tbuckley/cabot-search huggingface dataset:
Circular RNAs as biomarkers in liquid biopsy in colorectal cancer.
Authors: Manuel Valladares-Ayerbes, Carmen Garrigos, Miquel Taron, Angélica Figueroa, Enrique Aranda
Journal: Journal of Clinical Oncology (2020)

230 Background: Circular RNAs (circRNAs) are emerging as essential regulators of cancer- related biological hallmarks, as cell proliferation, apoptosis, differentiation, immune regulation and angiogenesis. CircRNAs are abundant, conserved, and have a tissue‐specific expression pattern. These characteristics make them candidate to serve as biomarkers in liquid biopsy (LB) in cancer. The aim of this study is to analyse differential expression of circRNAs in the colorectal cancer (CRC) scenario. Methods: To comprehensively understand the expression patterns of circRNAs we characterized 13,617 circRNAs using a microarray [Arraystar v2 (8x15K)] in 10 human samples, five CRC cell lines, one colorectal human tumour, one normal colon healthy control, vs. Peripheral Human Blood Leukocytes (2 pools) and Human Bone Marrow. Differentially expressed circRNAs were identified using fold change (FC) cut-off or through Volcano Plot filtering respectively. CircRNAs having FC ▪2 and P-values ▪ 0.05 were selected. CircRNA/microRNA interaction was predicted with target prediction software. Results: Hierarchical clustering showed distinguishable circRNA expression profiling among 10 samples. These data indicated that circRNAs have a different expression pattern in colorectal tissues compared with that in blood and bone marrow tissues. The microarray data showed 2329 circRNAs differentially expressed (FC &gt; 2.0, P &lt; 0.05). Among them, 964 circRNAs were upregulated and 1365 were downregulated in colon tissues compared with blood and bone marrow. Using a stringent criterion (FC &gt; 10, P≤ 0.01 and false discovery rate [FDR] &lt; 0.05) we have identified 30 circRNA upregulated in colorectal cancer versus non tumour samples. CircRNA/microRNA interaction prediction analysis showed that most upregulated circRNAs contain miRNA Binding Sites (MREs) for cancer-related miRNA, including among others, miR-17, miR-103, miR-let-7g. Conclusions: Microarray analysis was used to comprehensively identify dysregulated circRNAs in CRC. We identify novel circRNAs could be valuable as blood-based CRC biomarkers.
Effect of the nano/microscale structure of biomaterial scaffolds on bone regeneration
Authors: Lisha Zhu, Dan Luo, Yan Liu
Journal: International Journal of Oral Science (2020)

Abstract Natural bone is a mineralized biological material, which serves a supportive and protective framework for the body, stores minerals for metabolism, and produces blood cells nourishing the body. Normally, bone has an innate capacity to heal from damage. However, massive bone defects due to traumatic injury, tumor resection, or congenital diseases pose a great challenge to reconstructive surgery. Scaffold-based tissue engineering (TE) is a promising strategy for bone regenerative medicine, because biomaterial scaffolds show advanced mechanical properties and a good degradation profile, as well as the feasibility of controlled release of growth and differentiation factors or immobilizing them on the material surface. Additionally, the defined structure of biomaterial scaffolds, as a kind of mechanical cue, can influence cell behaviors, modulate local microenvironment and control key features at the molecular and cellular levels. Recently, nano/micro-assisted regenerative medicine becomes a promising application of TE for the reconstruction of bone defects. For this reason, it is necessary for us to have in-depth knowledge of the development of novel nano/micro-based biomaterial scaffolds. Thus, we herein review the hierarchical structure of bone, and the potential application of nano/micro technologies to guide the design of novel biomaterial structures for bone repair and regeneration.
Genomic correlates of extreme pathologic response following neoadjuvant chemotherapy in locally advanced gastric cancer to reveal distinct vulnerabilities.
Authors: Jashodeep Datta, Henry S. Walch, Ashley Russo, Walid Khaled Chatila, Elvira Vos, Umesh Bhanot, Yelena Yuriy Janjigian, Nikolaus Schultz, Laura H. Tang, Vivian E. Strong
Journal: Journal of Clinical Oncology (2020)

441 Background: Clinical factors associated with pathologic response (PResp) following neoadjuvant chemotherapy (NCT) in locally advanced gastric cancer (LAGC) are well studied; however, genomic correlates of such response have not been previously investigated. Methods: Evaluable pre-NCT tumor samples from patients with LAGC who underwent resection and demonstrated extreme pathologic response (EPR; ≤10% PResp: n = 21, ≥80% PResp: n = 19) were sequenced using a targeted exome capture platform. Gene- and signaling pathway-level correlates of EPR and disease-specific survival (DSS) were examined. Results: Of 40 patients, a majority had ≥cT2/N+ disease and were treated with predominantly platinum (98%) or 5-FU (88%) based NCT regimens. Two patients with MSI-high tumors had ≤10% PResp and were excluded from analysis. The EPR cohorts did not differ significantly in demographic or clinical (i.e., tumor location, cT/N status, NCT regimen, extent of gastrectomy, number of lymph nodes examined, or margin status) characteristics. Although EPR cohorts did not differ with respect to tumor differentiation/grade, Lauren classification, proportions of TCGA consensus CIN or GS subtypes, tumors with ≤10% PResp were more likely to have vascular (P &lt; 0.001) and perineural (P = 0.007) invasion. At median follow-up of 31m (IQR 21-57), ≥80% PResp was associated with improved DSS compared with ≤10% PResp (median NR vs. 32m, P = 0.04). On gene-level analysis, tumors with ≤10% PResp were significantly more likely to be ERBB2-altered (32% vs 5%, P = 0.04) compared with ≥80% PResp tumors. Conversely, ARID1A truncating mutations were enriched in tumors with ≥80% vs ≤10% PResp (32% vs 5%, P = 0.04). There was no difference in pathway-level alteration frequency between EPR cohorts. While frequency of oncogenic TP53 alterations was similar between EPR cohorts, TP53-altered tumors were associated with worse DSS vs TP53-wildtype tumors (median 80m vs 24m, P = 0.005) in patients demonstrating ≤10%, but not ≥80%, PResp. Conclusions: Genomic comparison of cohorts demonstrating EPR after NCT in LAGC reveal molecular vulnerabilities with distinct prognostic and therapeutic implications.
A multicenter phase II trial of tumor treating fields plus chemotherapy for first-line treatment of gastric adenocarcinoma.
Authors: Jin Li, Winnie Yeo, Ka-On Lam
Journal: Journal of Clinical Oncology (2020)

TPS474 Background: Gastric carcinoma (GC) is the third-leading cause of death in China (291,000 deaths in 2015). Current therapies include surgery, chemotherapy, radiotherapy and targeted therapy, which prolong PFS and OS to 6 months and 8-14 months, respectively. Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality approved by the FDA for glioblastoma and malignant pleural mesothelioma. TTFields at specific frequency (100- 500 kHz) are delivered via transducer arrays placed on the skin of the upper abdomen, back, right and left hypochondriac regions where the primary tumor lesion is located. TTFields were effective in preclinical models of gastric cancer and there are several ongoing Phase 3 trials of TTFields in multiple solid tumors. In this phase 2, single arm, open-label, multi-center study, we will investigate for the first time the efficacy and safety of TTFields concomitant with XELOX (oxaliplatin/capecitabine) as the first-line treatment of GC. Methods: Patients (N = 50) with histologically confirmed unresectable, locally advanced or metastatic Gastroesophageal Junction (GEJ) or Gastric Adenocarcinoma (GC), aged ≥ 18 years, ECOG PS 0-1, who had no previous systemic treatment for the recurrent or metastatic disease will be enrolled. Patients will receive TTFields (150 kHz via the NovoTTF-100L (P) medical device for average monthly use of 18 hrs/day) plus XELOX chemotherapy (Oxaliplatin: 130 mg/m2 on day 1 every 3 weeks; Capecitabine: 1000 mg/m 2 , PO, BID on day 1-14 every 3 weeks). For HER-2 positive patients, trastuzumab is allowed. The primary endpoint is investigator-assessed Objective Response Rate (ORR) per RECIST 1.1. Secondary endpoints are time to tumor progression (TTP), progression-free survival (PFS), overall survival (OS), and 12-month OS rate. Adverse events (AEs) will be graded for severity according to CTCAE 5.0. Based on the historical ORR data in first-line chemotherapy in GC, we assumed that ORR will be higher than 45% with TTFields concomitant with chemotherapy. At least 45 patients need to be enrolled to ensure the lower boundary is 30% of the 95% CI. Estimating a patient drop-out rate of 10%, 50 patients will be actually enrolled.
Transcarotid Artery Revascularization With Flow Reversal
Authors: Kosmas I. Paraskevas
Journal: JAMA Surgery (2020)

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Pemetrexed (Pem) with pembrolizumab (Pembro) maintenance: A post hoc subgroup safety analysis of KEYNOTE-189.
Authors: Joachim Aerts, Edward B. Garon, Chunxiao Wang, Catherine Muehlenbein, Jong Seok Kim, Shirish M. Gadgeel
Journal: Journal of Clinical Oncology (2020)

51 Background: KEYNOTE-189 showed that Pembro+Pem and platinum (Plat) followed by Pembro+Pem improved survival vs Placebo(Plac)+Pem+Plat followed by Plac+Pem in nonsquamous metastatic non-small cell lung cancer. Real-world data suggest Pem is being discontinued after the first 4 cycles with Plat (data on file), perhaps due to toxicity concerns. This study evaluated changes in toxicities and renal impairment in patients (pts) receiving Pem maintenance. Methods: Using KEYNOTE-189 patient data, pts receiving ≥5 cycles of Pem (including the first 4 cycles with Plat) were selected, and a subgroup with renal adverse events were identified by system organ class and preferred term (MedDRA 20.1). Pts with treatment-emergent adverse events (TEAEs) and changes in serum creatinine (sCR) were summarized every 4 cycles. Results: 310 pts in the Pembro+Pem+Plat arm and 135 in the Plac+Pem+Plat arm received ≥5 cycles of Pem. 30 and 5 pts experienced renal events in each arm, respectively. Table shows pts with Gr. 3-5 TEAEs in each period of 4 cycles. Gr. 3-5 TEAEs generally decreased after cycle 4. Pts with renal events had increasing maximum sCR changes from baseline with every 4 cycles. Conclusions: The percentage of pts with renal and Gr. 3-5 TEAEs did not increase with prolonged treatment with Pembro+Pem. Toxicity increased moderately with Pembro+Pem vs Plac+Pem in later cycles. The incidence of Gr. 3-5 renal toxicity was consistently low across the cycles. These data support the safety of prolonged Pem and Pembro in pts after 4 cycles of Pembro, Pem, and Plat along with careful monitoring of renal function. Clinical trial information: NCT02578680 . [Table: see text]
EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4–Positive Solid Tumors, Including Metastatic Urothelial Carcinoma
Authors: Jonathan Rosenberg, Srikala S. Sridhar, Jingsong Zhang, David Smith, Dean Ruether, Thomas W. Flaig, Joaquina Baranda, Joshua Lang, Elizabeth R. Plimack, Randeep Sangha, Elisabeth I. Heath, Jamie Merchan, David I. Quinn, Sandy Srinivas, Matthew Milowsky, Chunzhang Wu, Elaina M. Gartner, Peiying Zuo, Amal Melhem-Bertrandt, Daniel P. Petrylak
Journal: Journal of Clinical Oncology (2020)

PURPOSE To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4. METHODS EV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4–expressing solid tumors (eg, metastatic urothelial carcinoma [mUC]) who progressed on ≥ 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] inhibitor, including a cohort of patients with mUC who received prior anti–PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective. RESULTS Enrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving ≥ 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients ≥ 75 years of age with and without prior anti–PD-(L)1 treatment, liver metastases, or upper-tract disease. CONCLUSION Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing.
First-in-human phase I study of intraperitoneally administered interferon-activated autologous monocytes in platinum-resistant or refractory ovarian cancer.
Authors: Christopher Browning Cole, Christina M. Annunziata
Journal: Journal of Clinical Oncology (2020)

1 Background: This phase I study evaluated the safety and tolerability of autologous intraperitoneal monocytes treated with SYLATRON (Peginterferon alfa-2b) and ACTIMMUNE (Interferon gamma-1b). Methods: For the dose escalation portion, 3-6 patients with platinum-resistant or refractory ovarian cancer were enrolled into 4 cohorts and treated intraperitoneally (IP) with Peginterferon alfa-2b (25-250 mcg) and Interferon gamma-1b (5-50 mcg), with or without autologous monocytes (75-750 x 10 6 cells), in order to determine the recommended phase II dose (RP2D). A total of six patients were treated at the RP2D. Patients received the combination of interferons+/- monocytes via IP catheter once every 28 days. Results: 18 patients were enrolled (median age, 61 years; median 5 prior therapies). 1 of 3 patients at the second dose level experienced a dose-limiting toxicity (DLT, grade 3 anemia) and so this cohort was expanded to 6 patients; no subsequent DLTs were observed. The RP2D was defined as 250 mcg/50/mcg/750 x 10 6 cells on the basis of overall safety and tolerability. The only treatment–related grade 3 or higher adverse events occurring in more than one patient were lymphocyte decrease (33.3%) and abdominal pain (11.1%). Preliminary assessment of efficacy is ongoing. The best response observed has been partial response (PR) in 2/11 evaluable patients, with one patient having a 61% reduction in target lesion size. An additional 4/11 patients had stable disease, and 3 patients remained on treatment for &gt;6 cycles. Exploratory biomarker analyses are ongoing to to further elucidate changes in the immune cell population and correlate with response. An expansion cohort of 10 patients at the RP2D is currently enrolling. Conclusions: This is the first-in-human study of the combination of IP peginterferon alfa-2b, interferon gamma-1b, and autologous monocytes, and the combination displays good tolerability and antitumor activity in a heavily pretreated population, supporting further investigation. Clinical trial information: NCT02948426.
48P Comparison of an Rna-Based Multigene Test Between Core Biopsies and Corresponding Surgical Breast Cancer Sections
Authors: J.C. Brase, B.M. Müller, F. Haufe, K.E. Weber, J. Budzies, C. Petry, J. Prinzler, R. Kronenwett, M. Dietel, C. Denkert
Journal: Annals of Oncology (2012)
RBP EIF2S2 Promotes Tumorigenesis and Progression by Regulating MYC-Mediated Inhibition via FHIT-Related Enhancers
Authors: Jiwei Zhang, Shengli Li, Ling Zhang, Juan Xu, Mingxu Song, Tingting Shao, Zhaohui Huang, Yongsheng Li
Journal: Molecular Therapy (2020)

RNA-binding proteins (RBPs) play fundamental roles in cancer; however, we still lack knowledge about to what extent RBPs are dysregulated, as well as about perturbed signaling pathways in cancer. In this study, we integrated analysis of multidimensional data across >10,000 cancer patients and >1,000 cell lines. We identified a top candidate RBP: eukaryotic translation initiation factor 2 subunit beta (EIF2S2). EIF2S2 is highly expressed in tumors and is associated with malignant features as well as patient prognosis. Functional assays performed in cancer cells revealed that EIF2S2 promotes cancer cell proliferation, migration, and invasion in vitro as well as tumor growth and metastasis in vivo. Mechanistic investigations further demonstrated that EIF2S2 promotes tumorigenesis and progression by directly binding to a long non-coding RNA, LINC01600, which physically interacts with the MYC protein and increases its stability. Interestingly, we revealed that the EIF2S2-LINC01600-MYC axis can activate the Wnt/β-catenin pathway by inhibiting the activity of FHIT-related enhancers and FHIT expression. Finally, EIF2S2 knockdown combined with oxaliplatin treatment could be a potential combination therapy in cancer. Our integrated analysis provided detailed knowledge of the function of the EIF2S2-LINC01600-MYC axis, which will facilitate the development of rational combination therapies for cancer. RNA-binding proteins (RBPs) play fundamental roles in cancer; however, we still lack knowledge about to what extent RBPs are dysregulated, as well as about perturbed signaling pathways in cancer. In this study, we integrated analysis of multidimensional data across >10,000 cancer patients and >1,000 cell lines. We identified a top candidate RBP: eukaryotic translation initiation factor 2 subunit beta (EIF2S2). EIF2S2 is highly expressed in tumors and is associated with malignant features as well as patient prognosis. Functional assays performed in cancer cells revealed that EIF2S2 promotes cancer cell proliferation, migration, and invasion in vitro as well as tumor growth and metastasis in vivo. Mechanistic investigations further demonstrated that EIF2S2 promotes tumorigenesis and progression by directly binding to a long non-coding RNA, LINC01600, which physically interacts with the MYC protein and increases its stability. Interestingly, we revealed that the EIF2S2-LINC01600-MYC axis can activate the Wnt/β-catenin pathway by inhibiting the activity of FHIT-related enhancers and FHIT expression. Finally, EIF2S2 knockdown combined with oxaliplatin treatment could be a potential combination therapy in cancer. Our integrated analysis provided detailed knowledge of the function of the EIF2S2-LINC01600-MYC axis, which will facilitate the development of rational combination therapies for cancer.
A phase II trial of atezolizumab and bevacizumab in patients with advanced, progressive neuroendocrine tumors (NETs).
Authors: Daniel M. Halperin, Suyu Liu, Arvind Dasari, David R. Fogelman, Priya Bhosale, Armeen Mahvash, Shannon Dervin, Jeannelyn Estrella, Patricia Cortazar, Dipen M. Maru, Edward Francis Mckenna, Ignacio Ivan Wistuba, Katja Schulze, Phillip Andrew Futreal, Walter C. Darbonne, Cindy Yun, Patrick Hwu, James C. Yao
Journal: Journal of Clinical Oncology (2020)

619 Background: Neuroendocrine tumors (NETs) are relatively rare and heterogeneous tumors arising throughout the aerodigestive tract, which are incurable and life-limiting when metastatic. Prior studies of checkpoint inhibitors in NET patients have yielded minimal evidence of efficacy. Historically, effective therapies for advanced, progressive NET yield response rates less than 10% and progression-free survival (PFS) durations of approximately 11 months, as compared to approximately 4.5 months with placebo. Methods: We undertook a phase II basket study of atezolizumab in combination with bevacizumab in patients with rare cancers, and present here the data from the pancreatic NET (pNET) cohort and extrapancreatic NET (epNET) cohort, each of which included 20 patients with grade 1-2 NET that was progressive under any prior therapy. Patients received 1200mg of atezolizumab and 15mg/kg of bevacizumab IV q 21 days. The primary endpoint was confirmed objective response by RECIST 1.1. Results: The confirmed objective response rate with this combination was 20% (95% CI 6-44%) in the pNET cohort and 15% (95% CI 3-38%) in the epNET cohort. The median PFS in the pNET cohort is 19.6 months (95% CI 10.6-NR), while it was 14.9 months (95% CI 6.1-NR) in the epNET cohort, 1-year PFS was 75% and 52%, respectively. The combination was well-tolerated in this patient population, with the most common related treatment-emergent adverse events being hypertension (47.5%), proteinuria (37.5%), and fatigue (35%). The most common related grade 3/4 adverse events were hypertension (20%) and proteinuria (7.5%). Conclusions: The combination of atezolizumab and bevacizumab demonstrated moderate clinical activity in patients with advanced NETs. As pre-treatment and on-treatment biopsies were obtained for all patients, correlations with immune infiltration, mutations, and transcriptome alterations should provide additional insight into the mechanisms of response and resistance. Clinical trial information: NCT03074513.