bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibody-drug conjugate (ADC) joint disposition properties and their clinical utilities for comparative assessments in terms of favorable pharmacokinetic (PK) characteristics.
Authors: Williams Jason H. , Liao Kai H. , Palani Santhosh , Yin Donghua , Meng Xu 
Published: June 2022

e15005 Background: PK characterization of ADCs is often fragmented using separate analyses of individual analytes. As such it is difficult to compare among ADCs in terms of PK characteristics critical for understanding the fate of an ADC complex as a whole and its clinical implications. While several integrated PK models have been applied to clinical datasets, these have been mostly for the purpose of identifying covariate effects on PK parameters. In this abstract, we propose 3 joint disposition metrics for integrated PK characterization of ADCs based on a combination of concentrations of ADC, payload (PL), conjugated payload (CPL), and total mAb (TAb, ADC plus unconjugated mAb) in the blood, and for defining what are favorable PK characteristics for ADCs. Methods: The joint disposition metrics representing linker stability (AUCmAb/AUCTab), therapeutic exposure ratio (CLPL/CLADC) and effective drug-antibody ratio (DAR) (AUCCPL/AUCADC), were derived mathematically from a framework of typical ADC designs and verified via modeling approaches using PK data of 3 clinical candidates, an anti-Trop2 ADC (PF-06664178) [King GT, et al. Invest New Drugs 2018;36(5):836-847], an anti-Notch3 ADC (PF-06650808) [Rosen LS, et al. Invest New Drugs 2020;38(1):120-130], and an anti-PTK7 ADC (PF-06647020) [Maitland ML, et al. Clin Cancer Res 2021;27(16):4511-4520]. Furthermore, the joint disposition metrics were calculated for a number of FDA-approved or otherwise well documented ADCs, which were selected as the information on ADC, payload and TAb analytes is available, to examine their clinical utilities in assessing among ADCs in terms of favorable PK characteristics. Results: The validity of the joint disposition metrics was demonstrated and verified for integrated PK characterization of ADCs. Estimates of the joint disposition metrics, for the linker stability, therapeutic exposure ratio and effective DAR, were obtained for the selected ADCs products and candidates (Table below), consistent with the expectation based on clinical experience. Conclusions: Three joint disposition metrics were derived for integrated PK characterization of ADCs using conventional PK analytes. Their clinical utilities were explored in assessing among ADCs in terms of favorable PK characteristics. Analyses of additional ADCs may be needed to further validate these metrics for broader usage.[Table: see text]
Integrative analysis of plasma cell-free DNA fragmentation and methylation patterns for colorectal cancer detection.
Authors: Shin Seungho , Jo Shin-Sang , Charton Clémentine , Kim Stephanie , Lim Hyeyeun , Kim Sol-yi , Chung Jongsuk , Hong Hye Kyung , Cho Yong Beom , Kim Jinho , Park Donghyun 
Published: June 2022

e15022 Background: Recently, the analysis of epigenetic traits of cfDNA has been ben proven to be effective in early non-invasive cancer detection. Although integrating the DNA fragmentation and methylation information is expected to improve cancer detection performances, there are technical hurdles for effective integration of these data for detecting cancer non-invasively. In this study, we generated and analyzed targeted methylation sequencing data to develop a cancer detection method that uses both methylation and DNA fragment size patterns, optimized parameters for the model and evaluated the accuracy of the model in colon adenocarcinoma patients. Methods: Plasma cfDNA was collected from a total of 215 donors (111 COAD patients and 104 healthy adults) and targeted methylation sequencing data was generated using a customized panel covering 196k CpG sites containing robustly evaluated cancer specific markers. A total of 60 COAD and healthy samples, respectively, were used to train the model using elastic net and logistic regression. The remaining COAD 51 and healthy 44 samples were used as the test dataset in evaluating the model. Results: The integrative method achieved a high performance (94.12% sensitivity and 97.93% specificity) in classifying COAD patients and healthy individuals. Interestingly, when we decreased the bin size for cfDNA fragment length analysis, the performance of the model was significantly improved even with the same number of bins. Since the model with smaller bin size performed better, we could decrease the size target regions and data size. Our results proposed that analyzing fragment size at high resolution was an effective way to use the feature for cancer detection. By designing targeted Methyl-seq panel and generating high depth sequencing data (> 1000X), we could effectively integrate DNA methylation and fragmentation patterns for non-invasive cancer detection. Conclusions: In this study, we propose a novel non-invasive CRC detection method using targeted Methyl-seq data based on the integration of DNA methylation and fragmentation patterns. The adding of fragmentation features to the methylation information was effective in improving the sensitivity and specificity of CRC detection.
Blood based multigene testing using next generation sequencing to guide management in solid tumors: Experience from Augusta-Georgia.
Authors: Karki Nabin Raj , Parikh Jigar , Raval Priyanka , Nayak Asha , Abdel Karim Nagla Fawzy 
Published: June 2022

e15023 Background: The pool of somatic alterations with prognostic and predictive significance in management of solid tumors is rapidly expanding. Multigene panel testing using next generation sequencing (NGS) technology from peripheral blood specimen is convenient and readily available in most oncology practices. Widespread adoption is lagging, in part due to anticipation of low probability of finding an actionable information. We share our experience of real-world utilization of this technology. Methods: Blood based next generation testing ordered by providers in Georgia (outside Atlanta) between January 1, 2015, and December 31, 2021, via Guardant platform for all solid tumors was included in this analysis. Guardant360 and Guardant360CDx assays sequenced circulating cell-free DNA to detect somatic alterations in up to 83 cancer associated genes. Data was obtained from Guardant360 on site of cancer, comprehensive genomic profile, and therapeutic options at the time of report. Results: 25 providers in Georgia from 11 institutions sent 335 blood samples from solid cancer patients. There were 192 males and 143 females. Most common cancers were lung and bronchus (45%), prostate (13%), breast (11%), pancreaticobiliary (8%), colorectal (4%), melanoma (3%) and kidney (3%). Any somatic mutations were detected in 85% (285/335) patients. A total 1524 alterations comprising of 977 unique alterations involving 83 genes were detected, with an average of 5.3 unique genomic alterations per patient. The genes that were altered at least 2% of times were TP53 (20%), ATM (5.5%), PI3KCA (4.3%), KRAS (3.8%), APC (3.5%), AR (2.8%), PDGFRA (2.8%), ARIDIA (2.5%) and BRAF (2.2%). Of all alterations, 11% (170/1524) were synonymous and 31% (474/1524) were variant of unknown significance. 85 samples had tumor mutational burden (TMB) results available, with 55% (47/85) having TMB > 10 mut/Mb. The average TMB was 14.9 mutations/Mb. Out of 252 specimens evaluated for microsatellite instability (MSI), 1 had high MSI. An FDA approved drug targeting the alteration/pathway was available for the same cancer in 4% (77/1524) and for other cancers in 19% (291/1524) of alterations. An approved drug matched to the alteration was available for the same cancer in 16% (54/335) patients and for other cancers in 45% (153/335) patients. 12.5% (42/335) patients were predicted not to benefit from certain drugs. 74% (249/335) had a clinical trial available for the mutations present. Conclusions: Eighty five percent solid tumor patients had a positive result in blood based NGS. Seventy four percent patients had at least one therapeutically applicable (suggestion for a drug to target the alteration approved for the same/different cancers or lack of benefit due to the alteration) information. Thus, blood based NGS yields clinically relevant and actionable information to guide management in solid tumors.
Real-world frequency of non-small cell lung cancer with ERBB2 exon 20 insertion (Exon20ins) mutations by site of insertion.
Authors: Yang Li , Huang Tanxiao , Qu Yuan , Wang Qichen , Teng Jiaman , Yang Bo , Chen Shifu , Kong Feng-Ming Spring 
Published: June 2022

e15026 Background: ERBB2 Exon20ins mutations are in-frame insertions or duplications clustered around 2 key regions of Exon 20: the α-C helix (amino acid [AA] 770-774), the loop following the α-C helix (amino acid [AA] 775-783). The site of insertion can influence the outcome to selective EGFR/ERBB2 tyrosine kinase inhibitor therapy; ERBB2 exon 20 insertion mutation remains an unmet clinical need. The next-generation sequencing technology is a powerful tool to investigate the detailed ERBB2 mutations sites. Methods: We used real-world HaploX genomic data from patients (pts) with non-small cell lung cancer (NSCLC) to determine the frequency of ERBB2 Exon20ins mutations by site of insertion.The tumor tissue or serial blood sample was collected for each individual and the next-generation sequencing was performed using customized target captured HapOncoCDx panels. Results: From HaploX genomic data, 284/18205 pts (1.56%) with NSCLC had ERBB2 Exon20ins mutations: 72.2% were located in the helix, 27.8% in the loop (Table). The top 3 most frequent sites of insertion were Y772_A775dup (71.5%), G776delinsVC (11.3%), and G778_P780dup (6.0%). Conclusions: This real-world databases identified the helix as the most frequent insertion region of Exon 20 (∼72%). Exon20ins mutations were found less frequently in the loop (∼28%).[Table: see text]
HTG transcriptome panel (HTP): An accurate and robust tool for transcriptome-wide gene expression profiling.
Authors: Jaramillo Melba C. , Reinholz Greg , Rounseville Matthew , LaRoche Dominic , Kankipati Vidya 
Published: June 2022

e15063 Background: Analysis of transcriptome-wide gene expression has the potential to provide insights into biological pathways and molecular mechanisms that regulate disease progression and treatment response. RNA-Seq is considered the gold standard for transcriptome analysis; however, it may not perform well with older, archival formalin-fixed paraffin embedded (FFPE) tissues or low-quality/low-quantity RNA. To help researchers overcome these challenges, HTG Molecular Diagnostics developed a Research Use Only, extraction-free, targeted human transcriptome panel with an automated, proprietary web-based data analysis pipeline that provides fast, accurate, and repeatable quantitative gene expression data for 19,398 protein-coding mRNA targets from lysed FFPE tissue samples or extracted RNA (eRNA). Methods: Panel precision was evaluated by Lin’s Concordance Correlation Coefficient (Lc) using FFPE tissue lysates and eRNA from FFPE and fresh frozen tissues, including FFPE blocks that were older than ten years. The accuracy of the HTP to perform differential expression analysis was assessed by comparing it to RNA-Seq using FFPE samples from different cancer indications. The agreement of the log fold changes between the two platforms was measured by Pearson Correlation Coefficient (Pc). Additionally, a cohort of 83 breast cancer FFPE samples, that had also been evaluated for estrogen (ER) and progesterone (PR) receptor expression by immunohistochemistry (IHC), were used to determine the correlation between HTP gene expression and orthogonal IHC data. Results: The precision of the panel measured by Lc, ranged from 0.90-0.94 across multiple operators, instruments, lots, and processing days, demonstrating that the HTP is a precise and robust panel. In addition, HTP is a competitive alternate to RNA-seq (estimated log-fold changes, Pc = 0.83 between the platforms). Archival samples demonstrated high repeatability (Pc > 0.9) with sample pass rates of 100% for HTP, which further confirms panel’s robust performance. Furthermore, the HTP gene expression results correlated with the IHC markers for ER (Pc = 0.92) and PR (Pc = 0.88) receptor status in a cohort of 83 breast cancer samples, which highlights the potential of the panel to replace IHC staining while providing expression data on thousands of additional genes. Conclusions: The results demonstrate the HTP is a powerful tool for comprehensive gene expression analysis that addresses several key limitations of RNA-Seq. The HTP is precise, accurate, user-friendly (avoids extraction-bias, fewer steps, automated data analysis), and efficient (quicker, requires lower amounts of sample, works well with samples of low quality and archival samples). Collectively, the data demonstrate HTP has the potential to be used for biomarker discovery and the development of clinical solutions.
Retrospective study on the safety and efficacy of pyrotinib in the treatment of HER2-positive non-breast advanced solid tumors.
Authors: Wang Jianzheng , Zhang Baiwen , Cheng Xiaojiao , Li Qingli , Lv Huifang , Nie Caiyun , Chen Beibei , Xu Weifeng , Zhao Jing , He Yunduan , Tu Shuiping , Chen Xiaobing 
Published: June 2022

e15064 Background: Human epidermal growth factor receptor 2 (HER2) is a member of the ErbB family and a key oncogene in solid tumors. Pyrotinib has been approved for the treatment of HER2-positive, recurrent or metastatic breast cancer. However, there are very few clinical studies on pyrotinib in other HER2-positive solid tumors. Therefore, more clinical evidence is urgently needed to guide pyrotinib-based therapy in HER2-positive non-breast advanced solid tumors. Methods: We retrospectively analyzed HER2-positive non-breast advanced solid tumors patients with HER2 amplification or mutations who were treated with pyrotinib-based therapy in Henan Cancer Hospital between July 1, 2019 and December 2, 2021. In this study, 25 eligible patients were included with 16 patients with lung cancer, 6 with gastric cancer, 2 with colorectal cancer and 1 with cholangiocarcinoma. The primary end point was progression-free survival (PFS). Results: The median PFS and overall survival (OS) were 188 days (95% CI: 83–NA days) and 250 days (95% CI: 188–NA days), respectively. 16 patients with lung cancer and 6 patients with gastric cancer had a median PFS of 204 days (95% CI: 55–NA days) and 142 days (95% CI: 83–NA days), respectively. The median OS was 366 days (95% CI: 248–NA days) in patients with lung cancer and 179 days (95% CI: 90–NA days) in patients with gastric cancer. Patients receiving > 3 lines of therapies had a numerically lower median PFS and OS than those receiving≤ 3 lines of treatments (PFS:188 vs 204 days, p=0.92; OS:188 vs 366 days, P = 0.43). All 25 patients were available for efficacy evaluation. The objective response rate (ORR) was 24% and disease control rate (DCR) was 68%. The ORR for lung cancer was 25% and for gastric cancer was 16.7%. In addition, the DCR for lung cancer was 62.5% and for gastric cancer was 66.7%. Moreover, patients receiving≤3 lines of treatments had a numerically higher ORR and DCR than those receiving >3 lines of treatment (ORR:35.7% vs 9.1%,p=0.18; DCR:71.4% vs 63.6%, P＞0.99). The most common treatment-related adverse events (TRAEs) were diarrhea (84%), but only 3 (12%) patients reported grade 3 diarrhea which could be well controlled. Conclusions: These results indicated that pyrotinib-based therapy exhibited good anti-tumor activity and acceptable safety profile in HER2-positive non-breast advanced solid tumors. This retrospective study is a pilot study aimed at promoting larger-scale studies to further clarify the safety and efficacy of pyrotinib in the treatment of non-breast solid tumors. Keywords: pyrotinib, HER2-positive, solid tumor, retrospective study, advanced solid tumors.
Influence of albumin and methotrexate clearance on high-dose methotrexate-induced mucositis.
Authors: Taylor Zachary L. , Miller Tamara P. , DeGroote Nicholas , Pommert Lauren , Awoniyi Oluwafunbi , Board Sarah , Poweleit Ethan , Kastner Samuel , Ugboh Ngozi , Joshi Vivek , Ambrosino Nicholas , Weisnicht Allison , Hsiao Heidi , Bernhardt Brooke , Schafer Eric Scott , O'Brien Maureen Megan , Castellino Sharon M. , Ramsey Laura 
Published: June 2022

e15081 Background: Methotrexate (MTX) is a cornerstone of therapy for several types of cancer. HDMTX-induced mucositis can impact quality of life and delay subsequent chemotherapy. Objective: The objective of this study was to understand the factors increasing risk for mucositis in patients receiving HDMTX in a multicenter cohort. Methods: A multi-center retrospective study collected data on pediatric and young adult patients ages 0-32 years at diagnosis who received at least one dose of HDMTX (>500 mg/m2) at Children’s Healthcare of Atlanta or Cincinnati Children’s Hospital Medical Center from January 2010 through December 2020. Demographic and clinical variables were manually abstracted, while medications and lab values were electronically pulled from the electronic medical record. Common Terminology Criteria for Adverse Events v5 was used to identify the presence and grade of mucositis after HDMTX administration. Institutional review board approval was obtained at each site. Chi-square and t-tests, as appropriate, were calculated using GraphPad Prism v9. MTX concentrations were fit to a published pharmacokinetic model to estimate clearance using NONMEM. Results: The cohort is described in Table. The rate of mucositis was highest after the first HDMTX administration (54.6%), when the MTX clearance is slowest (30.1%<10 L/hr/1.73m2 and albumin was lowest (14.3%<2.5g/dL). Mucositis was significantly more likely in patients with hypoalbuminemia and in patients with MTX clearance <10 L/hr/1.73m2 (OR 1.75 (CI: 1.503 to 2.028), p<0.0001 and OR 1.43 (CI: 1.236 to 1.653), p<0.0001, respectively). Conclusions: Mucositis after administration of HDMTX is common, with 72% of patients experiencing at least grade 1 mucositis and a third of HDMTX administrations leading to mucositis. Chart abstraction is ongoing at a third hospital to increase the sample size, particularly those of Hispanic/Latino ethnicity, in order to investigate differences by race and ethnicity. In addition, current analyses are evaluating the impact of changes in supportive care on HDMTX-induced mucositis and other adverse events. The results of this study will demonstrate who is at highest risk for adverse events so supportive care can be tailored during this potentially toxic chemotherapy.[Table: see text]
Real-world analysis of BRAF inhibitors with patients positive for BRAF V600E mutations diagnosed with rare tumors.
Authors: Peelay Zoya , Patil Vijay Maruti , Noronha Vanita , Pathak Shruti , Menon Nandini Sharrel , Prabhash Kumar 
Published: June 2022

e15085 Background: BRAF mutation is seen in multiple cancers and BRAF inhibitors have a tumor agnostic nature. However there is very limited real world data for BRAF inhibitors and hence we have performed this analysis. Methods: In Tata Memorial Hospital, the medical oncology solid unit 2 maintains a prospective database of all patients who undergo molecular testing. A query was raised from this database and 17 patients were identified who were BRAF mutant positive. The demographic details of these patients, the previous treatment details, the therapy received by these patients, the response to the therapy, the date of progression and the date of death was recorded. Descriptive statistics were performed and Kaplan-Meier analysis was used to estimate the progression-free survival (PFS) and overall survival (OS). Results: In all the 17 patients the mutation was BRAF V600E.The median age of the patients was 58 years (16-77). The m:f ratio was 13:4. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 9 patients (52.9%) and 2-3 in 8 patients (47.1%). The primary sites included in the analysis were lung cancer in 8 (47.1), glioma in 3 (17.7), thyroid in 2 (11.8%) and one each of parotid, melanoma, esophagus, thymoma. BRAF inhibitors could be provided in 9 patients (52.9%) and its was dabrafenib-trametinib in 8 patients and vemurafenib then dabrafenib-trametinib in 1 patient. The median progression free survival was 203 days (95% CI 25.1-380.9) and overall survival was 220 days (95% CI 49.8-408.2) . Conclusions: The real world data suggests that the efficacy of BRAF inhibitors seems to be lower than that seen in pivotal studies. The reasons for which is unknown.
Precision medicine: Novel PI3K inhibitor as cancer treatment.
Authors: Hutchings Kasen Reed , Beck Patrick , Qiu Rebecca , Bui Vincent , Sheng Zhi 
Published: June 2022

e15093 Background: Phosphoinositide 3-kinase (PI3K) is an attractive anti-cancer drug target due to its promotion of cell growth and proliferation; however, available pan-PI3K inhibitors currently lack specificity, leading to excessive drug toxicity and adverse effects. Selectide-18 is a novel PI3K inhibitor that targets PI3K’s catalytic subunit p110β, resulting in reduced viability of cancer cells. The p110β subunit is the most prominent PI3K subunit in many chemoresistant tumors. Previous research has revealed a unique 18-residue long motif within the C2 domain of p110β. This motif is not found in other catalytic subunits (p110α, p110δ, or p110γ), making it a promising drug target. Selectide-18 is a memetic peptide drug modeled after this motif and has been shown to effectively inhibit p110β binding without affecting other isoforms, separating it from currently available pan-PI3K inhibitors. While Selectide-18 has been successful in inhibiting PI3K in previous studies, it has poor cell permeability due to its large size. Previous findings have revealed functional redundancies among Selectide-18’s residues. This study aims to remove these redundancies and determine the optimal formulation of Selectide-18 through in silico analysis. Methods: An in silico protocol was developed to determine the optimal formulation of Selectide-18. By utilizing the PEP-FOLD server, 455 peptide models were created using 91 unique fragments of the Selectide-18 amino acid sequence ranging in size from 6 to 17 residues. Physical conformation of each model was compared to wild-type Selectide-18 using root-mean-square deviation data collected using PyMOL and UCSF Chimera software. Computational docking through AutoDock Vina was performed to test the binding affinity of each model to the active site of regulatory subunit p85α. The distance between each drug and the active site was measured with UCSF Chimera’s distance function. Finally, ClusPro docking of drug-bound p85α/p110β was compared to wild-type p85α/p110β, as well as non-truncated Selectide-18-bound p85α/p110β. Statistical significance was determined using a Student's t-test. Results: Select truncated models demonstrated physical confirmation (RMSD = 0.024), binding affinity (-8.74 kcal/mol), and simulated inhibitory capabilities comparable to Selectide-18. A specific group of variants comprised of 9 amino acids (9 residue_6K-14Q) had the shortest formulation without significant declines in binding affinity. Conclusions: Selectide-18 is a selective PI3K inhibitor that can be optimized by removing functionally redundant amino acids. A 9-residue variant ranging from amino acids 6Lys to 14Gln showed the most promise and will be used in future studies to reformulate Selectide-18. Being half the size of Selectide-18, this optimized drug is anticipated to have improved cell permeability without sacrificing inhibitory function.