bluuebunny/crossref_metadata_2025_split huggingface dataset:
SYNERGY-AI: Artificial intelligence-based precision oncology clinical trial matching and registry.
Authors: Kurnaz Selin , Loaiza-Bonilla Arturo 
Published: October 2019

22 Background: Precision oncology encompasses the implementation of high level of evidence disease-specific and biomarker-driven diagnostic and treatment recommendations for optimized cancer care. Artificial Intelligence (AI), telemedicine and value-based care may optimize clinical trial enrollment (CTE) and overall cost-benefit. This ongoing, international registry for cancer pts evaluates the feasibility and clinical utility of an AI-based precision oncology clinical trial matching tool, powered by a virtual tumor boards (VTB) program, and its clinical impact on pts with advanced cancer to facilitate CTE, as well as the financial impact, and potential outcomes of the intervention. Methods: The SYNERGY-AI Registry is an international prospective, observational cohort study of eligible adult and pediatric pts with advanced solid and hematological malignancies, for whom the decision to consider CTE has already been made by their primary providers (PP). Using a proprietary application programming interface (API) linked to existing electronic health records (EHR) platforms, individual clinical data is extracted, analyzed and matched to a parametric database of existing institutional and non-institutional CTs. Machine learning algorithms allow for dynamic matching based on CT allocation and availability for optimized matching. Patients voluntarily enroll into registry, which is non-interventional with no protocol-mandated tests/procedures—all treatment decisions are made at the discretion of PP in consultation with their pts, based on the AI CT matching report, and VTB support. CTE will be assessed on variables including biomarkers, barriers to enrollment. Study duration anticipated as ~36 mo. The impact time to initiation of CTE on PFS and OS will be estimated by Kaplan-Meier and Cox multivariable survival analysis. Enrollment is ongoing, with a target of ≥ 1500 patients. Key inclusion criteria: Pts with solid and hematological malignancies; Pts cancer-related biomarkers. Key exclusion: ECOG PS > 2; abnormal organ function; hospice. Results: To be presented. Conclusions: AI-based, patient-driven CTE is feasible, highly effective and paradigm-changing. Clinical trial information: NCT03452774.
A pilot course of intensive training in radiation biology and physics for oncologists in sub-Saharan Africa.
Authors: Taniguchi Cullen M. , Jhingran Anuja , Stecklein Shane Richard , Melancon Adam , Court Laurence , Ohrt Jared , Kupferman Michael Elliot , Msadabwe Susan Citonje 
Published: October 2019

24 Background: Radiation therapy is an essential component of cancer care used for palliative and curative treatments access a wide spectrum of disease, but many low- and middle-income countries do not have equitable access to this technology or training in the radiation sciences. Towards this end, we launched a pilot program to teach the principles of radiation biology and radiation physics that are a basic component of training and credentialing of radiation oncologists in the United States. Methods: We designed a 5 days curriculum for radiation biology and radiation physics that were similar in depth and scope to the courses taught to residents at MD Anderson. Medical oncologists, medical students and radiation therapists from Zambia, Tanzania, Lesotho, as well as Papua New Guinea attended the course. All have experience with direct patient care in oncology, but no formal training in radiation biology or physics. A pre-test of 50 multiple choice questions for radiation biology and 40 multiple choice questions for radiation physics was administered to all students prior any instruction on the first day of the course, and the same test was given on the last day. Each question stem had 4 possible choices. Instructions consisted of lectures and problems sets with an emphasis on practical applications of radiation biology and physics. Results: The students (N = 22) scored a mean of 30.6±13.5% correct on the radiation biology pre-test and this improved to a mean of 57.7±13.1% after 5 days of instruction (P < 0.0001). Similarly, the students who took the medical physics exam (N = 22) had a mean 33.0±8.8% correct at baseline, which improved to 61.7±18.1% on the post-test (P < 0.0001). Conclusions: Despite almost no prior exposure to these complicated concepts, students exhibited nearly a two-fold increase in scores on a standardized test of radiation biology and medical physics. This pilot study demonstrates a proof-of-concept that this material can be taught effectively in a short time frame. Further refinement of this material may allow similar in-person intensive courses, teleconferencing, or archived videos to improve the education of radiation therapists in low- and middle-income countries.
Tumor-associated myeloid-derived suppressor cells as a potential biomarker for prognostication of response in treatment of diffuse large cell lymphoma.
Authors: Mukherjee Kalyan KUSUM , Dhar Sukanya , Bhattacharjee Rajib , Das Subhadip , Chakraborty Mohona , Bhanja Shayani , Ghosh Sarbari , Sarkar Madhurima , Dasgupta Shayani , Ghosh Diptendu , Bose Anamika , Baral Rathindranath 
Published: October 2019

30 Background: NHL is a type of lymphoma either B or T cell origin. However, 85% is of B cell type, especially diffuse large B cell lymphoma (DLBCL) with CD20+ in nature. Standard of care of CD20+DLBCL is R-CHOP 6 to 8 cycles and 66% patients generally respond to this treatment. Remaining 34% is still unresponsive to R-CHOP. Thus, establishment of a biomarker is required to intensify the treatment.Out of different scope of biomarker development, alterations in immune cellular components within tumor microenvironment may be tried as a potential biomarker to assess the possibility of occurrence of residual disease and relapse within 2 years for the DLBCL patients with 6-8 cycles of R-CHOP. Methods: : Selected CD20+ DLBCL patients (n=51) were treated with 6-8 cycles of R-CHOP and included in the present study with their informed consent. A panel of immune cells, like, T (CD4+, CD8+)-cells, regulatory T (CD4+CD25+FoxP3)-cells, MDSCs (CD33+CD11b+CD14-/+), memory T (CD8+CD45RO+)-cells and multidrug resistance (MDR) phenotypes (P-gp, MRP1), were studied by flow-cytometry and RT-PCR at different phases of treatment. Results: Within 51 selected patients, 9 were disease free and 11 patients exhibited stable disease for 2 years following the completion of treatment. Rest of the patients (n=31) showed relapse in different time periods. Among several immune cells studied, CD33+CD11b+MDSCs were remarkably elevated in high-grade residual-and-relapsed DLBCL patients compared to non-relapsed patients and normal healthy individuals. CD33+CD14+ monocytic, but not CD33+CD14-granulocytic MDSCs were mostly increased in relapsed patients than control. Moreover, expression of MDR phenotypic markers was found to be elevated in these relapsed patients. Among relapsed patients CD8+CD45RO+ memory T cells were increased, however, these cells are mostly corrupted in nature. Conclusions: Observed correlation between increased monocytic MDSCs with the occurrence of residual disease and/or relapse suggests monocytic MDSCs might be a potential biomarker for prediction of residual-and-relapsed DLBCL patients.
CENP-U function on TNBC.
Authors: Zhang Jin 
Published: October 2019

31 Background: Centromere protein (CENP-U) gene, as an important constitutive kinetochorecomponent, plays significant roles in cell caryomitosis. Our previous research found that about 25% of transgenic mice with CENP-U amplified had suffered breast cancer in body surface. Also, in highly aggressive breast cancer cell lines, CENP-U presented the highest expression. Furthermore, the CENP-U protein expression obviously increased in human invasive breast carcinoma compared with the normal gland and intra-ductal tissue.Here we aimed to investigate the biological functions and potential molecular mechanism of CENP-U in breast cancer tumorigenesis. Methods: Gene knockdown was accomplished by transient transfection. In addition, cell proliferation was analyzed with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay while cell apoptosis was measured by flow cytometry using an annexin V-FITC apoptosis detection kit. Then, VEGF secretion in the supernatant was detected with an enzyme-linked immunosorbent assay (ELISA). Furthermore,Vascular endothelial markers of nude mouse were discovered by immunohistochemistry. And the signaling activation in the breast cancer cells was accessed by western blot using specific antibodies. Results: We observed higher CENP-U expression in breast cancer compared to adjacent normal breast tissue, especially in TNBC.The MTT and EdU assay showed that CENP-U promoted the proliferation of the triple negative breast cancer (TNBC) cells while CENP-U downregulated promoted cell apoptosis. Furthermore, the ELISA results revealed that CENP-U significantly promoted the production and secretion of VEGF in TNBC cells. In addition, CENP-U downregulated inhibits tumor growth and angiogenesis in vivo. Importantly, CENP-U targeted HIF-1α,VEGFA and COX-2, which were shown by the specific antibodies in the western blot. Conclusions: The results showed that CENP-U influence the proliferation, apoptosis and angiogenesis especially of TNBC cells. But the affected signaling pathways require further study.
XenoSarc: A comprehensive platform of patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) for early drug testing.
Authors: Schoffski Patrick , Van Renterghem Britt , Cornillie Jasmien , Wang Yannick , Gebreyohannes Yemarshet Kelemework , Lee Che-Jui , Wellens Jasmien , Vanleeuw Ulla , Nysen Madita , Hompes Daphne , Stas Marguerite , Sinnaeve Friedl , Wafa Hazem , Topal Baki , Verbelen Tom , Debiec-Rychter Maria , Sciot Raf , Wozniak Agnieszka 
Published: October 2019

37 Background: STS is a family of rare, heterogeneous tumors with > 70 subtypes. There is an urgent need for reliable preclinical models, especially for orphan subtypes of STS, given the limited treatment options. Methods: A panel of PDX models was established by s.c. implantation of fresh tumor specimens in athymic NMRI mice. Growing pieces of tumor were re-transplanted to next generations of mice. At each passage fragments were collected for histological/molecular characterization. A model was considered “established” after observing stable features for at least 2 passages. Ex-mouse tissue samples were stored, characterized by immunohistochemistry/flow cytometry and used for in vitro drug testing. Results: Between 2011-2019, 329 samples from 301 consenting patients were transplanted; 56 models are established, 16 additional models are in early passaging. Clinical information about donor and tumor (including sensitivity to standard and experimental agents) is available. The platform includes models of dedifferentiated lipo- (10 models), myxofibro- (8), leiomyo- (7), synovial (2), intimal (2), CIC-positive round cell (1), mesenchymal chondro- (1), extraskeletal osteo- (1), myxoid lipo- (1), myxoinflammatory fibroblastic (1), rhabdomyo- (2) and high-grade undifferentiated pleomorphic sarcoma (7), as well as GIST (8), MPNST (4) and epithelioid hemangioendothelioma (1). Models are well-characterized, with molecular information on copy number changes (low-coverage whole genome sequencing) and gene expression profile (RNA-Seq) available. We also constructed tissue microarrays from the xenografts which are used for target identification and model selection for preclinical studies. Xenografts are available for in vivo testing of novel agents, and results already served as a rationale for a number of prospective clinical trials. Conclusions: XenoSarc offers opportunities for studying the biology of a variety of sarcoma subtypes including ultra-rare entities and is a valuable tool for early drug screening in preparation of clinical STS trials. The platform is well maintained and continuously expanded, and available to collaborators from academia and industry.
Establishment of a tissue microarray (TMA) platform as an efficient tool for soft tissue sarcoma (STS) research available for collaboration.
Authors: Schoffski Patrick , Lee Che-Jui , Van Cann Tom , Wellens Jasmien , Zlobec Inti , Bovée Judith V.M.G. , Britschgi Christian , Sciot Raf , Wozniak Agnieszka 
Published: October 2019

38 Background: STS is a very heterogeneous family of orphan malignancies, characterized by morphological and genetic diversity. Tissue samples from individual STS patients are commonly used for routine diagnostic and research purposes. TMAs from multiple sarcoma tissue blocks have potential advantages over conventional tissue analysis in terms of efficiency and cost-effectiveness. We have established a comprehensive sarcoma TMA research platform. Methods: TMAs were constructed using left-over tissue from STS patients diagnosed at University Hospitals Leuven (B), Leiden University Medical Center (NL) and University Hospital Zürich (CH), and from patients with orphan sarcomas enrolled in EORTC trial 90101 “CREATE”. The clinical cases are well annotated in terms of diagnosis, treatment and follow-up. Each TMA block contains duplicate/triplicate 1.0-1.5 mm tissue cores from representative areas selected by sarcoma pathologists. The construction of TMAs was performed using TMA Grand Master (3DHistech) at University of Bern (CH) and in Leiden (NL). Results: The following subtype-specific TMAs have been created: clear cell sarcoma (CCSA, 54 cases), alveolar soft part sarcoma (ASPS, 59), inflammatory myofibroblastic tumor (IMFT, 33), alveolar rhabdomyo- (24) and leiomyosarcoma (55). For CCSA, ASPS and IMFT we have matching TMAs from clinical routine and patients entered in EORTC 90101. As a tool for broader drug- and target-screening purposes in STS we also produced a multi-sarcoma TMA combining multiple, more common subtypes on one block: angio-, dedifferentiated, pleomorphic and myxoid lipo-, leiomyo-, myxofibro-, rhabdomyo-, synovial and undifferentiated pleomorphic sarcoma, and MPNST, with 7-11 individual cases per tumor type. TMA construction is ongoing in other relevant sarcoma subtypes. Conclusions: We are currently expanding a very useful TMA platform representing the broad heterogeneity of STS, from more common to ultra-rare variants. TMAs are available for rapid, cost-effective morphological, histochemical and molecular characterization and identification of novel drug targets in collaboration with academic and commercial partners.
Image-guided vacuum-assisted biopsy to assess pathologic complete response in breast cancer patients with exceptional response to neoadjuvant chemotherapy.
Authors: Teoh Victoria , MacNeill Fiona , Roche Nicola , Gui Gerald , Pope Romney , Downey Kate , Bishop Briony , Nerurkar Ashutosh , Tasoulis Marios Konstantinos 
Published: October 2019

39 Background: Image-guided vacuum-assisted biopsy (VAB) is increasingly used after completion of neoadjuvant chemotherapy (NAC) to assess residual disease in the breast, facilitate risk-adaptive surgery and potentially identify exceptional responders who may not require surgical intervention. The aim of this analysis was to investigate the diagnostic performance of a standardized post-NAC VAB protocol, developed following retrospective analysis of institutional data (1). Methods: Prospective cohort study of patients with HER2 positive and triple negative (TN) invasive ductal carcinoma, treated with NAC, who had partial/complete imaging response and underwent post-NAC VAB to aid surgical planning between 02/2018 and 06/2019. The aim of VAB was to sample the site of residual imaging abnormality (breast residuum <2cm) previously marked by clip insertion. Pathologic complete response (pCR) was defined as no residual disease in the breast (ypT0). Diagnostic accuracy of VAB was calculated using final surgical pathology as the reference standard. Simple descriptive statistics were performed. Results: 26 eligible patients underwent post-NAC VAB. This was representative in 23 cases. The overall pCR rate was 46.2% (42.1% for HER2 positive, 57.1% for TN phenotypes). The post-NAC VAB false negative rate (FNR) was 9.1% (95% CI: 0-26.1) and the negative predictive value (NPV) was 90.91% (95% CI: 60.27-98.51) with an overall accuracy of 86.96% (95% CI: 66.41-97.22). Conclusions: This data suggests that post-NAC VAB may reliably predict pCR in patients with HER2 positive and TN invasive ductal carcinoma with good response to NAC. Further technical refinements in VAB technique, standardization in patient selection and prospective trials are warranted to further explore the role of post-NAC VAB in supporting minimal or no surgery trials. References 1. Tasoulis MK, Roche N, Rusby JE, Pope R, Allen S, Downey K, Nerurkar A, Osin P, Wilson R, MacNeill F. Post neoadjuvant chemotherapy vacuum assisted biopsy in breast cancer: Can it determine pathologic complete response before surgery? J Clin Oncol 2018;36 (Supplement): abstr 567.
Clinical validation of GAGE family protein as a biomarker for radiotherapy resistance in cervical cancer.
Authors: Wujanto Caryn , Nin Dawn Sijin , Leong Yiat Horng , Tan David Shao Peng , Low Jeffrey Jen Hui , Ng Joseph Soon Yau , Arunachalam Ilancheran , Lim Diana , Choo Bok Ai , Deng Lih Wen 
Published: October 2019

42 Background: Cervical cancer is the 4th most common cancer in females. Treatment recommendation for locally advanced cervical cancer includes concurrent chemo-radiotherapy (RT) followed by brachytherapy. However, primary treatment failure is not uncommon and is attributed to RT resistance. In view of RT-associated complications, identification of RT-resistant groups at diagnosis will help to minimize exposure to unnecessary toxicities. Methods: Our initial studies analyzing the genetic profile of RT-sensitive and RT-resistant tumours from xenograft models have identified the GAGE-family protein as a genetic marker that is selectively upregulated in RT-resistant xenograft tumours in vitro & in animal studies and is associated with more aggressive phenotypes of these tumors. To clinically validate these findings, we carried out a pilot study on 8 patients and also analyzed GAGE-family protein levels in retrospective study samples obtained from initial biopsy samples from from patients who have completed chemoRT and brachytherapy for cervical cancer to correlate their initial GAGE-family protein levels with treatment response. Results: Immuno-histological staining of pathology samples from 8 patients in our pilot study have shown that those with a higher expression of GAGE-family protein at mRNA and protein levels are more resistant to standard RT. Our retrospective analysis of 43 cervical cancer biopsy samples showed significantly elevated levels of GAGE-family protein mRNA ( P= 0.0028) and GAGE-family protein intensity score ( P= 0.026) in the 20 patients who were found to be resistant to standard definitive RT on subsequent follow-up compared to 23 patients who responded well. Median follow-up was 42 months. Conclusions: GAGE-family protein mRNA and protein expressions are elevated in patients resistant to standard definitive RT. We aim to develop a classification system to stratify patients into responders versus poor responders based on their GAGE-family protein levels at initial diagnosis in order to personalize treatment regimen whereby good responders can be treated with reduced RT dose and poor responders can receive escalated RT dose and further therapies in order to improve outcome.
A novel computational OMICS and non-OMICS approach for identifying true pathogenic risk variants for Asian prostate cancer.
Authors: Chimmiri Anusha , Wang Hai-Tao , Yeo Eugenia Li Ling , Low Kar Perng , Tan Agnes Chong Yin , Woo Wai Yee , Ong Enya Hui Wen , Tan Terence Wee Kiat , Looi Wen Shen , Nei Wen Long , Tuan Jeffrey , Wang Michael Lian Chek , Tan Janice Ser Huey , Lee Lui Shiong , Tay Kae-Jack , Kanesvaran Ravindran , Khor Li Yan , Yeong Joe Poh Sheng , Tan Chien sheng , Chua Melvin Lee Kiang 
Published: October 2019

47 Background: Large-scale genome-wide association studies have established germline polygenic risk loci that underpin the susceptibility to prostate cancer (PCa). However, most trials conducted are in men of European ancestry with data missing for Asian male PCa. Here, we report on an in-house multidimensional bioinformatics pipeline that integrates OMICS and non-OMICS approaches in identifying true germline risk-variants for PCa in Asian men. Methods: We utilized a prospective cohort study of Asian men who were newly diagnosed with PCa. Whole exome sequencing (Illumina Hiseq, CA) of blood (100X) was performed. The OMICS-based approach entailed a stepwise screen for hallmarks of cancer-specific pathways. A genome-proteome network was then developed to filter for known pathogenic variants; this was followed by comparison against a large artificial database of aggregated germline variants (N = 95,000) with reported linkage to PCa susceptibility. Finally, mutations were filtered through a non-OMICS pipeline that entailed data synchronization with population-level statistics and clinical outcomes (recurrence and survival). Results: Preliminary analyses were based on 277 PCa cases; of which 50 were M1 cases. Screening using a non-combined unbiased approach yielded 36,157 germline variants. This contrast against our OMICS-based approach, which reduced the variant calls to 6,144 significantly associated mutations. Next, by focusing on pathway-specific genes related to hormonal regulation and known cancer hotspot mutations, we could further tighten our variant calls to 3,562 hormone-related variants (rs9269958 on HLA-DRB1) and 2,125 variants in known cancer genes, notably (rs8176320 on BRCA1/2, rs2555691 on LILRA2, rs8036934 on TP53BP1). Conclusions: Here, we show that application of an OMICS approach that combines pathway-driven analyses and an artificial dataset, along with population-level statistics and clinical relevance resulted in more robust annotation of germline variants that were associated with PCa.