tbuckley/cabot-search huggingface dataset:
A multicenter, open label, first-in-human study of an oncolytic viral vector expressing an agonistic anti-CD40 antibody (NG-350A) in patients with epithelial tumors (FORTITUDE).
Authors: Aung Naing, Ecaterina Elena Ileana Dumbrava, Ravi Murthy, Funda Meric-Bernstam, Andrew Fox, David Krige, Jo Carter, Brian Champion, Paul Cockle, Barbara Koetz, Hilary McElwaine-Johnn
Journal: Journal of Clinical Oncology (2019)

TPS2668 Background: NG-350A is a transgene modified variant of the oncolytic platform virus enadenotucirev (EnAd) which expresses a fully human agonist anti-cluster of differentiation 40 (anti-CD40) antibody. The principal advantage of encoding anti-CD40 within an oncolytic virus is the ability to potentially achieve very high levels within the tumor coupled with direct cytotoxicity due to viral lysis and stimulation of the immune-system. NG-350A infects and selectively replicates in tumor cells. The anti-CD40 antibodies are expected to activate the patient’s own dendritic cells, macrophages and B-cells to drive CD4+ and CD8+ T-cell immuno-inflammatory responses and immune mediated tumor cell killing. EnAd is a tumor-selective chimeric Ad11/Ad3 group B oncolytic adenovirus developed using directed evolution. Phase I clinical studies have identified a well-tolerated systemic dose and regimen for EnAd monotherapy. EnAd shows a high level of selective replication and cell killing for a broad range of carcinoma cell lines (of epithelial origin) with little replication in normal and non-carcinoma cells. Methods: This first in human study will evaluate the safety, tolerability and preliminary efficacy of NG-350A together with virus kinetics, immunogenicity and other pharmacodynamic effects to elucidate the mechanism of action of NG-350A in patients with advanced or metastatic epithelial tumours. In the dose escalation phase up to 33 patients evaluable for dose-limiting toxicity will receive NG-350A by IV infusion on Day 1, 3 and 5 at 6 US sites. The first IV cohort in the dose-escalation phase will utilize the conventional ‘3+3’ design; thereafter dose recommendations will be based on a continual reassessment method. Following determination of the recommended phase 2 dose up to 20 patients will be treated in a dose-expansion cohort. In a parallel cohort, up to 12 patients will receive a single dose of NG-350A by intratumoural (IT) injection on Day 1 for direct delivery of high viral titres to tumor. Up to six patients are planned to undergo surgical resection of a tumor lesion to optimize translational research. Clinical conduct of the study was initiated in February 2019.
GPR30 signaling to regulate epithelial-mesenchymal transition and predict survival in ovarian cancer.
Authors: Satoe Fujiwara, Shinichi Terada, Yuhei Kogata, Hiroshi Maruoka, Yoshimichi Tanaka, Tomohito Tanaka, Satoshi Tsunetoh, Hiroshi Sasaki, Masahide Ohmichi
Journal: Journal of Clinical Oncology (2019)

e17041 Background: G protein-coupled receptor 30 (GPR30) is a 7-transmembrane estrogen receptor that functions alongside traditional estrogen receptors to regulate the cellular responses to estrogen. Recent studies suggest that the high expression of GPR30 is associated with a poor prognosis in breast cancer or endometrial cancer. Although the role of GPR30 in ovarian cancer was unclear, we revealed that GPR30 is associated with poor prognosis in ovarian cancer. On the other hand, Epithelial-to-Mesenchymal Transition (EMT) is involved in cancer metastasis. The purpose of this study is to reveal how GPR30 was associated with poor prognosis and whether associated with EMT in ovarian cancer. Methods: We examined whether GPR30 signaling activates the EGFR-Akt pathway in an ovarian cancer cell line (Caov-3) by a Western blotting analysis. We also examined the effect of GPR30 on EMT were evaluated in Caov-3, which were cultured both in two-dimensional (2D) culture and three-dimensional (3D) culture model. GPR30 agonist, G1, was used to confirm the regulatory effects of GPR30 on the change of phenotypic modulation and EMT markers expression. Results: The phosphorylation of the EGFR and Akt could be significantly enhanced by G1 (p &lt; 0.05) and inhibited by a Src family kinase inhibitor. In 3D culture, the stimulation of GPR30 leads the floating and sphere formation in Caov-3. G1-induced EMT was observed with related regulation of EMT markers expression at both mRNA and protein level. G1 induced the decrease of E-cadherin level and the increase of Snail and Vimentin in RT-PCR and Western blotting. Knockdown of GPR30, using siRNA, blocked G1-induced EMT. Conclusions: GPR30 increases the phosphorylation of Akt via the EGFR in ovarian cancer cells and changes ovarian cancer cells to the EMT state.GPR30 might be an important molecule related to metastasis process in ovarian cancer.
Effectiveness of ASCO’s adverse event reporting decision aid: Results from an interventional study.
Authors: Kathryn Finch Mileham, Andrea D. Buchmeier, Meredith Kathleen Chuk, Courtney Davis, Anne Marie Forest, Elizabeth Garrett-Mayer, Patricia A. Hurley, Laura Levit, Raymond P. Perez, Caroline Schenkel, Julie Vose
Journal: Journal of Clinical Oncology (2019)

3065 Background: Investigators often send adverse event (AE) reports to sponsors that are incorrectly categorized as serious or attributed to the investigational drug. Such errors contribute to a high volume of uninformative IND safety reports that sponsors submit to FDA and all participating investigators, straining stakeholder resources and impeding the detection of valid safety signals. To improve the quality of AE reporting, ASCO developed and tested a Decision Aid Tool (DAT). Methods: An interventional study with a cross-over design was conducted. Physician investigators and research staff were randomized to receive case studies. Cases were assessed for seriousness and attribution, first unassisted and then with the DAT. Participants completed a feedback survey. Effectiveness of reporting and attribution were assessed using logistic regression. Results are reported as odds ratios (OR) with 95% confidence intervals (CI). Results: Most of the 29 participants reported that the DAT was helpful (93%), improved their decision-making time (69%) and confidence in reporting (83%), and that they would use it in practice (83%). The DAT did not significantly affect accuracy of determining seriousness (OR, 0.87; 95% CI: 0.31, 2.46) but it did significantly increase accuracy of attributing a serious AE to a drug (OR, 3.60; 95% CI: 1.15, 11.4). Conclusions: The DAT shows promise as a method to reduce errors in attribution of AEs, which may help to ensure the detection of valid safety signals. Many participants were experienced clinical trialists, and the DAT may show greater utility as an educational tool for novice investigators, research staff, and students.
Outcomes after early initiation of nonsteroidal immunosuppressive therapy in patients with immune checkpoint inhibitor-induced colitis.
Authors: Yinghong Wang, Hamzah Abu-Sbeih, Faisal Ali, Mehmet Altan, Ramona Dadu, Amir A. Jazaeri
Journal: Journal of Clinical Oncology (2019)

2571 Background: Current treatment guidelines for immune-mediated colitis (IMC) recommend 4 to 6 weeks of steroids as first-line therapy, followed by nonsteroidal immunosuppressive therapy (NSIST) (infliximab or vedolizumab) in patients who do not respond to steroids. We assessed the effect of early NSIST introduction and number of NSIST infusions on clinical outcomes. Methods: We performed a retrospective review of patients with IMC who received NSIST between January and December 2018. Logistic regression analyses were used to assess associations between clinical features and outcomes of IMC (Table). Results: Of the 1,459 patients who received immune checkpoint inhibitor, 179 developed IMC of any grade; 84 of them received NSIST. Of the 84 patients who received NSIST, 79% were males with mean age of 60. Compared with patients who received NSIST &gt;10 days after IMC onset, patients who received early NSIST (≤10 days) required fewer hospitalizations ( P=0.03), experienced steroid taper failure less frequently ( P=0.03), had fewer steroid tapering attempts ( P&lt;0.01), had a shorter course of steroid treatment ( P=0.09), and had a shorter duration of symptoms ( P&lt;0.01). Risk factors of IMC recurrence after weaning off steroids included: 1) needing multiple hospitalizations ( P&lt;0.01), 2) experiencing steroid taper failure after NSIST ( P=0.02), 3) receiving infliximab rather than vedolizumab ( P=0.02), 4) receiving fewer than three infusions of NSIST ( P=0.02), 5) having higher fecal calprotectin levels after NSIST ( P=0.01), and 6) receiving a longer course of steroids ( P=0.02), hospitalization ( P&lt;0.01) and IMC symptoms ( P&lt;0.01). Unsuccessful weaning from steroids after NSIST was associated with high IMC grades ( P&lt;0.01); multiple hospitalizations ( P&lt;0.01); steroid-resistant IMC ( P&lt;0.01); long interval from IMC to NSIST initiation ( P=0.01); and long duration of steroids ( P&lt;0.01), IMC symptoms ( P&lt;0.01), and hospitalization ( P&lt;0.01). Conclusions: NSIST should be introduced early in the disease course of IMC instead of waiting until failure of steroid therapy or steroid taper. Patients who received three or more infusions of NSIST had more favorable clinical outcomes.
Role of neoadjuvant therapy (NAT) in pancreatic adenocarcinoma (PAC): A single center experience.
Authors: Rami Mohamad Nassabein, Corentin Richard, Jean-Pierre M. Ayoub, Francine Aubin, Marie-Pierre Campeau, Guila Delouya, David Donath, Michel Dagenais, Real W. Lapointe, Richard Letourneau, Marylene Plasse, Simon Turcotte, Andre Roy, Franck Vandenbroucke-Menu, Damien Olivié, Bertrand Routy, Mustapha Tehfe
Journal: Journal of Clinical Oncology (2019)

e15747 Background: Surgical resection of PAC followed by adjuvant therapy is the standard of care for non-metastatic resectable tumors. Surgical resection with clear margins of borderline (BR) or locally advanced (LA) tumors is either challenging or impossible. Furthermore, there are no clear recommendations concerning NAT for non-upfront resectable PAC. Thus we reviewed our own experience with different NAT modalities for BR and LA PAC. Methods: Medical records of patients identified by Tumor Board as BR or LA PAC and treated with NAT at Centre Hospitalier de l’Université de Montréal (CHUM) were retrospectively reviewed. Survival curves were estimated by the Kaplan-Meier method and compared with the Log-rank test. For both univariate and subgroup analyses, hazard ratio and 95% confidence interval were estimated by Cox proportional hazard regression. Results: Between 2009 and 2017, 90 patients (50 BR, 40 LA) were identified. Chemotherapy, mostly FOLFIRINOX, was the only NAT in 51 patients (56.6%), 23 patients (25.3%) received chemoradiotherapy alone and 16 patients (17.7%) received sequential treatment of both modalities. Tumor resection was achieved in 44 patients, with 32 BR patients (R0: 68.7%) and 12 LA patients (R0: 75%). Median Disease free survival (DFS) of patients that underwent resection was 12.3 months. mPFS was 29 vs 10 months (HR:0.2; p &lt; 0.001) and mOS was 41.7 vs 15.7 months (HR:0.3; p &lt; 0.001) in resected and non-resected patients, respectively. In subgroup analysis, resection statistically improved PFS and OS regardless of age, sex, T stage and type of vessel involvement. Treatment with more than one modality showed better clinical outcomes (PFS and OS) and a non-statistically higher R0 resection rate that was 100% in BR tumors. OS in patients with resected cancers was not reached for the multimodality group, 41.7 months for chemotherapy alone group and 22.4 months in patients treated with chemoradiotherapy group (p = 0.017). Conclusions: In this retrospective single center analysis, NAT with chemotherapy and/or chemoradiotherapy appears to improve patients’ clinical resection results and outcomes. These results validate previous retrospective studies but warrant large prospective trials to define the best NAT.
Optimal dose of ropivacaine for relieving cough-pain after video-assisted thoracoscopic lobectomy by single intrapleural injection: A randomized, double-blind, controlled study
Authors: Sisi Chen, Xiaona Zhu, Lvdan Huang, Wei Chen, Sainan Zhang, Hongying Shi, Yun Xia, Thomas J. Papadimos, Xuzhong Xu
Journal: International Journal of Surgery (2019)
AB0796 DIFFERENCES AND SIMILARITIES OF THE BONE-CARTILAGE UNIT IN PATIENTS WITH PRIMARY OSTEOARTHRITIS AND SECONDARY OSTEOARTHRITIS CAUSED BY RHEUMATOID ARTHRITIS
Authors: Rasmus Klose-Jensen, Anne Friesgaard Christensen, Louise Brøndt Hartlev, Lene Warner Thorup Boel, Mogens Berg Laursen, Kresten Krarup Keller, Ellen Margrethe Hauge
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Despite distinct aetiologies of joint diseases, the osteoarthritic end-stage of primary osteoarthritis and rheumatoid arthritis are described using similar radiological features. However, primary and secondary osteoarthritis may be different at the bone-cartilage unit depending on the pathogenesis. <h3>Objectives</h3> The main purpose was to investigate the histological differences in the bone-cartilage unit of the hip joint in patients with primary osteoarthritis and patients with secondary osteoarthritis due to rheumatoid arthritis. <h3>Methods</h3> Femoral heads were obtained during arthroplasty from 12 patients with primary osteoarthritis and six patients with secondary osteoarthritis due to rheumatoid arthritis. Twelve femoral heads from healthy age- and sex-matched subjects were obtained post-mortem. Femoral heads were investigated, using stereological methods to provide unbiased quantitative data. The femoral head, articular cartilage, calcified cartilage, subchondral bone, and osteophytes were measured. <h3>Conclusion</h3> Patients with secondary osteoarthritis due to rheumatoid arthritis had thinner articular cartilage and calcified cartilage but were otherwise not significantly different from patients with primary osteoarthritis. Thus, the inflammatory joint in rheumatoid arthritis was associated with a more pronounced loss of cartilage than the degenerative joint disease in primary osteoarthritis. The thicker calcified cartilage in primary osteoarthritis has been attributed to endochondral ossification; this does not seem to be the case in rheumatoid arthritis. <h3>Acknowledgement</h3> The authors are grateful for the technical assistance of Jette Barlach and Rita Ullerup. This work was financially supported by the Danish Rheumatism association. <h3>Disclosure of interests</h3> Rasmus Klose-Jensen: None declared, anne Friesgaard Christensen: None declared, Louise Brøndt Hartlev: None declared, Lene Warner Thorup Boel: None declared, Mogens Berg Laursen: None declared, Kresten Krarup Keller Speakers bureau: Have received speaking fee from Pfizer, Ellen Margrethe Hauge Grant/research support from: Have received grants from Roche and Novartis, outside the submitted work., Speakers bureau: Have received personal fees from MSD, Pfizer, UCB and Sobi
High incidence of advanced stage cancer and prolonged rectal bleeding history before diagnosis in young-onset patients with colorectal cancer.
Authors: Gurprataap Singh Sandhu, Rebekah Anders, Amy Walde, Alexis Diane Leal, Gentry Teng King, Stephen Leong, S. Lindsey Davis, William T. Purcell, Karyn A. Goodman, Whitney Herter, Cheryl Lauren Meguid, Elisa H Birnbaum, Steven Arthur Ahrendt, Ana Gleisner, Richard D. Schulick, Marco Delchiaro, Martin McCarter, Swati Patel, Wells A. Messersmith, Christopher Hanyoung Lieu
Journal: Journal of Clinical Oncology (2019)

3576 Background: In contrast to the older population, the incidence of colorectal cancer (CRC) in younger patients (aged &lt; 50 years) has been increasing in the last three decades. Younger patients tend to present with more advanced disease, thought to be in part related to lack of routine screening colonoscopies. The goal of this study was to examine characteristics of young-onset CRC and potentially identify factors that may aid in earlier diagnosis and treatment. Methods: We collected data for patients available through the University of Colorado Cancer Center Cancer Registry. Inclusion criteria included: 1) Diagnosis of colon or rectal cancer between the years 2012-2018 and 2) age at diagnosis of less than 50 years. Pertinent data including baseline characteristics, clinical presentation, family history, pathology, molecular testing, staging, and treatment were collected. Results: 211 patients with young-onset CRC were available for review. Mean age at diagnosis was 42.4 years and 55.5% were males. A total of 42.1% had rectal cancer and a majority of the colon cancer diagnoses had left-sided tumors (66%). Regarding clinical presentation, 52.2% presented with rectal bleeding prior to diagnosis. Of those who presented with rectal bleeding, the average time from the onset of bleeding to diagnosis was 271.17 days. 42.9% of young-onset CRC were stage IV at the time of initial diagnosis. Evaluation of the pathology specimens showed that 89.6% were adenocarcinomas and 63.5% were grade 2 or higher. At diagnosis, the mean BMI was 26.6 and the mean CEA was 135.5. A total of 72.5% of young-onset patients had a positive family history of any cancer. KRAS or NRAS mutations were present in 49.6% of patients, BRAF V600E mutations were present in 3.8%, and 10.8% were MSI-H. Conclusions: Prolonged rectal bleeding history prior to diagnosis was noted in a significant proportion of young-onset patients with colorectal cancer. Patients and primary care physicians should be made aware of this finding in order to facilitate timely referral for colonoscopy which may lead to earlier diagnosis, less advanced disease at diagnosis, and improved outcomes.
Atlas of group A streptococcal vaccine candidates compiled using large-scale comparative genomics
Authors: Mark R. Davies, Liam McIntyre, Ankur Mutreja, Jake A. Lacey, John A. Lees, Rebecca J. Towers, Sebastián Duchêne, Pierre R. Smeesters, Hannah R. Frost, David J. Price, Matthew T. G. Holden, Sophia David, Philip M. Giffard, Kate A. Worthing, Anna C. Seale, James A. Berkley, Simon R. Harris, Tania Rivera-Hernandez, Olga Berking, Amanda J. Cork, Rosângela S. L. A. Torres, Trevor Lithgow, Richard A. Strugnell, Rene Bergmann, Patric Nitsche-Schmitz, Gusharan S. Chhatwal, Stephen D. Bentley, John D. Fraser, Nicole J. Moreland, Jonathan R. Carapetis, Andrew C. Steer, Julian Parkhill, Allan Saul, Deborah A. Williamson, Bart J. Currie, Steven Y. C. Tong, Gordon Dougan, Mark J. Walker
Journal: Nature Genetics (2019)
Identification of clinically actionable mutations and immunotherapy biomarkers in Chinese esophageal squamous cell carcinoma patients.
Authors: Minghui Wang, Junkai Zhang, Weiquan Gu, Yun Li, RongFeng Song, Wenjing Wang, Qiang Cui, Shuirong Zhang, Xiaoqian Chen, Weiwei Shi
Journal: Journal of Clinical Oncology (2019)

e15576 Background: Esophageal squamous cell carcinoma (ESCC), the major esophageal cancer histological type in East Asia, has limited therapeutic options and is associated with poor prognosis. Here, we identified clinically actionable genomic alteration (GA) for potential targeted and immunotherapy in Chinese ESCC patients by next generation sequencing (NGS). Methods: Clinical data were collected from 150 ESCC patients from March 2011 to December 2018, with a median follow-up of 34 months. NGS-panel sequencing of 466 cancer genes was performed on FFPE tumor and matched blood sample. Tumor mutational burden (TMB) was assessed in all patients by standard NGS algorithms. PD-L1 expression was evaluated in 61 samples by IHC (28-8 Ab). Results: Overall, 75.5% of ESCC patients harbored at least one clinically actionable GAs with the most frequent being CCND1 (40%), CDKN2A (40%), CDKN2B (24%), PIK3CA (14%) and FGFR1 (8%). Most clinically actionable GAs occurred in genes involved with cell cycle (61%) and with PI3K pathway (23%). Clinically actionable GAs also distributed in BRCA2 (5%), ATM (3%), MET amp (3%), KIT (3%), EGFR mut (2%), PDGFRA (2%) and ERBB2 amp (1%). The lowest 25% (TMB-L), median and highest 25% TMB (TMB-H) value was 4.6, 6.9 and 9.2 muts/Mb, respectively. Compared with younger patients, patients ≥50 years had higher TMB ( p= 0.047). Compared with TMB-L ESCCs, frequencies of NOTCH2 (15.9% vs 0%, p= 0.015), PIK3CA (22.7% vs 2.8%, p= 0.019) and KMT2D (25.0% vs 5.6%, p= 0.031) were significantly higher in TMB-H. Notably, amplification in 11q13 region, MDM2/ MDM4 and EGFR, which potentially relates to immunotherapy hyperprogression, accounted for 48% of TMB-H. Eleven patients (18%) showed PD-L1≥1%, in which 7 pts were also TMB-H. Conclusions: In Chinese ESCCs, clinically actionable GAs were detected in most patients, which highlights the promise of molecularly directed therapies. Patients with PD-L1 positive/TMB-H/both, who could potentially benefit from immunotherapy, accounted for 41%. Older age, NOTCH2, PIK3CA and KMT2D mutations correlated with TMB-H.
Randomized phase II study with or without induction chemotherapy combined with accelerated high dose radiotherapy and cetuximab in locally advanced unresectable HPV positive squamous cell carcinoma of the head and neck.
Authors: Signe Friesland, Clas Mercke, Helena Sjödin, Gabriella von Dobeln, Hanna Carstens, Gregory Margolin, Einar Bjorgvinsson, Ingmar Lax, Michael Gubanski, Anna Embring, Pedro Farrajota Neves Da Silva, Josef Nilsson, Gun Wickart-Johansson
Journal: Journal of Clinical Oncology (2019)

6077 Background: Concomitant chemoradiotherapy (CT/RT) is the standard treatment for locally advanced non- resectable squamous cell carcinoma of the head and neck. Acute side effects can be serious and late effects important. Patients with HPV+ tumors carry a better prognosis than other patients. De-escalation studies are explored with respect to RT, dose, fractionation, target volumes, adjuvant pharmacotherapy, with encouraging results. However, several patients still recur locoregionally, also in high dose RT volumes. Some patients have distant metastases, often with massive tumor burden and late during follow up (FU). Purpose of the study: 1.To evaluate the effect of induction chemotherapy (IC) on (a) progression free survival (b) distant metastases as first site of failure (c) locoregional failure (d) pattern of tumor response, spatial and timely, exploring the possibility to reduce RT dose and/or target volume(s) in future protocols. 2. to address the impact of high dose RT for bulky disease, T3/T4 given concurrent with cetuximab (E). Methods: Patients had previously untreated stage III/IV (&gt;80 % st IV; TNM 7th), M0 disease, WHO 0-1, unresectable squamous cell carcinoma of the head and neck, HPV positive as evaluated with p16 and/or PCR. Pts were randomised between 2 arms. Pts in arm A were scheduled for 2 cycles of TPF : T (docetaxel) 75 mg/m2 day 1, P (cisplatin) 75 mg/m2 day 1 and F (fluorouracil) 1000 mg/m2 over 24 hours day 1-4. RT was delivered with IMRT to all pts : 68 Gy in 6 weeks for T1/T2 tumors, 76 Gy in 6.5 weeks for T3/T4 tumors with E given one week before and weekly during RT. Tumor response was evaluated according to RECIST with CT, MRI or PET/CT after IC, at 6-8 weeks, 1 and 2 years FU. Results: From january 2011 to february 2016, 152 consecutive pts were enrolled, 77 in arm A. All pts had oropharyngeal cancer. In arm A, 7 pts had CR after TPF, 19 had PR out of 36 evaluable pts. At 2 years FU 70/77 pts (91%) were alive in arm A, 69/75 (92%) in arm B. Distant metastases as first site of failure was 3 (3.9%) in arm A and 7 (9.3%) in arm B. Adverse events grade 3-4, ever registered, were seen in 71 pts in arm A and 63 in arm B, were transient, most often related to RT. Conclusions: Survival and locoregional control at 2 years was high and similar in both arms. Distant metastases as first site of failure was more than doubled in arm B, not having induction chemotherapy (IC). Clinical trial information: EudraCT number: 2009-013438-26.