tbuckley/cabot-search huggingface dataset:
Gastric Cancer Registry: A comprehensive patient-reported resource for multidisciplinary and translational genomic approaches to gastric cancer.
Authors: Alison Figueroa Almeda, Anna Hooker, Hojoon Lee, Meredith Mills, Paul Van Hummelen, James M. Ford, Hanlee Ji
Journal: Journal of Clinical Oncology (2020)

432 Background: Gastric cancer (GC) is the fifth leading cancer diagnosis and third frequent cause of cancer death globally. GC results from a cascade of molecular and genetic changes owing to environmental and genetic factors. While there are known risks to GC, more is to be learned about its development so to establish effective screens for early stages of cancer. Methods: The Gastric Cancer Registry (GCR) was built to investigate GC and discover informative genomic biomarkers. The GCR comprises medical, family, and social history and genomics data from patients with GC, a family history of GC, and/or a known mutation in the gene CDH1. Samples of saliva and gastric tumors are collected when available. The GCR allows us to leverage several genome sequencing datasets to construct a complete molecular landscape of GC. Early analysis of GC tissue includes whole exome sequencing (WES) to identify mutations, whole genome sequencing (WGS) for copy number variation, and RNA sequencing (RNAseq) for expression profiling. Results are used to inform of clonal neoantigens, microbiome, and immune cell populations. Saliva will be analyzed with linked reads sequencing to unearth germline mutations not picked up in standard clinical gene panels. Results: Datasets from 455 patients and samples from 159 patients have been collected. In a pilot study, we pinpointed specific mutations using WES and revealed extensive changes in genome copy number involving clinically actionable genes through WGS. Most tumors had a high degree of genomic instability and exhibited candidate markers for treatment decisions and response. Additionally, we found that RNAseq revealed tumor subgroups through gene expression signatures. Conclusions: The GCR is an informative resource enabling the identification of biomarkers for GC. With the GCR we are integrating expertise in translational cancer genomics with molecular biology, statistics, and bioinformatics to build a platform for discovery and the development of tools that will ultimately improve the detection, treatment, and prevention of GC.
Prognostic and predictive value of DNA mismatch repair status in patients with locally advanced rectal cancer following neoadjuvant therapy.
Authors: Huabin Hu, Chao Wang, Zehua Wu, Yan Huang, Jianwei Zhang, Yue Cai, Xiaoyu Xie, Jiayu Ling, Yanhong Deng
Journal: Journal of Clinical Oncology (2020)

210 Background: DNA mismatch repair deficient (dMMR) is a distinct molecular phenotype of colon cancer related to favorable outcome and resistant to 5-FU based adjuvant chemotherapy, however, little is known about dMMR rectal cancers. We investigated the value of dMMR on prognosis and predicted response to neoadjuvant therapy in rectal cancer patients. Methods: Between January, 2013 and December, 2018, a total of 855 consecutive patients with determined MMR status who underwent neoadjuvant therapy followed by curative surgery for locally advanced rectal cancer were included this retrospective study. Associations of MMR status with clinicopathologic variates and response to neoadjuvant therapy were determined using Chi-square or Fisher Exact tests. Local recurrence-free survival (LRFS) and disease-free survival (DFS) were analyzed using Cox proportional hazard models. Results: In this study population, dMMR was detected in 69 of 855 (8.1%) cases. Patients with dMMR showed similar clinicopathological characteristics including grade of differentiation, location from anal verge, clinical stage, neoadjuvant therapy regimen, pathological stage and postoperative chemotherapy to those who with pMMR, except younger age ( &lt; 65 years, 89.1% vs. 77.7%, P = 0.034) and more mucinous adenocarcinoma in dMMR tumors. MMR status were not predictive for response to neoadjuvant therapy including pCR rate (18.8% vs. 12.9%, P = 0.185), downstaging rate (76.6% vs. 68.9%, P = 0.200) and tumor regression grade 0-1 (31.3% vs. 43.7%, P = 0.052), regardless of chemoradiation or chemotherapy. Multivariable analysis revealed that patients whose tumors had dMMR vs. pMMR had significantly longer DFS (HR = 0.39, 95%CI = 0.18 - 0.83, P = 0.014), but the correlation was not observed for LRFS (HR = 0.81, 95%CI = 0.25 - 2.60, P = 0.724). In the subgroup analysis, dMMR was a statistically significant prognostic factor for DFS only in patients with ypstage II-III (HR = 0.39, 95%CI = 0.17 - 0.88, P = 0.024). Conclusions: dMMR was significantly associated with longer DFS in patients with locally advanced rectal cancer, whereas was not a predictive marker for neoadjuvant therapy.
Molecular landscape of gastric cancer (GC) harboring mutations of histone methyltransferases.
Authors: Jingyuan Wang, Joanne Xiu, Yasmine Baca, Richard M. Goldberg, Philip Agop Philip, Andreas Seeber, Francesca Battaglin, Hiroyuki Arai, Shivani Soni, Ryuma Tokunaga, Wu Zhang, Jimmy J. Hwang, Anthony Frank Shields, John Marshall, Igor A. Astsaturov, Albert Craig Lockhart, Zoran Gatalica, W. Michael Korn, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2020)

418 Background: Alteration of histone modifications participating in transcription and genomic instability, has been recognized as an important role in tumorigenesis. Aberrant expression of histone-lysine N-methyltransferase 2 ( KMT2) family, which methylate histone H3 on lysine 4, is significantly correlated with poor survival in GC. Understanding how gene mutations of KMT2 family interact to affect cancer progression could lead to new treatment strategies. Methods: A total of 1,245 GC were analyzed using next-generation sequencing (NGS) and immunohistochemistry (IHC; Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations, and MSI status was evaluated by a combination of IHC, fragment analysis and NGS. PD-L1 status was analyzed by IHC (SP142). Gene fusions were detected by Archer (N = 59) or whole-transcriptome sequencing (N = 129). Results: The overall mutation rate of genes in KMT2 family was 10.6% ( KMT2A: 1.7 %, KMT2C: 4.7%, KMT2D: 7.1%). Overall, the mutation rates were significantly higher in KMT2-mutated (MT) GC than KMT2-wild type (WT) GC, except for TP53 (43% vs 63%, p &lt; .0001). Interestingly, among the genes with significant higher mutation rates in KMT2-MT GC, 28% (21/76) of them were related to DNA damage repair (including BRCA1/ 2, RAD50) and 33% (25/76) of them were related to chromatin remodeling (including ARID1A/ 2, SMARCA4). Overexpression of HER2, amplifications of KRAS, CDK6 and HER2 were significant lower, while PCM1 and BCL3 amplifications were significant higher in KMT2-MT, compared to KMT2-WT GC ( p &lt; .05). Significantly higher prevalence of TMB-high ( &gt; 17mut/MB) (49% vs 3%), MSI-H (53% vs 2%), and PD-L1 overexpression (20% vs 7%) were present in KMT2-MT GC, compared to KMT2-WT GC ( p &lt; .001). The rates of fusions involving ARHGAP26 (19% vs 3%, p &lt; .01)and RELA (29% vs 0%, p &lt; .0001) were significantly higher in KMT2-MT than those in KMT2-WT GC. Conclusions: This is the largest study to investigate the distinct genomic landscape between KMT2-MT and WT GC. Our data indicates that KMT2-MT GC patients could potentially benefit from agents targeting DNA damage repair and immunotherapy, which warrants further in-vitro and in-vivo investigation.
A phase II randomized placebo-controlled study investigating the combination of yiv-906 and sorafenib (SORA) in HBV (+) patients (Pts) with advanced hepatocellular carcinoma (HCC).
Authors: James J. Harding, Ghassan K. Abou-Alfa, Yuankai Shi, Jacqueline Whang-Peng, Man Fung Yuen, Wasif M. Saif, Aiping Tian, Shanzhi Gu, Wing Lam, Shwu-Huey Liu, Yung-Chi Cheng, Edward Chu, Yun Yen
Journal: Journal of Clinical Oncology (2020)

TPS601 Background: First-line systemic treatment options for advanced HCC pts are limited to the multi-targeted tyrosine kinase inhibitors, SORA and lenvatinib. Both agents improve outcomes for pts with advanced disease, but are associated with increased rate of grade ≥ 3 treatment-related adverse events. YIV-906 (PHY906, KD018) is derived from Huang-Qin-Tang, a traditional Chinese medicine documented 1800 years ago to treat gastrointestinal ailments. Preclinical data indicate YIV-906 increases inflammation in the tumor microenvironment by M1 macrophages activation/proliferation resulting in HCC tumor rejection in vivo and reduces SORA associated toxicity. Clinical experience with YIV-906 plus SORA suggests safety and potential clinical benefit to HCC pts with chronic HBV infection. Methods: This is a proof-of-concept, international, multicenter, double-blind, placebo-controlled, randomized phase 2 study designed to compare the efficacy of YIV-906 and SORA to SORA alone in advanced HCC pts (NCT04000737). Key eligibility criteria include age ≥ 18 years, HBV-associated HCC, ≥ 1 measurable untreated lesion, Child-Pugh A liver function, and no prior systemic therapy. An estimated 125 pts will be randomized 2:1 to receive the investigational (YIV-906 plus SORA) or control (placebo plus SORA) arm until disease progression or unacceptable toxicity. Pts will be stratified by metastatic status (extrahepatic/vascular invasion vs none) and ECOG performance status (0 vs. 1). The primary endpoint is progression-free survival (PFS). Secondary endpoints include objective response rate and disease control rate by mRECIST, time to progression, overall survival, quality of life, and safety by CTCAE version 4.0. Translational correlatives include pharmacokinetics, effects on oral/gut microbiota, and exploratory soluble biomarkers analysis. For the primary endpoint, sample size of 41 pts in control arm and 84 pts in the investigational arm achieves 90% power at a 0.05% significance level to detect a hazard ratio of 0.5 assuming the median PFS of the control SORA arm is 3.6 months and that of the combination arm is 7.3 months. Clinical trial information: NCT04000737.
The potential of Tenascin C in the tumor-nerve microenvironment to enhance perineural invasion and correlate with locoregional recurrence-related poor prognosis in pancreatic ductal adenocarcinoma.
Authors: Satoru Furuhashi, Takanori Sakaguchi, Ryuta Muraki, Ryo Kitajima, Mayu Fukushima, Makoto Takeda, Yoshifumi Morita, Hirotoshi Kikuchi, Mitsutoshi Setou, HIROYA TAKEUCHI
Journal: Journal of Clinical Oncology (2020)

748 Background: Perineural invasion (PNI) is commonly seen in pancreatic ductal adenocarcinoma (PDAC) and worsens the postoperative prognosis. However, the detail mechanisms of PNI in PDAC remain unclear. Tenascin C (TNC), an extracellular matrix glycoprotein, is abundant in cancer stroma and modulates tumor progression. In this study, we hypothesized that TNC could enhance PNI in PDAC. The aim of this study was to investigate the roles of TNC in the tumor-nerve microenvironment of PDAC. Methods: We immunohistochemically examined TNC expression in 78 resected PDAC specimens. TNC staining intensity in perineural sites at the invasive front was classified as low or high, by comparison with adjacent non-cancerous tissues in the same section. The relationships between TNC expression and clinicopathological features were retrospectively analyzed. Furthermore, interactions between cancer cells and nerves after supplementation with TNC were investigated using in vitro co-culture model with a PDAC cell line and neonatal mouse dorsal root ganglion (DRG). Results: High perineural TNC expression at the invasive front, seen in 30 (38%) patients, was associated with the presence of PNI (p = 0.006), pathological T stage ≥ 3 (p = 0.01), and postoperative locoregional recurrence (p = 0.002). It was independently associated with postoperative, poor recurrence-free survival in multivariate analysis (p = 0.045). In the in vitro co-culture model, TNC supplementation significantly enhanced both neurotropism of PDAC cells and tumor tropism of a DRG. On the other hand, when PDAC cells and a DRG were cultured separately, TNC did not affect cancer cell proliferation or neural outgrowth. Furthermore, the knockdown of Annexin A2, which is known to be a receptor for TNC, cancelled the neurotropism of PDAC cell toward DRGs. Conclusions: Strong perineural TNC expression was a prognostic indicator of locoregional recurrence-related poor prognosis. The neurotropism of PDAC induced by TNC and TNC-Annexin A2 signaling pathway could be the potential therapeutic target for PDAC by regulating PNI.
Sex-Specific Risks of Major Cardiovascular and Limb Events in Patients With Symptomatic Peripheral Artery Disease
Authors: Axel Haine, Sarah Kavanagh, Jeffrey S. Berger, Connie N. Hess, Lars Norgren, F. Gerry R. Fowkes, Brian G. Katona, Kenneth W. Mahaffey, Juuso I. Blomster, Manesh R. Patel, W. Schuyler Jones, Frank W. Rockhold, William R. Hiatt, Iris Baumgartner
Journal: Journal of the American College of Cardiology (2020)
Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group
Authors: Manuela A. Hoechstetter, Raymonde Busch, Barbara Eichhorst, Andreas Bühler, Dirk Winkler, Jasmin Bahlo, Sandra Robrecht, Michael J. Eckart, Ursula Vehling-Kaiser, Georg Jacobs, Ulrich Jäger, Hans Jürgen Hurtz, Georg Hopfinger, Frank Hartmann, Harald Fuss, Wolfgang Abenhardt, Ilona Blau, Werner Freier, Lothar Müller, Maria Goebeler, Clemens Wendtner, Kirsten Fischer, Carmen D. Herling, Michael Starck, Martin Bentz, Bertold Emmerich, Hartmut Döhner, Stephan Stilgenbauer, Michael Hallek
Journal: Leukemia (2020)
Alternative measure of therapy impact (TXI): Length of sojourn on treatment—Value of early restaging imaging for prediction of response to nivolumab among patients with advanced cancer.
Authors: Milos Josef Janicek
Journal: Journal of Clinical Oncology (2020)

106 Background: Cross-sectional Imaging (CI) plays an essential role in early assessment of patients on immune checkpoint inhibitors (ICIs), yet often remains inconclusive in the setting of advanced disease, prior cancer treatment, toxicity, and cancer unrelated findings. We propose a robust, reproducible imjScore based on measurable tumor response on the first two re-staging scans that may predict TXI. We are testing prognostic value of early imaging, time lag of ICIs effect, against Duration of clinically effective treatment as a Measure of Treatment Impact. Methods: Retrospective review of CI studies in 92 patients with advanced stage solid tumors treated with Nivolumab (Nivo) during 6/2015-8/2018 at BMC on standard clinical protocols. Time on therapy (TOTx) was used as a surrogate marker of therapy impact. Modified imRECIST score utilizing ∑ of 5 discrete cancer lesions at baseline, 1st, and 2nd CI since initiation of Nivolumab were adjusted for TOTx. Our imjSCORE averages "predicted days on therapy" from best fit function of tumor change/day [%] at each time point vs. TOTx and ratios between 1st and 2nd scan. Results: Median TOTx was 70 days (range 1-1029). Differences in imRECIST scores derived from two early restaging CI studies adjusted for TOTx were able to identify with high statistical significance two groups of "SHORT" vs "LONG" sojourn on Nivolumab around Median of 70 days. Early Progression curve was associated with shorter benefit of Nivo; Pseudo-progression curve showed significantly shorter sojourn on Nivolumab compared to initial Regression or Stable score curves (P &lt; .002). Conclusions: The imjScore may differentiate with high likelihood patients with short versus long sojourn on Nivo as a novel measure of TXI. Our CI-based imjSCORE validates early imaging with a response curve and standardized analysis of the 1st and 2nd post-treatment scans. If validated with other ICIs, this scoring tool may allow early prediction of ICIs treatment response and clinical outcome. Further correlation with clinical biomarkers may lead to development of predictive nomograms of "short" versus "long" TXI.
Interferons alpha and gamma with monocytes as a therapeutic strategy for ovarian cancer.
Authors: Christina M. Annunziata, Anna Duemler, Franklin Ning
Journal: Journal of Clinical Oncology (2020)

9 Background: In the presence of pro-inflammatory cytokines, monocytes are cytotoxic to tumor cells. We previously showed that monocytes stimulated with interferon alpha and gamma result in synergistic killing of ovarian cancer cells in vitro. Here we better characterize monocyte differentiation and their ability to induce cell death through co-culture experiments with spheroids and in mouse xenografts. Methods: OVCAR8 cells were grown in ultra-low attachment conditions for three days before being co-cultured with human monocytes as well as interferon gamma and interferon alpha. Monocytes and OVCAR8s were assayed by flow cytometry for markers of differentiation and viability, respectively. Mouse studies were performed to confirm the viability of human monocytes stimulated with interferon alpha and gamma within the peritoneal cavity seventy-two hours after injection. Subsequent mouse experiments analyzed monocyte differentiation towards M1 or M2 phenotypes by flow cytometry with or without exposure to tumor cells and/or interferons. Results: OVCAR8 spheroids showed decreased viability in the presence of monocytes combined with interferon. We show that monocytes also express a hybrid M1/M2 phenotype when stimulated to IFN and exposed to tumor cells. In mice, monocytes demonstrated a unique differentiation towards both M1 and M2 macrophages as well as plasmacytoid and classic DCs. Various immune cell subsets also differed when comparing peritoneal washes versus tissue digests. Mouse survival studies are ongoing. Conclusions: Monocytes with the combination of interferons alpha and gamma are effective at killing ovarian cancer cells in laboratory models. Phenotypic analyses show a novel pattern of differentiation markers. Our ongoing clinical trial with these agents will incorporate similar studies to correlate monocyte differentiation with anti-tumor activity.
コクラン共同計画の無作為化試験におけるバイアスリスク評価ツール | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Higgins Julian P T, Altman Douglas G, Gotzsche Peter C, Jueni Peter, Moher David, Oxman Andrew D, Savovic Jelena, Schulz Kenneth F, Weeks Laura, Sterne Jonathan A C
Journal: BMJ (2011)
Phase Ib trial of pembrolizumab and XL888 in patients with advanced gastrointestinal malignancies: Results of the dose-escalation phase.
Authors: Mehmet Akce, Olatunji B. Alese, Walid Labib Shaib, Christina Wu, Gregory B. Lesinski, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2020)

830 Background: XL888 is a selective inhibitor of heat shock protein 90 (HSP90). It modulates several oncogenic signaling pathways, and the tumor microenvironment. In preclinical models, XL888 potentiates efficacy of PD-1 inhibition. We report the results of the dose escalation (DE) portion of a phase Ib trial of combined XL888 and pembrolizumab (P) in advanced gastrointestinal adenocarcinomas. Methods: XL888 was administered orally (PO) in three dose levels of 45 (DL1), 90 (DL2), 60 (only if DLT on DL2) mg twice weekly with P 200 mg IV on day 1, in 21-day cycles. Eligible patients included stage IV or locally advanced unresectable gastrointestinal adenocarcinomas with at least one prior therapy (patients with colorectal (CRC) adenocarcinoma must have received oxaliplatin, irinotecan, and fluoropyrimidine), age ≥18 years, ECOG PS 0-1, adequate organ function, no prior anti-PD-1 or anti-PD-L1 agent. The primary endpoint was recommended phase II dose (RP2D), while secondary endpoints included safety and tolerability. Pre-treatment and on-treatment correlative peripheral blood specimens were collected. Results: A total of 14 patients were enrolled in the DE phase. 9 male, median age 66.5. Diagnoses included CRC (6), pancreatic adenocarcinoma (5), biliary tract cancer (1), ampullary (1), and duodenal (1). Two patients were ineligible for assessing the primary endpoint (DL2) due to biliary stent obstruction and sepsis. One DLT (grade 3 autoimmune hepatitis) was observed on DL2. We enrolled three patients on DL3. Five additional patients were subsequently enrolled on DL2 with no additional DLT. Three patients (1 duodenal, 2 CRC) had prolonged stable disease (6, 9 and 15 cycles). The most common treatment-related toxicities included autoimmune hepatitis (G3; n = 1), retinopathy (G2; n = 2), nausea (G2; n = 1), constipation (G2; n = 1), and diarrhea (G2; n = 3). Conclusions: The XL888 and pembrolizumab combination had an acceptable safety profile and the RP2D of XL888 was 90 mg twice weekly combined with P 200 mg, every 3 weeks. The dose expansion portion and a robust series of immunologic correlative laboratory studies for this study is ongoing. Clinical trial information: NCT03095781.
Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors
Authors: Milton Packer
Journal: European Journal of Heart Failure (2020)

Abstract In five large‐scale trials involving &gt;40 000 patients, sodium–glucose cotransporter 2 (SGLT2) inhibitors decreased the risk of serious heart failure events by 25–40%. This effect cannot be explained by control of hyperglycaemia, since it is not observed with antidiabetic drugs with greater glucose‐lowering effects. It cannot be attributed to ketogenesis, since it is not causally linked to ketone body production, and the benefit is not enhanced in patients with diabetes. The effect cannot be ascribed to a natriuretic action, since SGLT2 inhibitors decrease natriuretic peptides only modestly, and they reduce cardiovascular death, a benefit that diuretics do not possess. Although SGLT2 inhibitors increase red blood cell mass, enhanced erythropoiesis does not favourably influence the course of heart failure. By contrast, experimental studies suggest that SGLT2 inhibitors may reduce intracellular sodium, thereby preventing oxidative stress and cardiomyocyte death. Additionally, SGLT2 inhibitors induce a transcriptional paradigm that mimics nutrient and oxygen deprivation, which includes activation of adenosine monophosphate‐activated protein kinase, sirtuin‐1, and/or hypoxia‐inducible factors‐1α/2α. The interplay of these mediators stimulates autophagy, a lysosomally‐mediated degradative pathway that maintains cellular homeostasis. Autophagy‐mediated clearance of damaged organelles reduces inflammasome activation, thus mitigating cardiomyocyte dysfunction and coronary microvascular injury. Interestingly, the action of hypoxia‐inducible factors‐1α/2α to both stimulate erythropoietin and induce autophagy may explain why erythrocytosis is strongly correlated with the reduction in heart failure events. Therefore, the benefits of SGLT2 inhibitors on heart failure may be mediated by a direct cardioprotective action related to modulation of pathways responsible for cardiomyocyte homeostasis.
Interleukin-17 in rheumatoid arthritis: Trials and tribulations
Authors: Leonie S. Taams
Journal: The Journal of Experimental Medicine (2020)

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine with well-characterized biological effects on stromal cell activation, angiogenesis, and osteoclastogenesis. The presence of this cytokine in the inflamed joints of patients with rheumatoid arthritis (RA), together with compelling data from in vitro and experimental arthritis models demonstrating its pro-inflammatory effects, made this cytokine a strong candidate for therapeutic targeting. Clinical trials, however, have shown relatively modest success in RA as compared with other indications. Guided by recent insights in IL-17 biology, this review aims to explore possible reasons for the limited clinical efficacy of IL-17A blockade in RA, and what we can learn from these results going forward.