bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of a clinically relevant humanized mouse model for the safety assessment of 4-1BB agonists utomilumab and urelumab.
Authors: Keck James G. , He Wenqian , Buetow Bernard S. , Vitsky Allison , Liu Maggie , Yang Jiwon , Yang Guoxiang , Cai Danying , Jessen Bart 
Published: June 2022

e14602 Background: Immunotherapy is proven to be powerful and effective in treating cancer. One of the strategies for the therapy is to boost a patient’s immune system by stimulating tumor necrosis factor receptors via the activation of 4-1BB (CD137) costimulatory molecule. Urelumab was the first 4-1BB agonist investigated in clinical trials and showed clinical promise but doses were limited by severe liver toxicity. Preclinical assessment of toxicity failed to predict the clinical safety outcome. Methods: To address the critical needs of in vivo evaluation of toxicity in a preclinical setting, we have developed an animal model using PBMC humanized mice to assess the safety of immunotherapy. In this model, agents targeting human immune system including monoclonal and bispecific antibodies can induce an acute response of cytokine release within hours of treatment and with some therapies a systemic response can manifest in tissue damage and lethality of mice days later. Results: The potential clinical relevance of the PBMC humanized mouse model was demonstrated using 4-1BB agonists urelumab and utomilumab. The antibody-treated PBMC humanized mice were evaluated daily for clinical score and assessed for clinical chemistry and liver histopathology at study terminus. Animals dosed with urelumab at 10 mg/kg exhibited body weight loss and underwent early euthanasia, while animals dosed with utomilumab survived to scheduled euthanasia with minimum body weight loss. Urelumab showed marked liver toxicity relative to utomilumab and controls with more necrosis in the tissue and higher mean ALT, AST and GLDH activities, and the tolerability of urelumab was increased by lowering the dose to 1 mg/kg. The differences captured by the humanized mouse model presented a safety profile similar to the findings about urelumab and utomilumab from the clinical trials. Utomilumab was well tolerated at the dose that caused severe toxicity for urelumab in patients, and the toxicity of urelumab could be reduced by lowering the dose. Conclusions: Our data suggest that the PBMC humanized mouse model could identify human 4-1BB agonists that caused potentially severe liver toxicity. Preclinical safety assessment using humanized mouse models as used for these studies could be an important step in the course of the development of novel immunotherapy for the safety of patients as well as mitigating drug development cost.
Justifying integration of liquid biopsy into routine molecular diagnostics to complement tissue genomic profiling: Experience at Fox Chase Cancer Center.
Authors: Baldwin Don A , Gigli Cheyenne , Su Yanrong , Fernandez Sandra Viviana 
Published: June 2022

e15029 Background: Plasma-based liquid biopsy has rapidly evolved from a novel research tool toward translation into clinical use for many diseases including cancer. While there are still some gaps regarding standardization and clinical utility, as tissue next-gen sequencing had previously faced and overcome, there is a growing body of evidence supporting integration of liquid biopsy into standard of care as a diagnostic tool for precision oncology. Selected from a larger cohort, several cases are presented here illustrating the use of the PGDx elio plasma resolve assay to profile circulating tumor DNA (ctDNA) from patients whose tumor and matched normal DNA had also been characterized by a next-generation sequencing panel. Methods: The PGDx elio plasma resolve assay and bioinformatics detects single and multi-nucleotide variants in 33 genes, select amplifications and translocations, as well as microsatellite instability by sequencing on the Illumina NextSeq 500/550 platform. DNA from matched tumor and normal FFPE samples were assessed using the 275 gene Molecular Diagnostics Laboratory’s Comprehensive Cancer Panel (CCP), also on the NextSeq platform. Selected cases represent the range of diagnostic utility that might be expected from ctDNA. Results: Across all cases, there were varying levels of concordance between tissue and plasma as well as novel variants in the plasma that were not present in the tissue DNA demonstrating the benefit of incorporating ctDNA profiling to capture critical genomic information. In one rectal adenocarcinoma case, DNA variants from the primary tumor were detected in ctDNA eight months later during evaluation of a recurrent tumor, suggesting that plasma profiling might have provided early biomarker detection of recurrence. An aggressive and recurrent melanoma, however, showed no concordance between ctDNA and tumor DNA variants, indicating that some tumors may not shed sufficient DNA into the bloodstream to make ctDNA clinically relevant. Another case of melanoma had concordant detection of the driver BRAF V600E mutation in tumor and ctDNA, but ctDNA also contained a pathogenic ATM truncation not observed in the tumor sample. Current clinical trials are investigating the combination of PARP- and ATR-inhibiting drugs, which causes excessive DNA damage and cell death in the context of ATM-deficient cancers. Conclusions: These cases show that combined tissue and ctDNA profiling at the time of initial diagnosis can reveal tumor heterogeneity or distinct metastases not observed in a selected tissue sample, and that profiling during and after therapy may provide early detection of recurrence, appearance of resistance mutations, or monitoring of measurable residual disease.
Pan-Cancer analysis of the mutation frequency of genes in TGF-beta pathway.
Authors: Fu Qiang , Su Junyan 
Published: June 2022

e15113 Background: The TGF-β signaling pathway governs key cellular processes under physiologic conditions and deregulates in cancer, including a diverse and varied set of gene responses that range from cytostatic and apoptotic tumor-suppressive ones in early-stage tumors to proliferative, invasive, angiogenic, and oncogenic ones in advanced cancer. However, the genomics profiles of TGF-β signaling pathway genes are unclear. In this study, we evaluated the genomic features in Chinese pan-cancer patients and investigated the mutation frequency of genes in the TGF-β pathway. Methods: A total of 5420 patients consisting of 22 cancer types were enrolled in this study. Utilizing target next-generation sequencing (NGS) platform, genomic profiling of 599 cancer-related genes, including genes of TGF-β pathway (SMAD2/3/4, PDGFRB, CDH1, MDM2, CDKN1A, and CDKN2B), was performed on tumor tissue or blood samples. Results: We observed 25.57% (1386/5420) of cases harbored at least one alteration in the TGF-β pathway genes. The mutation frequency ranges 9.09% to 39.77% among the 22 cancer types, including 39.77% (247/621) in gastric cancer, 39.31 (320/814) in bowel cancer, 36.84% (7/19) in endometrial cancer, 11.11% (8/72) in esophageal cancer, 10.46% (7/67) in kidney cancer, and 9.09% (2/22) in the gastrointestinal stromal tumor, respectively. The mutation of tumor-promoting effects genes SMAD2/3/4, PDGFRB, CDH1and MDM2 in the TGF-β pathway were found in all cancer types and mainly occurred in CNS tumor, gastrointestinal stromal tumor, pancreatic cancer, sarcoma, gastric cancer, and bowel cancer. The tumor-suppressing effective genes CDKN1A and CDKN2B primarily mutated in melanoma, endometrial cancer, and kidney cancer. Approximately 21.77% of patients had CNV in the TGF-β pathway of all tumor types. The most frequently mutated TGF-β genes were MDM2 and CDKN2B, mainly altered in sarcoma, melanoma, and CNS Tumor. Conclusions: We found a unique genomic feature of the TGF-β pathway of Chinese pan-cancer patients. Targeting mutant of TGF-β pathway genes remains a potentially effective treatment in the future.
Comprehensive analysis of FGFR mutations in Chinese cancer patients.
Authors: Yu Tao , Fu Zhichao 
Published: June 2022

e15117 Background: Fibroblast growth factor receptors (FGFRs) are highly conserved transmembrane tyrosine kinase receptors (RTKS) that regulating several cellular processes such as proliferation, differentiation, migration and survival. In recent years, some studies have documented that signaling through FGFRs impact progression of cancer and the survival of patients with cancer. As a potential therapeutic target, exploring the mutation frequency of FGFRs in more different cancers are necessary. Here we performed a comprehensive analysis of the frequency and types of FGFRs mutations in Chinese cancer patients and provided reference for targeted therapy development. Methods: From January 2020 to December 2021, a total of 4,102 patients with nine common cancers were included in the study. The next-generation sequencing was utilized for detecting genetic mutations. Results: A total 328 patients (7.9%) with FGFR mutation were identified. The FGFR 3 was the most frequently gene in our cohort. Among all the cancer patients, the highest frequency of FGFR mutations was observed in bladder cancer (32.5%) and the percentages in FGFR1, FGFR2 and, FGFR3 were 2.7%, 1.35%, and 6.76% respectively. Furthermore, the proportion of FGFR mutation in lung carcinoma, cholangiocarcinoma, colorectal carcinoma, melanoma, breast carcinoma and ovarian carcinoma was 8.64%, 11.58%, 13%, 16.7%, 9.62% and 10.81% respectively. Additionally, FGFR mutation have been detected in other tumor types, including renal cell carcinoma (5.63%), prostate cancer (5.45%), and gastric carcinoma (13.72%). Conclusions: The present study provided the comprehensive FGFR mutation data of Chinese cancer patients. A high frequency mutation in FGFR have been found in Chinese patients with different cancers, which mean that patients with multiple cancer types might benefit from development of efficient EGFR inhibitors.
Molecular features differences between patients with BRAF mutant melanoma and thyroid cancer.
Authors: Huang Yingying , Zhao Yun-Bo , Ye Ke , Xiao Liang , Long Guo , Fang Tongdi , Yuan Mingming , Xia Xuefeng , Zhou Ledu 
Published: June 2022

e15128 Background: The efficacy of BRAF inhibitors varies extremely among patients with different cancers, such as malignant melanoma (MM) and differentiated thyroid carcinoma (TC) (constituting > 95% of thyroid cancer). This study aims to investigate molecular biomarkers that may explain the efficacy difference of BRAF inhibitors in patients with MM and TC. Methods: Tumor tissue and paired peripheral blood samples from patients with MM and TC were sent for matched tumor-normal next-generation sequencing of 1021 cancer-related genes. MM and TC patients harboring known BRAF activating mutations were retrospectively recruited in this study. Concomitant mutations, tumor mutation burden (TMB) and other mutational features were compared between these two populations. Results: A total of 69 patients with MM and 315 patients with TC were included. The total and median number of mutations in these two groups were 503/6 and 605/1, respectively. Correspondingly, TMB was higher in MM compared with TC (median: 2.88 muts/Mb vs. 0.69 muts/Mb, p = 0.0002). Compared with TC, more copy number variants (CNV) (total number: 142 vs 5, p < 0.001) and less single nucleotide variants (total number: 353 vs 569, p < 0.001) were identified in MM. Most BRAF mutations in MM were located on V600, and other mutations including D594A/G/N, K483E/Q and K601E were identified. In TC, nearly all mutations were BRAF V600E. Excluding CNV and structural variants, the mutation frequency of 28 genes in MM was higher than TC. Pathway enrichment analysis suggested that 9 out of 28 genes (APC, ARID1B, ARID2, CDKN2A, CTNNB1, EGFR, PTEN, TERT, TP53) were significantly enriched on the hepatocellular carcinoma signaling. TERT, CDKN2A and PTEN were frequently mutated in MM, which may contribute to the efficacy difference of BRAF inhibitors in patients with MM and TC. Conclusions: This study found specific molecular features may explaining the efficacy difference of BRAF inhibitors in MM and TC, which requires further validation in patients treated with BRAF inhibitors.
Molecular phenotypes of colorectal cancer.
Authors: Krashikhina Tatiana 
Published: June 2022

e15506 Background: Despite the positive results of colorectal cancer treatment, there is a group of patients that progresses despite successful treatment for I–II stage of the disease. it may be that modern predictors in do not fully cover the entire spectrum of molecular genetic traits, especially the tumor microenvironment. Perhaps expression analysis is not only tumor tissue, but resection margin could also reach a consensus on the molecular gene phenotypes of colorectal cancer with the achievement of the goal of prognostic efficiency and therapeutic and prophylactic diagnostic tactics. Methods: The expression level of 64 genes in tumor tissue in samples obtained from 172 patients with stage I–III CRC was analyzed by real-time Polymerase chain reaction (PCR). The mean follow-up time was 28.15±14.7 months. Data analysis and predictive modeling arrays using the R 3.6.3 Computation Evaluation Framework (R Foundation for statistical computing, Vienna, Austria) using additional packages rms 5.1-4, survival 3.2-7 and pROC 1.16.2. Results: As a result of statistical analysis, data were obtained on the presence of predictors of the studied unfavorable source code among the selected sets of genes carcinogenesis in colorectal cancer. The next step revealed progression status with BIRC5, IL2, SCUBE2, MYC and P16INK4A gene expression as in tissues tumors, and in resection margin. 2 regression models were built to predict survival without progression in patients with the inclusion of the level of expression in the tumor tissue- nor, the inclusion of the level of gene expression in tumor and resection margin. Model with inclusion only tumor transcripts statistics did not differ from models without predictors. Conclusions: In this study, it was possible to identify a group of genes associated with certain favorable prognosis and responsible in one way or another for proliferation, angiogenesis, immune status of the tumor. It can be concluded that the study of the level of expression of numerical genes in tumor tissue can become a promising direction for the selection of patients in the group of poor prognosis in colorectal cancer.
Update of a phase II, multicenter clinical trial: Efficacy and safety of anlotinib plus XELOX regimen as first-line treatment followed by maintenance monotherapy of anlotinib for patients with mCRC.
Authors: Yan Jin , Han Yunwei , Zhang Li , Jin Yongdong , Sun Hao 
Published: June 2022

e15566 Background: The combination of anti-VEGF or anti-EGFR targeted drugs with chemotherapy is the standard first-line therapy for metastatic colorectal cancer (mCRC), and the followed maintenance treatment is an optional approach to balance the efficacy and toxicity. However, studies regarding the maintenance strategies based on antiangiogenic TKIs are limited currently. Anlotinib, a novel oral multi-target TKI which can inhibit both tumor angiogenesis and tumor cell proliferation simultaneously, substantially prolonged the PFS with manageable toxicity for refractory mCRC in the phase III ALTER0703 clinical trial. Here we report an update of efficacy and safety results which provide a longer follow up and increased number of patients. Methods: In this open label, single-arm, multi-center, phase II clinical trial, 29 mCRC patients without prior systemic treated, aged 18-75 and an ECOG performance status of 0 or 1 were planned to recruit. Eligible patients received capecitabine (1000 mg/m2, po, d1-14, q3w) and oxaliplatin (130 mg/m2, iv, d1, q3w) plus anlotinib (10mg, po, d1̃14, q3w) treatment for 6 cycles. After 6 cycles of inducing therapy, patients would receive anlotinib (12mg, po, d1̃14, q3w) as maintenance therapy until disease progression or intolerable adverse events (AEs). The primary endpoint was PFS; Secondary endpoints included ORR, DCR, DOR and safety. Results: At data cut-off date (January 18, 2022), the total 29 patients were enrolled, of which 23 patients were available for efficacy assessment. In best overall response assessment, there were 56.5% PR (13/23), 34.8% SD (8/23) and 8.7% PD (2/23). The ORR was 56.5% (95% CI, 34.5-76.8%) and DCR was 91.3% (95% CI, 72.0-98.9%). The longest duration of treatment was 17.5 months. The median PFS was not reached. The most common treatment related adverse events (TRAEs) of any grade (≥30%) were hypertension, leukopenia, nausea/vomiting, hypertriglyceridemia, neutropenia, hypohemoglobinemia, hypoalbuminemia. Grade 3/4 TRAEs (≥10%) were neutropenia (13.8%), hypertension (13.8%) and hypertriglyceridemia (10.3%). One grade 5 TRAE was pancytopenia that occurred at 2.7 months. Conclusions: The update results suggested that anlotinib combined with XELOX as first line regimen followed by anlotinib monotherapy showed favorable anti-tumor activity and manageable safety for patients with mCRC. And the conclusions needed to be confirmed in randomized study continued subsequently. Clinical trial information: ChiCTR1900028417.
PD-1 inhibitors combined with apatinib for advanced diffuse gastric cancer: A retrospective study.
Authors: Chen Beibei , Zhao Huichen , Wang Saiqi , Lv Huifang , Xu Weifeng , Nie Caiyun , Wang Jianzheng , Zhao Jing , He Yunduan , Chen Xiaobing 
Published: June 2022

e16009 Background: Numerous studies have shown that immunotherapy has a synergistic effect when combined with targeted drug therapy. Apatinib has been proven effective in advanced gastric cancer. Based on these facts and to assess the efficacy and safety of programmed death 1 (PD-1) inhibitors and apatinib as combination therapy in patients (pts) with unresectable locally advanced or metastatic diffuse gastric cancer(DGC), a retrospective clinical research study was carried out. Methods: Retrospective analysis of a cohort of pts with advanced diffuse gastric cancer received treatment of apatinib combined with PD-1 inhibitors enrolled in our institution between January 2019 and January 2021.Pts (n = 34) received PD-1 inhibitors and apatinib (250mg once daily) in this retrospective study. Overall survival (OS) and progression free survival (PFS) were estimated by Kaplan Meier curves, and other endpoints included objective response rate(ORR), disease control rate(DCR), prognostic factors. Results: A total of 34 pts were enrolled in a real-world dataset from Henan Cancer Hospital. 2 pts achieved partial response(PR),17 pts had stable disease(SD),and 15 pts had progressive disease (PD). The ORR and DCR were 5.88% (2/34) and 55.88% (19/34), respectively. The median PFS(mPFS) was 2.47 months (95%CI:1.9-3.0), and the median OS (mOS) was 6.80 months (95%CI 3.7-9.9). Pts with less than 3 metastatic sites had longer mOS than those with more metastatic sites(2.70 vs. 7.73 P < 0.05). And in this study, the levels of platelet, albumin, CEA, CA199, CA125 and LDH affect patients’ prognosis. Kaplan-Meier analyses revealed that patients with normal platelet had better mOS than those with higher platelet(mOS 7.10 vs 0.3; P < 0.05).And similar results were found in the pts with normal albumin. The mOS of those was longer than the pts with lower or higher albumin(7.73 vs 2.20 vs 2.53, P < 005). And we demonstrated that positive groups of CEA(> 4.7ng/ml), CA125(> 35U/ml), CA199(> 27U/ml) and LDH(> 245U/L) were significantly associated with worse outcomes than that of negative groups(all P < 0.05). The incidence of grade 3 or 4 treatment-related adverse events (TRAEs) was 26.5%(9/34). These adverse events (AEs) included pruritus, rash, hand-foot syndrome, hypertension and increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT). No treatment-related deaths occurred. Conclusions: Combination therapy of PD-1 inhibitors and apatinib showed encouraging clinical activity and demonstrated tolerable toxicity in pts with advanced DGC. The level of platelet, albumin, CEA, CA199, CA125 and LDH could predict the prognosis of DGC patients.
Study on the efficacy and safety of sintilimab combined with nab-paclitaxel as second-line treatment for advanced or metastatic gastric cancer (GC)/ gastroesophageal junction (GEJ) cancer.
Authors: Wang Jianzheng , He Yunduan , Zhang Baiwen , Cheng Xiaojiao , Li Qingli , Lv Huifang , Nie Caiyun , Chen Beibei , Xu Weifeng , Zhao Jing , Tu Shuiping , Chen Xiaobing 
Published: June 2022

e16016 Background: Advanced gastric cancer has poor prognosis and short survival period. Anti-PD-1 antibodies have shown some efficacy in second-line treatment of advanced or metastatic GC/GEJ cancer, but were not superior to monotherapy. The combination of chemotherapy and anti-PD-1 antibody has been proved to have synergistic effect. Nab-paclitaxel is one of the most commonly used second-line regimens in China. Therefore,we aimed to evaluate the efficacy and safety of sintilimab combined with Nab-paclitaxel in the treatment of advanced GC/GEJ cancer patients. Methods: We retrospectively analyzed patients with advanced GC/GEJ cancer that progressed after first line systemic therapies and treated with sintilimab combined with Nab-paclitaxel from April 1, 2019 to December 31, 2021. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), and safety. Results: Thirty-nine patients were enrolled and eligible for response assessment. Complete response (CR) was not observed, 15 patients achieved partial response (PR), 16 patients had stable disease (SD) and 9 patients had progression disease (PD). The ORR and DCR were 15 (38.5%) and 31 (79.5%), respectively. Median PFS was 5.4 months (95%CI: 3.072-7.728). We further analyzed PFS between different subgroups of chemoimmunotherapy regimens in order to find which patients could benefit more. Firstly, The PFS of HER2 positive and HER2 negative patients was 7.1months (95%CI:3.367-10.833) and 5.3 months (95%CI:4.018-6.582), respectively (p = 0.947). The median PFS of PD-L1 positive, PD-L1 negative and PD-L1 unknown patients was 5.3months (95%CI:3.744-6.856), 8.1months(95%CI:3.371-12.829) and 6.1 months(95%CI:2.649-9.551)(p = 0.918). Finally, we analyzed the effect of chemoimmunotherapy cycles on PFS. The results showed that PFS of > 4 cycles was numerically longer than that of ≤ 4 cycles, and PFS were 7.1 months (95%CI:4.378-9.822) and 5.2months (95%CI:3.091-7.309)(p = 0.424), respectively. Most of the adverse events (AEs) were grade 1-2.The most common treatment-related adverse events (TRAEs) of grade 3-4 were anemia 5(12.8%), neutropenia 5(12.8%), leukopenia 4(10.3%). The potential immune-related adverse events (irAEs) were grade 1 pneumonia 1(2.6%). Only one patient developed grade 4 hepatitis (2.6%). Conclusions: These results indicated that sintilimab combined with Nab-paclitaxel exhibited good anti-tumor activity and acceptable safety profile as second-line treatment for advanced or metastatic gastric cancer. These results warrant further accrual and evaluation and explore which patients can benefit more from the combined treatment strategy.