tbuckley/cabot-search huggingface dataset:
Effect of ARK5 on the anti-tumour activity of OSI-027 via regulation of epithelial-mesenchymal transition in pancreatic cancer.
Authors: Xiao Zhi, Tingbo Liang
Journal: Journal of Clinical Oncology (2019)

e15758 Background: Pancreatic cancer (PC) is one of the most common lethal malignancies,OSI-027, a selective inhibitor of mTOR, has anti-tumour activity in PC and is currently in phase II clinical trials. According to the results of our previous study, OSI-027 sensitivity varies across pancreatic cancer cell lines; however, the underlying mechanisms are unclear. Methods: In this study,We sought to investigate the regulatory mechanisms underlying OSI-027 resistance in PC under both in vitro and in vivo conditions. Results: We demonstrated that in PC, sensitivity to OSI-027 was negatively correlated with ARK5 expression, and ARK5 knockdown could enhance OSI-027 sensitivity. Further, the mechanistic experiments showed that ARK5 inhibition could reverse EMT induced by OSI-027. Suppression of EMT by Twist siRNA could sensitize pancreatic cancer cells to OSI-027, but the combination of Twist siRNA and ARK5 siRNA did not enhance the anti-tumour effect of OSI-027. Moreover, under hypoxia-induced EMT, the cancer cells were less sensitive to OSI-027, but ARK5 siRNA could block the EMT process. The in vivo experiments showed that the combination of ARK5 and Twist siRNAs could enhance the anti-tumour effect of OSI-027 and restrain OSI-027-induced EMT. Conclusions: The results indicate that ARK5 plays a role in the resistance of pancreatic cancer cells to OSI-027 by regulating EMT and lay the groundwork for future clinical studies.
Prognostic differences and the effect of radiotherapy on survival in Merkel cell carcinoma: A retrospective analysis of a Swedish cohort.
Authors: Hannah Bjorn-Andtback, Giuseppe V. Masucci, Viveca Björnhagen-Säfwenberg, Weng-onn Lui, Lisa Elena Esther Villabona
Journal: Journal of Clinical Oncology (2019)

e21047 Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. The pathogenesis is linked to the immune system and Merkel cell polyoma virus (MCPyV) is present in about 80% of MCC. Reports have shown that patients with a virus-negative MCC have a worse prognosis. Adjuvant radiotherapy given after surgery has previously been shown to give a survival benefit in retrospective data. Our aim is to analyze clinical variables and their prognostic impact in a Swedish cohort. Methods: All patients with confirmed diagnosis of MCC referred to Karolinska University Hospital in Sweden from 1989-2018 were included and retrospective data was collected. Results: 113 patients were included. Median age at operation was 75.4 years (range 19-99); 64 (57%) were female. Treatment included surgery with (n = 46) or without adjuvant radiotherapy (RT). 43% of female patients and 37% of male patients received RT. Median overall survival (OS) was 2,6 years (range 0,1-25,8), for female patients 3,4 years (range 0,1-25,8) and for male patients 1,8 years (range 0,1-19,0). Median OS in surgery group was 1,8 years (range 0,4-25,8). With adjuvant RT median OS improved with 1,7 years (p = 0,0001) to 3,5 years (range 0,2-22,1), for female patients 4,0 years (range 0,2-22,1) and for male patients 2,0 years (range 0,3-8,8). MCPyV status was available in 53 patients. 74% were MCPyV positive, 26% negative. MCPyV gave no difference in OS, however when gender was added in to multivariate analysis, female patients with virus negative disease had better outcome than virus negative males (p = 0.03). In virus positive MCC there was no difference in OS between female and male patients. Conclusions: Our data confirms the positive impact of adjuvant radiotherapy on survival and illustrates the difference in outcome between female and male patients, with women having a better outcome. In the MCPyV group the tendency is that men with virus negative MCC has the worst outcome. Our findings indicate that MCPyV positive and negative MCC act as two different diseases and it also raises questions if there is a difference in the disease itself or the immune response towards MCC between male and female patients.
NISCAHN: A phase II, multicenter nonrandomized trial aiming at evaluating nivolumab (N) in two cohorts of patients (pts) with recurrent/metastatic (R/M) salivary gland carcinoma of the head and neck (SGCHN), on behalf of the Unicancer Head &amp; Neck Group.
Authors: Jerome Fayette, Caroline Even, Laurence Digue, Lionnel Geoffrois, Frederic Rolland, Didier Cupissol, Joel Guigay, Christophe Le Tourneau, Anne-Francoise Dillies, Sylvie Zanetta, Laurence Bozec Lemoal, Christian Borel, Aurélie Guyennon, Sophie Couchon-Thaunat, Valerie Costes, Isabelle Jallut, Jessy Delaye, Audrey Lardy-Cleaud, Sylvie Chabaud
Journal: Journal of Clinical Oncology (2019)

6083 Background: SGCHN are rare tumors including adenoid cystic carcinoma (ACC) and non-ACC, with no standard systemic treatment for R/M pts. We evaluated N monotherapy in R/M SGCHN pts. Methods: R/M SGCHN pts (ACC or non-ACC) not eligible to local treatment and with centrally confirmed RECIST 1.1 disease progression over the last 6 months were enrolled and received N 3 mg/kg IV, every 2 weeks for a maximum of 12 months (mo). Possibility was given to re-start N in case of progression during the 2-year follow-up phase. Primary endpoint was 6-mo non-progression Rate (NPR 6m ) as per RECIST 1.1. Secondary endpoints included ORR, PFS, OS, and safety. Considering that N would be uninteresting if NPR 6m ≤ 20% and promising if ≥ 40% and using a Fleming’s single-stage design (α: 5% unilateral, power: 90%), at least 14 successes/42 evaluable pts were required for each cohort to be positive. Results: 46 ACC and 52 Non-ACC pts (median age 61 yrs (range 29-81), 43.9% female, 55.1% PS1 and 2.0% PS2) were enrolled and received at least one dose of N. Median treatment duration was 5.5 mo (ACC) and 3.3 (Non-ACC). Median FU was 10.8 mo (ACC) and 8.3 mo (Non-ACC). 95 patients were evaluable for the primary endpoint. NPR 6m was 15/45 pts (33.3%, 90%CI :21.8;46.6) and 7/50 pts (14.0%, 90%CI:6.8;24.7) for ACC and non-ACC pts respectively. 4 (8.7%) partial responses (PR) and 26 (56.5%) stable diseases (SD) were observed in ACC cohort while 2 (3.8%) PR and 22 (42.3%) SD were observed in non-ACC. Median PFS was 4.9 mo (95%CI = 3.4;5.6) in ACC pts and 1.8 mo (95%CI = 1.7;3.5) in non-ACC pts. The most common related adverse events (AE) ( &gt; 10% by cohort) were asthenia, hyperthyroidism, diarrhea, rash, pruritus and hypothyroidism. 7/98 pts (7.1%) presented at least one related AE Grade 3-4 (mainly hepatic) and 9 pts (9.2%) prematurely discontinued Nivolumab due to toxicity. Conclusions: Limited efficacy was observed with N in R/M SGCHN pts. N in combination might be of interest and deserves exploration in ACC pts. Clinical trial information: NCT03132038.
Application of deep learning for clinical predictive modeling: An artificial intelligence recognition in spinal metastases.
Authors: Hui Zhao, Guangyu Yao, Yiyi Zhou, Zhiyu Wang
Journal: Journal of Clinical Oncology (2019)

e18050 Background: Spinal metastases are very common outcomes within solid malignant tumors, which could lead to various skeletal related events (SREs). The accurate and timely diagnosis is the key to improve prognosis. Recently, artificial intelligence(AI) has assisted doctors in many ways by different AI technologies. In this study, we applicated a deep learning model to classify and locate the metastatic lesions on spinal CT images. Methods: We set up a dataset consisting of 800 patients’ spinal CT images, which contained over 300,000 CT slices. And we built a multi-label classification and vertebrae segmentation model to recognize the metastatic lesions on spinal CT images. Then we trained and tested this model within our dataset, using a data augmentation by random flips and random rotations. Sensitivity and specificity were used to evaluate the performance of the model. Results: Our model showed that the diagnostic utilities of normal lesions were: sensitivity 81.7% and specificity 92%; while the diagnostic utilities of metastatic lesions were: sensitivity 84.7% and specificity 84.5%. Conclusions: Our model can effectively and accurately discriminate spinal metastases on spinal CT images. [Table: see text]
A multidisciplinary-guided digital solution to data capture in early-phase clinical trials.
Authors: Donna M. Graham, Joanna Clarke, Gemma Wickert, Leanna Goodwin, Carla Timmins, Dilshad Chang, Alison Walker, Amanda Rees, Steffan Stringer, Adam Theis, Louise Carter, Natalie Cook, Matthew Krebs, Fiona Thistlethwaite, Andrew M. Hughes, Jennifer Bradford
Journal: Journal of Clinical Oncology (2019)

e18063 Background: Data capture in early phase cancer clinical trials (EPCCT) is usually via paper records with manual transcription to the sponsor’s case report form. Capturing real time trial data directly to computer (eSource) may reduce errors and increase completeness and timeliness of data entry. A simulated system pilot took place between Oct 2018 and Jan 2019 at an EPCCT facility to appraise Foundry Health’s eSource system “ClinSpark”. Aims were to assess consistency and effectiveness of creating electronic templates for source data capture and live data collection compliance. Methods: A multidisciplinary focus group (2 research nurses, 1 doctor, 3 data managers) was created to collaborate with Foundry Health staff. The focus group agreed on a 52 item user acceptance test listing ideal features for a data collection tool, classifying items as high, medium or low priority. Specialised features of the eSource system were adapted to handle the complex needs of EPCCT. The pilot incorporated a 5 day boot camp for familiarisation to the digital platform; a conference room test using simulated patient data; construction of a trial template including contingency planning; and a clinic floor test with live simulated patient data collection using digital tablets. Results: During the 3 month pilot, templates for 2 EPCCT were planned and created. Using eSource, 43 items (83%) of the acceptance test were passed compared with 27 items (52%) for the current (paper-based) system. The paper system did not pass any of the 9 items for which eSource failed. For the 30 high priority items, eSource passed 30 (100%) compared with 22 for the paper system (73%). Time saving and potential error reduction were noted as additional benefits. Conclusions: This process demonstrates that a multidisciplinary approach can be used to successfully integrate a customised eSource system working with previously untrained staff. Improved performance across pre-specified domains and potential additional benefits were noted. As FDA encourages the use of digital solutions in clinical trials, using eSource provides a potential solution for compliant and efficient capture of data from protocol assessments at investigator sites and rapid data transfer to sponsors.
Characteristics and outcomes of patients with colorectal cancer and bone metastasis.
Authors: Faisal Shahjehan, Saivaishnavi Kamatham, Jordan Cochuyt, Zhuo Li, Dorin Colibaseanu, Amit Merchea, Pashtoon Murtaza Kasi
Journal: Journal of Clinical Oncology (2019)

e15063 Background: Bone metastasis from colorectal cancer is a relatively rare phenomenon. The aim of this study is to identify the risk factors and survival patterns of bone metastasis after colorectal cancer diagnosis. Methods: A total of 23,846 colorectal cancer patients who were diagnosed between 1972 and 2017 at Mayo Clinic were included in the analysis. Freedom from bone metastasis since diagnosis at 5, 10, 15, 25 and 35-years were estimated using Kaplan-Meier method. Multivariable Cox regression models were used to assess the differences in overall survival rate for patients with different cancer sides and cancer locations. All tests were two-sided with alpha level set at 0.05. Results: A total of 798 (3.3%) patients had a diagnosis of bone metastasis after colorectal cancer diagnosis over a median follow up of 3.2 years. Thirty-five year freedom from bone metastasis was 83% (95%CI: 80%-86%) for all patients, and were 87.13%, 82.29% and 77.26% for left colon, right colon and rectal cancer patients. Male gender, recent surgical years, and higher cancer stage were associated with higher risk of developing bone metastasis after colorectal cancer diagnosis. Rectal cancer patients had higher hazard of developing bone metastases compared to left and right colon cancer patients. Conclusions: We were able to identify several patient and tumor-related factors associated with the development of bone metastasis in patients with colorectal cancer. The proportion and factors identified are similar to other studies. Future directions would be to analyze other molecular determinants within this subset of patients.[Table: see text]
Correlation between TopIIα and ki-67 expression in tumors of luminal, primary operable breast cancer without HER2/neu overexpression in postmenopausal women as a prognostic factor.
Authors: Elena P. Ulianova, Oleg I. Kit, Vasilij V. Tokmakov, Iuliana S. Shatova, Inna A. Novikova, Aleksandr B. Sagakyants, Evgeniya M. Nepomnyashchaya, Oksana G. Shulgina, Elena N. Chernikova, Svetlana M. Bakulina, E. P. Lysenko, Elena S. Bondarenko, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2019)

e12065 Background: Assessment of proliferative activity is important in terms of tumor prognosis. Topoisomerase IIα (TopIIα) and ki-67 are common markers of breast cancer (BC) cell proliferation. The purpose of the study was to assess the correlation between TopIIα and ki-67 expression as a prognostic factor in luminal, primary operable breast cancer without Her 2 neu overexpression in postmenopausal women. Methods: 60 postmenopausal patients with BC (invasive ductal carcinoma) were equally divided into 3 groups: I –luminal A BC, surgical treatment with subsequent radiotherapy and hormonal therapy; II – luminal B BC, surgical treatment with subsequent radiotherapy and hormonal therapy; III – luminal B BC, surgical treatment with subsequent radiotherapy, polychemotherapy and hormonal therapy. Mean age of patients: I – 76.16±3.14 years, II – 65.0±3.91, III – 74.0±2.54 years. Immunohistochemical study was performed with mouse monoclonal ki-67 (Thermo scientific) and TopIIα (Santa Cruz Biotechnology) antibodies using the Reveal Polyvalent HRP-DAB Detection System. Results were analyzed using the STATISTICA 10.0 program (StatSoftInc., USA). Results: The average expression levels of the ki-67 marker in the groups were: I - 12.3±1.4%, II - 15.1±3.1%, III - 37.0±7.1%; TopIIα expression – 3.5±1.6%, 16.0±5.9%, 21.7±6.4%, respectively. The statistically significant Spearman correlation between TopIIα and ki-67 was observed both as general in groups (r = 0.787 at p &lt; 0.001) and in groups with luminal B subtype (groups II and III). Strong positive correlation between TopIIα and ki-67 was registered in groups II (r = 0.941 at p &lt; 0.01) and III (r = 0.864 at p &lt; 0.001) with luminal B subtype. Weak correlation was observed in group I with luminal A subtype (r = 0.477 at p≥0.05). Conclusions: The study revealed a correlative increase in the level of TopIIα with simultaneous overexpression of the ki-67 protein in the studied groups. This indicator can be considered predictive for breast cancer.
Additional prognostic value of OncoMasTR multigene prognostic signature to clinicopathological information in patients with HR-positive, HER2-negative, lymph node-negative breast cancer from the TAILORx Tissue Bank, Ireland.
Authors: Darran O'Connor, Catherine Margaret Kelly, John Crown, Niamh Russell, Stephen Barron, Tony Loughman, Seodhna Lynch, Anthony O'Grady, Katherine M Sheehan, Joanna Fay, Anurati Saha, Peter Dynoodt, Bozena Fender, Chan-Ju Angel Wang, Desmond O'Leary, Adrian P. Bracken, Arman Rahman, Claudia Aura Gonzalez, Nebras Al Attar, William M. Gallagher
Journal: Journal of Clinical Oncology (2019)

535 Background: Multigene prognostic signatures (MGPS) can identify early stage breast cancer patients who may require less aggressive treatment. To be clinically useful, MGPSs must provide additional prognostic information to clinicopathological information routinely used by clinicians. The OncoMasTR MGPS was discovered via a novel bioinformatic transcriptional network analysis. OncoMasTR consists of genes – Master Transcription Regulators (MTRs) – that regulate previously known prognostic genes and have identified functional roles in several hallmarks of cancer including proliferation, invasion and metastasis. The OncoMasTR Molecular Score (OM) consists of just 3 MTRs. The OncoMasTR Risk Score (OncoMasTR) combines OM with lymph node status and tumour size, and categorises patients as low or high risk. The OncoMasTR Test has been analytically and clinically validated. Methods: MTR expression was measured by RT-qPCR in tissue from 404 patients enrolled in an independent translational trial (NCT02050750) that collected tissue and clinical data from patients enrolled in TAILORx in Ireland. OM, OncoMasTR and Oncotype DX Recurrence Score (RS) were compared on the additional prognostic value they provided to Ki67, Nottingham Prognostic Index (NPI) and other clinicopathological information for distant recurrence (DR) and invasive disease (ID). Results: OM (LRχ 2 = 20.3, p &lt; 0.00001, c-index = 0.84) and OncoMasTR (LRχ 2 = 22.6, p &lt; 0.00001, c-index = 0.85) were significantly prognostic, and more prognostic than RS (LRχ 2 = 8.4, p = 0.004, c-index = 0.73) for DR. OM and OncoMasTR provided more additional prognostic information than RS to Ki67, NPI, tumour size, tumour grade, and age for DR. Similar results were found when OM, OncoMasTR and RS were compared on prognostic performance for ID. Conclusions: OM and OncoMasTR were significantly prognostic for DR and ID and added significant prognostic value to Ki67, NPI, and other clinicopathological information. Furthermore, OM and OncoMasTR showed superior prognostic performance to RS.
Molecular characterization of NSCLC-like and SCLC-like subsets in Chinese pulmonary large cell neuroendocrine carcinoma (LCNEC).
Authors: Lin Wu, Liming Cao, Likun Chen, Bo Zhu, Xiaohua HU, Lin Gen, Yingcheng Lin, Sheng Zhang, Cheng Huang, Wenying Peng, Meilin Jiang, Xinru Mao, Tengfei Zhang, Junyi Ye, Lu Zhang
Journal: Journal of Clinical Oncology (2019)

e13125 Background: LCNEC is an aggressive, biologically heterogenous carcinoma which can be molecularly characterized as SCLC-like and NSCLC-like. Accurate distinction of molecular subset is of major clinical relevance since it may guide treatment choices in LCNEC. Here we determined the genomic characteristics of the two LCNEC subsets in a Chinese cohort to clarify their correlations with traditional lung cancer histologies. Methods: FFPE samples from 31 LCNECs were sequenced using a 520-cancer-related gene panel, with an average sequencing depth of 1353X. Comparative mutational analysis was conducted between NSCLC-like LCNECs from our cohort and adenocarcinomas from TCGA dataset. Results: Despite similar clinical features in terms of stage and age at diagnosis, NSCLC-like (42%, 13/31) and SCLC-like (32%, 10/31) subsets from LCNEC displayed distinct molecular characteristics. NSCLC-like subset harbored significant higher mutation frequencies of STK11, KEAP1 and FAT3 (53.8%, 38.5% and 38.5%, p = .007, .046 and .046), while SCLC-like subset was characterized by highly mutated RB1 (100%, p &lt; .001) and PTEN (50%, p = .007). Compared with TCGA adenocarcinomas, NSCLC-like LCNEC displayed more frequent mutations in TP53, STK11, APC, KMT2D and SMARCA4 (76.9%, 53.8%, 30.8%, 30.8% and 23.1%; p = .043, .004, .045, .005 and .049). In addition, potential targetable alterations were present in 46.2% (6/13) pts of NSCLC-like subset. For those advanced stage pts, 2/5 NSCLC-like and 5/5 SCLC-like pts received relevant chemotherapy according to their molecular characteristics. The clinical outcomes of these pts are still under follow-up. Conclusions: This study demonstrates the distinct molecular features between NSCLC-like and SCLC-like subsets, and highlights the predominant genomic similarity and separate entities between NSCLC-like LCNEC with adenocarcinoma. Given the evidence that genomic profiling may aid in informing treatment decisions for pts with LCNEC, our study indicates that, based on accurate molecular typing, 46.2% NSCLC-like pts may benefit from potential targeted therapy and the rest of them may be more suitable to receive NSCLC-chemotherapy.
Reasons for discordance in treatment approaches between oncology practice and clinical decision support in China.
Authors: Jun Liang, Tianle Li, Shan-shan Zhang, Cheng Chen, Courtney VanHouten, Anita Preininger, Irene Dankwa-Mullan, Gretchen Purcell Jackson
Journal: Journal of Clinical Oncology (2019)

6555 Background: Therapeutic clinical decision-support systems (CDSS) are often evaluated by comparisons between CDSS options and actual practice decisions or expert opinions. Few such studies have carefully examined reasons for discordance. Methods: We reviewed 11 concordance studies from different hospitals across 8 provinces in China, published between 2017 and 2018. The studies compared IBM Watson for Oncology (WfO) therapeutic options to treatments selected by oncologists or a tumor board involved in review of cases for lung, colon, rectal, breast, gastric, and gynecological cancers. We identified given reasons for discordance and summarized themes across studies. Results: Of the 11 studies, 9 provided 1 or more reasons for discordance which could be analyzed. We found three major themes related to discordance: formulary restrictions, treatment-protocol differences, and physician or patient preferences (Table). Formulary differences between WfO and regional practices included off-label drug uses or unavailable therapies. Treatment-protocol differences included variations in regimens, such as simultaneous versus sequential treatments. Physician or patient preferences included factors such as the cost of treatment and logistics associated with various treatments. Conclusions: This study identified multiple reasons for discordance between an oncology CDSS option and oncologists’ treatment choices in China. Treatment differences arose from local formulary or protocol differences as well as provider and patient preferences. Future studies of CDSS should include reasons for discordance when assessing system performance in this manner. [Table: see text]