bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic and biomarker analysis of immunotherapy combined with chemotherapy treated for patients with metastatic BTC cancer: A real world study.
Authors: Gou Miaomiao , Dai Guanghai , Wang Zhi-Kuan 
Published: July 2024

e16373 Background: Biliary tract cancer (BTC) is a heterogeneous group of diseases with dismal prognosis. The TOPAZ-1 phase III trial and KENOTE 966 reported a survival benefit with the immune checkpoint inhibitor (ICI) plus chemotherapy (GemCis,GC) in patients with advanced BTC. Consequently, immunotherapy plus chemotherapy has become a new standard care for advanced BTC. Understanding the association between genomic alterations and immunotherapy outcomes of BTC could further improve the clinical benefits. Therefore, we conducted this real-world study in China. Methods: This study included 47 patients with metastatic BTC treated with PD-1/PD-L1(ICI) antibodies in combination with chemotherapy from January 2019 to January 2023 in Medical Oncology department of Chinese PLA General Hospital. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), disease control rate (DCR). The exploration endpoint was genomic and biomarker analysis. Genomic tumor DNA was isolated from 30 patients and used for targeted next-generation sequencing genes to identify the genomic profiles. Results: 47 patients received immune checkpoint inhibitor (ICI) plus with chemotherapy in first line were enrolled in this study. The median PFS were 5.4m (95%CI,4.4-6.3), ORR and DCR was 21.3% and 83.0%, respectively. Patients were grouped into two group:AS+PD1(n=34) group and GC+ICI(n=13) group. In the AS(Albumin paclitaxel+S1)+PD1 group, mPFS was 5.0m (95%CI 3.8-6.1), ORR were 20.6% and DCR were 79.4% as we reported previously. In the GC+ ICI, mPFS was 7.9m (95%CI 4.7-11.1), ORR was 23.1% and DCR was 92.3%. There was no difference in terms of PFS, ORR and DCR between two groups. With regard to biomarker analysis, PD-L1 expression positive were 16 patients, which of mPFS were 4.2m and ORR were 18.8%, otherwise 12 patients were PDL1 expression negative, of whom mPFS were 9.1m and 33.3% as unexpected. Average TMB were 4.5mt/MB for MSS type patients. There is no difference of PFS between TMB high(>4.5mt/MB) or low(<4.5mt/MB). As for genomic analysis, the most common gene alterations were TP53(N=13, 43%))KRAS(N=8, 26.7%), NTRK1\2\3(N=8, 26.7%), IDH1/2(N=6, 20%), PIK3CA(N=6, 20%), BRCA2(N=5, 16.7%). MDM2(N=5,16.7%), BRAF(N=4,13.3%). The mutations are mainly concentrated in the DDR (20) pathway followed by the RTK-RAS (16), TP53 (13), CPF (9), FA (9), HRR (9), and PI3K (8) pathways. Compared between long term survival(PFS>5.4m)and short term survival(PFS<5.4m), MDM2 was only predictor for short survival(p<0.05). Conclusions: Compared to AS+pd-1, patients received GP+ ICI numerically had better outcomes. It seems PD-L1 and TMB were not good predictors to select patients who can more benefit from immunotherapy plus chemotherapy. MDM2 mutation suggest patients tend to less active to immunotherapy-based modality.
Predicting PAM50 subtypes from whole slide images of prostate cancer biopsies.
Authors: Nateghi Sarjezeh Ramin , Ayad Marina , Saft Madeline , Li Eric Victor , Kumar Sai , Neill Clayton , Patel Hiten D. , Schaeffer Edward M. , Liu Yang , Davicioni Elai , Yang Ximing J , Cooper Lee A.D. , Ross Ashley 
Published: July 2024

e17001 Background: Computational analysis of digitized pathological images has been shown to have diagnostic and prognostic applications. Recent research suggests that molecular features, previously defined at the genomic level, might be additionally recognized. In prostate cancer, transcriptomic PAM50 molecular subtypes may correlate with patient response to systemic therapy. Here we investigate whether computational analysis of digital prostate biopsy slides can predict PAM50 category. Methods: Our study utilized digitized images of 704 prostate biopsy slides from 336 patients with prostate cancer at Northwestern Memorial Hospital with Decipher testing (Veracyte, Inc San Diego, CA). All slides analyzed contain carcinoma with the majority being primary Gleason pattern 3 (545 out of 704). Hematoxylin and eosin stained slides were scanned on a Leica GT450 scanner at 40x magnification. PAM50 subtypes were derived from the Decipher Genomic Resource Information Database (GRID). Data were split at the subject level using 80% for training, 10% for validation, and 10% for evaluation, facilitating model development and assessment. We devised a model comprising two decoupled parts: a multi-instance learning model that utilizes a multi-class attention mechanism to explore relevant class-specific information from slides, and a pre-trained network to extract high-dimensional semantic features from the tiles of WSIs. The model trained based on the WSIs of the training set to predict PAM50 subtypes (luminal A, luminal B, and basal). This attention-based training approach allowed the model to capture relevant patterns and information present in the WSIs. Following the training phase, the model was subsequently evaluated on the testing set. Results: Model AUC on the evaluation set was 0.78. Among evaluation set misclassifications, no luminal samples were misclassified as basal subtype. Conclusions: Our investigation provides preliminary results on the ability to predict RNA expression-based subtypes from prostate cancer biopsy histology. This approach may help to preserve tissue, minimize costs, and decrease turnaround time associated with molecular testing in prostate cancer while offering patients with prostate cancer opportunities for precision medicine.
Clinicopathological features and genomic profiles of prostate cancer with elevated carbohydrate antigen 19-9.
Authors: Li Yilin , Liu Yang , Yang Ping , Liu Ruiqi , Gao Jianming , An Xin , Li Yonghong , Zhou Fangjian , He Liru 
Published: July 2024

e17003 Background: The elevated carbohydrate antigen 19-9 (CA199) is commonly observed in digestive system tumors, but rarely in prostate cancer (PCa). Due to the rarity and the poor understanding of the special subtype of PCa, the clinicopathological and genomic characteristics and survival outcomes in PCa patients with elevated CA199 in our center were analyzed. Methods: Cases were collected retrospectively from 2012 to 2023 in Sun Yat-sen University Cancer Center. The tumor genomic profiles were analyzed by R (http://www.rproject.org). Kaplan-Meier survival analyses were performed to compare survival outcomes. All statistical analyses were performed using SPSS version 26.0 and GraphPad Prism version 8.0. All analyses were two‐tailed, and the significance level was set at P<0.05. Results: A total of 137 PCa patients with elevated CA199 (>35ng/ml) were identified, with an exclusion of 47 patients with secondary cancers and 40 patients with other diseases that may cause elevated CA199, finally 50 cases (22 with primary and 28 with secondary elevated CA199) were included. The median initial PSA and the median time from diagnosis to CRPC were 102ng/ml and 14 months. Most patients were with a high GS score (GS≥8: 82%) and an advanced stage (M1: 84%). Poorly differentiated adenocarcinoma (22%) was frequently observed. Compared with patients with primary elevated CA199, patients with secondary elevated CA199 had higher levels of CA199 (102ng/ml vs. 78ng/ml, p=0.0456), lower levels of PSA at diagnosis (65ng/ml vs. 132ng/ml, p=0.0131) and higher proportion of poorly differentiated adenocarcinoma (36% vs. 5%, p=0.0138). The level of CA199 in patients with primary elevated CA199 was correlated with the level of CEA (R2=0.2658, p=0.0168), but not with the level of NSE or PSA. At a median follow-up of 31 months, the median OS of the whole group, primary elevated CA199 and secondary elevated CA199 subgroups was 49 months, 31 months and not reached. Secondary elevated CA199 (p=0.0009), abiraterone treatment (p<0.0001) and chemotherapy treatment (p=0.0331) were significant prognostic factors of OS. To study the genomic characteristics of PCa patients with elevated CA199, 29 PCa patients with normal CA199 were included as a control (genomic data available in 13 and 29 cases respectively). Patients with elevated CA199 were more likely to have mutations in castration resistant associated genes (AR, FOXA1, ASXL1, KMT2B, JAK2 and AKT1), malignant progression associated genes (RARA, BLM, PIK3R1) and CA199 metabolism associated gene (ERBB2). Conclusions: PCa with elevated CA199 is highly malignant and with poor prognosis. Intensive treatment with abiraterone and chemotherapy could benefit such patients. Poor pathological differentiation and the gene mutation profile may partly explain the clinical outcome.
Molecular characterization of growing teratoma syndrome in patients with testicular germ cell tumor.
Authors: Mego Michal , Horak Samuel , Hadzega Dominik , Kalavska Katarina , Kolnikova Georgina , Lesko Peter , Orszaghova Zuzana , Obertova Jana , Palacka Patrik , Rejlekova Katarina , Sycova-Mila Zuzana , Aziri Ramadan , Pindak Daniel , Chovanec Michal , Kucerova Lucia , Cierna Zuzana 
Published: July 2024

e17017 Background: Teratomas are unique neoplastic growths that encompass a diverse array of tissue types derived from multiple germ layers, often exhibiting varying degrees of differentiation. Among the phenomena associated with teratomas, the growing teratoma syndrome (GTS) stands out as a rare yet clinically significant occurrence. GTS, characterized by the persistence or regrowth of teratomatous elements despite initial treatment, poses challenges for both diagnosis and management. In this abstract, we present the results of our expression array analysis of teratomas, aiming to uncover novel insights into their molecular composition, heterogeneity, and potential implications for clinical management. Methods: This study included 53 patients with retroperitoneal teratoma (7 chemotherapy naïve and 46 with postchemotherapy teratoma) and 20 patients with viable postchemotherapy germ cell tumor from retroperitoneum that had surgery at National Cancer Institute in Slovakia and for whom formalin-fixed paraffin-embedded (FFPE) tumor tissue was available. Study also includes samples from 5 patients with normal testis as control group. Ten patients (18.9%) in this cohort had growing teratoma syndrome. Analysis was performed by HTG EdgeSeq Oncology Biomarker panel (HTG Molecular Diagnostics, Inc., Tucson, USA). Identified candidate genes associated with GTS were further validated by immunohistochemistry on FFPE. Results: Molecular profiling indicates no differences in expression profile in retroperitoneal teratomas regardless of previous chemotherapy. Expression analysis indicates 1586 genes being differently expressed with high significance ( p < 0.05) in teratomas compared to normal testis and 1571 genes differentially expressed compared postchemotherapy viable tumors. We identified 14 genes being differently expressed in growing teratoma syndrome compared to teratoma without growth (CYP4A22, IGFBP1, CXCL6, LTF, CYP2C8, CFTR, CCL20, PFKFB3, SLC2A3, LIPA, HMOX1, GPNMB, CCL18, DLK1. Pathway analysis revealed MAPK and PI3K−Akt signaling pathways are mostly dysregulated in GTS. Conclusions: This molecular profiling identify genes differentially expressed in teratomas that are potential biomarkers for prediction of teratoma element in postchemotherapy residues in testicular germ cell tumor patients. Moreover, inhibition of identified signaling pathways associated with GTS could represent potentially novel therapeutic targets in case of unresectable disease.
Elucidating the role of RBM10 in brain metastasis of EGFR19del lung adenocarcinoma.
Authors: Yu Yan , Xu Gang , Jia Dexin 
Published: July 2024

e20501 Background: The EGFR mutation was detected in 66.3% of Asian patients with lung adenocarcinoma. Among these mutations, EGFR 19del exhibited the highest sensitivity and best response. However, it is worth noting that patients with EGFR 19del have a high cumulative incidence of brain metastases, which contributes significantly to treatment failure. Based on previous WES analysis of primary lung cancer cases and their corresponding brain metastases, RBM10 co-mutation was observed in four out of ten cases with EGFR 19del mutation, leading to decreased expression levels of RBM10. These findings suggest a potential role for RBM10 in modulating the development of brain metastases in patients with EGFR 19del lung cancer. Methods: To investigate the role of RBM10 in brain metastasis, we performed RNA-seq on the PC9 cell line to identify metabolic pathways and genes associated with RBM10 and brain metastasis. Additionally, the brain metastasis model was established by injecting PC9 cells into the left ventricle of nude mice, and the ability of PC9 cells to form brain metastases after knocking down RBM10 was confirmed through two rounds of in vivo screening using the PC9 cell line. Lipidomics analysis further validated that RBM10 affects key metabolite production. Clip-seq and RNA-seq were employed to analyze how RBM10 regulates sphingolipid metabolism. Finally, we identified key targets affecting blood-brain barrier function within the sphingolipid metabolism pathway and verified their ability to inhibit brain metastasis using both in vitro and in vivo models. Results: RNA-seq results demonstrated the regulatory role of RBM10 in the sphingolipid metabolism pathway, specifically in GALC regulation. In vitro and in vivo models revealed an enhanced brain metastasis ability of the PC9shRBM10 group. Lipidomics analysis revealed that the knockdown of RBM10 resulted in a reduction in ceramide and an elevation in SPH. Integrated RNA-seq and Clip-seq analyses demonstrated that the splicing regulation on GALC was attenuated upon RBM10 knockdown, leading to an increase in GALC expression. Furthermore, this perturbation enhanced the downstream sphingosine-1-phosphate signalling axis (SPH-SK1/2-S1P), consequently promoting increased S1P production and elevated blood-brain barrier permeability. Finally, fingolimod, an S1P inhibitor, was employed to validate its efficacy in inhibiting brain metastasis; moreover, a combination therapy comprising osimertinib and fingolimod exhibited superior capacity for suppressing brain metastasis. Conclusions: This study aims to elucidate the regulatory mechanism underlying the impact of RBM10 on sphingolipid metabolism in brain metastasis of EGFR 19del lung adenocarcinoma, to identify novel therapeutic targets for preventing brain metastasis in patients exhibiting EGFR 19del lung adenocarcinoma with low RBM10 expression.
The efficacy and safety of a novel PD-1/CTLA-4 bispecific antibody cadonilimab (AK104) in advanced non-small cell lung cancer: A multicenter retrospective observational study in China.
Authors: Li Jisheng , Yu Shuwen , Zhao Wen , Li Hongxin , Li Chengming , Shen Hongchang , Li Meiying , Wang Chengjun , Wang Jian , Yi Cuihua , Han Chunyan , Meng Xue , Wang Jun , Wang Xiuwen , Liu Lian 
Published: July 2024

e20518 Background: Treatment choice for advanced non-small cell lung cancer (NSCLC) after front-line immuno-chemotherapy therapy is limited. As the first approved dual programmed cell death-1(PD-1) / cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) bispecific antibody worldwide, cadonilimab combined with anlotinib, a vascular epidermal growth factor tyrosine kinase inhibitor, showed potential anti-tumor activity in advanced NSCLC patients resistant to anti-PD-1/ programmed cell death ligand-1(PD-L1) antibodies in a phase Ib/II clinical trial. Methods: We retrospectively collectedthe efficacy and safety data in advanced NSCLC patients treated with cadonilimab in later therapy lines. The primary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety results. The secondary endpoints were overall survival (OS). Results: Totally, 41 advanced NSCLC patients who were refractory to previous chemotherapy and anti-PD-1/PD-L1 therapy and treated with later line cadonilimab-based regimens were enrolled. More than half of patients received cadonilimab as a fourth or later line of treatment. Until the data cut-off date (August 29, 2023), the treatment efficacy of 23 patients could be evaluated. One (4.3%) patient had partial response, 8 (34.8%) patients had stable disease, and 14 (60.9%) patients progressed. The ORR and DCR were 4.3% and 39.1%, respectively. The median PFS of all evaluated patients was 108.0 days (95% confidence interval: 62.3-153.7). Due to the short follow-up, median OS has not been reached yet. Treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) occurred in 26(63.4%) and 9(22%) patients, respectively. The most common AEs included gamma-glutamyl transferase elevation (17.1%), coughing (14.6%), and fatigue (12.2%). Five patients (12.2%) experienced grade≥3 AEs. Two patients temporarily paused medication due to Grade 2 rash. One patient and 2 patients permanently discontinued medication due to Grade 3 myocarditis and Grade 2 infusion reactions, respectively. Metabolomics results showed that lipids and lipid-like molecules were rich in stools of patients responsive to cadonilimab treatment. Conclusions: In this heavily treated advanced NSCLC patient cohort, cadonilimab-based regimens only showed moderate anti-tumor efficacy with a generally tolerable and manageable safety profile. More evidence supporting administration of cadonilimab is needed in NSCLC patients refractory to previous anti-PD-1/PD-L1 therapy.
Population pharmacokinetics of trastuzumab deruxtecan (T-DXd) in subjects with HER2-mutant and HER2-overexpressing non-small cell lung cancer (NSCLC).
Authors: Khatri Amit , Cobbina Enoch , Cheng Shen , Abutarif Malaz , Garimella Tushar 
Published: July 2024

e20537 Background: T-DXd is a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, approved globally at the dose of 5.4 mg/kg in HER2-positive or HER2-low breast cancer (BC) and HER2-mutant (HER2m) NSCLC1,2. The aim of the analysis was to characterize the populaton pharmacokinetics (PopPK) of T-DXd and its released payload, deruxtecan (DXd), in HER2m or HER2-overexpressing (HER2-OE) NSCLC subjects using data across tumor types (BC, NSCLC and others) from 12 Phase 1 to 3 studies with T-DXd doses ranging from 0.8-8.0 mg/kg. Methods: Analysis wasperformed using nonlinear mixed-effects modeling methods in NONMEM (version 7.4.3), similar to the previous analysis in HER2-positive BC1. Covariate effects were explored on the PK parameters of T-DXd and DXd. Results: Analysis included data across 1822 subjects, including 346, 1128, and 348 subjects with NSCLC, BC, and other cancers, respectively. The PK of T-DXd and DXd were adequately described by a PopPK model, judging by standard model diagnostics3. Covariate effects on T-DXd and DXd steady-state area under the concentration-time curve (AUC) were not clinically meaningful (within 0.8 to 1.25 AUC ratio interval for tested covariate level versus reference), except for subjects with high body weight (e.g., 90 kg; 95th percentile) showing a 31% and 37% higher T-DXd and DXd AUC, respectively, relative to typical subject with 58 kg body weight (median).The T-DXd and DXd AUC were also similar across subjects with BC, HER2m or HER2-OE NSCLC, with the same T-DXd dose. T-DXd and DXd AUC in NSCLC subjects were similar across subjects with mild hepatic or mild or moderate renal impairment (vs. normal counterparts), region (Asia, North America, Europe, and rest of the world), and race-country (Asian-Japan, Asian-Non-Japan, and Non-Asian) groups. Conclusions: T-DXd and DXd exposures were similar across subjects with BC and HER2m or HER2-OE NSCLC, as well as across hepatic function, renal function, region, and race-country groups within NSCLC supporting the use of 5.4 mg/kg dose (approved dose in BC) in HER2m or HER2-OE NSCLC from PK perspective. Reference: Enhertu [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2022. Enhertu [summary of product characteristics]. Daiichi Sankyo Europe GmbH, Munich; 2022 Yin O et al. Clin Pharmacol Ther. 2021;109(5):1314-1325. Clinical trial information: NCT04644237 , NCT03505710 .
Sugemalimab in locally advanced and advanced Chinese NSCLC: A real-world retrospective study.
Authors: Liu Jiayu , Wang Yan , Wang Qi , Yang Ke , Xie Tongji , Sun Dantong , Wu Lige , Junling Li , Xing Puyuan 
Published: July 2024

e20575 Background: Lung cancer is a major cause of cancer deaths in China. Immunotherapy has emerged as a promising treatment approach for advanced NSCLC without sensitive mutations. Sugemalimab, a fully human immunoglobulin G4 monoclonal antibody, retains its Fc function, inducing antibody-dependent cellular phagocytosis. This study aims to evaluate the real-world effectiveness and safety of Sugemalimab in various treatment patterns, particularly with radiotherapy, in Chinese NSCLC patients with locally advanced or metastatic disease. Methods: We retrospectively evaluated locally advanced (LA-) and metastatic (m-) NSCLC patients (pts) treated with Sugemalimab in Cancer Hospital, Chinese Academy of Medical Sciences from Feb. 2022 to Sep. 2023. Demographic characteristics, clinical features, genetic landscape and therapy patterns were collected. We employed descriptive statistics to determine the Objective Response Rate (ORR) and Disease Control Rate (DCR), and used the Kaplan-Meier method for estimating Progression-Free Survival (PFS) and Overall Survival (OS). Safety profiles, including adverse events and immune-related pneumonitis, were similarly analyzed. Results: 76 pts with LA-NSCLC and mNSCLC were enrolled. Majority were male (92.1%) and smokers (84.2%) and ECOG PS 0-1 (78.9%). Median age was 66. Squamous-cell carcinoma was found in 44 pts (57.9%). The main metastatic sites were bone, brain, liver, lung and lymph node for mNSCLC pts. Genetic profiling in 39 pts revealed TP53 mutations in 19 (48.7%) and KRAS mutations in 10 (25.6%). A total of 38 pts (51.3%) received 1L Sugemalimab therapy, while 21 pts (27.6%) receiving 2L. Main treatment pattern was Sugemalimab plus platinum-based chemo. Radiotherapy (RT) was main local therapy approach, concurrent with Sugemalimab in 18 pts. Majority of pts received either volumetric modulated arc therapy or intensity-modulated radiation therapy to thoracic lesions. Tomotherapy was administered to brain metastases in 2 pts. The median follow-up time was 9.18m at this cut-off date. 16 pts receiving Sugemalimab plus chemo achieved objective response (ORR 44.4%) and DCR was 91.5% in 1L therapy. Median PFS (mPFS) has not been reached. PFS rate at 6m, 12m was 75.6%, 62.1% respectively. 1L OS was immature. For pts receiving additional thoracic RT concurrent with 1L systematic therapy, mPFS was still not mature. PFS rate was 82.4% at 6m and 74.9% at 12 m. Common RT-related side effects were radiation pneumonitis, radiation esophagitis and skin injury. None immune-related pneumonitis was found in this population. Only one case of immune-related pneumonitis was observed in a pts without RT. Conclusions: Our study demonstrated Sugemalimab-based therapy provide clinical benefits to LA-NSCLC and mNSCLC with good safety in real-world setting. The combination treatment of Sugemalimab with radiotherapy illustrates low pulmonary toxicity and superior tolerability.