bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of prolonged exposition to growth factors differently on proliferation of CRC cell cultures encapsulated in alginate.
Authors: Filippova Svetlana Yu. , Sitkovskaya Anastasia O. , Mezhevova Irina V. , Timofeeva Sofia V. , Shamova Tatiana V. , Novikova Inna A. , Kolesnikov Vladimir E. , Kolesnikov Valeriy V. , Sidorenko Maria , Panchenko Pavel , Kit Oleg I. 
Published: June 2021

e15610 Background: Cancer stem cells (CSCs) are promising targets in modern oncology. A lot of CSCs enrichment and cultivation techniques are being currently developed. Most of the approaches deploy high doses of growth factors in culture media, - EGF and FGF2 above all, - without prior testing. Since prolonged exposition to growth factors may cause paradoxical growth inhibition it is worth developing test systems to evaluate culturing conditions before establishing the main experiment. Encapsulation in alginate may serve as a promising approach to develop such test-systems due to alginate reduced ability to adsorb proteins and maintain proper attachment to the ECM of non-stem cell even in the presence of serum. It is important to notice that serum addition may be crucial during initial stages of primary CSCs culture establishment. The aim of the study was to test EGF and FGF2 effects on anoikis resistant cells growth in permanent colorectal cancer cell lines. Methods: The cells of Caco-2, HT-29, and HCT 116 cultures were encapsulated in 1% alginate beads at a concentration of 100 000 cells/ml. Subsequently encapsulated cells were kept in 2 variants of culture media: DMEM/F12 + 10%FBS with and without addition of growth factors (EGF 20 ng/ml, FGF2 10 ng/ml). The cultivation was carried out for 10 days, after that the colonies area (A) was measured. Data are given as: Mean ± 95% confidence interval. Results: The average area of Caco-2 culture colonies increased significantly with the addition of growth factors (FBS only A = 1755.16±195.87 μm2, with additional growth factors Af = 3270.57±274.91 μm2), the difference was significant (t = 8.83, n = 300, p < 0,05). The area of HCT116 colonies after growth factors addition increased only slightly (A = 2844.89±461.57 μm2, Af = 3530.31±503.85 μm2), the difference nevertheless did not reach significant values (t = 1.94, n = 300, p > 0.05). At the same time, the area of HT-29 colonies significantly decreased in the culture medium containing additional growth factors (A = 4605.10±324.02 μm2, Af = 3167.85±249.07 μm2), the difference was significant (t = 6.92, n = 300, p < 0.05). Conclusions: Combining alginate encapsulation and colonies size measurement enabled us to evaluate culturing conditions of anoikis resistant cells in permanent CRC cultures and proved growth factors addition to be an ambiguous practice in CSCs research. This tactics can be applied in a broad spectrum of tasks concerning more effective CSCs medium formulations development.
Association of genomic characterization with clinical benefits of anti-PD-1 antibody combined with FOLFOX as neoadjuvant therapy on locally advanced gastric or gastroesophageal junction adenocarcinoma.
Authors: Liu Ying , Han Guangsen , Li Hongle , Zhao Yuzhou , Li Zhi , Liu Zhentian , Zhuang Jing , Wang Gangcheng , Li Baodong , Wang Jinbang , Li Zhimeng , Xia Qingxin , Zhang Chengjuan , Yu Juan , Gao Xuan , Li Ke , Xu Shuning , Qiao Lei , Kuang Gaizhen , Li Danyang 
Published: June 2021

e16025 Background: Anti-PD-1 antibody combined with chemotherapy showed promising efficacy in gastric adenocarcinoma. However, little is known about biomarkers that identify clinical response. Here, we focus on genomic alteration patterns to predict response of neoadjuvant immunotherapy in patients with locally advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC). Methods: Patients with locally advanced GC/GEJC were received 4 cycles of FOLFOX plus anti-PD-1 antibody (camrelizumab) as neoadjuvant therapy in the study. We prospectively conducted whole exome sequencing (WES) in paired biopsy specimens from enrolled patients at baseline. According to Tumor Regression Grading (TRG) assessment by postoperative pathology, patients were classified into group A (TRG0 & TRG1) and group B (TRG2 & TRG3). Results: We eventually performed WES in 23 patients who had adequate available tumor tissues. The clinical characterizations were not significantly different between two groups. All 23 cases were microsatellite stable (MSS). Alterations of AHNAK2 (50.0%/6.67%), TG (50.0%/6.67%), CTNNB1 (37.5%/0.0%) and ZFHX2 (37.5%/0.0%) significantly enriched in group A (n = 8) compared to group B (n = 15).Furthermore, we inspecting 10 hallmark oncogenic pathways, alterations of WNT pathway also occurred more frequently in group A than those of group B. Genomic alterations in WNT pathway were identified in 5 of 23 cases (21.74%), of which the most frequently mutated genes were CTNNB1 (13.04%), LRP5 (8.69%) and RNF43 (8.69%). Tumor mutation burden (TMB, p = 0.357), whole genome duplication (WGD) status (p = 0.667), copy number variant burden (p = 0.825), fraction of loss of heterozygosity (LOH) in chromosome level (p: 0.07-1), tumor neoantigen burden (TNB) (p = 0.65), HLA type (p: 0.49-1) and HLA LOH status (p: 0.37-1) were not significantly associated with neoadjuvant therapy response. Conclusions: Aberrant activation of WNT pathway was reported to be associated with immune evasion. Our study demonstrated that CTNNB1/WNT-pathway-mut may be a promising predictor for clinical response of neoadjuvant immutherapy in GC/GEJC. Clinical trial information: NCT03939962.
Detection of genes related to peritoneal metastasis of primary gastric cancer based on large-panel Next Generation Sequencing.
Authors: Tao Si , Liu Xin , Jin Chunhui , Chen Rongrong 
Published: June 2021

e16026 Background: Peritoneum is a common site of recurrence and metastasis of gastric cancer. The traditional clinical methods have poor sensitivity for the diagnosis of peritoneal metastasis, and there is no effective marker for predicting peritoneal metastasis of gastric cancer. In this study, the genetic profiles of primary tumors in gastric cancer patients with and without peritoneal metastasis, as well as the genetic alterations before and after metastasis in the same patient were analyzed to explore the genetic alterations associated with peritoneal metastasis. Methods: 232 patients with stage Ⅳ gastric cancer were divided into PM group and non-PM group according to whether there was peritoneal metastasis, DNA based Next Generation Sequencing (NGS) with a 1021 gene panel was performed on their samples. Clinical information was obtained synchronously from physicians and surgeons. Results: There was no significant difference in baseline clinical characteristics between patients in PM and non-PM groups. Molecular analysis revealed that in the PM group, the incidence of CDH1, CDH23, HDAC1, IDH1, KRAS, MED12, RHOA, NOTCH2, TGFBR1 mutations was significantly higher in PM group than that in non-PM group, and these mutated genes were mostly located in wnt/β- catenin and MAPK signaling pathway. On the contrary, the incidence of ERBB2 and CCNE1 amplification was significantly higher in non-PM group than in the other group. Further analysis of samples before and after peritoneal metastasis of 13 patients did not find significant differences in genetic alterations. Conclusions: Compared with other sites, the primary tumor of gastric cancer patients with peritoneal metastasis seems to have its unique molecular characteristics, and large-panel NGS can help us identify this part of patients. Future research may need to clarify whether more radical treatment strategies are needed for these patients.
Correlation of E- and N-cadherin expressions as a prognostic factor in metastatic and nonmetastatic gastric tumors.
Authors: Ulianova Elena P. , Sagakyants Aleksandr B. , Novikova Inna A. , Nepomnyashchaya Evgeniya M. , Chernikova Elena N. , Bakulina Svetlana M. , Pushkareva Tatiana F. , Dzhenkova Elena A. , Shaposhnikov Aleksandr V. , Kolesnikov Evgeniy N. 
Published: June 2021

e16028 Background: Over the past 10 years, gastric cancer has been in the top five most common malignant tumors with a high mortality rate. Its poor prognosis is determined by the aggressive disease course with the development of distant metastases. Additional markers of tumor progression are required, and a special role in tumor progression is assigned to the epithelial-mesenchymal transition (EMT). E- and N-cadherins are among the key EMT regulators. Our purpose was to reveal possible prognostic value of EMT markers in different forms of gastric cancer. Methods: The study included patients (aged 30-80 years) with gastric cancer: control group (n = 20, 58.9±9.7 years) – non-metastatic gastric cancer T3-4аN0-3M0 (G2); main group (n = 20, 53.4±11.9 years) – gastric cancer T3-4аN0-3M1 (G2) with peritoneal metastases. IHC analysis was performed on sections from paraffin tumor blocks using mouse monoclonal antibodies to E-cadherin (SMP471, Diagnostic BioSystems) and N-cadherin (SP90, Spring Bioscience) diluted 1:30, and the Reveal Polyvalent HRP-DAB Detection System. Expression of E- and N-cadherins was analyzed semi-quantitatively according to the percentage of cells showing membrane positivity and the intensity of staining: 0 (from 0 to 10%); 1+ (from 11 to 30%); 2+ (from 31 to 70%); 3+ ( > 70%). Expression was considered positive in ≥2. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA) using the Pearson's chi-square test and the Spearman's correlation. Results: Maximal staining for E-cadherin was observed in the control group (in 90%), staining for N-cadherin – in the main group (in 70%). Average expressions of E- and N-cadherins were: in controls – 34.5±4.5 and 24.1±5.7; in the main group – 24.6±5.8 and 28.3±4.3. The Pearson's test showed the statistically significant prevalence of patients with E-cadherin+ tumors in the control group (7.619, p = 0.006), and the prevalence of patients with N-cadherin+ tumors in the main group (4.912, p = 0.027). However, when considering the correlation between E-cadherin and N-cadherin in the groups, the Spearman's correlation was not statistically significant (rs = -0.342 in the control group and rs = -0.430 in the main group at p > 0.05). Conclusions: The study revealed only a tendency towards the loss of E-cadherin and increased expression of N-cadherin, which is often associated with a poor prognosis. However, a more extensive study is required to assess the possible prognostic value of these EMT markers in metastatic and non-metastatic gastric cancer.
Efficacy and safety of PD-1 inhibitors as first- and second- line treatments for advanced gastroesophageal cancers: A network meta-analysis of phase III clinical trials.
Authors: Lopes Da Silva Laercio , Park Robin , Aguiar Pedro Nazareth , Edleman Saul Eduardo , Haaland Benjamin , Lopes Gilberto 
Published: June 2021

e16032 Background: Advanced gastroesophageal tumors are among the most prevalent and burdensome cancers worldwide. They have a poor prognosis and limited treatment options. Recent studies show that PD-1/PD-L1 inhibitors can improve outcomes, but the results are inconsistent across trials. Herein, we compare the effectiveness and safety of PD-1/PD-L1 inhibitors with chemotherapy in patients with ERBB2 negative advanced/metastatic gastric and esophageal cancers. Methods: We searched bibliographic databases (PubMed, Embase, Cochrane Central, Web of Science, Medline, Scopus) and ClinicalTrials.gov from January 1, 2010, to November 23, 2020. We included phase III randomized clinical trials comparing anti-PD-1/PD-L1 single-agent or in combination with chemotherapy (chemoimmunotherapy) for advanced gastric or esophageal cancers in the first- or second-line settings. We performed a network meta-analysis with a frequentist approach and a random-effects model using the package ‘netmeta’ for R statistical software. A prospective protocol was uploaded to PROSPERO (CRD42020221822). Results: The final analysis included a total of 8 trials that compared different anti-PD-1 agents; none of them involved anti-PD-L1 agents. The four first-line studies involved 3817 patients. Chemoimmunotherapy improved OS and PFS with no significant safety difference: Nivolumab + chemotherapy, OS (HR, 0.83; 95% CI, 0.75-0.92), PFS (HR, 0.68; 95% CI, 0.57-0.81), SAE (OR 0.54; 0;95% CI, 0.1-2.92); Pembrolizumab + chemotherapy: OS (HR, 0.77; 95% CI, 0.67-0.88), PFS (HR, 0.72; 95% CI, 0.60-0.85), SAE (OR, 1.31; 0;95% CI, 0.23-7.35). Pembrolizumab monotherapy was the safest first-line treatment, SAE (OR, 0.02; 95% CI, 0.00-0.2), but did not improve survival, OS (HR, 0.91; 95% CI, 0.71-1.16), PFS (HR, 1.62; 95% CI, 1.23-2.14). The four second-line studies totalized 2087 individuals. Anti-PD-1 drugs were significantly safer but did not significantly improve survival: camrelizumab, OS (HR 0.71; 95% CI, 0.54-0.93), PFS (HR 0.69; 95% CI, 0.45-1.06), SAE (OR, 0.37; 95% CI, 0.24-0.56); nivolumab, OS (HR 0.77; 95% CI, 0.58-1.02), PFS (HR 1.08; 95% CI, 0.77-1.66), SAE (OR, 0.13; 95% CI, 0.08-0.2) pembrolizumab, OS (HR 0.86; 95% CI, 0.72-1.04), PFS (HR 1.28; 95% CI, 0.96-1.71), SAE (OR, 0.4; 95% CI, 0.30-0.53). Conclusions: the combination of PD-1 inhibitors with chemotherapy improves OS and PFS in previously untreated gastroesophageal cancers. Single-agent anti-PD-1 drugs improve safety in refractory disease, with no significant change in OS and PFS.
The association of renal function with safety and efficacy of cisplatin plus S-1 (CS) therapy and docetaxel plus cisplatin plus S-1 (DCS) therapy in patients with advanced gastric cancer (AGC): An additional analysis of JCOG1013.
Authors: Hironaka Shuichi , Sadachi Ryo , Machida Nozomu , Iwasa Satoru , Yamada Yasuhide , Sasako Mitsuru , Yoshikawa Takaki , Boku Narikazu , Terashima Masanori 
Published: June 2021

e16035 Background: A phase III study, JCOG1013, did not show the superiority of docetaxel plus cisplatin plus S-1 (DCS) to cisplatin plus S-1 (CS) in overall survival (OS) (Yamada Y, Lancet GH 2019). It is known that cisplatin and gimeracil (an inhibitor of dihydropyrimidine dehydrogenase contained in S-1) are excreted in urine. We previously reported (abstr 197, ASCO-GI 2021) exploratory analysis of JCOG1013 which showed creatinine clearance (CrCl) was associated with safety (Grade [G]4 hematological toxicity for CS, and G3-4 non-hematological toxicity for CS and DCS), but not with efficacy in either group. Here, we report the additional detail results of this exploratory analysis. Methods: Among 741 participants in JCOG1013, patients with serum creatinine level < 1.2 mg/dL were included in this analysis and categorized by CrCl and treatment into A1 (CrCl ≥ 80 mL/min, CS), A2 (60 < CrCl < 80, CS), A3 (CrCl < 60, CS), B1 (CrCl > 80, DCS), B2 (60 < CrCl < 80, DCS), and B3 (CrCl < 60, DCS). The dose (mg/m2) of C/S was 60/80 regardless renal function in group A (A1, A2 and A3), and that of D/C/S was adjusted in group B as follows: 40/60/80 in B1, 40/50/80 in B2, and 40/40/65 in B3. Adverse events, OS, progression-free survival (PFS), and objective response rate (ORR) were compared by CrCl in group A (A1 vs. A2 vs. A3) and group B (B1 vs B2 vs B3), respectively. Results: Of 723 pts (169/136/57 in A1/A2/A3 and 170/138/53 in B1/B2/B3), the median CrCl (mL/min) was 94.1/71.9/53.4 in A1/A2/A3 and 98.2/70.0/55.6 in B1/B2/B3. The relative dose intensity of C/S was 90.4/75.3%, 87.8/74.9% and 85.7/72.8% in A1, A2 and A3, and that of D/C/S was 87.5/77.7/74.9%, 85.8/61.2/72.7% and 87.8/49.4/58.3% in B1, B2 and B3. The incidence of G4 white blood cell decreased, G4 neutrophil count decreased, and G3-4 anorexia were 1.2/4.4/9.3% (P < 0.01), 4.8/11.1/18.5% (P < 0.01), 14.4/28.1/28.6% (P < 0.01) in A1/A2/A3, and 1.8/3.0/4.0% (P = 0.36), 27.3/24.8/20.0% (P = 0.28), 22.4/29.3/32.0% (P = 0.11) in B1/B2/B3, respectively. No significant association between CrCl and other adverse events was observed either in CS or in DCS group. The median OS was 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.89) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.72). The median PFS was comparable among A1/A2/A3 (7.1/6.8/6.2 months, P = 0.88) and B1/B2/B3 groups (7.5/7.2/7.8 months, P = 0.85). ORR showed no significant difference in A1/A2/A3 (58.9/57.8/46.9%, P = 0.31) and B1/B2/B3 groups (62.0/61.5/51.5%, P = 0.36). Conclusions: Dose modification according to renal function in the DCS arm could control the increase of severe toxicities, which were observed frequently in patients with low renal function in patients receiving fixed dose of CS. Clinical trial information: 000007652.
Phase II trial of surufatinib plus toripalimab for disease progression after first-line chemotherapy with platinum and fluoropyrimidine in advanced gastric or gastroesophageal junction adenocarcinoma.
Authors: Shen Lin , Lu Ming , Chen Zhendong , Ye Feng , Zhang Yanqiao , Li Zhiping , Zhang Xing , Yin Fei , Chen Wei , Sheng Wang , Ma Yue , Zhao Yaqin , Weng Desheng , Yin Xiaolei , Zhou Jinghong , Shi Haiyan , Tan Panfeng , Su Weiguo 
Published: June 2021

e16040 Background: Surufatinib is a novel small-molecule kinase inhibitor targeting VEGFRs, FGFR and CSF-1R, simultaneous targeting of angiogenesis through VEGFRs/FGFR1 and modulating tumor immune microenvironment through CSF-1R may be a uniquely potent strategy to enhance antitumor activity. Toripalimab is a monoclonal humanized IgG4 PD-1 antibody. Encouraging efficacy of surufatinib plus toripalimab treating patients with advanced solid tumors was reported at 2020 AACR. This is an ongoing, multicenter, open-label, single-arm, phase II study to evaluate the efficacy and safety of surufatinib in combination with toripalimab in various solid tumors. Here we report the results of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods: Patients with histologically confirmed gastric or GEJ adenocarcinoma who have failed first-line of systemic chemotherapy were enrolled. Surufatinib 250 mg once a day (QD) will be orally administrated and toripalimab 240 mg will be intravenously administered every 3 weeks. Primary endpoint was the objective response rate (ORR) per RECIST v1.1. Results: As of Dec 31, 2020, a total of 21 gastric or GEJ adenocarcinoma patients were enrolled. The median age was 58 years old, and 81% of the patients were male. Median duration of treatment was 3 months (surufatinib, 3 months; toripalimab, 3 months). Among 15 patients with at least one post-baseline efficacy evaluation, 2 patients achieved confirmed partial response (PR), with 3 additional unconfirmed PR. And there were 6 in stable disease (SD), 3 in progressive disease (PD) and one not evaluable per RECIST v1.1. There were 5 in PR, 7 in SD and 2 in PD per irRECIST, respectively. The confirmed and unconfirmed ORR were 13.3% (95% CI: 1.7%-40.5%) and 33.3% (95% CI: 11.8%-61.6%), respectively. The disease control rate (DCR) was 73.3% (95% CI: 44.9%-92.2%) per RECIST v1.1. Median PFS was 3.71 months (95% CI: 1.41-unknown). 14.3% (3/21) of patients had treatment-related adverse events (TRAEs) of ≥ Grade 3. The most common TRAEs of ≥ Grade 3 were herpes zoster (4.8%), lymphopenia (4.8%), lymphocyte count decreased (4.8%), white blood cell count decreased (4.8%), liver injury (4.8%) and anaemia (4.8%). 4.8% (1/21) of patients had serious TRAEs. One patient died due to unknown reasons. Conclusions: Surufatinib plus toripalimab appeared to show encouraging activity in advanced gastric or GEJ adenocarcinoma with manageable safety profile. Such combination could be a promising strategy for advanced gastric or GEJ adenocarcinoma in the future. Clinical trial information: NCT04169672.
Association between timely targeted therapy initiation and clinical outcomes in patients with advanced HER2+ gastroesophageal adenocarcinoma.
Authors: Lau-Min Kelsey S. , Li Yimei , Eads Jennifer Rachel , Mamtani Ronac , Getz Kelly D. 
Published: June 2021

e16048 Background: Delayed treatment initiation is associated with increased mortality in early-stage cancers. Few studies have examined the impact of timely initiation in advanced cancers. Timely targeted therapy initiation can be especially challenging due to the additional biomarker testing required to identify patients eligible for these treatments. We examined the impact of timely targeted therapy initiation on survival among patients with metastatic HER2+ gastroesophageal adenocarcinoma (GEA). Methods: We performed a retrospective cohort study of patients with metastatic HER2+ GEA treated with first line systemic therapy between 1/2011 and 12/2017 using the nationwide Flatiron Health EHR-derived deidentified database. Timely targeted therapy, defined as initiation of the anti-HER2 monoclonal antibody trastuzumab up to 14 days after first line chemotherapy initiation, was entered as a time-varying exposure on the day of initiation. Patients who initiated trastuzumab after the 14-day cut point or who lacked documentation of having received trastuzumab were classified as having non-timely targeted therapy initiation. Extended Cox regression models were used to compare progression-free (PFS) and overall survival (OS) from the date of first line treatment initiation, adjusted for potential confounders. Pre-planned sensitivity analyses assessed alternative “timeliness” definitions as well as the impact of any trastuzumab administration, regardless of the timing of initiation. Results: We included 459 patients with metastatic HER2+ GEA; 293 (63.8%) received trastuzumab, of whom 223 (76.1%) initiated in a timely manner. The median age was 65.0 years, and patients were predominantly male (82.4%) and non-Hispanic White (78.2%) with an ECOG performance status of 0-1 (85.9%). Relative to non-timely initiation, timely targeted therapy was associated with significantly higher OS (2-year OS 29.6% vs 14.6%; adjusted HR 0.72, 95% CI 0.57-0.91, p = 0.006) and PFS (2-year PFS 8.3% vs 3.9%; adjusted HR 0.78, 95% CI 0.62-0.98, p = 0.030). Results remained similar in sensitivity analyses 1) using alternative “timeliness” definitions (up to 70 days after chemotherapy initiation), and 2) comparing any trastuzumab administration, regardless of the timing of initiation, to no trastuzumab administration (OS - adjusted HR 0.75, 95% CI 0.60-0.95, p = 0.018; PFS - adjusted HR 0.81, 95% CI 0.64-1.02, p = 0.069). Conclusions: OS and PFS were higher among patients with metastatic HER2+ GEA treated with trastuzumab, regardless of the timing of targeted therapy initiation. Although our results provide reassurance to clinicians that delays in targeted therapy may not be detrimental to patient outcomes, efforts should still be made to ensure that all patients with metastatic HER2+ GEA receive first line trastuzumab.