Search

Introduction: Hepatitis often occurs after the initiation of immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI initiates and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remains unclear. Methods: In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns. Results: One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of all patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and similarly, after excluding progressive disease ( p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0 th –15.9 th weeks. Multivariate analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with late elevated bilirubin ( p = 0.003) and AST ( p = 0.005) would indicate poor survival. Discussion/ Conclusion: Hepatitis patterns in patients with aHCC under ICI therapy can predict OS. Close monitoring of hepatitis could help to promptly predict the outcomes of patients receiving ICIs.

This is a retrospective cohort study by analyzing a multi-institutional electronic medical records database in Taiwan to compare long-term effectiveness and risk of major adverse cardiac events (MACE) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate-specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P = .01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63-1.17) and OS (0.68: 0.41-1.14) between the use of ENZ and AA in chemotherapy-naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07-0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy-naïve mCRPC patients with high CV risk profile.

Advanced in local treatment technology and early detection methodology, distant metastasis became a critical issue in Nasopharyngeal carcinoma (NPC). Recently, cancer immunotherapy especially immune checkpoint inhibitors (ICIs) including anti-programmed death-1 (PD-1) and PD-1 ligand (PD-L1) monoclonal antibodies (Mabs) had a rapid progress in cancer patient management. We try to clarify the clinical scenario of immune-related parameters in metastatic NPC. We had check 81 metastatic tissue PD-L1 expression without ICI treatment from the tissue bank of CGMH, Linkou, during 2005~2019. Using anti-PD-L1 antibody, 22C3 Dako, tumor proportional score (TPS) was positive in 43.2% (35/81) checked tissue and combine positive score (CPS) was positive in 58.0% (47/81) tissue respectively. For overall survival (OS) combined with PD-L1 expression in metastatic tissue analysis, positive CPS but not TPS correlated with longer survival with statistical significance (TPS: >0% vs =0%, median survival, 24m vs 22.5m, p=0.615186; CPS: >0% vs =0%, median survival, 28m vs 16m, p=0.003709). Retrospectively analysis of metastatic NPC treatment of combination of chemotherapy, ICIs, and local treatment in our institute in the past 6 years, total 40 patients was enrolled with median overall survival of 34.1 months. Objective response rate by RECIST criteria for immunotherapy-based regimen was 75% (CR:40%; PR:35%) and disease control rate was 85%. According to response by RECIST criteria, median overall survival were 34.1 months vs. 16.7 months respectively for responders and non-responders. With pre-treated NLR as cutoff value of 1.6, difference of median overall survival between two groups (responder vs nonresponder) was statistically significant (p=0.021). We also found that lower median post-treatment NLR in responders than in non-responders (1.4 vs. 3.2, p=0.013). Using rapid lymphocyte amplification protocol via IL-2 stimulation, the PBMC from most of the patient received ICIs treatment can be amplified 1~10 folds and positively correlated with total lymphocyte count. Through flowcytometry analysis, we found these amplified PBMC was lymphocyte dominant and rich in CD8+. We also found these amplified PBMC can kill the NPC EBV-positive cell line and xenograft in vitro and in vivo. These results demonstrated that combination of chemotherapy, ICIs, and local treatment will benefit metastatic NPC patients. Citation Format: Cheng-Lung Hsu, Yung-Chia Kuo. Clinical scenario of immune checkpoint inhibitor treatment in metastatic nasopharyngeal carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6404.

Background Laparoscopic procedure has inherent merits of smaller incisions, better cosmesis, less postoperative pain, and earlier recovery. In the current study, we presented our method of purely laparoscopic feeding jejunostomy and compared its results with that of conventional open approach. Methods We retrospectively reviewed our patients from 2012 to 2019 who had received either laparoscopic jejunostomy (LJ, n = 29) or open ones (OJ, n = 94) in Chang Gung Memorial Hospital, Linkou. Peri-operative data and postoperative outcomes were analyzed. Results In the current study, we employed 3-0 Vicryl, instead of V-loc barbed sutures, for laparoscopic jejunostomy. The mean operative duration of LJ group was about 30 min longer than the OJ group (159 ± 57.2 mins vs 128 ± 34.6 mins; P = 0.001). There were no intraoperative complications reported in both groups. The patients in the LJ group suffered significantly less postoperative pain than in the OJ group (mean NRS 2.03 ± 0.9 vs. 2.79 ± 1.2; P = 0.002). The majority of patients in both groups received early enteral nutrition (P = 0.143). Conclusions Our study demonstrated that purely laparoscopic feeding jejunostomy is a safe and feasible procedure with less postoperative pain and excellent postoperative outcome. It also provides surgeons opportunities to enhance intracorporeal suture techniques.

Background: Decisions regarding the staging, prognosis, and treatment of patients with head and neck squamous cell carcinomas (HNSCCs) are made after determining their p16 expression levels and human papillomavirus (HPV) infection status. Methods: We investigated the prognostic roles of p16-positive and p16-negative circulating tumor cells (CTCs) and their cell counts in HNSCC patients. We enrolled patients with locally advanced HNSCCs who received definitive concurrent chemoradiotherapy for final analysis. We performed CTC testing and p16 expression analysis before chemoradiotherapy. We analyzed the correlation between p16-positive and p16-negative CTCs and HPV genotyping, tissue p16 expression status, response to chemoradiotherapy, disease-free survival, and overall survival. Results: Forty-one patients who fulfilled the study criteria were prospectively enrolled for final analysis. The detection rates of p16-positive (&gt, 0 cells/mL blood) and p16-negative (≥3 cells/mL blood) CTCs were 51.2% (n = 21/41) and 70.7%, respectively. The best responses of chemoradiotherapy and the p16 positivity of CTCs are independent prognostic factors of disease progression, with hazard ratios of 1.738 (95% confidence interval (CI): 1.031–2.927), 5.497 (95% CI: 1.818–16.615), and 0.176 (95% CI: 0.056–0.554), respectively. The p16 positivity of CTCs was a prognostic factor for cancer death, with a hazard ratio of 0.294 (95% CI: 0.102–0.852). Conclusions: The p16-positive and p16-negative CTCs could predict outcomes in HNSCC patients receiving definitive chemoradiotherapy. This non-invasive CTC test could help stratify the risk and prognosis before chemoradiotherapy in clinical practice and enable us to perform de-intensifying therapies.

Simple Summary Our findings indicated that the EGF-EGFR pathway was highly activated in very young patients with recurrent or metastatic NPC. High EGFR expression in patients with metastatic NPC resulted in poor clinical outcomes. To examine whether the EGFR pathway serves as a therapeutic target for NPC, NPC patient-derived xenograft (PDX) and NPC cell lines were treated with EGFR inhibitors (EGFRi) and a cell cycle blocker. Either EGFRi or cell cycle blocker treatment alone could reduce NPC cell growth and PDX tumor growth. Furthermore, combination treatment exerted an additive suppression effect on PDX tumor growth. This study provides promising evidence that EGFRi used in combination with a cell cycle blocker may be used to treat patients with NPC. Abstract Background: Nasopharyngeal carcinoma (NPC) involves host genetics, environmental and viral factors. In clinical observations, patients of young and old ages were found to have higher recurrence and metastatic rates. Methods: Cytokine array was employed to screen druggable target(s). The candidate target(s) were confirmed through patient-derived xenografts (PDXs) and a new EBV-positive cell line, NPC-B13. Results: Overexpression of epithelial growth factor (EGF) and EGF receptor (EGFR) was detected in young patients than in older patients. The growth of NPC PDX tumors and cell lines was inhibited by EGFR inhibitors (EGFRi) cetuximab and afatinib when used separately or in combination with the cell cycle blocker palbociclib. Western blot analysis of these drug-treated PDXs demonstrated that the blockade of the EGF signaling pathway was associated with a decrease in the p-EGFR level and reduction in PDX tumor size. RNA sequencing results of PDX tumors elucidated that cell cycle-related pathways were suppressed in response to drug treatments. High EGFR expression (IHC score ≥ grade 3) was correlated with poor survival in metastatic patients (p = 0.008). Conclusions: Our results provide encouraging preliminary data related to the combination treatment of EGFRi and palbociclib in patients with NPC.

Objective Studies have rarely explored the efficacy of S‐1 in treating advanced pancreatic cancer outside Japan. This study compared the survival outcomes of patients with advanced pancreatic cancer treated with S‐1 with the survival outcomes of those without S‐1 treatment before and after S‐1 reimbursement was introduced in Taiwan in June of 2014. Method We retrospectively analyzed 838 patients with locally advanced or metastatic pancreatic cancer who underwent palliative chemotherapy from 2010 to 2016 at 4 institutes in Taiwan. For survival analysis, patients were categorized into two groups according to whether they received S‐1 treatment as palliative chemotherapy after diagnosis: (a) S‐1‐treated (n = 335) and (b) non‐S‐1‐treated (n = 503) groups. Results The median overall survival was longer in the S‐1‐treated group than in the non‐S‐1‐treated group (10.7 vs 6.0 mo, P

Liver resection is a standard treatment for hepatocellular carcinoma (HCC). The purpose of this study was to investigate the clinicopathological characteristics and long-term outcomes of octogenarians with HCC treated with liver resection. Records of patients who underwent liver resection for HCC were reviewed, and patients older and younger than 80 years were compared. There were 77 patients 80 years of age or older and 3,309 younger than 80 years. Hepatitis C virus infection was the most common etiology among the octogenarians (43.1%), followed by non-viral causes (37.5%). The older group had more co-morbidity but less hepatitis B virus infection and cirrhosis. More than 70% of the non-viral older group had diabetes mellitus, as compared to only 21.6% in the viral older group. The older group had rates of perioperative morbidity, mortality, disease-free survival, and overall survival comparable to the younger group (all p>0.1). Multivariate analysis revealed that α-fetoprotein ≥400 ng/mL, tumor size ≥10 cm, and vascular invasion were independent prognostic factors for overall survival in the older patients. These findings demonstrate that liver resection is a justified treatment for HCC in octogenarians, and it can achieve surgical outcomes comparable to those in younger populations.

Summary: Background: Determining the survival outcome for gastric cancer patients with metastases to more than 15 regional lymph nodes is difficult. This study aims to develop a lymph node metastatic ratio (LNR)-based prognostic model to predict the survival outcome after D2 surgery in such patient groups. Methods: Our study retrospectively enrolled 139 gastric cancer patients with metastases to more than 15 regional lymph nodes who underwent D2 surgery between 2007 and 2014. Clinicopathologic variables to predict overall survival (OS) using multivariate Cox regression were selected to create a prognostic model. Results: The prognostic model for predicting OS was developed based on five independent factors, namely, T-classification (T2 or T3 vs. T4), LNR (

Background Patient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets. Methods We established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to assess their anti-cancer activities. RNA sequencing and transcriptomic analysis were performed in one NPC PDX mice to correlate with the efficacy of the anti-cancer drugs. Results A relative high incident rate of copy number variations (CNVs) of cell cycle-associated genes. Among the five NPC-PDXs, three had cyclin D1 (CCND1) amplification while four had cyclin-dependent kinase inhibitor CDKN2A deletion. Furthermore, CCND1 overexpression was observed in > 90% FFPE clinical metastatic NPC tumors (87/91) and was associated with poor outcomes. CNV analysis disclosed that plasma CCND1/CDKN2A ratio is correlated with EBV DNA load in NPC patients’ plasma and could serve as a screening test to select potential CDK4/6 inhibitor treatment candidates. Based on our NPC PDX model and RNA sequencing, Palbociclib, a cyclin-dependent kinase inhibitor, proved to have anti-tumor effects by inducing G1 arrest. One NPC patient with liver metastatic was treated with Palbociclib, had stable disease response and a drop in Epstein Barr virus (EBV) EBV titer. Conclusions Our integrated information of sequencing-based genomic studies and tumor transcriptomes with drug treatment in NPC-PDX models provided guidelines for personalized precision treatments and revealed a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for NPC.

Background: Stage III gastric cancer is characterized by locally advanced disease with varying anatomic extent as measured by the 7th edition of the American Joint Committee on Cancer (AJCC) staging system. There are no prognostic factors specifically identified in patients with stage III gastric cancer following extended lymph node dissection (D2) surgery. Materials and Methods: From 2007 to 2014, 534 patients with stage III gastric cancer underwent radical gastrectomy and D2 dissection at the Chang Gung Memorial Hospital. Patients' characteristics and the impact of adjuvant chemotherapy were analyzed using univariate and multivariate analyses to identify variables associated with overall survival (OS) and disease-free survival (DFS). Results: There were 320 deaths (60.0%) and 284 recurrences (53.2%) by the end of the study. The median OS and DFS were 30.7 months (95% confidence interval [CI]: 27.5-33.9) and 26.4 months (95% CI: 21.2-31.6), respectively. The multivariate analysis identified 7 variables that were independent prognostic factors both for OS and DFS including ratio of metastatic lymph nodes to total resection lymph nodes, carcinoembryonic antigen level, Eastern Cooperative Oncology Group performance status, gastrectomy method, vascular invasion, surgical margin, and adjuvant chemotherapy. Patients with stage IIIA-IIIC disease who received adjuvant chemotherapy had better OS and DFS outcomes than those who did not. Conclusions: Our study identified several independent prognostic factors that might help determine the appropriate counseling patients following surgical treatment. D2 surgery alone was inadequate to achieve long-term survival. As the only correctable independent prognostic factor, postoperative adjuvant chemotherapy should be recommended for eligible patients with stage III gastric cancer.

4143 Background: The triplet regimen of S-1, leucovorin, oxaliplatin and gemcitabine (SLOG) has shown promising efficacy for metastatic pancreatic ductal adenocarcinoma (PDAC) in our previous study. Current multicenter randomized, phase II study compared the efficacy and safety of SLOG versus modified FOLFIRINOX (mFOLFIRINOX) in patients with advanced/metastatic PDAC. Methods: Patients with chemo-naïve, histologically confirmed advanced/metastatic PDAC, were randomly assigned to either SLOG (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2 on day 1, plus daily 40/50/60 mg of S-1 based on BSA and 30 mg of oral leucovorin, twice daily, on days 1-7, every 2 weeks) or mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2 and leucovorin 400 mg/m2 on day 1 plus 5-FU 2400 mg/m2 for 46 hrs, every 2 weeks). Patients were stratified according to disease extent, ECOG PS and primary tumor location. The primary endpoint was 6-month progression-free survival (PFS) rate. The secondary endpoints were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS) and safety profile. Tumor response was assessed by CT/MRI every 8 weeks according to RECIST v1.1. As an exploratory trial, 130 (65 per arm) patients were estimated to detect a two-sided 15% difference in 6-month PFS (60% in SLOG and 45% in mFOLFIRINOX) with a significant level of α = 0.1 and β = 0.25. Results: Between March 2018 and October 2019, 130 patients were accrued. One patient who was assigned to mFOLFIRINOX arm didn’t receive assigned treatment. Of them, 62.3% were male, 45.4% were ECOG PS0, 81.5% had metastatic diseases, and 16.9% had prior surgery. The 6-month PFS rate was 55.4% in SLOG arm (n = 65) and 50% in mFOLFIRINOX arm (n = 64) (p = 0.850). The ORR and DCR in the SLOG and the mFOLFIRINOX arms were 40% versus 26.6% (p = 0.135) and 76.2% versus 71.9% (p = 0.550), respectively. The median PFS was 7.5 months in SLOG arm and 6.5 months in mFOLFIRINOX arm (p = 0.395); while the median OS was 12.9 months in SLOG arm and 12.1 months in mFOLFIRINOX arm (p = 0.88). Ten patients underwent conversion surgery, of whom 7 had SLOG and 3 had mFOLFIRINOX. The incidence of grade 3/4 neutropenia was significantly higher in mFOLFIRINOX arm (53.2% vs. 16.9% in SLOG arm, p < 0.0001). Conclusions: SLOG could achieve comparable but numerically better ORR, and median PFS and OS as compared to mFOLFIRINOX in patients of advanced PDAC. SLOG can be an alternative first-line regimen for advanced PDAC patients. Clinical trial information: NCT03443492.

Purpose Data on end-of-life care practices in Asia are scarce. This study aimed to analyze the clinical factors associated with the recommended premedication protocol for mechanical ventilation withdrawal, in Taiwan. Methods A total of 135 terminally ill patients who had mechanical ventilation withdrawn between 2013 and 2016 from a single medical center in Taiwan were enrolled. A premedication protocol of morphine and midazolam intravenous bolus was routinely recommended for the patients before mechanical ventilation withdrawal. Receipt of opioids and/or benzodiazepines during the withdrawal process was defined as full (both), partial (1 drug), and no (none) adherence. The clinical factors relevant to the adherence of recommended premedication protocol for mechanical ventilation withdrawal were analyzed. Results Overall, 126 (93.3%) patients died, 8 (5.9%) patients were transferred to other institutions for further care, and 1 (0.7%) patient was discharged to home after mechanical ventilation withdrawal. The median survival time was 45 minutes, and 102 (75.6%) patients died within 1 day after the withdrawal process. The full, partial, and no adherence rates for premedication guideline were 17.8%, 40.0%, and 42.2%, respectively. The main diagnosis of cancer, receipt of hospice care, and preservation of spontaneous respiration were independent variables associated with the partial or full adherence to the premedication protocol. Conclusion Our data show that adherence to the premedication protocol for mechanical ventilation withdrawal in terminally ill patients was inadequate in Taiwan. Promoting hospice care and educating medical personnel in the compassionate withdrawal of mechanical ventilation, especially in patients with noncancer disease, are warranted.

// Cheng-Lung Hsu 1 , Jai-Shin Liu 2 , Ting-Wei Lin 3 , Ying-Hsu Chang 4 , Yung-Chia Kuo 1 , An-Chi Lin 1 , Huei-Ju Ting 5 , See-Tong Pang 4 , Li-Yu Lee 6 , Wen-Lung Ma 7 , Chun-Cheng Lin 3 and Wen-Guey Wu 2 1 Division of Hematology-Oncology, Departments of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan 2 Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan 3 Department of Chemistry, National Tsing-Hua University, Hsinchu 300, Taiwan 4 Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan 5 Department of Biological Science and Technology, National University of Tainan, Tainan 700, Taiwan 6 Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan 7 Sex Hormone Research Center, China Medical University Hospital, Taichung 104, Taiwan Correspondence to: Cheng-Lung Hsu, email: hsu2221@adm.cgmh.org.tw Wen-Guey Wu, email: wgwu@life.nthu.edu.tw Chun-Cheng Lin, email: cclin66@mx.nthu.edu.tw Keywords: FxxLF, RIPK1, androgen receptor, prostate cancer, oxadiazole Received: November 04, 2016 Accepted: April 27, 2017 Published: May 13, 2017 ABSTRACT Using bicalutamide-androgen receptor (AR) DNA binding domain-ligand binding domain as bait, we observed enrichment of FxxFY motif-containing peptides. Protein database searches revealed the presence of receptor-interacting protein kinase 1 (RIPK1) harboring one FxxFY motif. RIPK1 interacted directly with AR and suppressed AR transactivation in a dose-dependent manner. Domain mapping experiments showed that the FxxFY motif in RIPK1 is critical for interactions with AR and the death domain of RIPK1 plays a crucial role in its inhibitory effect on transactivation. In terms of tissue expression, RIPK1 levels were markedly higher in benign prostate hyperplasia and non-cancerous tissue regions relative to the tumor area. With the aid of computer modeling for screening of chemicals targeting activation function 2 (AF-2) of AR, we identified oxadiazole derivatives as good candidates and subsequently generated a small library of these compounds. A number of candidates could effectively suppress AR transactivation and AR-related functions in vitro and in vivo with tolerable toxicity via inhibiting AR-peptide, AR-coregulator and AR N-C interactions. Combination of these chemicals with antiandrogen had an additive suppressive effect on AR transcriptional activity. Our collective findings may pave the way in creating new strategies for the development and design of anti-AR drugs.

// Bo-Ru Lai 1, * , Yu-Tung Wu 1, * , Yung-Chia Kuo 2 , Hung-Chih Hsu 2 , Jen-Shi Chen 2 , Tse-Ching Chen 3 , Ren-Chin Wu 3 , Cheng-Tang Chiu 4 , Chun-Nan Yeh 1 , Ta-Sen Yeh 1 1 Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan 2 Department of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan 3 Department of Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan 4 Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Ta-Sen Yeh, email: tsy471027@adm.cgmh.org.tw Keywords: GIST, second primary cancer, cancer driver gene, c kit, colorectal cancer Received: June 08, 2016 Accepted: September 17, 2016 Published: October 28, 2016 ABSTRACT The association of non-hereditary (sporadic) gastrointestinal stromal tumors (GISTs) and second primary malignancies is known to be nonrandom, although the underlying molecular mechanisms remain unknown. In this study, 136 of 749 (18.1%) patients with sporadic GISTs were found to have additional associated cancers, with gastrointestinal and genitourinary/gynecologic/breast cancers being the most prevalent. Gene mutations in GISTs and their associated colorectal cancers (CRCs) (n=9) were analyzed using a panel of 409 cancer-related genes, while a separate group of 40 sporadic CRCs not associated with GISTs served as controls. All 9 of the GISTs had either KIT (8 of 9) or PDGFRA (1 of 9) mutations that were not present in their associated CRCs. Conversely, all but one of the 9 GIST-associated CRCs exhibited an APC mutation, a TP53 mutation or both, while none of their corresponding GISTs harbored either APC or TP53 mutations. The genetic profile of CRCs with and without associated GISTs did not differ. Although population-based studies and case series worldwide, including ours, have unanimously indicated that the GIST-CRC association is nonrandom, our targeted ultra-deep sequencing unveiled a lack of driver-gene mutations linking sporadic GISTs to highly prevalent second primaries. Further studies are needed to elucidate other genetic alterations that may be responsible for this puzzling contradiction.

// Hung-Ming Wang 1, * , Tung-Liang Lin 1, * , Yung-Chia Kuo 1 , Hsin-Pai Li 2 , Kai-Ping Chang 3 , Chien-Yu Lin 4 , Hsien-Chi Fan 1 , An-Chi Lin 1 , Chia-Hsun Hsieh 1 , Ngan-Ming Tsang 4 , Li-Yu Lee 5 , Sheng-Chieh Chan 6 , Kar-Wai Lui 7 , Yu-Sun Chang 2 , Cheng-Lung Hsu 1 1 Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 2 Department of Cell and Molecular Biology, Chang Gung University, Taoyuan, Taiwan, ROC 3 Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 4 Department of Radiation Oncology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 5 Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 6 Department of Nuclear Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 7 Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC * These authors contributed equally to this work Correspondence to: Cheng-Lung Hsu, email: hsu2221@adm.cgmh.org.tw Keywords: nasopharyngeal carcinoma, metastasis, EB virus, EBV DNA, IP-10 Received: March 10, 2016 Accepted: June 09, 2016 Published: July 18, 2016 ABSTRACT Differential overall survival of nasopharyngeal carcinoma (NPC) with different organ site metastases has been documented. Here, we attempted to determine the underlying mechanisms by assessing plasma and tumor tissue markers in relation to patient survival. Pretreatment plasma Epstein-Barr virus (EBV) DNA concentrations, cytokines and tissue macrophages, proliferation and apoptosis markers were determined in 178 patients with metastatic NPC. The median overall survival (OS) was 19 months. Patients with single organ metastases had better outcomes than those with multiple organ metastases (median OS: 26 months vs. 16 months), with statistical significance. Among the single organ involvement cases, patients with lung metastasis only showed longer survival than those with bone or liver involvement (median OS: 50 months vs. 21 months vs. 18 months; P < 0.001). Pretreatment plasma EBV DNA concentrations were lower in patients with lung metastasis than bone or liver metastasis among single organ site groups. Plasma interferon-γ-inducible protein-10 (IP-10) and monocyte chemotactic protein-1 (MCP-1) expression levels were correlated with differential single organ site metastasis OS and EBV DNA load. Liver metastatic tissue had higher density of infiltrating macrophages and proliferative index than the lung metastatic group. Low pretreatment plasma EBV DNA load, expression of cytokines, such as IP-10 and MCP-1, tissue macrophage infiltration, and proliferative index may contribute to the differences in overall survival.

Summary: Background: Radical gastrectomy and extended lymph node (D2) dissection followed by adjuvant chemotherapy is the optimal treatment for patients with stage III gastric cancer in Asian population. The clinical factors associated with patient propensity to receive adjuvant chemotherapy and outcomes were analyzed. Methods: In total, 509 patients with stage III gastric cancer who had undergone D2 surgery between 2007 and 2017 at a single medical center in Taiwan were analyzed. The patients' preoperative clinical characteristics relevant to adjuvant chemotherapy adherence were analyzed using multivariate regression. Significant variables were analyzed using recursive partitioning analysis (RPA) for identifying specific patient groups with the lowest and highest probabilities of adjuvant chemotherapy adherence. Results: After surgery, 361 (70.9%) patients in the cohort had received adjuvant chemotherapy. All patients were categorized into five probability groups with adherence to adjuvant chemotherapy according to age, Eastern Cooperative Oncology Group (ECOG) performance status grade, and American Society of Anesthesiologists (ASA) class, which were discovered to be independent factors in the RPA-based probability prediction. In general, adjuvant chemotherapy improved survival across broad categories of stage III gastric cancer patients (overall survival hazard ratio: 0.53–0.75 and disease-free survival hazard ratio: 0.47–0.76). Conclusions: Our study identified that age, ECOG grade, and ASA class were independent clinical factors associated with patient propensity to receive adjuvant chemotherapy in stage III gastric cancer. Knowledge of the clinical factors of patients may help clinicians identify and encourage specific patients to receive the adjuvant chemotherapy. Keywords: Stage III gastric cancer, Adjuvant chemotherapy, Clinical factors, Survival outcome

13 Background: For de novo metastatic prostate cancer (mPC)) patients, their prognosis may be really different. Some of these patients response very well to hormone therapy with durable survival, but others may be not. For those poor prognosis patients, if we could predict them as high risk patients when diagnosed, and provide aggressive upfront chemotherapy or novel hormonal therapy, they might get better treatment outcomes. Methods: We used data of prostate cancer patients from 2000 to 2016 in Chang Gung Research Database. There are 799 de novo mPC patients with castration. We predicted the possibility for these patients progressed to metastatic castration-resistant prostate cancer (mCRPC) in 1 year and find the high risk group patients. Then we figured out the best features for prediction from the best classifier with Recursive Feature Elimination. Results: The de nove mPC patients who pregressed to mCRPC in 1 year, whose mOS is 21.9 months is worse than who progressed to mCRPC beyond 1 year significantly, whose mOS is 80.7 months. (adjusted hazard ratio[aHR]: 6.43, P

Table S3. The summary of the cancer-related somatic mutations and CCND1 CNV gain and CDKN2A CNV loss of the 5 NPC-PDX tumors. (PDF 314 kb)

Table S7. Immnunohistochemical (IHC) staining of cyclin D1 in 139 NPC tissues from year 2002 to 2016. (PDF 415 kb)

Figure S3. C666.1 cells and PDX-C666.1 xenograft drug screening. Drug sensitivity tests in (A) C666.1 cells and (B-D) PDX-C666.1 xenograft. The changes in PDX-C666.1 (B) tumor volume, (C) tumor weight (g), and (D) mice body weight are indicated. Abbreviation, GSK, GSK126; DEC, decitabine; GEM, gemcitabine; PAL, palbociclib. (E) Flow cytometry analysis of C666.1 cells in the presence of PAL (0, 0.1, 0.5 and 1Â ÎźM). (PDF 485 kb)

Figure S4. Drug screening in PDX-LN (NPC02F12). PDX-LN (A) tumor volume; (B) tumor weight; and (C) mice body weight change in the presence of DMSO (control), DEC (reduced dose) and PAL. (PDF 395 kb)

Table S4. RNA-seq mapping statistics of PDX-Bone in the presence of five drug treatments. (PDF 407 kb)

Figure S2. CNV profile comparison between CP-409 FFPE-LN and PDX-LN. CNV profiles of NPC (A) FFPE-LN and (B) PDX-LN based on ultra-deep sequencing of CP-409. Observed copy number for each evaluated position is shown on the y-axis as a log 2 scale. Genes associated with or without copy number alteration are indicated in different colors or in grey, respectively. Correlation plots with Pearsonâ s correlation coefficient, r, is indicated. (PDF 467 kb)

Figure S1. Single nucleotide variations (SNV) of five metastatic NPC-PDX tumors. Somatic mutations (including non-synonymous missense and splice site mutations) of the five NPC-PDX tumors identified from sequencing data are listed (upper panel). Each bar represents the number of base substitutions. For the 282 SNVs, the percentage of each base substitution is indicated (lower panel). (PDF 402 kb)

Table S1. Characteristics of total 17 metastatic NPC patients and the final 5 NPC-PDX lines (grey). (PDF 401 kb)

A previous study demonstrated that cytokeratin 19 (CK19) expression in hepatocellular carcinoma (HCC) is an indicator of HCC invasiveness, including lymph node metastasis (LNM), tumor infiltration/non-encapsulation and poor prognosis. The exact mechanism by which CK19 expression results in poor prognosis remains unclear. Through the use of an Affymetrix U133A oligonucleotide microarray [20 patients with hepatitis B virus (HBV)-HCC], it was demonstrated that cadherin 17 (CDH17) significantly correlated with CK19 expression (R2, 0.867; P10% and CDH17 expression were independent prognostic factors for disease free survival (P=0.010 and 0.002, respectively). In vitro studies showed that epidermal growth factor can induce the expression of both CK19 and CDH17, and CDH17 in turn can enhance the expression of CK19 in HCC. In summary, this study demonstrated that the early recurrence and poor prognosis of CK19(+) HCC may be due to the expression of CDH17, a gene known to be associated with vascular invasion, tumor metastasis, and advanced tumor stage of HCC. Thus, novel therapeutics by targeting CDH17 may be beneficial for CK19(+) HCC.

Nasopharyngeal carcinoma (NPC) is an Epstein Barr virus (EBV)-related malignancy in which the tumor microenvironment plays a pivotal role in tumor progression. Here, we developed two patient-derived xenograft (PDX) mouse lines from engrafted NPC metastatic tumors. Positive staining for EBV-encoded small RNAs confirmed that these tumors harbored EBV, and gene expression profile analyses further showed that the PDX was highly similar to the primary parent tumor. In vivo drug screening using the PDX system demonstrated that gemcitabine had the best antitumor effect among the tested drugs. The donor of this PDX also showed excellent responsiveness to gemcitabine treatment. The combination of gemcitabine and valproic acid exerted synergistic antitumor effects. Further addition of ganciclovir to this two-drug combination regimen enhanced cytolytic viral activation, yielding the best antitumor response among tested regimens. Treatment with this three-drug combination regimen decreased plasma EBV-DNA load, tumor viral concentration, and the number of viable tumor cells to a greater extent than the two-drug gemcitabine and valproic acid combination. These results highlight the value of PDX models in the development of EBV-targeted strategies to treat NPC.

Carcinoma of unknown primary origin (CUP) is characterized by diverse histological subtypes and clinical presentations, ranging from clinically indolent to frankly aggressive behaviors. This study aimed to identify prognostic factors of CUP and to develop a simple risk model to predict survival in a cohort of Asian patients. We retrospectively reviewed 190 patients diagnosed with CUP between 2007 and 2012 at a single medical center in Taiwan. The clinicopathological parameters and outcomes of our cohort were analyzed. A risk model was developed using multivariate logistic regression and a prognostic score was generated. The prognostic score was calculated based on 3 independent prognostic variables: the Eastern Cooperative Oncology Group (ECOG) scale (0 points if the score was 1, 2 points if it was 2–4), visceral organ involvement (0 points if no involvement, 1 point if involved), and the neutrophil-to-lymphocyte ratio (0 points if ≤3, 1 point if >3). Patients were stratified into good (score 0), intermediate (score 1–2), and poor (score 3–4) prognostic groups based on the risk model. The median survival (95% confidence interval) was 1086 days (500–1617, n = 42), 305 days (237–372, n = 75), and 64 days (44–84, n = 73) for the good, intermediate, and poor prognostic groups, respectively. The c-statistics using the risk model and ECOG scale for the outcome of 1-year mortality were 0.80 and 0.70 (P = 0.038), respectively. In this study, we developed a simple risk model that accurately predicted survival in patients with CUP. This scoring system may be used to help patients and clinicians determine appropriate treatments.

Introduction: Background: Chemotherapy with a fluoropyrimidine with or without a platinum is currently the standard care for metastatic gastric cancer (GC). Randomized trials have established the role of either a taxane- or an irinotecan-containing regimen as second line chemotherapy. However, medical insurance systems don't permit the reimbursement of both taxane and irinotecan in some countries, including Taiwan. Patients who fail the first line chemotherapy in Taiwan usually receive a regimen containing a fluoropyrimidine / platinum different from the prior regimen, or a self-paid regimen containing paclitaxel, docetaxel or irinotecan. The impact of selecting an identical vs. a class switch chemotherapy on the outcomes of patients is not known. Procedures: The medical records of patients who were diagnosed with metastatic gastric adenocarcinoma from 2008 to 2012 and had received a second line chemotherapy after a first line regimen of fluoropyrimidine (5-fluorouracil, UFT, capecitabine or S-1), and/or platinum (cisplatin, carboplatin or oxaliplatin) were retrospectively obtained from two medical centers in Taiwan. In a second line situation, we defined an identical regimen as a regimen containing another fluoropyrimidine with or without a platinum; and a class switch regimen as a regimen containing paclitaxel, docetaxel or irinotecan. The characteristic and clinical outcomes of the two groups of patients were compared. Kaplan-Meier curves were used to demonstrate the progression free survival (PFS) and overall survival (OS) function of each treatment group. All reported p values were two-sided with the alpha set at a significance of 0.05. Findings: A total of 201 patients met the study criteria. Patients in the identical regimen group were older (p=0.001) and were less likely to stop first line treatment due to disease progression (PD; p=0.026) compared to the class switch group. Although the response rates (CR+PR) were similar (7.8% vs. 8.3%), toxicity occurred more frequently in identical group than in class switch group by 5%. The survival outcomes measures for the identical regimen group and class switch group included 9 and 6.8 weeks (p=0.949) median PFS since second line treatment, 16 and 12 weeks (p=0.585) median OS since second line treatment, and 48 and 58 weeks (p=0.457) median OS since disease diagnosis, respectively. Conclusions: Patients receiving an identical chemotherapy after failure of a fluoropyrimidine with/without a platinum regimen have similar PFS and OS compared to patients receiving a class switch chemotherapy for GC. A higher percentage of PD as the reason to stop first line therapy was noted in patients receiving a class switch chemotherapy and might influence the assessment of a class switch regimen. Further prospective clinical trials are needed to clarify this potential confounding factor. Citation Format: Li-Yuan Bai, Yung-Chia Kuo, Jen-Shi Chen, Wen-Chi Chou, Chang-Fang Chiu, Yu-Min Liao. Class switch or identical regimen as a second-line chemotherapy for patients with metastatic gastric adenocarcinoma: A retrospective analysis of two medical centers in Taiwan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1640.

The role of chemoradiotherapy (CRT) in the management of locally advanced pancreatic cancer is controversial. We aimed to explore this issue by retrospectively comparing the efficacy of concurrent CRT with or without induction (CT) versus CT alone in patients with locally advanced pancreatic cancer (LAPC).Between January 2006 and December 2012, 55 patients with biopsy-proven LAPC were treated either with CRT (n=31) or CT alone (n=24) at the authors' Institution. CT before or after CRT were allowed. Radiation therapy was delivered with a median dose of 50.4 Gy in a single fraction of 1.8 Gy and concurrent CT was typically given with gemcitabine at a dose of 400 mg/m2 weekly. The majority of CT was gemcitabine-based (96%). Progression-free survival and overall survival were calculated from the date of diagnosis to the date of progression and to the date of death or last follow-up, respectively.Patients' characteristics were not significantly different between the CRT group and CT-alone group. Nineteen (61%) patients received scheduled radiation dose of 50.4 Gy. The median cumulative dose of maintenance CT with gemcitabine after CRT was 6,500 mg/m2. The median survival was 14.6 versus 8.1 months (p=0.001) and progression-free survival was 8.7 versus 4.9 months (p0.001) for the CRT group and CT-alone group, respectively.Patients with LAPC treated with CRT conferred more favorable survival than those who did not receive CRT. CRT should be considered integrating into the management of LAPC.

Differential overall survival of different organ site metastases in nasopharyngeal carcinoma (NPC) had been reported but the underlying mechanism was unclear. We try to find out the possible mechanism from plasma and tumor tissue markers. Total 178 patients of metastatic NPC were enrolled. Their pre-treatment plasma EBV DNA concentrations and cytokines and tissue macrophage, proliferation and apoptosis markers were determined. The overall patient response rate after treatment was 51.7% and median overall survival (OS) was 19 months. Single organ site metastasis had better outcome than multiple organs involved (median OS: 26 months vs. 16 months) with statistical significance. Among single organ site involved, pure lung metastasis had longer survival than bone or liver involved (median OS: 50 months vs. 21 months vs. 18 months) with P Citation Format: Cheng-Lung Hsu, Hung-Ming Wang, Tung-Liang Lin, Yung-Chia Kuo. Correlation between number and sites of metastases and differential pretreated EBV DNA load profiles and their effects on outcomes in patients with metastatic nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2262. doi:10.1158/1538-7445.AM2017-2262

Background: We modified 3-week XELOX regimen with oxaliplatin to 85 mg/m 2 on Day 1 and capecitabine 1000 mg/m 2 BID for 10 days every 14 days to be more practical in clinical practice for advanced gastric cancer. The aim of this retrospective analysis is to evaluate the safety profile and efficacy of the modified oxaliplatin plus capecitabine (XELOX) regimen as the first-line treatment for patients with advanced gastric cancer in a medical center in Taiwan. Methods: From March 2009 to December 2010, among the 614 patients diagnosed with gastric cancer in a medical center, 49 patients with unresectable advanced or metastatic gastric adenocarcinoma were treated with oxaliplatin (85 mg/m 2 ) on Day 1 and capecitabine (1000 mg/m 2 BID) for 10 days every 2 weeks (mXELOX). CT scan was performed for tumor response evaluation. Clinical outcome and adverse events after mXELOX treatment were analyzed retrospectively. Results: A total of 354 mXELOX sessions (median: 6) were administered in 49 patients. The overall tumor response rate was 39.1% among 46 evaluated patients: three complete response (6.5%) and 15 partial response (32.6%). Seven patients had stable disease (15.2%) and 21 (45.7%) patients had progressive disease. The median progression-free survival and median overall survival were 4.37 months and 12.26 months, respectively. The most common grade III/IV hematologic toxicity was anemia (10.2%), and non-hematologic toxicity effects were numbness (8.2%), hand-foot syndrome (10.2%), diarrhea (6.1%), thrombocytopenia (6.1%), and abdominal pain (6.1%). Conclusion: This modified biweekly oxaliplatin and capecitabine combination chemotherapy is practical and effective for unresectable advanced or metastatic gastric cancer in our daily practice.

Nasopharyngeal carcinoma (NPC) was an Epstein Barr virus (EBV)-related malignancy and tumor microenvironment had a pivotal role in tumor progression. Paucity of good NPC animal models hindered the research in this field. Recently, patient-derived xenograft (PDX) had been shown to be a good preclinical model for drug screening and cancer related research. We had developed two PDX mice lines from engrafting NPC metastatic tumors. Positive EBV-encoded small RNAs staining confirmed these tumors harboring EBV. Further gene expression profile analysis showed higher similarity of PDX to primary parent tumor than NPC cell line xenograft. In vivo drug screening in the PDX system demonstrated gemcitabine had the best antitumor effect among the tested drugs. In this PDX corresponding patient also showed excellent response to gemcitabine treatment. Combination of gemcitabine and valproic acid had synergistic antitumor effect. Further adding ganciclovir in this two combined regimen enhancing cytolytic viral activation had the best antitumor response among the tested regimens. This three combined regimen treated group had lower plasma EBV-DNA load and tumor viral concentration and less viable tumor cells than gemcitabine + valproic acid group. These promising results would open a new era for EBV-targeting therapy in NPC treatment. Citation Format: Cheng-Lung Hsu, Yung-Chia Kuo, Yenlin Huang, Yin-Cheng Huang, Kar-Wai Lui, Kai-Ping Chang, Tung-Liang Lin, Hsien-Chi Fan, An-Chi Lin, Chia-Hsun Hsieh, Li-Yu Lee, Hung-Ming Wang, Hsin-Pai Li, Angel Chao, Yu-Sun Chang. Application of patient-derived xenograft model in nasopharyngeal carcinoma research. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 626.