bluuebunny/crossref_metadata_2025 huggingface dataset:
The characterization of ERBB family mutations in Chinese biliary tract cancers.
Authors: Song Tianqiang , Zhang Wei , Li Huikai , Chen Ping , Chen Xiaoqian , Shi Junping , Zhang Shuirong , Yao Ming , Wang Kai
Published: May 2019

e15595

Background: Next generation sequencing has been applied to identify actionable mutations in biliary tract cancers (BTCs). ERBB family genes, especially ERBB2 and ERBB3, serve as effective biomarkers for BTCs targeted therapy as shown in MyPathway and SUMMIT clinical trials. However, the distribution and major mutation types of ERBB family genes were not clear in Chinese BTC patients. Methods: Deep sequencing targeting 450 cancer genes was performed on FFPE and matching blood samples collected from a cohort of 716 Chinese BTC patients. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indels), copy number variations, gene rearrangements and fusions were analyzed. Results: A total of 14% (101/716) of patients with a median age of 62 years old, including 45 males and 56 females, were identified harboring ERBB family mutations. Somatic ERBB family mutations occurred with a rate of 29% in gallbladder carcinoma (GBCA), 13% in extrahepatic cholangiocarcinoma (EHCCA), 12% in hilar cholangiocarcinoma (HCCA) and 8% in intrahepatic cholangiocarcinoma (IHCCA). No germline mutation was detected. A high rate of ERBB2 gene amplification was observed in GBCA (17%). In IHCCA and EHCCA, SNV/Indel accounted for 3% and 5%, respectively, and was the major variation in ERBB2. In HCCA, SNV/Indel was the most common mutation in ERBB3 (8%). In BTC patients, TP53 (81%) and CDK12 (36%) were the top-ranked co-mutant genes with ERBB2. The mutant frequency of CDK12 was significantly different between patients with or without an ERBB2 mutation ( p< 0.001). ERBB2 S310F/Y, ERBB3 V104L/M were hotspot mutations within the ERBB family in BTCs. Conclusions: ERBB family mutations were detected in 14% of Chinese BTC patients. Similar to Western populations (PMID: 27622582), ERBB2 gene amplification was the most common mutation in GBCA in Chinese patients. Unlike ERBB2/ ERBB3 amplification which has been reported as the major mutation in previous studies, our study of other BTC types revealed ERBB2/ ERBB3 SNV/Indel as the major mutation. BTC patients harboring ERBB family mutations have the potential to benefit from pan-HER inhibitors.
Microvascular invasion may guide selection of candidates for combination treatment with sorafenib and TACE for intermediate recurrent hepatocellular carcinoma.
Authors: Peng Zhen-Wei , Chen Shuling , Han Xiao , Wang Yuanqi , Kuang Ming
Published: May 2019

e15601

Background: To investigate the role of sorafenib combined with transarterial chemoembolization (TACE) for the treatment of intermediate recurrent hepatocellular carcinoma (rHCC) after initial hepatectomy and whether the status of microvascular invasion (MVI) could help screen out the appropriate candidates for the combination treatment. Methods: The study was approved by the ethics committee of two tertiary medical centers in China. From Jan 2010 to Dec 2016, 260 consecutive patients with intermediate rHCC after initial hepatectomy who underwent combination treatment or TACE were enrolled. Overall survival (OS) and progression-free survival (PFS) were compared between these two treatments according to MVI status. Results: The 1-, 3-, 5-year OS (77.1% vs. 62.0%, 49.3% vs. 35.2%, 38.9% vs. 20.5%, P = 0.011) and PFS (74.2% vs. 56.5%, 37.5% vs. 18.7%, 37.5% vs. 18.7%, P = 0.003) rates were significantly higher in the combination group than those in the TACE group for intermediate rHCC. For MVI-positive patients, the median OS (17.2 months vs. 12.1 months, P = 0.024) and PFS (17.0 months vs. 11.0 months, P = 0.022) after combination treatment (n = 55) were significantly longer than those after TACE alone (n = 72). For MVI-negative patients, the median OS (42.7 months vs. 32.6 months, P = 0.247) and PFS (24.6 months vs. 17.2 months, P = 0.113) were comparable between combination therapy (n = 73) and TACE alone (n = 60). Multivariate analysis revealed that tumor number, MVI status and treatment allocation were significant predictors of OS and PFS, while the tumor size was another prognostic factor for PFS. Conclusions: Patients with intermediate rHCC can benefit from sorafenib plus TACE treatment, while MVI-positive patients were good candidates for combination treatment.
Density of CD8+ and CD68+ lymphocyte cell infiltration is associated with clinic outcome in hepatocellular carcinoma.
Authors: Xin Haibei , Chen Huan , Wu Lihong , Chen Yanhui , Luo Hongli , Zhang Henghui , Li Nan
Published: May 2019

e15612

Background: The achievements of immune checkpoint blockade strengthen the concept that tumor outgrowth and development are comprehensively regulated by immune system. The aim of the study was to explorer whether distinct infiltrated immune cell features differentially affect clinical outcome in hepatocellular carcinoma (HCC). Methods: We obtained respectable stage II HCC specimens, along with adjacent para-tumor tissues from 221 patients who underwent surgical resection at Eastern Hepatobiliary Surgery Hospital, (in Shanghai, China) from 2015 through April 2018. CD8+ and CD68+ tumor-infiltrating lymphocytes (TILs) in the cancer area (CA) and stroma area (SA), as well as PD-1/PD-L1 expression, were analyzed by multiple immunohistochemistry. Results: The density of CD8+ TILs were significantly associated with gender, tumor size, and cirrhosis; while the density of CD68+ TILs were associated with copies of HBV DNA and anti-viral treatment. Multivariate Cox regression analysis revealed that high densities of CD8+ TILs and low densities of CD68+/CD8+ ratios independently predicted better outcomes. Of note, a prognostic signature combining clinic features [portal vein tumor thrombus (PVTT) and tumor size (TS)] and CD8+ TILs densities discriminated HCC patients into four subtypes with increasing risk of mortality: PVTT-negative/TS-small/CD8-high (6.8% of cases), PVTT-negative/TS-small/CD8-low (45.7%), PVTT-negative/TS-large (34.4%) and PVTT-positive (13.1%). Further association studies suggested that the four subgroups correlated with gender, tumor envelope, microvascular invasion (MVI), and SA-PD1 expression. Similarly, a prognostic signature combining PVTT, TS and CD68+/CD8+ ratios discriminated HCC patients into four subtypes with increasing risk of recurrence. Conclusions: Combined immune features including CD8+ and CD68+ lymphocyte infiltration and clinic characteristics are useful prognostic biomarkers for HCC patients.
Randomized phase II trial of sorafenib, capecitabine, and oxaliplatin (SECOX) versus single agent sorafenib in patients with advanced hepatocellular carcinoma.
Authors: Kwok Gin Wai , Tang Vikki , Leung Roland Ching-Yu , Lee Ann-Shing , Law Ada , Chiu Joanne Wing Yan , Li Bryan , Cheung Tan To , Yau Thomas
Published: May 2019

e15630

Background: We aimed to compare the efficacy and tolerability of SECOX regimen with sorafenib alone as first-line treatment of advanced hepatocellular cancer (HCC) in a multicenter, open-label and randomized setting. Methods: Patients not suitable for surgery or various loco-regional therapies and no prior systemic therapy for advanced HCC were recruited in 3 centres. Eligible patients were randomly assigned to receive either SECOX (sorafenib 400 mg BD continuously, oxaliplatin 85 mg/m2 on D1, and capecitabine 1700 mg/m2 on D1-7 q2w) or sorafenib alone continuously in 1:1 ratio. Primary endpoint was time-to-progression (TTP). Secondary endpoints were tolerability, overall tumor response rate, overall survival (OS) and progression-free survival (PFS). Results: Forty-six patients were randomized and treated, of whom 22 were in the SECOX arm. Median age was 64 years and majority of the patients were male (72%). 40 patients (87%) were hepatitis B carrier, and 42 patients (91%) had Child-Pugh A liver function. Thirty patients (65%) had received prior non-systemic treatment for HCC. Median duration of follow-up was 7.8 months (mos) (range 0.3-25.8). At the time of analysis,one patient in the SECOX arm is still receiving treatment. Median TTP was 3.2 mos (95% CI 1.7-5.8) for SECOX vs 2.8 mos (95% CI 1.8-4.0) for sorafenib. The hazard ratio (HR) for TTP was 0.91 (95% CI 0.5-1.7; p = 0.77; predetermined futility boundary HR ≥ 0.86). Median OS was 7.1 mos (95% CI 3.0-15.3) for SECOX vs 12.5 mos (95% CI 7.2-15.4) for sorafenib (p = 0.29). Median PFS was 3.1 mos (95% CI 1.6-5.8) for SECOX vs 2.7 mos (95% CI 1.8-4.0) for sorafenib. 2 patients (9%) and no patients achieved partial response in the SECOX and sorafenib arms, respectively. The clinical benefit rate (CR+PR+SD) was 36% for the SECOX arm and 21% for the sorafenib arm (p = 0.50). Incidence of treatment-related adverse events (trAEs) was common in both SECOX and sorafenib arms (64% and 71% respectively, p = 0.75). The most common grade 3-4 trAE was ALP increase (14%) for SECOX and hand-foot skin reaction (25%) for sorafenib. Conclusions: The addition of capecitabine and oxaliplatin to sorafenib did not result in significant improvement in TTP. Clinical trial information: NCT02716766.
Impact of HCV treatment in patients with advanced hepatocellular carcinoma on sorafenib.
Authors: Herman Michael , Zhang Yuhua , Wang Lisa , Sim Hao-Wen , Knox Jennifer J.
Published: May 2019

e15645

Background: Hepatocellular carcinoma (HCC) is the 4th leading cause of global cancer deaths. In North America, HCC is most commonly caused by Hepatitis C virus (HCV). Direct acting antivirals (DAAs) have dramatically increased sustained virologic response (SVR) rates for HCV. Studies of DAAs in early stage HCC have had conflicting results on HCC outcomes. A small Asian study of 58 advanced HCC patients treated with sorafenib demonstrated SVR improved survival, but whether the same effect occurs in North American patients is unknown. Methods: Inclusion criteria for this retrospective study were: biopsy or clinically proven advanced incurable HCC, sorafenib treatment at Princess Margaret Cancer Centre between January 1 2008-June 30 2018 and a history of HCV. Survival was analyzed using the Kaplan Meier method and a cox proportional hazards model was fit to determine the effect of SVR on OS. Results: 93 patients were included with a median duration of sorafenib therapy of 3 months. 89% were ECOG 0-1 and 96% were BCLC-C (See table 1). Of those receiving antivirals, 95% were given before sorafenib. Overall, SVR was achieved in 23 (50%) patients. Median OS of patients achieving SVR vs not in SVR was 10.3 vs 8.9 months respectively (HR 0.67, 95% CI 0.36-1.24, p = 0.20). Median PFS was 6.4 vs 5.0 months in patients with or without SVR (HR 0.66, 95% CI 0.39-1.13, p = 0.13). There was no significant difference between mean dose of sorafenib or discontinuation due to toxicity in patients by SVR status. Conclusions: Antiviral therapy with SVR lead to a non-statistically significant improvement in OS in patients with Child-Pugh A-B liver disease, advanced HCC treated with sorafenib and HCV. These results should be validated in larger data-sets. [Table: see text]
The combined treatment of 150 kHz tumor treating fields (TTFields) and sorafenib inhibits hepatocellular carcinoma in vitro and in vivo.
Authors: Weinberg Uri , Davidi Shiri , Tempel- Brami Catherine , Munster Mijal , Gotlib Karnit , Zeevi Einav , Schneiderman Rosa S. , Voloshin Tali , Giladi Moshe , Kinzel Adrian , Kirson Eilon David , Palti Yoram
Published: May 2019

e15653

Background: Hepatocellular carcinoma (HCC) is the third cause of cancer related mortality and the primary cause of cancer death. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. Sorafenib, an oral multikinase inhibitor is approved for patients with advanced HCC, yet its survival benefit is still limited. In this work we explored the potential of the use of TTFields alone and in combination with Sorafenib as a treatment for HCC. Methods: HepG2 and Huh-7D12 cells were treated with various TTFields frequencies for 72 hours using the inovitro system. Efficacy of the combined treatment of TTFields and Sorafenib (36-3000 nM) was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, induction of apoptosis, cell cycle and clonogenic potential were determined. TTFields (1.2 V/cm) and Sorafenib (10 mg/kg) were applied for 6 days to rats injected to the liver with N1S1 HCC cells. Tumor growth was followed using MRI. Results: The optimal TTFields frequency was 150 kHz for both cell lines. TTFields application (1.0 - 1.7 V/cm, 72 hours) at 150 kHz led to 36-40% reduction in cell counts and to additional reduction of over 70% in the clonogenic potential. The combined treatment of TTFields and Sorafenib led to a significant reduction in the number of cells (p < 0.001) as compared to each treatment alone. The averaged tumor volume fold increase of the combination treatment group was significantly lower than the one observed in the: control group, the TTFields group and the Sorafenib group. Conclusions: The results presented in this work demonstrate that TTFields can be an effective treatment against HCC cells and that the combination with Sorafenib may further enhance treatment efficacy.
Association of liver-directed local therapy with overall survival in metastatic intrahepatic cholangiocarcinoma.
Authors: Sebastian Nikhil , Miller Eric David , Williams Terence M , Noonan Anne M. , Hays John L. , Diaz Pardo Dayssy Alexandra
Published: May 2019

e15659

Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive hepatobiliary malignancy characterized by local infiltration and lymph node, lung, and bone metastases. The majority of patients die from tumor-related liver failure. The standard of care for metastatic ICC is chemotherapy (CHT) and the role of local therapy to the liver is unclear. We used the National Cancer Database (NCDB) to compare overall survival (OS) of patients treated with CHT, with and without local radiotherapy (RT) or surgery of the liver. Methods: We evaluated patients with metastatic ICC who received CHT with or without hepatic surgery or external beam RT to a dose ≥ 45 Gy. We used multiple imputation followed by cox proportional hazards and nearest neighbor propensity score matching (1:1, caliper = 0.1) on the basis of age, sex, race, comorbidity score, T-stage, tumor size, N-stage, primary tumor focality, primary tumor vascular invasion, year of diagnosis, insurance status, and treatment facility, as well as presence of bone, lung, and lymph node metastases. Results: We identified 2201 patients who received either CHT alone (n = 2097), or with hepatic surgery (n = 76) or RT (n = 28). Liver-directed local therapy was associated with improved OS on univariate (hazard ratio [HR] = 0.57; 95% CI 0.15 - 0.71; p < 0.001) and multivariate analysis (HR = 0.61; 95% CI 0.49 - 0.75; p < 0.001). There was no difference in OS between RT versus surgery (HR = 1.37; 95% CI 0.76 - 2.46; p = 0.30). After propensity score matching, there were 104 patients in each cohort. Liver therapy continued to be associated with improved OS (HR = 0.60; 95% CI 0.45 - 0.81; p = 0.001). Conclusions: We found that addition of local therapy to the liver with surgery or RT is associated with higher OS when compared to CHT alone in metastatic ICC. These findings should be validated in an independent cohort.
RISE-HEP project part 1: Treatment sequences evaluation in hepatocellular carcinoma cell lines.
Authors: Faloppi Luca , Nabissi Massimo , Santoni Matteo , Maggi Federica , Galizia Eva , Miccini Francesca , Bianconi Maristella , Puzzoni Marco , Astara Giorgio , Battelli Nicola , Santoni Giorgio , Scartozzi Mario
Published: May 2019

e15663

Background: For over ten years the most stimulating results in systemic therapy for advanced HCC derived from the use of sorafenib (S). But in the last two years several drugs, in particular other multikinase inhibitors like lenvatinib (L), regorafenib (R), cabozantinib (C), proved to be effective both as an alternative or a sequential therapy to sorafenib. In this widened and rapidly increased scenario, without any head-to-head trial, clinicians struggle to define the best drug and the best treatment sequence. Aim of the first part of this project is to evaluate the activity of different treatment sequences in HCC cell lines to pave the way to a future clinical trial investigating their efficacy. Methods: Compounds of S, R, L and C were dissolved in DMSO and aliquoted. HepG2 cell line, obtained from ECACC (Salisbury, UK), was seeded at the density of 3 x 104 cells/ml. After 24 h of incubation, compounds or vehicle (DMSO) were added. Treatments were performed in single administration and six replicates were carried out for each dose. At 48h post-treatment, cells were fixed and stained with acid solution. The absorbance was measured at 520 nm using an ELISA reader (BioTek Instruments, USA). The assay was also performed with the sequences of: S-R, S-C, L-R, L-C (first line treatments for 48h followed by the second compound for 48h). Higher doses than the minimum inhibiting one were tested. Results: S showed superior activity than L as first line compound. In the sequence assay S-C and S-R seems to have the best results in terms of cell viability. After L the best compound appears to be R. See table. Conclusions: Our results showed relevant variations in cell viability with different drug sequences. Already planned analyses in the RISE-HEP project in vivo and in humans are mandatory to confirm which sequence would have the highest efficacy.[Table: see text]
Clinical predictors of radiographic progression of a hepatic lesion from Li-RADS 3 to Li-RADS 5 among a population of individuals at high risk of hepatocellular carcinoma.
Authors: Hannan Lindsay Marie , Ojeda Patricia I , Hippe Daniel S , Mieloszyk Rebecca , Johnson Guy E , Park James Oh , Harris William Proctor , Bhargava Puneet
Published: May 2019

e15668

Background: We sought to identify clinical predictors of radiographic progression of a Li-RADS (LR) 3 lesion (i.e. indeterminate for hepatocellular carcinoma (HCC)) to a LR 5 lesion (i.e. definitely HCC) among patients (pts) at high risk of HCC. Methods: Radiology reports from the University of Washington with an LR assignment, 2013-2017, were reviewed (5037 reports, 1954 patients(pts)). Pts with an LR 3 lesion, a follow-up scan within 1 year of date of LR 3 lesion detection, and radiographic evidence of cirrhosis OR a diagnosis of chronic HBV were included in the analysis. Results: Of the 167 pts, 38 (23%) progressed to LR 5 status, 10 progressed to LR 4, and 12 were downgraded to LR 1-2. The remaining 64% were unchanged at LR 3. Radiographic data including year of LR 3 detection (2013-2014 47%) and LR 3 imaging modality (CT 50.3%, MR 49.7%) were obtained. Clinical data were abstracted from medical record review, including sex (65% male), age (80% < 65), race (66% White), cirrhosis etiology (45% HCV, 27% EtOH, 22% NASH, 8% HBV), HCV genotype, HCV treatment status, AFP, and ALBI score (G2 54%, G3 16%, unk 15%). Variables of interest (age, sex, race, cirrhosis etiology, AFP, ALBI score, year of LR 3 detection, imaging modality) were included in proportional hazards modeling with the underlying time metric defined as time from LR 3 detection to date of LR 5 detection or date of last scan up to one year after LR 3 identification. Backwards elimination modeling was performed until remaining variables were associated with the outcome at a level of significance of p < 0.05 (Table 1). Among those with chronic HCV, risk of progression to LR 5 did not differ by HCV genotype (1a, 1b, 2, 3, other, unknown) or sustained viral response status at the time of LR 3 detection. Table 1: Multivariate hazard ratios (HR) and 95% confidence interval (CI) estimates. Conclusions: Chronic HCV, older age at LR 3 detection, earlier year of LR 3 detection, and male sex appear independently associated with risk of progression to LR 5. The identification of clinical factors associated with LR 3 progression may allow for the development of risk modeling tools to assist clinicians in determining frequency of follow-up imaging and optimal timing of intervention.[Table: see text]
Benefit of early-phase targeted, basket, and immune-based trials for patients with chemorefractory gastrointestinal (GI) cancers.
Authors: Agarwal Rajiv , Cangemi Nicholas Anthony , Epstein Andrew S. , Harding James J. , Segal Neil Howard , Reidy Diane Lauren , Hyman David Michael , Saltz Leonard B.
Published: May 2019

e15700

Background: Historically, phase I trials were designed to establish phase II tolerable doses of new drugs. Efficacy concerns were secondary. In the modern era of targeted and immune-based therapies, investigator and patient expectations of efficacy in such trials have increased. Patients (pts) who have exhausted standard treatment options often seek participation in phase I drug development or phase II basket studies, with hope for therapeutic benefit. We assessed the benefit to pts with chemorefractory GI cancers from investigational early drug development trials at our institution. Methods: We reviewed the referral records of our Early Drug Development and Immunotherapy Services to identify pts referred from our GI Oncology Service in 2018. As pts are typically not referred unless with performance status 0-1, and normal liver, renal, and marrow function, those requesting early phase studies but not meeting these criteria were excluded from this analysis. End points were enrollment on a trial, 3 and 6-month PFS, and tumor shrinkage. Results: Of 245 GI Oncology pts referred in 2018, 26 (11%) were accrued to a trial: 14 to immune-based (1 withdrew before treatment) and 12 to targeted (3 to phase II basket): median age 53 (range 23-76); 15 female. GI cancer types included: colon (7), pancreas (7), cholangiocarcinoma (4), rectal (3), and appendiceal, peritoneal mesothelioma, small bowel, unknown primary, and gastric (1). Most common reasons for non-accrual were lack of available treatment spots and failure to meet eligibility criteria for specific trials. Of 22 pts with adequate follow up at time of analysis, none achieved 6-month PFS; one (5%) met 3-month PFS with tumor growth below RECIST criteria at 3 months and came off study for progression at 4 months. No pts achieved any degree of tumor shrinkage while receiving trial drugs. Conclusions: Phase I and phase II basket options for chemorefractory GI cancers were limited relative to demand. Benefit from investigational treatment in this patient population was limited; expectations may be overstated. Further research is underway to evaluate pts’ expectations for therapeutic benefit from early phase targeted and immune-based trials.
Alpha-1-acid glycoprotein 1 (AGP1) as a novel biomarker for pancreatic cancer.
Authors: Zhou Qimin , Andersson Roland , Hu Dingyuan , Bauden Monika , Sasor Agata , Bygott Thomas , Pawłowski Krzysztof , Pla_Parada Indira , Marko-Varga György , Ansari Daniel
Published: May 2019

e15708

Background: Pancreatic cancer is a heterogeneous disease with an aggressive clinical course. Most patients are detected late due to the insidious onset of symptoms and lack of effective molecular markers. The purpose of this study was to develop protein markers for improved prognostication and non-invasive diagnosis. Methods: A mass spectrometry (MS)-based discovery approach was applied to pancreatic cancer tissues and healthy pancreas. In the verification phase, extracellular proteins with differential expression were further quantified in targeted mode using parallel reaction monitoring (PRM). Next, a tissue microarray (TMA) cohort including 140 pancreatic cancer resection specimens was constructed, in order to validate protein expression status and investigate potential prognostic implications. The levels of protein candidates were finally assessed in a panel of 80 serum samples with ELISA. Results: Protein sequencing with nano-liquid chromatography tandem MS (nano-LC-MS/MS) and targeted PRM identified alpha-1-acid glycoprotein 1 (AGP1) as a potential pancreatic cancer biomarker. Using TMA and immunohistochemistry, AGP1 expression was significantly associated with shorter overall survival (HR = 2.217; 95% CI 1.296-3.794, p = 0.004). Multivariable analysis confirmed the results (HR = 1.867; 95% CI 1.078-3.235, p = 0.026). Circulating levels of AGP1 yielded an area under the curve (AUC) of 0.85 for the discrimination of resectable pancreatic cancer and IPMN from healthy controls. Combining AGP1 with CA 19-9 displayed an AUC of 0.98 with an overall sensitivity of 96% at 90% specificity. Conclusions: This study suggests that AGP1 is a valid biomarker for pancreatic cancer.
Patient and physician preferences for NIH PROMIS patient-reported outcome (PRO) domains in pancreatic ductal adenocarcinoma (PDA).
Authors: Guan Michelle , Gresham Gillian , Shinde Arvind Manohar , Placencio-Hickok Veronica , Gong Jun , Tuli Richard , Hendifar Andrew Eugene
Published: May 2019

e15721

Background: PDA is associated with high symptom burden. However, treatment and palliation decisions currently weigh on physician interpretation of clinical parameters and may not consider patient values and preferences. The NIH PROMIS tool was created to capture various health domains through PROs. The objective of this study was to identify the most important PROMIS domains to PDA pts and physician providers. Methods: Using the 31 domains in NIH’s PROMIS, we conducted online surveys with PDA pts and PDA physicians from 17 academic centers. These domains are categorized into mental, physical, and social health. Values for the PRO domains were quantified using Maximum Differences Scaling (Sawtooth Software). Results: A total of 116 PDA pts (55% males, 45% females; median age: 68 years, range 42-95) and 33 physicians (78% males, 22% females; median years of experience: 15) completed the surveys. The top five domains identified by pts and providers are listed in the table. Physical functioning (PF), ability to perform activities of daily living (ADLs) and symptom management were among the top domains for both pts and physicians regardless of age, gender, resection status, or years of physician experience. However, social domains such as ability to do things for yourself, family, and friends, and interactions with family/friends were ranked significantly higher by pts versus pain, anxiety, and depression by physicians (p < 0.01). Conclusions: Our findings suggest PDA pts value PF and engaging in work and social activities while physicians focus more on pain, depression, and symptom management. PROs need to become more important endpoints in clinical trials to better inform treatment decisions and develop therapies that address the health priorities of pts. [Table: see text]
Efficacy and safety of FOLFIRINOX in elderly patients with advanced pancreatic adenocarcinoma.
Authors: Jung Jae Hyup , Kang Jingu , Lee Jong-Chan , Hwang Jin-Hyeok
Published: May 2019

e15729

Background: Although FOLFIRINOX showed improved efficacy in advanced pancreatic ductal adenocarcinoma (PDA), physicians still hesitate to administrate FOLFIRINOX in elderly patients despite of being in a good performance status. We investigated the efficacy and toxicity of FOLFIRINOX in elderly patients with advanced PDA. Methods: We retrospectively reviewed electronic medical records of advanced PDA patients administrated a first-line FOLFIRINOX from January 2012 to July 2017 in a single tertiary teaching hospital. All the patients were divided into two groups: non-elderly group A (age < 70) and elderly group B (age≥70). Overall survival (OS), progression free survival (PFS) and toxicities were compared between two groups using Cox proportional hazard model. Results: A total of 214 patients (Group A 176; B 38) met the eligible criteria. Median age was 61 years old (29-80, group A 59; B 73) and median cycle of FOLFIRINOX was 7.0 (1–75, group A and B 7.0). Median OS and PFS did not differ between group A and B (OS, 11.8 vs 12.0 months, hazard ratio [HR] 1.165, 95% confidence interval [CI] 0.785–1.728; PFS 6.5 vs 7.3 months, HR 1.003, 95% CI 0.694–1.451, respectively). When we analyzed OS according to tumor stage (locally advanced and metastatic), group A and B showed comparable median OS (15.8 vs 13.5 months in locally advanced PDA; 8.6 vs 9.8 months in metastatic PDA, respectively) There were no significant differences in terms of hematologic toxicities except Gr 3 or 4 thrombocytopenia (Group A 3.4%; B 13.2%, P = 0.028). Fatigue and diarrhea were observed more often in Group B than in group A (47.4% vs 10.2%, P = 0.000; 18.4% vs 4.5%, P = 0.010, respectively), all of which were manageable. More patients in group B received dose adjusted FOLFIRINOX than in group A, although there was no statitical significance. Conclusions: FOLFIRINOX could be considered as the first-line chemotherapy for elderly patients with advanced PDA as well as non-elderly patients when dosage modified appropriately, given comparable efficacies and acceptable and manageable toxicities. More studies are warranted to confirm this issue.
Prognostic value of lymph node positivity and number of lymph nodes required for accurate staging of pancreatic neuroendocrine tumors.
Authors: Hua Jie , Shi Si , Wei Miaoyan , Zhang Yiyin , Liang Chen , Meng Qingcai , Liu Jiang , Zhang Bo , Xu Jin , Yu Xianjun
Published: May 2019

e15736

Background: The prognostic role of the number of positive lymph nodes (PLNs), as well as the minimum number of lymph nodes needed to accurately stage patients with pancreatic neuroendocrine tumors (pNETs), remain controversial. The aim of this study was to assess the effect of the number of PLNs on prognosis in pNETs and to determine the ideal number of examined lymph nodes (ELNs) for accurate staging of pNETs. Methods: The SEER database was reviewed from 2004 to 2014 for pts with surgically resected, pathologically confirmed pNETs. Pts with missing data for pathological stage, tumor size, ELNs or PLNs were excluded. Kaplan-Meier survival analysis was used to evaluate the association between lymph node involvement and disease-specific survival (DSS). The optimal number of ELNs was identified using the log odds of positive lymph nodes (LODDS). A large single institutional cohort with 203 patients was used for validation. Results: Of the 1,813 patients included, 686 (37.8%) had lymph node-positive disease. Patients with lymph node-positive disease had a significantly worse DSS than those with lymph node-negative disease (Log-rank P < 0.001). Patients with 4 or more positive lymph nodes had a worse DSS compared with those with 1 to 3 positive lymph nodes (Log-rank P < 0.001). In order to capture 95% of pNETs with PLNs at the time of surgery, 12 lymph nodes need to be examined (LODDS: -2.344). Findings were reproducible with the validation cohort. Conclusions: The number of PLNs leads to better prognostic discrimination of lymph node-positive patients with pNETs. The current staging systems may include an N-stage that distinguishes lymph node-positive disease into N1 (1 to 3 PLNs) and N2 (4 or more PLNs) categories. The minimum number of ELNs for accurate staging of pNETs is 12. [Table: see text]
Microbiome signature of bile from pancreatic and biliary tract cancer patients: A pilot study.
Authors: Poudel Shyam K. , Padmanabhan Roshan , Chahal Prabhleen , Sanaka Madhusudhan , Stevens Tyler , Guinta Kathryn , Khorana Alok A. , Sohal Davendra , Eng Charis
Published: May 2019

e15744

Background: Recent studies especially in murine models have linked meta-organismal pathways in the gut microbial community to cancers of the pancreas and the biliary tract. However, data on microbiome in the biliary pool in patients to establish models for oncogenesis in the pancreatobiliary (PB) habitat have been limited. We analyzed bile collected from a pilot series of patients to identify microbiome signatures associated with malignancy. Methods: We collected bile samples from patients during routine endoscopic retrograde cholangiopancreatography in this study approved by the Cleveland Clinic Institutional Review Board for Human Subjects’ Protection. Of 10 patients, there were 5 with pancreatic ductal adenocarcinoma (PDA), 3 with cholangiocarcinoma (CC), 1 with ampullary adenocarcinoma, and 1 with gallstone pancreatitis. DNA was extracted from bile specimens using PowerViral RNA/DNA Isolation kit. Bacterial 16S rRNA gene amplification and library construction were performed according to the 16S Metagenomic Sequencing Library Preparation guide from Illumina. Post-sequencing analysis was done using QIIME (Quantitative Insights Into Microbial Ecology) and MICCA (MICrobial Community Analysis). Results: Most reads were from phyla Firmicutes (57.9%) and Proteobacteria (14.9%). One benign specimen (pancreatitis) separated clearly from the rest showing 98.9% of reads from Clostridium sensu stricto (phylum Firmicutes). Analysis of beta diversity showed six samples clustering tightly. Of these, 5 were PDA and 1 was CC. A second cluster included remaining 3 samples, 2 with CC and 1 with PDA; this latter had higher abundance of phyla Fusobacteria (90.6%) and Verrucomicrobia (92.9%). Conclusions: Select bacteria are differentially increased in malignant and benign PB diseases. Furthermore, distinct microbiome signatures may be associated with cancer in the pancreatic and biliary habitats. We intend to evaluate these findings in larger sample sizes and determine associations with clinical outcomes and response to treatment.
Exposure-response (E-R) analysis of efficacy of pegvorhyaluronidase alfa (PEGPH20) in combination with nab-paclitaxel + gemcitabine (AG) in patients (Pts) with metastatic pancreatic ductal adenocarcinoma.
Authors: Liu Yong , Bullock Andrea J. , Passarell Julie , Bihorel Sebastien , Fiedler-Kelly Jill , Heineman Thomas C , Sekulovich Rose E.
Published: May 2019

e15746

Background: PEGPH20 depolymerizes extracellular matrix hyaluronan (HA) and is an investigational agent for the treatment of pts with HA-accumulating tumors. HALO-109-202 (260 pts) was conducted to evaluate the effect of PEGPH20 + AG in pts with mPDA. Methods: E-R models were developed to evaluate the relationship between PEGPH20 exposure and efficacy, including time to PFS, time to OS, and overall response (OR). Results: The final E-R PFS model was a Cox proportional hazards model that included effects of PEGPH20 Cmax and baseline tumor biopsy HA (high or low). Higher PEGPH20 Cmax was associated with a lower risk of radiological progression. Pts with baseline HA≥ 50% (HA-high) tumor biopsy were at a lower risk of radiological progression with PEGPH20 treatment. A similar E-R model evaluated the effect of PEGPH20 on OS, including effects of dose-adjusted PEGPH20 concentration 7 days postdose (D7 Conc), liver metastases, and baseline tumor burden. The model-predicted influence of PEGPH20 D7 Conc on risk of death indicated that with increasing PEGPH20 D7 Conc, the predicted risk of death decreases. Pts with liver metastases and higher baseline tumor burden were predicted to have a higher risk of death. The final E-R efficacy model for OR probability was a linear function of dose-adjusted PEGPH20 AUC in Cycle 1, where increasing exposure was related to a higher predicted OR probability. Conclusions: The E-R analyses demonstrate that improvements in PFS and OS with PEGPH20 + AG is PEGPH20 exposure-dependent, supporting 3 µg/kg as an appropriate dose for further development and emphasizing the need for sufficient PEGPH20 exposure for improved therapeutic effect. Clinical trial information: NCT01839487. [Table: see text]
Effect of neoantigen reactive T cells combined with chemotherapy and radiation on survival in advanced pancreatic cancer.
Authors: Liu Qin , Zou Zhengyun , Liu Baorui , Kong Weiwei , Chen Fangjun , Shao Jie
Published: May 2019

e15756

Background: Pancreatic cancer (PC) is one of the most aggressive and death-relating malignancy. Gemcitabine (GEM) is the key agent in the first-line standard regimen for advanced PC, which is mostly diagnosed at advanced stage and unsuitable for curative resection. The objective responsive rate (ORR) and medium progression free survival (PFS) of various GEM-based regimens are still unsatisfied. Therefore, development of new therapeutic modalities, including immunotherapy, is needed. This study is to investigate the efficacy, safety and clinical beneficial of combination neoantigen based immunotherapy with GEM and radiotherapy in locally advanced and metastatic PC patients. Methods: Three locally advanced unresectable and seven metastatic PC patients received at least two cycles of GEM (1000mg/m2 on day 1 and day 6), radiotherapy combing with neoantigen induced DC vaccination on day 7 and cytotoxic T lymphocyte transfer from day 12 to 15 (repeated every 21 days). The locally advanced unresectable PC patients received stereotactic body radiotherapy (SBRT) with a total amount of 50-66Gy during the first cycle. For metastatic patients, their partial lesions received a low dose radiation (0.5Gy bid*2days ) on day 10 and 11 in each cycle. Results: Two cases were observed with partial remission (PR), five with stable disease (sd), and three with progressive disease (PD). The disease control rate (DCR) was 70%. Median progression free survival (PFS) was 6.4 months. After the first treatment cycle, the total effectiveness for pain easement and increasing appetite are 100% (8/8)and 66.7%, respectively. Haematotoxicities with a 40% incidence rate were the most common adverse drug reactions. Two patients had grade 1 to 2 neutropenia, two with grade 3 to 4 thrombocytopenia. Three patients suffered grade 1 to 2 gemcitabine-induced skin rash. No treatment-related mortality occurred. Conclusions: Neoantigen reactive T cells combined chemoradiotherapy demonstrated an acceptable response and safety in advanced pancreatic cancer patients.
Effect of ARK5 on the anti-tumour activity of OSI-027 via regulation of epithelial-mesenchymal transition in pancreatic cancer.
Authors: Zhi Xiao , Liang Tingbo
Published: May 2019

e15758

Background: Pancreatic cancer (PC) is one of the most common lethal malignancies,OSI-027, a selective inhibitor of mTOR, has anti-tumour activity in PC and is currently in phase II clinical trials. According to the results of our previous study, OSI-027 sensitivity varies across pancreatic cancer cell lines; however, the underlying mechanisms are unclear. Methods: In this study,We sought to investigate the regulatory mechanisms underlying OSI-027 resistance in PC under both in vitro and in vivo conditions. Results: We demonstrated that in PC, sensitivity to OSI-027 was negatively correlated with ARK5 expression, and ARK5 knockdown could enhance OSI-027 sensitivity. Further, the mechanistic experiments showed that ARK5 inhibition could reverse EMT induced by OSI-027. Suppression of EMT by Twist siRNA could sensitize pancreatic cancer cells to OSI-027, but the combination of Twist siRNA and ARK5 siRNA did not enhance the anti-tumour effect of OSI-027. Moreover, under hypoxia-induced EMT, the cancer cells were less sensitive to OSI-027, but ARK5 siRNA could block the EMT process. The in vivo experiments showed that the combination of ARK5 and Twist siRNAs could enhance the anti-tumour effect of OSI-027 and restrain OSI-027-induced EMT. Conclusions: The results indicate that ARK5 plays a role in the resistance of pancreatic cancer cells to OSI-027 by regulating EMT and lay the groundwork for future clinical studies.
Effect of LAT2 on glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.
Authors: Qiu Jiangdong , Feng Mengyu , Cao Zhe , Yang Gang , Liu Yueze , Zhang Taiping
Published: May 2019

e15759

Background: Reprogrammed energy metabolism has become the characteristic of cancer recently. Transporters act as amino acid sensors involved in mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), a Na+ -independent neutral amino acid transporter, is encoded by the SLC7A8 gene and responsible for transporting neutral amino acids, including a mTOR activator, glutamine. LAT2 was reported to be overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains unclear. Methods: The effects of LAT2 on biological behaviors of pancreatic cancer cells were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated. Results: We demonstrated that LAT2 played an oncogenic role and decreased the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. Survival analysis indicated that high expression of both LAT2 and LDHB was related to a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, the combination of gemcitabine with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, LAT2 promoted glycolysis and decreased gemcitabine sensitivity via regulating two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) in pancreatic cancer. Conclusions: Our data indicates that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease gemcitabine sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.
Mutant KRAS and TP53 with high mutation allelic frequency in ctDNA as poor outcome predictors in metastatic pancreatic cancer.
Authors: Guan Shasha , Shi Yan , Han Quanli , Li Jie , Lv Yao , Yan Huan , Han Lu , Chen Yang , Qian Niansong , Wang Zhikuan , Shi Huaiyin , Dai Guanghai
Published: May 2019

e15763

Background: This study was to investigate the feasibility and the prognostic value of circulating tumor DNA (ctDNA) in metastatic pancreatic cancer (MPC). Methods: From 2015 to 2018 in our center, 40 MPC patients treated with nab-paclitaxel based first-line chemotherapy were prospectively collected both tumor tissue and blood samples, in which the genomic profiling of 425 genes was identified by next-generation sequencing. High mutation allelic frequency (MAF) was defined > 30% and > 5% in tumor tissue and blood, respectively. Kappa statistics were used to compare mutant (mt) genes in tissue and ctDNA. Progression-free and overall survival (PFS, OS) were assessed with Kaplan-Meier and Cox methods. Results: Among 40 MPC patients, tumor tissue and blood samples were available in 34 and 38 patients for somatic and germline alternation test, respectively. The most commonly mutant gene were KRAS (31/34 in tissue with a median MAF of 29.4%, 29/38 in ctDNA with a mMAF of 8.2%), and TP53 (28/34 in tissue with a mMAF of 31.1%, 25/38 in ctDNA with a mMAF of 7.4%). Moderate agreement was seen between ctDNA and tumor tissue (mt KRAS: κ = 0.54, P = 0.001; mt TP53: κ = 0.74, P < 0.001). Mutation in CDNK2A and SMAD4 genes were detected in 8 and 6 patients in tissue and ctDNA, respectively. Germline alternation was found in 7 genes in 9 patients (9/40). High MAF of mt KRAS (r = 0.51, P = 0.005) or mt TP53 (r = 0.50, P = 0.005) in ctDNA was correlated with high CA199 levels (> 5000 u/ml) at baseline. MT KRAS in tissue with high MAF was associated with poor OS (high 7.5m vs low 10.1m, P = 0.001) in univariate and multivariate analyses (HR 3.87, 95%CI 1.47 to 10.19). Univariate analyses showed mt KRAS and mt TP53 in ctDNA with high MAF were associated with poor PFS ( KRAS and TP53: high 3.4m and 3.0m vs low 6.1m and 5.7m, P = 0.001 and P = 0.004, respectively) and OS ( KRAS and TP53: high 5.3m and 5.3m vs low 12.6m and 10.1m, P < 0.001, respectively). The presence of ctDNA in any above four mt driver gene with high MAF was associated with poor PFS (HR 3.79, 95%CI 1.71 to 8.42) and OS (HR 7.21, 95%CI 2.69 to 19.34) in multivariate COX model, when adjusted by age, sex, tumor differentiation, and baseline CA199 level. Conclusions: The presence of mt KRAS and mt TP53 with high MAF in ctDNA was associated with worse PFS and OS in MPC patients. Peripheral ctDNA testing demonstrated an alternative promising prognostic biomarker for MPC patients before treatment.
Pancreatic cancer: Assessment of neoadjuvant chemotherapy outcome based on radiomics of pretreatment computed tomography.
Authors: Li Xiang , Tang Tianyu , Bai Xueli , Liang Tingbo
Published: May 2019

e15767

Background: The objective response rate to neoadjuvant chemotherapy (NAC) was limited to around 35% in pancreatic cancer and as more as 30% patients show no benefit to NAC. In this instance, predicting the response to NAC may play an important role in individual treatment for pancreatic cancer patients. We aim to evaluate contrast enhanced-computed tomography (CE-CT) features in predicting treatment response and survival after neoadjuvant chemotherapy (NAC) for patients with borderline resectable and locally advanced pancreatic cancer. Methods: Sixty-one pancreatic cancer patients receiving NAC were enrolled and underwent abdominal CE-CT before treatment. All patients were divided into groups according to the changes of tumor size after treatment. 396 radiomics features were extracted from three-dimensional ROIs (region of interest) based on pretreatment CE-CT images of each patient. The optimal features were selected and three supervised machine learning classifiers were developed. Finally, univariate and multivariate analyses were performed to evaluate the capability of the selected features in predicting histopathologic response and outcomes. Results: Nine, seven and five radiomics features were selected as optimal features for three experiments respectively. Two features, Haralick Entropy and Histogram Entropy, were found consistent in experiments and were both higher in patients with tumor enlargement. Moreover, lower Histogram Entropy was significantly associated with a better histopathologic response (p = 0.008) and smaller tumor size (p = 0.041) in patients with tumor resection. In univariate Cox regression analysis, lower Histogram Entropy (P = 0.006) and lower Haralick Entropy (P = 0.001) predicted a better prognosis. Meanwhile, lower Haralick Entropy (p = 0.048) was independent predictor for longer survival time in multivariate Cox regression analysis. Conclusions: Radiomics features are strongly correlated with NAC treatment response and prognosis in pancreatic cancer, suggesting the great potential of imaging radiomics to help tailoring the treatment into the era of personalized medicine