6), and fusions (n = 5) were tested in 2 multi-site replicates. Results: Sensitivity of detection at 0.5% variant allele fraction (VAF) was &gt; 95% and &gt; 97% for SNVs and indels, respectively. All expected CNVs were identified at the targeted threshold of ≥1.3X change and showed strong correlation with matched digital PCR results. All fusions were identified at ≥0.4% VAF. Specificity in HD was &gt; 99.99%. In 22 temporally matched tumor and blood samples from late-stage patients, 58% of all reportable mutations in tumor were identified in cfDNA. Preliminary TMB analysis identified one TMB high case with POLE p.P286R observed in both tissue and cfDNA. Conclusions: In this initial validation study the TSO500 cfDNA assay exhibited high sensitivity and specificity consistent with requirements for clinical applications. Ongoing studies will further evaluate TSO500 as a complement or potential alternative to tissue biopsy for the genomic profiling of cancer patients.
In-depth gene expression analysis of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with ribociclib-containing therapy in the Phase III MONALEESA-7 trial.
Authors: Yen-Shen Lu, Sara A. Hurvitz, Fei Su, Wei He, Debu Tripathy, Saul Campos Gomez, Kyung Hae Jung, Marco Colleoni, Paul Wheatley-Price, Sherko Kuemmel, Nadia Harbeck, Fabio Andre Franke, Seock-Ah Im, Louis Chow, Tetiana Taran, Karen Rodriguez-Lorenc, Naveen Babbar, Aditya Bardia
Journal: Journal of Clinical Oncology (2019)

1018 Background: The Phase III MONALEESA-7 study (NCT02278120) is the first dedicated trial of endocrine therapy (ET) ± a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in premenopausal patients (pts) with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) ABC. The study demonstrated that the addition of ribociclib (RIB) to a nonsteroidal aromatase inhibitor (NSAI) or tamoxifen (TAM) + goserelin (GOS) significantly extended progression-free survival (PFS; hazard ratio [HR] 0.55; Tripathy D, et al. Lancet Oncol. 2018). Here we present a gene expression analysis of baseline tumor mRNA from MONALEESA-7. Methods: Premenopausal pts with HR+/HER2− ABC were treated with RIB or placebo (PBO) + GOS with either an NSAI (letrozole or anastrozole) or TAM. Baseline archival tumor samples from 360 of 672 intent-to-treat (ITT) pts were evaluated for gene expression (RIB n = 185; PBO n = 175) using a customized NanoString nCounter ® GX 800-gene panel containing relevant breast cancer, CDK, and proliferation pathway–related genes. Pt subgroups were classified as having low or high mRNA expression using median expression as the cutoff. Results: PFS benefit in the biomarker-assessed group was similar to that in the ITT population. A trend toward a more pronounced PFS benefit with RIB was observed in pts with high vs low expression of CCND1 (HR 0.38 vs 0.67, respectively), IGF1R (HR 0.33 vs 0.77), and ERBB3 (HR 0.33 vs 0.76). The PFS benefit seen with RIB also trended to be greater in pts with low vs high expression of CCNE1 (HR 0.38 vs 0.65, respectively) and MYC (HR 0.37 vs 0.69). The PFS benefit with RIB was similar in pts with high vs low expression of FGFR1 (HR 0.45 vs 0.61, respectively), ESR1 (HR 0.57 vs 0.57), and tumor proliferation genes, such as MKI67 (HR 0.50 vs 0.51). Conclusions: This is the first gene expression analysis of a large set of premenopausal pts with ABC. The benefit with RIB was generally consistent across gene expression subgroups, although the magnitude varied in certain subsets. This analysis suggests that there may be unique resistance mechanisms to ET ± CDK4/6 inhibitors in premenopausal pts with ABC. Clinical trial information: NCT02278120.
EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with temozolomide-based radiochemotherapy versus temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma.
Authors: Patrick Roth, Thierry Gorlia, Jaap C. Reijneveld, Filip Yves Francine Leon De Vos, Ahmed Idbaih, Jean-Sebastien Frenel, Emilie Le Rhun, José Manuel Sepulveda Sánchez, James R. Perry, Laura Masucci, Pierre Freres, Hal W. Hirte, Clemens Seidel, Anna Maria Elisabeth Walenkamp, Frederic Dhermain, Martin J. Van Den Bent, Christopher J. O'Callaghan, Maureen Vanlancker, Warren P. Mason, Michael Weller
Journal: Journal of Clinical Oncology (2021)

2004 Background: Patients with newly diagnosed glioblastoma receive postoperative standard therapy with radiotherapy (RT), and concomitant and up to six cycles of maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Marizomib is a novel, irreversible and brain-penetrant pan-proteasome inhibitor with encouraging findings in preclinical models and early-stage clinical trials for patients with newly diagnosed and recurrent glioblastoma. Therefore, a phase 3 trial was designed to explore the activity of marizomib in addition to TMZ/RT→TMZ. ClinicalTrials.gov Identifier: NCT03345095 Methods: EORTC 1709/CCTG CE.8 is a multicenter, randomized, controlled, open label phase 3 superiority trial. Eligibility criteria included histologically confirmed newly diagnosed glioblastoma and a Karnofsky performance status (KPS) &gt; 70. Eligible patients were stratified for institution, age, KPS as well as extent of surgery, and centrally randomized in a 1:1 ratio. The primary objective of this study is to compare overall survival (OS) in patients receiving marizomib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include progression-free survival (PFS), safety, neurocognitive function, and quality of life. Results: The study was opened at 49 EORTC sites in Europe, 23 CCTG sites in Canada, and 8 sites in the US. Patient enrolment started in June 2018 and was close to completion at the time of a planned interim analysis in September 2020. A total of 749 patients (of the planned 750) were randomized when the IDMC recommended to discontinue enrollment. Age, KPS and extent of resection were well balanced between the 2 study arms. No difference in median OS was observed between the standard arm (15.9 months) and the marizomib arm (15.7 months; HR = 0.99). Median PFS was 6.1 vs. 6.2 months (HR = 1.02). Patients in the marizomib group had more often grade 3/4 treatment-emergent adverse events (TEAE) compared to the standard therapy group (42.6% vs. 20.5%), including ataxia, hallucinations and headache. Conclusions: The addition of marizomib to standard radiochemotherapy did not improve OS or PFS in patients with newly diagnosed glioblastoma. Final survival analyses including determination of MGMT promoter methylation status and analyses of other secondary endpoints are ongoing. Clinical trial information: NCT03345095.
A phase II open labeled, randomized study of poly-ICLC matured dendritic cells for NY-ESO-1 and Mean-A peptide vaccination compared to Montanide, in melanoma patients in complete clinical remission.
Authors: Anna C. Pavlick, Ana Blazquez, Marcia Meseck, Michael J. Donovan, Mireia Castillo-Martin, Tin Htwe Thin, Rachel Sabado, John P. Mandeli, Sacha Gnjatic, Philip Adam Friedlander, Nina Bhardwaj
Journal: Journal of Clinical Oncology (2019)

9538 Background: Dendritic cells (DC) play a critical role in tumor immune-surveillance. Combination therapies by utilizing check point inhibitors may revert tumor-induced-T cell exhaustion; however, DCs are necessary to prime/activate T cells to target tumor cells. Montanide is a mineral oil-based adjuvant that enhances the immune response to vaccination. In this study, we compared the immunogenicity of Montanide and poly-ICLC-matured DCs. Methods: This is a Phase II open label, randomized two arm study to compare Poly-ICLC matured DC with systemic administration of Poly-ICLC on days 1 and 2 (ARM A) to Montanide ISA-51 and Poly-ICLC as adjuvants for NY-ESO-1 and Melan-A/MART-1 peptide vaccination with systemic administration of Poly-ICLC on day 2 (ARM B) in study subjects with melanoma in complete clinical remission but at high risk of disease recurrence (NCT02334735). Evaluation of primary tumor expression of NY-ESO-1 and Melan-A tumor was determined by immunohistochemistry (IHC). Humoral responses were assessed by Seromics (ELISA) and T-cell responses were performed ex-vivo by interferon (IFN)-g enzyme-linked immunospot assay (ELISPOT) and after expansion by intracellular cytokine staining (ICS). Results: Twenty-nine patients have been enrolled in this study. IHC studies demonstrated tumor expression of NY-ESO-1 and Melan-A in 78% and 81% of the patients, respectively. 100% of patients within arm B became seropositive for NY-ESO-1 peptide by cycle 2 day 8 (C2D8). 80% of patients within arm A also seroconverted to this antigen but titers were significantly lower. Melan-A-specific antibody responses were also found in arm B patients, but to a lesser degree. However, arm A patients failed to develop seroreactivity to Melan-A. Cellular responses are under analysis. Preliminary data show that subjects in both arms develop T cell responses to both antigens. Conclusions: This vaccine trial reached the primary endpoint of safety and tolerability. Patients vaccinated with either DC or Montanide had demonstrable antibody titers to immunizing antigens, although the latter reproducibly induced higher titers. Evaluation of cellular responses is ongoing. Clinical trial information: NCT02334735.