tbuckley/cabot-search huggingface dataset:
A randomized phase II study with ilixadencel, a cell-based immune primer, plus sunitinib versus sunitinib alone in synchronous metastatic renal cell carcinoma.
Authors: Magnus Lindskog, Anna Laurell, Anders Kjellman, Bohuslav Melichar, Jacek Niezabitowski, Pablo Maroto, Henryk Zieliński, Felipe Villacampa, Pierre Bigot, Zoltan Bajory, Omi Parikh, David Vazquez Alba, Asa Jellvert, Tibor Flasko, Enrique Gallardo Diaz, Maria Jose Ribal, Gunta Purkalne, Peter Suenaert, Alex Karlsson-Parra, Borje Ljungberg
Journal: Journal of Clinical Oncology (2020)

11 Background: Ilixadencel is a cell-based allogeneic off-the-shelf product aimed to prime anti-cancer immune response when injected intratumorally. The present randomized Phase II multicenter trial (MERECA; NCT02432846) evaluated intratumoral ilixadencel administration (2 doses 2 weeks apart) pre-nephrectomy followed by sunitinib post-nephrectomy compared with sunitinib monotherapy post-nephrectomy as first-line systemic therapy in patients with newly diagnosed synchronous metastatic renal cell carcinoma (mRCC). Methods: Patients were randomly assigned at two-to-one ratio to the combination (COMBO) or sunitinib (SUN) arm. Overall survival (OS) was assessed from enrollment while progression free survival (PFS) and tumor response was assessed per RECIST 1.1 (independent blinded central review) from start of sunitinib. Results: From April 2014 to January 2017, 88 patients (58 COMBO, 30 SUN) were randomized. In the COMBO arm, 2 patients did not receive ilixadencel, 10 did not receive sunitinib, and 1 did not have any follow up CT-scan. Five patients in the SUN arm never received sunitinib. Five patients (11%) in the COMBO arm had a complete response as best response versus one patient (4%) in the SUN arm. Confirmed ORR was 42.2 % (19/45) versus 24.0% (6/25). Median Duration of Response was 7.1 months versus 2.9 months. Median PFS was 11.8 months versus 11.0 months. Median OS has still not been reached in either group. As of July 2019, 57% and 43% were alive in the COMBO and SUN arms, respectively. Treatment with ilixadencel did not add any treatment-related Grade 3-4 Adverse Events. Conclusions: Compared to sunitinib monotherapy, combined treatment with ilixadencel followed by sunitinib demonstrated higher confirmed ORR, including several complete responses and longer duration of response, in patients with newly diagnosed synchronous mRCC. Clinical trial information: 02432846.
LINE-1 hypo-methylation as a distinct phenotype in non-EBV/non-MSI-H esophagogastric junction adenocarcinoma.
Authors: Yu Imamura, Manabu Takamatsu, Norio Tanaka, Seiichi Mori, Eiji Oki, Masaru Morita, Hideo Baba, Takeshi Sano, Masayuki Watanabe
Journal: Journal of Clinical Oncology (2020)

411 Background: Most esophagogastric junction (EGJ) adenocarcinoma exhibits chromosomal instability (CIN) type with wide range of CpG site methylation. However, it is still uncertain if epigenetic alteration is clinically useful. LINE-1 methylation level is representative of genome-wide methylation status. The aim of this is to examine clinicopathological and molecular characteristics of LINE-1 methylation, and its prognostic role, in non-EBV/non-MSI-H EGJ adenocarcinoma. Methods: After removing EBV-associated or MSI-H tumors, which are the distinct molecular subtype with hyper methylation, a total 335 case of chemo-naïve non-EBV/non-MSI-H EGJ adenocarcinoma from four academic institutions in Japan, were eligible. LINE-1 methylation was examined by Pyrosequencing. Results: LINE-1 methylation level was successfully sequenced in 319 cases (92.5%). LINE-1 methylation level was associate with tumor differentiation. Intestinal type was frequently observed in the lowest quartile Q1 cases (P = 0.0006). Of note, TP53 mutation rate was significantly frequent in Q1-2 cases (P &lt; 0.0001). Ki-67 index was also higher in Q1-2 cases. Tumor PD-L1 expression, or CD8+ cell infiltration was not associated with LINE-1 methylation level. In survival analysis, the patients with the lowest LINE-1 methylation level (Q1), experienced the worst outcome in disease-specific survival, relapse-free survival, and overall survival rates. Conclusions: Tumor with LINE-1 hypomethylation harbors significantly higher TP53 mutation and higher Ki-67 index, resulting in worse outcome in EGJ adenocarcinoma patients.
Racial disparity of stage III rectal cancer among young adults: A combined NCDB/SEER analysis.
Authors: Thomas J. Quinn, Peyman Kabolizadeh
Journal: Journal of Clinical Oncology (2020)

85 Background: With the advent of screening colonoscopy in 1997, there has been an overall decreasing incidence in rectal cancer. Recently, the ACS updated guidelines to started screening patients at 45 years old. The purpose of this study was to further investigate incidence and overall survival trends for rectal cancer among young white and African-American (AA) patients using the SEER and NCDB databases. Methods: Rectal cancer incidence trends in SEER-9/SEER-18 were analyzed for patients &lt; 50 years old. Treatment and survival outcomes were also evaluated using the NCDB (2004-2014). White and AA patients were matched using propensity score analysis and inverse probability of treatment weighting (IPTW). Baseline characteristics were compared with Pearson Chi Square, before and after matching. Univariate and multivariable analyses were performed with Kaplan-Meier and Cox proportional hazard modeling, incorporating the IPTW-adjusted population. Results: 6,144 (SEER) and 17,819 (NCDB) young, white or AA patients were identified. There was an overall increase in incidence of stage III (APC 5.57, P &lt; 0.05) and IV (APC 4.66, P &lt; 0.05) rectal cancer among young white patients. For the entire population, there was improved overall survival for white patients compared to AA patients, even after adjusting for confounding factors. Subset analysis of both the SEER and NCDB databases revealed that the largest disparity was between AAn and white rectal cancer patients, is among the Stage III subset with HR of 1.6 (P &lt; 0.001) and HR of 1.4 (P &lt; 0.001), respectively. Conclusions: There is an alarming increase in younger patients being diagnosed with rectal cancer. Specifically, there appears to be more locally advanced rectal cancer among younger patients and a racial disparity favoring whites for survival outcomes was identified. This research further supports the utility of earlier screening and to identify the factors involved in this rise in rectal cancer incidence.
Noninvasive In Vivo Assessment of Cardiac Metabolism in the Healthy and Diabetic Human Heart Using Hyperpolarized <sup>13</sup> C MRI
Authors: Oliver J. Rider, Andrew Apps, Jack J.J.J. Miller, Justin Y.C. Lau, Andrew J.M. Lewis, Mark A. Peterzan, Michael S. Dodd, Angus Z. Lau, Claire Trumper, Ferdia A. Gallagher, James T. Grist, Kevin M. Brindle, Stefan Neubauer, Damian J. Tyler
Journal: Circulation Research (2020)

The recent development of hyperpolarized
Promise of autologous CD34+ stem/progenitor cell therapy for treatment of cardiovascular disease
Authors: Megha Prasad, Michel T Corban, Timothy D Henry, Allan B Dietz, Lilach O Lerman, Amir Lerman
Journal: Cardiovascular Research (2020)

Abstract CD34+ cells are haematopoietic stem cells used therapeutically in patients undergoing radiation or chemotherapy due to their regenerative potential and ability to restore the haematopoietic system. In animal models, CD34+ cells have been associated with therapeutic angiogenesis in response to ischaemia. Several trials have shown the potential safety and efficacy of CD34+ cell delivery in various cardiovascular diseases. Moreover, Phase III trials have now begun to explore the potential role of CD34+ cells in treatment of both myocardial and peripheral ischaemia. CD34+ cells have been shown to be safe and well-tolerated in the acute myocardial infarction (AMI), heart failure, and angina models. Several studies have suggested potential benefit of CD34+ cell therapy in patients with coronary microvascular disease as well. In this review, we will discuss the therapeutic potential of CD34+ cells, and describe the pertinent trials that have used autologous CD34+ cells in no-options refractory angina, AMI, and heart failure. Lastly, we will review the potential utility of autologous CD34+ cells in coronary endothelial and microvascular dysfunction.
The Innate Biologies of Adaptive Antigen Receptors
Authors: Adrian C. Hayday, Pierre Vantourout
Journal: Annual Review of Immunology (2020)

Nonclonal innate immune responses mediated by germ line-encoded receptors, such as Toll-like receptors or natural killer receptors, are commonly contrasted with diverse, clonotypic adaptive responses of lymphocyte antigen receptors generated by somatic recombination. However, the Variable (V) regions of antigen receptors include germ line-encoded motifs unaltered by somatic recombination, and theoretically available to mediate nonclonal, innate responses, that are independent of or largely override clonotypic responses. Recent evidence demonstrates that such responses exist, underpinning the associations of particular γδ T cell receptors (TCRs) with specific anatomical sites. Thus, TCRγδ can make innate and adaptive responses with distinct functional outcomes. Given that αβ T cells and B cells can also make nonclonal responses, we consider that innate responses of antigen receptor V-regions may be more widespread, for example, inducing states of preparedness from which adaptive clones are better selected. We likewise consider that potent, nonclonal T cell responses to microbial superantigens may reflect subversion of physiologic innate responses of TCRα/β chains.
Synchronous pulmonary and esophageal cancers: Is combined esophagectomy and anatomic lung resection appropriate?
Authors: Hedi Zhao, Ana-Maria Misariu, Jose Ramirez-Garcia Luna, Wayne Lewis Hofstetter, Daniela Molena, Amit Katz, Tamar B. Nobel, Carmen L. Mueller, Jonathan Cools-Lartigue, Jonathan Spicer, David S. Mulder, Lorenzo Ferri
Journal: Journal of Clinical Oncology (2020)

341 Background: Resection is the best treatment for both esophagus and lung cancer, however, concerns that a combined resection of synchronous lung/esophagus tumors might be associated with higher morbidity may preclude surgical therapy. We sought to review a multi-institutional experience on combined esophagus/lung cancer resections. Methods: Patients undergoing esophagectomy and those with concurrent anatomic resection for bronchogenic carcinoma between 1997-2018 at three high-volume North American centers were identified from prospectively collected databases. Combined resection cases (E+L) were matched in a 1:3 ratio to patients who underwent esophagectomy alone (E), based on age, sex, stage, neoadjuvant therapy, procedure (2/3hole), and approach (MIE/open). Patient demographics, tumour characteristics, and post-operative outcomes were compared. Statistical analysis was performed using unpaired t-test or Wilcoxon sum-rank test for continuous variables and Fisher’s exact test for categorical data. Statistical significance was defined as p &lt; 0.05. Results: Of over 2500 patients undergoing esophagectomy, synchronous anatomic lung resection was performed in 20; 4 were excluded due to incomplete data (n = 16). Matching yielded 48 patients and 4 duplicates were removed (n = 44); there were no significant differences in patient demographics, neoadjuvant therapy, clinical stage, or procedure. Anatomic resection consisted of lobectomy (16/20), segmentectomy (3/20) and pneumonectomy (1/20), combined with 2-hole (14/20), 3-hole (4/20), or left thoraco-abdominal (2/20) esophagectomy. The proportion of patients with any complication in E+L was 50%, and 66% in E (p = 0.42). Pulmonary complications were 19% and 27% in the respective groups (p = 0.74). Mortality did not differ (E+L = 0/16:E = 1/44)NS. The median length of stay for both groups was similar (E+L = 10.5 days(IQR 5.7): E = 10.0 days (IQR 8.7))NS. Conclusions: Patients with synchronous localized lung and esophageal cancer, although rare, should not be biased towards non-surgery therapy, as the morbidity associated with combined esophagectomy and anatomic lung resection does not differ significantly from esophagectomy alone.
How the matrix metalloproteinase MMP14 contributes to the progression of colorectal cancer
Authors: Lena Claesson-Welsh
Journal: Journal of Clinical Investigation (2020)

Certain matrix metalloproteinase (MMP) family proteins have been associated with cell proliferation and invasion in aggressive cancers. However, attempts to target the MMPs with the hope of treating tumors have thus far failed. In this issue of the JCI, Ragusa and coworkers identified an intestinal cancer subgroup of slow-growing, chemotherapy-resistant, and very aggressive matrix-rich tumors that mimic a hard-to-treat colorectal cancer subtype in humans. These tumors showed downregulated levels of the transcription factor prospero homeobox protein 1 (PROX1), which relieved repression of the matrix metalloproteinase MMP14. Upregulated MMP14 levels correlated with blood vessel dysfunction and a lack of cytotoxic T cells. Notably, blockade of proangiogenic factors in combination with stimulation of the CD40 pathway in the mouse cancer model boosted cytotoxic T cell infiltration. The study illustrates how combinatorial treatments for aggressive, T cell-deficient cancers can launch an antitumor immune response.
SOURCE: Prediction models for overall survival in patients with metastatic and potentially curable esophageal and gastric cancer.
Authors: Héctor G. van den Boorn, Ameen Abu-Hanna, Nadia Haj Mohammad, Maarten C.C.M. Hulshof, Suzanne S. Gisbertz, Bastiaan R. Klarenbeek, Marije Slingerland, Laurens Victor Beerepoot, Tom Rozema, Mirjam A.G. Sprangers, Rob H. A. Verhoeven, Aeilko H. Zwinderman, Martijn G.H. van Oijen, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2020)

301 Background: Prediction models in cancer care can provide personalized prediction outcomes and can aid in shared decision making. Existing prediction models for esophageal and gastric cancer (EGC), however, are mostly aimed at predicting survival after a curative treatment has already been completed. The aim of this study is to develop prediction models, called SOURCE, to predict overall survival at diagnosis in potentially curable and metastatic EGC patients. Methods: The data from 12,756 EGC patients diagnosed between 2014-2017 were retrieved from the prospective Netherlands Cancer Registry. Four Cox regression models were created for potentially curable and metastatic cancers of the esophagus and stomach. Predictors, including treatment type, were selected using the Akaike Information Criterion. The models were validated with temporal cross-validation on their concordance-index (c-index) and calibration. Results: The validated model’s c-index is 0.76 for potentially curable cancer. For the metastatic models, the c-indices are 0.71 and 0.70 for esophageal and gastric cancer, respectively. The calibration intercepts and slopes lie in the 95% confidence interval of 0 and 1, respectively. The included model variables are given in Table. Conclusions: The SOURCE prediction models show fair c-indices and an overall good calibration. The models are the first in EGC to include treatment as a predictor. The models predict survival at diagnosis for a variety of treatments and therefore could have a high clinical applicability. Future research is needed to demonstrate the effect on shared decision making in clinical practice. [Table: see text]
FIDES-01, a phase II study of derazantinib in patients with unresectable intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions and mutations or amplifications (M/A).
Authors: Milind M. Javle, Walid Labib Shaib, Stephan Braun, Marc Engelhardt, Mitesh J. Borad, Ghassan K. Abou-Alfa, Andrea Boncompagni, Silke Friedmann, Christoph Georg Gahlemann
Journal: Journal of Clinical Oncology (2020)

TPS597 Background: Deregulation of the FGFR signaling pathway is implicated in various cancers. In iCCA, FGFR genetic aberrations include FGFR2 fusions and, less commonly, FGFR2 M/A. iCCA prognosis is poor, and chemotherapeutic and targeted treatment options are limited. While FGFR2 fusions are acknowledged oncogenic drivers, the oncogenic potential of FGFR2 M/A is less well defined. Derazantinib (DZB) is an investigational, oral small-molecule kinase inhibitor with activity against FGFR1, 2 and 3, which demonstrated antitumor activity in patients with unresectable iCCA with FGFR2 fusions. Based on preliminary efficacy data demonstrating durable responses of &gt; 6 months and a clinically meaningful progression-free survival in a subset of iCCA patients harboring FGFR2 M/A (NCT01752920), the multicenter, multicohort open-label phase 2 study FIDES-01 is evaluating the effect of DZB in separate cohorts of iCCA patients with FGFR2 fusions or FGFR2 M/A. Methods: The new cohort evaluates 300 mg once daily dosing of DZB in patients with unresectable iCCA with FGFR2 M/A per liquid or tissue biopsy-based next generation sequencing and at least one previous systemic therapy. Treatment will continue until progressive disease, intolerance, withdrawal of informed consent, or death. Using a Simon’s two-stage design, the primary endpoint to assess the antitumor activity of DZB is the proportion of patients with PFS at 3 months (PFS3; per RECIST 1.1 central review). Secondary objectives are evaluation of median PFS, objective response rate, duration of response, safety profile, quality of life (incl., QLQ-C30, QLQ-BIL21, EQ-5D), and symptom response from baseline. Current status: The study was initiated in July 2019 with planned enrollment of 43 patients with confirmed FGFR2 M/A. Clinical trial information: NCT03230318.
A phase II, randomized, controlled trial of nivolumab in combination with BMS-986253 or cabiralizumab in advanced hepatocellular carcinoma (HCC) patients.
Authors: Theodore Welling, Nina Beri, Despina Siolas, Deirdre Jill Cohen, Daniel Jacob Becker, Hua Zhong, Jennifer J. Wu, Paul Eliezer Oberstein, Thomas Benjamin Karasic
Journal: Journal of Clinical Oncology (2020)

TPS598 Background: Tyrosine kinase inhibitors can prolong survival in advanced HCC patients, but response rates have been minimal. Recently, immune checkpoint inhibition with nivolumab (nivo) demonstrated objective response rates (ORR) of 15% (escalation phase) and 20% (expansion phase) in the Checkmate 040 study. Pre-clinical and translational studies have demonstrated that IL-8 and tumor associated macrophages (TAMs) contribute to HCC progression and recurrence following treatment. Therefore, rationale exists to evaluate combinatorial approaches to target TAM function combined with checkpoint inhibitory therapy. This phase II, randomized study will evaluate the safety and efficacy of combined anti-CSF1R (Cabiralizumab) or anti-IL-8 (BMS-986253) in combination with Nivo in advanced HCC. Methods: Advanced HCC patients without prior systemic treatment and disease measurable by RECISTv1.1 with Childs A liver function are eligible. Patients will be enrolled (n=25 per arm) to Nivo 240 mg IV Q2 weeks monotherapy, Nivo 240 mg IV + BMS-986253 1200 mg IV Q2 weeks, or Nivo 240 mg IV + Cabiralizumab 4 mg/kg IV Q2 weeks. Primary endpoints include safety and ORR determined by RECISTv1.1. Secondary endpoints include time to response, duration of response, progression free survival, and overall survival. Exploratory endpoints include analysis of tumor microenvironment immune and tumor cell profiling of pre- and on-treatment tumor tissue. Clinical trial information: NCT04050462.
Antibody blockade of semaphorin 4D to sensitize pancreatic cancer to immune checkpoint blockade.
Authors: Luis I. Ruffolo, Nicholas A. Ullman, Benjamin Dale, Katherine M. Jackson, Paul Burchard, Mary Georger, Rachel Jewell, Brian A. Belt, Eva Galka, Luke O. Schoeniger, Crystal L. Mallow, Elizabeth E. Evans, Terrence Lee Fisher, Maurice Zauderer, David Linehan
Journal: Journal of Clinical Oncology (2020)

26 Background: Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, and will soon become the second leading cause of cancer mortality. Unfortunately, T-cell directed immunotherapies have failed to demonstrate efficacy in PDAC. These failures may in part be mediated by an immunosuppressive tumor microenvironment (TME). Semaphorin 4D (Sema4D) is a glycoprotein which binds its cognate receptors Plexin B1/B2. Here we present our work in blocking Sema4D in a murine model of PDAC. Methods: C57b/6 mice were orthotopically injected with PDAC line (KP2) derived from KRAS G12D ,TP53 Flox/Wt ;P48-Cre autochthonous tumors and confirmed for disease by ultrasound. Mice were treated with FOLFIRINOX (5-FU, Irinotecan, Oxaliplatin, weekly), immune checkpoint blockade (ICB) (anti-PD1, anti-CTLA-4 mAbs bi-weekly), and anti-Sema4D mAB (bi-weekly). Human and mouse circulating and tumor infiltrating leukocytes were interrogated through flow cytometry (FACS) for immune subset and expression of Sema4D and Plexin receptors. Archived human PDAC tissues were assessed through quantitative immunohistochemistry (IHC) for presence of Sema4D positive infiltrate. Results: Both FACS and IHC analysis of human PDAC specimens confirm the presence and increased prevalence over normal pancreata of Sema4D lymphocytes and Plexin B1/B2 expressing tumor associated macrophages (TAMs). KP2 orthotopically injected mice exhibited longer survival when treated with the triple combination of FOLFIRINOX, ICB, and anti-Sema4D antibody, compared to FOLFIRINOX alone, FOLFIRINOX plus ICB, or FOLFIRINOX plus anti-Sema4D antibody (P &lt; 0.02). Flow cytometric analysis of anti-Sema4D and ICB treated murine tumors show a doubling of penetration by CD 8+ effector T cells within tumors compared to control groups (P = 0.03). A loss in Sema4D fluorescence signal via FACS in tumor-infiltrating CD3+ leukocytes was observed in mice treated with anti-SEMA4D, confirming penetration and target blockade within the TME. Conclusions: Sema4D and Plexin B1/B2 leukocytes penetrate human PDAC tumors, and treatment with Sema4D blocking antibody improved response to ICB in combination with standard of care FOLFIRINOX in preclinical murine studies.
scMAGeCK links genotypes with multiple phenotypes in single-cell CRISPR screens
Authors: Lin Yang, Yuqing Zhu, Hua Yu, Xiaolong Cheng, Sitong Chen, Yulan Chu, He Huang, Jin Zhang, Wei Li
Journal: Genome biology (2020)

Abstract We present scMAGeCK, a computational framework to identify genomic elements associated with multiple expression-based phenotypes in CRISPR/Cas9 functional screening that uses single-cell RNA-seq as readout. scMAGeCK outperforms existing methods, identifies genes and enhancers with known and novel functions in cell proliferation, and enables an unbiased construction of genotype-phenotype network. Single-cell CRISPR screening on mouse embryonic stem cells identifies key genes associated with different pluripotency states. Applying scMAGeCK on multiple datasets, we identify key factors that improve the power of single-cell CRISPR screening. Collectively, scMAGeCK is a novel tool to study genotype-phenotype relationships at a single-cell level.