bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune checkpoint inhibitor-related reproductive adverse effects: A pharmacovigilance analysis based on the FAERS database.
Authors: Köylü Bahadır , Oktem Ozgur , Esen Bugra Han , Bektas Sevval Nur , Ozbek Lasin , Selcukbiricik Fatih 
Published: June 2024

e14707 Background: There exists a critical need to systematically understand the extent and magnitude of immune checkpoint inhibitor (ICI)-related reproductive adverse effects, which may not only pose long-term implications for patients who may desire future fertility, but also impact the quality of life. We aim to better understand this underexplored area. Methods: Our focus was on ICIs approved by the FDA as of June 31, 2023, including anti-PD-1 agents (nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab), anti-PD-L1 agents (atezolizumab, avelumab, durvalumab), anti-CTLA-4 agents (ipilimumab, tremelimumab), and an anti-LAG-3 agent (relatlimab). We analyzed 13,702,373 cases from January 1, 2015, to June 30, 2023. We included adverse reactions under the 'Reproductive system and breast disorders' category in the SOC (System Organ Classes). For signal detection, we used the reporting odds ratio (ROR) method. Results: We identified 133,512 patients administered with ICIs, among whom 568 reported irRAEs. Abnormal spermatogenesis (ROR025: 7.91), scrotal irritation (ROR025: 3.83), scrotal oedema (ROR025: 1.90), perineal rash (ROR025: 1.38), prostatitis (ROR025: 1.25), acquired phimosis (ROR025: 1.20), and scrotal erythema (ROR025: 1.08) in males and genital tract fistula in females (ROR025: 2.72) were detected as significant irRAEs. Among them, the most commonly reported irRAEs were prostatitis (n=29), scrotal oedema (n=12), and abnormal spermatogenesis (n=6) in males and genital tract fistula (n=34) in females. Male patients had a lower risk compared to females (OR=0.68 [0.57-0.81], p<0.0001). There was no marked difference between the patients on polytherapy vs. monotherapy (OR=0.90 [0.71-1.13], p=0.36). PD-1 inhibitors pose the greatest risk when compared with CTLA-4 inhibitors (OR=1.65 [1.05-2.79], p=0.045). Gynecologic cancers in females (OR=3.77 [2.82-4.99], p<0.0001) and urogenital cancers in males (OR=1.56 [1.17-2.06], p=0.0018) were strong risk factors. Additional targeted therapy, particularly lenvatinib (OR=3.79 [2.71-5.15], p<0.0001) and cabozantinib (OR=2.69 [1.66-4.09], p<0.0001) significantly increased the risk (OR=1.87 [1.52-2.29], p<0.0001) and this risk appeared to be more pronounced in females (OR=2.32 [1.76-3.02], p<0.0001). Additional chemotherapy was associated with a significantly reduced risk in males (OR=0.65 [0.42-0.96], p=0.042). However, doxorubicin (OR=2.58 [1.10-5.05], p=0.013) and cyclophosphamide (OR=2.36 [0.93-4.83], p=0.038) were linked to an elevated risk. Conclusions: Our findings demonstrated that ICIs could lead to a wide range of irRAEs in both males and females. Additional therapies could change the risk of irRAEs. Despite the current lack of high-quality clinical data on this topic, it is reasonable to inform patients about the plausible risk of irRAEs.
A phase I clinical study to evaluate the safety, tolerability, immunogenicity, pharmacokinetics and preliminary efficacy of SCB-219M in patients with chemotherapy-induced thrombocytopenia (CIT): An interim analysis.
Authors: Wang Yongsheng , Xie Ke , Xu Nan , Yi Yuyao , Huang Shan , Ye Bin , Gao Xing , Tan Wei , Yang May , Su Danmei , Xu Rong , Yuan Jing , Liang Peng 
Published: June 2024

e15015 Background: CIT is a serious, chemotherapy-associated complication observed in a wide range of cancer patients with various types of cancer. Incidence of CIT can occur in about 15-25% of patients undergoing standard chemotherapy regiments with platinum, taxane and/or gemcitabine-based regimen. CIT can lead to chemotherapy dose delay or dose reduction, and potentially bleeding events. Currently, there is no FDA-approved therapy for CIT. SCB-219M, a thrombopoietin receptor agonist (TPO-RA) mimetic bispecific Fc-fusion protein produced from CHO cells can efficiently raise PLT count under normal and pathological conditions in laboratory animals. Methods: This is a single-arm, multi-center, open-label, dose escalation Phase Ia clinical study to evaluate the safety, tolerability, and immunogenicity, PK profile and preliminary efficacy of a single ascending dose of SCB-219M administered one day after a chemotherapy in prior CIT patients with malignant solid tumors and lymphoma. The study design of accelerated titration combined with "3 + 3" is used, and the number of subjects planned to enroll is 12 to be assigned to 4 cohorts with 2, 6, 10 and 15 mg/kg subcu administration of SCB-219M, respectively. Enrollment criteria include episode of CIT experienced (<75 × 109/L in PLT count) in prior cycle of chemotherapies and PLT count has recovered to >75 × 109/L prior to initiation of this study . The chemotherapy regimen allowed include either mono or combination chemotherapy (including targeted therapy and/or immunotherapy). The observation period of dose-limiting toxicities (DLTs) is 21 days. Chemotherapy is planned at each study site. There will be no change in the planned dose or frequency of chemotherapy in the study. Results: As of Dec 20, 2023, 9 prior CIT patients including 3 at 15 mg/kg were enrolled. SCB-219M was well tolerated. There were no SAEs or AESIs (Adverse Event of Special Interest) observed. DLT was not reached. A favorable PK profile, in particular in serum availability (AUC) and half-life (T1/2) was obtained. All 9 prior CIT patients in the study maintained PLT counts >75 x 109/L from 1-week following chemotherapies with a single dose of SCB-219M, and durable responses experienced through at least 3 weeks. Conclusions: In this interim analysis, drug safety, PK profile and durable efficacy are expected to support SCB-219M dosing interval of ≥2-weeks or a single dosing regimen within a chemotherapy cycle. Accordingly, a Phase Ib trial evaluating repeated dosing of SCB-219M is planned to initiate in 2024. Clinical trial information: NCT05426369 .
SCR-A002, a novel FGFR2b-targeting antibody-drug-conjugate for solid tumors.
Authors: Fu Yayuan , Ge Yuanjie , Shao Xiaohui , Deng Qi , Xia Chunlei , Tang Renhong 
Published: June 2024

e15019 Background: FGFR2b (fibroblast growth factor receptor 2 IIIb), a transmembrane tyrosine kinase, is overexpressed in various cancers, including gastric, esophageal, breast, hepatocellular, pancreatic, ovary, uterine, cervical, endometrial, lung, colorectal cancers. Bemarituzumab (FPA144), an afucosylated humanized IgG1 monoclonal antibody targeting FGFR2b with enhanced ADCC activity, showed promising clinical efficacy in phase 2 study of FGFR2b-selected gastric or gastroesophageal junction adenocarcinoma. We have developed a potential first-in-class FGFR2b-targeting ADC (SCR-A002) at IND-enabling status, displaying significantly superior anti-tumor potency compared to Bemarituzumab. Methods: SCR-A002 is comprised of a humanized anti-FGFR2b IgG1 monoclonal antibody conjugated with proprietary TOPO1 inhibitor payload (DAR 8) via a cleavable linker. Anti-FGFR2b antibody was generated by immunization of FGFR2b protein in mice followed by hybridoma technique. Binding activity and cytotoxicity were assessed in FGFR2b+ tumor cell line. And anti-tumor efficacy was evaluated in several CDX and PDX models. Results: SCR-A002 could specifically bind to FGFR2b on cancer cells and be internalized, and the TOPO1 inhibitor could be cleaved intracellularly to kill the cancer cells potently in vitro. After single-dose administration of SCR-A002, tumor regression was achieved in different FGFR2b expression level CDX and PDX models, even with big-size tumor or Bemarituzumab resistance. Conclusions: SCR-A002 showed potent anti-tumor efficacy in preclinical data, which suggest that SCR-A002 is expected to provide a new treatment option as single agent or combo with SoC for patients with FGFR2b-overexpressing solid tumor.
Development of novel MUC1-C targeting antibody-drug conjugate for pancreatic cancer treatment.
Authors: Ahmad Rehan , Panchamoorthy Govind , Raina Deepak , Lawney Brian , Kharbanda Surender , Jasuja Ravi 
Published: June 2024

e15025 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancers, which is usually diagnosed in advanced stages and presents an abysmal 5-year survival rate of 3-10%. With late detection of metastasized/advanced disease, curative surgery is not an option for most patients. Accordingly, there is an urgent unmet need for development of therapeutics targeting the pancreatic cancer cells. MUC1 is one such cell surface antigen that is aberrantly overexpressed in most solid tumors including pancreatic cancer. In this study we report preclinical efficacy of pharmacological inhibition of MUC1 signaling by GO-203 and targeted delivery of toxin conjugated to novel MUC1-C antibodies (7B8 and 3D1) binding to the extra cellular domain (ECD) to the PDAC xenografts. Methods: Subjects from TCGA-PAAD were stratified into high (75th percentile) and low (25th percentile) MUC1-expressing cohorts. Differential expression was performed using DESeq2, followed by GSEA, and signaling network analysis using partial correlation networks, ARACNE, and BC3NET. Anti-MUC1 antibody-drug conjugates (ADCs) were generated by coupling monomethyl auristatin E (3D1-MMAE, 7B8-MMAE) via V-C-PAB linker and characterized for anti-tumor activity against pancreatic cancer cells including MIA PaCa-1, CAPAN2 and HAPF-II. Paired-end RNA-seq (50bp) was aligned and quantified to the Human Ensembl GRC38 reference using STAR aligner. Subcutaneous xenografts were obtained in nude mice by injecting 5X106 HPAF-II tumor cells. Results: Differential expression, pathway, and network analyses revealed consistent dysregulation of cancer survival-related processes, and P53-related pathways in the cohort with increased MUC1 expression. The ADCs (DAR of ~3.5) exhibited efficient internalization in cancer cells and associated apoptotic cell death (Kds = 2 - 5nM). Pharmacological inhibition of MUC1 signaling by GO-203 demonstrated reduction in canonical pathways including P53 and EMT. Treatment with 3D1-MMAE compared to both vehicle and GO-203 showed dysregulation of cellular metabolism pathways (cholesterol homeostasis, glycolysis) and exhibited several strong indicators of cellular stress including activation of unfolded protein response processes and mTorc1 signaling. Excellent tumor-suppressive effects of ADCs were observed in HPAF-II xenografts in nude mice. The 7.5 mg/kg (i.v., q7dx3), treatment showed complete tumor regression from 14th day (end of treatment) till the date of termination (Day 50). Doses up to 40 mg/kg were well tolerated by the mice and this anti-tumor efficacy was observed without any appreciable loss in body weight or adverse effects on tissues. Conclusions: Targeted delivery of MMAE toxin to the pancreatic cancer cells presents an exciting opportunity for a novel therapeutic intervention for the treatment of pancreatic cancer patients with MUC1 over expression in tumors.
Blood metabolites–based MCTarg for multi-cancer screening and clinical diagnosis.
Authors: Li Yan , Xu Xinping , Zeng Chunyan , Qing Bei , Liu Li , Song Guodong , Yu Shuqi , Shao Tianqi , Wei Qingyan , Wen He , Hu Junyuan , Zhang Wei , Chen Youxiang , Xia Zhenkun 
Published: June 2024

e15028 Background: Multi-cancer early detection (MCED) tests have emerged as promising tools for reducing cancer-related healthcare costs and mortality. As metabolome is closely linked to the phenotype of bio-individual, metabolomics analysis enables the high throughput investigating of the pathophysiological conditions. Based on metabolomics and machine learning, we developed the Multiple Cancer Target (MCTarg) analysis for multiple cancer screening and diagnosis by a single blood draw. Methods: A total of 1153 individuals (172 healthy participants, 623 patients with lung cancer, gastric cancer, and colorectal cancer, and 358 these organ-related benign disease patients) were enrolled from three independent clinical sites in China. Plasma samples were collected and measured by mass spectrometry (MS)-based platforms (LC-MS polar and lipid). MCTarg was developed with three machine learning modules for three scenarios (community screening for non-healthy individuals, clinical diagnosis for classifying malignant and benign diseases, and tracing tumor of origin). Results: MCTarg exhibited an Area Under the Curve (AUC) of 0.96 with 92.82% sensitivity at 80% specificity to differentiate the non-healthy individuals from healthy controls, and an AUC of 0.86 with 75.41% sensitivity at 79.66% specificity in discriminating multi-cancer from benign diseases. Notably, the classification accuracy for distinguishing between malignant and benign conditions in the colorectal organ was reached 90.74%, with a sensitivity of 83.87% and a specificity of 100%. Furthermore, the overall accuracy for detecting the cancer origin reached 84.78% with an average sensitivity and specificity of 78.08% and 90.7%, respectively. Conclusions: The outstanding results indicated that blood-metabolites-based MCTarg is poised to be a cost-effective, precise, and versatile tool for diagnosing multi-cancer and discriminating tumor of origin. Its potential applications encompass health checkups and supplementary diagnostic scenarios. More deadly cancer types will be extended and the performance of MCTarg will be validated by prospective and population-scale cohorts with longitudinal follow-up.
Baseline value and longitudinal kinetics of circulating nucleosomes during neo-adjuvant chemotherapy in newly diagnosed ovarian cancer: Results from the randomized phase II trial CHIVA (GINECO).
Authors: Corbaux Pauline , Colomban Olivier , Lescuyer Gaelle , Haon Christine , Ray-Coquard Isabelle Laure , De Rauglaudre Gaetan , Joly Florence , Abdeddaim Cyril , Combe Pierre , Lortholary Alain , Hamizi Salima , Deldycke Clothilde , Ferron Gwenael , Meunier Jérôme , Alexandre Jerome , Berton-Rigaud Dominique , Kaminsky Marie-Christine , Pujade-Lauraine Eric , Payen Lea , You Benoit 
Published: June 2024

e15029 Background: Nucleosomes (DNA wound around histone proteins) were reported as potential cancer biomarkers (1). The links between circulating nucleosomes and clinical endpoints in advanced ovarian cancer (OC) patients treated with neo-adjuvant chemotherapy (NACT) +/- interval debulking surgery (IDS) were retrospectively assessed in the randomized phase II CHIVA trial (2). Methods: The diagnostic concentration and the longitudinal kinetics of 2 nucleosomes (H3K27 and H3K36, log-scale) were investigated at baseline, during NACT, after IDS, and at progression. The baseline titer measured with Nu.Q prototype immunoassays (H3K27Me3, H3K36Me3 (Belgian Volition SRL, Belgium)) was compared to those of a cohort of 201 cancer-free subjects. Their prognostic values regarding the probability of obtaining a complete IDS and progression-free survival (PFS) were assessed with respect to the modeled CA-125 KELIM (3), classical clinical covariates and treatment arms. The maximum selected rank statistics was used to determine the optimal cut-off at different disease management times. Results: H3K27 and H3K36 nucleosome concentrations were available for 148/188 patients. H3K36 and H3K27 baseline concentrations were correlated and significantly higher in OC patients compared to cancer-free subjects (H3K36, 2.8 vs 2.4 ng/mL, P<0.0001; H3K27, 3.2 vs 2.1, P<0.0001), without difference according to BRCA status. The baseline titer of H3K36 was an independent predictor of the completeness of IDS (OR=0.33; 95% CI=0.13-0.71, p=0.009). The baseline concentration of H3K27 was independently associated with PFS (< or ≥3.8 ng/mL, HR=1.84, 95%CI=1.11-3.02, p=0.016), complementary to the CA-125 KELIM. Both nucleosome longitudinal kinetics showed a decrease during NACT, but there was no significant statistical association between their kinetics and radiological response rate, completeness of IDS or PFS. Conclusions: Baseline values of H3K36 and H3K27 could represent a non-invasive method for detecting OC, with potential relevant prognostic value of initial titers in newly diagnosed OC patients. 1. McAnena, Cancers 2017. 2. Ferron, Gynecol Oncol 2023. 3. You, CCR 2020.
Circulating tumor cells enumeration and characterization in patients with lung cancer treated with immunotherapy.
Authors: Raphael Jacques , Breadner Daniel Adam , Warner Andrew , Black Morgan , Goodale David , Vincent Mark David , Kwan Keith , Blanchette Phillip S. , Slade Megan , Gupta Santosh , Wenstrup Rick , Allan Alison L 
Published: June 2024

e15030 Background: Programmed death-ligand 1 (PD-L1) is a predictive biomarker for immunotherapy in the treatment of non-small cell lung cancer (NSCLC). Assessing PD-L1 expression from the tumor specimen can be challenging because of tissue accessibility, heterogeneity, and dynamic changes in PD-L1 expression that may impact the status of PD-L1 during disease evolution and treatment. Hence, assessing PD-L1 status from archival tumor might not reflect its actual state on the tumor and having a real-time assessment of its expression with the use of non-invasive techniques such circulating tumor cells (CTCs) is useful. Methods: We conducted a single centre prospective study to detect CTCs in the blood of patients with stage III-IV NSCLC treated with immunotherapy using the standard CellSearch technology for CTC enumeration and the Epic Sciences technology for CTCs enumeration and assessment of PD-L1 protein expression on CTCs. CTCs were detected at baseline before treatment initiation and after 2 cycles of treatment. Study endpoints included CTCs detection and concordance between the 2 technologies, PD-L1 expression assessment on CTCs with the Epic Sciences technology, and concordance with tissue-based expression. Comparisons were made using Pearson correlation coefficient (PCC) and intraclass correlation coefficient (ICC) for count data and percentage of perfect agreement. Results: Between 2019 and 2022, 48 patients treated with immunotherapy were enrolled in the study. The mean ± standard deviation (SD) age was 66.8 ± 10.3 years, 63% were females, 42% received combination chemotherapy and immunotherapy, and 44% had adenocarcinoma histology. The tissue PD-L1 expression was high (≥50%), intermediate (1-49%), and low (<1%) in 36%, 31% and 33% of patients respectively. The mean ± SD baseline CTCs count per 7.5ml was 1.97 ± 4 with CellSearch and 1.38 ± 2.72 per ml with Epic Sciences. After 2 treatment cycles, 22% and 41% of patients had an increase in their CTCs count with CellSearch and Epic Sciences, respectively and 30% and 29% had a decrease in their CTCs. The PCC and ICC for baseline CTCs detected by CellSearch and Epic Sciences were 0.72 and 0.61, respectively and for CTCs detected after 2 cycles of treatment by the 2 technologies were -0.16 and 0.45 respectively. One patient had PD-L1 expression on their CTCs with the Epic Sciences technology and there was no association between the PD-L1 expression on CTCs and on matched tissue samples. Conclusions: This study showed a moderate to strong correlation between the 2 technologies for baseline CTCs detection and moderate to poor correlation for CTCs detection after 2 cycles of therapy. No association was found between CTCs and tissue PD-L1 expression. Future work needs to further investigate the role of PD-L1 expression on CTCs.
Concordance between tissue (tumor DNA) and liquid (ctDNA) biopsy next-generation sequencing (NGS) data in detection of PIK3CA, AKT1, and PTEN alterations in breast cancer: A retrospective analysis.
Authors: Vasan Neil , Chaki Moumita , Benrashid Mona , Puri Subir , Sivakumar Smruthy , Sokol Ethan 
Published: June 2024

e15033 Background: In the Phase 3 CAPItello-291 trial (NCT04305496), the addition of capivasertib (a potent, selective pan-AKT inhibitor) to fulvestrant significantly improved progression-free survival in patients with HR+/HER2− advanced breast cancer, especially in those with PIK3CA/AKT1/PTEN-altered tumors identified using tissue biopsy-based FoundationOneCDx. Given the growing utility of circulating tumor DNA (ctDNA) and interest in liquid biopsy-based tests to detect PIK3CA/AKT1/PTEN alterations, we performed a retrospective analytical comparison of FoundationOneCDx and blood-based FoundationOneLiquidCDx NGS data. Methods: We utilized the FoundationCORE database of breast cancer cases profiled during routine clinical care with FoundationOneCDx and/or FoundationOneLiquidCDx (covering the same genomic regions). Analytical comparison of all pathogenic PIK3CA/AKT1/PTEN alterations as well as alterations defined in the CAPItello-291 protocol (CAPItello-291 alterations) was performed in paired data from cases with both tissue and liquid biopsies, sampled within 90 days of each other. Subgroup analysis was conducted based on ctDNA tumor fraction (TF). Data from liquid biopsies were analyzed for co-occurring mutations. Results: CAPItello-291 alterations were detected in 44.9% of 35,730 tissue biopsies and 34.3% of 7056 liquid biopsies profiled from Jan 2017–Jun 2023. In paired NGS data (n=289), the overall positive percent agreement (PPA) for CAPItello-291 alterations across ctDNA TF subgroups was: TF ≥10% (n=99): 92.5%; TF 1–10% (n=66): 97.1%; TF <1% (n=124): 33.9%. The PPA for all PIK3CA/AKT1/PTEN short variants (base substitutions, indels) analyzed was: ctDNA TF ≥10%: PIK3CA, 93.9%; AKT1, 100%; PTEN, 100%, and ctDNA TF 1–10%: PIK3CA, 96.3%; AKT1, 100%; PTEN, 100%. For PTEN biallelic deletions, the PPA was 50% (2/4) in cases with ctDNA TF ≥10%. In liquid biopsies with CAPItello-291 alterations (n=2421), the most frequent co-occurring mutations were in TP53 (49.9%), ESR1 (31.2%), CDH1 (23.7%), NF1 (13.0%), RB1 (12.8%), CHEK2 (12.4%), ATM (11.9%), FGF3 (11.4%), FGF19 (11.0%), and FGF4 (10.5%). Mutations in BRCA1 (2.4%), BRCA2 (4.8%), and PALB2 (1.3%) were also observed. Conclusions: PPA between liquid and tissue biopsy NGS data for the detection of PIK3CA/AKT1/PTEN short variants was high in cases with ctDNA TF ≥1%. Liquid biopsies offer a minimally invasive approach for the detection of some CAPItello-291 alterations. However, limitations posed by ctDNA TF <1% and sample and variant types should be considered. Together, these data can help clinicians make informed decisions regarding suitable diagnostic tests to determine patient eligibility for breast cancer therapies.