bluuebunny/crossref_metadata_2025 huggingface dataset:
Is there a correlation between clinic-pathological features, MSI, PD-L1 and survival outcomes in resected gastric cancer? Looking for optimal biomarkers.
Authors: Ratti Margherita , Valeri Nicola , Hahne Jens Claus , Lampis Andrea , Ghidini Michele , Tomasello Gianluca , Fassan Matteo , Donida Bianca Maria , Senti Chiara , Passalacqua Rodolfo
Published: May 2019

e15566

Background: Identification of prognostic biomarkers for gastric cancer (GC) patient selection is compelling to improve survival outcomes. Microsatellite instability (MSI) is related with a positive prognostic effect in GC, whereas perioperative chemotherapy resulted detrimental in this subgroup. In metastatic GC, immunotherapy with anti-PD1/PD-L1 drugs has shown promising results. Nevertheless, in early stages, data on the relation between MSI, clinic-pathological features, PD-L1 expression and overall survival (OS) remains sparse, especially in Western population. In our study, the prognostic role of MSI, clinic-pathological features and PD-L1 expression in a cohort of Italian GC patients was examined. Methods: CP data of 148 consecutive stage I-III GC pts resected in Cremona Institute between 2010 and 2014 (mostly chemo and/or radio-naive) were collected. MSI analysis was performed on tissue samples for all cases by polymerase chain reaction. PDL-1 expression, evaluated by immunohistochemistry, was assessed in MSI group. Differences between subgroups were evaluated with Chi-square test; Kaplan-Meier method and Long Rank test were used to calculate OS. Results: Female sex (p=0.012), earlier TNM stages (p=0.011) and limited nodal involvement (p=0.29) significantly correlated with MSI status. MSI is significantly associated with better prognosis, exhibiting an advantage of 28.6 months in OS compared with microsatellite stable subgroup (p<0.001). Most MSI patients expressed PD-L1. MSI patients without PD-L1 expression showed higher percentage of clinical features correlated with better prognosis compared with PD-L1 expressing MSI patients and MSS subgroup. Conclusions: MSI is an independent prognostic biomarker in GC and identifies a subset of patients with better OS and specific clinic-pathological features, including high percentage of PD-L1 expression. MSI could represent a promising biomarker to select patients for chemotherapy versus immunotherapy in non-metastatic disease.
Identification of clinically actionable mutations and immunotherapy biomarkers in Chinese esophageal squamous cell carcinoma patients.
Authors: Wang Minghui , Zhang Junkai , Gu Weiquan , Li Yun , Song RongFeng , Wang Wenjing , Cui Qiang , Zhang Shuirong , Chen Xiaoqian , Shi Weiwei
Published: May 2019

e15576

Background: Esophageal squamous cell carcinoma (ESCC), the major esophageal cancer histological type in East Asia, has limited therapeutic options and is associated with poor prognosis. Here, we identified clinically actionable genomic alteration (GA) for potential targeted and immunotherapy in Chinese ESCC patients by next generation sequencing (NGS). Methods: Clinical data were collected from 150 ESCC patients from March 2011 to December 2018, with a median follow-up of 34 months. NGS-panel sequencing of 466 cancer genes was performed on FFPE tumor and matched blood sample. Tumor mutational burden (TMB) was assessed in all patients by standard NGS algorithms. PD-L1 expression was evaluated in 61 samples by IHC (28-8 Ab). Results: Overall, 75.5% of ESCC patients harbored at least one clinically actionable GAs with the most frequent being CCND1 (40%), CDKN2A (40%), CDKN2B (24%), PIK3CA (14%) and FGFR1 (8%). Most clinically actionable GAs occurred in genes involved with cell cycle (61%) and with PI3K pathway (23%). Clinically actionable GAs also distributed in BRCA2 (5%), ATM (3%), MET amp (3%), KIT (3%), EGFR mut (2%), PDGFRA (2%) and ERBB2 amp (1%). The lowest 25% (TMB-L), median and highest 25% TMB (TMB-H) value was 4.6, 6.9 and 9.2 muts/Mb, respectively. Compared with younger patients, patients ≥50 years had higher TMB ( p= 0.047). Compared with TMB-L ESCCs, frequencies of NOTCH2 (15.9% vs 0%, p= 0.015), PIK3CA (22.7% vs 2.8%, p= 0.019) and KMT2D (25.0% vs 5.6%, p= 0.031) were significantly higher in TMB-H. Notably, amplification in 11q13 region, MDM2/ MDM4 and EGFR, which potentially relates to immunotherapy hyperprogression, accounted for 48% of TMB-H. Eleven patients (18%) showed PD-L1≥1%, in which 7 pts were also TMB-H. Conclusions: In Chinese ESCCs, clinically actionable GAs were detected in most patients, which highlights the promise of molecularly directed therapies. Patients with PD-L1 positive/TMB-H/both, who could potentially benefit from immunotherapy, accounted for 41%. Older age, NOTCH2, PIK3CA and KMT2D mutations correlated with TMB-H.
The regulation effect of EGFR signaling pathway on PD-L1 expression on esophageal squamous cell carcinoma cell lines.
Authors: Wang Ran Lin , Li Tao , Huang Jianming , Lv Jiahua
Published: May 2019

e15577

Background: To explore the effect of radiation combined with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKI) on the expression of PD-L1 in ESCC cell lines, and to provide theoretical support for radiotherapy combined with EGFR-TKI for esophageal cancer. Methods: Reverse transcription-polymerase chain reaction (RT-PCR) method was used to assess EGFR and PD-L1 mRNA expression on ESCC cell lines when different doses of X-ray irradiation were conducted on ESCC cell lines TE-1 and ECA-109 combining with EGFR-TKI or not. Results: In ESCC cell lines TE-1 and ECA-109, the expression of EGFR and PD-L1 mRNA was increased significantly by the activation of EGFR signaling pathway and decreased after the use of gefitinib (P > 0.01). Both EGFR (P < 0.01) and PD-L1(P < 0.01) mRNA expression of ESCC cell lines TE-1 and ECA-109 were increased by radiotherapy alone. EGFR-TKI could block the increase of both EGFR mRNA (P < 0.01) and PD-L1 mRNA (P < 0.01) which was induced by radiation. Conclusions: EGFR signaling pathway is involved in the regulation of PD-L1 expression in ESCC cell lines. Radiation could up-regulate the expression of EGFR and PD-L1 mRNA in ESCC cells which could be blocked by the use of EGFR-TKI.
Surveillance and outcomes after curative resection for gastroesophageal adenocarcinoma (GEAC).
Authors: Jiang Di Maria , Suzuki Chihiro , Espin-Garcia Osvaldo , Lim Charles Henry , Ma Lucy Xiaolu , Sun Peiran , Sim Hao-Wen , Natori Akina , Chan Bryan Anthony , Yokom Daniel , Moignard Stephanie , Chen Eric Xueyu , Liu Geoffrey , Swallow Carol Jane , Darling Gail Elizabeth , Wong Rebecca , Jang Raymond Woo-Jun , Elimova Elena
Published: May 2019

e15579

Background: Although commonly performed, evidence supporting routine surveillance testing (SvT) in patients (pts) with resected GEAC is lacking. We evaluated patterns of relapse, frequency of salvage therapy and outcomes among pts with resected GEAC who underwent surveillance. Methods: Between 2011 and 2016, 210 consecutive pts with GEAC followed at Princess Margaret Cancer Center after resection were reviewed. SvT was any investigation performed in the absence of pt-reported symptoms, abnormal physical exam findings, or bloodwork. Relapse patterns were classified as locoregional (LRR; surgical anastomosis/gastroesophageal lumen/regional nodes) or distant (DR; beyond locoregional). Time-to-relapse (TTR) and overall survival (OS) were calculated from initial diagnosis, post recurrence survival (PRS) from initial relapse. Results: Median age was 64.1 years. Esophageal (14%), gastroesophageal junction (40%), and gastric adenocarcinomas (45%) were treated with surgery alone (29%), surgery plus perioperative chemotherapy (26%) or surgery plus chemoradiation (45%). SvT included imaging (71%), endoscopy (19%), tumor markers (6%), and clinical visits alone (9%). After median follow-up of 38.3 months (mo) (range 5.6-122.3), 3- and 5-year OS rates were 68% (95% confidence interval (CI) 62-75%) and 56% (95% CI 49-64%) respectively. Among 97 relapses (46%), 51 were detected by SvT, 45 by symptoms. Relapse patterns included LRR alone (4%), DR alone (86%) and both (10%). The majority of relapses (93%) occurred within 3 years. Pts with SvT-detected relapse had similar median TTR (16.2 vs 13.3 mo, p = 0.40) but longer PRS (16.5 vs 4.6 mo, p < 0.001) and OS (36.2 vs 23.7 mo, p = 0.004) than pts with symptomatic relapse. Salvage therapy in 4 pts (2%) resulted in post recurrence disease-free survival ≥2 years. Duration of palliative chemotherapy was similar between 28 pts with SvT-detected relapse and 18 pts with symptomatic relapses (3.9 vs 3.3 mo, p = 0.64). Conclusions: Following curative resection, 96% of relapses were distant. Routine SvT rarely enabled successful salvage therapy and did not extend duration of palliative chemotherapy. Longer OS in SvT-detected relapses was not due to earlier disease detection. These findings do not support routine SvT in pts with resected GEAC.
Genome-wide copy number alteration (CNA) of circulating cell-free DNA (cfDNA) as a prognostic biomarker in esophageal squamous cell carcinoma (ESCC).
Authors: Im Hyeon-Su , Bang Yeonghak , Jeong Hyehyun , Kang Jihoon , Cho Eunhae , Jang Ja-Hyun , Lee Junnam , Park Sook Ryun
Published: May 2019

e15582

Background: Although neoadjuvant chemoradiation (nCRT) plus surgery or definitive CRT (dCRT) are the standard treatment for locally advanced ESCC, there are no reliable clinical tools for predicting prognosis or monitoring treatment response for CRT in ESCC. We aimed to identify a biomarker for predicting outcomes using cfDNA in ESCC patients (pts) receiving CRT. Methods: This prospective biomarker study analyzed pretreatment plasma cfDNA from pts with nCRT plus surgery (n = 23) and pts with dCRT for locally advanced ESCC (n = 17) at Asan Medical Center in South Korea from Jul. 2017 to Jun. 2018. Low depth whole-genome sequencing of cfDNA was used to identify CNA and I-score was developed to express genomic instability. I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. Results: The pathologic complete response (pCR) was achieved in 7 pts (30.4%) in the nCRT group, and the clinical complete response (cCR) was achieved in 3 pts (17.6%) and clinical partial response (cPR) in 8 pts (47.1%) in the dCRT. The baseline cfDNA concentrations were no significant association with the clinical T stage (cT 1-2 vs. cT 3-4; 0.27 vs. 0.28 ng/μL; p = 0.752), pathologic response (pCR vs. non-pCR; 0.26 vs. 0.30 ng/μL; p = 0.270), ypT stage (ypT 0-2 vs. ypT 3-4; 0.28 vs. 0.36 ng/μL; p = 0.161) and ypTNM stage (ypTNM 1 vs. ypTNM 2-4; 0.26 vs. 0.36 ng/μL; p = 0.065). When analyzing cfDNA concentration before and after CRT, cfDNA concentration was significantly increased after CRT (0.31 vs. 0.55 ng/μL; p = 0.007). The baseline I-score was not associated with baseline clinical stage, but was significantly associated with ypT stage (ypT 1-2 vs. 3-4; 30.4 vs 839.1; p = 0.009), time to progression (median TTP; 11.8 mo in the I-score-low group vs. 6.1 mo in the I-score-high group; p = 0.036), and overall survival (median OS; not reached vs. 10.4 mo; p = 0.046) in the nCRT group. In the dCRT group, I-score was significantly associated with higher disease progression rate (33.3 vs. 58.8%; p = 0.024) with tendency of distant metastasis (33.5 vs. 57.1%; p = 0.490), and short response duration (median, 5.7 mo in the I-score-high group vs not reached in the I-score-low group). Conclusions: The cfDNA concentration is not a good biomarker for prognostication and monitoring the course of treatment in ESCC pts treated with CRT. But the I-score, an indicator of genomic instability in ctDNA, was a significant predictor of poor prognosis.
Genomic analysis of hepatocellular carcinoma (HCC) with active hepatitis B virus (HBV) replication.
Authors: Lim Huat Chye , Gordan John Dozier
Published: May 2019

e15593

Background: HBV replication contributes to HCC initiation and is associated with worse patient outcomes. Prior tumor genomic studies of HBV-positive and -negative (HBV+/-) HCC have used detection of HBV surface antigen (HBsAg) in serum to annotate HBV status. However, a substantial proportion of HBsAg+ patients lack HBV replication in tumor, suggesting a potentially distinct patient subset. In this study, we determined HBV status by measuring tumor HBV RNA, a proxy for active replication. We then investigated HBV RNA+/- association with somatic mutations, gene sets, homologous recombination deficiency (HRD) and tumor mutation burden (TMB). Methods: RNA-Seq data for 371 HCC tumors were obtained from TCGA. Tumors were classified as HBV RNA+ if they harbored more than 1 HBV RNA read per million human reads, as measured using GATK PathSeq software. Associations between HBV RNA status and somatic mutations, gene sets, HRD and TMB were investigated. HRD score was calculated as the sum of 3 independent HRD measures (large scale state transitions, loss of heterozygosity and telomeric allelic imbalance). Results: HBV RNA+ status was associated with a higher rate of nonsynonymous somatic mutations in multiple genes, including the tumor suppressors TP53, CDKN2A, CHD5 and TET1, as well as AXIN2 and the proto-oncogene BCL11A ( p < 0.05 for all), while HBV RNA- status was associated with a higher rate of nonsynonymous mutations in the chromatin modifier BAP1 ( p = 0.03). In gene set enrichment analysis of normalized RNA-Seq expression data, HBV RNA+ status was associated with increased transcription of DNA repair genes, as well as genes upregulated by mTORC1 and MYC (FDR < 0.03 for all). HBV RNA status was also associated with HRD score (22.19 for HBV RNA+ vs. 15.97 for HBV RNA-, p = 1e-6), but not with TMB. A substantial subset of HBV RNA+ patients (33/100) were not annotated as HBV+ in the TCGA clinical database. Conclusions: HBV status based on tumor HBV RNA detection identifies a genetically distinct subset within all HBV-infected HCC patients that is associated with nonsynonymous somatic mutations in several genes and differential transcription of gene sets, some of which have not been previously reported, as well as with HRD score. These findings suggest potential for differential responsiveness to targeted therapies.
The impact of geography and center volume on access to care and outcomes in advanced hepatocellular carcinoma (HCC): A retrospective population based study.
Authors: Yu Irene S. , Liu Shiru Lucy , Zaborska Valeriya O. , Raycraft Tyler , Lim Howard John , Gill Sharlene , Davies Janine Marie
Published: May 2019

e15597

Background: Treatment of advanced HCC is complex and involves specialized multidisciplinary care. We aimed to characterize the impact of geography and center volume on access to care and outcomes in HCC patients (pts). Methods: HCC pts who received sorafenib in British Columbia from 2008 to 2016 were included. Pts were stratified by rural vs urban status (distance from cancer center), and high volume (HVC) vs lower volume (LVC) centers. Chi-square tests and Kaplan Meier were used to test for differences between groups. Results: Of 288 pts identified, median was age 62 (IQR 56-72), 81% male, 40% Asian, 82% ECOG 0/1 and 90% Child Pugh A. Hepatitis C (32%), hepatitis B (31%) and alcohol (25%) related liver disease were most common. Most pts resided within 100 km (85%) and 173 (60%) were treated at HVC. Ethnicity, liver disease etiology, ECOG and M1 disease varied by stratification (Table). Rural pts were more likely to see an internist (30% vs 16%, p=0.04); access to other subspecialists was similar (all p>0.05). HVC pts were more likely to see a hepatologist (83% vs 19%), hepatobiliary surgeon (57% vs 42%), and/or interventional radiologist (32% vs 13%) compared to LVC pts (all p<0.01). Number of specialists seen correlated with survival (36.4 vs 20.3 vs 12.6 mo for ≥ 3 vs 2 vs 1 specialist(s), p<0.01). Median OS from time of diagnosis was higher for HVC pts (24.7 vs 13.2 mo, p<0.01), but similar when stratified by distance (p=0.44) and from sorafenib initiation (p=0.66). Conclusions: HCC patients treated at a HVC are more likely to see specialized clinicians and have improved survival outcomes. Further research is needed to understand social and clinical factors that influence these findings. [Table: see text]
ET140202 t-cells: A novel therapy targeting AFP/MHC complex, that is both safe and effective in treating metastatic hepatocellular carcinoma.
Authors: Liu Chang , Liu Hong , Wang Yun , Zhang Xiaogang , Fan Fengling , Wang Ruitao , Qu Kai , Nejadnik Bijan , Shi Bingyin , Liu Cheng
Published: May 2019

e15614

Background: CAR-T cells has emerged as novel cancer treatment, particularly for hematologic malignancies. However, treatment of solid tumors using redirected T-cells remains challenging. We developed a novel T-cell platform ET140202 targeting AFP/MHC complex enhanced by GPC3-guided co-stimulation. Herein we report a case study of ET140202 for a male subject with 3 liver HCC lesions, multiple lung metastases and with no response to sorafenib and regorafenib. Methods: The schedule and dose of ET140202 T cell infusion was summarized in Fig 1a. The subject received 16 i.v. infusions of ET140202 T cells at doses ranging from 0.42-6 ×106 cells/kg, totaling 2.461×109 cells. Vital signs, blood cell count, and blood chemistry were monitored on Days 1, 3, 7, and 14. Clinical responses were assessed at Month 1, 3, 5, 9 and 12. Results: T-cell expansion was observed shortly after each infusion. No treatment-related Grade 3 or higher AEs observed. Grade 1 or 2 events that were possibly attributable to therapy included dry mouth, dry skin peeling from hand and foot, and voice hoarseness and oral mucosal ulceration. All events resolved in 3-5 days with symptomatic treatment. At Day 40, the subject developed Grade 2 mucositis, which improved in 5 days following vitamin C treatment and oral hygiene care. The subject did not experience any signs of CRS or neurotoxicity. Cytokines including IL-2, IL-6, GM-CSF, INFg and TNFa were below detection at most time points post-infusion. All 3 liver lesions regressed at month 5 and the regression persisted to the last follow-up timepoint at month 12. All 4 lung nodules appeared to slightly increase in size at month 1, which may be attributed to pseudo-progression and substantially decreased at month 5. The decrease of the lung lesions also persisted to month 12. AFP levels were increased above the baseline shortly after T-cell infusion, possibly due to the lysis of tumor and gradually decreased to the normal level of 10 ng/mL on Day 135 and persisted to the last follow-up on day 365. Conclusions: ET140202 T cells has the potential to be used safely and effectively in AFP+/HLA-A2+ HCC to induce regression of primary and metastatic lesions.
An exploratory analysis based on tumor location of REACHIN, a randomized double-blinded placebo-controlled phase II trial of regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced (nonresectable) and metastatic biliary tract tumors.
Authors: Demols Anne , Borbath Ivan , Van Den Eynde Marc , Houbiers Ghislain , Peeters Marc , Maréchal Raphaël , Delaunoit Thierry , Goeminne Jean Charles. , Laurent Stéphanie , Holbrechts Stephane , Paesmans Marianne , Van Laethem Jean-Luc
Published: May 2019

e15622

Background: The REACHIN trial met its primary endpoint of improving PFS for patients with biliary tract cancer (BTC) treated with regorafenib (R) as compared to placebo (P): Median (m) PFS for R was 3.0 months (mo) (95% CI: 2.3-4.9) and 1.5 mo (95% CI : 1.2-2.0) for P with an HR= 0.49 (95% CI: 0.29-0.81), p=0.005 (Demols A et al, ASCO-GI 2019, Abstr 345). We exploratory analyzed the benefit of R according to tumor location: intra-hepatic (ICC), extra-hepatic (ECC), gallbladder (GB) or peri-hilar (PH). Methods: Tumor locations were recorded at randomization of patients in REACHIN (NCT02162914), a multicenter double-blinded P-controlled randomized phase II study to evaluate the safety and efficacy of R in patients with locally advanced (non resectable) and metastatic histologically proven BTC, progressing after gemcitabine-platinum. We analyzed mPFS according to tumor location and their respective 95% CI. Results: 66 patients were randomized and the mPFS data are summarized in the table. Conclusions: Most of the patients had ICC location (64%). The mPFS in the P arm is similar according to the tumor location. Despite its exploratory value and the small number of patients per tumor location, R seems superior to P in ICC, GB and PH. Data in ECC are not conclusive. Additional biomarkers (FGFR, NGS analysis) are ongoing and will be presented at the meeting. Clinical trial information: NCT02162914. [Table: see text]
Characterizing PD-L1/PD-1 expression in hepatocellular carcinoma and implications on postresection treatment response.
Authors: Farha Mark , Green Michael , El Naqa Issam
Published: May 2019

e15626

Background: Despite recent progress in the treatment of liver cancer, its outcomes remain poor and recurrence rates are as high as 70% in 5 years. Here we seek to use PD-1 and PD-L1 expression to characterize the tumor immune microenvironment and determine whether the expression profile can be associated with response to specific treatments and be applied to personalize treatment regimens in the post-resection setting. Methods: Patients in the study had a mean age of 59, and the majority were caucasian (73%). Most were classified as Child-Pugh A (60%) and TNM stage 1-2 disease (63%). RNA Seq by Expectation Maximization (RSEM) values from the TCGA hepatocellular carcinoma (HCC) dataset for the PD-1 and PD-L1 genes were collected and normalized. RSEM values above the median were labeled “high”, while values below the median were labeled “low”. Corresponding clinical and demographic data were recorded. Survival analysis and multivariate Cox regression analyses were performed, and the Estimation of STromal and Immune cells in MAlignant Tumors using Expression data (ESTIMATE) scores were included to further characterize the tumor purity and the immune cell infiltration. Results: The median post-treatment survival of all patients was 32.4 months. Significant covariates impacting survival were age (HR = 1.05), AJCC TNM stage (HR = 1.61), and high PD-L1 expression (HR = 0.37). When stratified by ESTIMATE, the PD-1 high/PD-L1 high patient cohort had a mean immune score of 450, which was significantly higher than the other cohorts and the only positive score. Furthermore, when patients in this cohort were treated with chemotherapy, radiation, or sorafenib, their time-to-death was 20 months longer than patients from the same cohort treated with local embolization or ablation. Conclusions: We have provided data suggesting a survival advantage for patients with a positive ESTIMATE immune score and high PD-L1 and PD-1 expressions when treated with chemo, radiation, or sorafenib. Existing data suggests that immunotherapy can further synergize with these treatments in HCC and offer another promising approach to improve survival after resection for about 30% of HCC patients with this immune profile.
FOXO1, an AKT downstream substrate, plays a role as tumor suppressor in HCC pathogenesis.
Authors: Zhang Shu , Chen Xin
Published: May 2019

e15627

Background: Hepatocellular carcinoma (HCC) represents the fifth most common tumor types in the world. However, the signaling pathways underlying hepatic pathogenesis are still poorly understood. Activation of PI3K/AKT signaling cascade has been implicated in HCC development. It has been well-established that the mammalian target of rapamycin complex 1 (mTORC1), is a major downstream effector of AKT. The reason why mTORC1 can be consistently activated is partly due to inactive mutations of a negative element regulating mTORC1, tuberous sclerosis 2 (TSC2), found in 10% human HCCs. Beyond TSC2, forkhead Box O transcription factor 1 (FOXO1), is another AKT substrate. It has been proved that FOXO1 plays a crucial role in the insulin signal pathway and liver regenerationrelying on AKT isoforms. However, the role of FOXO1 in HCC development has not been well established. Methods: FOXO1 expression was analyzed in human liver cancer from TCGA database and multiple HCC cell lines were used to verify the mechanism of how FOXO1 regulate HCC cell growth downstream of AKT activation and we further confirmed the role of FOXO1 in HCC development in vivo. Results: By using TCGA database the mRNA level of FOXO1 significantly decreases among the FOXO family, comparing tumor tissue to the surrounding tissue. The overall survival rate favors patients with high FOXO1 expression. The inhibition efficacies of MK2206, a pan-AKT inhibitor, in both TSC2 wide type cells and TSC2-null ones are not significantly different, indicating TSC2 is not the only target downstream of AKT. As FOXO1 is another major target, we knockdown endogenous FOXO1 in the same HCC cell lines, the activation of mTORC1 was no longer inhibited. Furthermore, we overexpress the activated FOXO1 (FOXO1 AAA) in TSC2-null HCC cell lines. Cell growth are significantly prohibited, implicating FOXO1 is a tumor suppressor in HCC cells. Overexpression of activated FOXO1 can also delay AKT depended HCC in met/β-catenin FVB mice model. Conclusions: AKT/mTORC1 can be a classic molecular pathway for HCC pathogenesis. Nevertheless, the parallel substrate of AKT, FOXO1, may also be an important factor in the TSC2 independent way.
The efficacy and safety of lenvatinib in patients who did not meet the inclusion criteria of the phase 3 trial (REFLECT trial) in real-world practice in Japan: A nationwide multicenter study in Japan.
Authors: Tsuchiya Kaoru , Kurosaki Masayuki , Marusawa Hiroyuki , Abe Takehiko , Ogawa Chikara , Sohda Tetsuro , Kimura Hiroyuki , Kondo Masahiko , Tsuji Keiji , Furuta Koichiro , Shigeno Masaya , Joko Kouji , Narita Ryoichi , Uchida Yasushi , Yoshida Hideo , Akahane Takehiro , Kobashi Haruhiko , Mitsuda Akeri , Kojima Yuji , Izumi Namiki ,   Japanese Red Cross Liver Study Group
Published: May 2019

e15629

Background: Lenvatinib (LEN) has been approved as a single agent for patients with unresectable hepatocellular carcinoma (u-HCC) since Mar 2018 in Japan. We conducted a nationwide multicenter study and especially focused on the efficacy and safety in the patients who did not meet the inclusion criteria of the phase 3 trial (REFLECT trial). Methods: A total of 202 patients received LEN from March 2018 at 21 sites in Japan was registered. Tumour assessments in accordance with modified RECIST were done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Adverse events (AEs) were graded according to the CTCAE ver4.0. Results: In this study, 128 of 202 (63%) patients did not meet the inclusion criteria of the REFLECT trial. For the reasons, 69 patients received TKI therapy before LEN, 37 patients were Child-Pugh B, 6 patients showed main portal vein invasion,13 patients had HCC which occupied ≥ 50% of liver, and 22 patients were with lower platelet ( < 75 × 10⁹ per L) . Median observation time was 4.1 months in all patients, 22 patients died, and median overall survival (OS) was not reached. As the 2nd-line therapy (after sorafenib), 45 patients received LEN and 24 patients did as the 3rd-line (after regorafenib). The OS between TKI naïve and experienced patients was not significantly different, even though baseline albumin level and ALBI score were significantly lower in TKI experienced patients than TKI naïve (p = 0.001 and 0.005). Objective response rate (ORR) and disease control rate (DCR) of TKI naïve patients were 37% and 84%, while those of TKI experienced were 27% and 76%. Child-Pugh B patients (n = 36) had significantly shorter OS than Child-Pugh A (p = 0.01) and median OS in Child-Pugh B patients was 6.1 months. Drug discontinuation due to AEs and elevated aspartate aminotransferase were significantly higher in Child-Pugh B patients (p = 0.005 and 0.001). The OS, treatment duration and drug discontinuation were not significantly different between patients with or without lower platelets. ORR and DCR in patients with lower platelets (n = 22) were 18% and 63%. Conclusions: The response rate of LEN in patients who experienced TKI therapies was similar to that in TKI naïve patients. The median OS in Child-Pugh B patients was 6.1 months and elevated aspartate aminotransferase during LEN was frequently reported in such patients. The OS and treatment duration were not significantly different between patients with or without lower platelets at the cut off of < 75 × 10⁹ per L.
Can artificial intelligence support the clinical decision making for Barcelona clinic liver cancer stage 0/a hepatocellular carcinoma in China?
Authors: Chen Ze-bin , Chen Shu-Ling , Liang Rui-Ming , Peng Zhen-Wei , Shen Jing-Xian , Zhu Wan-Jie , Li Bin , Peng Sui , Kuang Ming
Published: May 2019

e15634

Background: Artificial intelligence (AI) is emerging as a revolutionary technology with the power to transform healthcare. IBM Watson for Oncology (WFO), as an AI clinical decision support system (CDSS), has been investigated about its impact on clinical decision making in some cancer types and shown potential to be an effective CDSS in cancer care. However, the feasibility of WFO in Chinese patients with hepatocellular carcinoma (HCC) has not been reported. Methods: Artificial intelligence (AI) is emerging as a revolutionary technology with the power to transform healthcare. IBM Watson for Oncology (WFO), as an AI clinical decision support system (CDSS), has been investigated about its impact on clinical decision making in some cancer types and shown potential to be an effective CDSS in cancer care. However, the feasibility of WFO in Chinese patients with hepatocellular carcinoma (HCC) has not been reported. Results: The overall concordance rate was 60.5%, with 53.7% and 61.4% in BCLC stage 0 and A respectively. After the MDT re-review, the overall, BCLC stage 0 and A concordance rate increased to 67.3%, 65.9% and 67.3%. The main discordance was that MDT recommended more aggressive treatment options (eg. hepatectomy) than WFO did. The increase in concordance rate may be due to the progress of treatment of HCC in the past 5 years. Conclusions: With the concordance and reasonability verified by MDT in this study, WFO may provide practical reference in BCLC stage 0/A HCC. Localization is required to cover the disparity in guideline and patient characteristics between China and the US.
Histone deacetylase 6-EGFR axis in recurrent hepatocellular carcinoma.
Authors: Yeh Yao-Tsung , Dai Hong-Ying , Wang Shen-Nien , Chang-Chien Pin-Jou
Published: May 2019

e15638

Background: Alterations of histone deacetylases (HDACs) and related signaling have been increasingly associated with cancer development and treatment. Among those HDACs, HDAC6 uniquely functions in maintaining mRNA stability of certain genes. The aim of this study was to determine the clinical impacts and associated mechanisms of HDAC6 in hepatocellular carcinoma (HCC). Methods: Immunohistochemistry is firstly applied to analyze the distribution patterns of HDAC6 in 122 patients and the obtained results are statistically analyzed with clinicopathological characteristics and patient survival. XTT, flowcytometery, transwell assay, real-time PCR, IF, IB, immunoprecipitation (IP), and RNA-IP are used to determine the bio-impacts and underlying mechanisms of HDAC6 in liver cancer cells. Results: Both cytoplasmic and nuclear staining of HDAC6 proteins were mainly decreased in cancerous lesions. Nevertheless, increased cytoplasmic HDAC6 staining was positively correlated with disease recurrence (p = 0.002). Increased nuclear frequency, but not cytoplasmic intensity, of HDAC6 was associated with a poor survival rate in HCC patients (p = 0.041). Restoration of HDAC6 expression increased the proliferation, S phase, migration and invasion of the HepJ5, Huh7 and Mahlavu cells, lacking detectable HDAC6 expression. More interestingly, ectopic HDAC6 overexpression increased a ligand-independent expression of p-AKT, beta-catenin and cyclin D, and subsequently promoted the entry of beta-catenin into the nucleus. Both transcripts and proteins of the EGFR, a dominant trigger of AKT signaling, were unexpectedly increased upon HDAC6 restoration in HepJ5, Huh7 and Mahlavu cells. The expression of EGFR was not restored by treatment with MG132 (proteasome inhibitor) in HepJ5, Huh7 and Mahlavu cells, and HDAC6-specific siRNA decreased both HDAC6 and EGFR expression in Hep3B and SK-Hep1 cells, having detectable HDAC6 and EGFR expression. IP and RNA-IP analysis revealed that HDAC6 interacted with HuR and increased EGFR mRNA stability. Accordingly, the expression of HDAC6 and EGFR were positively correlated in cancerous lesions. Conclusions: Our results suggest that the contribution of HDAC6 to recurrent HCC may act through its maintenance of EGFR mRNA stability. HDAC6 may serve as a rational treatment target in recurrent HCC.
First-in-class hafnium oxide nanoparticles NBTXR3 in the treatment of liver cancers.
Authors: Chajon Enrique , Pracht Marc , Rolland Yan , De Baere Thierry , Nguyen France , Bronowicki Jean-Pierre , Vendrely Veronique , Sa Cunha Antonio , Baumann Anne-Sophie , Valérie Laurent , Rio Emmanuel , Le Sourd Samuel , Gustin Pierre , Perret Christophe , Peiffert Didier , Deutsch Eric
Published: May 2019

e15642

Background: Hafnium oxide nanoparticles, NBTXR3, increase the effect of radiotherapy (RT) by enhancing local energy dose deposit within tumor cells, resulting in increased cell death compared to the same dose of RT alone. NBTXR3 efficacy was demonstrated in a phase II/III study in soft tissue sarcoma (NCT02379845) and is currently evaluated in other solid tumors including liver cancers. The use of this radio enhancer is particularly relevant in liver cancer management, a difficult to treat heterogenous population, due to the presence of underlying liver dysfunction. Methods: Phase I/II study of NBTXR3 activated by RT in patients (pts) with HCC (with/without portal vein tumor thrombus) or liver metastasis (mets) [NCT02721056]. The dose escalation part followed a 3+3 design with tested dose levels equivalent to 10%, 15%, 22% and 33% of baseline tumor volume. Patients were treated with a single intralesional injection (ILI) of NBTXR3 followed by Stereotaxic Body RT (SBRT: 45 Gy/3 fractions/5 to 7 days). Determination of recommended dose(s) and early dose limiting toxicities (DLT) were primary endpoints. Secondary endpoints include assessment of global safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and response rate (mRECIST/RECIST 1.1). Results: The 4 levels of ILI dose escalation were finalized (n = 17): 6 pts at 10% (2 SBRT doses tested due to organs constraints), 4 pts at 15% and 22% (due to fiducial displacement and ILI shift) and 3 pts at 33% were included. ILIs were successful and SBRT was delivered as planned with no observed DLT or NBTXR3-related SAE at all levels. Only one grade 1 AE (fatigue) related to NBTXR3 was reported at dose level 33%. No relevant change of CPS or APRI was observed over time. Among 7 evaluable HCC pts the best target lesion responses by mRECIST were: 3 CR and 4 PR and among 5 evaluable mets pts: 2 PR, 1 SD and 2 PD. Conclusions: This study demonstrated the feasibility and good tolerance of the first in class NBTXR3 ILI. These results have supported a protocol amendment adding a higher dose of NBTXR3 (42% of the tumor volume). This innovative approach might constitute a valuable solution for patients with unresectable liver tumors and liver dysfunction. Clinical trial information: NCT02721056.
Dynamic changes in the immune infiltrate within hepatocellular carcinoma tumor correlate with response to PD-1 blockade.
Authors: Marron Thomas Urban , Desland Fiona , Lavin Yonit , Schwartz Myron E. , Tabrizian Parissa , Fernandez Nicholas , Kim Joel , Tabachnikova Alexandra , Kamphorst Alice O. , Schanoski Alessandra Soares , Brown Brian , Kenigsberg Effi , Sung Max W. , Taouli Bachir , Rahman Adeeb , Merad Miriam
Published: May 2019

e15644

Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths in men worldwide, and is the most rapidly rising cause of cancer mortality in the US. Patients with resectable disease experience high rates of locoregional recurrence, and there are few effective systemic treatment options available. PD-1 blockade was recently approved for 2nd line therapy, and there are promising response rates seen in the 1st-line setting. However, only 20% of patients achieve significant response, thus we must investigate further the tumor-immune microenvironment to understand how to better modulate the immune system in this highly immunosuppressive organ. Methods: We used mass cytometry (CyTOF) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to study protein and transcriptomics of untreated tumor and tumor adjacent tissue, on a single-cell level. Results: Paired CyTOF analysis of 10 tumor lesions/adjacent tissues identified a significant increase in frequency of CD4+ T cells and T regulatory cells, a significant decrease in NK cells and neutrophils, and no difference in CD8+ T cells, macrophages, or dendritic cells (DCs) in the tumor microenvironment compared to the adjacent liver tissue. We also analyzed four patients who received nivolumab and subsequently went on to have their liver tumors resected; two out of the four patients treated had near-complete necrosis of their tumors (radiographically and histologically). Of note, the tumors of the two patients with significant pathologic response contained a significantly higher number of CD103+ tissue resident CD8+ and CD4+ T cells, compared to adjacent tissue. Moreover, activated CD8+ T cells (TIGIT+, PD-1+, TIM3+, and/or CD38+) were significantly higher in the tumor of nivolumab responders, indicating a tumor-specific response. We will also present single cell transcriptomic analyses of T cell and myeloid populations in responders and non-responders. Interestingly, high levels of nivolumab were detected on PD-1+ T cells in the tumor in all 4 patients; we will discuss transcriptional differences between nivolumab-targeted T cells in responders and non-responder patients. Conclusions: Based on this preliminary data we will be opening a clinical trial of neoadjuvant PD-1 blockade in HCC (NCT# pending) in March 2019.
Liver resection in elderly patients over the age of 70 with primary liver cancer: A retrospective analysis.
Authors: Tan Elinor , Sandroussi Charbel
Published: May 2019

e15647

Background: Liver surgery in the elderly remains controversial amidst growing incidence in developed countries. This study compares perioperative outcomes of elderly with non-elderly patients undergoing curative hepatectomy for primary liver malignancies. Methods: 310 patients underwent liver resection for primary tumours between 2000 and 2018. There were 71 elderly (≥70 years) and 239 non-elderly patients ( < 70 years). Survival analyses, stratified according to pathology (Hepatocellular carcinoma (HCC), n = 262 and Cholangiocarcinoma (CC) n = 48), were compared between the elderly and non-elderly group. Multiple regression analyses were performed to evaluate independent predictors of major complications and overall survival. Results: Elderly patients had higher frailty score (modified Frailty Index, mean, 1.14 v 0.51, p < 0.001), more comorbidities (Comorbidities ≥4: 28% v 14%, p = 0.005), had non viral-induced primary liver cancers (Non-Hep B Non-Hep C: 65% v 19%, p < 0.001) with lower AST (p = 0.014) and ALT (p = 0.004) levels. 46% of patients underwent major hepatectomy and were similar between both groups (p = 0.502). The overall complication rate and duration of stay were comparable (p > 0.05). Post-Hepatectomy Liver Failure occurred in 10 (3%) patients with no difference between both groups (p > 0.05). There were 11 (4%) postoperative deaths with higher mortality in the elderly group (8% v 2%, p = 0.011). Multiple logistic regression revealed that MELD ≥11 (OR 2.415, p = 0.480) and a positive surgical margin (OR 2.549, p = 0.024) were independent predictors for major complications. The overall survival (OS) and disease free survival (DFS) for both HCC and CC were similar between elderly and non-elderly group respectively (HCC: 5-yr OS, 62% v 68.5%, p = 0.712; 5-yr DFS, 30.4% v 38.8%, p = 0.323; CC: 5-yr OS, 62.2% v 48.3%, p = 0.919; 5-yr DFS, 43.6% v 28.2%, p = 0.618). Multiple Cox regression revealed that albumin < 40g/L (HR 2.533, p = 0.002) and the presence of vascular invasion (HR 2.417, p = 0.004) were independent predictors of poor survival. Conclusions: Long-term survivals were comparable between the elderly and non-elderly patients following surgical treatment for primary liver cancers. Low albumin and vascular invasion predicted poor survival. Age alone should not be a contraindication to liver surgery. Major complications may be minimised by carefully selecting patient and paying particular attention to the MELD score in elderly patients with primary liver disease. Further prospective studies are required to confirm the findings here.
Transcriptional characterization of microenvironment and their prediction role for the prognosis of hepatocellular carcinoma after surgery.
Authors: Chen Kehe , Wei Haiming , Liu Tianqi , Chen Zhenxiang , Pan Deng , Huang Jingning , Gao Ting , Huang Min , Ren Xiaoshuang , Zhang Jiao , Mao Beibei , Yang Ying , Han Wenbo , Zheng Hongbo , Zhang Henghui
Published: May 2019

e15650

Background: Hepatocellular carcinoma (HCC) is one of the most common prevalent fatal cancers worldwide with poor prognosis due to high incidence of recurrence. For patients with HCC, surgical treatment is a potentially cutative therapy. However, the puzzle in the therapy was the rapid recurrence after surgery. The purpose of this study was to integrate the impact of different immune context present in HCC microenvironment on patients’ prognosis, provide the molecular prediction clue of HCC recurrence. Methods: RNA targeted sequencing was performed on 12 primary tumor specimens from HCC patients. Transcripts of 395 immune related genes expressed in FFPE tumor samples were analyzed. The lima package was used to analyze the different expressed genes (DEGs) between patients with different prognosis. The gene set variance analysis (GSVA) analysis was performed to explore gene sets enrichment related to the recurrence post-resection. Results: 15 DEGs were detected in tissue samples between the two groups (group A: patients who relapsed within one year after surgery; group B: patients who hadn't relapsed beyond two years after surgery). The Antigen processing pathway enrichment may associate with the favorable prognosis (p < 0.05). HLA-A gene expression in group A was lower than that in group B; The gene expression of IL23A, TP63, ALOX15B, BUB1, CXCR2, CCL20, CLEC4C, PTK7, MPO, IL1B, MMP9, GAGE2C, GAGE2A, GAGE2E, DMBT1, FOXM1 in group A was higher than that in group B. Additionally, the combination of 3 genes (TP63, IL23A and BUB1) can distinguish the patients recurrent within 1 year or beyond 2 years post-resection. The joint diagnostic equation is logit (Y = 1) = 0.073 +0.740 *(TP63) + 0.589 * (IL23A)+0.959(BUB1), (Optimal threshold: 0.667, specificity: 1, sensitivity: 0.833). Conclusions: Our results suggest that RNA-seq of immune related genes from FFPE sample can effectively profile the specific landscape of tumor immune microenvironment and predict the survival of HCC. 3 genes’ expression (TP63, IL23A and BUB1) might correlate with recurrence in HCC patients after surgery.
Neutrophil/lymphocyte ratio (NLR) may predict prognostic factor with gemcitabine/cisplatin/S-1 (GCS) for patients with advanced biliary tract cancer (MITSUBA /KHBO1401-1B).
Authors: Otsuru Toru , Ioka Tatsuya , Nagano Hiroaki , Hatano Etsuro , Eguchi Hidetoshi , Kanai Masashi , Kobayashi Shogo , Seo Satoru , Baba Hideo , Taketomi Akinobu , Yoshimura Kenichi
Published: May 2019

e15656

Background: There is little information available about prognostic markers of gemcitabine, cisplatin, and S-1 (GCS) in patients with advanced biliary tract cancer (aBTC). Neutrophil/lymphocyte ratio (NLR) in several cancers including aBTC was reported to be a prognostic and/or predictive factor associated with clinical outcomes. There are no data about relation between NLR and clinical outcome in patient with aBTC who underwent GCS. Methods: Baseline demographics and NLR at enrollment were retrospectively evaluated in 119 patients who received GCS treatment in MITSUBA / KHBO1401 randomized phase III trial, which showed significant superiority of GCS to GC. The clinical utility of the NLR was evaluated by receiver operating characteristic (ROC) curves, and the cutoff values for NLR were 3.7. We divided these patients based on estimated NLR, and evaluated the clinicopathological factors and survival in the two groups (NLR ≧ 3.7 or < 3.7). Results: 32 patients were in NLR ≧ 3.7group and 87 patients were in NLR < 3.7 group. The progression-free survival between two groups was not significantly different (p = 0.45). Although, the median overall survival (OS) of NLR ≧ 3.7 group was 10.4 months, while OS of NLR < 3.7 group was 18.5 months (HR 0.55, 95% confidential interval [CI] 0.36-0.87; p = 0.01).The ratio that was able to continue chemotherapy from initial administration six months later was 83.4%of NLR < 3.7 group, and 65.6% of NLR ≧ 3.7 group (p = 0.04). Conclusions: Our study confirmed that high NLR is associated with worse OS, and suggested it may be a predictive marker for GCS chemotherapy in patients with aBTC.
Postsurgical multiple-sites sampling procedure for the precise detection of microvascular invasion of hepatocellular carcinoma.
Authors: Zhou Qian , Chen Lili , Chen Shuling , Cao Qinghua , Peng Sui , Liao Bing , Kuang Ming
Published: May 2019

e15657

Background: Microvascular invasion (MVI) is an important risk factor of recurrence for hepatocellular carcinoma (HCC). We aimed to explore the relationship of the number of sampling sites (NuSS) and sampling location with positive rate of MVI, and investigate cut-off values for NuSS. Methods: From May 2010 to Feb 2017, 910 HCC patients undergone hepatectomy with well-preserved tissue blocks were retrospectively enrolled. Associations between NuSS and positive rates of MVI were investigated. The thresholds of NuSS according to different factors were determined by Chow test and Breakpoints function, and validated prospectively in 118 patients. In validation cohort, MVI positive rates in different sampling locations were estimated. Results: The positive rates of MVI increased as NuSS increased ( P < 0.001). Tumor size and number were two factors influencing NuSS. A minimum of four, six, eight and eight sampling sites were required for detecting MVI in solitary tumors measuring 1.0-3.0 cm, 3.1-4.9 cm and ≥ 5.0 cm and multiple tumors. The positive rates of MVI as per developed thresholds were significantly higher in all the tumor subgroups of validation cohort than those in routine clinical practice in training cohort (46.7% vs. 20.6%, P= 0.048; 44.4% vs. 24.4%, P= 0.025; 73.3% vs. 50.3%, P= 0.004; 67.7% vs. 45.4%, P= 0.026). The positive rates of MVI in tumor interface were higher than those in proximal and distal paracancerous and normal liver parenchyma. Conclusions: The different thresholds of NuSS according to tumor size and number, and sampling distribution according to location provided evidences of standardized sample collection of liver cancer specimen for accurate MVI diagnosis.