bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive value of C reactive protein (CRP) and D-dimer in patients with advanced cervical cancer treated with sintilimab and anlotinib.
Authors: Liu Jing , Chang Lele , Li Li , Zang Lele , Zhu Fei , Zhang Huiqi , Zhu Mingxuan , Xu Qin 
Published: July 2024

e17525 Background: The Sintilimab plus Anlotinib in patients with advanced cervical cancer trial was a single-arm, phase II study that showed promising activity of the programmed death-1 (PD-1) inhibitor sintilimab plus the vascular endothelial growth factor receptor inhibitor Anlotinib in patients with advanced cervical cancer. We aimed to identify prognostic values of inflammation biomarkers and coagulation biomarkers in advanced cervical cancer treated with Sintilimab and Anlotinib. Methods: We conducted a post-hoc analysis of the data from the ALTER-C201 study (Clinical trial information: ChiCTR1900023015). The predictive value of coagulation variables and inflammation variables was evaluated by receiver operating characteristic (ROC) curves. Through Cox hazards regression models, prognostic factors were determined for overall survival (OS). Survival curves were visualized by Kaplan–Meier method and compared through Log-rank analysis. Results: We involved 41 patients and followed up for 38.0 (range, 0.6–44.0) months. According to the ROC curve, the predictive values of baseline CRP and D-dimer are better than other indicators, with area under the curve (AUC) values of 0.748 and 0.848, respectively. The cut-off values for D-dimer and CRP are 1.75ug/ml and 10.9mg/L, respectively. Through regression analysis, we demonstrated that CRP (HR 2.591; 95%CI 1.099–6.106; P = 0.030) and D-dimer (HR 2.669; 95%CI 1.154–6.173; P = 0.022) were independent prognostic factors. Compared to patients with CRP ≥ 10.9mg/L, those with CRP < 10.9mg/L have a longer OS (28.93 months, 95% CI, 15.23 to not reached v 10.57 months, 95% CI, 6.14 to not reached; log-rank test, P = 0.007). Compared to patients with D-dimer ≥ 1.75ug/ml, those with D-dimer < 1.75ug/ml have a longer OS (28.93 months, 95% CI, 17.09 to not reached v 10.73 months, 95% CI, 4.63 to not reached; log-rank test, P = 0.005). Conclusions: CRP and D-dimer predict survival in advanced cervical cancer patients undergoing combined ICI/ VEGF-TKI therapy. We advocate further work to validate utilisation of CRP and D-dimer as prognostic biomarkers for advanced cervical cancer in clinical practice.
Survival in patients with cervical cancer undergoing chemo-radiotherapy in a middle-income country.
Authors: Argüello Mario , Pulla Fausto Emiliano , Morquecho Walter , Reyes José Luís , Campoverde Felipe , Engracia Ruth , Tamayo Patricia Rocío , Paulson Guillermo , Santacruz Mayra 
Published: July 2024

e17527 Background: Cervical cancer (CC), being a high-incidence pathology in Ecuador, requires a priority multidisciplinary therapeutic approach to obtain an optimal benefit in overall survival. The objective of the present study is to describe overall survival (OS) in patients with locally advanced CC treated with chemoradiation according to histological type and clinical stage. Methods: It is an observational, analytical, retrospective, longitudinal study of patients with stage IIB-IVA CHD who received treatment with chemoradiation from January 2010 to December 2014 with a 10-year follow-up. The SPSSv29 statistical system was used. Survival analysis was performed using the Kaplan-Meier method and the Log-Rank test. Results: Of 1909 patients, 1581 were excluded because they did not meet eligibility criteria. 328 received chemoradiation. The overall survival result was 43%. According to histological type, 276 patients presented squamous cell carcinoma (SCC) and 52 adenocarcinoma (AC), presenting a survival of 44% for SCC and 35% for AC. The calculation by clinical stage, II-B shows a survival of 46%. For stage IV-A 20% up to 46 months. The Log-Rank test (p=0.04) shows a significant statistical value. Conclusions: The 10-year overall survival was 43%, showing an essential difference for the histological type, being higher for squamous cell carcinoma, and also showing a significant difference between the stages. [Table: see text]
Clinical phosphoproteomics reveals aberrant signalling pathways and kinases in treatment-resistant cervical cancer.
Authors: Kumar Prashant , Chauhan Richa , George Irene A. , Sambath Janani , Dhawale Ekta R. , Singh Manisha , Trivedi Vinita , Venkataramanan R. 
Published: July 2024

e17529 Background: Cisplatin-based concurrent chemoradiation therapy (CCRT) is the standard for locally advanced cervical cancer. While cisplatin stands out as a highly effective chemotherapeutic option for cervical cancer, resistance to the drug often triggers relapses. Moreover, previous studies have highlighted the detrimental impact of cisplatin's toxicity, which extends beyond treatment efficacy to influence the overall prognosis of patients. Combination treatment with drugs targeting different molecular pathways increases the effectiveness of the treatment by disrupting multiple critical processes that cancer cells rely on for survival. Herein, we analyzed the phosphoproteomic profile of cervical cancer patients resistant to concurrent chemoradiotherapy to identify the crucial kinases responsible for therapeutic resistance. Methods: We used mass spectrometry for phosphoproteomic analysis to study signaling pathways and dysregulated kinases in CCRT resistance. Biopsy samples collected pre-therapy were processed by protein extraction, digestion, and labeling with 10-plex TMT. Peptides were fractionated by basic pH liquid chromatography, enriched using IMAC, and analyzed on an Orbitrap-Fusion-Tribrid mass spectrometer. Data analysis was performed using Proteome Discoverer and various bioinformatics and statistical methods. Results: The phosphoproteomic analysis revealed distinct phosphorylation signatures between the responders and non-responders. In concordance with the phosphoproteomic data the expression of phospho-SMC1A and CSNK2A1 is preserved in non-responder cohort of cervical cancer patients in concordance with the phosphoproteomic data. Further, the pathway analysis showed elevated presence of the DNA repair pathway in the treatment-resistant cohort. Furthermore, dysregulation in the phosphorylation of key DNA repair proteins, such as SMC1A, HMGN1, MGMT, DDB2, and MSH6, suggests their involvement in treatment. The kinase prediction analysis suggested the activation of kinases such as CSNK2A1, PRKDC, PLK1, NEK2 and ATM in non-responders. Subsequently, cell line based functional experiments indicated the potential of CSNK2A1 inhibitor silmitasertib in sensitizing the cells to cisplatin treatment. Conclusions: Phosphoproteomicanalysis of the cervical cancer revealed distinct phosphorylation signature and kinases involved in treatment resistance. Our findings indicated that dysregulated phosphorylation and increased expression of the kinase CSNK2A1 play a pivotal role in the treatment response of cervical cancer patients. Moreover, CSNK2A1 can sensitizes the cells to cisplatin uncovering the potential of combination treatment strategies. Our study uncovers the potential of clinical phosphoproteomics to design tailored treatment strategies in patients resistant to standard treatments.
Liquid biopsy detection of structural variant breakpoints to monitor ovarian cancer clonal evolution.
Authors: Li Jian , Takamatsu Shiro , Little Latasha , Celestino Joseph , Lawson Barrett , Hillman Robert Tyler 
Published: July 2024

e17538 Background: Chemotherapy is effective at inducing remission for most patients with high grade serous ovarian cancer (HGSOC), yet relapse is frequent. Methods to interrogate the clonal composition and molecular properties of minimal residual disease are needed to better understand the mechanisms of HGSOC relapse. To address this unmet need, we developed and validated a novel cfDNA-based approach for tracking on-treatment clonal evolution using tumor-informed structural variants (SVs). Methods: Genomic DNA (gDNA) was isolated from cryopreserve multisite pre-treatment HGSOC biopsies and matched germline samples and whole genome sequencing (WGS) was performed. cfDNA was isolated from contemporary pre-treatment plasma. High confidence SVs were identified from multisite WGS using a consensus method incorporating five published SV calling algorithms. Tumor-informed bespoke quantitative PCR primer/probe sets were designed to interrogate SVs breakpoints in tumor gDNA and matched cfDNA. Results: Optimization of the methodology was first performed using synthetic cfDNA generated by ultrasonication of DNA from ovarian cancer cell lines. WGS was used to identify SVs and SV breakpoint-spanning PCR assay exhibited 90% sensitivity and 89% specificity in detection of WGS-informed SVs. 11 validated SVs breakpoint-spanning PCR assays had specific amplifications in synthetic cfDNA. 8 SVs breakpoint-spanning quantitative PCR primer/probe sets were synthesized for qPCR (real-time PCR) and ddPCR (digital droplet), the custom TaqMan probe assays had significant increased sensitivity and superior specificity. When cutoff value of negative was set to “undetected” in qPCR and 0 copies/ul in ddPCR, the sensitivity and specificity of custom TaqMan probe assays can still be 100%. . After screening 18 SVs by tumor-informed SV breakpoint-spanning PCR assays, 8 SVs custom TaqMan probe qPCR assays demonstrated 100 % sensitivity and specificity in multisite biopsy samples. 3 shared and 3 private SVs custom TaqMan probe ddPCR assays were selected for absolute quantification, none of these assays had false positive or false negative when 0 copies/ul was used for cutoff value. 1 shared SV custom TaqMan probe ddPCR assay measured 0.947 copies/ul in cfDNA and 0 copies/ul in matched germline control. Altogether, our multi-layer screening approach yields the “perfect”- high sensitivity and specificity- SV breakpoint-spanning assays that are ready to apply for SVs detection in cfDNA. Conclusions: Detection of SVs from pre-treatment cfDNA using tumor-informed breakpoint-spanning ddPCR is feasible and may enable a novel and sensitive method for monitoring on-treatment disease burden. Work is ongoing to extend this method to private SVs with a goal of tracking treatment-induced tumor clonal dynamics using cfDNA.
Identification of tumor-marker gangliosides for early cancer detection: A multi-platform approach.
Authors: Blackler Adele , Culp-Hill Rachel , Law Robert A , Radnaa Enkhtuya , Tyler Abby , Halstead Susan , Willison Hugh 
Published: July 2024

e17551 Background: Tumor-marker gangliosides (TMGs) have enormous potential for early-stage cancer detection as diagnostic biomarkers despite being relatively understudied in this context. AOA Dx is focused on the analytical development of three separate platforms for the quantitation of TMGs in human serum. The development of these platforms for TMG quantitation may allow for the identification of diagnostic signatures for early-stage cancer detection. Methods: First, we are developing a pipeline of antibody-based assays to target TMGs. To aid in development of multiple immunoassays, we collected specificity and affinity data on commercial and proprietary antibodies targeting TMGs using glycoarrays. We are also currently using two immune-based platforms to target TMGs. We have developed an enzyme-linked immunosorbent assay (ELISA) and we have implemented high-performance thin-layer chromatography (HPTLC) to detect individual and total gangliosides. Additionally, we are applying both targeted and untargeted mass spectrometry to human serum from confirmed cancer diagnoses. Results: The specificity and affinity data from the glycoarrays confirm that our TMG antibodies have negligible cross-reactivity and are suitable for diagnostic platform development. Additionally, our developed ELISA allows for the quantification of TMGs in diverse and complex matrices including human serum and plasma, cell lines, and exosomes. HPTLC also detects individual and total gangliosides in each of these matrices, which allows for high-throughput analysis for TMG quantitation. Finally, the application of both targeted and untargeted mass spectrometry has identified multiple TMGs characterized by unique lipid tails. Notably, MS analysis shows that the serum of melanoma and ovarian cancer patients exhibited significantly increased levels of several ganglioside species compared to age-matched healthy serum, further highlighting the potential of TMGs as a promising avenue for cancer diagnosis. Further experiments will focus on refining all platforms. We will also expand the demographic representation of our human serum sample cohort to confirm the initial findings from our mass spectrometry experiments and continue to use this platform to identify additional TMGs of interest. Conclusions: AOA Dx is advancing the development of a multi-platform approach for the detection of TMGs. Our objective is the identification of a diagnostic disease signature for early-stage cancer detection. The validation of this type of diagnostic panel would allow for expedited diagnosis and treatment of cancers currently diagnosed at late stages, ultimately reducing healthcare costs and increasing survival rates. Future research will aim to validate these biomarkers in independent prospective studies.
Prevention of pemetrexed-induced rash with low-dose dexamethasone in patients with NSCLC receiving immunotherapy: A prospective, single-arm clinical trial.
Authors: Zhang Jing , Zhou Xue , Jia Yuming , Huang Shenglan , Wang Qiu , Jiang Mao-Qiong , Li Ting , Jiang Jian , Liqiang Zhong , Ye Xujuan , Lei Kaijian 
Published: July 2024

e20596 Background: Pemetrexed is highly active in non-small cell lung cancer (NSCLC). Rashes associated with pemetrexed are more commonly than other chemotherapies. It is recommended that patients receive pemetrexed are required dexamethasone as a pretreatment. However, the immunosuppressive effects of dexamethasone especially high doses of glucocorticoids may reduce the efficacy of immune checkpoint inhibitors (ICIs). This study aims to prospectively evaluate the efficacy of low-dose dexamethasone in pretreatment of pemetrexed-induced rash, particularly in NSCLC patients receiving immunotherapy. Methods: This is a prospective, single-arm clinical trial that enrolled NSCLC patients scheduled to receive chemotherapy including pemetrexed, with/without immunotherapy. Patients received low-dose dexamethasone: 8mg, 4mg, 2 mg of dexamethasone for 3 days recpectively from the day preceding pemetrexed (the recommended administration is 8 mg/day of dexamethasone for 3 days) . Rash severity is described according to CTCAE v5.0 (Common toxicity criteria for adverse events version 5.0). The primary endpoint was the 3-week incidence of rash after pemetrexed. Results: A total of forty-seven stage IIB-IVB patients were enrolled between February 2022 and December 2023, including eighteen patients were combined with immunotherapy. They all received the low-dose dexamethasone regimen prior to a total of 149 cycles of chemotherapy. The incidence of skin rash after 3 weeks was of 7 episodes in 149 cycles (4.70%), 7 patients (12.77%) presented rash. In the eighteen patients receiving immunotherapy, rash within 3 weeks after pemetrexed administration occurred in 4 episodes in 72 cycles (5.56%), 4 patients ( 22.22%) presented rash. And one patient presented two episodes of cutaneous toxicity. Most skin rash episodes were of grade 1 (approximately 85%), while the rest were grade 2 (approximately 15%). No grade 3 or 4 skin rash was reported in the entire study population. Most cutaneous toxicities occurred during the first or second cycle. The incidence of rash in this study was significantly lower than the rate of 67.5-93% reported in patients treated without corticosteroids and did not increase compared with the rate of 14-56% reported in patients treated with corticosteroids. Conclusions: Administration of low-dose dexamethasone (8mg, 4mg, 2 mg of dexamethasone for 3 days from the day preceding pemetrexed) significantly reduces the incidence of rash after pemetrexed. The regimen may provide a standard preventive strategy for pemetrexed-induced rash, especially in NSCLC patients combined with immunotherapy(This study is registered with the Chinese Clinical Trial Registry (ChiCTR2400079622). Clinical trial information: ChiCTR2400079622.
First-line of penpulimab and chemotherapy for advanced non-melanoma cutaneous carcinoma: A single center, single arm, exploratory study.
Authors: Xu Jing , Zhu Dongyuan , Liu Zengjun , Cui Jinfang , Liu Mengyao , Hu Wenyu , Xu Ni , Li Minghuan , Fu Heng , Zhao Junkai 
Published: July 2024

e21510 Background: Non-melanoma cutaneous carcinoma is a rare subtype malignancy including basal cell carcinoma, squamous cell carcinoma and appendage carcinoma. This study aims to explore the efficacy and safety of penpulimab combined with chemotherapy in advanced non-melanoma cutaneous carcinoma. Methods: Patients were eligible if they were aged 18 through 80 years; had histologically confirmed basal cell carcinoma, squamous cell carcinoma and appendage carcinoma with TNM clinical stage IIIB-IV; had received no previous systemic therapy. Penpulimab (200mg, every 21 days) was given on day 1 until disease progression, unacceptable toxic effects, withdrawal of consent, death, or initiation of new antitumor therapy, whichever occurred first. Fluorouracil (2.5g/m2) and cisplatin or nedaplatin (75mg/m2) were given for 6 cycles. The primary endpoint was objective response rate (ORR) defined by the RECIST v1.1 guideline, and the secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) and adverse effects (AEs). Results: 15 patients were enrolled from June 3, 2021, through December 24, 2023. The median age was 66 years (range, 42-78 years). 13 patients were males (86.7%) and 2 were females (13.3%). There were 7 cases of appendage carcinoma (46.7%), 6 cases of squamous cell carcinoma (40%), and 2 cases of basal cell carcinoma (13.3%). Among them, there were 4 cases of stage IIIB (26.7%) and 11 cases of stage IV (73.3%). Among the 15 patients, 12 underwent efficacy evaluation, including 4 partial response (PR), 5 stable disease (SD), and 4 progression disease (PD). The objective response rate was 33.3%, and the disease control rate was 66.7%. There was 8 patients experienced disease progression, with a median progression free survival of 3.83 (range,1.5-18.7) months. 4 patients died, and the median overall survival has not yet been reached. AEs related to any component of the trial regimen occurred in 13 (86.7%) patients, the most frequent AEs were grade 1-2. The most common AEs included nausea/vomiting (86.7%), fever (26.7%), thrombocytopenia (26.7%), leukopenia (26.7%), anemia (20%), hypothyroidism (13.3%), hypokalemia (6.7%), rash (6.7%). Only two patients (13.3%) refused therapy because of experiencing unacceptable nausea/vomiting. Conclusions: Penpulimab combined with chemotherapy achieved high response rate and disease control rate in the treatment of newly diagnosed advanced non-melanoma cutaneous carcinoma, with good safety, and may become a new treatment option. Disclosure: All authors have declared no conflicts of interest. Clinical trial information: ChiCTR2200063777.
Efficacy and safety of combined anti-angiogenic chemoradiotherapy with PD-1 monoclonal antibody in advanced melanoma: A retrospective study.
Authors: Zou Zhengyun , Ren Yu , Zhao Lianjun 
Published: July 2024

e21516 Background: Malignant melanoma, characterized by its aggressiveness and early metastasis, poses significant challenges in terms of treatment efficacy. This retrospective study aimed to assess the efficacy and safety of the integrated treatment regimen in patients (pts) with advanced melanoma. Methods: 42 pts with histologically confirmed inoperable stage III or IV melanoma and ECOG PS 0 or 1 were included in this retrospective study conducted from September 2020 to August 2023. Pts received combination therapy with albumin-bound paclitaxel, bevacizumab (bev), and toripalimab (tor) (Q3W). Maintenance therapy with bev and tor was given after 6-8 cycles without disease progression or intolerable adverse reactions. Personalized radiotherapy was delivered. Radiological evaluations were performed every 2 cycles during combination therapy and every 3 cycles during maintenance therapy using RECIST 1.1 criteria. Adverse events were graded according to NCI-CTCAE version 4.03. Results: All pts underwent at least one efficacy evaluation. The male-to-female ratio was 1:1, with a median age of 61.5 years (range: 34-80 years). Treatment-naïve pts accounted for 47.6% (n = 20), second-line pts for 35.7% (n = 15), third-line pts for 11.9% (n = 5), and fourth-line pts for 4.8% (n = 2). There were 25 cases (59.5%) of acral melanoma, 4 cases (9.5%) of cutaneous melanoma, 12 cases (28.6%) of mucosal melanoma, and 1 case (2.4%) with an unknown primary site. During the treatment period, 66.7% (n = 28) of pts received radiotherapy. As of December 2023, 26 out of 43 pts showed tumor shrinkage, including 2.4% (n = 1) achieving CR through conversion surgery following PR, maintaining it for 30 months. The ORR was 61.9%, with a confirmed ORR of 57.1%, and a DCR) of 92.9%. The median PFS was 14.4 months, and the median OS has not yet been attained. Common adverse events included alopecia (100%), hypertriglyceridemia (61.9%), elevated transaminases (59.5%), anemia (59.5%), leukopenia (52.4%), hypercholesterolemia (52.4%), peripheral neuropathy (50%). No treatment-related deaths were reported. Conclusions: This study demonstrates that PD-1 monoclonal antibody in combination with chemotherapy, anti-angiogenic therapy and radiotherapy offers a promising therapeutic option for advanced melanoma. Keywords:Malignant melanoma; Albumin-bound paclitaxel; Bevacizumab; PD-1 monoclonal antibody; Radiotherapy.
Genome-Scale Multimodal Analysis of Cell-Free DNA Whole-Methylome Sequencing for Noninvasive Esophageal Cancer Detection
Authors: Li Yulong , Liu Bing , Zhou Xuantong , Yang Hechuan , Han Tiancheng , Hong Yuanyuan , Wang Ciran , Huang Miao , Yan Shi , Li Shaolei , Li Jingjing , Liu Yanfang , Zhang Enli , Ni Yang , Shen Ning , Chen Weizhi , Huang Yu S. , Wu Nan 
Published: July 2024

PURPOSE Simultaneous profiling of cell-free DNA (cfDNA) methylation and fragmentation features to improve the performance of cfDNA-based cancer detection is technically challenging. We developed a method to comprehensively analyze multimodal cfDNA genomic features for more sensitive esophageal squamous cell carcinoma (ESCC) detection. MATERIALS AND METHODS Enzymatic conversion–mediated whole-methylome sequencing was applied to plasma cfDNA samples extracted from 168 patients with ESCC and 251 noncancer controls. ESCC characteristic cfDNA methylation, fragmentation, and copy number signatures were analyzed both across the genome and at accessible cis-regulatory DNA elements. To distinguish ESCC from noncancer samples, a first-layer classifier was developed for each feature type, the prediction results of which were incorporated to construct the second-layer ensemble model. RESULTS ESCC plasma genome displayed global hypomethylation, altered fragmentation size, and chromosomal copy number alteration. Methylation and fragmentation changes at cancer tissue–specific accessible cis-regulatory DNA elements were also observed in ESCC plasma. By integrating multimodal genomic features for ESCC detection, the ensemble model showed improved performance over individual modalities. In the training cohort with a specificity of 99.2%, the detection sensitivity was 81.0% for all stages and 70.0% for stage 0-II. Consistent performance was observed in the test cohort with a specificity of 98.4%, an all-stage sensitivity of 79.8%, and a stage 0-II sensitivity of 69.0%. The performance of the classifier was associated with the disease stage, irrespective of clinical covariates. CONCLUSION This study comprehensively profiles the epigenomic landscape of ESCC plasma and provides a novel noninvasive and sensitive ESCC detection approach with genome-scale multimodal analysis.