bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of clinical equations on carboplatin dosing: A systematic review to determine appropriate dosing of carboplatin in adult cancer patients.
Authors: Leiva Maya , Yamauchi Sabrine 
Published: June 2023

e15005 Background: The Calvert formula is used to estimate the carboplatin dose needed to achieve the desired Area Under the Curve (AUC) despite little consensus on which estimated Glomerular Filtration Rate (eGFR) equation best reflects renal clearance. Cockcroft-Gault (CG) is often used when calculating estimated Creatinine Clearance (CrCl) for the Calvert formula. Equations like Modification of Diet in Renal Disease or CKD-EPI (based on serum creatinine (SrCr) or cystatin C), take into account parameters such as race, gender, weight. We compared several publications to determine the most effective dosing strategy for carboplatin. Methods: Utilizing PubMed, 19 articles were found with the keywords “carboplatin, dosing, eGFR, measure GFR, creatinine clearance, muscle mass.” Our inclusion criteria consisted of being published within the last 10 years, included carboplatin dosing, and evaluated either measured GFR, measured CrCl, carboplatin clearance or toxicities caused by carboplatin. Studies not meeting these parameters were excluded. Of the 19 articles, 11 articles were identified regarding the accuracy of eGFR and its effects on carboplatin dosing and/or dose limiting toxicities. An extensive literature review of each article was used to find a consensus among the clinical equations used in carboplatin dosing. Results: There remains no consensus on the most accurate eGFR equation. Eight studies evaluated accuracy of varying equations in estimating GFR, creatinine clearance or carboplatin clearance. Two studies created new equations (one measuring GFR and the other measuring CrCl) and compared them to current equations for accuracy. Ultimately, only two studies were in agreement that CKD-EPI was the most viable option when GFR uses SrCr. Based on four studies, CG is an inadequate measurement of eGFR. CG ranked low due to a high mean percent error when compared to measured GFR, indicating a larger discrepancy between measured GFR and the estimated value of CG, as compared to other equations. Three of the studies evaluated for a correlation in skeletal muscle mass and hematological toxicities, indicating that changes in muscle mass could correlate with hematological toxicities. One small study developed a new equation based on muscle mass and SrCr and showed positive results for accuracy when compared to measure CrCl. Conclusions: Although a definitive equation to estimate renal clearance could not be established, equations like CG have limited accuracy due to race, weight, age, and gender. The single study that utilized muscle mass demonstrated the most promise and presents a better option for patients, particularly when muscle mass changes over time. Other studies illustrated that muscle mass is significantly correlated with carboplatin toxicity and should be considered for future studies to determine the safest method for dosing carboplatin.
A phase 1, multi-center, open-label, dose-escalation and dose expansion study of CBP-1018, a bi-ligand-drug conjugate, in patients with heavily treated advanced solid tumors.
Authors: Li Kaiwen , Wu Junyan , Ye Suiwen , Liu Yanqiong , Huang Hao , Fan Fan , Lai Yiming , Zhuang Suili , Zhou Liyan , Huang Robert , Teng Yan , Chai Xiaoyan , Shi Yehui , Huang Hai 
Published: June 2023

e15007 Kaiwen Li and Junyan Wu contributed equally to this work. Yehui Shi and Hai Huang are the corresponding authors. Background: Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer and folate receptor α (FRα) overexpressed in various malignant tissues which both related to tumor invasiveness. CBP-1018 is a first-in-class bi-ligand-drug conjugate targeting both PSMA and FRα with monomethyl auristatin E (MMAE) as payload. Methods: This phase 1 study included both a dose-escalation and expansion stage. In the dose-escalation stage, an accelerated titration was conducted in single patient at 0.03mg/kg followed by an i3+3 design for dose levels (DLs) ≥ 0.06 mg/kg, Q2W in a 4-week cycle. This stage mainly enrolled patients (pts) with metastatic castration resistant prostate cancer (mCRPC) received a median 3.5 prior lines of treatment. The primary objectives were to evaluate the safety and tolerability, determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Additionally, pharmacokinetics (PK) and preliminary efficacy will also be evaluated. Results: As of 24 Nov 2022, 14 pts (12 mCRPC, 1 bladder cancer and 1 ureteral carcinoma) were enrolled at 5 DLs (1 pt at 0.03 mg/kg, 3 pts each at 0.06, 0.08, 0.10 mg/kg, 4 pts at 0.12 mg/kg). No DLTs or drug-related deaths were observed. For 9 pts (64.3%) experienced treatment-related adverse events (TRAEs) ≥ grade 3, most common were neutrophil decrease (35.7%), WBC decrease (28.6%), lymphocyte decrease (14.3%), elevated GGT (14.3%) and hypertriglyceridaemia (14.3%). Among 10 efficacy evaluable pts with mCRPC, 3 SD were observed at DLs of 0.08, 0.10, and 0.12mg/kg, 4 non-PD at 0.06, 0.10, and 0.12 mg/kg, and 3 PD at 0.06 and 0.08 mg/kg. Decrease of prostate-specific antigen (PSA) was detected in 3 pts at 0.10 mg/kg. Overall median PFS was 7.2 months (95%CI, 1.7-9.3) and not reached in mCRPC pts. For PK profile of CBP-1018 and free MMAE, t1/2z was ranged 0.54-1.15 h and 40.28-57.27 h, respectively, no accumulation of both substances after multiple doses. Conclusions: CBP-1018 was well-tolerated at DLs of 0.03-0.12 mg/kg Q2W with no DLTs. Multiple SD were observed at DLs of 0.08-0.12 mg/kg, conferred a promising preliminary antitumor activity in pts with mCRPC. MTD was not reached and dose-escalation to establish the RP2D is continuing. Clinical trial information: NCT04928612 .
Development of a CUB domain-containing protein 1 (CDCP1)-targeting antibody-drug conjugate for triple-negative and metastatic breast cancer.
Authors: Gough Madeline , Kwah Kayden , He Yaowu , Snell Cameron Edward , Hooper John D. , Kryza Thomas 
Published: June 2023

e15012 Background: CUB-domain containing- protein 1 (CDCP1) is a transmembrane receptor involved in the progression of several cancers. Recent studies demonstrate that CDCP1 is a rational target for the development of innovative targeted therapies for cancer including theranostics agents and antibody-drug conjugates. Methods: To determine the therapeutic potential of CDCP1 in breast cancer, we investigated its expression in multiple cohorts of breast cancer tissues by immunohistochemistry, as well as in various preclinical models including cell lines, primary cells and patient-derived xenografts using flow cytometry, western blot and immunofluorescence staining. Then, we evaluated the capacity of the CDCP1-targeting chimeric antibody ch10D7 to specifically accumulate in breast cancer lesions in in vivo preclinical models including patient-derived xenografts and breast cancer metastasis models. Finally, we determined the efficacy of the ch10D7-MMAE antibody-drug conjugate to kill breast cancer cells in vitro and breast tumours ex-vivo and in vivo. Results: The CDCP1 receptor is expressed at targetable level in a significant proportion of breast cancer cases with high/intermediate expression detected in ~30% of localized ER-positive cases, ~50% of metastatic ER-positive cases and > 70% of Triple-negative or HER2-positive cases. Similar proportion of expression was detected in cellular models. We demonstrated that ch10D7 antibody labelled with the radionucleotide Zircodium-89 specifically accumulates in breast cancer lesions in vivo allowing the detection of mammary-fat pad implanted patient-derived xenografts and of breast cancer metastasis by PET/CT imaging. Finally, we confirmed that the ch10D7-MMAE antibody-drug conjugate is very efficient at inducing cell death in vitro as well as controlling primary tumour and metastatic tumour burden in pre-clinical models, conferring a significant survival advantage compared to classical therapy. Conclusions: Our work demonstrates that CDCP1 is a potential target to detect and limit the progression of breast tumours in both the primary and metastatic disease setting, particularly in triple-negative and HER2-positive breast cancer subtypes. Furthermore, we show that biomolecules specifically recognising this receptor are promising therapeutic agents which could improve survival of patients.
Impact of panel size on minimum residual disease (MRD) assay performance.
Authors: Battey Christopher Jon , Acevedo Ashley , LaBella Matt , Ganesh Sangita , Patel Ravi , Trettin Kyle , Buser Elise , Xu Nafei , Gould Genevieve M. , Muzzey Dale 
Published: June 2023

e15022 Background: Sequencing circulating tumor DNA is a promising method for monitoring cancer treatment response and detecting recurrence, but sensitivity at the low tumor fractions typical of early-stage, post-treatment, and early recurrent tumors is limited by the small number of variants targeted in commercially available assays. Methods: We developed a tumor-informed minimum residual disease (MRD) assay using tumor-normal whole-genome sequencing (WGS) followed by interrogation of select somatic variants in cell-free DNA (cfDNA). We describe theoretical limits on panel designability as a function of tumor purity and sequencing depth using simulations and a discovery cohort of 31 patient samples. cfDNA assay performance was tested by creating serial dilutions of patient plasma before somatic enrichment and sequencing. Simulations and in-silico downsampling of target sites were used to test sensitivity as a function of panel size. A bioinformatics pipeline incorporating somatic calling, copy number inference, error assessment, and tumor-fraction estimation was developed to analyze results. Results: Across a range of tissues, tumor-normal WGS identified from hundreds to tens of thousands of somatic variants to inform an MRD capture panel. 97% of samples tested returned at least 300 high-confidence somatic variants, and targeted sequencing demonstrated over 95% positive predictive value in somatic variant calls. In cfDNA dilution experiments, we observed > 99% sensitivity at a tumor fraction of 0.01%. Expanding the panel size from 16 to 300 target variants increased sensitivity at 0.005% tumor fraction from approximately 20% to > 95%. Our tumor fraction model returned accurate quantification down to the parts per hundred thousand (0.001%) range, even when only a single tumor molecule could be observed at each target site. Conclusions: Increasing the number of targeted variants in an MRD assay increases sensitivity at low tumor fractions, and WGS-driven panel design ensures a sufficient number of interrogated variants while minimizing the failure rate due to panel designability. High sensitivity MRD has the potential to enable earlier recurrence detection while also giving researchers and clinicians new tools for monitoring patient treatment responses.
Candidates for early detection: Effect of pluripotent very small embryonic-like stem cells (VSELs) to transform into cancer stem cells (CSCs) and candidacy for early detection of cancer in a liquid biopsy.
Authors: Tripathi Ashish , Pansare Kshama , Jha Nitu , Bhartiya Deepa , Ranade Anantbhushan , Joshi Deepa , Tripathi Anish 
Published: June 2023

e15024 Background: Prevailing somatic mutation theory (SMT) is mired with several paradoxes and still there is no clarity on how cancer initiates. No distinct pattern of somatic driver mutations specific to cancers affecting solid tissues has yet emerged even after massive NGS studies since 2007. Rather than cancer being a genetic disease, we postulate that endogenous, tissue-resident VSELs get transformed into CSCs to initiate cancer. Under normal conditions, VSELs along with tissue-specific progenitors work in a subtle manner to maintain life-long homeostasis in adult tissues. VSELs express steroid and gonadotropin hormone receptors, are directly vulnerable to environmental insults, and their dysfunction initiates various pathologies, including cancer. Recent mice studies have shown that environmental insults resulted in global hypomethylation, genomic instability and loss of imprinting (LOI) at IGF2/H19 loci that transformed quiescent VSELs into CSCs. Unlike VSELs, CSCs undergo excessive self-renewal, acquire bad-luck mutations during clonal expansion and oncogene activation to initiate cancers, and can also further mobilize to distant sites to cause metastasis. A 1000-sample clinical study based on OCT-4A expression by qRT-PCR suggested that CSCs that get mobilized from affected organs can serve as potential novel candidates for early detection of cancer through liquid biopsy. Methods: CSCs were enriched from the peripheral blood using our proprietary technology. They were enumerated by flow cytometry. VSELs undergo epigenetic changes and LOI to transform into CSCs. TaqMan based qRT-PCR was carried out to study OCT-4A and ALDH-1 positive CSCs and IGF2 expression to monitor LOI at the IGF2/H19 loci. LOI of IGF2 is commonly associated with initiation and also progression of multiple cancers and is also responsible for pushing VSELs out of quiescence and enter the cell cycle as CSCs. Results: Increased numbers of CSCs (epigenetically altered VSELs) were detected in peripheral blood samples of cancer subjects compared to normal subjects (p < 0.0001) by flow cytometry studies. The median absolute count of circulatory VSELs/CSCs was 190 per ml (IQR: 105-295) in normal subjects and 690 per ml (IQR: 370-1265) in cancer subjects. The qRT-PCR study conducted on 100 subjects showed increased expression of OCT-4A, IGF2 and ALDH1 genes in cancer compared to non-cancer subjects. Conclusions: Early detection of cancer by evaluating circulating tumor cells (CTCs) or tumor DNA (ctDNA) holds promise, but their scarce nature and mobilization in late stages only when tumor is > 3 mm in size, are major limitations for widespread translation. Circulating VSELs/CSCs in peripheral blood are evidently promising candidates to screen and classify subjects for cancer absence, likely risk, or presence.
An in-house testing for detection of homologous recombination repair deficiency (HRD) in patients with solid tumors.
Authors: Tan Shuguang , Guo Weifeng , Cai Bin , Mu Tianhao , Liu Ming , Wang Zhouyang , Zhou Yanqing , Yin Yan 
Published: June 2023

e15025 Background: HRD is associated with sensitivity towards PARP inhibitors (PARPi) in various cancer types, such as ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer, and its determination is used as a biomarker for therapy decision making. HRD leads to the larger genome alterations, called “genomic scars“, which comprise loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large scale state transitions(LST). The detection of SNPs is capable of measuring chromosomal abnormalities including genomic scars as mentioned above. Methods: Using a panel targeting more than 50,000 SNPs that evenly spaced across the entire human genome and the next generation sequencing technique, we developed an in-house testing for HRD detection, namely HRD score, which was computed by combining the measurements of large genomic defects including LOH, TAI, and LST. Then, we detected 44 ovarian cancer patients without BRCA1/2 mutations and 14 ovarian cancer patients harboring BRCA1/2 mutations to explore the application possibility of HRD score 42 as the threshold for HRD patients. Furthermore, we studied the HRD score distribution of 494 solid tumor patients. Results: For the 44 ovarian cancer patients without BRCA mutation, 50% (22/44) of them had the HRD score greater than 42. For the 14 ovarian cancer patients harboring BRCA1/2 mutations, 100%(14/14) of them had the HRD score greater than 42. For the 494 solid tumor patients, 38.66% (191/494) of them had the HRD score greater than 42. Conclusions: For this in-house HRD testing, the percentage of ovarian cancer patients without BRCA mutation who had HRD score greater than 42 was consistent with former report. Besides, the HRD score of all the 14 ovarian cancer patients harboring BRCA1/2 mutations were greater than 42, which was consistent with the facts. Therefore, it seems applicable to define the patients with HRD score greater than 42 as HRD positive. In addition, there is a wide range of demands for comprehensive implementation of HRD testing for other tumor entities.
Comparison of cfDNA content in different cancer types with different extraction methods.
Authors: Zhang Wenlong , Zhao Yanan , Li Jun , Cong Dan , Zhou Di , Yang Yang , Bai Yuansong , Mu Tianhao , Liu Ming , Yin Yan , Chen Shifu , Liu Yuanyuan 
Published: June 2023

e15026 Background: ctDNA liquid biopsy technology has been widely used in the whole course of cancer management, from early screening and early diagnosis of tumors to tumor monitoring and medication guidance. However, the performances of ctDNA as a biomarker in these scenarios are different among different cancer types. One possible reason is that different types of cancer release different amounts of ctDNA or cfDNA, therefore, we explored the cfDNA levels in different cancer types in this study. Methods: We collected 15913 peripheral blood samples from 14686 cancer patients with different clinicopathologies, 256 patients with pulmonary nodules, and 971 healthy people. We isolated their plasma and extracted the cfDNA using QIAamp Circulating Nucleic Acid Kit, Apostle MiniMax cfDNA Extraction Kit or HaploX magnetic bead method cfDNA extraction kit. We calculated the average concentration of cfDNA (ng/ml) for different groups. Results: The number of samples of cervical cancer, liver cancer, glioma, colon cancer, prostate cancer, nasopharyngeal carcinoma, gallbladder carcinoma, melanoma, cholangiocarcinoma, colorectal cancer, breast cancer, gastric cancer, endometrial carcinoma, lung cancer, urothelial carcinoma, rectal cancer, ovarian cancer, healthy people, and pulmonary nodule patients are 93, 469, 113, 277, 139, 76, 89, 132, 171, 4010, 407, 547, 68, 7750, 46, 203, 96, 971 and 256, respectively. The cfDNA level of corresponding groups are 88.07, 79.51, 75.57, 63.58, 61.37, 59.09, 57.59, 57.16, 42.67, 34.73, 31.75, 31.37, 31.33, 29.84, 28.72, 28.69, 23.83, 17.82 and 12.54 ng/ml, respectively. The main groups are shown in the table below. Conclusions: The cfDNA concentrations of healthy people or pulmonary nodule patients were significantly lower than that of tumor patients, and there were also significant differences between different types of cancer. What's interesting, the cfDNA concentrations of lung cancer patients, pulmonary nodule patients and healthy people were quite different. What’s more, there were differences between Colon cancer and Rectal cancer patients. So, the cfDNA concentration maybe a good dimention to be used in early cancer screening and tracing of tumor types. [Table: see text]
Detecting variation of clonal hematopoiesis using machine-learning in liquid biopsy.
Authors: Zhang Yiqun , Pei Zhihua , Zhao Yuting , Hu Yifan , Li Zhencong , Wang Dongliang , Zhou Qiming 
Published: June 2023

e15027 Background: Tumor‐derived DNA released to the plasma of cancer patients which could be captured and detected by ultra-deep sequencing. NGS provides the technical probability of somatic mutations detection from circulating cell‐free DNA (cfDNA) in plasma samples, while clonal hematopoiesis (CH) mutations affect the accuracy of liquid biopsy for clinical diagnosis or choice of drug and tracing of minimal residual disease (MRD). CH mutation screening of cfDNA samples still an unsolved issue, herein we propose a method that based on multi-variable tree model which screen the CH mutation effectively. Methods: We sequenced 1992 cfDNA (raw depth 35000x) and matched peripheral blood lymphocyte (PBL, raw depth 2000x) samples by 1123 genes target capture sequencing from cohorts which include 962 non-small cell lung cancers (NSCLC), 631 gastric cancers (GC), 379 other non-hematological cancers and 40 healthy normal control. First, we compared the coherence patterns of cfDNA-PBL between CH genes (ASXL1, DNMT3A, TET2) hotspot mutation and tumor associated mutation (EGFR L858R T790M, KRAS G12D G13D, TP53 R43H R141H). Next, we labeled canonical mutations by: point mutation and indels; top frequent tumor genes (from cbioportal collected TCGA cancers); published frequent CH genes; known hotspots and unknown significance genes. Furthermore, hotspot tumor mutation and hotspot CH mutations and other mutations were labeled. kNN classify all mutation to labeled mutations groups, and decided the next steps tree model’s node thresholds build a classify tree model screen the confident CH and somatic mutations. Finally, we validated 6 TP53 CH mutation from healthy normal control by ddPCR. Results: Previous published imbalance test model: 'fisher test p.value > 0.5 & 0.5 < OR < 1.5' only covered 23.2%, 26.9%, 17.5% top 10 hotspot CH mutations (ASXL1, DNMT3A, TET2) correspondingly, while 0.75 quantiles both g_VAF and t_VAF less than 1% and alter reads count less than 20. In terms of tumor associated mutations only 3/155,6/123,7/108,7/71,323/998,16/189 exceed the imbalance test models threshold, especially L858R with median t_VAF 3.4% and t_alter_count 60. Population frequency distribution of CH and tumor genes mutation were different significantly (median 0.776% and 0.569%; p.value < 1.44e-05, F-test). After assign hotspot and CH mutations classify by kNN, The tree model screened 42.9% and 83.6% CH mutations in cancer and healthy normal samples respectively. TP53 were common both in tumor and CH mutation ambiguously, tree model screened 6 TP53 CH mutation (c.12G > A, R43H, G113D, R70C, c.16C > T, A80T) from normal plasma sample all validated by ddPCR. Conclusions: CH mutations were ubiquitous in plasma sample and abundance pattern different from common tumor mutations significantly. CH mutation could be screened by optimal condition assembled decision trees effectively.