bluuebunny/crossref_metadata_2025 huggingface dataset:
Regorafenib plus PD-1 inhibitors in Chinese patients with microsatellite stable/mismatch repair proficient metastatic colorectal cancer: A real-world study.
Authors: Yang Kaili , Han Lu , Zhao Yun-Bo , Ge Yang , LI Qin , Wang Yusheng , Wu Shikai , Zhang Yan , Zhao Chuanhua , Zhou Jing , Zhao Lin
Published: June 2021

e15585

Background: A previous phase 1b trial has shown encouraging efficacy of regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair proficient (MSS/pMMR) metastatic colorectal cancer (mCRC). We aimed to evaluate the efficacy and safety of this regimen in Chinese patients in the real world. Methods: We retrospectively identified patients with MSS/pMMR mCRC who received at least one dose of programmed cell death-1 (PD-1) inhibitors plus regorafenib from 5/2019 to 2/2021 in 10 Chinese medical centers. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and the safety. Results: Fifty-two patients were identified. Liver metastases were presented in 35 patients (67%). A total of 48 patients (92%) received regorafenib plus a PD-1 inhibitor as the third or later line treatment. At the data cut-off, 11 patients (21%) were still on treatment. Other patients terminated treatment because of progressive disease (45%), treatment-related adverse events (TRAEs) (14%) or treatment-unrelated deaths (6%). The median treatment cycle was 3 (range, 1-18). At a median follow-up of 4.9 months, the median OS was 17.3 months (95% CI, 10.2-NR) and the median PFS was 3.1 months (95%CI, 2.5-6.0). Baseline liver metastases were associated with inferior PFS (2.7 versus 6.3 months, p <0.05), but not OS (17.3 months versus NR, p =0.6). Among 38 patients evaluable for response, two patients (5%) achieved partial response, and 17 patients (45%) experienced stable disease as the best response. The DCR was 50% (95%CI, 5.0-NR) and was similar among different PD-1 inhibitors (Table). TRAEs were observed in 30 patients (58%). Fatigue (21%), hand-foot syndrome (19%) and rash (13%) were the most common TRAEs. Eight patients (15%) experienced grade 3-4 TRAEs, including rash (n=3), hand-foot syndrome (n=2), hypertension (n=1), myocardial enzyme elevation (n=1) and visual field loss (n=1). No treatment-related death occurred. Conclusions: The combination of regorafenib plus PD-1 inhibitors was generally tolerated and exhibited potential benefit in terms of OS and DCR. The presence of baseline liver metastases was predictive for shorter PFS but requires further investigation. Disease control rate of different PD-1 inhibitors.[Table: see text]
Demographic differences of colorectal cancer in the community and academic setting in patients over the age of 75 compared to those aged 50 to 75.
Authors: Busari Kafayat Adebukola , Williams Renee , Huston Jamie , Stewart Oliver , Gachette Darrel , Meredith Kenneth Lee
Published: June 2021

e15594

Background: The age of life expectancy in the United States is 78.9 years of age and continues to increase with the help of public health initiatives along with scientific and technological breakthroughs in medicine. However, colorectal cancer screening guidelines for those over age 75 are individualized and not recommended in those over 85. We aimed to investigate the demographic differences of colorectal cancer by sex and race in patients aged 75 vs those aged 50-75, in the community and academic practice. Methods: Data were analyzed from the National Cancer Database between 2010-2014. Results were divided into two categories (50-75 year old, >75 year old) and included number of patients, sex and race. Patient characteristics were compared with Mann-Whitney U, Pearson’s Chi-square, and the Kaplan-Meier method. Data was further analyzed comparing sex and race using chi-square analysis. Results: 167, 059 patients were included in the analysis. 49,551 cases identified in the academic practice and 117, 508 in the community practice. In the academic practice, group A (age 50-75), 57.3% (20,810) were male vs. 42.7% (15,488) female. In community practice, group A, 56.5% (43, 915) were male vs 43.5% (33, 742) female (p-value <0.05). Conversely, in the academic practice-group B (age >75), 46.2% (6127) were male vs 53.8% (7126) female. In the community practice-group B, 55.3% (22,027) were female vs 44.7% (17,824) male; (p-value <0.05).For Black patients, decline in cases is seen by age. In academic practice, 16.5% of cases were aged 50-75 vs. 11.9% over age 75. In community practice; 11.5% were aged 50-75 vs. 6.5%, p<0.05). Comparatively there was an increase in cases in White patients by age diagnosed in academic and community practice; 77.5% vs 84.2 in 50-75 and 84.8 vs. 90.9% in >75, respectively (p<0.05). Conclusions: Women age >75 comprised a statistically significant greater proportion of colorectal cancer cases compared to men age >75 in both the community and academic setting. Contrary to established reports detailing higher incidence rates in males aged 50-75. Furthermore, there is an increase in cases with age in White patients in comparison with a decrease in cases in Black patients. These findings may suggest the need for a more universal and less individualized approach for individuals over age 75.
Comparison of colorectal cancer location and metastasis site in patients aged 50 to 75 versus age 75 and older in community and academic practice.
Authors: Busari Kafayat Adebukola , Williams Renee , Huston Jamie , Gachette Darrel , Stewart Oliver , Meredith Kenneth Lee
Published: June 2021

e15595

Background: Current guidelines recommend cessation of average risk colorectal cancer screening at age 75, after which a more individualized approach is endorsed. There is limited data on characteristics of colorectal cancer in patients over the age of 75. We aimed to determine if colorectal cancer site and metastasis is greater in the community vs academic setting in patients aged 50-75 compared to those age 75 or older. Methods: Data were analyzed from the National Cancer Database (NCDB) between 2010-2014. Results were divided into two categories (50-75 year old, >75 year old) and included number of patients, site of cancer and site of metastasis. Patient characteristics and survival were compared with Mann-Whitney U, Pearson’s Chi-square, and the Kaplan-Meier method. Results: 167, 059 patients were included in the analysis. In the academic setting, group A (age 50-75) contained 36, 298 patients and group B (>75) contained 13,253 patients. In the community setting, group A involved 77, 657 patients and group B, 39,851 patients. In the academic setting, group A identified 57.7% of cases involving the colon vs 42.3% involving the rectum. In group B, 71.4% cases involved the colon vs 28.6% involving the rectum. In the community setting, group A identified 64.4% of cases involving the colon compared to 35.6% involving the rectum. For group B, 76.2% of cases diagnosed were in the colon vs. 23.8% of cases involving the rectum. Overall, indicating a statistically significant increase seen in colon involvement in the older age group (<0.001). In community and academic practice, there is a statistically significant increase in the cases involving metastasis for group A, compared to group B (p<0.001) This is seen for specific sites as well, including bone, liver and lung, (p< 0.001) but not brain involvement in academic practice. Conclusions: In this study, we found a statistically greater number of cases of involving metastasis in patients aged 50-75 compared to patients aged 75 and older in both academic and community practices. In both the academic and community setting, older patients demonstrated statistically greater involvement of the colon compared to patients aged 50-75. Overall, there were more cases of colon and rectal cancer for both age groups seen in the community setting compared to the academic setting.
Type of 5-fluorouracil and risk of cardiovascular events in early-stage colon cancer.
Authors: Huang Wen Kuan , See Lai-Chu
Published: June 2021

e15596

Background: Older patients with colorectal cancer are at increased risk of developing cardiovascular (CV) disease. 5-FU-based chemotherapy was found to increase CV morbidity; however, whether CV risks differ among different fluorouracil types, including infusional 5-FU, capecitabine, and tegafur-uracil (UFT), remains unclear. We aimed to assess the association between CV morbidities, including myocardial infarction and heart failure, and different 5-FU types in patients with colorectal cancer. Methods: We evaluated patients from Taiwan Cancer Registry linked with national health insurance research database with stage I to III colorectal cancer between January 1, 2004, and December 31, 2014. A multivariate Cox proportional model with age as the time scale was conducted for comparison. UFT alone was set as the control group. Results: In the cohort of 29176 patients (median [interquartile range] age, 65 [43-79] years), 2241 (7.6%) received UFT, 25181 (86.3%) received infusional 5-FU or capecitabine, 1754 (6%) received mixed. Overall, 290 patients were diagnosed with myocardial infarction (1.78 per 1000 person-years) during a median (interquartile range) follow-up of 5.5 years. Compared with those received UFT, those using infusional 5-FU or capecitabine showed no increased risk of myocardial infarction (weighted hazard ratio [HR], 0.84; 95% CI, 0.57-1.24). There were 376 patients diagnosed with heart failure, corresponding to 2.3 per 1000 person-years. The risks of heart failure between the UFT group and infusional 5-FU/capecitabine were similar (weighted HR, 0.9; 95% CI, 0.62-1.31). Conclusions: In this study, we did not observe any increased CV risk using infusional 5-FU or capecitabine compared with UFT alone use.
Clinical features, treatments and survival of HER2 positive gastric cancer with elevated alpha-fetoprotein: An analysis of 16 cases.
Authors: Ge Shaohua , Ba Yi , Deng Ting , Yang Yuchong , Ning Tao , Li Hongli , Bai Ming , Zhang Le , Duan Jingjing , Liu Rui , Wang Xia , Ji Zhi
Published: June 2021

e16000

Background: Gastric cancer with elevated alpha-fetoprotein (AFP) is a special type of gastric cancer with elevated serum AFP. It is often misdiagnosed as primary hepatic cancer due to abnormal AFP and liver metastasis. The AFP level is related to the prognosis of these patients in whom there is prone to high HER2 positive rate. Therefore, anti-HER2 treatment is optional, as well as the emerging immunotherapy with immune checkpoint inhibitors. Methods: Gastric cancer patients with HER2 and serum AFP examination were collected in our hospital from May 2017 till now. Serum AFP level over 7 ng/ml was defined as elevated AFP. The clinical characteristics, treatments and survival of the patients with HER2 positive and elevated AFP were picked and analyzed. Results: Among 135 gastric cancer patients with elevated AFP, 16 (11.9%) were HER-2 positive (12 with HER2 3+, 3 with HER2 2+/FISH+ and 1 with HER2 gene amplification in NGS). The mean serum AFP is 201.4± 476.7ng/ml (range: 7.74 -1335). There were 9 males and 7 females. The mean age was 55 years (range: 38-90). The tumors were located in stomach cardia and fundus in 5 cases, body in 5 cases, antrum in 4 cases, body and antrum in 1 case and whole stomach in 1 case. There were 2 patients in stage III and 14 patients in stage IV with metastasis to lymph node metastasis in 15, liver in 9, abdominal cavity in 3 and peritoneum in 3. As for the treatments, three patients underwent surgery, one of whom with exploratory laparotomy (no antitumor treatment after surgery, died from infection). In 13 advanced patients, 12 patients received systemic antitumor therapies (8 with chemotherapy+Trastuzumab+ immunotherapy, 2 with chemotherapy+Trastuzumab, 1 with chemotherapy+ immunotherapy and 1 with chemotherapy). The chemotherapy regimens were XELOX in 5 cases, SOX in 4 cases and FLOT in 2 cases. The response rate was 50% (6 in 12 patients) and the disease control rate was 100%. The median PFS was 7.5 months in first line therapy with six patients without progression disease yet. The longest PFS with PR lasted for 16.5 months with chemotherapy, trastuzumab and immune checkpoint inhibitor. Conclusions: Gastric cancer with HER2 positive and elevated serum AFP is a disease with special clinical characteristics. Patients with advanced diseases can be treated with chemotherapy, trastuzumab +/- immune checkpoint inhibitors. This combination is expected to become a new regimen to improve survival of such special patients.
Pyrotinib combined with SHR6390 in the treatment of refractory advanced HER2 positive gastric cancer or solid tumors: Safety and efficacy results from a phase Id trial.
Authors: Liu Dan , Xu Yingying , Gong Jifang , Yang Fen , Shen Lin , Li Huajun
Published: June 2021

e16009

Background: Pyrotinib (an irreversible pan-ErbB inhibitor) combined with SHR6390 (a novel oral small molecule CDK4/6 inhibitor) had shown anti-tumor activity in pyrotinib-resistant PDX models. A phase Id trial was conducted to evaluate the safety and efficacy of pyrotinib combined with SHR6390 in the treatment of refractory advanced HER2 positive gastric cancer or solid tumors (NCT03480256). Methods: A standard “3+3” design was conducted in this trial. Patients (Pts) received pyrotinib (qd, d1-28; q4w) combined SHR6390(qd, d1-21; q4w) at dose of 400/100mg (cohort A), 320/100mg (cohort E) and 400/75mg (cohort F) until disease progression or intolerable toxicity. The primary endpoint was safety and maximum tolerated dose. Results: From Sep. 2019 to Dec. 2020, 19 pts (14 gastric cancer, 3 colorectal cancer, 2 other solid tumors) were enrolled (A: n = 6; E: n = 6; F: n = 7). 15 pts received and progressed on Herceptin before enrollment. In cohort A, one DLT was observed (Grade 4 neutropenia), and another 3 pts suffered G3 neutropenia, anemia or thrombocytopenia. Considered of safety, the dose levels were decreased and designed as cohort E and F. In cohort E, one DLT was observed (G4 neutropenia). No DLT was observed in cohort F. The most common hematologic toxicities were neutropenia (95%), anemia (74%) and thrombocytopenia (74%). The most common non-hematologic toxicities were diarrhea (53%), mucositis (26%) and nausea (21%). The most common G3/4 AEs were leukopenia (37%) and anemia (16%). No G3/4 non-hematologic toxicity was observed. 18 pts were included in efficacy analysis. The overall response rate was 38.9%, with 7 PR (A: n = 3; E: n = 2; F: n = 2) and 7 SD. The median PFS was 3.83 months, with 2 pts received treatment over 12 months (A: n = 1; F: n = 1). Conclusions: Pyrotinib combined with SHR6390 had shown acceptable safety profile and encouraging efficacy in refractory advanced HER2 positive solid tumors. Further study would be carried out at the dose in cohort A. Clinical trial information: NCT03480256.
Efficacy and safety of toripalimab combination with SOX regimen as a first-line treatment in patients with unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer: Preliminary data from a single-armed, exploratory study.
Authors: Lin Xiaolin , Xia Qing , Han Ting , Zhuo Meng , Yang Haiyan , Qiu Xiaoxia , Wang Liwei , Xiao Xiuying
Published: June 2021

e16015

Background: Gastric cancer (GC) is one of the most common malignancies of the digestive system with a poor prognosis and limited treatment option. Currently immunotherapy is approved for the third-line treatment of GC, but there are limited data on first-line treatment. Therefore, this study will further explore the efficacy and safety of the domestic PD-1 antibody toripalimab combined with S-1 plus oxaliplatin (SOX) regimen as the first-line treatment of unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer. Methods: A prospective, single-armed, exploratory, investigated initiated trial explores the efficacy and safety of toripalimab combined with SOX regimen as first-line treatment of unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer. The primary objectives are objective response rate (ORR). Secondary objectives include disease control rate (DCR), DOR, PFS, and OS. The dosage regimen is: Toripalimab, 240mg D1; oxaliplatin, 130mg/m2, D1 ; S-1, 40mg/m2, bid oral D1-14 days, every 21 days as a cycle and plan 6 cycles of treatment. Tumor responses were assessed radiologically every two cycles. Major eligibility requirements include: unresectable advanced, recurrent or metastatic gastric/gastroesophageal junction cancer with diagnoses confirmed histologically or cytologically, age 18 and 80 years, first-line treatment, at least one measurable lesion according to RECIST 1.1, ECOG 0-1, adequate organ function and HER-2 negative. Results: So far, 17 of planned 20 patients have been enrolled. 14 patients completed 2 cycles of treatment, the ORR rate was 57% (8/14) and the disease control rate (DCR) was 93% (13/14). 10 patients completed 4 cycles of treatment, the ORR rate was 60% (6/10) and the disease control rate (DCR) was 90% (9/10). 7 patients completed 6 cycles of treatment, the ORR rate was 43% (3/7) and the disease control rate (DCR) was 57% (4/7). Common adverse reactions during treatment in 17 patients included rash 17.6% (3/17), diarrhea 41.2% (7/17), hypothyroidism 11.8% (2/17), elevated amylase 35.3% (6/17), decreased platelets 41.2% (7/17), mostly grade I-II. Conclusions: Toripalimab combination with SOX regimen as a first-line treatment demonstrated promising anti-tumor activity in unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer patients with a good ORR and controllable safety. Clinical trial information: NCT04202484.
Real-world clinical effectiveness and safety of camrelizumab in esophageal squamous cell carcinoma.
Authors: Yao Qiwei , Fu Zhichao , Chen Qisong , Huang Jianli , Wu Jintong , Ke Chunlin , Ma Liangyun , Li Shouguo , He Rongqi , Lin Yuyi , Li Jiancheng
Published: June 2021

e16023

Background: Camrelizumab, a programmed death 1 (PD-1) inhibitor, has recently demonstrated efficacy for esophageal squamous cell carcinoma (ESCC) patients in a phase III trial. We report real-world clinical outcomes of camrelizumab therapy for ESCC patients in a multicenter prospective cohort. Methods: Eligible patientswereadvanced esophageal squamous cell carcinoma with stage II-IV confirmed by pathology (including histology or cytology). All patients had received at most one systematic treatment and ECOG performance status of 0 or 1. Camrelizumab monotherapy(200mg) or combined with chemo-radiotherapy, chemotherapy, chemotherapy and antiangiogenic therapy as a first or second line of therapy were included. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and overall survival (OS) and safety data were evaluated. This abstract summarizes the findings of an exploratory interim analysis (cut-off Dec 2020). Results: From Oct 2019-Dec 2020, 63 patients were enrolled (19 centers in China; mean age 62.26 years; 97% ECOG PS 1; 54% first line therapy). Patients received camrelizumab monotherapy (8; 13%), camrelizumab/chemo-radiotherapy combination therapy (22, 35%), camrelizumab/chemotherapy combination therapy (26, 41%), camrelizumab/chemotherapy/antiangiogenic therapy combination therapy (7, 11%). One patient achieved a complete response and 27 patients achieved a partial response, leading to an ORR of 41.26%. The DCR was 95.24%. The median progression-free survival (PFS) was 6.33 months (95% confidence interval [CI] 4.73-NA). Among patients with adequate samples test for LBH level and (lung immune prognostic index) LIPI score, 15.7% (8/51) patients had a high LBH level;63% (29/46), 32.6% (15/46) and 4.3% (2/46) patients had a good, middle and poor LIPI score, respectively. A significantly longer PFS was observed in patients with a normal LBH level (NA vs. 6.33 months, P = 0.049), and also in patients treated with first-line therapy (6.33 months vs. NA, P = 0.0338). Among adverse events, 4 patients (6.35%) reported grade 3-4 AEs, including pneumonia (n=2 [3.17%]), and bone marrow suppression (n=2 [3.17%]). 10 of 63 patients (15.87%) experienced any grade pneumonia, and 21 of 63 patients (33.33%) experienced grade 1-2 RCCEP. Conclusions: This real-world population showed that camrelizumab as the first- or second-line therapy was an effective and safe treatment for patients with ESCC. Clinical trial information: CHICTR2000039499.
Lymph node metastases of gastric cancer and blood cell circuit.
Authors: Kshivets Oleg
Published: June 2021

e16024

Background: Significance of blood cell circuit in terms of detection of gastric cancer (GC) patients (GCP) with lymph node metastases was investigated. Methods: We analyzed data of 793 consecutive GCP (age = 57±9.4 years; tumor size = 5.4±3.1 cm) radically operated (R0) and monitored in 1975-2021 (m = 555, f = 238; distal gastrectomies = 460, proximal gastrectomies = 163, total gastrectomies = 170, combined gastrectomies with resection of pancreas, liver, diaphragm, colon transversum, esophagus, duodenum, splenectomy, small intestine, kidney, adrenal gland = 244; D2-lymphadenectomy = 513, D3-4 = 280; T1 = 235, T2 = 220, T3 = 182, T4 = 156; N0 = 433, N1 = 109, N2 = 251; G1 = 222, G2 = 162, G3 = 409; early GC = 162, invasive = 631; only surgery = 621, adjuvant chemoimmunotherapy-AT = 172 (5-FU+thymalin/taktivin). Variables selected for study were input levels of blood cell circuit, sex, age, TNMG. Differences between groups were evaluated using discriminant analysis, clustering, nonlinear estimation, structural equation modeling, Monte Carlo, bootstrap simulation and neural networks computing. Results: It was revealed that separation of GCP with lymph node metastases (n = 360) from GCP without metastases (n = 433) significantly depended on: eosinophils (%, abs, total), thrombocytes (abs, total), ESS, Hb, erythrocytes (abs), residual nitrogen, protein, cell ratio factors (CRF) (ratio between cancer cells- CC and blood cells subpopulations), T, G, tumor size, histology, tumor growth, blood group, procedures type (P = 0.043-0.000). Neural networks computing, genetic algorithm selection and bootstrap simulation revealed relationships of lymph node metastases and CRF: thrombocytes/CC (rank = 1), healthy cells/CC (2), erythrocytes/CC (3), monocytes/CC (4), segmented neutrophils/CC (5), lymphocytes/CC (6), leucocytes/CC (7), eosinophils/CC (8), stick neutrophils/CC (9). Correct classification N0—N12 was 99.9% by neural networks computing (area under ROC curve = 1.0; error = 0.0). Conclusions: Lymph node metastases of gastric cancer significantly depended on blood cell circuit.
Changes in neutrophil /lymphocyte ratio and platelet count after chemotherapy correlate with cheomtherapy response and predicition of prognosis in patients with advanced gastric cancer.
Authors: Liu Yibing , Meng Qingju , Zhou Zhiguo , Jing Li
Published: June 2021

e16030

Background: The aim of the study was to investigate the predictive value of neutrophil to lymphocyte ratio(NLR) and platelet count(PLT) in the prediction of chemotherapy response and prognosis in patients with advanced gastric cancer. Methods: In this retrospective study, a total of 260 advanced gastric cancer patients were analyzed and the correlation between NLR, PLT and overall survival (OS) were investigated. The receiver operating curve (ROC) was drawn to determine the optimal critical value of NLR. These cases were included and separated into different groups according to the median values of NLR or PLT. Results: Low baseline NLR level correlated with improved clinicopathological characteristics, including organ-free metastasis, Borramn type I and II, tubular adenocarcinoma and papillary carcinoma. Low baseline PLT level also associated with Borramn classification. Alterations in the NLR and PLT levels were associated with therapeutic efficacy and prognosis. The patients who remained in or switched to the low NLR level had an improved objective response rate(ORR), disease control rate(DCR) and survival ratios. The patients who remained in or switched to the low PLT level had an improved DCR. Univariate analyses showed that pathological type, Borramn typing, changes of NLR, and efficacy of chemotherapy were significant predictors of OS. Multivariate analyses showed that pathological type and efficacy evaluation were independent prognostic factor. Conclusions: This study demonstrated that the changes of NLR and PLT following chemotherapy can predict the chemotherapy results in patients with advanced gastric cancer. But, baseline NLR and PLT level haven’t prognostic value in patients with advanced gastric cancer. However, pathological types and the results of the first therapeutic evaluation could have prognostic value in patients with advanced gastric cancer.
Effects of Qingre Huatan Huoxue prescription on biological characteristics and cell cycle proteins of esophageal cancer stem cells.
Authors: Si Fuchun
Published: June 2021

e16052

Background: Esophageal cancer (EC) stem cells characterized with immature differentiation, high invasion, high tumorigenesis and other biological characteristics, which are the root of the occurrence, development, recurrence, metastasis of EC. In this study, its purpose is to select and identify EC stem cells from serum-free cultured EC9706 cells, explore the effect of Chinese herbal prescription and its separated prescriptions on the biological characteristics of EC9706 stem cells, and to reveal the cytological and molecular mechanisms of Chinese herbal prescription anti-cancer. Methods: Firstly, MTT method was applied to explore the serum-free culture conditions of EC9706 stem cells in diameter of 60 mm low adhesion culture dish, at the same time, applying flow cytometry to identify the p75NTR mark ratio of each passage of cell to screenEC9706 stem cells. Next, Plotting the growth curve of EC9706 stem cells, detecting the proliferation inhibition rate EC9706 stem cells by cisplatin, soft agar clone formation, cell cycle to identify the characteristics of EC9706 stem cells by MTT method, soft agar assay, flow cytometry. Then applying MTT method and orthogonal test to screen and optimize Qingre Huatan Huoxue prescription (QHHP), using flow cytometry and western blot to test the effects of QHHP and its separated prescriptions on EC9706 stem cells appraisal indicators and Cell Cycle Proteins. Results: EC9706 cells with concentration of 8×104 cells/dish inoculateed on diameter of 60mm low adhesion culture dish, with adding 5 ml DMEM/F12 medium, a daily supplement of 20ng EGF, 10ng bFGF, per 10 to 14 days to passage one generation. After 5 generations of cell passage, the expression rate of p75NTR was 4-5%, was selected as the experimental object.EC9706 stem cells with the biological characteristics of slower adhesive growth, stronger cisplatin resistance, higher soft agar clone formation and p75NTR expression rate than that of EC9706 cells, and The cell cycle distribution was concentrated in the G0/G1 phase. 6 Chinese herbs were screened out ( Coptis coptidis, Rhizoma officinalis, Cucurbita pedicle, Toona bark, Cantharidopsis cantharidis, Augustia japonica) and compose QHHP. QHHP and its separated prescriptions could change the morphology, colony formation ability and cycle distribution of EC9706 stem cells in serum-free culture condition, which were related to the BMI1/CyclinB1 signaling pathway. Conclusions: Serum-free cell culture is a method to enrich stem cell-like cells in EC9706 cells. Qingre Huatan Huoxue prescription and its separated prescriptions inhibited the proliferation of EC9706 stem cells and change esophageal cancer stem cells characters. The mechanism of QHHP and its separated prescriptions on stem cells in EC9706 cells was related to BMI1 /CyclinB1 signaling pathway.
Time to review the role of intraluminal brachytherapy for dose escalation after concurrent chemoradiation in cancer esophagus: A retrospective audit.
Authors: Mehta Ankita , Kumar Piyush , Gupta Richa , Garg Ayush , Agarwal Shubhi
Published: June 2021

e16054

Background: Intraluminal brachytherapy (ILBT) for dose escalation after concurrent chemoradiation (CRT) in cancer esophagus is not routinely practiced. This is particularly attributable to radiotherapy toxicity in terms of strictures and fistulas. Cancer esophagus has poor locoregional control and overall survival rates in comparison to head and neck cancers. Dose escalation may be an option to counteract the high failure rates. Methods: A retrospective analysis was conducted for esophageal cancer patients treated between 2008 to 2016 planned for radical CRT to a minimum dose of 59.4 Gy in 33 fractions along with concurrent cisplatin 35 mg/m2 and 5 FU 375 mg/m2 on weekly basis. Further, the patients who received dose escalation after external beam radiotherapy (EBRT) completion by ILBT to a dose of 6 Gy in a single fraction to the pre EBRT volume were also analysed. The patient, tumor, treatment characteristics along with response rates, survival outcomes, and toxicities were evaluated and compared between the two groups - the patients who received ILBT and those who did not. Statistical significance between variables was analysed with the Chi-Square or Fischer’s exact test and t-test. Survival analysis was done by Log-Rank test. The analysis was done on a worst-case scenario basis where the patients lost to follow-up were considered dead. Results: The total number of patients treated by CRT was 69, out of which 13 patients received ILBT for dose escalation. The median age was 60 years (Range - 40 to 80 years) and the male: female ratio was 1.09, mean tumor length was 6.4 ± 2.4 cms (Range-1.5-12 cms). The commonest tumor site was the middle third observed in 58% patients. The median EBRT dose was 59.4 Gy (Range- 9 to 63 Gy). The median concurrent chemotherapy cycles were 5. The median follow-up period was 15 months (range 1-100 months). In terms of complete response rates, there was a trend towards significant improvement in patients receiving ILBT compared to those receiving EBRT alone (84.61% versus 57.49%, p=0.07). Also, the overall survival (OS) was significantly higher in the ILBT group (45.31 months versus 19.20 months; p = 0.005). The other patient, tumor, and treatment characteristics analyzed showed no significant impact on OS. There was no significant difference in the incidence of strictures (p=0.206) and severity (p=0.764) of strictures amongst both the groups. Grade ≥3 late toxicity was reported in 10 patients (17.85%) receiving EBRT alone and in 3 patients (23.07%) receiving ILBT. None of the patients receiving ILBT developed a fistula. Conclusions: The present study reveals a dramatic increase in OS by dose escalation with ILBT. The limitations of the present study were a small sample size and a lesser number of patients in the ILBT group. Recapitulating the concept of ILBT to increase the local tumoricidal dose may improve the survival rates.
Predictors of clinical outcomes in patients undergoing curative treatment for esophageal or gastroesophageal junction adenocarcinoma.
Authors: Magge Tara , Van Haren Robert , Starnes Sandra Lynne , Wilson Gregory , Patel Sameer H. , Kharofa Jordan , Sohal Davendra
Published: June 2021

e16067

Background: Management of locally advanced esophageal and gastroesophageal junction (E/GEJ) adenocarcinoma is typically managed with neoadjuvant treatment followed by surgery. Clinical outcomes remain suboptimal and a considerable proportion of patients develop recurrence. However, prognostic and predictive factors are not well-defined. We thus aimed to identify any factors that were associated with disease recurrence and decreased overall survival (OS) among patients with E/GEJ adenocarcinoma treated with curative intent. Methods: A retrospective study spanning 2011-2020 was performed, which identified 56 patients who underwent esophagectomy for E/GEJ adenocarcinoma at the University of Cincinnati. Data on baseline demographic and clinical characteristics, treatment details, pathologic outcomes, recurrence patterns, and survival were extracted from the electronic medical record. Predictors of recurrence and OS, using multivariable logistic regression and Cox proportional hazards analyses, respectively, were identified using all potential predictors and parsimonious modeling. The study was approved by the UC IRB; statistical analyses were performed using SAS 9.2; 95% confidence intervals and two-sided p-values were calculated. Results: Of the 56 patients included, 50 (89%) were White and 6 (11%) were Black; 46 (82%) were male and 48 (85%) were current or former smokers. Tumor location was E in 37 (66%) and GEJ in 19 (34%) patients; 30 (64%) had cT3 or cT4 tumors and 27 (55%) had node-positive disease. Neoadjuvant treatment included platinum-based chemotherapy for 43 (77%) and radiation for 40 (71%) patients; all patients underwent esophagectomy. Median OS for the entire cohort was 4.2 (95% CI 1.8-NR) years and 23(41%) had recurrence after resection. Multivariable modeling showed body mass index (BMI) < 25 (OR vs. BMI ≥ 25: 5.41, 95% CI 1.4-20.4, p = 0.01) to be associated with recurrence; a higher pathologic T stage showed a trend toward increased risk (pT stages 1, 2, and 3 patients (vs. pT 0) were 0.2, 1.1, and 2.5 times more likely to have recurrent disease, respectively. OS was inferior for patients with recurrence (HR for death, vs. no recurrence: 5.42, 95% CI 2.1-13.8, p < 0.001) and a baseline ECOG PS ≥2 (HR vs. ECOG PS < 2: 2.36, 95% CI 0.87-6.4, p = 0.09). Conclusions: In this dataset of patients with E/GEJ adenocarcinoma treated with curative-intent resection, baseline clinical parameters of lower BMI and worse ECOG PS (rather than disease characteristics such as T and N stage) were the main predictors of recurrence and decreased OS. These findings suggest that improving clinical outcomes may at least partly depend on prehabilitation targeting nutrition and physical therapy for patients undergoing curative treatment for E/GEJ adenocarcinoma.
Development and validation of a nomogram for distant metastasis in esophageal cancer based on radiomics and clinical factors.
Authors: Chao Zhu , Qiu Qingtao , Ji Youxin , Wang Songping , Ding Jialin , Wang Linlin
Published: June 2021

e16071

Background: Distant metastasis with an incidence of 25% in esophageal cancer(EC) represents a poor prognosis. However, there was few study for prediction of distant metastasis in EC, due to unsatisfactory specificity of clinical factors and lack of reliable biomarkers. Methods: Two hundred and ninety-nine patients were enrolled and randomly assigned to a training cohort(n = 207) and a validation cohort(n = 92). Logistic univariate and multivariate regression analyses were used to identify clinical independent predictive factors and construct a clinical nomogram. Radiomic features were extracted from contrast-enhanced CT performed before treatment, and Lasso regression was used to screen the optimal features, which were developed a radiomics signature subsequently. Four machine learning algorithms were used to establish radiomics models respectively based on the screened features. The joint nomogram incorporating radiomics signature and clinical independent predictors was developed by logical regression algorithm. All models were further validated by discrimination,caliberation, reclassification and clinical usefulness. Results: The joint nomogram had a better performance [AUC(95%CI): 0.827(0.742-0.912)] than clinical nomogram [AUC(95%CI): 0.731(0.626-0.836)]and radiomics predictive models[AUC(95%CI): 0.747(0.642-0.851),SVM algorithms]. Caliberation curve, and decision curve analysis also revealed joint nomogram outperformed the other models. Compared with the clinical nomogram, net reclassification Improvement(NRI) of the joint nomogram was improved by 0.114(0.075, 0.345),and integrated discrimination Improvement (IDI) was improved by 0.071(0.030-0.112), P= 0.001. Conclusions: We constructed and validated the first joint nomogram for distant metastasis in EC based on radiomics signature and clinical independent predictive factors, which could help clinicians to identify patients with high risk of distant metastasis.
Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and hemoglobin (Hb) predict immunotherapy outcomes in patients with advanced or metastatic gastric cancer.
Authors: Gou Miaomiao , Zhang Yong , Yan Huan , Si Haiyan , Wang Zhikuan , Dai Guanghai
Published: June 2021

e16075

Background: This study aimed to confirm the prognostic role of pretreatment neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), hemoglobin (Hb) levels as effective and convenient biomarkers for patients with advanced or metastatic gastric cancer (AGC or MGC) receiving immunotherapy. Methods: patients with AGC and MGC who received anti-PD-1 treatment at the Chinese PLA General Hospital between January 2016 and November 2020 were reviewed. The receiver operating characteristic analyses for predicting 6 months PFS by the NLR, PLR was used to identify an appropriate cut-off value. The study analyzed the association of NLR, PLR, Hb and overall survival (OS) or progression-free survival (PFS) and anti-tumor response rate with immunotherapy respectively. Results: 137 patients were included in the final analysis. 71 patients were administered immunotherapy in the first line and the rest of the patients in the second or further line. 92 patients had received immunotherapy combined with chemotherapy, whereas 45 patients had undertaken immunotherapy monotherapy or with anti-angiogenesis. The best cut-off value for NLR was 3.23 and for PLR was 816.43. NLR <3.23 was associated with longer OS (HR = 0.38, 95% CI, 0.26-0.57, p < 0.001) and PFS (HR = 0.42, 95% CI, 0.29-0.62, p < 0.001) in patients with AGC or MGC. Patients in PLR<816.43 group had prolonged PFS (7.9m vs 4.3m, p<0.001) and OS (11.1m vs9.2m, p<0.001) than in PLR>=816.43 group. The median PFS was 7.8m in the normal Hb level group (Hb>=110g/L) and 4.3m in the decreased Hb group (Hb<110g/L) (HR=0.5, 95% CI 0.31, 0.81, P=0.004). The OS was 14.4m with normal Hb level as compared with 8.2m with decreased Hb level( HR=0.59, 95% CI 0.37, 0.94, P=0.024). No significant difference was observed in objective response rate (ORR) and disease control rate (DCR) in the different NLR, PLR, Hb group, respectively. Univariate and multivariate analysis found that NLR, PLR, Hb were independent prognostic biomarkers for PFS and OS (p<0.05). Conclusions: pre-treatment NLR, PLR, Hb was significantly associated with PFS and OS in patients with AGC and MGC who received immunotherapy. Clinicians need to consider patients with elevated NLR and PLR or decreased Hb level for decisions on immunotherapy strategy.
Integrated DNA and RNA sequencing to reveal early drivers of metastasis in gastric cancer.
Authors: Zhang Jieyun , Liu Fatao , Yang Ya'nan , Weng Xiaoling , Yang Yue , Gong Zhe , Huang Shenglin , Gan Lu , Zhang Xiaowei , Gong Yiwei , Liu Yun , Guo Weijian
Published: June 2021

e16096

Background: Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy to identify early drivers in primary gastric tumors. In this study, we conducted an integrative genomic analysis on GC patients and identified early drivers that lead to metastases. Methods: Tumors and matched normal tissues from 400 Chinese GC patients were characterized by whole-exome sequencing (WES), transcriptome sequencing and targeted exome sequencing (TES), especially the comparative analysis results between higher metastatic potential (HMP) group with T1 stage and lymph-node metastases, and lower metastatic potential (LMP) group without lymph-nodes or distant metastases. Functional experiments on candidate driver mutations were applied in GC cell lines to explore their roles in metastasis and immune escape. Results: HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, lower tumor purity, more stromal and immune cell infiltration than LMP group. We identified 262 differentially expressed mRNA, lncRNA and miRNA between HMP and LMP group (with more than twice proportion of 2-fold increased or decreased tumor than normal tissue in HMP than LMP group, and with significantly 2-fold higher or lower in HMP tumors than LMP tumors). 168 candidate prometastatic mutations were found by WES and 8 were selected for following TES to detect their association with distant metastasis. We found that four candidate mutations were related to distant metastasis and mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. It’s worth noting that though with low mutational rate, MADCAM1 mutations were only observed in patients with metastasis within three years after surgery or at diagnosis. We demonstrated that MADCAM1-mutated proteins act as GOF mutants and could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing complicated immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages (TAMs). Conclusions: Our results showed that the GCs with different metastatic potential are distinguishable at the genetic level. A number of potential metastatic driver mutations was revealed in this study including known cancer-associated genes TP53. We also discovered some novel driver mutations, such as MADCAM1. The results indicate driver mutations in early-onset metastatic GC could promote metastasis not only by directly empower cancer cells to disseminate but also by establishing an immunosuppressive microenvironment. This study increased the understanding of molecular landscape of GC patients and provided possibility for future target therapy.
Pre-treatment status of inflammation-based biomarkers in the patients with advanced gastric cancer who will be treated with nivolumab.
Authors: Kusumoto Tetsuya , Kudou Kensuke , Nanbara Sho , Tsuda Yasuo , Kusumoto Eiji , Hashimoto Kenkichi , Sakaguchi Yoshihisa , Ikejiri Koji , Oki Eiji
Published: June 2021

e16107

Background: Nivolumab is currently proved to be one of the most recommended regimens as the third-line chemotherapy for patients with advanced gastric cancer (AGC) in Japan. A variety of scores based on the systemic inflammation-based biomarkers have been reported to reflect survival in cancer patients. Kudou et al. recently reported that newly designed combined score of 5 inflammation-based prognostic scores (IBPSs), composed of neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, Glasgow prognostic scale, prognostic index and prognostic nutritional index, might be predictive for the prognosis of resected gastric cancer (Ann Surg Oncol, 2020). The aim of the study is to investigate the clinical significance of nivolumab monotherapy in patients with AGC, associated with pre-treatment status of IBPSs including Kudou’s combined score (min 0 to max 10). Methods: Thirty-six patients received nivolumab monotherapy in our institute and enrolled to this retrospective study. We conducted a retrospective review of the data of 24 patients with AGC who received ≧ 2 cycles of nivolumab as the 3rd-line chemotherapy. Adverse events, tumor responses, the IBPSs and survival data were analyzed. Results: Three patients quitted the continuation of nivolumab except for the progressive disease, due to non-hematological toxicities higher than grade 3 including myositis, hypothyroidism, dermatitis and liver dysfunction. The rate of hematological toxicities, which showed severe anemia of higher than grade 3 was 20.8%. The ORR and the DCR were 4.2% and 41.7%, respectively. The median PFS and the OS after nivolumab administration were 69 and 274 days, respectively. Pre-chemotherapeutic combined score of IBPSs below 7 was significantly associated with the longer OS (P=0.014) in exposure of nivolumab, compared with the patients group presenting more than 7. Conclusions: Nivolumab monotherapy as the 3rd-line is one of the best regimens for patients with AGC showing better PS or lower combined score of IBPSs.
Preoperative pembrolizumab for MSI high, EBV positive or PD-L1 positive locally advanced gastric cancer followed by surgery and adjuvant chemoradiation with pembrolizumab: Interim results of a phase 2 multi-center trial (NCT03257163).
Authors: Kennedy Timothy , Shah Mihir Maheshkumar , In Haejin , Chuy Jennifer W. , Moore Dirk F. , Kooby David A. , Kabarriti Rafi , Szabo Stephen M. , Hochster Howard S. , Jabbour Salma K.
Published: June 2021

e16111

Background: Despite advances in therapy, outcomes of patients with gastric cancer in the US remain poor. Recent data demonstrated that certain subtypes of gastric cancer are less responsive to perioperative chemotherapy. Preliminary data suggest that patients with microsatellite unstable tumors (MSI-H), EBV expressing tumors, and tumors with high PD-L1 expression may benefit from immunotherapy. We initiated a clinical trial to evaluate the benefit of PD-1 checkpoint immunotherapy in this subset of patients with resectable gastric cancer. Methods: Interim analysis performed on this phase 2 multi-institutional clinical trial (NCT03257163) is presented. Patients with clinically staged T2-T4, N0-N3, M0 gastric adenocarcinoma are evaluated for loss of mismatch repair proteins, expression of EBV or PDL1 expression with CPS > 1%. Consented patients receive 2 cycles of neoadjuvant pembolizumab followed by surgical resection. Following surgery, patients receive adjuvant chemoradiation (45 Gy) with 5 cycles of capecitabine and concurrent pembrolizumab, followed by up to 1 year of pembrolizumab. The primary endpoint is disease-free survival. Results: Of the 15 patients currently enrolled (planned enrollment = 40), 6 patients were MSI-H, 2 EBV (+), and 7 had PDL1 expression with CPS > 1%. Two patients did not undergo surgical resection as 1 patient was found to have peritoneal disease at time of exploration and second was deemed too frail to proceed with surgery. In the 13 patients who underwent surgical resection, all are alive without evidence of recurrent disease (follow up 1 month – 22 months). After 2 cycles of pembrolizumab, 2 patients with MSI-H tumors had pathologic complete response. Clinical T stage was downstaged in 5 patients and clinical N stage was downstaged in 2 patients. PD-1 checkpoint immunotherapy was well tolerated with minimal need for dose reduction and limited toxicity. Conclusions: Early results from our phase 2 clinical trial show immunotherapy to be well tolerated with limited toxicity. Following 2 cycles of pembrolizumab, 2 patients with MSI-H had complete pathologic response and above a third of our patients were downstaged. No recurrences have been observed in the short-term follow-up of surgically resected patients. Clinical trial information: NCT03257163.