bluuebunny/crossref_metadata_2025_split huggingface dataset:
INTASYL self-delivering RNAi therapy specifically dual-targeting BRD4 and PD-1 to elicit complete tumor responses and evidence of synergy in a subcutaneous Hepa1-6 model of murine hepatoma in C57BL/6N mice.
Authors: Cuiffo Benjamin , Maxwell Melissa , Yan Dingxue , Rivest Brianna , Cardia James , Fricker Simon P 
Published: June 2021

e14537 Background: The therapeutic potential of targeting bromodomain and extra-terminal motif (BET) protein BRD4 is supported by promising preclinical data in multiple cancer contexts. However, clinical trials of BET inhibitors (BETi) have overall shown limited clinical efficacy and only passable safety profiles as monotherapy. BET proteins are now also understood to control a wide range of immunoregulatory pathways. Preclinical data suggests a synergistic impact with immune checkpoint blockade (ICB) targeting PD-1. Trials assessing the potential of BETi in rational combination with ICB are underway. The INTASYL platform is a self-delivering RNAi technology enabling efficient delivery into target cells without need for specialized drug delivery systems. INTASYL provides specific, robust, and durable on-target gene silencing. Furthermore, INTASYL moieties targeting multiple specific targets can be formulated together, providing a highly versatile platform for providing multi-targeted combination therapy in a single drug substance. Methods: Here we assessed the efficacy of mouse/human BRD4-targeting INTASYL PH-894 as monotherapy or co-formulated with mouse PD-1 targeting INTASYL mPH-762, in treating a subcutaneous Hepa1-6 model of murine hepatoma in C57BL/6N mice. On-target, specific silencing of BRD4 and PD-1 was demonstrated in vitro. In vivo, mice bearing tumors of ̃150 mm3 (N = 12/arm) were treated intratumorally on Days 1, 3, 7, 10 & 14 with of PH-894 or mPH-762 as single-agent, or PH-894/mPH-762 in combination at sub-optimal doses (0.1 mg/INTASYL/dose), or with PH-894/mPH-762 at half-suboptimal dose (0.05mg/INTASYL/dose) to assess potential synergistic impacts. Positive control groups received systemic (IP) (+)-JQ-1 (13.33mg/dose; qdx5), anti-mouse PD-1 antibody (75 µg; Days 1, 3, 7, 10, 14), or both treatments. Negative control animals received vehicle only. Tumor volumes and body weights were recorded longitudinally. Results: Compared to vehicle, suboptimal (+)-JQ-1, anti-PD-1, PH-894 or mPH-762 each elicited tumor control but not resolution as expected; while treatment with suboptimal PH-894/mPH-762 combo produced complete response (CR) in 75% (9/12) mice, outperforming combination treatment with (+)-JQ-1 and anti-PD-1 mAb [CR 58% (7/12) of mice]. Treatment with half-suboptimal doses of PH-894/mPH-762 resulted in CR for 42% (5/12) mice and tumor control exceeding that elicited by each monotherapy, suggesting potential synergy of the dual-targeting formulation. Tumors were isolated for mechanistic analyses of immune and tumor cells. Conclusions: These data demonstrate proof-of-concept of the therapeutic potential of rational dual-targeted INTASYL provided as single formulation in vivo, suggesting potential for meaningful clinical therapeutic impact.
Nephrotoxicity in patients with cancer treated with immune checkpoint inhibitors.
Authors: Eleutherakis Papaiakovou Evangelos , Kastritis Efstathios , Zagouri Flora , Grapsa Dimitra , Ntanassis-Stathopoulos Ioannis , Stefanou Dimitra , Evangelou Georgios , Kotteas Ilias , Dimopoulos Meletios A. , Syrigos Konstantinos 
Published: June 2021

e14558 Background: Despite their efficacy in various cancer types, administration of immune checkpoint inhibitors (ICIs) may be complicated by the development of immune-related adverse events (IrAE). Nephrotoxicity represents a relatively rare but clinically significant adverse event, associated with the administration of ICI. Methods: The medical records of 294 patients with solid tumors or hematological malignancies that received ICIs for at least 4 weeks were retrospectively reviewed. Demographic, clinicopathological, treatment, toxicity and outcome data were recorded. ICI-associated nephrotoxicity was correlated with the remaining clinicopathological parameters as well as with progression-free survival (PFS) and overall survival (OS). Results: The majority of patients were male (70.4%), with bladder cancer or renal cell carcinoma (38.1% and 27.6%, respectively), and stage IV disease (56.8%), and had received ICI as monotherapy (68,7%). Nephrotoxicity during immunotherapy administration was observed in 20/ 294 (6.8%) patients, was mild (grade 1) and reversible in 55% and 75% of these cases, respectively, and was significantly associated with nephrotoxicity from previously administered therapy (p = 0,008), impaired renal function at initiation of ICIs (p = 0.044). and advanced disease stage at diagnosis (p = 0,028). No correlation between ICI-nephrotoxicity and PFS or OS was observed. Conclusions: ICI-associated nephrotoxicity was a relatively infrequent IrAE in our patient population, most commonly mild and reversible, and with no significant effect on survival. Preexisting treatment-related nephrotoxicity, impaired renal function and/or advanced disease stage at diagnosis may represent significant predisposing factors for its development.
Repurposing infectious diseases vaccines against cancer.
Authors: Bouche Gauthier , Vandeborne Liese , Pantziarka Pan , Van Nuffel An M. T. 
Published: June 2021

e14564 Background: Vaccines used to prevent infection have long been known to stimulate immune responses to cancer as illustrated by the approval of the Bacillus Calmette–Guérin (BCG) vaccine to treat bladder cancer since the 1970s. The recent approval of immunotherapies has rejuvenated this research area with reports of anti-tumour responses with existing infectious diseases vaccines used as such, either alone or in combination with approved immune checkpoint inhibitors. This prompted us to review recent research activities using approved vaccines to treat cancer. Methods: PubMed and clinicaltrials.gov databases were queried for all 31 infectious diseases having at least one preventive vaccine approved, and all hits were reviewed for relevance. Only articles and trial registrations about infectious diseases vaccines used in an unmodified form as treatment for cancer, were included. The search was restricted in time, capturing articles from the year 2000 until November 2020. Results: A total of 1,754 PubMed abstracts and 549 trial registrations were screened. Data supporting a cancer therapeutic use was found for 16 of the 31 infectious diseases vaccines. For 10 (BCG, diphtheria, tetanus, human papillomavirus (HPV), influenza, measles, pneumococcus, smallpox, typhoid and varicella-zoster), clinical trials have been conducted or are ongoing. Within the remaining 6, preclinical evidence supports further evaluation of the rotavirus, yellow fever and pertussis vaccine in carefully designed clinical trials. The mechanistic evidence for the cholera vaccine, combined with the observational data in colorectal cancer, is also supportive of clinical translation. There is limited data for the hepatitis B vaccine and for the mumps vaccine alone. Four findings are worth highlighting: first, the superiority of intra-vesical typhoid vaccine instillations over BCG instillations in a preclinical bladder cancer model, which is now the subject of a phase I trial; second, the perioperative use of the influenza vaccine to limit and prevent the NK cell dysfunction induced by cancer surgery; third, objective responses following intra-tumoral injections of the measles vaccine in cutaneous T-cell lymphoma; fourth, objective responses induced by the HPV vaccine in skin squamous cell carcinoma. Conclusions: Sixteen infectious diseases vaccines have been or are currently being explored for repurposing in oncology. All vaccines are intended to induce or improve an anti-tumour (immune) response. Next to biological and immunological mechanisms, that are very different from one vaccine to another, also the mode of administration and combinations and sequence with other (immuno-)therapies deserve more attention in future research.
Association of immune checkpoint inhibitors (ICI) and venous thromboembolism (VTE): A single healthcare system experience.
Authors: Ananthula Aneesha , Chapple Andrew G , Mani Shyam , Nguyen Anh , Del Toro Alejandra Matilde , Boulmay Brian C. 
Published: June 2021

e14567 Background: Cancer and some anti-cancer therapies increase risk of VTE. ICIs cause immune activation and inflammation which are known to potentiate VTE formation. The risk of VTE associated with ICI is unclear, with conflicting evidence of association. Our study assessed the risk of VTE in patients treated with ICI compared to those receiving other cancer treatments. Methods: EPIC Slicer Dicer was used to collect data from three university-affiliated hospitals in New Orleans, LA. All patients >17 years of age, with an oncology treatment plan (TP) between January 1 2012 – January 31 2021 were considered the base population (n=6,894) for the study. The base population was divided into two cohorts - those that received ICI (n=794) versus those who did not (n=6,100). ICIs included pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, ipilimumab. An encounter diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE) which was preceded by a TP in the last 1 year was used to identify patients with VTE after initiation of a TP. Categorical covariates compared across VTE groups using Chi-squared tests of independence. Two sample t-tests were used to compare continuous covariates based on VTE status. Logistic regression used to predict VTE as a function of ICIs and other potential confounders including age, BMI, gender, race and cancer subtypes. Results: Patients who experienced VTE were significantly more likely to have received ICI (1.43 times odds of VTE (95% CI = 1.12-1.83; p <0.005), be black or African American (p < 0.05 compared with White and Asian races), and have GI cancer (1.82 times odds, 95% CI= 1.41 – 2.36, p< 0.001), GU cancer (1.7 times odds, 95% CI = 1.3 – 2.23; p<0.001). Patients with VTE were significantly less likely to have breast cancer or other cancer types. Males had a decreased odd of VTE (0.73 odds, 95% CI= 0.62 – 0.85, p< 0.001). Conclusions: Based on the above results, there appears to be an increased likelihood of VTE in patients that receive ICI when compared to other types of cancer treatment. This study is a preliminary analysis and has limitations. At this time, it is unclear if prophylactic anticoagulation can reduce risk of VTE after ICI initiation. Further investigation is warranted in the form of individual chart review, or a prospective study.
Six-gene model based on expression predicts distinct disease-free survival in early-stage microsatellite stability (MSS) endometrial, colorectal and stomach tumors.
Authors: Chen Tufeng , Liu Jianpei , Liu Xinyi , Huang Mengli 
Published: June 2021

e14578 Background: Microsatellite stability (MSS) tumors hardly benefit from immunotherapies and are more probable to occur postoperative recurrence. However, some studies have revealed that a subset of MSS patients harbor “hot immune microenvironment” tumors, indicating high heterogeneity in such wide range of patient population. On the other hand, researches of mechanism of MSI formation found potential similarities in endometrial and gastrointestinal tumors. We hypothesized the transcriptomic features in these cancers correlated with immune-related signatures and patients’ prognosis. Methods: Early stage (I-III stage) MSS tumors, including endometrial, colorectal, and gastric from TCGA project were analyzed as training cohort (n=170). A combined cohort consisting of 604 colorectal and stomach cancers from GEO datasets (GSE39582，GSE62254) was validation cohort. The RNA-Seq profiling data and disease-free survival (DFS) data of patients were collected. Cibersort tool was used to evaluate twenty-two immune cells’ enrichment. The prediction model was developed by three steps: Univariate cox regression of DFS was conducted to select 9 immune cells. Then the train cohort was divided into two groups based on non-negative matrix factorization (NMF) method using this 9 immune cell features. Differentially expressed genes of these two groups were identified and screened further by lasso regression. Log-rank test was used to evaluate the difference of DFS. Results: A six-gene lasso-cox model was developed. The genes were LYZ, WFDC2, CAPS, RHPN1, TFF2 and TGFBR2. Based on the score evaluated by this model, patients in training cohort were divided into high-risk and low-risk groups. Low-risk population had much longer DFS (HR 0.07, 95%CI 0.03-0.18, p<0.001). In validation cohort, lower risk score was also verified to be associated with a lower likelihood of recurrence (HR 0.66, 95%CI 0.5-0.88, p=0.0047). Conclusions: We developed a model of six-genes predicting disease-free survival based on RNA-Seq data in early stage MSS patients. Further validation was needed to implement in larger clinical cohorts.
The landscape of intergenic-breakpoint fusion in lung cancer.
Authors: Liang Hua , Wu Yaqing , Luo Ningning , Zhang Qin , Qi Yingxue , Duan Qianqian , Qi Chuang 
Published: June 2021

e15002 Background: Kinase fusions have been proved as driver factors and drug targets for lung cancer. DNA-based next-generation sequencing (NGS) has been widely used for gene fusion detection in patients with lung cancer and intergenic-breakpoint fusions can be detected, in which breakpoints localize to intergenic regions. Theoretically, intergenic-breakpoint fusions are unlikely to be functional, but recent studies have found that intergenic-breakpoint fusions are potentially activated. However, the proportion of intergene-breakpoint fusion occurrence in lung cancer is still unclear. Hereby, next generation sequencing was performed to describe lung intergenic-breakpoint fusions for further research. Methods: Tumor tissue, pleural effusion, or blood samples of 6798 patients with lung cancer from Simceredx were collected for targeted NGS panel sequencing from June 2020 to January 2021. Gene rearrangements of ALK, ROS1, RET, NTRK(1-3) were assessed. Results: We found gene fusions in 4.43% (301/6798) patients with lung cancer totally, of which 59.1% (178/301) ALK fusions, 18.9% (57/301) RET fusions, 15.9% (48/301) ROS1 fusions and 6.64% (20/301) NTRK(1-3) fusions. The intergenic-breakpoint fusions accounted for all fusions of ALK, RET and ROS1 genes were 24.2% (43/178), 22.8% (13 /57) and 18.8% (9/48), respectively. In patients with NTRK intergenic fusions (50.0%, 10/20), NTRK1, NTRK2 and NTRK3 was involved in 2, 1, 7, respectively. Co-occurrence of different fusions was rare. Conclusions: Our data firstly revealed the specific intergenic-breakpoint fusions ( ALK, RET, ROS1, NTRK1-3) in lung cancer. The functional consequences identifying by RNA or protein assay and clinical validation need to be carried out in the future.
Deep learning to identify and predict cardiotoxicities of anticancer drugs.
Authors: Sarangdhar Mayur , Kolli Venkatesh , Seibel William , Perentesis John Peter 
Published: June 2021

e15012 Background: Recent advances in cancer treatment have revolutionized patient outcomes. However, toxicities associated with anti-cancer drugs remain a concern with many anti-cancer drugs now implicated in cardiotoxicity. The complete spectrum of cardiotoxicity associated with anti-cancer drugs is only evident post-approval of drugs. Deep Learning methods can identify novel and emerging safety signals in “real-world” clinical settings. Methods: We used AERS Mine, an open-source data mining platform to identify drug toxicity signatures in the FDA’s Adverse Event Reporting System of 16 million patients. We identified 1.3 million patients on traditional and targeted anti-cancer therapy to analyze therapy-specific cardiotoxicity patterns. Cardiotoxicity training dataset contained 1571 molecules characterized with bioassay against hERG potassium channel and included 350 toxic compounds with an IC50 of < 1μM. We implemented a Deep Belief Network to extract a deep hierarchical representation of the training data, and the Extra Tree Classifier to predict the toxicity of drug candidates. Drugs were encoded using 1024-bit Morgan fingerprint representation using SMILES with search radius of 7 atoms. Pharmacovigilance metrics (Relative Risks and safety signals) were used to establish statistical correlation. Results: This analysis identified signatures of arrhythmias and conduction abnormalities associated with common anti-cancer drugs (e.g. atrial fibrillation with ibrutinib, alkylating agents, immunomodulatory drugs; sinus bradycardia with 5FU, paclitaxel, thalidomide; sinus tachycardia with anthracyclines). Our analysis also identified myositis/myocarditis association with newer immune checkpoint inhibitors (e.g., atezolizumab, durvalumab, cemiplimab, avelumab) paralleling earlier signals for pembrolizumab, nivolumab, and ipilimumab. Deep Learning identified signatures of chemical moieties linked to cardiotoxicity, including common motifs in drugs associated with arrhythmias and conduction abnormalities with an accuracy of 89%. Conclusions: Deep Learning provides a comprehensive insight into emerging cardiotoxicity patterns of approved and investigational drugs, allows detection of ‘rogue’ chemical moieties, and shows promise for novel drug discovery and development.
Translational relevance of baseline NLR and LMR ratio in predicting response of EGFR-TKI.
Authors: Varayathu Hrishi , Tiwari Rashi Yogendranath , Somayaji Shalaka , Mathew Smruthy Ann , Thomas Beulah Elsa , Sangi Lalram , Thomas Renjan , Balaram Gautam , Ghosh Mithua , Thungappa Satheesh Chiradoni , Mufti Suhail Sayeed , Bj Sriniivas , Munirathnam Vinayak , Naik Radheshyam , Ajaikumar Basavalinga Sadasivaiah 
Published: June 2021

e15020 Background: Neutrophil-Lymphocyte Ratio (NLR) and Lymphocyte-Monocyte Ratio (LMR) have been under scrutiny for their potential as a prognostic tool in various cancers. While there have been conflicting opinions on their reliability, NLR has shown rather near accurate predictions in previous studies. Targeted tyrosine kinase inhibitors have shown good results in improving OS and PFS of patients with EGFR-mutated NSCLC but the prognostic indicators are limited. This study aims to decipher if baseline NLR and LMR ratios are valid tools to predict prognosis of patients with EGFR-mutated NSCLC. Methods: We analyzed 78 advanced NSCLC patients harboring Exon 19 Deletion and Exon 21 L858R mutation undergoing EGFR-TKI therapy. Baseline NLR and LMR were measured in peripheral blood within two weeks prior to the initiation of TKIs. Overall survival was used as an outcome measure for TKI therapy and it is defined as from the initiation of TKIs to death by any cause. The cut-off for NLR and LMR was calculated using an X-tile plot (version 3.6.1, Yale University, New Haven, CT, USA) by dividing marker data into three populations: low, middle, and high (i.e., two divisions), with randomized 1:1 “training” and “validation” cohorts. Results: Overall median survival of the study group was 31.5 months and median age was found to be 60 years. Gefitinib (35.9%) and afatinib (34.6%) were the most commonly prescribed followed by erlotinib (21.8%) and osimertinib (7.7%). With cut-points of 1.8 and 4.9 we analyzed three populations for baseline NLR as ≤1.8, 1.9-4.9 and > 4.9. Similarly, for LMR cut-points of 3.49 and 5 were found and we analyzed patients with LMR of ≤3.49, 3.5-5 and >5. There was a statistically significant overall median survival observed as per the obtained NLR as well as LMR cut-off as given in the table. Conclusions: A statistically significant co-relation was observed with baseline NLR and LMR ratio in predicting response to EGFR TKIs in NSCLC. Our study further strengthens the concept of using NLR and LMR as peripheral blood biomarkers for prognostic assessment in cancer patients undergoing treatment.[Table: see text]
Consistent performance of highly multiplexed RNA fusion detection with low RNA input and limit of detection.
Authors: Debruyne David , Li Chenyu , Spencer Julia , Kapoor Vidushi , Liu Lily Y. , Lee Lucie , Feigelman Rounak , Burdon Grayson , Liu Jeffrey , Liu Guoying , Liu Zhitong 
Published: June 2021

e15029 Background: Gene fusions are usually caused by chromosomal rearrangements and frequently associated with various cancers. Detection of fusion mutations is an important part of cancer management, and are usually detected in RNA purified from biopsies of fresh tissue or FFPE sections. However, the amount of RNA from these samples is usually limited. We developed a new, PCR-based fusion detection method, which allows detection of unknown and novel fusion mutations. We demonstrate its consistent performance across various RNA inputs, and sequencing depths, in terms of technical performance and limit of detection. Methods: A multiplex PCR RNA fusion panel was designed to cover known RNA fusion targets and unknown fusion targets for target enrichment via single primer multiplex PCR. SeraSeq fusion Reference RNA was used to evaluate the limit of detection of the method. The amplicons were about 110 bp on average to allow for target amplification from challenging fragmented samples such as FFPE RNA. After reverse transcription, the panel was used in a multiplex PCR to amplify the targets, and a final PCR was used to add sequencing adapters and sample indexes. The resulting libraries were sequenced on Illumina sequencers. The data was analyzed for the detection of known fusion variants across varying initial inputs of targets, as well as the performance in terms of mapping and on-target rates, as well as the presence of human ribosomal RNA. Results: We found that the fragmented RNA length had little effect on the performance of the libraries. The required numbers of PCR cycles were optimized based on testing with various amounts of starting RNA input material. We observe a linear relationship between the library yields and RNA input amounts from 10 to 50ng, which had R1 mapping rates above 95% and 98%, respectively. We report the detection of all twelve fusion variants, which are targeted by our panel and present in the Seraseq Fusion RNA Mix v4 reference standard, and which are covered with an average sequencing depth of 0.2M reads, or 3600 reads/amplicon, across all assays. Even at inputs as low as 3 ng, all 12 fusions were typically detected. In general, the results for individual fusions among the different replicates were concordant, with limited observed variance in reads across some fusion junctions between assays and replicates. Over 90% of the reads supported the fusion calls from all inputs (ranging from 1.6 to 50 ng). Over 97% of the reads supported the fusion calls between 12 and 50 ng. Conclusions: A multi-lab validation confirmed the above results, and were also comparable when using an additional distinct CleanPlex fusion panel. To conclude, our CleanPlex fusion technology allows for reliable and simultaneous detection of 12 designed clinically relevant RNA fusions even at low input amounts.