bluuebunny/crossref_metadata_2025 huggingface dataset:
The microbial characteristics of esophageal squamous cell carcinoma (ESCC) and healthy subjects.
Authors: Lv Wenjing , Zuo Jing , Wang Yudong , Fan Zhisong , Feng Li , Wang Long , Zhang Xue , Zhang Qi , Jiang Da
Published: May 2020

e16546

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive human malignancies. Investigation of the esophageal microbiome is a relatively new field. Recently, we discovered the microbial characteristics among the healthy subjects and patients with ESCC. Methods: DNA was extracted from blood, oral mucosa, saliva, urine, faeces samples from 28 healthy and 26 ESCC cases. Pfu high fidelity DNA polymerase was used for PCR amplification. The PCR amplification products were quantified. Then the sequencing library was prepared. The V3V4 region of the 16S ribosomal RNA gene was sequenced with Novaseq-PE250. In order to comprehensively evaluate the α diversity of microbial communities, we used Chao1 and Observed Species indices to characterize the richness, Shannon and Simpson indices to characterize the diversity. PCoA, NMDS and Distance Matrix were used to analyze differences in β diversity. Results: At the phylum level, the top 5 microbes in both ESCC and healthy samples are Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria. At the genus level, the microbial composition of patients with ESCC and healthy samples was significantly different. However, the bacteria composition in blood samples was the same as the urine samples not only in patients with ESCC but also in healthy samples. Blood and urine samples of patients with ESCC contained Cupriavidus, Vogesella, Acinetobacter, Sphingomonas, Ochrobactrum, Sediminibacterium and the healthy samples contained Ochrobactrum, Sediminibacterium, Acinetobacter. The same rule occurred in oral mucosa and saliva samples. Faeces samples of esophageal cancer patients included Streptococcus, Lactobacillus, Bifidobacterium, Gemmiger, Blautia, Coprococcus. However, the healthy samples included Gemmiger, Roseburia, Faecalibacterium, Bacteroides, Dialister, Bifidobacterium. A comparison of esophageal cancer patients and healthy samples showed that α diversity was significantly different both in blood samples and urine samples. No statistically significant differences were detected within oral mucosa, saliva, faeces samples of esophageal cancer patients and healthy samples. β diversity was different in urine samples. Conclusions: Further understanding of the changes in the esophageal microbiome may help us understand the pathogenesis and the natural history of disease and present potential therapeutic approaches.
Exploration of the expression and significance of IL-6, STAT3 and PD-L1 in esophageal squamous cell carcinoma.
Authors: Zhou Yicheng , Zhu Honglei , Pang Xuezhou , Shen Yang , He Yu , Ma Daiyuan
Published: May 2020

e16554

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide and has a very high morbidity and mortality rate. The IL-6/STAT3 axis can simultaneously promote the expansion of immunosuppressive cells.This study detected IL-6, STAT3 and PD-L1 in ESCC and analyzed the potential clinical application value. Methods: Between July 2018 and April 2019, 70 ESCC patients underwent radical thoracic surgery at Affiliated Hospital of North Sichuan Medical College. RT-PCR was used to detect PD-L1, IL-6, and STAT3 mRNA expression in cancer and adjacent normal tissues. Western blot detection of PD-L1, IL-6, and STAT3 was performed in 40 cancer and adjacent normal tissues. The correlation of PD-L1, IL-6 and STAT3 protein expression with tumor invasion depth, tumor size, lymph node metastasis,clinical stage and other clinicopathological characteristics as well as the correlation between the three proteins were analyzed statistically. Results: The mRNA levels of PD-L1, IL-6, and STAT3 in 70 ESCC patients were significantly different between cancerous and adjacent normal tissues (P < 0.001). In 40 ESCC patients, 28 ESCC tissues showed significantly higher PD-L1 expression than adjacent normal tissue (28/12, P < 0.001), 29 ESCC tissues showed significantly higher STAT3 expression (29/11,P = 0.009 ), and 27 ESCC tissues showed significantly higher IL-6 expression (27/13,P = 0.042). There was no correlation between PD-L1 expression and age, sex, tumor site or maximum tumor diameter, but PD-L1 expression showed a positive correlation with T stage (P = 0.009), lymph node metastasis (P = 0.044), and clinical stage (P = 0.033). There was no correlation between STAT3 expression and age, sex, tumor site, maximum tumor diameter, lymph node metastasis or clinical stage, but STAT3 expression showed a positive correlation with T stage (P = 0.025). IL-6 expression was not correlated with age, sex, maximum tumor diameter, lymph node metastasis or clinical stage, but IL-6 expression showed a positive correlation with T stage ( P = 0.003)and tumor site (P = 0.011). In addition, PD-L1 expression showed a positive correlation with STAT3 (P = 0.013) and IL-6 ( P = 0.008), and STAT3 showed a positive correlation with IL-6 ( P = 0.027). Conclusions: PD-L1, IL-6, and STAT3 are highly expressed in ESCC and their protein levels exhibit a positive correlation. The IL-6/STAT3 signaling pathway proteins may be a potential biomarker predicting the efficacy of immunotherapy by affecting the expression of PD-L1.
Safety of double and a half-layered esophagojejunal anastomosis in total gastrectomy with gastric cancer.
Authors: Ma Pengfei , Zhao Yuzhou , Zhang Xijie
Published: May 2020

e16563

Background: Esophageal jejunal anastomotic fistula is still one of the serious postoperative complications of gastric cancer, the incidence was 1% ~ 16.5%. The aim of this study was to evaluate the safety of double and a half layered esophagojejunal anastomosis in total gastrectomy. Methods: The new method was called double and a half layered esophagojejunal anastomosis: esophagojejunal anastomosis was performed with a tubular stapler, then the anastomosis was reinforced by absorbable suture (Full-layer continuous suture, slurry muscularis embedding). The new method was used in observation group (n = 295). In the control group(n = 469),the esophagojejunal anastomosis was performed with a tubular stapler, then reinforced by intermittent suture with absorbable sutures. Data analysis including operating time, blood loss, anastomosis time, types and cases of postoperative complications, and postoperative hospitalization time. Results: The data of 764 patients who performed radical gastrectomy between May 2015 and May 2019 were analyzed retrospectively. 1.Surgery situations: The operating time (140.66±26.96 min vs 139.61±22.75min, t= 0.581, P> 0.05) blood loss (200.61±111.03ml vs214.45±114.09ml, t= -1.481, P> 0.05), anastomosis time (20.44±4.31min vs19.92±4.58min, t= 1.573, P> 0.05), postoperative hospitalization time (15.35±6.46 d vs15.89±5.58d, t= -1.229, P> 0.05) .2. Postoperative situations: the rates of anastomotic complications in observation group was 1.69% (5/295) and 4.69% (22/469) in control group, with a statistically significant difference between two groups( χ2 = 4.768, P< 0.05). The rates of anastomotic leakage in observation group was lower than that in the control group 1.02% (3/295) vs 3.41% (16/469) ( χ2 = 4.282, P< 0.05) . The severity of anastomotic leakage, anastomotic stenosis, anastomotic bleeding were no statistically significant differences between two groups( χ 2= 2.030,1.261,0.075, P> 0.05). Total postoperative complications: 101 cases (34.24%) in the observation group, 14 cases (4.75%) with severe complications, and 1 case death. 151 cases (32.2%) in the control group, 34 cases (7.25%) with serious complications, and 2 cases death ( χ2 = 0.838, Z = -1.465, P > 0.05). Conclusions: Double and a half layered esophagojejunal anastomosis is safe and feasible in total gastrectomy, which can reduce the incidence of anastomosis complications.
Survival benefit of oophorectomy in stage IV gastric cancer patients with Krukenberg tumors.
Authors: Abdelhakeem Ahmed , Badgwell Brian D. , Ikoma Naruhiko , Meyer Larissa , Zhao Meina , Ta Anh , Das Prajnan , Sagebiel Tara L. , Waters Rebecca E , Estrella Jeannelyn , Ajani Jaffer A. , Blum-Murphy Mariela A.
Published: May 2020

e16566

Background: The management of Krukenberg tumors from primary gastric cancer remains unclear and it is unknown if oophorectomy improves survival. The purpose of this study was to compare the overall survival (OS) of patients with ovarian metastases from gastric cancer treated with standard chemotherapy to chemotherapy and oophorectomy. Methods: Between January 2008 and August 2019, we retrospectively analyzed the clinicopathological features and treatment data of 97 patients with stage IV gastric cancer patients with ovarian metastases. Patients were categorized into two groups: Oophorectomy plus standard chemotherapy treatment vs. standard chemotherapy only (non-oophorectomy). The primary objective was to assess OS. Results: A total of 97 patients were identified. 37 (38.1%) patients had oophorectomy and 60 (61.9%) patients did not have oophorectomy. OS was better in the oophorectomy group relative to the non-oophorectomy group (37 months vs. 20 months; P= 0.0554). Survival from the time of diagnosis of ovarian metastases was significantly better in oophorectomy group relative to the non-oophorectomy group (26 months vs. 12 months; P= 0.0006). Conclusions: Our results showed that Oophorectomy in addition to systemic chemotherapy in this unique population seems to confer survival advantage in this retrospective analysis. Prospective evaluation is warranted.
Totally laparoscopic plus one transthoracic port esophagogastrectomy for Siewert-type Ⅱ adenocarcinoma of esophagogastric junction.
Authors: Wang Wei , Xiong Wenjun , Xue Yuling , Li Jin , Huang Haipeng , Zheng Yansheng , Luo Lijie , Wan Jin
Published: May 2020

e16568

Background: The incidence of Siewert type Ⅱ adenocarcinoma of esophagogastric junction (AEG) is increasing, especially in Asia, but laparoscopic surgery for type Ⅱ AEG is not widely accepted due to the technical challenges and unknown prognosis. To address this problem, we developed a novel technique of totally laparoscopic plus one transthoracic port esophagogastrectomy. Methods: From May 2017 to December 2019, 24 patients with advanced Siewert type Ⅱ AEG underwent the procedure. The surgical technique is that after completely abdominal lymphadenectomy and mobilization of the stomach laparoscopically, the left diaphragm was incised 5 to 7 cm, followed by one transthoracic port was inserted into the thoracic cavity through the left axillary frontline at the sixth to eighth intercostal spaces. Then lower mediastinal lymphadenectomy and transection of the lower esophagus were completed through the transthoracic supplementary port. An intrathoracic Roux-en-Y esophagojejunostomy was performed also through this port, which was finally used for thoracic drainage. Results: All procedures containing 5 proximal gastrectomies and 19 total gastrectomies were completed successfully without surgical morbidity and mortality. The median operative time was 344 (205 to 540) min. The time for reconstruction was 38 (25 to 60) min. The median blood loss was 100 (20 to 300) ml. The median tumor diameter was 3.8 (1.5 to 6.7) cm with a median esophagus invasion of 2.5 (0.6 to 4.5) cm. The median number of lymph nodes harvest was 37 (18 to 60). The median number of lower mediastinal lymph nodes was 5 (1 to 13) and its metastasis rate was 33.3%(8/24). The median time of first flatus was 4 (2 to 7) days. The median hospital stay was 11 (7 to 45) days. One patient developed a thoracic infection and one esophagojejunostomy leakage, both cured with thoracic drainage and antibiotic treatment. The median follow-up was 22(1-32). The DFS was 83.3% and OS was 91.7%. Conclusions: Our initial result suggested that this novel technique was safe and feasible for Siewert type Ⅱ AEG, associated with the advantages of complete lower mediastinal lymphadenectomy and easy intrathoracic Roux-en-Y esophagojejunostomy by using the transthoracic assisted port.
Gastric juice piR-1245: A promising prognostic biomarker for gastric cancer.
Authors: Peng Wei , Liu Jianhong , Zhou Xiaorong , Fan Hong , Lu Jianwei , Chen Senqing , Feng Jifeng
Published: May 2020

e16574

Background: Emerging reports demonstrated that PIWI-interacting RNAs (piRNAs) played an indispensable role in tumorigenesis. However, it still remains elusive whether piR-1245 in gastric juice specific in stomach could be employed as a biomarker for gastric cancer (GC). The present work is aiming at exploring the possibility of piR-1245 in gastric juice as a potential marker to judge for diagnosis and prognosis of gastric cancer. Methods: Gastric juice was collected from 66 GC patients and 66 healthy individuals. Quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) was employed to measure the levels of piR-1245 expression. Then, the pattern of piR-1245 expression in gastric juice was determined between GC patients and healthy individuals. A receiver operating characteristic (ROC) curve was constructed for distinguishing GC from healthy individuals. Results: Gastric juice piR-1245 levels in GC were higher than those of controls (P < 0.0001). The value of area under ROC (AUC) was 0.885 (sensitivity, 90.9%; specificity, 74.2%; 95% confidence interval, 0.8286 to 0.9414). High gastric juice piR-1245 expression was signally correlated with tumor size (P = 0.013) and TNM stage (P = 0.001). GC patients with high piR-1245 expression in gastric juice exerted a poorer overall survival (OS) (P = 0.0152) and progression-free survival (PFS) (P = 0.013). COX regression analysis verified that gastric juice piR-1245 expression was an independent prognostic risk variable for OS (P < 0.05). Conclusions: The current study suggested that piR-1245 in gastric juice had the potential to be a useful biomarker for GC detection and prognosis prediction.
Clinicopathological features and treatment outcomes of young patients with gastric and esophageal cancers.
Authors: Beck Lauren Amanda , Ma Lucy Xiaolu , Espin-Garcia Osvaldo , Suzuki Chihiro , Jiang Di Maria , Liu Geoffrey , Chen Eric Xueyu , Knox Jennifer J. , Wong Rebecca , Brar Savtaj Singh , Swallow Carol Jane , Yeung Jonathan , Darling Gail Elizabeth , Conner James , Elimova Elena , Jang Raymond Woo-Jun
Published: May 2020

e16577

Background: Gastric and esophageal (GE) cancers most commonly occur in older adults in their 60’s.However, there are inconsistent reports about prognosis in adolescent and young adult (AYA) pts, and treatment patterns and outcomes in this population have not been well characterized. Methods: A retrospective analysis was performed for AYA (age 18-40 years) pts with histologic diagnosis of GE cancers who presented to Princess Margaret Cancer Centre from 2008 to 2016. The Kaplan-Meier method was used to analyze progression free (PFS) and overall survival (OS). Results: We identified 57 AYA GE cancer pts (30 gastric, 27 esophageal). Baseline features included: median age 35 years, 51% female (70% in gastric, 30% in esophageal), 82% with Eastern Cooperative Oncology Group performance status 0-1, 82% Charlson Comorbidity Index 0, 54% stage IV. For gastric pts, 53% had diffuse subtype and 47% had signet ring adenocarcinoma. Most had negative family history (77%). Curative intent and palliative treatment was used in 23 (40%) and 34 pts (60%) respectively. In curative pts, 48% had neoadjuvant therapy, 52% had upfront surgery. Of pts who underwent curative resection, 62% had pT3/T4 and 38% had pN2/N3 disease; 5-year OS rate was 37% (95% CI 20-67). Of the palliative pts, 91% received systemic therapy. First-line regimen included triplet (81%) and doublet chemotherapy (13%), administered for a median of 6 cycles. Median PFS was 7.4 months. Second- and third-line treatments were administered in 14 and 3 pts respectively, 1 pt was treated beyond third-line. Median OS in palliative pts was 12.1 months (95% CI 8-21.3). Conclusions: Our gastric AYA pts had increased female predominance and diffuse histology. Many AYA pts had advanced GE cancer at diagnosis, with over half of pts presenting with metastatic disease. In both the curative and palliative setting, AYA pts did not appear to have better survival outcomes despite having few comorbidities, suggesting they may have more aggressive biology.
Deep learning-based unsupervised morphological subtyping in histopathology images of gastric cancer.
Authors: Jung Kyu-Hwan , Park Jeonghyuk , Kim Kyungdoc , Kim Yeong Won , Park Hyunho , Kook Myeong-Cherl , Kim Dong-Il
Published: May 2020

e16580

Background: Gastric cancer subtyping system such as Lauren classification is widely used in clinical practice since it is an independent prognostic factor, and also provides the basis for individualized treatment. However, Lauren classification showed low reproducibility because it is based on qualitative method. Thus, a more reproducible system has been required. In this study, we explore the concordance between a cancer detection model (CDM)-based unsupervised subtyping and a current classification system. Methods: We focused on Lauren classification since it has relatively simple major subtypes: intestinal and diffuse types. 88 resection cases of gastric cancer are collected. Two experienced gastrointestinal pathologists evaluated each case independently by Lauren’s criteria. 200 cancer region image patches per case and its features extracted by the CDM were clustered into five groups via k-means clustering. We then defined the ratio of the number of patches in each cluster group as the case-level feature. Cases are clustered into two groups via k-means clustering using the features. We named this case-level clustering result as a deep learning-based subtyping (DLS), hereafter. Results: DLS showed a high correlation with Lauren classification: intestinal and diffuse subtype. The kappa scores between the pathologists and algorithm (0.765 and 0.796) were higher than between pathologists (0.700). The cluster centers corresponding to intestinal and diffuse types were [44.6, 21.5, 47.5, 63.7, 22.7] and [35.5, 148.2, 4.0, 9.0, 2.3], respectively. Further review of the patches contributing to the second feature (21.5 and 148.2) confirmed that they demonstrate typical morphological characteristics of diffuse type. Conclusions: Our analysis showed that the morphological characteristics of Lauren classification were inherent in gastric cancer detection task and WSIs can be subtyped by the data-driven, and unsupervised manner. Furthermore, DLS was more reliable than human from the concordance results. This suggests that the DLS can supplement current classification systems or be a new subtyping system. [Table: see text]
Chemoradiation versus chemotherapy after D2 gastrectomy: A meta-analysis including randomized and real-world trials.
Authors: Rim Chai Hong , Shin In-soo , Lee Hye yoon , Park Sunmin
Published: May 2020

e16590

Background: The ARTIST trial failed to achieve positive result regarding benefit of chemoradiation (CRT) after D2 gastrectomy. In most of clinical guidelines and practices, postoperative CRT has been recommended only for those with R1 resection or lesser extent surgery than D2. Our study is to evaluate oncologic benefit of CRT after D2 gastrectomy, integrating data from randomized clinical trials (RCTs) and real-world studies so far. Methods: Systematic searches for Medline and Embase were performed for controlled trials comparing CRT and chemotherapy (CT) arms after D2 gastrectomy with R0 resection, for gastric cancer. Subgroup analyses were performed including RCTs, and balanced studies without significant difference regarding major clinical indicators. Primary endpoint was disease free survival (DFS), and secondary endpoints included overall survival (OS), locoregional recurrence rate (LRR), distant recurrence rate (DRR), and grade ≥3 complications. Results: A total of 13 studies, comprised of 6 RCTs and 7 non-RCTs, involving 2,603 patients were included. DFS benefit was found in overall pooled analysis [odds ratio (OR): 1.264, p = 0.053, I2= 37.5%], and more evident in subgroup analyses using RCTs (OR: 1.440, p = 0.006, I2= ~0%) and balanced studies (OR: 1.417, p < 0.001, I2= ~0%). OS benefit was not significant. LRR reduction was noted in overall pooled analysis (OR: 0.559, p = 0.012, I2 = 46.1%), and clearer in the subgroup analyses with RCTs (OR: 0.495, p < 0.001, I2= ~0%) and balanced studies (OR 0.472, p < 0.001, I2= 9.2%). Pooled LRR rates were 11.3% (95% confidence interval: 7.5-16.8) and 18.1% (13.1-24.4) in CRT and CT arms. DRR was lower in CRT arms (OR: 0.768, p = 0.023, I2= ~0.0%), but the difference was less significant in subgroup analyses. A grade 5 complication was found in each of the two arms among all studies. Comparison of complications varies and will be shown descriptively in the manuscript. Conclusions: Benefit of DFS and LRR with CRT after D2 gastrectomy was well shown in the present study. Identifying subgroup population mostly benefitable from CRT might yield positive results regarding OS and DRR in future studies.
The prognostic significance of the advanced lung cancer inflammation index(ALI) in patients with advanced biliary tract cancer: A retrospective study.
Authors: Kim Jung Hoon , Oh Sung Yong , Kang Jung Hun , Kang Myoung-Hee , Jeong Chi-Young , Ji Jun Ho
Published: May 2020

e16613

Background: Intrahepatic cholangiocarcinoma is the second most common primary cancer, but the prognosis is poor and aggressive therapies provide only limited benefit when it is in advanced stage. Many studies were conducted to find significant prognostic factors to predict clinical outcomes, but there is no definitive parameter or scoring model yet in this disease. This study is a retrospective analysis to test various kinds of prognostic scoring systems including the advanced lung cancer inflammation (ALI) index, a new prognostic model, for patients treated for advanced intrahepatic cholangiocarcinoma. Methods: We retrospectively searched medical records of patients who were diagnosed with advanced intrahepatic cholangiocarcinoma between January 2012 and December 2017 and actively treated at a single tertiary regional cancer center. Patients who received only supportive care, or had active infection concomitantly were excluded. 60 patients were identified, and we reviewed and analyzed their baseline characteristics and clinical outcomes. Various types of inflammation or nutritional scoring systems, neutrophil to lymphocyte ratio (NLR), Onodera’s prognostic nutritional index (OPNI), the advanced lung cancer inflammation (ALI) index were concurrently calculated and significance for patients’ survival was evaluated. Results: In 50 patients with metastatic stage and 10 patients with locally advanced disease, the median overall survival was 13.97 months (95% confidence interval (CI) 7.99 – 19.95). ALI of 28.5 was determined as the optimal cut-off value for prediction of 1-year survival by receiver operating characteristics (ROC) curve with an AUC value of 0.671 (sensitivity and specificity were 77.8% and 60.6%, respectively). 26 patients with ALI > 28.5 had significantly better overall survival compared with 34 patients with ALI≤28.5 (19.2 months vs. 8.73 months, p= .007). NLR above 2.8 only showed mildly significant difference for overall survival (OS), and the OPNI failed to predict prognosis of these patients. In multivariate analysis, there was no independent prognostic factor observed to have association with overall survival. Conclusions: The advanced lung cancer inflammation (ALI) index showed a potential to be a new prognostic model for advanced intrahepatic cholangiocarcinoma. Further cohort studies to expand population size may be worth.
Characterization of advanced hepatocellular carcinoma patients via a multi-omic cancer registry.
Authors: Ryan Joseph S , Xu Xiaojun , Tamayo Pablo , Burgoyne Adam
Published: May 2020

e16617

Background: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and has significant cancer-related mortality worldwide. Molecularly matched therapy has an emerging role in HCC treatment; however, HCC poses a unique challenge as patients are frequently diagnosed radiographically rather than by tissue biopsy, limiting our ability to utilize tumor tissue data for therapy selection. The purpose of this study is to establish a multi-omic database with matched demographic and clinical data to identify patterns of shared molecular aberrations in HCC tumors. Methods: An institutional HCC cancer registry was created, and a retrospective review was performed using data from 2017-2020 at a tertiary cancer center. 56 patients with advanced HCC were identified, and tissue samples were analyzed with multi-omic profiling assays (next generation DNA sequencing, RNA sequencing, protein expression via immunohistochemistry) versus ctDNA from peripheral blood. Results: Next generation sequencing was obtained for 38 (76%) patients using either tissue or ctDNA. While the results were similar, a higher number of total mutations were identified using tumor tissues rather than ctDNA. The average variant allele fraction for tumor tissues was approximately 10x higher than the variant allele fractions identified by ctDNA. However, ctDNA sequencing identified a higher number of potentially actionable mutations, on average, than did tissue testing. The most commonly mutated genes included TERT (42% of patients), TP53 (47%), CTNNB1 (34%), ARID1A (18%), CCND1 (16%), and NEF2L2 (13%). Several patients had serial ctDNA sequencing, which showed an increase in actionable and total mutations over time as well as changes in variant allele fractions in response to therapy. Conclusions: Next generation sequencing of ctDNA can be used in lieu of tumor tissue in patients diagnosed with HCC radiographically to identify actionable mutations, but it may underestimate the mutational burden of HCC tumors. Serial analyses with cell free DNA may be useful to monitor clonal evolution in response to targeted treatment and may identify new actionable mutations as patients progress on systemic therapies. [Table: see text]
TP53 R249G/S mutation as an independent prognosis indicator in hepatocellular carcinoma.
Authors: Zhou Ledu , Xu Ying , Wang Dong , Ye Ke , Xiao Liang , Long Guo , Chen Rongrong , Xia Xuefeng
Published: May 2020

e16622

Background: Many cancers could be driven by some specially mutations exampled as EGFR in lung cancer, influenced prognosis prominently. However, there were few related studies in liver cancer, although primary liver cancer was a common malignant tumor causing high morbidity and mortality. Methods: 97 patients diagnosed with primary hepatocellular carcinoma were enrolled in this study. Operative tissue samples were collected and analyzed using hybridization capture based NGS ERSeq method from all patients. Results: 1088 somatic mutations were identified in tissue samples. Targeted-capture sequencing of 1,021 genes that are frequently mutated in solid tumors revealed that the most frequently mutated genes were TP53 (59%), TERT (32%) and AXIN1 (19%). By using the least absolute shrinkage and selection operator (LASSO), the recurrence risks were constructed on the basis of five-gene mutations, AXIN1, CTNNB1, LRP1B, PDGFRA and TP53. The ROC curve was 0.813 and 0.882 in training and validation cohorts, respectively. TP53 R249G/S point mutation was predicted prognostic independently. Up to 60% TP53 R249S mutated patients occurred recurrence, while less than 30% TP53 R249 wildtype patients occurred recurrence ( P = 0.0002). Patients with R249G/S point mutation showed a worse prognosis. The median disease-free survival time was 8.0 VS 45.0 months in R249G/S mutated group (n = 79) and R249- wildtype (n = 18) group, respectively (Log-rank test, P = 0.0364). Conclusions: In various cancer types, TP53 has a broad-spectrum mutation, but only in hepatocellular carcinoma, TP53 mutations are highly concentrated at the R249 point, which was considered to be related to aflatoxin infection, and mutations at this site can significantly affect the prognosis of patients. The discovery of this target also provide clue for subsequent targeted treatment of liver cancer.
Real-world experience of pembrolizumab plus lenvatinib in unresectable hepatocellular carcinoma in Taiwan.
Authors: Wu Chi-Jung , Hung Ya-Wen , Lee Pei_Chang , Lee ChiehJu , Chen Ming Huang , Chao Yee , Hou Ming-Chih , Huang Yi-Hsiang
Published: May 2020

e16627

Background: Multi-kinase inhibitors and immune checkpoint inhibitors (ICIs) are treatment options of systemic therapy for unresectable hepatocellular carcinoma (HCC). Targeted therapy can potentially enhance T cell infiltration and activation, consequently, cooperate with ICIs to produce synergistic anti-tumor effects. The ongoing clinical trial shows promising data by combining pembrolizumab with lenvatinib for advanced HCC. The study tried to evaluate the treatment response and adverse events of pembrolizumab plus lenvatinib for HCC in real-world setting. Methods: From Jul. 2019, patients who received pembrolizumab plus lenvatinib for unresectable HCC in a tertiary medical center in Taiwan were prospectively enrolled. The status of HCC was either in advanced HCC or failed by prior locoregional treatment. The dosage of pembrolizumab was 100mg every 3 weeks. The starting dose of lenvatinib was 10mg per day then titrating to weight-based dose according to recommendation. Patients who had received at least 2 cycles of pembrolizumab were evaluated in this report. The tumor response was assessed with Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modified RECIST (mRECIST). The treatment related adverse events (TRAEs) were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: Till the end of Jan. 2020, 27 patients had received at least 2 cycles of pembrolizumab, and 17 had evaluable post-treatment images either by CT or MRI. There were 6 (22.2%) in BCLC B, and 21 (77.8%) in BCLC C. Of them, 17 (63%) were treated as the first-line systemic treatment, 8 as the second-line and 2 as the third line systemic treatment. Of the 17 cases with post-treatment image studies, there were 6 (35.3%) in partial response (PR), 7 (41.2%) in stable disease (SD), and 4 (23.5%) in progressive disease (PD) by RECIST v1.1; and 1 (5.8%) in complete response (CR), 9 (52.9%) in PR, 3 (17.6%) in SD and 4 (23.5%) in PD by mRECIST, respectively. The objective response rate (ORR) and disease control rate (DCR) by mRECIST were 58.7% and 76.5%, respectively. The most common TRAEs in any grade were hypertension 24 (88.4%), palmar-plantar syndrome 19 (70.4%), hypothyroidism 19(70.4%). The Grade 3/4 TRAEs were 3 (11.1%) with psoriasis-like skin reaction, 3 (11.1%) with hypertension and 2 (7.4%) with palmar-plantar syndrome. Conclusions: Pembrolizumab plus lenvatinib can produce excellent ORR and DCR with tolerable safety profiles. Such combination could be a promising strategy for unresectable HCC in the future.
Landscape of immune-checkpoint inhibitors in hepatocellular carcinoma: A systematic review with meta-analysis.
Authors: Shek Dmitrii , Read Scott A. , Nagrial Adnan , Gao Bo , Ahlenstiel Golo
Published: May 2020

e16632

Background: The WHO estimates that liver cancer will cause 1 million deaths by 2030. Hepatocellular carcinoma (HCC) is a primary liver malignancy causing 4.3% of all cancer deaths in 2019 in Australia. Kinase inhibitors are standard of care (SoC) for metastatic HCC with median overall survival (mOS) of < 13 months. This meta-analysis primarily aimed to determine objective response rate (ORR) of immune-checkpoint inhibitors (ICIs) in advanced HCC. Methods: Potentially relevant clinical studies were identified through PUBMED, Scopus, ASCO and ESMO databases. Studies evaluating ICIs in patients with HCC and reporting efficacy outcomes were considered as eligible. Publication bias was assessed with Funnel plots. Data analysis was performed employing fixed and random effects model depending on study heterogeneity evaluating by I2 statistic. STATA v16 software was used for all statistical considerations. Results: 12 single arm phase II/III studies and 2 randomized clinical trials on ICIs in HCC were included into this analysis. First-line ICI: Primary forest plot established the median ORR was 26.2% (95% CI 24.7 to 27.9) in patients treated with first line ICIs monotherapy; in comparison, ORR of current SoC sorafenib is 2-3% and lenvatinib 18.8%. Moreover, nivolumab resulted in 9.8 months of OS in Child-Pugh class B (CPB) patients, previously eligible only for supportive care due to a low efficacy of sorafenib (mOS < 4.5 months). Second-line ICI: Secondary forest plot established that nivolumab at 1 mg/kg with ipilimumab 3 mg/kg Q3W resulted in mOS of 23 months with ORR of 32% in sorafenib-progressors. In comparison, current second line SoC regorafenib has mOS of 10.6 months and ORR of 17%. Conclusions: This meta-analysis suggests that ICIs may be superior (ORR) to SoC sorafenib in advanced HCC, particularly nivolumab. Secondly, nivolumab with ipilimumab were confirmed to provide higher OS in sorafenib progressors as compared to regorafenib. Of note, many of the studies included were only available in abstract form and final reporting is pending. Nevertheless, our results support higher efficacy of ICIs in HCC patients.
Demographic trends and in-hospital mortality data in patients with hepatocellular carcinoma.
Authors: Adepoju Bolanle , Perimbeti Stuthi , Kyung Daniel , Styler Michael , Jain Maneesh Rajiv
Published: May 2020

e16648

Background: Hepatocellular carcinoma (HCC) remains the 4th leading cause of cancer related mortality in the US. The incidence of HCC in the US appears to be increasing in specific demographic subgroups (Caucasian males, Hispanics and in the Southern US). Older studies identified substantial racial and ethnic differences in treatment and survival in HCC. There is a lack of large scale studies exploring the mortality patterns in patients hospitalized with HCC. Methods: The National Inpatient Sample was used to extract admissions for HCC using the ICD-9 code 155.0 from the years 2010 to 2014. The sample was weighted to approximate the full inpatient population of the U.S. over the 5-year interval. Univariate analysis was performed to determine the frequency distribution and bivariate analysis was performed using Chi Square test to determine the in-hospital mortality percentage. Results: A total of 52,868 (weighted = 262845) admissions were extracted from the years 2010 to 2014. While the number of patients admitted with HCC steadily increased over the 5-year study period, the overall in-hospital mortality decreased significantly from 9.35% to 7.68% (p < 0.0001). The mortality was highest for patients with African American ethnicity at 11.2% and for uninsured patients at 13%. The mortality rate among patients in the low income group (0-25th percentile) was 10.2 %, significantly higher (p = 0.0005) than other income groups. Conclusions: Even though the incidence of in-hospital mortality in HCC patients is decreasing, there appears to be a disparity in mortality data among patients of low socioeconomic status, self-pay or uninsured status and among African Americans. Our study further confirms the persistence of racial,economic and social disparities and highlights the need for additional equity research to understand the reasons for these differences and to improve outcomes for these subgroups of patients.
Hepatobiliary tumors in adolescents and young adults: Site, age and gender distribution.
Authors: Wong Evelyn , Goh Wei Lin , Hong Jiancheng , Wong Victoria , Quah Daniel , Tan Yee Pin , Tan Yung Ying , Chan Jason Yongsheng , Somasundaram Nagavalli , Harunal Rashid Mohamad Farid Rin , Poon Eileen Yi Ling
Published: May 2020

e16651

Background: Hepatobiliary cancer is one of the common cancers within Asia with 80% of global cases occurring in the continent alone. Currently little is known about the incidence of hepatobiliary cancer in the Adolescent and Young Adults (AYA). In this population, hepatobiliary cancer may present in an insidious manner due to low suspicion and management may result in a higher likelihood of survivors with long-term treatment-related toxicities. We aim to highlight the clinicopathological features and treatment outcomes in this age-group in an Asian high-volume tertiary cancer institution. Methods: Patients diagnosed between the age of 16-39 with hepatobiliary cancers between 1st January 2015 to 31st December 2019 in a single-centre institution in Singapore were included in this study. Results: There was a total of 84 AYA patients with hepatobiliary tumours who were referred to our institution. Median age of diagnosis was 35 years old (n = 84). 32 patients (38.1%) had hepatocellular carcinoma, 22 patients (26.2%) had biliary tract tumours, 11 patients (13.1%) had neuroendocrine cancers while 19 patients (22.6%) had other tumour types (Figure 1). Male incidence was highest in all hepatobiliary AYAs (n = 56, 66.7%, p = 0.002) and hepatocellular carcinomas (n = 25, 78.1%, p = 0.001) (Table). 65 patients (77.4%) remain alive as of 31st December 2019. Conclusions: Patterns of hepatobiliary incidence differ between sexes. In the young AYA population, hepatocellular precursor cells may have sex-specific features affecting malignant potentials. More studies should be done to further elucidate the genomic and epidemiology of hepatobiliary tumours in the younger population of patients to better outcomes in this population. [Table: see text]
Effect of neoadjuvant immunotherapy and targeted therapies on surgical resection in patients with solid tumors: A systematic review and meta-analysis.
Authors: Serrano Aybar Pablo Emilio , Tywonek Kasia , Faisal Noor , Lee Sandra , Alfayyadh Ali , O'Neill Connor , Gundayao Marylrose , Ruo Leyo , Parpia Sameer , Meyers Brandon M.
Published: May 2020

e16656

Background: Neoadjuvant immunotherapy with anti-programmed cell death protein-1 (PD-1) or anti-programmed cell death ligand-1 (PD-L1) and tyrosine kinase inhibitor (TKI) therapy is currently being used to treat certain solid tumours prior to surgery. Neoadjuvant therapy may cause delays to resection potentially losing a window of opportunity. We explored the pooled proportion of patients with solid tumours receiving neoadjuvant therapy who completed planned surgical resection. Methods: Medline, CENTRAL and Embase databases were searched for single arm or randomized controlled trials studying neoadjuvant PD-1/PD-L1 immunotherapy or TKI therapy. Random-effects model was used to estimate the pooled proportion of patients undergoing planned resection, and weights were estimated using inverse variance method. Statistical heterogeneity was calculated using the I2 and chi-squared test. Results: From 368 relevant articles, eleven studies with a total of 382 patients receiving neoadjuvant PD-1 immunotherapy (n = 234) or neoadjuvant TKI therapy (n = 148) were analyzed. The types of tumours included hepatocellular carcinoma (1 study), renal cell carcinoma (8 studies), bladder carcinoma (1 study) or non-small cell lung cancer (1 study). The pooled proportion of patients who completed planned surgery after neoadjuvant therapy was 95% (95% CI 0.92 to 0.99). The overall partial response rate prior to surgery was 12% (95% CI 0.07 to 0.16) in the PD-1 therapy group and 46% (95% CI -0.12 to 1.03) in the TKI group. The pooled serious adverse events rate was 17% (95% CI 0.02 to 0.32) in the PD-1 therapy group and 29% (95% CI -0.10 to 0.68) in the TKI group. For all patients receiving neoadjuvant therapy, the pooled median overall survival was 23.41 months (95% CI 16.21 to 30.62) and median progression free survival was 7.46 months (95% CI 4.41 to 10.51). Conclusions: Neoadjuvant PD-1 or TKI therapy prior to surgery for solid tumours is safe, does not delay surgical resection and can result in a partial radiological response prior to surgery.
Blood levels of steroid hormone precursors allow differentiation between pancreatic adenocarcinoma and neuroendocrine tumors.
Authors: Aleynov Viacheslav A. , Frantsiyants Elena M. , Bandovkina Valeria A. , Cheryarina Natalia D. , Trifanov Vladimir S. , Sanamyants Sergey V. , Averkin Mikhail A. , Kit Oleg I. , Shaposhnikov Alexander V. , Fomenko Yuriy A. , Petrov Dmitry S.
Published: May 2020

e16692

Background: The activity of some enzymes involved in the synthesis and transformation of sex hormones changes in some tumor tissues of the pancreas, which can affect the circulating concentrations of these hormones in the blood. The purpose of the study was to determine the possibility of differential diagnosis of pancreatic cancer at primary examination. Methods: Levels of 17OHP and DHEAS were measured by RIA in the blood of 25 men with chronic pancreatitis (CP), 34 patients with pancreatic adenocarcinoma (PA) and 15 patients with pancreatic neuroendocrine tumors (PNET). The results were compared with the levels in 23 healthy donors. All patients gave voluntary informed consent for the study. Results: Men with CP did not show statistically significant changes in 17OHP and DHEAS. The levels in pancreatic cancers were lower than in donors: in PA, DHEAS was 1.6 times and 17OHP - 1.4 times lower than the norm. DHEAS in PNET was 2.4 times lower than the norm and 1.5 times lower than in PA. 17OHP in PNET was 6.4 and 4.5 times lower, respectively. Conclusions: Measuring DHEAS and 17OHP in the blood can serve as an informative laboratory test for predictor assessment of the nature of pancreatic disease.
Effect of neuroendocrine component in pancreatic adenocarcinoma on blood levels of steroid hormones.
Authors: Aleynov Viacheslav A. , Frantsiyants Elena M. , Bandovkina Valeria A. , Cheryarina Natalia D. , Trifanov Vladimir S. , Chernyak Maksim N. , Mezentsev Stanislav S. , Grechkin Fedor N. , Katsieva Tanzila Beksultanovna , Kit Oleg I. , Shaposhnikov Alexander V. , Petrov Dmitry S. , Fomenko Yuriy A.
Published: May 2020

e16695

Background: 90% of pancreatic cancers are adenocarcinomas. Pancreatic neuroendocrine tumors (PNET) are much less common. However, some adenocarcinomas carry a neuroendocrine component and have an effect on the hormonal profile of the body. The purpose of the study was to analyze the content of steroid hormones and ACTH in the blood of patients with pancreatic cancer in dependence on the neuroendocrine component presence. Methods: Standard RIA methods were used to measure blood level of testosterone (T), estradiol (E2), progesterone (P4), cortisol and ACTH in 10 patients with pancreatic adenocarcinoma (PA), 12 patients with PNET and 20 patients with PA with a neuroendocrine component (PA+NEC). The results were compared with the levels in 23 healthy donors. All patients gave voluntary informed consent for the study. Results: Levels of all measured hormones were elevated in the blood of patients with PA: T by 1.8 times, P4 by 4.8 times, E2 by 2.7 times, cortisol by 2 times and ACTH by 2.5 times, compared to donors. In PNET, E2 was 1.5 times (p < 0.05) lower, and T 1.6 times (p < 0.05) higher than in donors. Levels of P4, ACTH and cortisol in PNET were similar to normal values. In PA+NEC, T was decreased by 1.3 times, P4 and ACTH increased by 1.4 and 2.2 times respectively. E2 and cortisol were similar to normal values. Conclusions: The hormonal profiles of patients with PNET and PA differ, except T with blood levels increasing in both tumors. The presence of NEC in PA decreases blood levels of T and normalizes E2 and cortisol.
Comprehensive study of genetic features of pancreatic neuroendocrine tumors.
Authors: Trifanov Vladimir S. , Kit Oleg I. , Gvaldin Dmitry Yu. , Timoshkina Natalya N. , Sanamyants Sergey V. , Myagkov Roman E. , Gaziev Umar Muhmadovich , Fomenko Yuriy A. , Petrov Dmitry S.
Published: May 2020

e16699

Background: Pancreatic neuroendocrine tumors (panNETs) are a heterogeneous, relatively rare type of neoplasm which distinguishes a long clinical course in a large number of cases, that leads to the fact that the prevalence rate of NETs is one of the highest. The purpose of this study was a research the mutational profiles of panNETs of various grades of malignancy and to search for new candidate genes involved in the oncogenic processes of this pathology. Methods: The study included a retrospective group of 24 patients (10 men, 14 women, median age - 60 years old) with a diagnosis of panNET, treated in the RRIO from 2011 to 2018. Comprehensive cancer panel (409 genes) were used for NGS procedure on the NextSeq 550 platform(Illumina, USA). To work with raw data, we used the standard pipeline proposed by BaseSpace (Illumina, USA). Interpretation of the identified variants was carried out in accordance with the recommendations of the Association for Molecular Pathology, American Society of Clinical Oncology and College of American Pathologists. Results: 119 mutations in 54 genes were detected in samples of panNETs. 26 genetic variations were characterized as new, not previously described for panNETs. 18% of the mutations were activating, 35% of the variants led to a loss of function of the encoded protein, 52% were not classified. Candidate genes that have not been previously described in the literature and which are potentially involved in pancreatic oncogenesis are identified: CREB1, TCF12, PRKAR1A, BCL11A and BUB1B. The largest number of mutational events occurred in the genes responsible for histone methylation; in addition, 38% described genetic alterations in the regulation of the SMAD2/3 signaling pathway. Conclusions: According to the NGS study of panNETs of low and moderate malignancy in the Russian cohort, a unique spectrum of 119 mutations was obtained, of which 26 were not previously described. The discovered molecular genetic changes in the signaling pathways underline the importance of impaired epigenetic control of transcription in pancreatic oncogenesis and open up new prospects for targeted therapy.
GETNE-SILVELUL study: A new immunohistochemical score (SPI) in patients (pts) with pancreatic neuroendocrine tumors (PanNET) treated with everolimus or captem.
Authors: Viudez Antonio , Crespo Guillermo , Gómez-Dorronsoro Maria Luisa , Benavent Marta , Hernando Jorge , Goñi Saioa , García Beatriz , Sevilla Isabel , Alonso Vicente , González-Borja Iranzu , Lopez Carlos , Custodio Ana , Hernandez Irene , Llanos Marta , Carmona Alberto , Pérez-Sanz Jairo , López San Vicente Borja , De Jesus-Acosta Ana
Published: May 2020

e16707

Background: Previously our group showed the potential use of a score based (SPI) on MGMT, NDRG-1 and PHLDA-3 immunohistochemistry (IHC) expression as predictor of outcome in operated PanNET (Viúdez et al. Oncotarget 2016). The present retrospective multicenter project is analyzing the predictive/prognosis role of MGMT, NDRG-1 and PHLDA-3 in patients treated with advanced PanNET treated CAPTEM or everolimus. Methods: IHC nuclear staining for MGMT and PHLDA-3 is being scored as 0, 1-5%, 6-50% and ≥ 51%. For NDRG-1, we are using a cytoplasmic score from 0 to 2 based on distribution pattern (null, patched or diffuse). Results: 60 of 105 pts have been fully analyzed., most of then women (53%) and median age of 63 (27-79). 30 pts were treated with CAPTEM and 30 pts with everolimus. Median previous lines were 1 (21,7% received chemotherapy previously), and 91,7% pf pts had ki67 < 20%. 65,5%, 10,2% and 29,1% were null for MGMT, NDRG-1 and PHLDA-3 IHC analysis. In the entire cohort K-M analysis showed significant differences for PFS or OS based on best response observed (p = 0,0001) and number previous lines received (p = 0,05), respectively. In pts treated with CAPTEM, log rank analysis showed significant differences for PFS (p = 0,047 HR:4,63 CI95%: 1,023-20,990) and OS (p = 0,040 HR:5,433 CI95%: 1,082-27,266) based on our SPI. Similar, although not significant, results were observed in everolimus-treated cohort for PFS (p = 0,529) and OS (p = 0,592) according to SPI. Conclusions: As it was described previously in operated PanNET, our SPI also seems to own predictive role in pts with advanced PanNET treated with CAPTEM or everolimus. More mature results of our work are needed and will be presented during 2020 ASCO Annual Meeting.