bluuebunny/crossref_metadata_2025 huggingface dataset:
Automate incidental findings in radiology reports using natural language processing and machine learning to identify and classify lung nodules.
Authors: French Christi , Kurbegov Dax , Spigel David R. , Makowski Maciek , Terker Samantha , Clark Paul Alexander
Published: October 2019

49

Background: Pulmonary nodule incidental findings challenge providers to balance resource efficiency and high clinical quality. Incidental findings tend to be under evaluated with studies reporting appropriate follow-up rates as low as 29%. The efficient identification of patients with high risk nodules is foundational to ensuring appropriate follow-up and requires the clinical reading and classification of radiology reports. We tested the feasibility of automating this process with natural language processing (NLP) and machine learning (ML). Methods: In cooperation with Sarah Cannon, the Cancer Institute of HCA Healthcare, we conducted a series of experiments on 8,879 free-text, narrative CT radiology reports. A representative sample of health system ED, IP, and OP reports dated from Dec 2015 - April 2017 were divided into a development set for model training and validation, and a test set to evaluate model performance. A “Nodule Model” was trained to detect the reported presence of a pulmonary nodule and a rules-based “Size Model” was developed to extract the size of the nodule in mms. Reports were bucketed into three prediction groups: ≥ 6 mm, <6 mm, and no size indicated. Nodules were placed in a queue for follow-up if the nodule was predicted ≥ 6 mm, or if the nodule had no size indicated and the report contained the word “mass.” The Fleischner Society Guidelines and clinical review informed these definitions. Results: Precision and recall metrics were calculated for multiple model thresholds. A threshold was selected based on the validation set calculations and a success criterion of 90% queue precision was selected to minimize false positives. On the test dataset, the F1 measure of the entire pipeline was 72.9%, recall was 60.3%, and queue precision was 90.2%, exceeding success criteria. Conclusions: The experiments demonstrate the feasibility of technology to automate the detection and classification of pulmonary nodule incidental findings in radiology reports. This approach promises to improve healthcare quality by increasing the rate of appropriate lung nodule incidental finding follow-up and treatment without excessive labor or risking overutilization.
Multidimensional integrative medicine applied to outpatient cancer treatment in southern Brazil: Preliminary cost-effectiveness analysis.
Authors: Fleck James Freitas , Preger Ricardo , Venegas Luis Fernando , Trasel Henrique de Araujo Vianna
Published: October 2019

5

Background: Cost-effective analysis as part of cancer treatment decision-making. Methods: We reviewed deaths of 52 metastatic cancer patients treated with multidimensional integrative medicine (MIM) approach. Patients received standard oncologic treatment plus a MIM predefined program of emotional, cognitive and social support. The method included empathy improvement, changes on physician attitude and office environment, modulation of staff behavior supporting patient’s needs and rights, promotion of belongingness, increasing on patient’s protagonism using multimedia interactive narrative and shared decision-making. Patients were categorised according to the tumor site, pathologic, molecular and IHC characteristics, clinical stage and treatment. Observed survival was defined as the time elapsed between the detection of first metastasis and death. The observed survival for each patient was compared with the median expected survival previously reported on prospective randomised trials which had accrued patients with similar prognostic factors based on a best fit model. Treatment monthly cost for each patient was converted in American dollars (USD) on a daily exchange basis. Cost of the treatment periods were compared with those analysed in four large USA commercial managed care plans. Results: Treatment of metastatic cancer patients using MIM showed a 44% increase in median survival and a 48% decrease in cost. The estimated ICER/QALY was of 32304 USD, which represented 2.0 of Brazilian PPP. Conclusions: Despite methodological limitations, this is the first study to indicate a cost-effective survival increase in metastatic cancer patients using a MIM-behavioral modulation model. [Table: see text]
AI for early-stage breast cancer screening.
Authors: Manjunath Geetha , Madhu Himanshu , Kakileti Sivateja
Published: October 2019

50

Background: In emerging markets, a routine mammogram is not feasible due to cost, accessibility and lack of skilled technicians. It is also not effective in women with dense breasts. We explore an alternative modality based on Artificial Intelligence over thermal images for early detection of breast cancer. Infrared imaging is a non-contact, radiation-free technique that detects breast abnormalities based on thermal changes in the body seen due to increased vascularity and metabolic activity of the tumour. Thermography is only approved as an adjunct modality by US FDA, as manual interpretation of thermal images is error prone and subjective. We have developed an AI- based software (called Thermalytix) for automatic analysis of Thermal images using machine learning to extract and analyse abnormal patterns based on thermal distribution, asymmetry and vascular structure; to identify malignancy in symptomatic and asymptomatic subjects. Methods: We compare performance of Thermalytix with Mammography on a total of 769 subjects who walked into 3 sites for mammography screening. Subjects were sent for NIRAMAI screening prior to other tests (mammography or sonomammography). Pregnant women, lactating mothers and cancer survivors were excluded from the study. 534 subjects had either lump or nipple discharge as a symptom and 235 subjects did not have any symptoms. Mammography was conducted on 407 subjects and rest went through sonomammography as per the discretion of radiologist. Results: Sensitivity of Thermalytix was 92% in symptomatic women with a specificity of 71.9%; while 100% sensitivity and 92.9% specificity was found in women without any symptoms. Mammography, on the other hand, presented 91% sensitivity and 70.7% specificity in symptomatic women. In asymptomatic women, mammography however showed 67% sensitivity and 98.9% specificity. Conclusions: Thermalytix was found to be a promising screening and diagnostic tool while mammography worked better as a diagnostic tool. [Table: see text]
Immune dysregulation underpins radioresistance in nasopharyngeal carcinoma (NPC).
Authors: Wang Hai-Tao , Yeo Eugenia Li Ling , Hwang Jacqueline Seok Gek , Tan Gek San , Ong Enya Hui Wen , Low Kar Perng , Chimmiri Anusha , Woo Wai Yee , Nei Wen Long , Lim Kiat Hon , Tan Michael Chien Sheng , Loh Josh Jie Hua , Teo Constance Ee Hoon , Heah Harold Hon Wei , Tay Gerald Ci An , Wee Joseph , Iyer N Gopalakrishna , Sun Ying , Bei Jin-Xin , Chua Melvin L.K.
Published: October 2019

52

Background: Radiotherapy (RT) is a primary modality in the treatment of NPC. However, 30% of patients present with disease recurrence following RT of this radiosensitive tumor. Here, we investigated the molecular and immune profiles associated with radioresistant (RR) NPC. Additionally, we investigated for aberrant molecular pathways in paired recurrences of patients to uncover new drivers underpinning radioresistance. Methods: We prospectively recruited a cohort of 100 NPC patients who completed definitive RT/chemoRT; including 30 cases who were recruited at recurrence. Whole exome sequencing (WES) at 200x was performed to identify low frequencies ( < 1%) of true somatic nucleotide variants (SNVs) and copy number alterations (CNAs). Transcriptomic profiles from RNAseq were interrogated using supervised and unsupervised statistical approaches to determine aberrant pathways that were significantly associated with RR. Results: Genomic instabilityas characterized by percentage genome alteration (PGA) was comparable in our cohort. Additionally, we did not observe any common or exclusive CNAs between RR- and nr-NPC cases. Based on a constellation of immune-related signatures, we observed an “immune-cold” profile that is associated with RR-NPC compared to nr-NPC controls, which is characterized by low expression of CD8+ T cell infiltration and interferon-γ response. Expectedly, pathways relating to angiogenesis, hypoxia and NOTCH signaling were upregulated in the RR-NPC cohort. Interestingly, we observed a reversal of the immune phenotype from “cold” to an enrichment of effector T cell infiltration in the paired recurrences. Conclusions: Here, we present a comprehensive mutational landscape of RR-NPC, which revealed the potential role of the immune environment in modulating RR. The longitudinal immune dysregulation of the tumor microenvironment between the de novo tumors and recurrences could be a driver or passenger event during the onset of recurrence.
Clinical utility of CDH17 biomarker in tumor tissues and liquid biopsies for detection and prognostic staging of colorectal cancer (CRC).
Authors: Tsoi Helen , Wong Kwong-Fai , Luk John M. , Staunton Don
Published: October 2019

53

Background: Cancer surveillance using blood-based biomarker tests allows for early cancer detection and more effective prompt treatment. Immunohistochemical staining of tumor-specific antigens can also provide valuable prognostic information and contribute to the design of treatment strategy. Our early studies and work from other investigators have identified cadherin-17 (CDH17) as a promising biomarker in both tumor tissues and liquid biopsies. CDH17 overexpression in cancer tissue was found predictive of poor prognosis in patients with gastric cancer, hepatocellular carcinoma and ovarian cancer. Plasma CDH17 was elevated in patients with gastric cancer when compared to healthy subjects. However, despite the diagnostic and prognostic value of CDH17, robust and accurate assays for CDH17 detection in liquid and tumor biopsies have yet to be developed. Methods: In order to establish CDH17 immunoassays, we have first generated a proprietary library of more than 300 antibodies against CDH17, and from this library, isolated a panel of monoclonal antibodies (mAbs) exhibiting specific and high-affinity binding to the different extracellular domains of CDH17. Results: The immunohistochemical staining of CRC tissues with one of our mAbs revealed a stepwise increase in CDH17 with the progression of cancer from early to late CRC. A sandwich-ELISA was also developed to show significantly elevated plasma CDH17 in patients with CRC when compared to healthy individuals. Like CDH17 expression in CRC tissues, plasma CDH17 also showed a gradual increase with progression to more advanced stages of CRC. The newly developed ELISA also demonstrated that the number of CDH17-containing exosomes was significantly higher in blood isolated from patients with CRC. Notably, our mAbs could also enumerate CDH17-positive circulating tumor cells (CTCs), of which the level was associated with tumor stage. Conclusions: All these findings clearly indicate the clinical utility of CDH17 in tumor tissues and liquid biopsies for detection and prognostic staging of CRC. Further validation of our proprietary CDH17 immunoassays are being conducted in multiple independent CRC cohorts.
Identification of sentinel lymph nodes using contrast-enhanced ultrasound in breast cancer patients who underwent neoadjuvant chemotherapy.
Authors: Wu Xiufeng , Tang Lina , Zeng Yi , Chen Xia
Published: October 2019

59

Background: The aim of this prospective study was to evaluate the feasibility of contrast-enhanced ultrasonography (CEUS) for the identification of sentinel lymph node (SLN) in breast cancer patients with cN0 following neoadjuvant chemotherapy (NAC). Methods: Patients with cN0 following NAC (n=66) received a periareolar injection of SonoVue followed by ultrasound (US) to identify contrast-enhanced SLN before surgery. All patients underwent axillary lymph node dissection for verification of axillary node status after the SLN biopsy. The identification rate, sensitivity, specificity, accuracy, false negative rate, negative predictive value, positive predictive value was recorded. Results: In almost all cases, the SLNs were easily identified with an identification rate of 98.5 % (65/66). Compared with pathological diagnosis, sensitivity, specificity, accuracy, and false negative rate of CEUS for SLN diagnosis were 66.7%, 95.8%, 78.8%, and 14.3% respectively. Conclusions: Identification of SLN by CEUS is a technically feasible method with an identification rate as high as 98.5%. [Table: see text][Table: see text]
Prognostic implication of forkhead box protein O1 (FOXO1) and paired box gene 3 (PAX3) in epithelial ovarian cancer.
Authors: Cho Hanbyoul , Han Gwan Hee , Kim Jae-Hoon
Published: October 2019

61

Background: Transcriptional factor, Forkhead box protein O1 (FOXO1) has been reported to play an imported role in human cancer, but the role in epithelial ovarian cancer (EOC) has not yet been clarified. Here, we evaluatedthe expression and clinical significance of FOXO1 in EOC. Methods: Immunohistochemical analyses of FOXO1 and PAX3 in 212 in EOCs, 57 borderline ovarian tumors and 153 benign epithelial ovarian tumors and 79 nonadjacent normal epithelial tissues were performed using tissue microarray analysis. The data were compared with clinicopathological variables including the survival of EOC patients. Also, the effect of FOXO1 on cell growth were assessed in EOC cell lines. Results: The expressions of FOXO1 and PAX3 protein were significantly higher in EOC tissues than in nonadjacent normal epithelial tissues, benign tissues and borderline tumors respectively (all p< 0.001). Overexpression of FOXO1 was significantly associated with poor grade ( p = 0.004). FOXO1 expression showed trend of positive correlation with that of PAX3 in EOC tissues ( Spearman’s rho0.118, p= 0.149). Multivariate survival analysis revealed that the high expression of FOXO1 (hazard ratio = 2.74 [95% CI, 1.22–13.10], p = 0.001) could be an independent prognostic factor for overall survival. Most importantly, high expression of both FOXO1 and PAX3 showed high hazard ratio (hazard ratio = 5.53 [95% CI, 2.47–12.40], p< 0.001) for overall survival. In vitro result revealed that knockdown of FOXO1 was associated decreased cell viability and migration. Conclusions: This study reveals that high expression of FOXO1/PAX3 is an indicator of poor prognosis in EOC. Our results not only suggest the promising potential of FOXO1 and PAX3 as a prognostic and survival marker, but also warrant further studies on a possible link between the biological function of FOXO1 and PAX3 of EOC.
Clinical factors associated with comprehensive genomic variation profiling of cervical cancer.
Authors: Xu Qin , Lin Yibin , Lin Xian , Liu Jing , Li Li , Zheng Peng , Liu Bin , Shi Huaijing
Published: October 2019

62

Background: To better understand the mechanism contributing to cervical carcinogenesis, we perform a comprehensive analysis of genomic alterations in cervical cancer (CC). Methods: We conducted whole-exome sequencing of 43 CCs and established strict integrated workflow of genomic analysis. Correlation analysis was performed to measure the relationships between gene mutations and clinical characteristics of CC patients. Results: Genomic analysis revealed 28 genes frequently mutated in CC including BRD4 (4/43), AXL (4/43), MED12 (4/43), which are undetermined genomic features in CC, and identified recurrent genetic mutations in PIK3CA (16/43), KMT2D (11/43), KMT2C (6/43), FBXW7 (5/43), FAT1 (5/43), ERBB2 (4/43), EP300 (3/43) and NFE2L2 (3/43). Intriguingly, CC patients harbored high frequent mutations in BRCA2 (7/43), but not in BRCA1. The relationship between BRCA2 mutations and clinical factors is yet to be determined. The identified mutations predominately resulted in the dysregulation of the PI3K/AKT/mTOR pathway. Interestingly, we found that AXL mutations were positively correlated with FIGO stage ( P = 0.028), regional lymph node metastasis ( P = 0.011) and distant metastasis ( P = 0.022). KMT2C mutations were positively correlated with FIGO stage ( P = 0.004) and distant metastasis ( P = 0.009). SF3B1 mutations were positively correlated with regional lymph node metastasis ( P = 0.027) and distant metastasis ( P< 0.001). NFE2L2, ERBB2, RAC1, MED12, MET, BAP1, PTPRD and HNF1Amutations were positively correlated with distant metastasis ( P = 0.045, P = 0.004, P = 0.022, P = 0.001, P< 0.001, P< 0.001, P = 0.014, P< 0.001, respectively). POLD1 mutations were positively associated with regional lymph node metastasis ( P = 0.029). However, NOTCH1 mutations were negatively associated with regional lymph node metastasis ( P = 0.047). STK11 mutations were negatively associated with FIGO stage ( P = 0.013). Conclusions: Our results highlight the application of deep sequencing for understanding the molecular mechanisms and uncovering potential diagnostic and therapeutic targets of CC.
Clinical actionability of universal sequencing for germline cancer susceptibility gene mutations among patients with colorectal cancer: A prospective study.
Authors: Jiang Wu , Ding Peirong
Published: October 2019

63

Background: Genetic predisposition is an important cause of colorectal cancer (CRC). Previous studies have demonstrated that universal sequencing in unselected CRC patients with multi-gene panel could detect more hereditary cancer syndromes. However, it is unclear whether this strategy would change clinical management for the affected individuals. Methods: We prospectively enrolled a consecutive cohort of 486 CRC patients, comprising of unselective patients aged no more than 70 years and patients older than 70 years with hereditary risk features. All participants received germline testing using a comprehensive panel of 81 genes associated with various hereditary cancer syndromes. Results: Fifty-two pathogenic or likely pathogenic mutations were discovered in 51 (10.5%, 51/486) patients, including 20 (4.1%) Lynch syndrome, 11 (4.1%) germline mutations with known CRC risk, and 20 (4.1%) in other cancer susceptibility genes not traditionally associated with CRC. Among them, 21 (4.3%) mutation-positive patients would have been left undiagnosed if they only adhered to present guidelines. Nearly seventy percent (36/51) of the mutation-positive patients were found to carry clinicalactionable germline mutations, for whom enhanced screening and/or tailored treatment was recommended.CRC location, multiple CRC diagnoses, personal history of malignancy, or family history of malignancy was not significantly related to the presence of a mutation in non-CRC susceptibility genes. Conclusions: Universal germline sequencing for cancer susceptibility gene among CRC patients substantially identified more individuals with hereditary cancer syndrome and actionable germline mutations, and these patients might benefit from enhanced surveillance and better tailored treatment. Clinical trial information: NCT03365986.
Metformin, aspirin and statin and risk of cancer: A population-based study in Thailand.
Authors: Oranratnachai Songporn , Thongmung Nisakorn , Phetchoo Piyaporn , Rattanasiri Sasivimol , Thakkinstian Ammarin , Lukerak Somthawin , Vathesatogkit Prin , Trachu Narumol , Sritara Piyamitr , Sirachainan Ekaphop , Reungwetwatttana Thanyanan
Published: October 2019

65

Background: There were the conflicted results of the association of ASA, metformin or statin and risk of cancer in the previous studies. This is a population-based study in Thai population which aims to investigate the association between these drugs and the risk of cancer. Methods: A population-based retrospective study was done in Electricity Generating Authority of Thailand (EGAT) 1 and 2 databases which have been contained the 27-year and 15-year follow-up time, respectively. This database composed of the clinical characteristics, onset of cancer, and history of interested drugs from the questionnaire, together with the laboratory result from January 2002 to December 2015. We adjusted for age, sex, BMI, smoking and alcohol consumption. The incidence rate ratio (IRR) was estimated for the association between incidence of cancer and interested drugs. Results: Among 2508 and 2731 participants in EGAT1 and 2 respectively, the incidence of cancer was 8.3% in EGAT 1 and 3.5% in EGAT 2. From univariate analysis, use of interested drugs was significant associated with increased risk of cancer with IRR 1.74 ( P< 0.001) for ASA, IRR 1.54 ( P= 0.043) for metformin and IRR 1.64 ( P= 0.001) for statin. In multivariate analysis, only ASA showed significant increasing risk of cancer with IRR 1.47 ( P= 0.021). There was a trend increasing risk of cancer for metformin and statin users but not significant. Older age, low BMI, and female significantly associated with higher risk of cancer. In sub-group analysis, age and alcohol were significantly increased risk of GI cancer, while ASA use showed a non-significant trend of increasing risk of GI cancer. HBV infection was a strongly risk factor for hepatobiliary cancer and statin use had a trend lowering risk of this cancer but it was not statistically significant. Metformin also showed a non-significant trend of increasing risk of thoracic cancer. Conclusions: ASA use significantly associated with increasing risk of cancer but metformin and statin showed a trend of higher risk of cancer. These drugs may associate with cancer metabolome pathway which maybe an important role of carcinogenesis. However, ASA, metformin or statin use and risk of cancer is needed to confirm in the longer follow-up and larger cohort.
Single nucleotide polymorphism within gene in NFKBIA is associated with the risks of nasopharyngeal carcinoma in Chinese Han population.
Authors: Zhang Hanyi , Lu Shun , Sun Chang , Deng Siyao , Lang Jin Yi
Published: October 2019

67

Background: Nasopharyngeal Carcinoma(NPC) is an Epstein-Barr virus(EBV) associated malignancy with remarkable ethnic and geographical distribution. The EBV oncoprotein latent membrane protein 1 (LMP1) is the primary oncogene of EBV infection through the its signaling cascade and its connections to other pathways including NF-κB, TGF-β and JNK signaling, which plays an important role in the pathogenesis of NPC. In GWASs (Genome-wide association studies) associations these pathways were also identified. Single nucleotide polymorphisms (SNPs) in the regulatory regions may regulate the expression of genes in these pathways, or affect the function of the coded protein. Methods: Altogether 149 SNPs were covered by the 15 SNPs in the TRAF2, TRAF3, NFKBIA, MAP2K4, and CHUK genes were genotyped in a hospital-based case-control study of 350 NPC cases and 587 healthy controls from the Chinese Han. The observed genotype frequencies in the controls were tested for Hardy–Weinberg equilibrium (HWE) using the chi-square test. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between genotypes and NPC risk and tumor characteristics were calculated by logistic regression, and they were adjusted for multiple testing using the SNP spectral deposition (SNPSpD) approach for multilocus analyses. Results: We found one NFKBIA SNP was associated with NPC risk after adjustment for multiple comparisons. Minor allele carriers of the NFKBIA had an increased risk of NPC (P 0.05). The analyses were adjusted for age and gender. For a polymorphism with a variant allele frequency between 10 %and 50%, the study had greater than 90% power to detect an OR of 1.50 at a significance level of 0.05 (PS—software for power and sample size calculation, http://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/PowerSampleSize). The other genotyped SNPs that we found were not associated with NPC risk. Conclusions: Our data suggests that genetic variation especially in the NFKBIA maybe a useful biomarker for NPC screening and further studies are warranted.
Building a survivorship care plan delivery process: Experience in an academic center.
Authors: Dayao Zoneddy R. , Tawfik Bernard , Abernathy Janet , Wiggins Charles , Gundelach Amy , Lauer Richard C.
Published: October 2019

69

Background: The Institute of Medicine endorses delivery of survivorship care plans (SCPs) to the growing number of cancer survivors in order to improve the coordination of care between oncologists and primary care providers (PCPs). In response, the Commission on Cancer (COC) has increased the SCP delivery requirement to >50% of eligible patients, a goal that is difficult to meet given limited resources. Here we outline the initiatives taken to achieve this goal at the University of New Mexico Comprehensive Cancer Center (UNMCCC). Methods: Prior to 2017, SCPs were not routinely delivered. Beginning 2017, providers were tasked to complete and deliver printed SCPs , resulting in a 17% rate of SCP completion. However, there was general lack of provider support and enthusiasm as the process was time consuming with no method for identifying eligible patients and tracking SCP delivery. In 2018, designated staff was assigned to partially complete the SCPs to assist providers, resulting in an increase in SCP delivery rate to 41%. However, the same barriers existed. SCP softwares, although available, were expensive. A cost effective process therefore was needed. A committee was then formed to create a system-wide process utilizing the existing electronic health record (EHR) MOSAIQ. ASCO based SCPs were created. Once providers identify eligible patients, an SCP electronic order was initiated. Designated staff then partially completes the SCPs based on review of medical records. The EHR extracts data items including demographics, PCP information, cancer type and stage. The EHR is programmed to flag SCPs ready for delivery which the provider then edits and approves. This system tracks multiple time points including referral, completion and delivery of SCPs. This new process was implemented in April 2019. Quarterly reviews are set to assess metrics. Results: Utilizing existing EHR (MOSAIQ), a new SCP delivery process was created that allows tracking of assembly, completion and timing of delivery. Conclusions: To overcome existing barriers to SCP completion and delivery, a new cost effective process was created utilizing existing staff and EHR resources. Institutional support is key to the success of this initiative.
Enhancing rural and regional access to clinical trial using the Australasian Teletrial Model (ATM): Experience from MonarchE adjuvant breast cancer trial in Queensland, Australia.
Authors: Sabesan Sabe S.
Published: October 2019

7

Background: Australasian Teletrial Model (ATM) was developed in Australia to enhance rural and regional access to clinical trials using Telehealth. Under this model, trial clusters are established by connecting smaller satellite centers with larger primary sites using telehealth; governed by standard operating procedures and streamlined approval and contractual processes recently developed by the department of health of state of Queensland. Principal Investigator oversight and roles and responsibilities of sites are documented on supervision plans. We describe the implementation of an Eli Lilly’s adjuvant breast cancer trial MonarchE using ATM in Queensland. Methods: Two larger trial sites as primary sites were linked to four smaller centres to form Northern and Goldcoast clusters. This is a descriptive study of implementation research including perspectives of clinical trial staff. Results: Between February 2018-Feb 2019, four new sites and eight new satellite staff acquired clinical trial capabilities locally. Site initiation and regular trial meetings within clusters were conducted via telehealth. 11 patients were enrolled at satellite sites. No protocol violations occurred at any of the sites including documentation and investigator product handling. Staff (six trial nurses, and 10 medical oncologists) welcomed the model for facilitating inter-site collaboration and enhancing trial access to patients. Eli Lilly incurred additional cost for conducting one-off site visits to satellites and managing medication transport to satellites. Staff spent additional time for cluster coordination and development of new processes. Conclusions: Regional sites and their staff can acquire capabilities to offer clinical trials locally using the teletrial model. Consequently, rural patients can gain access to clinical trials closer to home without needing to travel long distances. Staff welcome this model for its many benefits to patients and the system. Initial increase in set-up cost is likely to be offset by better recruitment rates. With maturity, set-up costs and time to coordinate cluster processes are likely to lessen.
Change in neutrophil-lymphocyte ratio after initiation of chemotherapy can be a prognostic indicator in de novo stage IV breast cancer patients.
Authors: Shin Hae-Na , Kim Jisun , Kim Hee Jeong , Lee Jong Won , Ko Beom Seok , Son Byung Ho , Ahn Sei Hyun
Published: October 2019

70

Background: The de novo stage IV breast cancer has poor prognosis, predicting response to treatment in the affected patients is difficult. We investigated whether the initial neutrophil to lymphocyte ratio (NLR) at diagnosis and NLR change after the first palliative chemotherapy cycle can be a prognostic indicators. Methods: We retrospectively reviewed 218 de novo stage IV breast cancer patients with available NLR values who underwent palliative chemotherapy as an initial treatment. We analyzed cancer specific survival (CSS) according to initial NLR (iNLR), NLR change after the first chemotherapy cycle (ΔNLR), and a combination of these two. Results: The mean patient age was 47.2 years; the median follow-up period was 29.8 months. The mean iNLR and ΔNLR values were 2.83 ± 2.19 and 0.39 ± 3.74, retrospectively, amd were used as cut off points. There was no significant difference between low and high iNLR groups (p = 0.431); however, there was a significant correlation between ΔNLR and CSS (p = 0.031). The 1-, 3-, and 5- year CSS rates of patients in the increased ΔNLR group were significantly lower than those of patients in the stationary or decreased group. (78.4%, 35.4%, 20.8% vs 88.9%, 52.6%, 27.1%; p = 0.031). Multivariate analysis suggested that ΔNLR was an independent prognostic factor (hazard ratio (HR) = 1.748, 95% confidence interval (CI) = 1.084 - 2.818). The analysis of the combination of iNLR and ΔNLR showed that patients in the high iNLR and increased ΔNLR group had poorer prognosis than those in the low iNLR and stationary or decreased ΔNLR group (HR = 4.294, 95% CI = 1.586 - 11.629). Conclusions: Initial NLR alone was not a prognostic indicator among de novo stage IV breast cancer patients. However, patients with increased NLR after palliative chemotherapy exhibited worse CSS. Patients with high initial NLR and increased NLR after treatment might be a non responder to treatment.
In rheumatoid arthritis, the incidence of malignancies that are indicated for immune checkpoint inhibitors is increasing.
Authors: Urata Yukitomo
Published: October 2019

72

Background: An important side effect of immune checkpoint inhibitors (ICI) is immune related side effects, and in autoimmune diseases, the incidence is increased. For this reason, ICI for autoimmune diseases are carefully administered. However, among the malignancies that develop in autoimmune diseases, the frequency at which the (ICI) is indicated is unclear. This study is to clarify the incidence of malignancies to which ICIs are indicated in rheumatoid arthritis (RA), a typical autoimmune disease. Methods: In RA patients, the development of malignant tumors that can be indicated for IC was investigated at every year from September 2014, (September 2014 - August 2015: 2014 group; September 2015 - August 2016: Group 2015; September 2016 - August 2017: 2016 Group; September 2017 - August 2018: 2017 group). Patients with a history of malignant tumor treatment within 10 years were excluded at registration. IC adaptation was judged by the presence or absence of IC adaptation approval at diagnosis of malignant tumor. Results: The number of RA patients, age (year), disease duration (year), malignant tumor incidence (%), IC adaptive malignant tumor incidence (%) of each group are shown; [n = 479, 68(61-77), 8.8 (4.4-13.9), 9 (1.9%), 0 (0%)], [n = 504, 68 (61-77), 8.0 (3.7-12.8), 12 (2.4%), 0 (0%)], [n = 514, 68(61-77), 7.4 (3.4-12.7), 7 (1.4%), 1 (0.2%)], [n = 526、67 (60-76), 7.3 (3.1-12.6), 37 (7.0%), 9 (1.7%)]. Conclusions: The incidence of IC-adapted malignancy has increased in RA due to an increase in malignant tumor incidence, development of a new IC (methods), combined use of IC and other cancer treatment methods, and expansion of IC indication diseases. Due to the coexistence of autoimmune diseases and malignancy therapy, familiarity with malignant tumor treatment is essential for rheumatologists.
ChemoPalRx: Development and implementation of a chemotherapy mobile provider order entry system in a safety net hospital.
Authors: Hung Kin Wai (Tony) , Banerjee Natasha
Published: October 2019

73

Background: Computerized provider order entry (CPOE) systems have been shown to enhance the safety and efficiency of prescribing chemotherapy over the handwritten ordering process. However, many institutions lack the financial ability, technological capability, or operational flexibility to invest in and implement such a system. In particular, Olive View-UCLA Medical Center (OVMC), a Los Angeles County safety net hospital, is among these institutions with unique restrictions that preclude the use of chemotherapy CPOE and mandate handwritten orders. Methods: In an effort to bridge the gap for safe chemotherapy prescribing, we aimed to develop and implement an effective, scalable, and sustainable chemotherapy provider order entry solution that was operationally sensitive to institutions without a chemotherapy CPOE. The solution was designed as a mobile application using Xcode, the integrative development environment of Apple Inc., with the Swift programing language. Results: On September 5th, 2018, we launched a free, chemotherapy provider order entry solution on the worldwide Apple App Store – ChemoPalRx. Using ChemoPalRx, providers can search, customize, and print common chemotherapy regimens in prescription format. Along with a reference library of over 120 order set and 450 medications, ChemoPalRx is equipped with the functions to automate dosage calculation, suggest pre-medications and safety parameters, and trigger alerts for missing prescribing information. As a quality improvement initiative, we implemented ChemoPalRx at OVMC. Implementation stages include obtaining administrative buy-in, consulting with multidisciplinary staffs, investing $100 USD for a prescription printer, and encouraging providers to download ChemoPalRx on their own mobile devices. An ongoing prospective cohort study is being conducted to determine ChemoPalRx effectiveness in reducing errors compared to handwritten orders. Conclusions: ChemoPalRx is developed to enhance the safety and efficiency of chemotherapy prescribing. Implementation of this mobile application is feasible in the safety-net hospital setting and has the potential to transform oncology practices globally.
Innovation in evidence synthesis: A living systematic review of immune checkpoint inhibitors in cancer patients.
Authors: Riaz Irbaz Bin , Rawal Samarth C , Siddiqi Rabbia , Asghar Noureen , Akhtar Maheen , Gajic Ognjen , Wang Zhen , Montori Victor , Herasevich Vitaly , Go Ronald S. , Baral Chitta , Rajkumar S. Vincent , Murad M. Hassan
Published: October 2019

80

Background: Several previous systematic reviews and meta-analyses have attempted to summarize toxicity of Immune Checkpoint inhibitors (ICIs). However, very soon after each one of these reviews has been published, it became outdated. ICIs are currently used in 14 different cancers and data is rapidly evolving from new clinical trials. A living Systematic review, which is defined as a systematic review that is continually updated to incorporate relevant new evidence as it becomes available, is necessary in this situations. Methods: In order to dynamically display content -- including textual data, tables, charts, and graphs – standard data formats and protocols were designed for various components of the systematic reviews carried out by researchers. Given these standardized formats, software was written to interpret this data and output the information in the appropriate format, such as a forest plot or data table. Finally, a dynamic interface that enables user inputs (such as which aspect of the meta-analysis to view) and displays the associated output was designed. The overall living Systematic Review infrastructure includes monthly literature searches, cumulative meta-analysis, and an online reporting platform. Results: We have developed a Living Systematic Review engine that can take in standardized data and reflect this data in an interactive, intuitive manner in the form of text, tables, and plots. This interface can also be manipulated via user input to organize and sort data tables or omit/highlight specific pieces of data. Conclusions: We have initiated the first living systematic review in immune-oncology that will be continuously updated, incorporating relevant new evidence as it becomes available, and will provide accurate and up to date toxicity estimates to support clinical decision making. The Living Systematic Review interface allows users to easily and intuitively access the most recent available clinical evidence on toxicity of ICIs.
Development of hematologic toxicity with sequential treatment of Y90 followed by PRRT in five patients at single institution with metastatic neuroendocrine patients.
Authors: Singh Jaswinder , Singh GINA J
Published: October 2019

81

Background: In metastatic neuroendocrine tumors (NET) peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogues (Lu-177-DOTATATE) and selective intra-arterial radio-therapy (SIRT) with Y-90-microspheres are increasingly used promising treatment options. Rarely patients have been treated with sequential use of both treatment modalities . Severe adverse effects are rare and mainly concern hematologic changes and development of prolonged cytopenias . There is no data about possible cumulative side effects particularly regarding hematologic toxicity in the case of sequential use of both treatments. Methods: 5 Patients with hepatic metastasized NET treated both with SIRT and PRRT during 2010 - 2019 were included. Average time interval between treatment of y90 and PRRT was 2.5 years. All of them were treated with y90 before PRRT. Average treatment with Y90 was 3 doses. Results: In the follow up Platelets (159 to 89), leukocytes (7.5 to 3.7) and hemoglobin (13 to 11.6 ) decreased significantly, LFTs, bilirubin and creatinine did not change significantly. No severe toxicity (Grade 3 or 4) was experienced. 80 % of the patients showed decreasing blood counts after the therapies and was prolonged for average of 9 months. Conclusions: In metastatic neuroendocrine tumors (NET) sequential treatment with peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogues (Lu-177-DOTATATE) after selective intra-arterial radio-therapy (SIRT) with Y-90-microspheres is possible and well tolerated except for hematological toxicity.
Adjuvant nab-paclitaxel plus gemcitabine versus gemcitabine in resected pancreatic ductal adenocarcinoma: A Chinese single institution experience.
Authors: Yin Zhuzeng , Liu Rong
Published: October 2019

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Background: Adjuvant chemotherapy with gemcitabine (GEM) is standard care for resected pancreatic ductal adenocarcinoma (PDAC). Nab-paclitaxel plus gemcitabine (AG) vs gemcitabine (GEM) have shown better survival and tumor response with in advanced or metastatic PDAC. We aimed to determine the efficacy and safety of AG compared with GEM for resected PDAC. Methods: We retrospectively reviewed resectable PDAC patients (pts) who received AG or GEM as adjuvant chemotherapy from January 2013 to December 2016 at the Chinese PLA General Hospital, Bei Jing, China. Pts received nab-paclitaxel (125mg/m2) followed by GEM (1,000 mg/m2) on days 1, 8 every 3 weeks or GEM (1,000 mg/m2) alone on days 1, 8 every 3 weeks for 6 cycles unless disease progression or there was unacceptable level of adverse events. Disease free survival (DFS), overall survival (OS) and toxicity were analyzed. Results: Among 70 pts received AG or GEM as adjuvant chemotherapy, 10 pts were excluded due to the serious complication or R2 resection. The analysis was based on 30 pts in each group undergone complete macroscopic (R0 or R1) resection. Median DFS was 15.8 months (95% CI 13.1-18.5) in AG group (6 pts not arrived) compared with 12.2 months in GEM group (95% CI 9.6-14.8, P = 0.039, 3 pts not arrived). Median OS was 28.3 months (95% CI 21.9-34.6) in AG group (11 pts not arrived) as compared with 20.6 months in GEM group (95% CI 11.2-29.9, P= 0.028, 7 pts not arrived). The 2 years survival rate was 63.3% versus 43.3% in AG group versus GEM group. The most common adverse events of grade 3 or higher were leukopenia (32.3% in AG group vs. 20.7% in GEM group, P= 0.387), neutropenia (45.2% vs.31%, P= 0.298), G-CSF use (41.9% vs. 24.1%, P= 0.177), sensory peripheral neuropathy (51.6% vs. 24.1%, P= 0.036) and fatigue (3.2% vs. 3.4%, P= 0.737). Conclusions: Our results provide the evidence that the adjuvant combination of nab-paclitaxel plus gemcitabine significantly improved DFS and OS of resected PDAC.
Generation of personalized tumor Biopsy-Derived Natural Killer (BDNK) cells.
Authors: Teo Hui Min Vivian , Goh Si Wei , Sari Intan Permata , Chew Wei Leong , Lim Hsuen Elaine , Dasgupta Ramanuj , Sharma Ankur
Published: October 2019

86

Background: Natural killer (NK) cells play promising roles in cancer surveillance and possess multiple unique characteristics for allogenic cell transfer (ACT) in the cancer immunotherapy. However, most studies were applicable to ex vivo expanded NK cells from the peripheral blood, which requires massive amount of cell numbers for the initial isolation and expansion. Moreover, recent studies have demonstrated a phenotypic heterogeneity between peripheral and tissue resident NK cells. Methods: In this study, we aim to establish the ex vivo expansion of tumor infiltrating NK cells directly from diagnostic breast core biopsies followed by functional validation through in vitro assays. Results: A total of 20 breast TILs models, including T and NK cells, were successfully established through genetically modified K562 feeder cells co-culture approach. These models represented all the major sub-types (hormone positive and negative) of breast cancers. Next, we extensively evaluated the tumor-reactivity of the selected NK models via effector:target cytotoxicity assays. Interestingly, non-invasive breast tumor line has exhibited a strong preferential kill by NK cells whereas the invasive line counterpart was able to escape NK cell-mediated cytotoxicity. Conclusions: The resource generated in this study has revealed tumor infiltrating NK cells as a potential tool for cell-based therapy in solid tumors. Furthermore, this study provides a platform to investigate the immune-resistance mechanism involved between tumor and NK cells, thus, paving the way to the discovery of novel cancer immunotherapy targets.
Progression-free survival as a predictor of overall survival in patients with advanced breast cancer: A real-world study from the China National Cancer Center and validation in the Memorial Sloan Kettering Cancer Center Cohort.
Authors: Mo Hongnan , Xu Binghe , Ma Fei , LI Qing , Zhang Pin , Yuan Peng , Wang Jiayu , Luo Yang , Cai Ruigang , Li Qiao , Li Yiqun , Guan Xiuwen , Lin Shaoyan , Chen Yimeng , Wang Zijing
Published: October 2019

88

Background: Breast cancer is a clinically heterogeneous disease. The aim of our study was to evaluate the effect of progression-free survival (PFS) in predicting overall survival (OS), and to explore whether PFS in the first-line treatment could help in the choice of posterior regimens. Methods: Data from the China National Cancer Center database that recorded 2061 women from February 1992 to March 2018 were pooled as the study cohort. Women were eligible if they had metastatic breast cancer and had not received systemic treatment for the advanced disease. The independent validation cohort was composed of 1756 patients with advanced breast cancer from the Memorial Sloan Kettering Cancer Center. Results: The correlation coefficient between PFS and OS was 0.862 in patients receiving endocrine therapy alone as first-line treatment, and 0.647 in the whole study cohort (all P < 0.0001).Receiver operating characteristic curve indicated that PFS = 12 months was the optimal cutoff value for predicting patient’s survival(P < 0.0001). In the study cohort, the median survival time among patients who experienced any PFS at 12 months was 29.0 months, compared with 72.6 months in those patients who did not experience any PFS at 12 months (HR = 2.736, P < 0.0001). Meanwhile, the median PPS after progression was 22.6months in patients whose PFS < 12 months, which was also significantly worse than that in patients who did not progress at 12 months (median 31.3 months, P = 0.001).Notably, in the subgroup analysis of 732 with hormone receptor positive and HER2 negative disease, combined chemotherapy assecond-line treatment could significantly improve patient survival compared with single agent chemotherapy (HR = 0.597, P = 0.040) in patients with first-line PFS > 12m, but not in patients with first-line PFS < 12m (P = 0.109).A similar pattern is observed in the validation cohort. Conclusions: First-line PFS at 12 months predicted OS in patients with advanced breast cancer, and could potentially serve as a convenient identifier in clinical practice to precision medicine approach.
The role of HOMER3 in liver cancer progression.
Authors: Makondi Precious Takondwa
Published: October 2019

89

Background: Liver cancer (LC) is in the seventh most common cancer and the fourth largest cause of cancer deaths. Although significant progress has been made in the prevention and treatment of viral hepatitis; alcoholic liver disease, obesity and diabetes are now emerging as major causes for LC. Recently there has been increase in identification of biomarkers which can predict LC risk and disease progression, but the roles of HOMER3 gene in LC are not known. Methods: First the expression of HOMER3 between normal and tumor tissues was determined using The Cancer Genome Atlas (TCGA), Genetic Expression Omnibus (GEO) and protein atlas datasets. HOMER3 expression at different clinical stage and overall survival (OS) was also determined. The role of HOMER3 on OS in relation to cancer stage, hepatitis virus infection and alcohol intake was also determined. STRING database determined HOMER3 interaction network and TCGA was used to verify the correlation status, and the roles of the network genes on OS. The pathways enriched by HOMER3 were determined by Gene Set Enrichment Analysis (GSEA). Results: HOMER3 was significantly highly expressed in tumor tissues as compared to normal tissues. The expression of HOMER3 correlated positively with clinical stage, with highest expression in advanced stages (Stage 3 and 4), and high HOMER3 expression was associated with poor OS. HOMER3’ s high expression was associated with poor OS in advanced stage, alcohol intake, and in those negative of viral hepatitis infection. HOMER3 interacted with HOMER1, SHANK1, GRM5, GRM1, DLGAP1, SHANK2, DLG4, SHANK3, DLG2 and DLGAP4, with positive correlation to HOMER1, SHANK1, GRM5, GRM1, DLGAP1, DLG4 and DLGAP4 and negative correlation to SHANK2, SHANK3 and DLG2. HOMER1 and DLGAP4 high expression were associated with poor OS while SHANK2, SHANK3 and DLG2 high expression were associated with favorable OS. GRM5 and GRM1 high expression were associated with favorable OS despite being positively correlated with HOMER3. ECM receptor interaction and Notch signaling were the upregulated pathways while Metabolism of xenobiotics by cytochrome p450 and PPAR signaling were the downregulated pathways. Conclusions: HOMER3 may is have a role in liver cancer progression of which its targeting may improve LC outcome.