bluuebunny/crossref_metadata_2025_split huggingface dataset:
Irradiated esophageal squamous cell carcinoma cells induced the increase of Treg by TGF-beta.
Authors: Wang Yuan , Li Tao , Lv Jiahua , Xiao Ling 
Published: June 2021

e16092 Background: The infiltration of CD4+CD25+Foxp3+ regulatory T cells (Treg) in the tumor microenvironment is one of the main reasons for radiation resistance and tumor recurrence after radiotherapy. It has been established that Treg is more resistant to radiation than other T cells, but the proliferation of immune cells after radiotherapy is affected by other factors, including tumor cells. Treg frequency in the tumor microenvironment after radiotherapy has not been defined. We studied the effect and mechanism of esophageal squamous cell carcinoma on Treg cells after radiation. Methods: After 2Gy irradiation, TE-1 cells were co-cultured with normal peripheral blood lymphocytes for 48 hours. Flow cytometry was used to detect Treg/CD4+T cell frequency. The mRNA expression of TGF-β1/2 in TE-1 was detected by qPCR, and the protein content of TGF-β1/2 in the medium was detected by ELISA. Results: Compared with non-irradiation group, the expression of TGF-β1 and TGF-β2 in TE-1 cells of irradiation group increased, and the protein content of TGF-β1 and TGF-β2 in culture medium increased, the difference was statistically significant(P < 0.001). Flow cytometry showed that CD4+CD25+/CD4+Tcell and CD4+CD25+Foxp3+/CD4+Tcell were increased in the radiotherapy group after co-culture, and the difference was statistically significant(P < 0.001). Conclusions: The expression of TGF-β1 and TGF-β1 in esophageal squamous cell carcinoma cells increased after irradiation, and the frequency of Treg induced by co-culture increased, suggesting that esophageal squamous cell carcinoma cells after radiotherapy can induce the increase of Treg cells, which may be achieved mainly through the mechanism of increasing the secretion of TGF-β1/2.
Sensitive and dynamic CTCs measurement for prediction and monitoring of PD-1 therapy in GC/EGJC patients: Results from a pilot phase 2 study.
Authors: Wei Qing , Qi Xu , Chen Lei , Yang Yanlian , Li Yankun , Hu Zhiyuan , Ying Jieer , Luo Cong , Jingjing Li 
Published: June 2021

e16094 Background: Programmed death-ligand 1 (PD-L1) expression is currently being explored as a predictive biomarker for anti-PD-1antibody treatment in patients with advanced gastric or esophagogastric junction cancer (GC/EGJC) patients. Circulating tumor cells (CTCs) can be collected non-invasively and sequentially, and may allow real-time monitoring of immune activation in tumor. The aim of this study was to investigate whether PD-L1 expression on CTCs can accurately represent tumor PD-L1 expression and the potential of CTCs as a companion diagnosis (CDx) biomarker. Methods: We evaluated the CTCs counts and PD-L1 status on CTCs during treatment in a phase 2 clinical trial, where patients with previously treated gastric cancer received JS001 in combination with Apatinib. The multi-center trial was registered with ClinicalTrials.gov, number NCT04190745. Blood samples were collected from patients. Sixteen patients with GC were analyzed to investigate the association between clinical outcome and changes of CTC counts pre and post JS001 plus Apatinib. The correlation between the binary clinical outcome (SD/PR/CR vs. PD) and the change in CTCs counts pre and post treatment was analyzed using a logistic regression adjusting for baseline CTCs counts. PD-L1 expression on CTCs were analyzed to determine whether they were in accordance with tissue biopsy. Results: CTCs were detected in all the patients (16/16，100%) ranging from 1 to 33 CTCs/ml. PD-L1+ CTCs were detected in 12 of 16 patients (75%) ranging from 1 to 5 PD-L1 + CTCs/ml. PD-L1 expression in tumor tissue was positive in 11 of 13 patients (84.6%, positive means CPS > = 1), the sensitivity of PD-L1+ CTCs is 90.9% (10/11) if using biopsy as gold standard. The only false negative patient though with CPS 40%, got no benefit from immunotherapy. The specificity of PD-L1+ CTCs detection is 100%, and the accuracy is 90.9%. Overall response rate of this regimen is 26.6% (4/15). Disease control rate is 53.3% (8/15). Progression free survival (PFS) was 2.43 months in all the evaluable patients. However, patients with PD-L1+ CTCs had a longer PFS compared to patients without PD-L1+ CTC (3.30months vs 1.37months, p = 0.001). Overall Survival is not reached. Change of CTCs counts after treatment was significantly correlated with clinical response (p = 0.024). The logistic model McFadden goodness of fit score was 0.435, which is a strong correlation value. Notably, one of the patients who had pseudo-progression shows remarked decreased CTCs count. Conclusions: Our results reveal the potential of CTCs as a noninvasive CDx biomarker in patients with advanced GC/EGJC.
Genomic profiling of Chinese esophageal squamous cell carcinoma patients and difference of genomic mutation between Chinese and American cohorts.
Authors: Li Lin , Wang Kefeng , Tan Binghua , Lyu Yingcheng , He Xiaotian , Wang Wenjian , Hu Xueting , Wu Duoguang , Lin Huayue , Wang Minghui 
Published: June 2021

e16108 Background: Esophageal squamous cell carcinoma (ESCC) remains an aggressive malignancy and most patients are diagnosed at advantage stage with limited treatments. Large amount of evidence has demonstrated that immune biomarkers such as PD-l/PD-L1 and tumor mutational burden (TMB) are associated with clinical outcomes and disease prognosis. Methods: A total of 475 ECSS patients enrolled in this study. Deep sequencing of 450 cancer genes performed on formalin-fixed paraffin-embedded tumor tissues and matched blood. Results: Genomic mutation landscape indicated the top five mutated genes are TP53 (95.0%), CCND1 (42%), FGF3 (42%), FGF19 (41%), FGF4（41%. We found that CCHD2, FOXL2 and PIK3CA were tumor-driver genes in 475 ECSS patients. BCL6 ( p< 0.02), CCND1 ( p< 0.03), FGF12 ( p< 0.04), FGF19 ( p< 0.04), FGF3 ( p< 0.02) and FGF4 ( p< 0.05) mutations are significantly associated with high expression of PD-L1 Moreover, we found that BCL6 ( p< 0.04), BRD4 ( p< 0.03), EP300 ( p< 0.03), HGF ( p< 0.02), KMT2C ( p< 0.005), KMT2D ( p< 0.04), MET ( p< 0.006), NSD1 ( p< 0.04), PBRM1 ( p< 0.003), PTCH1 ( p< 0.01), SPEN ( p< 0.006), SPTA ( p< 0.02), ZHF750 ( p< 0.004), TP53 ( p< 0.01) mutation are significantly associated with high TMB as well. The cutoff for TMB is set for 6.9 mut/Mb. The target gene analysis indicated that over half of Chinese ECSS patient might benefit from gene target therapy. By comparison between Chinese and TCGA cohorts, EBFR ( p< 0.05), FGRF1 ( p< 0.05) and CDKN2A ( p< 0.001) have significantly mutated frequency, which indicated the gene mutated profiling is significantly different between Chinese and American ECSS patients. Conclusions: This study identified certain gene alteration associated with PD-L1 and TMB status. It is necessary to conduct large clinical study to identify biomarker for evaluation the efficacy of novel adjunct immunochemotherapy.
Novel systemic therapies in the treatment of fibrolamellar carcinoma.
Authors: Gottlieb Sara , Gliksberg Ariel , Schadde Erik , Kent Paul 
Published: June 2021

e16161 Background: Fibrolamellar carcinoma (FLC) is an exceedingly rare liver cancer affecting children and young adults without underlying liver disease. Complete surgical resection is the primary treatment option, but recurrence is common. There are currently no established systemic therapies. We have treated patients in both the neoadjuvant and adjuvant setting with three novel combination therapies: 5-fluorouracil/interferon/nivolumab (“Triple Therapy” or TT), gemcitabine/oxaliplatin/lenvatinib (GOL), and nivolumab/lenvatinib/quercetin (NLQ). The purpose of this study was to evaluate objective responses and tolerability of three multi-agent systemic therapies in the treatment of FLC. Methods: Data from all patients with FLC who received TT, GOL, or NLQ between May 2018 and February 2021 were reviewed. Patients who received a minimum of six cycles of systemic therapy with follow up scans at least two months after initiation were assessed based on objective response, survival, and toxicity. Results: Twenty-nine patients with FLC who were treated with novel multi-agent systemic therapy were evaluable based on the above criteria. Median age at start of treatment was 20 (7-52; 16F, 12M, 1 non-disclosed). Twenty-three patients received one combination therapy (13 TT, 8 GOL, 2 NLQ), five received two different lines (3 TT/NLQ, 2 TT/GOL), and one patient received all three novel combinations. Between our 29 patients, they had relapsed 36 total times, and 11 had already tried 2+ systemic therapies. Best RECIST 1.1 objective response (clinical remission + partial response) and tumor control rate (clinical remission + partial response + stable disease) were 58%/95%, 55%/100%, and 33%/83% for TT, GOL, and NLQ respectively. The median longest Progression Free Survival (PFS) on any novel multi-agent regimen was 9 months (2-29; 9.5 for TT, 7 for GOL, 6.5 for NLQ), with 18 patients still receiving the therapy extending their PFS. Of those with previous relapses, 56% have a PFS longer than their previous longest remission and 69% have a PFS longer than their previous shortest time to relapse. Half of patients with previous relapses are still receiving the treatment responsible for their longest PFS. Fever, chills, and nausea were the most common adverse effects experienced throughout all three regimens. Seven patients experienced 1+ grade 3 adverse event. There were no toxic deaths or organ failure. Two patients died as a result of disease; their longest PFS (1 on GOL, 1 on TT) were nine and 10 months. Conclusions: FLC is a devastating cancer with patients often relapsing even after successful surgical remission. There is a strong need for effective and tolerable systemic therapies for those with unresectable, relapsed, progressive, or metastatic disease. We have had promising results in treating FLC and prolonging survival with minimal toxicities using novel multi-agent regimens.
Toripalimab with chemotherapy as first-line treatment for advanced biliary tract tumors: Update analytic results of an open-label phase II clinical study (JS001-ZS-BC001).
Authors: Li Wei , Yu Yiyi , Xu Xiaojing , Guo Xi , Wang Yueqi , Li Qian , Wang Yan , Cui Yuehong , Liu Houbao , Hao Qing , Qu Yueting , Huang Lujia , Liu Tianshu 
Published: June 2021

e16170 Background: A phase II clinical study was conducted to evaluate the safety and efficacy of toripalimab, a novel PD-1 inhibitor, combined with chemotherapy in patients with advanced biliary tract cancers (aBTCs) (NCT03796429). The preliminary results indicated the combination treatment is well tolerable and effective. Methods: Treatment naive patients with aBTCs received toripalimab (240mg intravenously every three weeks) combined with chemotherapy (gemcitabine 1000 mg/m2 d1, d8 + S-1 40-60mg bid D1-14, Q21d). The treatment continued until the disease progress or having intolerable effects. The primary endpoints of the study were progression free survival (PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR), safety and treatment biomarkers. Results: At data cutoff (January 24, 2021), fifty aBTC patients were enrolled at Shanghai Zhongshan Hospital. Among these patients, 56% are males. The median age of the study participants was 62 years of age. The median follow-up time was 10 months (ranged from 4 to 19 months). The primary tumor type was intrahepatic cholangiocarcinoma (ICC) accounting for 48% of total cases, followed by gallbladder cancer (GBC) (40.0%), and extrahepatic cholangiocarcinoma (ECC) (12.0%). At the time of data collection, 48 eligible patients were included for data analysis. The median PFS was 7.0 months（95%CI, 5.5-9.1 months）and median OS was 16.0 months (95%CI, 12.1 to unreachable). The ORR was 27.1 % and disease control rate was 87.5% including 13 partial response (PR) and 29 stable disease (SD) cases. The most treatment related AEs (TRAE) were leukopenia (92.0%), anemia (86.0%) and rash (52.0%). Grade III/IV non-hematological TRAEs were seen in 12 patients (24.0%), including rash (n = 3), infection (n = 6), immune-related colitis (n = 1), immune-related pneumonitis (n = 1) and mucositis (n = 1). Grade III/IV hematological TRAEs were seen in 62% patients. 6 patients discontinued the study drug due to TRAE. Serious adverse events (SAE) were seen in 8 patients and 2 patients died of biliary obstruction complicated with infection. Forty-nine patients were included in biomarker analysis. The most mutated genes were TP53 (51%), KRAS (20%), CDKN2A (18%) and SMAD4 (16%). Patients with activated PI3K signaling pathway had significantly shorter PFS (P = 0.026). Tumor mutational burden (TMB) could not serve as a predictor for the efficacy of immunotherapy combined with chemotherapy. Conclusions: The clinical study of toripalimab combined with chemotherapy continued to show tolerance and efficacy in patients with aBTCs. Gene mutation profiling by NGS suggested mutated PI3K pathway might assocate with shorter PFS. Clinical trial information: NCT03796429.
Association between antibiotic exposure and survival in patients with hepatocellular carcinoma treated with nivolumab.
Authors: Alshammari Kanan , Alsugheir Futoon , Aldawoud Mohammad , Alolayan Ashwaq , Algarni Mohammad Ahmad , Sabatin Fouad , Mohammad Mohammad F. , Alosaimi Abdulaziz , Sanai Faisal , Odah Hassan , Alshehry Ahmed , Aldibasi Omar , Al Saleh Abdullah S , Jazieh Abdul-Rahman 
Published: June 2021

e16186 Background: Nivolumab, an immune checkpoint inhibitor, has improved the outcomes of patients with hepatocellular carcinoma (HCC). It is approved for HCC patients previously treated with sorafenib. Outcomes have been reported in previous studies, in malignancies other than HCC, to be worse when patients have been exposed to antibiotics while receiving immune checkpoint inhibitors. We aimed to evaluate the effects of antibiotics on survival in HCC patients treated with nivolumab. Methods: We performed a retrospective review of 59 patients with advanced HCC that have been treated with nivolumab in two academic centers in Saudi Arabia. Patient characteristics, tumor data, antibiotic use (2 weeks prior, during, and 4 weeks after nivolumab therapy), survival data, and other factors were collected. Log-rank test analysis was performed to test the difference in overall survival (OS) time with and without antibiotics use. Results: The majority of patients were males (n=51, 85%), and 38 were Child-Pugh A (64%). A large number of patients had Barcelona Clinic Liver Cancer (BCLC) stage C tumors (n=42, 71%), and 20 patients (34%) used antibiotics. Most patients received nivolumab as second-line therapy after exposure to sorafenib (n=49, 83%). In patients who received nivolumab as first- or second-line therapy (n=57) and did not receive antibiotics, the median OS was double that of patients who received antibiotics (10 vs. 4.5 months, P=0.04). In child A patients who received nivolumab as second-line therapy (n=32), those who were exposed to antibiotics had a statistically significant shorter median OS compared to those who did not (5.5 vs. 20 months, P=0.04). More patients achieved partial response, or complete response (as per modified RECIST criteria) in the cohort that did not receive antibiotics compared to patients who received antibiotics (21% vs. 15%) but that was not statistically significant (P=0.6). Conclusions: This study shows that HCC patients receiving nivolumab have worse survival if they received antibiotics. Antibiotic mediated alteration of the gut microbiome may impact nivolumab response and shorten patient survival. Although this finding may warrant a prospective larger study but it is consistent with other previous studies. Antibiotics should be used very cautiously when treatment with checkpoint inhibitors is considered.
Molecular profiling of pancreatic neuroendocrine neoplasms (panNENs): A single-institution experience.
Authors: Azar Ibrahim , Yazdanpanah Omid , Bongu Shiva Swaroop , Al Hallak Mohammed Najeeb , Korn W. Michael , Shields Anthony Frank , Philip Philip Agop 
Published: June 2021

e16207 Background: PanNENs are rare with a heterogeneous pathophysiology and widely differing clinical course. Despite a recent update of the grading system, prognostication and prediction of response to therapy remain challenging. Somatostatin receptor aside, there are currently no predictive biomarkers or targeted agents for panNENs. Molecular profiling offers an opportunity to develop new drugs and personalize treatments. Methods: We compiled data from patients diagnosed with panNENs from Karmanos Cancer Institute between 2014 and 2020. Of the 35 patients with panNENs, 33 underwent Next Generation Sequencing (Caris Molecular Intelligence). Two tumor biopsies were insufficient for molecular analysis. Results: Of the 35 tumors analyzed, 11 were grade 1, 18 were G2, 2 were well-differentiated G3 and 4 were poorly differentiated pancreatic neuroendocrine carcinomas (panNEC). Median age at diagnosis was 61. 21 patients identified as White, 6 as Black and 8 as other. 21 were men. 28 patients were metastatic at diagnosis. The most frequently detected molecular alteration was MEN1 mutations (11 G1, 1 G1 and 1 G3). 3 G2 and 2 G3 tumors expressed PTEN mutations. All 3 p53 mutations were G3, 2 of them panNEC. An FGFR3 amplification was detected in a single G1 panNEN. Her2/Neu amplification was detected in a G2 tumor. Other frequent alterations were MGMT (4), TOP2A (4), ARID1A (3), TUBB3 (3) and TSC2 (3). 3 tumors were PD-L1 positive. All tumors were TMB non-high and MMR-proficient. Conclusions: Molecular profiling of panNEN can detect targetable alterations with currently validated commercial agents. panNENs are immunologically cold. Further genomic and epigenomic profiling studies can help understand the molecular underpinnings of pathophysiology and aid in the development of biology-driven targeted therapies.
Clinical performance of blood-based RNA signatures (GemciTest) for the gemcitabine response in advanced pancreatic cancer.
Authors: Piquemal David , Bruno Roman , Noguier Florian , Pierrat Fabien , Gamez Amelia , Cros Jerome , LoConte Noelle K. ,   BACAP and GemciPANC Consortia
Published: June 2021

e16238 Background: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal often presents at a later stage. Gemcitabine is still an important component in PDAC treatment however there is no routine biomarker to predict its efficacy. We had previously performed a discovery cohort of two separate RNA-blood signatures in 60 patients (NCT00789633) showing an association with PFS and OS. Called GemciTest, this CE-IVD molecular test requires 2.5ml whole blood sample before starting the patient's 1st line chemotherapy. From this liquid biopsy, IVD measures the expression levels of nine genes using real-time PCR processes. This abstract presents the clinical validation of GemciTest. Methods: In this study, clinical validations were done on 214 patients (mean 68.7-year-old; 37-88) from 3 distinct cohorts with the University of Wisconsin Biobank, GemciPANC trial (NCT03599154), and BACAP (NCT02818829). These cohorts included first-line treatment,with either a gemcitabine or fluoropyrimidine based regimen. Results: Patients with a clinical benefit response identified by GemciTest (31.5%) had a significantly longer progression free survival (PFS) (5.4 months vs. 3.1 months p = 0.0032) and a longer overall survival (OS) (13.1 months vs. 5.4, p < 0.0003). In multivariate analyses including tumor localization and performance status, this signature continued to be associated with PFS (HR = 0.52 (0.34–0.81) p = 0.003) and OS (HR = 0.44 (0.28 – 0.69) p = 0.0002).Conclusions: GemciTest validation was performed, showing a strong association with PFS and OS.[Table: see text]
Real-world treatment and outcomes of frontline chemotherapy in patients with metastatic pancreatic cancer.
Authors: Al Mutar Salwan , Beg Muhammad Shaalan , Hansen Eric , Belli Andrew J. , Vaz Maegan , Velamoor Sudhakar , He Ming , Wang Ching-Kun 
Published: June 2021

e16249 Background: The difference between the FOLFIRINOX and gemcitabine/nab-paclitaxel (GnP) regimens’ clinical trial designs limit the ability to generate cross-study comparisons. Therefore, there is a significant need to understand the impact of various demographic and clinical characteristics on the effectiveness of these systemic therapies in the real-world treatment setting. This study seeks to compare the real-world outcomes of patients with metastatic pancreatic cancer treated with frontline FOLFIRINOX or GnP. Methods: Patients with primary metastatic pancreatic cancer who received first-line (1L) FOLFIRINOX or GnP were identified in the COTA real-world database. The COTA database is a de-identified database of real-world data (RWD) derived from the electronic health records of healthcare providers in the United States. Real-world overall response rate (rwORR) was calculated as the proportion of patients achieving complete response (CR) or partial response (PR). Overall survival (OS) was calculated using the Kaplan-Meier method and multivariate analyses utilized Cox proportional hazards. Results: The overall qualified cohort (n=236) was stratified by 1L FOLFIRINOX (n=109) or GnP (n=127). Select patient characteristics are shown in table. Patients treated with 1L FOLFIRINOX showed greater rwORR as compared to those treated with GnP (68.8% vs. 55.9%, p=0.04). Additionally, patients treated with 1L FOLFIRINOX had longer median OS (14.4 vs 11.4 mos, respectively). In univariate analysis, patients treated with GnP had a greater chance of mortality (HR: 1.3, 95% CI: 1.0, 1.8, p=0.05). This relationship strengthened in multivariate analysis (GnP treated HR: 1.6, 95% CI: 1.1, 2.1, p=0.01). Conclusions: Due to lack of enrollment of representative patients in clinical trials and in the absence of a comparative clinical trial, real-world experience with chemotherapy regimens provide critical insights on the outcome of treatments. In our cohort, patients treated with frontline GnP had a significantly greater chance of mortality as compared to patients treated with frontline FOLFIRINOX. The FOLFIRINOX cohort also showed greater rwORR. Future research will continue to expand on treatment patterns in subsequent lines of therapy, as well as emerging therapy types, in order to better understand the optimal treatment sequence in metastatic pancreatic cancer.[Table: see text]