bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of different images in gross target volume delineating on VX2 nasopharyngeal transplantation tumor models.
Authors: Wen QingLian , Xiang ZhangQiang 
Published: October 2019

127 Background: To determine the optimum conditions for diagnosis of nasopharyngeal carcinoma, we established VX2 rabbit model to delineate gross target volume (GTV) in different imaging methods. Methods:The orthotopic nasopharyngeal carcinoma (NPC) was established in sixteen New Zealand rabbits. After 7-days inoculation, the rabbits were examined by CT scanning and then sacrificed for pathological examination. To achieve the best delineation, different GTVs of CT, MRI, 18F-FDG PET/CT, and 18F-FLT PET/CT images were correlated with pathological GTV (GTVp). Results: We found 45% and 60% of the maximum standardized uptake value (SUVmax) as the optimal SUV threshold for the target volume of NPC in 18F-FDG PET/CT and 18F-FLT PET/CT images, respectively (GTVFDG45% and GTVFLT60%). Moreover, the GTVMRI and GTVCT were significantly higher than the GTVp ( P ≤ 0.05), while the GTVFDG45% and especially GTVFLT60% were similar to the GTVp ( R = 0.892 and R = 0.902, respectively; P ≤ 0.001). Conclusions: Notably, the results suggested that 18F-FLT PET/CT could reflect the tumor boundaries more accurately than 18F-FDG PET/CT, MRI and CT, which makes 18F-FLT PET-CT more advantageous for the clinical delineation of the target volume in NPC. Keywords: Nasopharyngeal carcinoma; Gross tumor volume; Magnetic resonance imaging, Computed tomography; 18F-FLT PET/CT; 18F-FDG PET/CT
Ned-170: A combination anti-cancer therapy targeting late stage, heavily pre-treated solid tumor malignancies.
Authors: Garmey Edward Graeme , Meetze Kristan , Martell Bridget 
Published: October 2019

141 Background: NED-170 is a 7-component regimen of both marketed drugs and nutraceuticals with established safety and tolerability profiles and antineoplastic activity. These components, including metronomically-dosed cyclophosphamide (CTX), metformin, naltrexone, alpha lipoic acid, genistein, curcumin, and melatonin, target four key pathways driving tumor growth and metastasis. Methods: NED-170 was evaluated pre-clinically for tolerability and efficacy using a murine CT-26 syngeneic xenograft model. After tumor volume reached 80-120 mm³, mice were randomized into three groups of 10. Experimental arms included: NED-170 allometrically scaled to provide comparable exposure to human clinical trial doses, vehicle, CTX alone, or an anti-PD-1 antibody. In parallel to these studies, a compassionate expanded access program (EAP) was established in 2013 as a precursor to formal clinical trials. To date, 21 pts. with stage IIIc/IV advanced solid tumor malignancies (5 ovarian, 6 sarcoma, 4 Br. Ca, 2 NSCLC, & 4 other cancers) who either sought alternatives to standard-of-care (SOC) chemotherapy or whose tumors progressed through available SOC options have been enrolled. Results: In pre-clinical studies, NED-170 demonstrated 78% tumor growth inhibition (TBI) which exceeded vehicle in a statistically significant fashion (p < 0.001). In contrast, anti-PD-1 treatment failed to achieve anti-tumor activity and CTX alone achieved 50% TBI. In parallel, 21 EAP pts. have been treated with a combined 1,217 months (mos.) of NED-170 therapy (median = 11.8 mos; range = 1.0-60.2). For all pts., the regimen has been safe and well-tolerated with no drug-related grade-3-4 adverse events or dose reductions/discontinuations reported. Observational data reported by pts. or physicians demonstrated that 81% of pts. derived benefit and improved quality of life in this late stage setting. Conclusions: Based on these encouraging data, NED-170 may provide late stage cancer pts. with a safe, effective, and lower cost alternative to standard chemotherapy. A multinational phase 1-2b clinical trial commencing in late 2019 is planned.
Innovations at scale only, capable of offering access to care solution: Example of district cancer care model (Pendharkar model).
Authors: Pendharkar Dinesh , Verma Vijayendra Kumar , Kumar Vinod , Nagar Hemraj , Khatri Sanjay 
Published: October 2019

19 Background: Sustainable development goals and voluntary global NCD targets 2025 plan to achieve 80% coverage by essential NCD medicines and technologies and drug therapy and counselling coverage to the tune of 50%. This can only be achieved by making coverage wider, going to periphery and urgently creating workforce capable of doing such an activity at scale. District cancer care model (Pendharkar model) tried to involve these principles and shown a scalable acceptance by the health system. Methods: To expand the access administratively, most peripheral but medically most suitable, district hospitals, were used to create nodal cancer units. To achieve the scale, all districts of a state were targeted. For creating an alternate workforce existing medical officers and nurses were utilised. Results: Over a period of 5 years seven states of India, having a population of more than 250 million, have agreed to join the programme.176 districts have created nodal cancer units with physician and two nurses in-charge of the programme. They delivery variety of care including counselling, chemotherapy, supportive, palliative, follow up care. They serve as nodal units for public education driving government programmes including public education. At least 300-500 patients avail the services on a daily basis, including more than 200 chemotherapy procedures in a day. On world cancer day educational activities happened in all these districts simultaneously creating massive impact. Conclusions: This unique innovative model has proven that health system changes can be brought at very large scale using existing government possibilities. Available infrastructure, human resource, minimal financial changes with administrative reforms can lead to impactful change in access to cancer care at scale.
Mutational analysis of >14,000 NGS tests from community oncology practices: The Sarah Cannon molecular landscape.
Authors: Burris III Howard A. , Schlauch Daniel , Sharma Yasha , Picard Shaita , Higgins Connor , Misch Amanda , Lachs Rebecca , O'Connor Niall , Correll Mick , Spigel David R. , Jones Suzanne Fields , Dilks Holli Hutcheson , McKenzie Andrew 
Published: October 2019

26 Background: Utilization of NGS-based testing for patients in community oncology settings continues to grow. A comprehensive analysis of the molecular landscape of > 14,000 patients with commercial tissue-based and plasma-based NGS (tbNGS and pbNGS) testing from Sarah Cannon’s (SC) network of community oncologists between 2012 and 2018 was performed. These data aid clinical trial design/feasibility and identify rare and actionable mutations in the community oncology setting. Methods: Medical Oncologists in the SC network ordered NGS-based molecular profiling for their patients as standard of care. Data from multiple commercial vendors starting in 2012 were harmonized and analyzed. Results: On average, tbNGS (n = 8938) and pbNGS (n = 5419) tests revealed 14 and 4 mutations/sample, respectively. The top 10 mutated genes from both tbNGS and pbNGS - tests are in the table. The most predominant mutation-types detected were SNVs in both tbNGS and pbNGS tests, and gene amplifications were detected in ~40% of tbNGS and ~22% of pbNGS tests. MET amplifications (range: 2 - 40 copies (pbNGS) and 6 - 82 copies (tbNGS)) and ERBB2 amplifications (range: 2.1 - 90.2 copies (pbNGS) and 4 - 293 copies (tbNGS)) were detected in 1.6% (MET-tbNGS) and 4.6% (MET-pbNGS) and 4.2% (ERBB2-tbNGS) and 2.69% (ERBB2-pbNGS) of patients, respectively, and informed clinical trial enrollment. Of the fusions detected, 28 NTRK rearrangements were detected (NTRK1 – 16, NTRK2 – 5, NTRK3 – 7) by tissue-based testing and 3 (NTRK1) fusions were detected by plasma-based tests. Conclusions: These data describe the mutational landscape of NGS tests ordered within community oncology practices. SC’s data infrastructure links NGS-based testing data and clinical data to support real world evidence research, and highlights the need for healthcare IT systems to marry clinical and genomic data for clinical decision support and clinical research. [Table: see text]
Carcinoembryonic antigen (CEA) as a candidate prognostic marker of nonmucinous pneumonic adenocarcinoma (P-ADC) of the lung.
Authors: Nakamura Satoru , Fukuda Minoru 
Published: October 2019

28 Background: Serum level of CEA as a prognostic marker in NSCLC is well known. In patients with non-mucinous P-ADC, there were some paradoxical cases with high CEA, in spite of improved symptom and chest X-ray after chemotherapy including first-generation EGFR-TKI. Methods: We retrospectively comfirmed serum level of CEA of five patients, including four patients with non-mucinous P-ADC and one patient with mucinous P-ADC, between 2001-2007, all Japanese female without smoking history, 66-78 years old (mean 73.6 y.o.). All of them revealed abnormal pneumonic shadow on chest X-ray, and were diagnosed by TBLB or cytology. These cases were all stage IIIB or IV, and were applied to chemotherapy including first-generation EGFR-TKI. We had measured serum CEA as possible from initial diagnosis and pre or post chemotherapy including first-generation EGFR-TKI to death. OS were between 25~66 months with four patients of non-mucinous P-ADC, and 9 month with one patient of mucinous P-ADC. Other tumor marker such as CYFRA and Pro GRP were all almost normal range. Results: CEA of three patients with non-mucinous P-ADC was elevated according to worsened symptom and X-ray, and were all highly maintained or increased in spite of improved symptom and X-ray after chemotherapy including first-generation EGFR-TKI. CEA of one patient with non-mucinous P-ADC was normal range in initial diagnosis, and no more measured. She has got symptom free and improved chest X-ray after chemotherapy. In one patient with mucinous P-ADC, serum CEA was normal range, so no longer measured. This patient was no effective for chemotherapy, and was dead 9 month after the initial diagnosis. Number of cases was quite few, so further examination is favorable. Furthermore, All cases were exaggerated finally, they might be resistant to first-generation EGFR-TKI. Conclusions: In three patients with non-mucinous P-ADC of the lung, serum CEA was paradoxically highly maintained or elevated in spite of improved symptom and chest X-ray after chemotherapy including first-generation EGFR-TKI. Therefore, serum CEA is a candidate for useful prognostic marker of non-mucimous P-ADC of the lung.
Validation and utilization of NGS-based HEMEaccuTest panel and analysis software for hematological malignancies.
Authors: Choi Hyun-Jeung , Lee In-Seon , Lee Min Kyoung , Jung Kyongyong , Lee Keunsook Kathy , Moon YoungJoon , Kim Kwang Joong 
Published: October 2019

29 Background: Hematological malignancies are forms of cancer that originates in blood-forming tissue, such as bone marrow, or in the cells of the immune system. Detection of genetic alteration in hematological malignancies are increasingly important because of diverse variants associated with classification and diagnosis of subtypes, and prognostic and therapeutic-response prediction. Next-generation sequencing (NGS) is a powerful technology to simultaneously analyze multiple genes to identify clinically well-described variants, as well as rare variants related to hematological malignancies for clinical diagnostics. Methods: We developed the targeted NGS panel (HEMEaccuTest) and automatic analysis software (NGeneAnalySys) for estimating pathogenicity of genetic variants related to hematological malignancies. HEMEaccuTest covers entire coding region of 108 genes that have putatively known for associations with the diseases according to the WHO, NCCN and ELN guidelines. The diagnostic utility of HEMEaccuTest and NGeneAnalySys were validated using reference materials and clinical specimens. Results: The results showed that pathogenic variants were effectively detected with an average coverage depth of 600X and a minimum coverage depth of 100X. It demonstrated an excellent limit of detection, with 100% sensitivity for SNVs at 2% VAF and for indel at 4% VAF. In addition, the analytical sensitivity, specificity and precision of the panel were higher compared to conventional methods such as Sanger sequencing, FISH, and real-time PCR. Noticeably, the approximately 300-bp-size insertions of FLT3-ITD was efficiently detected by a simulating algorithm. Conclusions: This analytical validation study demonstrated that HEMEaccuTest and NGeneAnalySys can be an excellent and useful tool for disease definition and therapeutic strategy in hematological malignancies. NGeneAnalySys provides the evidence-based categorization and clinical interpretation supported by Tier classification (Therapeutic, Prognostic, Diagnostic) of professional guidelines (ACMG/AMP, AMP/ASCO/CAP. etc).
Predicting survival in advanced cancers by applying machine learning to clinical narratives.
Authors: Lin Frank Po-Yen , Jameson Michael B. , Epstein Richard J. 
Published: October 2019

32 Background: We previously showed that a text mining approach can identify clinical prognostic factors from electronic medical records (EMR) in patients with advanced cancers (1). Here we further examine whether clinical narratives can be exploited to build prognostic tools by applying a machine-learning (ML) approach. Methods: A retrospective study of all patients with stage IV tumors was conducted at a single tertiary cancer centre. The text corpus was formed by extracting narratives from initial consultation letters authored by oncologists, and a feature learning pipeline (2) was then used to extract text features correlating to survival. Five classes of ML algorithms was then applied for survival prediction. Classification performance was assessed by stratified cross-validation and compared with Eastern Cooperative Oncology Group (ECOG) performance scores. Results: EMR were available for analysis in 4791 of 7043 patients from 2001-2017, and in 2211 of these cases ECOG performance scores were available. By applying ML on features extracted from EMR text, survival of patients at 2, 6, 12, 26, 52, and 80 weeks was predicted, with areas under the receiver operating characteristic (ROC) curve of 0.82, 0.80, 0.77, 0.72, 0.72, and 0.76 respectively. ML outperformed ECOG score in predicting patient prognosis between 12-16 weeks ( p < 0.05) and after 52 weeks ( p < 0.05), and was non-inferior at all other time points. Random forest was the best algorithm for the prognostic classification task. Feature filtering threshold was important to classification accuracy ( p < 0.001). Conclusions: In patients with advanced cancers, ML analysis of clinical narratives can be used to automate prognostication with greater accuracy than is currently obtainable from ECOG status. References: 1. Int Med J 2018; 48: S5: 8, 2. Sci Rep 2017; 7: 6918.
AI oncology algorithm and dynamic real-world learning health care system for precision oncology.
Authors: Petak Istvan , Hegedus Csilla , Tihanyi Dora , Doczi Robert , Filotas Peter , Mate Attila , Bacskai Miklos , Schwab Richard , Valyi-Nagy Istvan T. 
Published: October 2019

35 Background: Most tumours harbor multiple driver genetic alterations and many driver alterations are linked to multiple targeted therapies with various level of evidence. In addition, a specific treatment can be linked to multiple genetic alterations in the same tumor. Several public and private databases and software solutions are available to link driver alterations to treatments options, but in clinical practice of precision oncology we need a solution to select the right treatment for our patients based on the highest level of evidence also in case of complex molecular profiles. Methods: We have developed an AI oncology algorithm and rule-engine to prioritise treatment options for every cancer patient based on the individual molecular of their tumor. This IT solution can now prioritise 1200 compounds in clinical use or clinical development based on the computing of 24,000 evidence-based associations (“rules”) between drivers, targets and compounds. The software calculates a numeric score, the “aggregated evidence level” for each driver alterations and compounds. We have linked this decision support software to a dynamic patient case management system, which records responds to therapy to create learning system to provide dynamic decision support through several lines of therapies of each patient and to use real-life evidence to further improve the algorithm. Results: Our first results indicate that system allows individualised decision of diagnostic option between single gene tests to comprehensive 600 gene NGS panels and identification of actionable alterations in 83% of cancer cases. Conclusions: This system can be a first working solution to standardise clinical decisions precision oncology, which also helps the real-life evaluation of novel multigene molecular diagnostic tests and therapies to find their best indications and accelerate their reimbursement by insurance companies and national health funds.
Pattern of expression of CDX2 in colorectal cancer and its role in prognosis.
Authors: Singh Jagdeep 
Published: October 2019

36 Background: CDX2 (Caudal Homeobox2), a nuclear protein, is essential for the proliferation and development of intestinal epithelial cells and is frequently down-regulated during tumorigenesis. We have evaluated the pattern of expression of CDX2 in all stages of CRC (Colorectal Cancer) and its association with prognosis. Methods: We performed CDX2 staining by immunohistochemistry (IHC) on the available biopsy block of patients of CRC registered with Medical Oncology, JIPMER, from January 2014-January 2018. CDX2 scoring was done in semi-quantitative method. Results: 286 patients were registered during this period, of which only 110 biopsy blocks were available for staining. Of 110 patients, 77 (70%) constituted colon cancer and 33(30%) were rectal cancer. The median age was 54.2 years, 62 (56.4%) being male and 48 (43.6%) female with male to female ratio 1.3:1. In the study cohort, 33(30%) patients had stage II, 30 (27.3%) stage III and 47(42.7%) were stage IV. 73 (66.4%) were positive for CDX2 and 37 (33.4%) were negative. Lack of CDX2 was significantly associated with advanced stage, rectal site, poor grade of differentiation and presence of lympho-vascular invasion (LVSI). With median follow-up of 16 months, PFS (progression free survival) at 2 years was 30% for CDX2 negative compared to 67% for CDX2 positive (P = 0.009), while OS (overall survival) ) at 2 years was 46% for CDX2 negative versus 77% for positive (P = 0.01). Conclusions: Lack of CDX2 is associated with significantly worse PFS and OS, serves as poor prognostic factor in CRC. Lack of CDX2 expression is associated with advanced stage, higher tumor grade and presence of LVSI.
Genetic mutations associated with lung cancer metastasis to the brain.
Authors: Su ChunXia , Zhou Juan , Chu Xiangling , Zhao Jing 
Published: October 2019

41 Background: Lung cancer is the most common cause of mortality in both men and women, accounting for one-quarter of all cancer deaths. Most lung cancer-associated deaths result from metastasis, especially brain metastasis. Metastasis associated mutations are important biomarkers for metastasis prediction and outcome improvement. The current study aimed to reveal the molecular mechanisms and the genetic alterations involved in metastasis from lung tumors to the brain. Methods: We carried out whole exome sequencing (WES) of the primary tumors and the corresponding brain metastases from 15 patients with metastatic non-small-cell lung carcinoma. Results: We identified novel lung cancer metastases associated genes (CHEK2P2, BAGE2, AHNAK2) and epigenetic factors (miR-4436A, miR-6077). Lung-brain metastasis samples have more similar Ti/Tv(transition/transversion) profile with brain cancer. Focal adhesion, PI3K-Akt signaling pathway, MAPK signaling pathway are some of the most important tumor onset and metastasis pathways. Alternative splicing, Methylation and EGF-like domain are important metabolic abnormal for the lung-metastasis cancers. Conclusions: We conducted a pairwise lung-brain metastasis based WES and identified some novel metastasis related mutations which provided potential biomarkers for prognosis and targeted therapeutics.
Expression of CD47 and CALR in myeloproliferative neoplasms: Potential new therapeutic targets.
Authors: Rinaldi Ciro Roberto , Boasman Kristian , Simmonds Matthew 
Published: October 2019

48 Background: In solid tumours, calreticulin (CALR) overexpression produces a pro-phagocytic signal and is counteracted by concomitant expression of anti- phagocytic CD47, reflecting an apoptosis vs survival mechanism. Increases of both CALR and CD47 on the cell membrane have been observed in response to chemotherapy, however their role in myeloid malignancies is poorly understood. We investigated the expression of CALR and CD47 in patients with essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF). Methods: Mononuclear cells were collected from peripheral blood of 27 MPN patients (8 PV, 16 ET, 3 MF), and from 4 controls. In total 14 patients received cyto-reductive therapies (Hydroxyurea, Anagrelide and Ruxolitinib). Cells were fractionised into 4 compartments: membrane, cytoplasm, cytosol and nucleus. Proteins were extracted using TRIzol, with CALR and CD47 protein expression analysed by western blotting. Results: Total CALR and CD47 protein expression increased in MPN samples comparing with controls (CALR- 7.9 vs 5.1; CD47- 2.7 vs 2.2 fold). CD47 showed higher expression on MPN cells membranes when compared with CALR (22% vs 13.9%). We observed a significant reduction of CALR when patients are treated with cyto-reductive agents (ET- untreated 43.3% vs treated 2%, PV- 3.6% vs 2.2%, ET- 21% vs 11%). Interestingly we have observed a significant increase in CD47 after treatment in MF and PV (CD47 in MF- untreated 11.8% vs treated 34.3%, PV-11.4% vs 35.9%), suggesting an anti-phagocytic effect induced by cytotoxic drugs. In ET however, CD47 expression is reduced after treatment (22% vs 16.6%), suggesting instead a pro-phagocytic effect. Conclusions: CD47, is overexpressed on the membrane of patients with MPN suggesting a role for CD47 as a strong anti-phagocytic signal responsible for immune survival in MPN. MPN patients decreased CALR expression during therapy, but we observed a significant difference in CD47 expression in different MPN types. Anti-CD47 antibodies could represent a new strategy to enhance the pro-phagocytic signal via increasing the CALR expression, and in combination with standard cyto-reduction therapy, might represent a new therapeutical strategy in MPN.