bluuebunny/crossref_metadata_2025_split huggingface dataset:
An open-label, fixed-sequence study to evaluate the effect of encequidar (HM30181) an oral P-gp inhibitor, on the pharmacokinetics of dabigatran etexilate (a P-gp substrate) in healthy male volunteers.
Authors: Jackson Christopher G. C. A. , Hung Noelyn Anne , Cutler David , Kramer Douglas , Zhi Jay , Chan Wing Kai , Kwan Min-Fun Rudolf , Hung Tak 
Published: June 2021

e15060 Background: Oral co-administration of encequidar (a selective, minimally absorbed oral P-gp inhibitor) 12.9 mg with paclitaxel (a P-gp substrate) 205 mg/m2 for 3 consecutive days per week can achieve comparable AUC exposure to that of IV paclitaxel 80mg/m2 with a significantly lowered Cmax and has been demonstrated its improved tumor response with reduced neuropathy compared to IV paclitaxel 175 mg/m2 Q3W for the treatment of patients with metastatic breast cancer. Because of its pharmacology as an inhibitor of P-gp, encequidar may increase the bioavailability of orally administered drugs that are substrates of P-gp, such as dabigatran etexilate. Methods: To determine the effect of a therapeutic dose and regimen (3 once-daily 12.9 mg doses) of encequidar on the single dose PK of dabigatran etexilate, an open-label, fixed-sequence study was performed in 20 healthy male subjects. Participants received a single oral dose of dabigatran etexilate 75 mg on Day 1 of Treatment Period 1 (reference) and, after a washout period of at least 7 days, on Days 3, 17 and 31 of Treatment Period 2, after receiving once-daily oral doses 12.9 mg encequidar on Days 1 to 3 of Period 2. The PK sampling for determination of plasma concentrations of total and unconjugated dabigatran lasted up to 48 hours postdose of each dabigatran etexilate dosr. Results: Mean AUC and Cmax values for dabigatran were both increased ̃ 95% without changing t½ when dabigatran etexilate was administered 1 hour post the 3rd dose of 12.9 mg encequidar compared to when dabigatran etexilate was administered alone. When dabigatran etexilate was administered 2 weeks after encequidar administration, no apparent differences in dabigatran AUC or Cmax were detected compared to those of dabigatran etexilate alone. When administered 4 weeks after discontinuation of encequidar, dabigatran AUC and Cmax were both slightly lower than Reference dabigatran etexilate (̃ 25% lower for AUC and 34% lower for Cmax). Both unconjugated and total dabigatran PK data were analyzed and shown to be similar. Encequidar and dabigatran etexilate were well tolerated and had acceptable safety findings in this healthy subject population. Conclusions: Concomitant dosing of encequidar with dabigatran etexilate resulted in < 2-fold increase in exposure to dabigatran, which had abated by the time of the first re-test, 14 days after the last dose of encequidar. The observed changes do not warrant dose adjustment of dabigatran etexilate when administered with encequidar. Clinical trial information: ACTRN12618000791235.
Synthetic lethality of LP-184, a next generation acylfulvene, in ex vivo PDX models with homologous recombination defects.
Authors: Kulkarni Aditya , Restifo Diana , Astsaturov Igor A. , Kathad Umesh , McDermott Joseph , Bhatia Kishor , Sharma Panna 
Published: June 2021

e15064 Background: The clinical success of PARP inhibitors (PARPi) in homologous recombination (HR) deficient (HRD+) solid tumors has broadened the scope of identifying additional agents and vulnerabilities in cancers with DNA repair deficiencies. However, with more than 40% of BRCA1/2-deficient patients failing to respond to PARPi or acquiring resistance with prolonged PARPi administration, newer agents are also needed. LP-184, an acylfulvene, is a prodrug activated by PTGR1. Threshold expression levels of PTGR1 are higher in several tumors, providing a window of specificity for its cytotoxic action. DNA damage inflicted by acylfulvene (AF) agents is reliant upon HR pathway genes including BRCA1 for correction and removal. We hypothesized that tumors with high PTGR1 expression and HR deficiency will therefore be uniquely targeted and demonstrate synthetic lethality when exposed to LP-184. Methods: We evaluated ex vivo antitumor activity of LP-184 in selected PDX models representing lung, pancreatic and prostate cancers with high PTGR1 and known HR defects. Dissociated tumor fragments were treated with LP-184 across a concentration range of 5 nM to 36 uM for 5 days. Cell viability was quantified by CellTiter Glo. LP-184 IC50s were compared with PARPi efficacy. We further confirmed the dependency of PTGR1 in HR deficient tumor cells by comparing LP-184 sensitivity in the BRCA2 deficient cell line CAPAN-1 and the ATM mutant cell line PANC03.27, with and without PTGR1 suppression following an engineered CRISPR knockout of PTGR1. We also analyzed TCGA data to estimate the percentage of tumors with elevated PTGR1 and co-occurring damaging mutations in a panel of 60 HR genes. Results: The mean LP-184 IC50 across 15 HRD+ PDX models tested was 288 nM (range 31 - 2900 nM). LP-184 turned out to be 6 - 340X more potent ex vivo than the PARPi Olaparib in these models. 9 of 15 models were associated with no clinical response to or initial response followed by progression on approved standard of care (SOC) agents. 6 of 15 models showed < 10% tumor growth inhibition in vivo with SOC treatment. Regardless of cancer type, models with high-impact, loss-of-function mutations in ATM, ATR and BRCA1 showed exquisite sensitivity to LP-184 (mean IC50 ̃ 60 nM). CRISPRi-mediated stable suppression of PTGR1 in the pancreatic cancer cell lines CAPAN-1 and PANC03.27 entirely abrogated LP-184 sensitivity relative to isogenic parental cell lines. 17.6% of lung adenocarcinomas (n = 517), 4.5% of pancreatic adenocarcinomas (n = 179) and 9.6% of prostate adenocarcinomas (n = 498) displayed elevated PTGR1 along with damaging HR related mutations, and are likely to be responsive to LP-184 based on analysis of TCGA data. Conclusions: LP-184 is broadly effective in HRD+ tumors that may be less responsive to SOC including PARPi and could be useful clinically in a subset of tumors with high PTGR1 and HR defects.
A small molecule LN435a targeting TGFβR1 exerts promising antitumor effects on breast cancer.
Authors: Zhang Yuzhu , Li Huachao , Zhang Hongyan , Liu Xiaoyuan , Luo Tianyu , Lin Huan , Xu Rui , Ren Liping , Li Dongmei , Chen Yihua , Chen Qianjun , Huang Luqi 
Published: June 2021

e15069 Background: Breast cancer has overtaken lung cancer as the most diagnosed cancer. Despite conventional treatment, metastases occur in 20-30% of patients, resulting in death. This study aims to screen of effective drugs by metastatic patient-derived organoid and the potential molecular mechanism. Methods: Breast Cancer patient-derived organoid (PDO) model was established from the patient who have multiple drug resistance, multiple visceral and contralateral breast metastases. The organoid morphologies was tested by hematoxylin-eosin (HE) staining and immunohistochemistry (IHC). Then, pharmacological activity assay of 2370 natural product monomer (from Selleck) was performed with organoids. we modified the structure of harmine(HM) and screened the best active drugs. Cell proliferation assay and wound healing assay were used to detect LN435a anticancer activity in vitro. Orthotopic, Metastatic Xenograft and Patient-Derived tumor Xenograft(PDX) model of Breast Cancer were used to detect LN435a anticancer activity in vivo. In order to explore the anti-cancer target of LN435a, we used RNA transcriptome and proteomics sequencing. To further validate anti-cancer targets,TGFβ receptor 1 (TGFβR1), we used real-time quantitative qPCR, western blot, lentiviral packing and biolayer interferometry assay. To investigate whether LN435a inhabition of EMT and stem cell markers, we performed flow cytometry, immunohistochemistry and fluorescence. Results: We observe that organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. In the first anti-cancer drug screening, HM showes the best effect on PDO. Because HM contains β-carbine alkaloids as the structural units, we designe a series of active drugs based on this and did anticancer screening. We find LN435a as one of the lead compounds exerting anti-metastatic activity in the nanomolar range in PDO and breast cancer cells. Proteomic and biochemical studies identify TGFβR1 as the direct target of LN435a. And then it inhibits EMT and stem cell markers. In parallel, loss of TGFβR1 or pharmacological inhibition of TGFβR1 by LN435a reduces breast cancer extravasation into the lung in an experimental metastasis mouse model, which reveals an essential role of TGFβR1 in breast cancer progression. Conclusions: Altogether, LN435a is a novel inhibitor of promising anti-tumor effects on breast cancer that works by blocking TGFβ signaling pathways.
AKT1 in Asia: A landscape analysis of 11,813 Chinese tumor samples.
Authors: Gan PingPing , Lu Yi , Li Xiaomin , Deng Wanglong , Han Tiantian , Xi Wenjing , Bu Fanfeng 
Published: June 2021

e15076 Background: AKT1 is a key gene of the PI3K/AKT/mTOR signalling pathway. The recent development of ATK1 targeting drug has shown great promise. It is thus important to understand the genomic landscape of AKT1 in a specific population. Methods: Sequencing data of 11,813 tumor samples collected in China were analyzed for AKT1 mutation status. Concomitant genomic aberrations were further analyzed in tumors with AKT1 mutations. Results: AKT1 mutations were observed in 173 of 11,813 tumor samples (1.46%). The most common cancer types in our study included cervical (5.17%), breast (5.15%), osteosarcoma (3.51%), brain (3.14%), head and neck (2.22%) and colorectal (2.02%). We included only the cancer types with more than 50 cases for analysis. Higher frequencies of AKT1 mutation were observed in several common cancers, including brain glioma (1.38% vs 0.67%), breast (5.15% vs 2.92%), cervical (5.17% vs 2.93%), head and neck (2.22% vs 0.95%) cancer in our study than reported in TCGA, but showed no statistically significant difference. The main common type of variation was SNV/Indel (67.63%), amplification (20.81%), deletion (11.56%), fusion (1.16%). Among SNV/Indel, E17K accounted for 32.9% of AKT1 mutations, Q79K only accounted for 0.79%. AKT1 E17K was more commonly found in breast (3.09%), brain (1.96%) and cervical (1.72%) cancer. There is no significant difference between wild type and AKT1 mutated groups in age and gender. III/IV patients were identified in 85.71% of AKT1 mutated group, which were significantly higher than that of wild type group (73.76%; p<0.05).MSI-H patients were identified in 12.16% of AKT1 mutated group, which were significantly higher than that of wild type group (1.8%; p<0.001). Frequencies of specific concomitant aberrations varied between AKT1 mutated and wild type groups. In AKT1 mutated groups, 57 genes are more frequently altered, and mainly enriched in PI3K-Akt signaling pathway (26, q= 2.97E-20, MAPK signaling pathway (count:20, q= 9.74E-15), Central carbon metabolism in cancer (19, q= 5.01E-25), EGFR tyrosine kinase inhibitor resistance (19, q= 3.36E-24). Conclusions: Higher frequencies of AKT1 mutation were observed in several common cancers, including cervical, breast, osteosarcoma, brain, head and neck and colorectal in our study. AKT1 E17K was more commonly found in breast, brain and cervical cancer. Given the fact that III/IV patients are more common in AKT1 mutated group, it coincides with AKT inhibitors therapeutic prospects in a variety of advanced malignant tumors. MSI-H patients are more common in AKT1 mutated group, and it provides possibility for immune checkpoint inhibitors combined with targeted signaling pathway therapy. The enrichment results of the common co-occurring genes with AKT1 in this study, further investigations are still needed.
NTRK genomic alterations in Latin-American cancer patients.
Authors: Carvajal Daniel , Salas Claudio , Marcelain Katherine , Perez Francisco , Rivas Solange , Feliu Evelin , Schalper Kurt , Armisén Ricardo 
Published: June 2021

e15088 Background: The neurotrophic receptor tyrosine kinase genes NTRK1-3 encode the tropomyosin receptor kinase proteins TRKA, TRKB, and TRKC, respectively. TRK fusions lead to overexpression of the chimeric protein, resulting in constitutively active, ligand-independent downstream signaling. NTRKs act as oncogenes, they can be targeted, and it is estimated that they are present in up to 0.3% of tumors. The incidence of actionable alterations in these genes is currently unknown in Latin-American patients. We investigated the presence of NTRK1-3 mutations/rearrangements in 3 independent patient series from several tertiary hospitals from Chile, Brazil and Peru. Methods: 1795 FFPE tumor samples from multiple institutions divided in 3 series were analyzed using 2 NGS panels: Oncomine Focus Assay (OFA; 52 genes) and Oncomine Comprehensive Assay (OCA; 161 genes. Data on NTRK1-3 SNVs, indels, CNVs and fusions was obtained. Bioinformatic workflows were used to study the biologic significance of these alterations. Results: Using OCA (series 1-2), 31 somatic variants were found in gastric, CRC, gallbladder, lung and pancreatic cases out of 300 patients. From these, 13 were located in the tyrosine kinase domain. Using OFA, no NTRK alteration were detected (series 3, 1495 NSCLC cases). Conclusions: NTRK alterations are rare events in Latin-American cancer patients. In 3 series including 1,795 patients, 31 somatic variants were detected. No NTRK fusions or CNVs were identified. The presence of NTRK mutations in the tyrosine kinase domain warrants further research into their potential to benefit from FDA/EMA-approved targeted therapies. [Table: see text]
Significance of scores generated by a cancer therapy matching engine for patient outcomes.
Authors: Romm Eden , Davtyan Emiliya , Bush Kevin , Sutton Ramsay , Patek Itamar , Imanirad Parisa , Sicklick Jason K. , Kato Shumei , Kurzrock Razelle , Perlina Ally 
Published: June 2021

e15099 Background: Oncologists need effective precision medicine tools to navigate the myriad of therapeutic options to best address each patient’s unique tumor profile. Described here is a digital solution, which analyzes tumor data (NGS, other), scores and ranks known and novel matching combinations of cancer drugs with molecular-level precision for decision support. Methods: All data was acquired through the published supplement of the I-PREDICT study (NCT 02534675). Patients with available progression-free survival (PFS) and sequencing data who received <3 matched non-experimental cancer drugs in combination were evaluated (n=77). To determine each patient’s score (represented as %), the system used expert-curated content integrated within an artificial intelligence (AI) reasoning framework that computed how well the therapy each patient received matched their tumor’s genomic profile. The dataset was binarized at 36 possible thresholds, which split the data into higher vs. lower score bins. Relationship with PFS and the degree of separation between bins were evaluated with Kaplan-Meier plots and assessed in terms of p-value, hazard ratios and related confidence intervals (Table). To prevent sampling bias at high and low thresholding extremes of this dataset, a limit was imposed of >25 patients per bin. Results: Significant separation between high and low scoring bins was observed in >73% of evaluable thresholds. The mean p-value was 0.044 (range, 0.011-0.13). The hazard ratio was consistently ̃2 (mean, 1.81, range, 1.50-2.08). A similar level of statistical significance was observed for all thresholds up to and including bracketing of 60% (Table). Despite the small size of this dataset and the disparity between sample counts per bin seen at the end of the range, significant p-values of <0.05 were achieved. Ex., a 68-year-old female with an ampullary adenocarcinoma harboring ERBB2, CDK6 and other alterations, received a combination of pertuzumab and trastuzumab scoring 56%. The PFS was 745+ days. However, had palbociclib, ribociclib, or abemaciclib been added to this combination, the resulting 3-drug options would have scored even higher due to also targeting CDK6. Conclusions: Our study indicates that therapies with higher scores were predictive of better PFS, while lower scores were predictive of worse PFS. The results will be validated on larger datasets but are already demonstrative of the utility of this system in providing digital guidance to oncologists in selecting the most suitable treatment. [Table: see text]
Comparing of pan-cancer tumor immune microenvironment.
Authors: Ye Jiaan , Cui Longgang , Zhao Xiaochen , Lan Guanghui 
Published: June 2021

e15100 Background: Cancer treatment has entered the era of immune checkpoint inhibitors (ICI), but different tumors have different responses to ICI drugs. For example, non-small cell lung cancer and melanoma have higher response rates to ICIs than colorectal cancer and liver cancer patients. Previous studies have shown that tumor immune microenvironment have a great impact on the efficacy of ICI. Methods: This study retrospectively included pan-cancer patient specimens, using multiple fluorescent labeling immunohistochemistry to explore the differences in the immune microenvironment of different tumors. Shapiro-Wilk was used for normality test, and ANOVA or Kruskal Wallis test was used according to the results. Two-sided P < 0.05 was considered a significant difference. Results: The study included 308 patients, including 119 (38.6%) NSCLC patients, 72 (23.4%) Colorectal cancer patients, 51 (16.6%) Hepatobiliary cancer patients and 66 (21.4%) Others types of cancer patients. Among them, there was 192 (62.3%) Male, and 116 (37.7%) Female, and the median age was 57 (50-66). The proportion of CD8+ T cells and natural killer cell in tumor was statistically different. The proportion of CD8+ T cells in NSCLC, Colorectal cancer, Hepatobiliary cancer and others was 2.16%, 1%, 1.77% and 2.63%, p < 0.01; the proportion of natural killer cell was 16.44 %, 4.91%, 5.58% and 3.29%, p < 0.01. Conclusions: Different tumor types have different immune microenvironments. These results may provide valuable clues for future ICI trail design.
External validation of a radiomic signature to predict HPV (p16) status from standard CT images of anal and vulvar cancer patients.
Authors: Leijenaar Ralph T.H. , Walsh Sean , Vaidyanathan Akshayaa , Zerka Fadila , Occhipinti Mariaelena , Danthine Denis , Kridelka Frederic , Hustinx Roland , Vos Wim , Guiot Julien , Leech Michelle , Gillham Charles , Lyons Ciara A. , Flavin Aileen , Lambin Philippe , Lovinfosse Pierre 
Published: June 2021

e15502 Background: HPV status of anal and vulvar cancers cannot be predicted by visual inspection as well as for oropharyngeal cancers. Radiomics applied on computed tomography images can extract features that may better characterize the structure and the underlying biology of the tumor. Methods: In this multi-center study, we validated a CT based radiomic signature to predict HPV (p16) status, developed in head & neck cancer, in anal and vulvar cancer patients. The patients cohort was composed of 68 anal cancer patients and 7 vulvar cancer patients, with p16 status determined by immunohistochemistry, while a control cohort was composed of 422 lung cancer patients. The patient cohorts come from 4 different centers (Maastro Clinic - the Netherlands, CHU Liege – Belgium, St Luke’s Hospital – Ireland, Cork University Hospital - Ireland). The primary tumor volume was manually delineated for each patient on axial CT images. Prior to analysis, all images were resampled to isotropic voxels of 2 mm, using linear interpolation. A total of 37 radiomics features were calculated from five groups: tumor intensity, shape, texture, Wavelet and Laplacian of Gaussian. The signature was built using regularized logistic regression [1]. The signature was evaluated according to the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) and the Radiomics Quality Score (RQS). Results: The signature classified anal and vulvar cancers based on their HPV status (positive or negative), with an AUROC of 0.760 comparable to the performance of the original signature developed in oropharyngeal squamous cell carcinomas (AUROC of 0.764) [1]. The model, tested in the control cohort of lung cancer patients, predicted the HPV positive status of 1% of the patients which is in line with expected European prevalence (0 – 10%). This signature is TRIPOD level 4 (57%) with an RQS of 61%. Conclusions: This study supplies an additional insight into HPV imaging phenotype, providing a proof of concept that molecular information can be inferred from standard medical images by means of radiomics. These preliminary but encouraging results may pave the road for further generalization of CT image features of HPV-related tumors and aid in the optimization of future therapy developments [2]. Reference [1] Ralph TH Leijenaar et al., The British Journal of Radiology 2018 91:1086 [2] Immunotherapy Drug with Two Targets Shows Promise against HPV-Related Cancers - accessed on 12/02/2021 - https://www.cancer.gov/
Definitive chemoradiotherapy for squamous cell carcinoma of the anal canal (SCCAC) with cisplatin and capecitabine: A prospective cohort—preliminary results.
Authors: Dornellas Abraão , Moraes Priscila Muniz , Victor Carolina Ribeiro , Bonadio Renata Colombo , Braghiroli Maria Ignez , Chen Andre Tsin Chih , Ortega Cinthia , Nahas Caio , Hoff Paulo Marcelo , Moniz Camila Motta Venchiarutti 
Published: June 2021

e15506 Background: SCCAC is a rare disease. The standard care treatment with curative intent is chemoradiation with mitomycin (MMC) or cisplatin (CDDP) plus infusional 5-FU. Capecitabine may replace 5-FU in MMC doublet. However, MMC and infusional pumps are unavailable in many underdeveloped countries, and there is a lack of prospective data regarding the feasibility and safety of capecitabine combined with CDDP in definitive chemoradiotherapy. Methods: A Prospective cohort study aimed to evaluate the safety and efficacy of treatment with chemoradiation with CDDP60mg/m2 D1 and D29 plus capecitabine 825mg/m2/day BID in a population without MMC and infusional pump access. Eligible pts had T2-4/N0-3/M0 disease and were candidates to full curative CRT. Toxicity evaluation was the primary endpoint, secondary endpoint was response by RECIST v.1.1 at 8 weeks(w) and 6 months(m). The study data were prospectively collected using REDCap. Results: 23 pts were enrolled from Aug/2019 to Oct/2020 with a median follow-up of 7m. Median age 59 years; 76% (n=16) were stage III, 48% (n=11) were ECOG1, and 15% (n=3) were HIV+. All pts received concomitant radiotherapy, MVAT, with a median dose 54Gy in the primary tumor and 45Gy in elective nodes. At 8w, 18 patients were evaluable for response, 56% (n=10) had complete response (CR),39% (n=7) had partial response (PR) and 5% (n=1) progressive disease (PD). At 6 months 11 patients were evaluable for response, 64%(n=7) had CR, 18% (n=2) PR and 18% (n=2) PD. Any grade 3/4 toxicity was present in six pts, four of them radiodermatitis. The most frequent grade toxicities were nausea and radiodermatitis in all pts, anemia 81% (n=17), diarrhea 62% (n=13). Two older pts had definitive suspension of treatment due to toxicity. Three pts had hospitalization because of a skin infection. Six pts had disease recurrence, and two died by the cutoff date. One death related to diarrhea and vomiting toxicity in an older 84-year pt. OS and PFS are not reached. Conclusions: Definitive chemoradiotherapy with cisplatin and capecitabine is feasible; however, the older population is more vulnerable to treatment complications. Further prospective studies with a higher number of patients and longer follow up are required to evaluate SLP and OS.