bluuebunny/crossref_metadata_2025 huggingface dataset:
Not all HLA loss facilitate immune escape.
Authors: Zhang Li , Peng Ping , Zhao Yongtian , Zhao Zhikun , Chen Yuan
Published: May 2019

e15540

Background: Evolution of tumor immunogenicity during immune checkpoint blockade therapy affects tumor response. This study is to investigate the potential mechanisms of the evolution by identifying the differences in immunogenetics between primary tumor and various metastaticlesions after immunotherapy. Methods: This study was approved by IRB. Three types of tissues from a patient with advanced squamous esophageal cancer were obtained three months after anti-PD-1 therapy. The primary tumor (E) was obtained from surgery, the metastatic tumor tissues were obtained from biopsy of the testicular (T)and skin (S) lesions. The presence of immune cell infiltrates and the availability of target antigens defined by mutated neoantigens in these 3 different tissues were examined. The genetic changes from these lesions were analyzed by whole-exome sequencing and RNA sequencing.The inter-lesional immunogenetic heterogeneity between responsive and non-responsive tumor lesions is interpreted. Results: The patient was evaluated at 1 and 3 months after anti-PD-1 therapy with image examinations. The skin metastatic lesion showed significantly decrease in size, but the testicular metastatic lesion failed to respond to the therapy. To correlate tumor response with immunogenetic heterogeneity, 3 specific genotypic changes were examined and compared. 1. Phylogenetic analysis of multi-site mutational profiles showed that metastases were more closely related to each other than to the primary tumor. Truncal and shared mutations were generally clonal with high cellular prevalence, whereas private mutations had medium to low cellular prevalence indicating subclonal status. 2. Although human leukocyte antigen (HLA) loss occurred in S, the numbers of high expression mutation that can be recognized and presented by HLA were the highest. Compared to E,S and T, an overall higher expression of HLA genes was observed in the S. 3. The number and state of different kinds of immune cell were evaluated. The analysesrevealed an increase in distinct immune cell subsets and activation of specific transcriptional networks that were more pronounced in S than T.s and activation of specific transcriptional networks that were more pronounced in S than T. Conclusions: Recent work has shown that HLA-LOH may result in reduced antigen presentation and thus facilitate immune evasion. This study analysis of inter-lesional heterogeneity during anti-PD-1 therapy demonstrated differential clonal evolution within tumors and potential impact of HLA-LOH on neoantigen presentation and expression.
Immune biomarker expression in the tumor microenvironment in Chinese patients with esophageal squamous cell carcinoma was explored.
Authors: Li Pengfei , Luo Hongli , Chen Yanhui , Wang Yating , Chen Huan , Wu Lihong , Ma Yegang , Zhang Henghui
Published: May 2019

e15542

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in China, of which the standard treatment of advanced esophageal cancer is chemotherapy followed by surgery. Recently, immunotherapy has shown great potential in ESCC treatment. The aim of this study was to explore the landscape of immune-related gene expression in the tumor microenvironment (TIME) and further explore the relationship between immune biomarkers and therapeutic effect. Methods: We retrospectively analyzed PDL1(clone sp142)/PD1 expression in a cohort of Chinese patients (male = 92, female = 18; median age = 64, range from 36 to 84) with ESCC. Patient samples were detected in Genecast. Co. from February 2017 to November 2018. Another 6 patients (male = 4, female = 2) who accepted anti-PD1/PD-L1 antibody treatment were analyzed. PD-L1/PD-1 expression and the incidence of CD8, CD57, CD68, CD163 TILs were immunohistochemically. Results: In tumor cells, more than 32% (36/110) samples of ESCC patients was stained with PDL1 (≥1%), while52.8% (21/36) of these patients highly expressed PDL1 (≥10%, 10%-98%). In tumor infiltrating lymphocytes (TILs), 31.82% (35/110) patients expressed PDL1 (≥1%) and 1.82% (2/110) highly expressed PDL1 (≥10%, 10%-50%). For PD1 expression in TILs, 17.27% (19/110) samples were positively stained with PD1 antibody (≥1%). In a subset of ESCC patients who received immune checkpoint blockade therapy (including 2 responders and 4 non-responders), the median percentage of CD163, CD68, PDL1, CD8, PD1 and CD57 were 1.49% (0.44%-9.98%), 0.40% (0.16%-19.08%), 3.74% (0%-45%), 9.52% (4.20%-13.79%), 4.51% (1.37%-33.43%) and 0.68% (0.08%-1.74%), respectively in tumor area and 4.14% (1.85%-15.99%), 1.62% (0.21%-11.47%), 4.87% (0.33%-18.97%), 7.74% (5.88%-14.35%), 3.93% (1.92%-20.54%) and 0.92% (0.27%-2.18%), respectively in stroma area. When compared with non-responders, samples from the responders showed higher CD8 expression in tumor area. Conclusions: Percentage of PDL1/PD1 expression is relatively high in Chinese patients with ESCC. High levels of CD8 positive TILs might be beneficial to patients with ESCC. Clinical investigations with large sample sizes are warranted to prove our findings.
Molecular mechanism of chemoresistance and restoration in human gastric cancer cells.
Authors: Chang Hye Jung , Choi Moon Young , Cho Min-Hee , Lee Kyoung Eun , Lee Soon-Nam
Published: May 2019

e15544

Background: Gastric cancer is characterized by a high rate of relapse and failure of chemotherapy because of the emergence of drug resistant cells. Hence, resistance to chemotherapy is a major obstacle for the management of gastric cancer. It might be related with the development of cancer stem cells (CSCs). The aim of this study is to investigate the characteristics of the 5-fluorouracil (FU) resistant gastric cancer and to study how to restore the chemosensitivity. Methods: We used the AGS gastric cancer cell line (AGS) and transformed it into a 5-FU resistant cell line (AGS-R). AGS-R was established by continuous exposure of the cells to progressively increasing concentrations of 5-FU for about 1 year and modulating mRNA expression levels of four genes associated with thymidylate synthase (TS). The research methods used were MTT assay, flow cytometry analysis, luciferase reporter assay, western blotting, and siRNA transfection. Results: 5-FU-resistant gastric cancer cell, AGS-R was established by continuous exposure to 5-FU with gradual increase of its concentration for about 1 year. Comparing with AGS, thymidylate synthase (TS) expression in AGS-R was highly increase at transcriptional and translational level. And decreased transcriptional activity of β-catenin in AGS-R was confirmed by Western blotting and luciferase assay. Even though treatment with ICG-001, an inhibitor of β-catenin, showed growth inhibition of AGS in a dose- and time-dependent manner, but it could not in AGS-R. The expression of CD44, well-known CSCs marker, was significantly higher on AGS-R compared to AGS. And the Notch pathway was remarkably up-regulated. Flow cytometry analysis revealed that CD44 expression was reduced on AGS-R transfected with specific siRNA for notch intracellular domain (NICD). Conclusions: This study suggests that chemoresistance of gastric cancer against continuous exposure to 5-FU is associated with decrease of β-catenin activity and development of stemness via the activation of Notch pathway. Therefore, the inhibition of Notch pathway might be a potential therapeutic target in 5-FU-resistant gastric cancer.
Comparison of D2 and D2 plus radical surgery for advanced distal gastric cancer: A randomized controlled study.
Authors: Yu Pengfei , Du Yian , Xu Zhiyuan , Huang Ling , Cheng Xiangdong
Published: May 2019

e15546

Background: The optimal extent of lymph node (LN) dissection for advanced distal gastric cancer remains controversial. The present study compared the safety and efficacy of extended LN dissection (D2 plus) with standard D2 radical surgery for advanced distal gastric cancer. Methods: Eligible patients were enrolled and randomly assigned into two groups: D2 group and D2 plus group. Patients in the D2 group received standard D2 LN dissection, while patients in the D2 plus group received an additional no. 8p, 12b, 13 and 14v LNs dissection. The clinicopathological and surgical data of these two groups was compared and the factors that may influence survival were analyzed. Results: 70 patients were enrolled, out of which 64 patients were analyzed. There were no significant differences in the operative time, blood loss and complications between the two groups. In the D2 plus group, the positive rate of the no. 12b, 13 and 14v LN was 3.1%, 9.4% and 12.5%, respectively. The positive rate of the no. 13 LN correlated with the duodenal involvement, while the positive rate of the no. 14v LN correlated with no. 6 LN metastasis. The survival analysis indicated that among patients with duodenum involvement, the 3-year disease free survival rate of the D2 plus group was significantly better than that of the D2 group. Conclusions: Duodenum involvement and positive no. 6 LN were high risk factors of advanced distal gastric cancer. D2 plus radical surgery turned out to be safe and feasible, and may improve the prognosis of these patients. However, further clinical trials are still warranted. Clinical trial information: #NCT01836991.
Factors predicting poor survival in early gastric cancer: A SEER analysis.
Authors: Alnimer Yanal Mufeed , Qasrawi Ayman , Katato Khalil
Published: May 2019

e15548

Background: The benefit of adjuvant treatment in gastric adenocarcinoma patients with muscularis propria involvement but not beyond is unclear. We aim to establish a model that identifies the factors that could adversely affect the prognosis in these patients, whom could potentially benefit from adjuvant treatment. Methods: We used the Surveillance, Epidemiology, and End Results Program (SEER) database to identify subjects with stage T2aN0M0 gastric adenocarcinoma according to the 6th AJCC TNM staging system who underwent tumor resection between 2004-2015. The effect of the following factors on the 5-year overall survival (OS) was evaluated using Kaplan-Meier analysis: demographics, tumor size, grade and site, number of lymph nodes (LNs) being examined and extent of surgery. Factors with a P value < 0.1% in log-rank test were entered in a Cox proportional hazard ratio (HR) model. Results: We identified 1337 patients who met the inclusion criteria. After a median follow-up of 42 months (1-60), the 5-year OS was 64% with the median being unreached. The following factors were significantly associated with shorter OS in univariate analysis: Age > 60 years with a HR = 1.86 (95% CI 1.49-2.32), Non-Hispanics excluding non-Hispanic Asian and Pacific Islanders with a HR = 1.87 (95% CI 1.54-2.28), patients with less than 15 lymph nodes examined at the time of surgery with a HR = 1.86 (95% CI 1.52-2.26), tumors at the fundus and cardia of the stomach compared to other sites with a HR = 1.73 (95% CI 1.37-2.15), those who underwent endoscopic resection with a HR = 2.27 (95% CI 1.16-4.4) and those who didn’t receive chemotherapy with a HR = 1.23 (95%CI 1.001-1.52) . On multivariate analysis; the following factors were predictors for worse OS; Age > 60 years with a HR = 1.97 (95% CI 1.46-2.65), Non-Hispanics excluding non-Hispanic Asian and Pacific Islanders with a HR = 1.45 (95%CI 1.10-2.00), those in whom less < 15 LNs were examined at the time of surgery with a HR = 1.75 (95% 1.38-2.22) and gastric adenocarcinoma at the cardia and fundus with a HR = 1.50 (95%CI 1.20-1.86). Conclusions: Patients with T2aN0M0 gastric adenocarcinoma, and one of the adverse prognostic factors in our Cox-proportional hazard ratio model need to be studied for possible benefit of adjuvant treatment.
Association of high copy number instability (CNI) score with prognosis in patients with gastric cancer after surgical resection.
Authors: Zhang Yanling , Ren Dandan , Mao Beibei , Song Xue , Yang Wanning , Zhang Henghui , Cai Lisheng
Published: May 2019

e15552

Background: As the fifth most common malignancies and the third leading cause of cancer death in the world, gastric cancer (GC) is often diagnosed in locally advanced or metastatic stage and, therefore, has a poor prognosis. Copy number instability (CNI) score, interpreted as the general measure of genomic instability, was reported as a prognosis predictor of some types of cancer, but its role in prognosis of GC patients remains unknown. The aim of the present study was to investigate its prognostic value in patients with GC after surgical resection and adjuvant chemotherapy. Methods: The present study included 120 patients who had received gastrectomy and adjuvant chemotherapy with stage II-IV GC. Follow-up was available for them. DNA was extracted from primary formalin-fixed paraffin-embedded (FFPE) tumor specimens and matched blood samples. Genomic profiles were analyzed by using a designed panel (1408 genes) based on next generation sequencing (NGS). Results: The most frequently mutated genes were TP53 (49%), PIK3CA (8%), RNF43 (6%) ERBB3 (6%) and APC (6%), and the most frequently amplified genes were TRPS1 (41%), COL1A2 (31%), CSMD3 (29%), ZFHX4 (29%), NAV3 (23%). CNI score was negatively correlated with OS, the CNI-high group had markedly shorter OS than CNI-low group ( p= 0.0093). In addition, there were statistically significant differences in OS between different clinical staging ( p= 0.0468). Moreover, the Cox proportional hazard model showed that CNI score was an independent prognosis factor in GC. Conclusions: The current study indicates that CNI score in primary tumor tissue is an independent predictive prognostic biomarker for GC.
Lactate dehydrogenase and baseline markers associated with clinical outcomes of advanced esophageal squamous cell carcinoma patients treated with camrelizumab (SHR-1210), a novel anti-PD-1 antibody.
Authors: Wang Xi , Zhang Bo , Chen Xuelian , Mo Hongnan , Wu Dawei , Lan Bo , Li Qun , Xu Binghe , Huang Jing
Published: May 2019

e15559

Background: A small proportion of patients with advanced esophageal squamous cell carcinoma (ESCC) could benefit from immune checkpoint inhibitors, and reliable peripheral blood biomarkers for outcomes of anti-PD-1 immunotherapy were not identified in ESCC. Methods: A total of 43 patients were retrospectively reviewed in the ESCC cohort of a phase I trial from our center. All patients received intravenous camrelizumab (SHR-1210), a novel anti-PD-1 antibody, at a dose of 60 mg, 200 mg or 400 mg (4-week interval after first dose followed by a 2-week schedule) and repeated every two weeks until disease progression or intolerable toxicity. The associations between lactate dehydrogenase (LDH) as well as other peripheral blood biomarkers at baseline and the efficacy of camrelizumab were also investigated. Results: With a median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free survival (PFS) and overall survival were 2.0 months (95% CI: 0-4.1 months) and 8.0 months (95% CI: 7.2-8.8 months), respectively. Notably, four patients achieved a PFS exceeding 12 months, including three patients with a long-lasting duration of response over 1 year. Patients with an elevated baseline lactate dehydrogenase had lower tumor response rates (8.3% vs. 32.3%, p = 0.02) as well as shorter PFS (median: 1.8 vs. 4.0 months; HR 0.39, p = 0.002) and overall survival (median: 4.2 vs. 10.4 months; HR 0.22, p < 0.0001) compared with patients with normal levels. An increase of lactate dehydrogenase level during treatment was significantly associated with disease progression (p = 0.014). Multivariate Cox analysis identified LDH (HR = 0.18), C-reactive protein (HR = 0.27), number of involved organs (HR = 0.31), absolute monocyte count (HR = 0.33) and Eastern Cooperative Oncology Group performance status (HR = 0.36) as independent prognostic factors. Conclusions: Serum LDH, as is readily available in routine clinical practice, is a potential marker for response and a powerful independent factor for survival in advanced ESCC patients receiving anti-PD-1 treatment.
The mutational profile analysis of different response to neoadjuvant chemoradiation therapy in local advanced esophageal squamous cell cancer patients.
Authors: Wang Xiaofeng , Shi Xinying , Yang Xu , Wang Wenqing , Deng Lei , Zhao Lili , Yang Wanning , Mao Beibei , Zhang Henghui , Liang Jun
Published: May 2019

e15560

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant diseases in the world and especially in China. The combined modality therapy neoadjuvant chemoradiation therapy (nCRT) has become the new standard of care. This study was aimed to investigate the molecular features in cell-free DNA (cfDNA) that is related with the response to nCRT in the local advanced ESCC. Methods: 24 eligible ESCC patients with received nCRT were included and baseline blood were collected from Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. 14 patients had response and the other 10 patients had no response to nCRT, respectively. Both cfDNA fragments and fragmented genomic DNA were extracted for enrichment of a 0.96M size panel covering exon regions of 1,408 genes. Gene alterations were analyzed to explore the relationship between genetic characterizations of cfDNA and response to nCRT. Results: The most common mutated genes were NOTCH1, IRS1, TP53. The somatic alternation of NOTCH1, IRS1, ZFHX4 occurred more frequently in response group than in non-response group. On the contrary, patients with response to nCRT had significantly less mutations of PDE11A, STK11. Moreover, the tumor mutation burden (TMB) of cfDNA in response group was significantly higher than non-response group(p = 0.024). Conclusions: The molecular features in cfDNA of patients with response to nCRT were different from those without response. Five genes’ mutational profile could identify the response and non-response patients with local advanced ESCC. However, prospective studies are needed to validate our findings.
Association between heart dosimetric parameters, cardiac events and overall survival for patients with stage III esophageal cancer treated with definitive radiotherapy.
Authors: Cai Guoxin , Yu Jinming , Meng Xue
Published: May 2019

e15561

Background: Heart exposure to irradiation can cause cardiac events (CEs). The impact of radiation heart dosimetric parameters (RHDPs) on overall survival (OS) in esophageal cancer is not known. The aim of this study was to determine the association between heart dosimetric parameters and CEs and OS in patients with stage III esophageal cancer. Methods: 346 patients with esophageal cancer treated with definitive radiotherapy (RT) from 2011 to 2013 were enrolled retrospectively. We mainly observed three types of CEs: ischemic diseases (myocardial infarction and unstable angina), pericardial diseases (symptomatic effusion and pericarditis), and arrhythmia. We performed logistic regression or Cox proportional hazards models to evaluate the relationship between RHDPs, CEs and OS. Results: Median follow-up was 28 months and median prescribed doses was 60 Gy. Three and five-year OS was 43.9% and 16.8%, respectively. The number of patients who had ischemic diseases, pericardial diseases and arrhythmia in five years since they received treatment was 19, 12 and 26, respectively. Ischemic diseases was associated with pre-existing heart disease (P = .0016) and percentage of heart volume receiving ≥5 Gy (heart V5) (P = .0037), arrhythmia was associated with pre-existing heart disease (P = .0020), heart V5 (P = .0003) and mean heart dose (MHD) (P = .0021), but pericardial diseases was not correlated with RHDPs. In univariate analysis, smoking status, performance status, tumor location, lung V5, mean lung dose (MLD), heart V30, MHD and gross tumor volume (GTV) were significantly associated with three-year OS, and performance status, tumor location, concurrent or sequential chemotherapy, lung V5, heart V5, heart V30, MHD and GTV were correlated with five-year OS. In multivariate analysis, only poor performance status (hazard ratio (HR) 1.56; 95% confidence interval (CI), 1.16-2.10; P = .003 and HR 1.80; 95% CI, 1.15-2.82; P = .010) and larger GTV (HR 1.53; 95% CI, 1.14-2.05; P = .004 and HR 1.64; 95% CI, 1.07-2.49; P = 0.023) independently indicate worse three and five-year OS, and smoking status (HR 1.37; 95% CI, 1.03-1.82; P = 0.032) predict three-year OS only. Conclusions: Heart dose is associated with the occurrence of CEs, but it could not independently predict OS for patients with stage III esophageal cancer treated with definitive radiotherapy.
A novel EUS-guided liquid fiducial marker for image-guided radiotherapy in esophageal cancer: The safety and efficacy in vitro and vivo evaluations.
Authors: Sun Liangchao , Meng Xue
Published: May 2019

e15573

Background: The true tumor extent of esophageal cancer is hard to visualize on current modalities during radiotherapy. In this study, we evaluated the safety and feasibility of the mixture of N-Butyl Cyanoacrylate and lipiodol to find the most optimal application as the fiducial marker to marking the true tumor extent in esophageal radiotherapy. Methods: Four types of injection matches (1:1-0.1ml, 1:1-0.15ml, 1:3-0.1ml, 1:30.15ml) were injected via syringes in subcutaneous tissue in rats model. Gross histopathological changes, weight, skin score, nodule volume, neutrophil counts and macrophage counts were observed to analyses the effect of different mixing ratios and injection volumes to find the best match. Evaluations following ISO standard criteria are further delivered to test the biocompatibility of the best applicable setting of this fiducial maker. Results: At 7th week, 42 markers (42/48, 87.5%) were still visualized on CT images. No serious adverse events or obvious artifacts were noted through the study. The overall review about the histopathological reaction of the NBCA/Lipiodol was considered to be a combination of acute inflammation, chronic inflammation, granulation tissue, foreign-body reaction and fibrous capsule formation in development. The quantitative analysis showed that when the density of NBCA was low (1:3), lower injection volume (0.1ml) brought the lower weights (p < 0.001). When the injection volume is high (0.15ml), the high NBCA (1:1) caused the lower weight (p < 0.001). At the most time points, the lower injection volume had the lower weights. High injection volume created a 0.079 cm3 increase in nodule size than low volume and high NBCA density also increased the nodule size. As for the inflammatory cells counts, the 3rd week was a key time point, before which the neutrophils decreased sharply and the macrophages keep almost steady, but after that the neutrophils stayed a low level and the macrophages started a rapid growth. On the comparisons of different index (Table), it is showed that the 1:3-0.15ml had an excellent performance as the fiducial marker and final biocompatibility test proved its safety. Conclusions: Overall, our results show that the mixture of NBCA/Lip as the fiducial marker is safe and feasible and the setting of 1:3-0.15ml was most optimal.[Table: see text]
Combining neoadjuvant chemoradiation with adjuvant chemotherapy in multimodality treatment for patients with potentially curable esophageal carcinoma.
Authors: Arays Ruta , Kibirova Albina , Auber Miklos L , Higa Gerald M. , Pahuja Shalu
Published: May 2019

e15574

Background: Optimal multimodality treatment followed by surgical resection results in cure for less than half of patients with operable adenocarcinoma of the lower esophagus or GEJ. The current standard of care is either neoadjuvant chemoradiation established by the CROSS trial or perioperative chemotherapy established by MAGIC trial. We aimed to investigate whether additional treatment beyond current standards of care might improve outcomes. Methods: We performed a phase II, single center, investigator initiated study assessing the combination of neoadjuvant chemoradiation followed by esophagectomy and adjuvant chemotherapy in patients with resected esophageal/GEJ cancer. All patients received neoadjuvant infusional 5-fluorouracil at 225mg/m2 for 5 days with concurrent radiation at a dose of 4500 cGy followed by esophagectomy and 6 cycles of adjuvant paclitaxel 200mg/m2 on day 1, carboplatin AUC 6 on day 1 and infusion 5-fluorouricil 225 mg/m2 on days 1-7 (PCF) on a 28-day cycle. Results: 27 patients with stage IIA-IIIB (AJCC7) esophageal/GEJ tumors were enrolled on the protocol between 1999 and 2007. There were 23 males and 4 females with a median age at diagnosis 58 years. Twenty-five patients had adenocarcinoma, 1 had squamous and 1 had adenosquamous histology with 14 tumors located in GEJ and 11 in lower 1/3 of esophagus. The time between the surgery to start of PCF was 2.4 months. Fifteen patients (55.6%) had an R0 resection margin at the time of surgery. Only 8 (30%) patients could complete all 6 cycles of planned adjuvant chemotherapy, median number of cycles of chemotherapy administered was 1. Patients were followed for 10 years. Median progression free and overall survival was estimated to be 11.9 and 18.8 months respectively. At present time only one patient is alive and free of disease. One patient passed from an unrelated malignancy. Conclusions: Inferior survival results in this small study may be attributed to difficulty delivering adjuvant chemotherapy after prior chemoradiation, extensive surgery and delayed recovery. Total neoadjuvant therapy may overcome these obstacles in management of esophageal/GEJ cancer patients and should be explored in future studies.
Derived neutrophil-to-lymphocyte ratio and platelet to lymphocyte ratio as a prognostic marker for patients with esophageal squamous cell carcinoma treated with definitive chemoradiotherapy.
Authors: Cai Guoxin , Yu Jinming , Meng Xue
Published: May 2019

e15575

Background: Increasing study indicates that inflammatory biomarkers play a important role in predicting prognosis and therapeutic effect in esophageal squamous cell carcinoma. This research is designed to evaluate prognostic value of inflammatory biomarkers at baseline including neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), prognostic nutritional index (PNI) and fibrinogen to Albumin ratio (FAR) and the association between inflammatory biomarkers at baseline and symptomatic radiation pneumonitis in patients with esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiotherapy. Methods: Patients with ESCC treated with definitive chemoradiotherapy from 2011 to 2015 were enrolled retrospectively. The operating characteristic analysis was used to determine optimal cut-off values of NLR, dNLR, MLR and PLR. The Kaplan-Meier method with a log-rank test and Cox regression model were used to evaluate the prognostic role of these biomarkers and the logistic regression was performed to investigate the association berween NLR and radiation pneumonitis. Results: 311 patients were included with a median follow-up of 24 months. The three-year survival rate is 24.12%. The optimal cut-of values of NLR, dNLR, MLR, PLR were 2.77, 1.70, 0.5 and 168.35, respectively. Univariate analysis revealed that tumor length, smoking and drinking status, performance status, tumor stage, tumor location, albumin level, NLR, dNLR, MLR, PLR, PNI, and FAR were significantly associated with progression-free survival (PFS) and overall survival (OS) (p < 0.05), but only tumor length, smoking status, performance status, tumor stage, dNLR and PLR were independent predictors of PFS and OS in multivariate model. Compared with separate marker, the prognostic predictive value of combined dNLR and PLR (coPLR-dNLR) was increased, and it was also a prognostic indicator when patients were stratified into early and advanced TNM stage. None of inflammatory biomarkers was significantly associated with symptomatic radiation pneumonitis in univariate and multivariate analysis. Conclusions: dNLR and PLR were powerful biomarker to predict prognosis in patients with esophageal squamous cell carcinoma treated with definitive chemoradiotherapy, however inflammatory biomarkers could not predict the occurrence of symptomatic radiation pneumonitis.
Prognostic stratification of locoregional esophageal cancer (EC) patients (pts) treated with definitive chemoradiotherapy (dCRT).
Authors: Jeong Hyehyun , Bang Yeonghak , Im Hyeon-Su , Kang Jihoon , Yoon Dok Hyun , Kim Jong Hoon , Kim Yong-hee , Kim Hyeong Ryul , Lee Hyun Joo , JUNG Hwoon-Yong , Lee Gin-Hyug , Song Ho June , Kim Do Hoon , Choi Kee Don , Lee Jeong Hoon , Ahn Ji Yong , Ryu Jin-Sook , Cho Kyung-Ja , Kim Sung-Bae , Park Sook Ryun
Published: May 2019

e15578

Background: Although dCRT is the standard treatment for pts who have locally advanced unresectable EC or refuse surgery, the prognosis of these pts remains dismal. There are urgent needs to develop the novel treatment strategy based on prognostic stratification after dCRT. Methods: A total of 382 pts with locoregional EC without distant metastasis except for supraclavicular lymph node who received dCRT at Asan Medical Center in South Korea from 2006 to 2015 were included. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier method. Risk factors were analyzed using Cox regression. Risk scores were calculated by multiplying coefficients in Cox proportional hazard model. Results: Baseline characteristics were as follows: median age = 66 yrs (range: 40-85); male = 359 pts (94.0%); squamous cell carcinoma = 375 (98.2%); cTNM stage (AJCC 8th) I = 40 (10.5%), II = 122 (31.9%), III = 128 (33.5%), IV = 92 (24.1%). During median follow-up of 52.9 mo, median PFS was 13.5 mo (95% CI, 10.9-16.1), and median OS was 26.7 mo (95% CI, 19.8-33.7). In the univariate analyses, sex (only for PFS), weight loss (≥ 5 kg) during dCRT, cT stage, cN stage, cTNM stage, clinical response after dCRT, reason for dCRT were significant prognostic factors for PFS and OS. In the multivariate analyses, clinical response after dCRT, cTNM stage, and weight loss were independent prognostic factors for PFS and OS (Table). Risk-scoring model using these factors stratified pts into four groups: for median PFS (p < 0.0001), group 1 = 58.2 mo (95% CI, 43.5-73.0), group 2 = 17.0 mo (95% CI, 11.9-22.1), group 3 = 9.0 mo (95% CI, 7.0-11.1), and group 4 = 3.9 mo (95% CI, 3.7-4.2); for median OS (p < 0.0001), group 1 = 106.2 mo (95% CI, 44.9-167.6), group 2 = 38.0 mo (95% CI, 24.4-51.5), group 3 = 13.0 mo (95% CI, 8.5-17.6), and group 4 = 8.0 mo (95% CI, 7.4-8.6). Conclusions: In dCRT-treated locoregional EC pts, survival outcome significantly varied according to baseline clinical stage, treatment response, and dynamic change in body weight. Different treatment and surveillance strategies based on the risk score might be needed in these pts.[Table: see text]
Clinical significance of peritoneal molecular markers in patients with locally advanced gastric cancer (LAGC) without macroscopic peritoneal implants treated with perioperative chemotherapy (ChT).
Authors: Del Carpio Huerta Luis Paul , Calvo Mariona , Serra Olbia , Varela Mar , Hormigo Gloria , Baixeras Nuria , Navarro-Perez Valentín , Aranda Humberto , Miró Mònica , Romero Natalia , Galan MaCarmen
Published: May 2019

e15583

Background: Presence of malignant cells in the peritoneal lavage (Cyt+) of patients with LAGC in absence of macroscopic peritoneal implants reflects bad prognosis and is a surrogate of metastatic disease. The presence of molecular markers (Mol+), such as CEA and CK20 mRNA, had also been suggested to carry the same bad prognosis as Cyt+ after upfront curative gastrectomy. There is no recommendation about the management of Mol+ patients (pts) within the current perioperative ChT. Methods: We retrospectively analyzed all pts treated in our high volume multidisciplinary team between 2011 – 2015, with LAGC amenable to surgical resection, without macroscopic peritoneal implants in laparoscopy staging and treated with perioperative ChT. Pre-treatment peritoneal Cyt and Mol analysis (CEA and CK20 mRNA detected by RT-PCR), as well other clinical factors were analyzed. Results: From a total a 310 pts, 60 were included. Median follow up was 72.9 months (m). Mean age was 60y, 37% had PS0, 37% had diffuse histology, 85% wereT4(a-b), 93% N+ stage and 50% were located in gastric body. Accordig Cyt and Mol markers: 3% were Cyt+ and 18% were Mol+, 63% were Cyt-/Mol-, 15% Cyt-/Mol+, 3% Cyt+/Mol+, 0% Cyt+/Mol-, and 18% were Cyt or Mol unknown (uk). 83% underwent gastric surgery, of them, 93% achieved R0. Median PFS (mPFS) was 61.9m. mPFS for Mol+ was 11.0m (95%CI 2.6-19.4) vs the rest (Mol-/uk and Cyt +/-/uk) 69.9m (95%CI 45.0-94.8), p < 0.001. HR = 3.8. mOS was 68.3m. mOS for Mol+ vs the rest was 20.7m (95%CI 4.5-36.8) and not reached, respectively, p = 0.002. HR = 3.4. Mol+ pts who underwent surgery had longer mOS than Mol+ pts which did not (not-reached vs 7.8m (95CI% 3.4-12.9), p = 0.03). In the multivariate adjusted analysis PS (0 vs 1-2) and Mol (- vs +) were significant both for mPFS and mOS. Mol+: HR = 4.0 (95%CI 2.0-11.0),p < 0.001 for mPFS and HR = 5.4 (95%CI 1.9-14.9),p = 0.001 for mOS. Conclusions: Molecular peritoneal analysis may identify a subset of LAGC patients with bad prognosis despite negative cytology and absence of peritoneal macroscopic implants (Cyt-Mol+). Gastric surgery and perioperative chemotherapy may improve prognosis in some Mol+ patients
Impact of Clostridium difficile infection on gastrointestinal malignancies.
Authors: Perimbeti Stuthi , Shrivastav Rishi , Jatwani Karan , Ward Kristine Marie , Styler Michael , Jain Maneesh Rajiv , Nandi Neilanjan
Published: May 2019

e15586

Background: According to the Centers for Disease Control and Prevention, there were half a million documented cases with 83,000 re-infections and 29,000 deaths due to Clostridium Difficile Infection(CDI) in the year 2011. The influence of CDI on outcomes in gastrointestinal(GI) malignancies is not well described, although the incidence is known to be higher in this subgroup of patients. Methods: National Inpatient Sample 1999-2014 was analyzed to identify adult admissions (>18 years of age) using ICD-9-CM codes with a primary diagnosis of esophageal(EC), Gastric(GC), Colorectal(CRC), Small intestinal(SIC), Hepatobiliary(HCC) and Pancreatic(PC) cancers. ICD-9 code 00845 was used to stratify these for the presence of CDI. We performed Chi-Square test to determine the in-hospital mortality percentage, and Cox Proportional Hazard model to control for confounders and determine the Hazard Ratio(HR) of death within 30 days of admission during hospitalization in patients with and without CDI. Results: See Table. Conclusions: Despite controlling for potential confounders, patients with GI cancers and CDI are at an increased risk of death compared to those without CDI. Taking the more detrimental effects of CDI in this subgroup of patients into consideration, healthcare professionals should strive to avoid the inordinate use of antibiotics and strictly maintain current guidelines designed to prevent spread. It may be prudent to treat these patients as severe CDI, even if current criteria are not met. More scientific research is warranted in analyzing the specific outcomes of CDI in GI cancer patients and if more aggressive therapy for CDI is warranted, considering the limitations of this study. [Table: see text]
Survival of gastric cancer (GC) patients is not determined by the predominant genomic ancestry (PGA): Results from an ethnically admixed Brazilian cohort of GC patients.
Authors: Freitas Helano C. , Araujo Luiza Ferreira , Nunes Diana Noronha , Begnami Maria D. , Bartelli Thais Fernanda , de Amorim Maria Galli , da Silva Israel Tojal , Valieris Renan , Defelicibus Alexandre , Xerfan Mariana Pinheiro , Costa Wilson L. , Jesus Victor Hugo Fonseca , Pizzi Melissa , Dias-Neto Emmanuel
Published: May 2019

e15588

Background: Clinical characteristics, treatment response and overall survival of GC patients differ between Asian and non-Asian countries. Here we evaluated the possible associations between PGA, clinical characteristics and survival in an admixed GC Brazilian cohort. Methods: We included 112 GC pts diagnosed and treated at AC Camargo Cancer Center (São Paulo, Brazil) before 2013. The study was approved by local IRB. Genomic DNA was used for capture-based enrichment of a customized gene panel including 99 genes. Libraries were sequenced in the NextSeq 500 platform (Illumina), using paired-end reads (2x75bp). Ancestries were determined through a set of ancestry informative markers (AIMs), covered by target and off-target reads, described by Elhaik et al. (2014). Results: An average of 406 AIMs were recovered from the available samples, revealing average ancestries was as follows: 55.4% European, 27.7% Asian, 8.9% African; 8% of subjects were highly admixed (HA; < 50% of any ancestry). We found no association between PGA and age at diagnosis (p = 0.58), tumor location (p = 0.34), Lauren (p = 0.24) and staging (p = 0.68). There was an association between PGA and gender (p = 0.04) and a marginal association between PGA and EBV (p = 0.056). BRCA2 was the only gene enriched in the Asian subgroup, compared to the other groups combined (p = 0.009). The median follow-up time was 95 months. We found no differences in median overall survival (OS) (p = 0.4) or disease-free survival (DFS) (p = 0.6) according to PGA. The HA subgroup presented worst survival outcomes compared to the other groups aggregated (mOS 34m; 95%CI 5-80 x mOS 71m; 95% CI 44-85, respectively), but the difference was not statistically significant (HR 1,73; 95% CI 0.74-4.05; p = 0.2). Even for patients with > 75% AIMs for any given ancestry, we found no differences in OS between Europeans (n = 25; mOS 86m; 95%CI 80-NA), Asians (n = 22; mOS 83m; 95%CI 51-NA) and Africans (n = 5; mOS 67m; 95%CI 22-NA), p = 0.4. Conclusions: The most prevalent ancestries in this Brazilian GC cohort were European, followed by Asian and African. Although we found associations between ancestry and a few clinical aspects, PGA was not associated with survival.
Dose-survival relationship in patients with hepatocellular carcinoma undergoing stereotactic body radiation therapy.
Authors: Su Ting-Shi , Liang Shi-Xiong , Li Lequn
Published: May 2019

e15592

Background: Stereotactic body radiation therapy (SBRT) has become a treatment for hepatocellular carcinoma (HCC) from palliative to radical treatment. But there is no clear evidence of a dose-survival relationship among commonly-utilized radiation therapy schedules. We aimed to determine the comparative effectiveness of different SBRT dosing regimens for HCC. Methods: The dataset collected from Guangxi Zhuang Autonomous Region in China was used. In this large single-centered retrospective study, 604 patients treated with SBRT were included from 2011 to 2017. Biologically effective dose (BED10) and equivalent dose in 2 Gy fractions (EQD2) were assumed at an α/β ratio of 10. Overall survival (OS) was the primary endpoint. OS rates were estimated using Kaplan–Meier curves with a log-rank test. Results: The median tumor size was 5.2 cm (interquartile range [IQR], 1.1–21.0 cm). Median follow-up was 21 months in surviving patients (IQR, 3–82 months). The 1-, 3-, and 5-year OSs were 87.1%, 64.7%, and 60.9% in Barcelona Clinic Liver Cancer (BCLC)-A group; 72.9%, 37.2%, and 30.7% in BCLC-B group; and 44.3%, 18.6%, and 12.8% in BCLC-C group; respectively. Increasing the RT dose was associated with improved overall survival. Stereotactic ablative radiotherapy (SART) with BED10≥100 Gy, SBRT with EQD2≥74 Gy and BED10 < 100 Gy, and stereotactic conservative radiotherapy (SCRT) with EQD2< 74 Gy have 3 separate curves for long-term survival post-SBRT. On multivariate analysis, Clinical factors associated with improved OS were BED, alanine aminotransferase (ALT) , and BCLC stage. On the subgroup analysis, BED10 ≥100 Gy was still beneficial against HCCs of BCLC stage A, B, and C. Conclusions: Individualized dose for SBRT are recommended for the treatment of HCC due to different degrees of cirrhosis and liver volume. The RT dose was classified into three levels. If tolerated by normal tissue, SART with BED10 ≥100 Gy as a first-line ablative dose or SBRT with EQD2 ≥74 Gy as a second-line radical dose is recommended. Otherwise, SCRT with EQD2< 74 Gy is recommended as palliative irradiation.
A MRI-based radiomics model for preoperative prediction of five-year survival status in hepatocellular carcinoma.
Authors: Wang Xiao-Hang , Long Liu-Hua , Cui Yong , Jia Angela Y , Zhu Xiang-Gao , Wang Hong-Zhi , Wang Zhao-Hai , Wang Wei-Hu
Published: May 2019

e15596

Background: Recurrence is the major cause of mortality in resected hepatocellular carcinoma (HCC) patients. However, without a standard approach to evaluate prognosis, it is difficult to select potential candidates for additional therapy. We aim to develop and evaluate a magnetic resonance imaging (MRI)-based radiomics model to predict 5-year survival status of HCC patients in the preoperative setting. Methods: A total of 201 HCC patients who were followed up for at least 5 years (unless death occurred) after curative hepatectomy were enrolled in this retrospective multicenter study. 3144 radiomics features were extracted from four conventional sequences of preoperative MRI (T1WI, T2WI, DWI and dynamic contrast-enhanced MRI). The random forest method was used for feature selection and radiomics signature building. 5-fold cross validation was used for robust estimation. A radiomics model incorporating the radiomics signature and clinical risk factors was developed. The model performance was evaluated by its discrimination and calibration. Results: Patients were divided into survivor (n = 97) and non-survivor (n = 104) groups based on survival status at 5 years from surgery. The 30 most survival-related radiomics features were selected to develop the radiomics signature. The preoperative alpha-fetoprotein level was integrated into the model as an independent clinical risk factor in multivariable logistic regression analysis (OR = 3.764; 95% CI 1.997-7.096). The radiomics model demonstrated good calibration and satisfactory discrimination, with the mean area under the curve of 0.9340 (95% CI 0.9222-0.9458) in training set and 0.7383 (95% CI 0.6914-0.7852) in validation set. Conclusions: The MRI-based radiomics model represents a valid method to predict 5-year survival status in HCC patients in the preoperative setting, and may be used to guide neoadjuvant or adjuvant treatment decisions in high-risk patients.
Additional prognostic value of metabolic parameters measured by dual time point pretreatment F-18 FDG PET/CT in patients with intrahepatic cholangiocarcinoma.
Authors: Hwang Jae Pil , Choi Seo Youn , Kim Hee Kyung , Moon Jong Ho , Park Jung Mi
Published: May 2019

e15598

Background: The aim of this retrospective study was to determine whether delayed glucose metabolism assessed by dual time point F-18 FDG PET/CT provides additional prognostic information independent of established prognostic factors in patients with intrahepatic cholangiocarcinoma (IHCC). Methods: We reviewed retrospectively the medical records of 96 patients (men 57, women 39, mean age 66 ± 10 years) with pathologically proven IHCC. They underwent dual time point F-18 FDG PET/CT as part of a pretreatment workup from July 2012 to December 2017. For the analysis, patients were classified by age, sex, stage, serum CA19-9, early SUVmax (eSUV), delayed SUVmax (dSUV), delta SUVmax (ΔSUV, difference between early and delayed SUVmax) and histopathology (pCEA, p53, Ki-67 index). The relationship between FDG uptake and survival was analyzed using the Kaplan-Meier with log-Rank test and Cox’s proportional-hazard regression methods. Results: Median survival for all 96 study subjects was 303 days and median SUVmax was 7.2 (range: 2.5 – 21.7). The survival was found to be significantly related to eSUV ( p < 0.0001), age ( p = 0.017), LN metastasis ( p = 0.03) and p53 index ( p = 0.04) and multivariate analysis study revealed that the patients with a higher SUVmax ( p = 0.0001, 95%CI = 1.80 to 5.89, HR = 3.26), prescence of LN metastasis ( p = 0.031), higher age ( p = 0.044) and a higher p53 index ( p = 0.007) showed worse overall survival. In addition, we carried out a subgroup analysis targeting the 55 patients with delayed SUVmax to evaluate a prognostic value of delayed image parameter. In univariate analysis, dSUV (cut-offvalue 7.3, p = 0.0006) and ΔSUV (cut-off value 3.2, p = 0.035), age ( p < 0.0001) and sCA19-9 ( p = 0.018) showed significant correlation and dSUV was an independent factor of overall survival in multivariate analysis. ( p = 0.014, 95%CI = 1.30 to 10.7, HR = 3.74) And then, we analyzed combinations of eSUV, dSUV and ΔSUV each other to evaluate additional prognostic information. The result revealed that higher dSUV ( p = 0.0001, AUC = 0.68) and ΔSUV ( p = 0.0002, AUC = 0.71) showed a poorer overall survival although the eSUV of IHCC was low. Conclusions: Higher delayed SUVmax and ΔSUVmax on pretreatment dual time point F-18 FDG PET/CT can predict poorer survival and additional information of risk stratification in patients with IHCC.
Nemesis: Non-inferiority meta-analysis of selective internal radiation therapy with yttrium-90 resin microspheres versus sorafenib in advanced hepatocellular carcinoma: A preliminary analysis.
Authors: Venerito Marino , Pech Maciej , Canbay Ali , Donghia Rossella , Guerra Vito , Chatellier Gilles , Pereira Helena , Gandhi Mihir , Chow Pierce K. H. , Vilgrain Valérie , Ricke Jens , Leandro Gioacchino
Published: May 2019

e15604

Background: No survival benefit has been observed for selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres versus (vs.) sorafenib in patients with advanced hepatocellular carcinoma (HCC). In NEMESIS, we assessed by an individual patient data meta-analysis whether SIRT, either as monotherapy or followed by sorafenib, is non-inferior to sorafenib and compared safety profiles. Here we present preliminary data. Methods: A systematic search of MEDLINE, EMBASE, and the Cochrane Library, up to 6 December 2018, found three randomized trials comparing SIRT as monotherapy, or followed by sorafenib, to sorafenib monotherapy among patients with advanced HCC. The main outcomes were overall survival (OS) and frequency of adverse events (AEs). Survival data were pooled (fixed effect analysis). The primary population for non-inferiority analysis was the per-protocol (PP) population. The non-inferiority margin for the hazard ratio (HR) upper boundary was set at 1.08 as specified in EASL guidelines. Results: The three included trials compared sorafenib to SIRT (SIRveNIB and SARAH) or to SIRT followed by sorafenib (SORAMIC) in 1243 patients. After randomization, 23.3% vs. 7.1% of patients (p < 0.0001) did not receive the allocated intervention, and 542/608 (89.1%) vs. 418/635 (65.8%), (odds ratio [OR] 4.3, 95% CI: 3.2-5.8, p < 0.0001) completed the study without major protocol deviations (PP population), in the SIRT and sorafenib arms, respectively. Baseline characteristics of the PP population did not differ between the two comparison groups. Median OS with SIRT followed or not by sorafenib was non-inferior to sorafenib (HR 0.90, 95% CI 0.78–1.02). Treatment-related AEs grades ≥3 were reported in 109/356 (30.6%) patients who received SIRT and 197/378 (52.1%) patients in the sorafenib arm (SIRveNIB and SARAH only, p = 0.0002). Conclusions: SIRT as initial therapy for advanced HCC is non-inferior to sorafenib in OS, and offers a better safety profile.