bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of LAG-3 expression in tumor infiltrating immune cells with prognosis in patients with microsatellite instability high colon cancer.
Authors: Lee Soo Jung , Kim Jong Gwang , Chae Yee Soo , Kang Byung Woog , Lee In Hee , Yoon Ghil Suk , Jun Sun-Young 
Published: September 2018

e15126 Background: Recent findings demonstrated that microsatellite instability high (MSI-H) colon cancer contains high T-cell infiltration and upregulated expression of multiple immune checkpoints. The aim of this study was to reveal the prognostic impact of MSI-H colon cancer showing immune checkpoint protein expressions, which are good candidates for immunotherapy. Methods: From January 2011 to April 2015, we included 98 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Medical Center. Inhibitory receptors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), programmed death-ligand 1 (PD-L1), programmed cell death 1 (PD-1) and indolamine 2’3’-dioxygenase (IDO) expression status were retrospectively analyzed using immunohistochemistry (IHC). Positivity in tumor cells (T) and immune cells (I) were separately evaluated. IHC values were determined to be positive when moderate or strong intensity of the membranous to cytoplasmic staining pattern were shown in more than 5% of the tumor cells or immune cells. Results: Among the 93 patients, 22 patients (23.9 %) and 63 (68.5%) were determined as PD-L1(T) positive and PD-L1 (I) positive, while 12 (13.2%) and 42 (45.7%) were determined as LAG-3(I) positive and PD-1 (I) positive. Twenty-seven patients (29.3%) and 66 (71.7%) were determined as CTLA-4 (T) positive and CTLA-4 (I) positive, while 66 (71.7%) and 26 (28.3%) were determined as IDO (T) and IDO (I) positive. During median follow-up duration of 39 months, 16 (17.4%) patients experienced recurrence. LAG-3 (I) positivity was significantly associated shorter relapse-free survival (p = 0.016). Moreover, LAG-3 expression was significantly correlated with PD-L1 (T) expression (p = 0.003). Co-expression of PD-L1 and LAG-3 showed worse prognosis for relapse-free survival (p < 0.001). Conclusions: In conclusion, LAG-3 positivity showed worse prognosis in patients with MSI-H colon cancer. Potential differential therapeutic implications LAG-3 should be further investigated.
Short course radiotherapy (SCRT) and delayed surgery by 8-10 weeks for MRI defined high-risk rectal cancer.
Authors: Al-Hajri Thuraiya Nasser , Wells Lucy , Samuel Leslie M. 
Published: September 2018

e15145 Background: Pelvic MRI can identify rectal cancer patients at risk of an incomplete (R1) resection, allowing pre-operative treatment, usually with pelvic chemo-radiotherapy (CRT) over 5 weeks. Co-morbidities (eg IHD) may make CRT high risk, & SCRT with delayed surgery 8-10 weeks later may be an option, but with relatively little published data on efficacy. Methods: Between 2004 & 2016 our database identified 573 patients with MRI defined high risk rectal adenocarcinomas, and 55 (9.6%) had SCRT & delayed surgery. Results: Patient characteristics: m 35, F 20, mean age 75 years (55- 90). Main co-morbidities were active IHD & frailty. Major post-operative complications were an anastomic leak in 1 (1.8%) patient & septicaemia/shock in 1 (1.8%) patient, with the latter being the only 30 day post-operative death (1.8%). The R1 resection rate was 7 (12.7%), affecting the circumferential resection margin (CRM) in 6, with 2 subsequently developing local recurrence. 4 CRM +ve patients are dead, all of systemic relapse. Distal margin involved in 1 patient, alive with no recurrence on follow up. Local recurrence (with systemic relapse) occurred in 1 patent with a clear CRM, 4 years after SCRT/surgery. Overall local recurrence rate was 5.4%. Pathology response was minimal 4 (7.3%), partial 28 (51%), good partial 15 (27%), & complete (pCR) 8 (14.5%). The 5 year disease specific survival rates, accepting small numbers in each group, were 60% for minimal, 96% for partial, 93% for good partial & 100% for pCR patients respectively. Systemic relapse occurred in 12 (22%) patients, with liver surgery & liver ablation in 2 patients respectively. 18 (33%) patients have died, 10 of infection, 2 of IHD, 2 of progressive disease, 2 of separate cancers, & 2 unknown. Conclusions: In a MRI defined high risk rectal cancer population & co-morbidities, the outcomes from SCRT with delayed surgery 8-10 weeks later are similar to CRT, & a reasonable option to consider.
Poor prognosis in patients with resectable KRAS-MUT colorectal liver metastases is improved by adjuvant hepatic arterial infusion chemotherapy.
Authors: Gholami Sepideh , Boucher Taryn Mary , Kemeny Nancy E. , Gonen Mithat , Cercek Andrea , Kingham T. Peter , Balachandran Vinod P. , Allen Peter J. , DeMatteo Ronald P. , Jarnagin William R. , D'Angelica Michael Ian 
Published: September 2018

e15161 Background: Patients with KRAS-mutated colorectal cancer liver metastases (CRLM) have worse outcomes after resection. Adjuvant hepatic artery pump chemotherapy (HAIC) improves overall survival. We investigated the impact of HAIC in relation to KRAS mutational status in patients with resected CRLM. Methods: Patients with resected CRLM treated with and without adjuvant HAIC and available KRAS status (wild-type, WT; mutated, MUT) were reviewed from a prospective institutional database. Correlations between KRAS status, adjuvant HAIC, clinical factors, and overall survival (OS) were analyzed. Cox proportional hazard model was used to adjust for confounders. Results: Between 1993-2012, 675 patients (419 KRAS-WT, 256 KRAS-MUT) with a median follow up of 6.5 years after resection were evaluated. Fifty-four percent received adjuvant HAIC. Tumor characteristics (synchronous disease, number of lesions, clinical-risk score, 2-stage hepatectomy) were significantly worse in the HAIC group, however, there were more patients with extrahepatic metastases in the no-HAIC group. Adjuvant HAIC was associated with improved OS in both KRAS-WT (5-yr OS 76% vs 57%, HR 0.51, p<0.01) and KRAS-MUT (5-yr OS 59% vs 40%, HR 0.56, p<0.01) patients. On multivariate analysis, HAIC remained associated with improved OS (HR 0.6, p<0.001) independent of KRAS status and other clinico-pathologic factors. Conclusions: Adjuvant HAIC after resection of CRLM is independently associated with improved OS regardless of KRAS status and may abrogate the poor prognosis in resectable KRAS-MUT CRLM. [Table: see text]
Peri/post-operative chemotherapy of oxaliplatin combined with S-1 (SOX) versus post-operative oxaliplatin with capecitabine (XELOX) in locally advanced gastric cancer: RESOLVE Trial.
Authors: Ji Jiafu , Liang Han , Xue Yingwei , Shen Lin , Wang Yanong , Zhou Zhiwei , Yu Jiren , Du Yian , Li Guoli , Chen Lin , Xiao Gan , Wu Dan , Dang Chengxue , Zhou Yanbing , He Yulong , Zhang Zhongtao , Li Yong , Li Ziyu , Zhang Xiaotian 
Published: September 2018

e15519 Background: Peri-operative treatment of locally advanced gastric cancer (LAGC) has always been argued. We aim to compare the survival benefit and safety for SOX as peri-opertative therapy versus SOX or XELOX as postoperative therapy after D2 dissection. Methods: RESOLVE is a phase III trial investigating effects of post-operative SOX and XELOX, and peri-operative SOX on LAGC. RESOLVE is the first RCT investigating different therapeutic timeframes in gastric cancer patients with stratification by Lauren classification. Clinical trials JCOG 0501 and RESOLVE exploring optimal chemotherapy modalities are compared in the table below. Results: The study enrolled the first patient in Aug 2012. By Dec 31, 2016, a total of 1061 patients were recruited. Currently 136 patients have died (arm A: 54; arm B: 44; arm C: 37) and 187 patients are under treatment (arm A: 60; arm B: 61; arm C: 66). Conclusions: The patient recruitment has completed and events of DFS will be achieved in 2 years. Clinical trial information: NCT01534546. [Table: see text]
RNA sequencing to highlight the heterogeneity in circulating exosomes from patients with esophageal squamous cell carcinoma.
Authors: Yang Lin , Zheng Wenjing , Wang Zheng , Ding Peikun , Ling Lijuan , Chen Bin , Zhai Rihong 
Published: September 2018

e15546 Background: Dissecting tumor heterogeneity is crucial for understanding tumor prognosis, response to therapy, and metastasis. But current tissue biopsy-based strategies for characterizing molecular heterogeneity are invasive and may be confounded by intra-tumor heterogeneity. Here we explore whether exosomes that contain bioactive molecules from the cell of origin can provide new noninvasive means to delineate the heterogeneity of human cancers. Methods: We used RNA-sequencing (RNA-seq) to perform unbiased profiling of mRNAs and long noncoding RNAs (lncRNAs) in plasma exosomes isolated from patients with esophageal squamous cell carcinoma (ESCC, n = 6), patients with esophagitis (n = 6), and healthy controls (n = 6). Results: The number of expressed genes detected in our data set is 63355, including 29615 lncRNAs. We found that exosomes from ESCC have dramatically distinct transcriptome and lncRNA landscapes from that of esophagitis and healthy controls, with 2278 genes and 584 lncRNAs showing differential expression between ESCC and controls; and 854 genes and 126 lncRNAs displaying differential expression between ESCC and esophagitis. We also observed variable expression of diverse transcriptional patterns related to immune response, signal transduction, cell mobility, and transmembrane protein binding, as well as differentially expressed 953 lncRNAs between Stage I and Stage II ESCC samples. Finally, we discovered that both gene and lncRNA expression profiles are variably across exosomal samples from different ESCC patients. Conclusions: Our data reveals that exosomes from ESCC contain distinct transcriptional and lncRNA profiles that separate ESCC from benign esophagitis and healthy controls. Our analysis also identifies unappreciated molecular heterogeneity in exosomes of ESCC, which may pave the way for using exosomal RNA-seq to decode molecular heterogeneity in cancers.
Escape of gastric cancer cell from metabolic stress via DLC3/MACC1 axis.
Authors: Lin Li , Pan Changqie , Li Xiaoyin , Liu Yantan , Wang Chunlin , Zhao Yang , Shi Min , Liao Wangjun 
Published: September 2018

e15550 Background: Metabolic stress usually occurs in rapidly proliferating cells when energy demand exceeds supply. Interestingly, cancer cells can somehow sustain the stress and get rid of it. The mechanisms remain unclear. Previously we discovered that MACC1 is an oncogene promoting gastric cancer (GC) growth and metastasis. Besides, it is upregulated by metabolic stress and promotes glycolysis [2014 ASCO annual meeting abstract e15054 & Oncogene 2015;34(21)]. In current study, we aim to further discover how it helps GC cell metabolize and metastasis. Methods: MACC1 and its correlated gene expression were analyzed via immunohistochemistry staining in GC patients. The mRNA and protein expressions were evaluated under glucose deprivation-induced metabolic stress in human GC cell lines. Cell metabolism, motility, invasiveness and viability were analyzed in GC cells. Promoter luciferase assay and Electrophoretic mobility shift assay (EMSA) were performed to confirm the transcriptional regulatory signals. Results: MACC1 expression is found to be negatively correlated with DLC3 in GC patients and DLC3 low expression indicates an adverse prognosis. Silencing DLC3 significantly promotes MACC1 expression, while silencing MACC1 showed no influence on DLC3, indicating that DLC3 is an upstream regulator of MACC1. Intriguingly, DLC3 is found significantly downregulated under metabolic stress in GC. Silencing DLC3 promotes GC migration and invasion via epithelial to mesenchymal transition (EMT), whereas overexpressing DLC3 demonstrates opposite functions. Moreover, DLC3 suppresses GC cell glycolysis but increases reactive oxygen species production and the mitochondrial membrane potential, which lead to more apoptosis. These DLC3 suppressive effects on GC are reversed by MACC1. Promoter luciferase assay and EMSA show that DLC3 inhibits MACC1 expression in a transcriptional manner, which is regulated via RhoA/JNK/c-JUN signaling. Conclusions: Metabolic stress transcriptionally upregulates MACC1 expression by suppressing DLC3, which facilitates GC glycolysis and metastasis. DLC3/MACC1 axis is one of the mechanisms that help GC cell escape from metabolic stress.
Treatment patterns, effectiveness, and safety of Trastuzumab in Chinese patients with metastatic gastric cancer: Interim analysis of the EVIDENCE registry study.
Authors: Qin Shukui , Lin Shen , Xu Ruihua , Su Wuyun , Tang Yong , Wang Xin , Xu Jian-ming , Zhou Weiping , Cui Tongjian , Luo Suxia , Wu Xiaohui , Ji Jiafu 
Published: September 2018

e15595 Background: Trastuzumab (TRA) was approved for HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma (mGC) in China in August 2012. However, real-world data on the treatment patterns, effectiveness, and safety of TRA in Chinese patients (pts) with mGC are limited. Methods: EVIDENCE is a prospective, multicenter, non-interventional, registry study of 5 cohorts (NCT01839500). Cohort I enrolled pts with HER2-positive mGC (IHC3+ or IHC2+/ISH+) diagnosed up to 6 months previously. This interim analysis evaluated the effectiveness and safety of TRA in the first 95 pts of cohort I who were treated at 33 hospitals in China between April 2013 and August 15, 2016. Results: 71 of the 95 pts (74.7%) were male and the median age at diagnosis was 61 years (range 21-87 years). At the data cut-off date, the preliminary median PFS was 9.5 months (95% CI 7.6-11.8 months), and the preliminary median overall survival (OS) was 30.0 months (95% CI 18.6-38.7 months). 90 pts were treated with TRA + chemotherapy; XELOX (capecitabine + oxaliplatin) (28 pts, 31.1%) and capecitabine (20 pts, 22.2%) were the mostly commonly used regimens with TRA for first-line therapy, while paclitaxel was most commonly used with TRA for second-line (7.8%) and third-line (2.2%) therapy. TRA was also used in neoadjuvant (7 pts) and adjuvant (8 pts) settings prior to recurrence. During follow-up, 48 pts had progressive disease, and 21 (43.8%) received TRA beyond progression; 7 pts (14.6%) continued TRA after their 2nd disease progression. TRA-related adverse events (AEs) were observed in 26 pts (27.4%), including neutropenia in 10 pts (10.5%), thrombocytopenia in 9 (9.5%), and a decreased white blood cell count in 7 (7.4%). Only 6 pts (6.3%) experienced grade > = 3 TRA-related AEs (which included neutropenia and thrombocytopenia). Conclusions: In routine clinical practice in China, TRA combined with various chemotherapy regimens proved effective and well tolerated for treating mGC HER2+ pts. In addition to its use in palliative settings, TRA was also used as neoadjuvant/adjuvant treatment. Clinical trial information: NCT01839500.
Survival of elderly patients with advanced hepatocellular carcinoma with distant metastasis in pre- and post- sorafenib era: A population based study.
Authors: Budhathoki Nibash , Shah Binay Kumar 
Published: September 2018

e15643 Background: Sorafinib was approved for advanced hepatocellular carcinoma in 2007. This study was conducted to study relative survival in elderly patients with advanced hepatocellular carcinoma in presorafinib and sorafinib era. Methods: We selected elderly patients (age ≥ 65 years) with advanced hepatocellular carcinoma (distant metastasis based on SEER’s LRD staging) from the Surveillance, Epidemiology, and End Results (SEER) database diagnosed during January 2000 to December 2013. We calculated one year and five year relative survival rates in pre- (2000-2006) and post- sorafinib (2008-2013) era by sex and ethnicity (Caucasians, African-Americans (AA) & Other) using SEER*Stat software. Results: There were total of 1533 patients in presorafinib era and 1694 patients in postsorafinib era. Of the total population, 71.30% were male and 28.70% female, 71% were Caucasian, 10% African-American and 19% were other race. Median age of patients was 73 years (65-99 years) and medial follow up period was 3 months (0-167 months) Survival rates improved significantly from pre- to post- sorafenib era (1 year RS: 10.60% ±0.80% vs 12.10±0.90%, p value = 0.001; 5 year RS: 1.10%±0.30% vs 1.8%±0.6%, p value = 0.001 ). The survival rate improved significantly for male (1 year RS: 11.60%±1.00% vs 12.30%±1.00%, p value = 0.006; 5 year RS: 1.00%±0.40% vs 1.3%± 0.6% , p value = 0.007) and Caucasian (1 year RS: 10.60%±1.00% vs 12.60%±1.10%, p value = 0.0008; 5 year RS: RS = 1.20%±0.40% vs 1.4%±0.7%, P value = 0.001) patients in post sorafenib era. There was no significant difference in the survival rates among any other cohorts examined.However in black (N = 153 vs 158 , RS = 6.80%±2.10% vs 7.80%±2.40% , p value = 0.77) or other races (N = 311 vs 311, RS = 12.20%±1.90% vs 12.80%±2.10%, p value = 0.30 ) , no significant improvement in survival was noted. Conclusions: Our study showed that relative survival rates of elderly patients with advanced hepatocellular carcinoma with distant metastasis has improved in the post-sorafenib compared to pre-sorafenib era. The improvement in survival is limited to male and Caucasian patients.
Down-regulation of neutral sphingomyelinase 1 to predict prognosis in hepatocellular carcinoma.
Authors: Lin Minglin , Liao Weijia , Jin Junfei 
Published: September 2018

e15647 Background:Neutral sphingomyelinase 1 (NSMase1) catalyzes sphingomyelin to generate ceramide and mediates tumor cell apoptosis; however, the roles of NSMase1 in hepatocellular carcinoma (HCC) remain unclear. This study aims to evaluate the clinical value and prognostic significance of NSMase1 in HCC. Methods:A total of 142 patients who underwent radical hepatectomy were involved in this study. The expression of NSMase1 in HCC tissues and adjacent nontumorous liver tissues (ANLTs) was detected by quantitative real-time polymerase chain reaction and immunohistochemistry, and the association between NSMase1 expression and clinicopathologic features as well as prognosis of HCC patients was analyzed. Univariate and multivariate analyses were applied to identify independent prognostic factors. Results: NSMase1, at both mRNA and protein levels, was significantly decreased in HCC tissues compared to ANLTs. Low NSMase1 expression was associated with tumor size ( P= 0.029), TNM stage ( P= 0.040) and recurrence ( P= 0.006). Statistically, both the overall survival (OS) and disease-free survival (DFS) of low NSMase1 expression group were significantly shorter compared with high NSMase1 expression group ( p= 0.001; p= 0.001; respectively). Remarkably, the multivariate analysis showed that the low NSMase1 expression was an independent prognostic factor for OS (hazard ratio = 1.840; 95% confidence interval, 1.178-2.875, P= 0.007) and DFS (hazard ratio = 1.706; 95% confidence interval, 1.096-2.655, P= 0.018) in all enrolled HCC patients. Conclusions: NSMase1 down-regulation might actually serve as an independent prognostic factor for HCC patients. However, the roles of “NSMase1-ceramide” metabolic network in HCC deserve further studies.
Correlation of mesothelin expression and CD8 tumor infiltrating lymphocytes with prognosis in cholangiocarcinoma.
Authors: Kunk Paul Raymond , Obeid Joseph Mounir , Winters Kevin , Pramoonjago Patcharin , Brockstedt Dirk G. , Whiting Chan C. , Enstrom Amanda , Stelow Edward B , Bauer Todd W. , Slingluff Craig L. , Rahma Osama E. 
Published: September 2018

e15650 Background: Cholangiocarcinoma (CC) is a rapidly progressing malignancy with an unmet treatment need. Little is known about the CC tumor immune microenvironment or about relevant antigenic targets. We hypothesized that lack of T cell infiltration or PD-L1 expression may identify patients at high risk of death, and that mesothelin may be a relevant antigenic target. Methods: A retrospective analysis was conducted of CC tumors at the University of Virginia from 2000-2014. TMAs were constructed of 3-4 cores from each tumor and were stained by IHC for CD4 and CD8 tumor infiltrating lymphocytes (TILs), mesothelin and PD-L1. TMAs were scanned using the Leica SCN400 and analyzed using the Digital Image Hub software. Stain intensity thresholds for defining positive cells were determined by two users and recorded as an average of all cores from each tumor. Mesothelin and PD-L1 expression were measured as a percentage of positive tumor cells. TILs and protein expression were analyzed for association with overall survival, grouped as high or low expression based either on the median or the 33rdpercentile. Correlation with overall survival was assessed using a log rank test and a classification and regression tree with p-values < 0.05 being considered statistically significant. Results: Ninety-nine tumors were available for analysis: 26 intrahepatic, 37 hilar, and 36 distal. PD-L1 and mesothelin expression > 1% of tumor cells were found in 16% and 92% of tumors, respectively. CD4 and CD8 TILs were found in nearly all tumors (98% and 96%), with the majority showing intraepithelial CD4 and CD8 infiltration (73% and 68%). There were no significant associations between survival and PD-L1, mesothelin, or CD4 and CD8 infiltration. However when considered together, the group with low mesothelin/low CD8 (each below 33rdpercentile) had worse survival (9.1 months) compared to high mesothelin/high CD8 (25 months), high mesothelin/low CD8 (30.1 months) and low mesothelin/high CD8 (26.1 months), p = 0.015. Conclusions: CC tumors that lack CD8 infiltration and mesothelin expression have a poor prognosis. Mesothelin represents an attractive target in cholangiocarcinoma, opening the door for future immunotherapy for CC.
Efficacy and safety of vitamin K with sorafenib combination treatment against hepatocellular carcinoma: Open-label, randomized phase II study.
Authors: Haruna Yoshimichi , Inoue Atsuo , Kawamoto Seiichi 
Published: September 2018

e15665 Background: Some animal studies showed that vitamin K enhances anti-cancer action of sorafenib for hepatocellular carcinoma (HCC). Our previous examination suggested that it might be because the vitamin K suppresses des-γ-carboxy prothrombin (DCP) production of tumor cells under ischemic status caused by sorafenib. The DCP is known as a tumor growth factor and a tumor angiogenesis factor. In order to clarify the efficacy and safety of vitamin K dosing in sorafenib treatment, we have performed a single center, open label, randomized, phase 2 study. Methods: Forty-four patients with advanced HCC were studied. They were randomly assigned in a 1:1 ratio, to receive vitamin K + sorafenib or to receive sorafenib alone, stratified according to macrovascular invasion and/or extrahepatic spread. The anti-cancer outcome was evaluated by modified RECIST. Results: There was no significant difference between the two groups in baseline characteristics (gender, age, Child-Pugh status and background liver disease). The progression-free survival (PFS) was significantly prolonged in the vitamin K + sorafenib group compared with sorafenib alone group (median time 3.7 months vs. 1.5 months, P = 0.001, hazard ratio 0.35). The disease control rates were 55% in vitamin K + sorafenib group and 18% in sorafenib alone group (P = 0.012). On the other hand, median overall survival (OS) times were 12 months in vitamin K + sorafenib group and 11.5 months in sorafenib alone group (P = 0.27, hazard ratio 0.67). However, 5 patients (23%) of 22 survived for more than 21 months in the vitamin K + sorafenib group, while one (5%) of 22 did in sorafenib alone group. There was no significant difference in incidence of adverse events between the two groups. Conclusions: The vitamin K dosing safely improved anti-cancer outcome of sorafenib treatment against advanced HCC. Clinical trial information: 000007855.