bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of peripheral blood markers of DNA damage and immune response with chemoradiation response in patients with locally advanced rectal cancer.
Authors: Arora Sanjeevani , Demidova Elena , Avkshtol Vladimir , Lesh Randy , Browne Amanda J , Handorf Elizabeth A. , Golemis Erica , Meyer Joshua E.
Published: May 2019

e15109

Background: Approximately 60% of newly diagnosed rectal cancers are locally advanced. The standard of care for these malignancies is neoadjuvant chemoradiation therapy (nCRT) followed by surgery. Unfortunately, only approximately 20% of patients experience a complete response, but all are at risk for toxicity. There are no biomarkers to predict who will derive the greatest benefit from CRT. We hypothesized that inherent DNA damage recognition and repair (DNA-DRR) capacity contributes to CRT response in rectal cancer. Methods: We used primary peripheral blood lymphocytes (pPBLs) from rectal cancer patients to study differences in DNA-DRR capacity. The blood samples used were either drawn prior to nCRT or post a standard course of ~5.5 weeks of nCRT. We used immunofluorescence and Luminex-based multianalyte approaches to study DNA-DRR capacity in pPBLs. To determine if the tested biomarkers correlated with CRT response, we segregated patients by neoadjuvant rectal (NAR) score, a validated surrogate endpoint in rectal cancer. Results: Using pPBLs, we found that a subset of patients had elevated phosphorylated histone H2AX (γ-H2AX) foci, a well-described marker of DNA double strand breaks. We found that poor responders (PoR; NAR score > 14; n = 21) had lower γ-H2AX foci then complete responders (CR; NAR score < 1; n = 21) (P < 0.0001, Kruskal-Wallis test). We also did not observe any significant differences in γ-H2AX foci from pPBLs drawn prior to CRT versus post nCRT (p = 0.519, n = 11, Wilcoxon rank sum test). Next, by multianalyte testing, we found that a combined score derived from six DNA-DRR markers (ATR, MDM2, phosphorylated forms of H2AX (γ), p53, Chk1, Chk2) strongly correlated with CR (p < 0.001). Finally, by multianalyte testing, we also detected a serum signature of inflammatory markers that significantly correlated with CRT response (p < 0.05). Conclusions: Our data suggest that rectal cancer patients who differ in their response to CRT differ in global, inherent DNA-DRR capacity, suggesting that DNA-DRR capacity in pre-treatment pPBLs can form the basis of a predictive biomarker. This predictive capacity may reflect underlying epigenetic or genetic differences, or inflammatory state. Validation and further development of this novel assay is warranted, as it has the capacity to substantially improve patient selection in an era with growing treatment options for these patients.
Sensitive detection of microsatellite instability in tumors and liquid biopsies using nuclease-based enrichment.
Authors: Ladas Ioannis , Mamon Harvey J. , Ng Kimmie , Yu Fangyan , Leong Ka Wai , Kulke Matthew H. , Makgrigiorgos G. Mike
Published: May 2019

e15117

Background: The role of MSI in colorectal cancer (CRC) is well characterized, and tumors are classified as MSI-High or MSI-Stable by screening specific microsatellites. MSI-H reflects mismatch repair deficiency, is predictive for CRC therapy outcome in chemotherapy and immunotherapy and has a higher 5-year survival. While tumor testing is the gold standard, a convenient approach to screen for MSI before and during cancer treatment is screening circulating DNA (liquid biopsy) using a blood draw. However, using electrophoresis or next generation sequencing for MSI detection presents challenges at low levels of MSI due to polymerase slippage (‘stutter’) that generate high false positive rates at positions of homo-polymers. We present a new approach for enrichment of altered micro-satellites prior to DNA-amplification thereby reducing stutter from wild-type alleles and facilitating detection of MSI. The method employs a double-strand-DNA-specific nuclease and overlapping oligonucleotide-probes interrogating multiple micro-satellite targets (‘NaMe-PrO’, nuclease-assisted minor-allele enrichment with probe-overlap). Following DNA denaturation, the probes form double-stranded regions with their targets, thereby guiding nuclease digestion to selected sites. Microsatellite indels create ‘bulges’ that inhibit digestion, thus subsequent amplification yields DNA with microsatellite alterations enhanced at multiple targets. Methods: We first validated the method by evaluating 5 MSI targets simultaneously, NR27, NR21, NR24, BAT25 and BAT26 using DNA from tumor biopsies and circulating-DNA from colorectal cancer patients. The technique detected microsatellite alterations down to 0.01% altered allele frequency, thus improving detection sensitivity by > 100-fold relative to current approaches. Next, a clinical study was performed. We screened microsatellites in circulating DNA from groups of early stage colon cancer patients with known MSI status in the tumor. Results: Combination of NAME-PRO with capillary electrophoresis demonstrated 100% sensitivity (10/10) and 90% specificity (9/10) in detecting MSI status in the blood, thereby opening the possibility of early cancer detection for MSI positive tumors, or for application in minimal residual disease detection. Conclusions: We anticipate application of this highly- multiplex-able method either with standard 5-plex reactions or with NGS-based detection of MSI on thousands of targets to enable sensitive detection in tumors and liquid biopsies.
Incidence of venous thromboembolic disease (VTE) in a cohort of patients with colorectal cancer (CRC) according to KRAS, NRAS and BRAF status.
Authors: Garcia-Alfonso Pilar , Ortega Morán Laura , Gallego Gallego Iria , García González Gonzalo , Torres Pérez-Solero Gabriela , Aguilar Caballero Iker , de Toro Carmena María , Morón García Blanca , Tirado Anula Victoria , Gutiérrez Alonso Natalia , Bringas Beranek Marianela , Soto Alsar Javier , Sandoval García Carmen , Aguado Orihuela Gema , Martínez Delfrade Íñigo , Blanco-Codesido Montserrat , Calvo Ferrándiz Aitana , Martin Miguel , Muñoz Martín Andres J.
Published: May 2019

e15136

Background: A recent study has suggested that KRAS mutation could increase the risk of VTE in patients with CRC. The role of others biomarkers, such as BRAF, in this setting is unknown. The aim of this study is to analyze the incidence of cancer-associated thrombosis in a cohort of patients with CRC based on KRAS, NRAS and BRAF status. Methods: We performed a retrospective review of patients with metastatic CRC and KRAS/NRAS/BRAF status known, attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Madrid, Spain) between January 2010 and January 2018. Results: 194 patients were identified and included in the analysis. The median age was 64 years (18-86). Most were metastatic at diagnosis (58.1%). Khorana’s predictive model: low-risk 67.7%, intermediate-risk 31.0%, high-risk 2.3%. The median follow-up was 35 months (2-240). 41 patients (21.1%) experienced VTE (11 pulmonary embolism, 15 lower extremity deep-vein thrombosis, 12 visceral vein thrombosis, 2 catheter-related thrombosis, 1 unknown). Most had metastatic disease at the moment of VTE (90.2%). 40% of the events occurred at the time of diagnosis or within the first 6 months. 65% were incidental events. Khorana’s predictive model in VTE patients: low-risk 63.4%, intermediate-risk 24.5%, high-risk 7.3%. According to biomarkers, the incidence was 19.1% (13/68) in KRAS/NRAS mutated patients, 28.6% (6/21) in BRAF mutated patients and 21% (22/105) in triple-wild-type patients. 6/38 patients (15.8%) developed recurrent thrombosis. In the univariate analysis, the presence of chronic kidney disease (p = 0.022), ECOG ≥ 2 (p = 0.038) and high-risk Khorana score (p = 0.011) were significantly associated with increased risk of VTE. Metastatic disease showed a trend towards the statistical significance (p = 0.053). In the multivariate model, including this variables, age, sex and biomarkers, only ECOG ≥ 2 remained independent predictor of VTE (OR 8.73; CI 95% 1.32-57.82; p = 0.025). Conclusions: The biomarkers have not been associated with the risk of VTE. We have observed a high incidence of VTE in BRAF mutated patients that should be investigated in further studies.
RAS analysis of circulating tumor cells from advanced colorectal cancer using BEAMing technology.
Authors: Cabezas-Camarero Santiago , García-Barberán Vanesa , De la Orden-García Virginia , Mediero-Valeros Beatriz , Paz Cabezas Mateo , López-Alfonso Ana , Sánchez Ruiz Antonio Carlos , Ruiz-Casado Ana , Díaz-Millán Isabel , Sastre Javier , Sotelo Lezama Miguel , Diaz-Rubio Eduardo
Published: May 2019

e15151

Background: RAS mutations predict a lack of response to anti-EGFR therapies in metastatic colorectal cancer (mCRC). BEAMing technology is useful for detecting hot-spot mutations in ctDNA in mCRC. Analysis of these mutations in DNA from Circulating Tumor Cells (CTC) may increase the predictive value in mCRC patients (pts). Our aim was to explore the feasibility of studying RAS status using BEAMing in DNA from CTC. Methods: First, spiking experiments (SE) using wild-type (WT) and KRAS-mutated (MUT) cell lines were performed to establish the limit of detection (LOD) for RAS analysis with BEAMing. Second, SE were performed with CTC collected by CellCelector (removes non-CTC background achieving 100% purity of CTC). Finally, BEAMing was used for RAS analysis in ctDNA and in DNA from CTC isolated either with IsoFlux or with CellCelector in 9 mCRC pts with confirmed RAS mutation in primary tumor. Total DNA from CTC was preamplified using RepliG. Results: In SE, 10 and 5 KRAS MUT-cells using different backgrounds of WT-cells (10-0.2% MUT-cells) were detected using BEAMing. However, 3 and 1 MUT-cells (0.009-0%) were not detected. In SE of CTCs collected with CellCelector, BEAMing detected KRAS mutations with 50, 20, 10, 6, 4, 2 and 1 cell (MAF: 23.8%±3.8). A mutation (codon 13) was detected in CTC from one patient positive in tissue and ctDNA (CellCelector; 15 CTCs; MAF: 11.4%). Discordant results were found in 8 patients when CTCs were isolated using Isoflux (min: 0, max: 9 CTCs). CTC from another patient were possibly mutated but WT in ctDNA. Conclusions: This pilot study indicates that RAS mutations can be detected in CTCs using BEAMing. Reducing the non-CTC cellular background may be needed in cases with low CTC number. Molecular information provided by CTC and ctDNA may prove complementary and useful for taking therapeutic decisions in mCRC. These results merit confirmation in larger, prospective studies.
Association between primary tumor site, perioperative CEA ratio, smoking status, and overall survival in patients with colorectal cancer.
Authors: Odeny Thomas A , Farha Nicole , Hildebrand Hannah , Allen Jessica , Vazquez Wilfred , Martinez Maximillian , Saeed Anwaar , Kasi Anup
Published: May 2019

e15156

Background: There are differences in the incidence, clinical presentation, molecular pathogenesis and outcome of colorectal cancer (CRC) based on tumor location. Emerging research suggests that perioperative carcinoembryonic antigen (CEA) ratio (post-op/pre-op CEA) is a prognostic factor for CRC patients. We aimed to determine the association between tumor location, CEA ratio, smoking status and overall survival (OS) among patients with CRC. Methods: We analysed 323 patients who underwent resection for CRC at KUMC. After excluding those without pre- or post-operative CEA data, 162 patients were classified as either high ( > = 0.5) or low ( < 0.5) ratio. Primary outcomes were: 1) OS stratified by tumor location; 2) OS stratified by CEA ratio; and 3) whether the association between CEA ratio and OS differed by tumor location, after adjusting for stage and smoking status. Kaplan-Meier method was used to estimate survival rates, and Cox proportional hazards models for multivariate analysis. Results: The median age was 63 years (inter-quartile range 53-72), 61% male, 43% smokers, 73% left-sided tumors, median pre-operative CEA was 3.0 (IQR 1.5-7), and 64% had CEA ratio > = 0.5. The OS rates were 85.7% and 91.9% in patients with left-sided vs right-sided tumors respectively (log-rank p-value = 0.9). The OS rates were 83.5% and 91.5% in patients with high vs low CEA ratios respectively (log-rank p-value = 0.3). The effect of CEA ratio on OS was significantly different when stratified by tumor location (p-value for interaction < 0.001). However, in the stratified analysis, the n was too small to permit further inferential analysis. In multivariate analysis, both tumor location (HR 0.6; p = 0.5) and CEA ratio (HR 1.5; p = 0.5) were not significantly associated with OS after adjusting for smoking status and tumor stage. Smoking was significantly associated with higher rates of death (HR 3.9; p = 0.04) when adjusted for tumor location, CEA ratio, and tumor stage. Conclusions: There was no difference in OS between left versus right-sided tumors. The association between CEA ratio and OS was significantly modified by tumor location. However, to attribute this modification to left vs right warrants validation in a larger cohort as our sample size was limited. Smoking increases mortality irrespective of right vs left sided CRC.
The prognostic significance of magnetic resonance imaging (MRI) following neoadjuvant concurrent chemoradiation (NCCR) in patients with locally advanced rectal adenocarcinoma (LARA).
Authors: Fahmawi Yazan , Smith Clayton , Grimm Leander , Khullar Shikha , Rider Paul , Hunter John , Iliff Greire , Mneimneh Wadad , Roveda Kelly , Wang Bin , Prodduturvar Pranitha , Campos Yesica , Mehta Ansh , McCormick Ben , Khushman Moh'd M.
Published: May 2019

e15166

Background: In patients with locally advanced rectal adenocarcinoma (LARA), the response to neoadjuvant concurrent chemoradiation (NCCR) correlates with long-term outcomes. Neoadjuvant rectal (NAR) score ([5 ypN - 3 (cT - ypT) + 12]2/9.61) is a novel short-term surrogate endpoint for disease free survival (DFS) and Overall survival (OS). The prognostic significance of magnetic resonance imaging (MRI) findings following NCCR is yet to be explored. Here, we evaluated the agreement between post NCCR MRI yT and yN and pathological ypT and ypN. In addition, we calculated the post NCCR MRI NAR (mNAR) score using the MRI yT and yN ([5 yN - 3 (cT - yT) + 12]2/9.61) and explored its prognostic significance. Methods: Between 2014 and 2018, all patients with LARA were identified. Among those, 43 patients received NCCR, had post NCCR MRI and underwent surgical resection. Weighted Kappa was used to measure the agreement between post NCCR MRI yT and yN and pathological ypT and ypN. Paired t-test was used to compare the means between NAR and mNAR scores. NAR and mNAR scores were classified as low ( < 8), intermediate (8-16) and high ( > 16). DFS and OS were analyzed using Kaplan-Meier curves. Results: In our cohort, the agreement was slight between post NCCR MRI yT and Pathological ypT (p = 0.111), and fair between post NCCR MRI yN and pathological ypN (0.278). The mean NAR score was 16 and the mean mNAR score was 20 (p = 0.0079). Low-intermediate and high NAR scores were seen in 31 (72%) and 12 (28%) patients respectively. However, low-intermediate and high mNAR scores were seen in 20 (47%) and 23 (53%) patients respectively. The median DFS in patients with low-intermediate and high NAR scores was not reached and 30 months (p = 0.00063) respectively. The median OS in patients with low-intermediate and high NAR scores was not reached and 40 months (p = 0.00056) respectively. The median DFS in patients with low-intermediate and high mNAR scores was not reached in both groups (p = 0.058). The median OS in patients with low-intermediate and high mNAR scores was not reached in both groups (p = 0.15). Conclusions: Post NCCR MRI yT and yN had slight and fair agreements with ypT and ypN respectively. In our cohort, there was a difference between NAR and mNAR. NAR demonstrated prognostic significance for DFS and OS, while mNAR did not at the time of analysis.
Stage of disease and initial surgical intervention in colon cancer patients: An exploratory analysis of the SEER database.
Authors: Denneny Rachel Gray , Delgado David J. , Nguyen Victoria , George Brandon , Mitchell Edith P. , Subramoney Jay
Published: May 2019

e15170

Background: Colorectal cancer (CRC) is the third-leading cause of cancer-related deaths in the United States. CRC’s decreasing mortality rate has been attributed to increased screening and early detection. This study explored the association between stage at diagnosis with initial surgical intervention for patients (pts) with colon cancer (CC), using data extracted from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data. Methods: Retrospective cohort study using the SEER database from 1998-2015. Included were pts with CC, aged 18 or older, and with disease in either the proximal or distal colon. Pts with rectal cancer were excluded. Stage was defined as local, regional versus distant, and initial treatment was defined as none versus any surgery. Multivariable logistic regression was used to describe the association between stage and initial surgical intervention, controlling for pts and tumor characteristics. Results: 354,640 CC pts were included in this analysis: 46%(localized), 36%(regional), 18%(distant), and 92.45%(received surgery). Multivariable analysis indicated that pts with regional disease were more likely to receive initial surgical intervention compared to those with localized disease (OR = 4.49,95% CI = 4.24,4.77). Pts with distant stage of disease were less likely to receive surgery compared to those with localized disease (OR = 0.11,CI = 0.11,0.12). Other factors significantly associated with an increased likelihood of initial surgical intervention included mucinous adenocarcinoma histology, papillary adenocarcinoma histology, having a partner relationship, adenomatous polyps on histology, white race, female sex, and lesion location in the proximal colon. Additionally, African American pts were significantly less likely than white pts to receive surgery as an initial intervention for colon cancer (OR = 0.76,CI = 0.73,0.79). Conclusions: We conclude that distant stage at diagnosis was associated with reduced odds of initial surgical intervention. This highlights the importance of screening and early detection to identify pts with operable disease and as a method of decreasing mortality.
Risk factors predicting colorectal cancer recurrence in a Latin American population.
Authors: Leon Jorge , Namuche Fernando , Montenegro Paola Catherine , Flores Claudio J.
Published: May 2019

e15180

Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. In our population more than 80% of patients are stage I-III. Recurrence is one of the most important factors to consider in the survival of CRC patients. The aim of this study was to identify which factors influence in the recurrence of CRC in our population. Methods: We retrospectively reviewed the electronic medical records of 506 patients with stage I-III CRC from one specialized Peruvian cancer center between 2006 and 2016. Survival analysis (with recurrence as the event to evaluate) was performed with Kaplan Meier curves and Long-rank test. We use a preliminary univariate analysis to do the multivariate analysis with Cox regression. We performed a ROC curve analysis to determine an appropriate cut-off value for the tumor size (≥4.2). Results: In the univariate analysis we found that sidedness, tumor size (cut-off ≥4.2), CEA, lymph node involvement, stage, histological grade, LVI, PNI, and chemotherapy were statistically significant. In the multivariate model, tumor size [HR, 1.462; 95% CI, 1.065-2.217; p<0.05], lymph node involvement [HR, 0.136; 95% CI,0.41-0.447; p<0.001], and stage III [HR, 0.003; 95% CI, 0.263-0.758; p<0.05] retained a significant association and were independent factors with relapse disease. Conclusions: In stage I-III CRC pts it is important to evaluate tumor size, lymph node involvement and clinical stage as they are possible prognostic factors that will help our diagnosis and treatment along with other standard features.
Regorafenib-associated adverse event management in colorectal and gastrointestinal stromal cancer patients: A systematic review and meta-analysis.
Authors: Xie Ganfeng , Gong Yuzhu , Wu Shuang , Li Chong , Yu Songtao , Wang Zhe , Chen Jianfang , Zhao Quanfeng , Li Jianjun , Liang Houjie
Published: May 2019

e15181

Background: Adverse events (AEs) observed in regorafenib treated metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumors (GIST) often require treatment modification. However, due to dearth of literature reporting AE management, we performed a systematic review and meta-analysis to assess the success of different methods of managing regorafenib-associated AEs and also determined risk factors of the AEs. Methods: A comprehensive search was conducted in PubMed, Embase and Cochrane Library, to retrieve RCTs and observational studies published from inception to May 2018, discussing the management methods of AEs with rate of improvement and risk factors of the AEs. The success rate for each method was evaluated as percentage and compared using chi2-test. Risk factors were presented using Pearson correlation. Results: We identified 28 studies for this analysis (N = 3120 patients; 305 GIST and 2,815 mCRC). Methods used for management included intermittent dose withdrawal (66.7%), delayed treatment schedules (54%), dose reductions (41%), complete drug withdrawal (19%) and preventive measures like dexamethasone and lactose administration or surgery (63.7%). Reduction or improvement in AEs was observed in 57%, 17% and 100% patients after lowering the initial dose, intermittent withdrawal of regorafenib and using other preventive measures, respectively. Patients aged < 65 years had significantly higher occurrence of AEs compared with patients aged ≥65 years (27.6% vs. 71.3%, p = 0.001). A significant positive correlation was observed between the occurrence of all and grade 3AEs with 160mg dose (r = 0.967 and 0.746 respectively; p = 0.001 for both) with no significant correlation observed for 120-mg and 80-mg doses and any gender. Conclusions: Initiating dose of 160mg is a major risk factor for regorafenib associated AEs in mCRC and GIST patients; with intermittent dose reduction, withdrawal, and delayed treatment being the commonly used management strategies. To allay the risk of AEs and maintain the efficacy, 120mg initial dose is recommended for mCRC and GIST patients. However, further studies are required to confirm the results.
Relationship between PET response and pathologic response in distal esophageal/gastroesophageal junction cancers: A provincial population-based analysis.
Authors: Yu Irene S. , Liu Shiru Lucy , Zhao Yizhou , Lau Sally CM , Schellenberg Devin , Gill Sharlene , Lim Howard John
Published: May 2019

e15506

Background: The utility of PET scans (PETs) to predict outcomes after neoadjuvant treatment of DE/GEJ cancers is unclear. We aimed to explore the relationship between PET response and pathologic/clinical outcomes in a real-world setting. Methods: Patients (pts) with DE/GEJ cancer treated with curative intent perioperative chemotherapy or neoadjuvant chemoradiation followed by surgery in British Columbia from 2009-2018 were included. Retrospective chart review was conducted; pts were stratified into PET responders (R, ≥ 35% decrease in max SUV) or PET non-responders (NR, < 35%) groups. Chi-square and Kaplan Meier were used to test for associations between variables and outcomes. Results: Of 576 pts with locally advanced DE/GEJ cancers, 232 pts were eligible for analysis. Treatment regimens comprised of CROSS (72%), MAGIC (24%) and FLOT (4%). Median age was 66 (IQR 57-72), 85% male, 91% ECOG 0/1, 62% GEJ involvement, and 81% adenocarcinoma histology. Characteristics and treatment regimens were balanced between the PET-R and PET-NR groups (all p>0.05). Median time from end of treatment to PETs was 30 days (IQR 22-36); 67% were PET-R. Pathologic complete response rates (14% vs 13%, p=0.079) were similar for PET-R vs PET-NR, respectively. Discordance rate was 34% between PET vs pathologic response (Table). Aborted surgery rate was higher in the PET-NR group (8% vs 3%, p=0.03); 70% of aborted cases were due to peritoneal involvement. Median overall survival was similar between the groups (PET-R 31.5 mo vs PET-NR 36.1 mo, p=0.616). Conclusions: In our population-based cohort, PET response did not demonstrate prognostic utility. PET-NR were more likely to have their surgeries aborted. The predictive ability of PET in determining surgical resectability should be further investigated to avoid unnecessary high morbidity surgeries.[Table: see text]
Decreased risk of esophageal squamous cell carcinoma among metformin users in a population-based cohort study.
Authors: Wang Qiao-Li
Published: May 2019

e15507

Background: Metformin, mainly used in the treatment of diabetes, may prevent various types of cancer, but no study has specifically examined its potential influence on the risk of esophageal squamous cell carcinoma, the major histological type of esophageal cancer. The aim of this study was to determine the association between metformin use and esophageal squamous cell carcinoma. Methods: This was a nationwide population-based prospective cohort study conducted in Sweden in 2005-2015. Among 8.4 million participants identified from the Swedish Prescribed Drug Registry, 411,603 (5%) were users of metformin. The metformin users were compared with 10 times as many frequency-matched non-users of metformin (n = 4,116,030) by age and sex. Multivariable cause-specific proportional hazards model was used to calculate hazard ratios (HR) with 95% confidence intervals (CI), adjusted for age, sex, calendar year, place of residence, tobacco smoking, alcohol overconsumption, and use of non-steroidal anti-inflammatory drugs or statins. Results: The incidence rates of esophageal squamous cell carcinoma were 3.5 per 100,000 person-years among the metformin users and 5.3 per 100,000 person-years in the non-users. Metformin users overall were at a decreased risk of esophageal squamous cell carcinoma compared with non-users (adjusted HR 0.68, 95% CI 0.54-0.85). The decrease in risk was more pronounced in new metformin users who were 56 years old when they started their metformin therapy (HR 0.44, 95% CI 0.30-0.65). Conclusions: Metformin therapy may decrease the risk of developing esophageal squamous cell carcinoma.
Association of CDH1 mutation with prognosis in gastric adenocarcinoma.
Authors: Yu Xiangyang , Yang Shimin , Du Rong , Zhang Jingbo , Fang Nan , Wang Junpo , Tang Yu , Wang Jianwei , Wu Qixi
Published: May 2019

e15514

Background: Stomach cancer is a major cause of cancer death in East Asia. The purpose of this study was to find a predictive marker to estimate the prognosis of stomach cancer. Methods: In this study, a total of 34 gastric cancer patients receiving therapy in Tianjin Nankai Hospital were enrolled. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue sections, including carcinoma and pericarcinous tissues. Targeted regions of 549 cancer-associated genes were amplified by PCR, barcoded and sequenced using an Illumina Next-Seq 500 platform. Results: 25/34 patients had tumor metastasis. 135 non-silent mutations in 62 genes were detected in 27 tumor samples, while 7 patients’ samples had no mutation detected. CDH1, BRCA2 and SMAD4 gene mutations only occurred among metastasis patients. CDH1, BRCA2 and KRAS gene mutations are associated with a lower overall survival rate. Among them, 5 patients had a CDH1 mutation, including one splicing mutation, three frameshift mutations, one non-frameshift mutation and two non-synonymous mutations. All five patients had tumor metastasis, with the survival time less than 17 months, compared with all patients’ average overall survival of 22 month. Conclusions: Previous studies showed that mutation in CDH1 is linked to gastric cancer (GC) susceptibility and tumor invasion. Our results indicated that the mutation of CDH1 was also associated with the prognosis of gastric adenocarcinoma (P < .01) and was an independent factor (P < .05).
Association between molecular subtype of esophageal squamous cell carcinoma and survival of patients.
Authors: Kutilin Denis S. , Kit Oleg Ivanovich , Maksimov Aleksey Yurievich , Petrusenko Natalia A. , Myagkova Tatiana Yu. , Kozhushko Mikhail A , Sanamyants Sergey V. , Kolesnikov Evgeniy N.
Published: May 2019

e15520

Background: Esophageal squamous cell carcinoma (ESCC) comprises a group of heterogeneous tumors with various prognoses which does not depend on clinical signatures (TNM, tumor location). In recent years, different molecular subtypes of ESCC have been identified in different populations; however, such studies have not been conducted in the population of Southern Russia. The purpose of the study was the molecular typing of ESCC in patients of the Southern Russia, and the assessment of survival of patients with different molecular subtypes of ESCC. Methods: Tissue sections from FFPE blocks from 124 ESCC patients were studied. Tumor and normal cells were isolated using laser microdissection (Palm MicroBeam, Carl Zeiss). Molecular typing of ESCC was performed by the determination of copy number variation (CNV) of 8 genes ( CUL3, ATG7, SOX2, TP63, YAP1, VGLL4, CDK6, KDM6А) using Real-Time qPCR and 7 somatic mutations (SNP) ( NFE2L2 (c.85G > A), NOTCH1 (c.1379C > T), NOTCH1 (c.1451G > T), ZNF750 (c.414C > A), ZNF750 (c.1621G > A), SMARCA4 (p.Q758*, c.2272C > T), KMT2D (Q5170* , c.15508C > T)) using Sanger direct sequencing method. The differences were assessed by the Mann-Whitney test. For the cluster analysis (Hierarchical Clustering, Euclidean distance), we used R scripts. Survival of patients was analyzed by the Kaplan–Meier method, and differences between survivals in groups were assessed by the log-rank test. Results: Cluster analysis allowed determination of 3 clusters of ESCC samples different in CNV (p < 0.005): cluster 1 (n = 39) demonstrated increased CNV of SOX2, TP63, YAP1 and decreased CNV of CUL3, ATG7 and VGLL4, cluster 2 (n = 82) – increased CNV of CDK6 and decreased CNV of KDM6А, cluster 3 (n = 3) – decreased CNV of ATG7. Samples of cluster 1 showed c.85G > A mutation in the NFE2L2 gene, cluster 2 - c.1379C > T and c.1451G > T in NOTCH1, c.414C > A and c.1621G > A in ZNF750, and cluster 3 - p.Q758* and Q5170* in SMARCA4 and KMT2D, respectively. Thus, we differentiated 3 molecular subtypes of ESCC (1,2,3). Overall survival rates were higher in ESCC2 (16.1±2.0 months), the lowest ones – in ESCC3 (0.88±0.56 months), with intermediate values in ESCC1 (4.6±0.74 months). Differences between the groups were statistically significant (p = 0.00001). Conclusions: Based on the differential distinctions in SNP and CNV of the genes, we verified 3 molecular subtypes of ESCC with different overall survival of patients.
Can hormone receptors prevent metastatic spread of gastric cancer?
Authors: Kaplieva Irina V. , Kit Oleg I. , Frantsiyants Elena M. , Bandovkina Valeria A. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Samoylenko Nikolay S. , Aleynov V. I. , Tishchenko Irina S. , Duritskiy Maksim N.
Published: May 2019

e15527

Background: The primary tumor and associated but distinct from it premetastatic niches include a number of important participants: immune cells, stromal cells, extracellular matrix and associated effectors, in particular hormone receptors. Cross-interaction between these components is key to tumor progression. The greater omentum and peritoneum are pre-metastatic niches for gastric cancer. The purpose of the study was to analyze levels of steroid hormone receptors in tissues of gastric cancer (GC) and its pre-metastatic niches: the peritoneum (P) and omentum (O). Methods: The main group included 21 patients with metastatic GC T3-4аN0-3M1; the comparison group – 24 patients with non-metastatic GC T3-4аN0-3M0. Tissues of tumors, intact gastric tissues, omentum and peritoneum tissues were studied. The control group included 17 non-cancer patients; omental and peritoneal tissues were studied. Levels of receptors of estrogens (RE-α, RE-β), androgens (RA) and progesterone (RP4) were measured by ELISA. Results: Levels of RE-α in tissue of GC T3-4аN0-3M1 were decreased by 1.7 times (P˂0.05) compared to controls, while in T3-4аN0-3M0 they were increased by 1.2 times (P˂0.05). RE-β and RА did not change in both cases. RР4 in T3-4аN0-3M1 was similar to control levels, and in T3-4аN0-3M0 – was increased by 3.5 times. Levels of RE-α and β, RА and RР4 in O and P in T3-4аN0-3M1 were similar to control levels, and in T3-4аN0-3M0 they were higher: RE-α - by 3.9 and 2.4 times, RE-β – by 2.5 and 1.5 times (P˂0.05), RР4 – by 2.2 and 1.5 times (P˂0.05). RA in O and P in T3-4аN0-3M0 was similar to control levels. Conclusions: Elevated levels of RE-α., RE-β and RR4 in peritoneal and omental tissues can be considered a factor associated with some characteristics of GC metastasis, and protective one at the same time. Obviously, levels of RE-α and RР in O and P correlate with the levels in tissues of GC T3-4аN0-3M0. However, this statement is disputable and requires further confirmation.
Role of angiogenesis factors in formation of metastatic niches.
Authors: Frantsiyants Elena M. , Kit Oleg I. , Kaplieva Irina V. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Dzhenkova Elena A. , Samoylenko Nikolay S. , Gabrichidze Petr N. , Milakin Anton G. , Poluektov Sergey I.
Published: May 2019

e15534

Background: A metastatic niche indicates a particular location with a specific cell type, epidermal-mesenchymal transition proteins and diffuse signals that are necessary for the growth of metastases. The purpose of the study was to determine levels of VEGFs, their receptors and TGFβ1 in tissues of gastric cancer (GC) and its metastatic niches: the peritoneum and omentum. Methods: The main group included 21 patients with metastatic GC T3-4аN0-3M1; comparison group – 17 non-cancer patients. Levels of VEGFA, VEGFC, sVEGFR1, sVEGFR3 and TGFβ1 in tissues were determined by standard ELISA methods. Results: Levels of growth factors in GC tissues were higher than in controls: VEGFA in T3-4аN0-3M1 – by 2.7 times, in T3-4аN0-3M0 – by 2.5 times; TGFβ1 in T3-4аN0-3M1 – by 5.6 times, in T3-4аN0-3M0 – by 3.5 times. VEGFA levels in primary gastric tumors were similar in all patients, while TGFβ1 in T3-4аN0-3M1 was 1.6 times (p < 0.05) higher than in T3-4аN0-3M0. VEGFA levels in T3-4аN0-3M1 exceeded control values: in the omentum – by 2.8, in the peritoneum – by 4.2 times. TGFβ1 in the omentum and peritoneum in T3-4аN0-3M1 was increased by 2.5 and 3.1 times respectively, compared to controls. Statistically significant differences in VEGFA and TGFβ1 levels in the omentum and peritoneum in T3-4аN0-3M0 were not found. Conclusions: GC is characterized by equally elevated levels of VEGFA, regardless of the presence or absence of metastases. In the omentum and peritoneum with metastases, high VEGF levels can be considered as one of the primary factors for the formation of signaling pathways between metastatic tumor cells and local non-tumor cells in premetastatic niches. Levels of TGFβ1 in the omentum and peritoneum increase only in patients with metastases, and in GC tissue they are increased to a greater extent than in patients without metastases. Probably, in case of T3-4aN0-3M0, the factor produced by the primary tumor was insufficient for its paracrine induction in the metastatic niche, and scattered cells could not transit from “sleeping” to the active state.
Targeting of survivin to overcome cisplatin resistance in esophageal adenocarcinoma.
Authors: Douglas Rosalie V. , Stevenson Leanne , Santos Ralph , Cairns Lauren , McCabe Niamh H , Kennedy Richard D. , Blayney Jaine K. , Turkington Richard C.
Published: May 2019

e15535

Background: The incidence of Esophageal Adenocarcinoma (EAC) has risen in the western world but response rates to chemotherapy are low and survival is poor. Increased molecular understanding is needed to develop novel treatments. Methods: Transcriptional profiling of 274 treatment naïve EAC biopsies was performed using the Almac Diagnostics Xcel array™. All patients received platinum-based neo-adjuvant chemotherapy prior to surgical resection at four United Kingdom centers between 2004-2012. Semi-supervised clustering was performed followed by functional enrichment using DAVID. Cluster membership was assessed for independence of prognostic factors using Cox proportional hazards. Candidate targets were identified by siRNA screening in OE33 cells. Treatment with the survivin inhibitor, YM155 in EAC cell lines was also assessed. Results: Semi-supervised hierarchical clustering identified two groups with significant differences in RFS [HR = 0.54 (0.29-0.99), p = 0.05] and OS [HR = 0.52 (0.28-0.96), p = 0.04]. There were significant associations between the clusters and both nodal and TNM downstaging but not with pathological response. The PI3K-AKT, p53, tight junction and HIF-1 signaling pathways were upregulated in the poor prognostic group. Eighty-four genes were selected and taken forward in a functional genomic siRNA screen. Twenty-seven genes showed a significant reduction in viability following siRNA-mediated knockdown and further verification resulted in twelve candidate genes. Finally, target knockdown in seven EAC cell lines resulted in four interrelated hits- BIRC5, JAK1, OSMR and SLC2A1. Knock down of BIRC5 (Survivin) induced apoptosis, as evidenced by PARP cleavage, in both the parental OE33 and cisplatin-resistant OE33CDDPR cell lines. YM155, a survivin inhibitor, is shown to induce apoptosis at nanomolar concentrations across a panel of parental and cisplatin-resistant EAC cell lines and further mechanistic work is ongoing. Conclusions: We have performed clustering of a large transcriptomic dataset and defined a poor prognostic group of EAC patients. We identified Survivin (BIRC5) as a mediator of cisplatin resistance in EAC and a potential novel drug target. Further pre-clinical and clinical work to assess the benefit of survivin inhibition in EAC is warranted.
Clinicopathological and prognostic significance of microsatellit instability (MSI) status and PDl-1 expression in Turkish patients with gastric cancer.
Authors: Yildiz Ibrahim , Bahsi Seyma , Erdamar Sibel , Goksel Suha , Demir Gokhan , Er Ozlem , Baca Bilgi , Karahasanoglu Tayfun , Hamzaoglu Ismail , Arican Ali , Ozer Leyla , Bozkurt Mustafa , Uras Cihan , Korkmaz Taner , Ince Umit
Published: May 2019

e15538

Background: The aim of this study was to evaluate the prognostic role of microsatellite instability (MSI) status and PD-L1 expression in surgically resected gastric cancer and the relationship of these parameters with clinicopathological features. Methods: Eighty six gastric cancer patients which had curative surgical resection at Acibadem Atakent and Maslak Hospitals between 2010 and 2017 were analysed. Tumor samples were evaluated with MSI and PD-L1 antibodies by immunohistochemical (IHC) methods. PD-L1 IHC scoring was performed using the combined positive score (CPS). Survival analysis was accomplished using the Kaplan-Meier method. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival. Results: The rate of PD-L1 expression in tumor cells was 34.9% (n = 30) and the frequency of PD-L1 expression in immune cells with CPS (≥1%) was 57% (n = 49). MSI-H was detected in 11.6%(n = 10), and more observed in PD-L1 positive cases (p = 0.021). MSI-H status was significantly correlated with older age, increased tumor size, presence of PD-L1 expression, and adenocarcinoma subtype. PD-L1 expression was associated with lymph node metastasis, adenocarcinoma subtype, microsatellite instability, presence of preoperative treatment and improved response to preoperative chemotherapy. In our study, the impact of MSI status on survival was not demonstrated, but PD-L1 expression positivity(≥1%) in both tumor cells (15.7 vs 53.4 months, p = 0.008)and in immune cells (20.4 vs NR; p = 0.027) was associated with short overall survival. PD -L1 expression in tumor cells was an independent prognostic factor for overall survival in multivariate analysis (HR: 2.28, p = 0.047). Conclusions: PD-L1 expression was related to a poor prognosis in patients with gastric cancer and can represent a rational approach for PD-1/PD-L pathway-targeted immunotherapy.
Neoadjuvant chemoradiotherapy combined with surgery in the treatment of potentially operable thoracic squamous cell carcinoma of the esophagus(ChiCTR-OIC-17011648): A phase II single center clinical study.
Authors: Liu Fang , Yan Maohui , Cai Boning , Qu Baolin , Yu Wei , Luo Yanrong , Wang Qianqian , Wang Yao , Liang Lanqing , Zeng Mingyue
Published: May 2019

e15543

Background: To investigate the efficacy and safety of neoadjuvant radiotherapy and chemotherapy combined with surgery in the treatment of potentially operable thoracic esophageal squamous cell carcinoma. Methods: Nineteen patients with advanced thoracic esophageal squamous cell carcinoma hospitalized in our hospital from July 2016 to June 2018 were prospectively studied. All patients received neoadjuvant concurrent radiotherapy and chemotherapy: intensity modulated conformal radiotherapy (40 ∽ 44Gy/20 ∽22f, 2 Gy/f), chemotherapy (paclitaxel 150 ∽ 175 mg/m2 d1, 22+lobaplatin 25-30 mg/m2 d2, 23, 2 cycles). After radiotherapy and chemotherapy, the efficacy and safety of the operation were observed. Results: Two case (10.5%) was completely remitted after neoadjuvant radiotherapy and chemotherapy, 17 cases (89.5%) were partially remitted, and the objective effective rate was 100%. All patients underwent radical surgery successfully, the R0 resection rate was 100% and the pCR rate was 52.6%. The main adverse reactions of neoadjuvant radiotherapy and chemotherapy were granulocytopenia and grade III-IV granulocytopenia. The rate of survival was 16.7%, and anastomotic leakage occurred in 1 patients after operation. Conclusions: Neoadjuvant chemoradiotherapy for thoracic esophageal squamous cell carcinoma can effectively reduce the volume of the tumor, significantly reduce the pathological grade, improve the resection rate, and have less adverse reactions, which is worthy of clinical application. Clinical trial information: ChiCTR-OIC-17011648.
KRAS amplification and mutation as independent events in gastroesophageal adenocarcinomas (GEA).
Authors: Chao Joseph , Madison Russell , Ross Jeffrey S. , Miller Vincent A. , Ali Siraj Mahamed , Schrock Alexa Betzig , Klempner Samuel Jacob
Published: May 2019

e15565

Background: KRAS mutations are common oncogenic events across cancers, but effective RAS-directed therapies are lacking. However, recent studies support use of PD-1 blockade in most subsets of lung cancer with KRAS short variant mutations (KRASSV) (PMID: 28039262), and preclinical data supports combined MEK and SHP2 inhibition in KRAS amplified ( KRASa) GEA (PMID: 30093730). We sought to explore the landscape of KRAS altered GEA and compare genomic profiles of KRAS-altered and KRAS wild-type (WT) cases for biomarkers of response to targeted therapies and immune checkpoint inhibitors. Methods: 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Descriptive statistics were used to compare among subgroups. Results: KRASSV and KRASa were identified in 11% and 5.8% of gastric adenocarcinoma (GA), respectively, and in 7.2% and 17% of esophageal adenocarcinoma (EA), respectively. KRASa and KRASSV were nearly mutually exclusive, co-occurring in only 4.4% of KRAS altered cases. ERBB2 alterations were less common in KRASSV and KRASa GEA (both 9%) as compared with KRAS WT GEA (19%) (p = 1.9E-16). EGFRa was less common in KRASSV vs KRASa GEA (1.9% vs 9.3%, p = 2.6E-8), whereas PIK3CASV was more common in KRASSV vs KRASa (16% vs 5.0%, p = 1.5E-11). Median TMB for all groups was similar; however, KRASSV GEA had a higher mean TMB (9.7 mut/Mb) as compared to KRASa (5.1 mut/Mb, p = 5.0E-12) and KRAS WT cases (5.8 mut/Mb, p = 2.2E-07). KRAS codon 12/13 accounted for > 80% of predicted pathogenic mutations. MSI-high was also more prevalent in KRASSV (11.3%) vs KRASa (0.9%, p = 4.8E-15) and KRAS WT GEA (2.4%, p = 1.8E-25). MSI-high KRASSV GEA was associated with older patient age (median 72 years) and with high TMB (median 40.9 mut/mb). Conclusions: GA was enriched for KRAS mutation whereas EA was enriched for KRAS amplification. KRAS WT vs KRASSV vs KRASa each presented distinct genomic profiles. KRASa in the absence of KRAS mutation exists in 11% of GEA and warrants further exploration to inform combination treatment strategies.
Evaluation of prognostic factors after esophagectomy in which preoperative chemotherapy was successful.
Authors: Ogata Takashi , Shimoda Yota , Nagasawa Shinsuke , Nakazono Masato , Hara Kentaro , Kumazu Yuta , Hayashi Tsutomu , Yamada Takanobu , Oshima Takashi
Published: May 2019

e15568

Background: Current standard treatment for Stage IB/II/III Japanese squamous cell carcinoma of the esophagus is esophagectomy after two courses preoperative chemotherapy with 5-FU/CDDP. Prognosis of cases in which preoperative chemotherapy was successful is usually good, but some cases were recurrence. On the other hand, some reports showed that the negative survival impact of infectious complications after esophagectomy is canceled out by succeeding preoperative chemotherapy. So we evaluate of prognostic factors after esophagectomy in which preoperative chemotherapy was successful. Methods: Between 2011 and 2015, 122 cases were performed esophagectomy after two courses of preoperative chemotherapy using 5-FU/CDDP for stage IB / II / III esophageal cancer, and 46 cases were achieved Grade 2 histopathological effect(2/3 or more disappearance of tumor). We examined 3-year survival rate and 3-year RFS in this 46 cases and examined what could be a prognostic factor. PS, ASA, sex, operation time, volume of bleeding , postoperative complications(C-D classification≧G2), pT, pN, tumor wall retentivity, preoperative nutritional status(Albumin, CRP, Prealbumin, RBP), nutritional indicators at discharge (weight change rate, fat mass change rate, muscle mass change rate) were evaluated as recurrence prediction factor. Results: 3-year OS of histological Grade2 cases were 84.5%, and 3 -year RFS were 88.8%. In 46 cases, relapse was found in 12 cases, and univariate analysis showed pT, pN as a risk of relapse, and multivariate analysis showed only pT as a risk of relapse. There were 5 cases of recurrence within 1 year after esophagectomy, and there was a significantly poor prognosis compared with recurrent cases later than 1 year after esophagectomy. Conclusions: The risk factor of recurrence in patients with squamous cell carcinoma after preoperative chemotherapy followed by esophagectomy was pathological T factor, and recurrent case within 1 year after esophagectomy was significantly poor prognosis.