bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors and scoring model for survival in advanced biliary tract cancer.
Authors: Park Hyung Soon , Park Ji Soo , Roh Yun Ho , Moon Jieun , Yoon Dong Sup , Jeung Hei-Cheul
Published: March 2017

264

Background: Metastatic biliary tract cancer (BTC) has dismal prognosis. We herein presented multivariate analysis using routinely evaluated clinico-laboratory parameters at the time of initial diagnosis, to implement a scoring model that can effectively identify risk groups, and we finally validated the model using independent dataset. Methods: From September 2006 to February 2015, 482 patients with metastatic BTC were analyzed. Patients were randomly assigned (7:3) into investigational (n = 340) and validation dataset (n = 142). Continuous variables were dichotomized according to the normal range or the best cutoff values statistically determined by Contal and O’Quigley method. Multivariate analysis using Cox’s proportional hazard model was done to find independent prognostic factors, and scoring model were derived by summing the rounded χ2 scores for the factors emerged in the multivariate analysis. Results: Performance status (ECOG 3-4), hypoalbuminemia ( < 3.4 mg/dL), carcinoembryonic antigen (≥9 ng/mL), neutrophil-lymphocyte ratio (≥3.0), and carbohydrate antigen 19-9 (≥120 U/mL) were identified as independent factors for poor survival in investigational dataset. When assigning patients into three risk groups based on these factors, survival was 14.0, 7.3, and 2.3 months for the low, intermediate, and high-risk groups, respectively (P < 0.001). Harrell’s C-index and integrated AUC for scoring model were 0.682 and 0.653, respectively. In validation dataset, prognosis was also well-divided according to the risk groups (median OS, 16.7, 7.5 and 1.9 months, respectively, P < 0.001). Chemotherapy gave a survival benefit in low and intermediate-risk group (11.4 vs. 4.8 months; P< 0.001), but not in high-risk group (median OS, 4.3 vs. 1.1 months; P = 0.105). Conclusions: We propose a set of prognostic criteria for metastatic BTC, which can help accurate patient risk stratification and aid in treatment selection.
Proposal of size-based surgical indication criteria for liver hemangioma based on a nationwide survey in Japan.
Authors: Sakamoto Yoshihiro , Kokudo Norihiro , Watadani Takeyuki , Shibahara Junji , Yamamoto Masakazu , Yamaue Hiroki
Published: March 2017

265

Background: Although hepatic hemangioma is one of the most frequent benign tumors in the liver, surgical indication for this neoplasm remains unclear. The objective of the present study was to conduct a nation-wide survey on resected cases of liver hemangioma and propose evidence-based surgical indication criteria for this disease (Research project of Japanese Society of Hepato-Biliary-Pancreatic Surgery). Methods: Of a total of 510 patients undergoing surgical resection for liver hemangioma in 118 Japanese centers between 1998 and 2012, abdominal symptoms, coagulopathy, diagnostic accuracy and surgical outcomes were analyzed according to the tumor status. Results: The patients were classified into 4 groups based on the tumor size; Group A) ≤ 5cm (n = 122, 24%), B) 5-10cm (n = 164, 32%), C) 10-15cm (n = 124, 24%), and D) > 15cm (n = 100, 20%) Hemangioma in Group A was most frequently diagnosed as a malignant tumor (43.5%) due to absence of typical imaging findings as cavernous hemangioma and with highest incidence of positive of HBV (15.7%). Diagnostic accuracy was 98.4% in Groups B-D. In Group B, 71% of patients presented no abdominal symptoms or Kasabach-Merritt syndrome. Symptoms associated with hemangioma increased in proportion as the size increased, and the incidence of abdominal distension, tumor rupture, and Kasabach-Merritt syndrome were 55%, 2.0%, and 26%, respectively, in Group D. The incidence of liver failure after hepatectomy was higher in Group D than in Groups A-C (3.0% vs. 0.5%, p = 0.02). There was only one operative death (0.2%) in Group D. Conclusions: In patients with = /< 5cm hemangioma, surgical resection is indicated when malignant tumor can not be ruled out. However, surgical indications for 5-10cm asymptomatic hemangiomas should be limited because preoperative diagnosis of benign disease is trustworthy in this subgroup. Tumor size > 10cm would be candidate for surgery when accompanied with abdominal symptom or coagulopathy, and hepatectomy for tumors > 15cm should be performed in high volume centers by experienced hepatic surgeons to avoid serious morbidity or mortality.
Visceral thromboses (VT) in pancreas adenocarcinoma (PDAC): A systematic review.
Authors: Mier Hicks Angel , Derosa Antonio , Raj Micheal , Do Richard Kinh Gian , Yu Kenneth H. , Lowery Maeve Aine , Varghese Anna M. , O'Reilly Eileen Mary
Published: March 2017

268

Background: Within the spectrum of gastrointestinal malignancies, primary liver (HCC) and pancreatic ductal adenocarcinoma (PDAC) are frequently associated with visceral thromboses (VT). Thrombus formation in the portal (PVT), mesenteric (MVT), or splenic vein (SVT) system leads to portal hypertension and intestinal ischemia. VT in PDAC may convey a risk of increased distal thrombosis and poses therapeutic uncertainty regarding the role of anticoagulation. An increasing number of reports describe VT associated with PDAC. It is possible that early diagnosis of these events may help reduce morbidity speculatively improve oncologic outcomes. Methods: Perform a systematic review to study occurrences of visceral thromboses (portal, mesenteric and splenic vein thromboses) associated with PDAC and provide a clinical review on this area. Main databased were searched; PubMed, EMBASE, Web of Science, Scopus, and the Cochrane library. Two blinded independent observers extracted and assessed the studies for diagnosis of PVT, MVT, and SVT in PDAC. Studies were restricted to English literature published after 2007 to 2016. Results: Eleven articles were identified. Five case reports and 7 retrospective studies were found with a total of N=127 patients meeting the inclusion criteria. The mean age at diagnosis was 64 years. PVT was found in 35% (N= 46), SVT in 52% (N= 65), MVT in 13 %( N= 15). Mean follow up time was 26 months. Only 3 of the selected articles studied the impact of anticoagulation in visceral thrombosis. All patients with non-visceral thrombosis (e.g. DVT, PE) were therapeutically treated, in contrast, to only rare occurrences with VT received treatment. Conclusions: Visceral thrombosis in PDAC can be a frequent finding at diagnosis or during disease progression. This literature analysis has shown VT to be a poor prognostic indicator for short term survival. Evidence to guide treatment choices are inadequate and current management is based on inferred experience from other non-oncologic populations. Anticoagulation appeared to be a safe modality in visceral thrombosis with most of the large studies recommending a careful assessment for patients with high risk of bleeding.
The clinical impact of PET/CT with 68Ga-DOTATATE in neuroendocrine tumors (NETs): The experience of a private institution in Brazil.
Authors: Tsukamoto Jessica Sayuri , Wassano Noelle Suemi , Barbosa Luiza Damian Ribeiro , Braga Virginia Moreira , Rigo Letícia , Racy Douglas Jorge , Soares De Souzsa Tercia Tarciane , Belotto Marcos , D'Alpino Renata D'Alpino
Published: March 2017

271

Background: The introduction of PET/CT with 68Ga-DOTATATE (68Ga-PET) determined an exponential increase of the accuracy in diagnosing and following up NETs. However, this exam is not frequently available in developing countries. Methods: We have retrospectively evaluated the efficacy of 68Ga-PET in patients with NETs and its impact on clinical decision at Hospital São José, Brazil. Results: Between February 2014 and July 2016, 28 patients (15 males) with histologically confirmed NETs underwent Ga68-PET at our hospital. Median age was 57 (range 21 - 82). Primary sites were pancreas (n = 10), small bowel (n = 7), lung (n = 3) and others (n = 8). The Ki-67 index was < 2% in 7 patients and > 20% in 6 patients. Five patients had unknown Ki67 index. There was 68Ga uptake in 82% of the patients (21,4% in patients with Ki67 > 20%). Median SUV was 16,3 (range 1,7- 129,8). Only 32% of the patients underwent concomitant Octreoscan. Results were divergent between both imaging methods in 55% of the patients, which resulted in therapeutic change. The main reason to request the exam was to measure the extent of metastatic disease (n = 14). Other reasons were to access response to therapy (n = 8), to evaluate the possibility of treatment with Lutetium (n = 3), to investigate the primary tumor (n = 2), and others (n = 1). Conclusions: Ga68-PET is an important imaging key to guide therapeutic management in NETs, especially among patients with Ki67 < 20%. When available, Ga68-PET is superior to Octreoscan.
Orally administered CCR2 selective inhibitor CCX872-b clinical trial in pancreatic cancer.
Authors: Noel Marcus Smith , Hezel Aram F. , Linehan David , Wang-Gillam Andrea , Eskens Ferry , Sleijfer Stefan , Desar Ingrid , Erdkamp Frans , Wilmink Johanna , Diehl Janet , Potarca Antonia , Zhao Niky , Deng Jun , Lohr Lisa , Miao Shichang , Charo Israel , Singh Rajinder , Schall Thomas J. , Bekker Pirow
Published: March 2017

276

Background: CCR2 inhibition decreases tumor-associated macrophages and Treg cells, and increases CD8+ and CD4+ T cells in pancreatic tumors. Single oral doses of 150 mg CCX872-B were well tolerated in patients with pancreatic cancer. The first stage results of the multiple dose part of this study are presented. Methods: Patients with locally advanced or metastatic pancreatic cancer, ECOG score ≤ 2 were studied. Patients received FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) q2weeks for up to 24 wks plus 150 mg CCX872-B once or twice daily until disease progression or intolerance to CCX872-B. The primary efficacy endpoint is progression-free survival (PFS) at 24 wks. Tumor control rate (TCR) and the objective response rate (ORR), a secondary endpoint, are presented. Results: Fifty patients were enrolled. Baseline: Mean ± SD age: 60 ± 8.6 years, male 52%; primary tumor location: head 57%, body/tail 41%, local recurrence 2%; metastatic disease 78%, ECOG score 0: 62%, ECOG score 1: 38%. Thirty five of 50 patients completed week 12. Most common reasons for early withdrawal were subject request (5 pts) and adverse events typically associated with FOLFIRINOX (4 pts). In the pre-specified analysis population, i.e., those with ≥ 1 post baseline CT scan, tumor control at wk 12 was achieved in 32 of 41 (78%) patients, with 15 of 41 (37%) partial responders, and 17 of 41 (41%) with stable disease. The ORR was 37% (all partial responders) in the primary analysis population (30% when all enrolled patients were included). Thirteen of 21 patients with available CT scan results at week 24 were progression-free. Mean trough CCX872 plasma level was ~8 μg/mL. CCR2 was covered 88% on average by CCX872-B based on receptor occupancy assays. CCX872-B appeared to be well tolerated and the incidence of ≥ Gr 3 AEs was not increased with CCX872-B plus FOLFIRINOX vs historical data with FOLFIRINOX alone. The complete set of PFS data will be available by the end of 2016. Conclusions: CCX872-B plus FOLFIRINOX resulted in a TCR of 78% and an ORR of 30 to 37% with no safety issues ascribed to CCX872-B use. Clinical trial information: NCT02345408.
Tumor interface stability on CT imaging is an early marker of response to cytotoxic therapy in pancreatic ductal adenocarcinoma.
Authors: Wilke Christopher , Amer Ahmed , Elganainy Dalia , Bhosale Priya , Le Ott , Lee Yeonju , Cloyd Jordan , Wang Huamin , Herman Joseph M. , Taniguchi Cullen M. , Rhim Andrew , Fleming Jason B. , Maitra Anirban , Wolff Robert A. , Varadhachary Gauri R. , Lee Jeffrey Edwin , Katz Matthew H. G. , Tamm Eric P. , Koay Eugene Jon
Published: March 2017

284

Background: There is currently no reliable biomarker for assessing the response to therapy of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated how changes in the tumor/parenchyma interface associate with response. Methods: We reviewed pre- and post-therapy scans of patients who received chemotherapy and/or chemoradiation for both localized and metastatic PDAC. We classified the interface between the PDAC tumor and surrounding pancreas parenchyma as stable (remains or becomes well-defined) or unstable (becomes poorly defined) using a novel visual scoring system and quantified changes in enhancement at this interface (Philips Intellispace Portal, quantitative European Association for the Study of Liver [qEASL]). Results: Three retrospective datasets were used to develop this method with consensus visual scoring performed by 3 radiologists. The first dataset included 99 patients with localized PDAC who received neoadjuvant chemoradiation. Patients who were classified as having a stable interface had significantly higher probability of achieving a complete or near-complete pathologic response (21% vs 0%, p = 0.01) and additionally demonstrated an improved median disease-free survival (DFS, 20.9 vs 7.9 mos., p < 0.01) and overall survival (OS, 47.7 vs 19.1 mos., p < 0.01). These results were validated in a separate dataset of 94 patients receiving protocol-based chemotherapy and chemoradiation (chemoRT cohort) and a cohort of 86 patients with stage IV disease. In both cohorts, a stable interface was associated with a significant improvement in progression free survival (PFS, Hazard Ratio [HR] 0.44, p = 0.01 for chemoRT and HR 0.70, p = 0.16 for stage IV) and OS (HR 0.42, p < 0.01 for chemoRT and HR 0.59, p = 0.05 for stage IV). Multivariate analyses for each cohort showed interface stability to be independently associated with both DFS/PFS and OS. Measurements obtained using qEASL were concordant with the visual scoring results. Conclusions: The interface stability of PDAC is an early readout of response to therapy. Integration of this imaging feature into clinical trials for localized and metastatic PDAC may aid in the future development of adaptive treatment strategies.
Health-related quality of life (HRQoL) in patients with advanced neuroendocrine tumors (NET) of gastrointestinal origin in the phase 3 RADIANT-4 trial.
Authors: Singh Simron , Strosberg Jonathan R. , Bubuteishvili-Pacaud Lida , Degtyarev Evgeny , Neary Maureen , Hunger Matthias , Eriksson Jennifer , Ricci Jean-Francois , Fazio Nicola , Kulke Matthew H. , Pavel Marianne E. , Yao James C.
Published: March 2017

285

Background: In the RADIANT-4 trial, everolimus (EVE) plus best supportive care (BSC) improved progression-free survival (PFS) compared to placebo (PBO) plus BSC in 302 patients with advanced progressive nonfunctional NET of gastrointestinal (GI) or lung origin (Yao, Lancet 2015) and in patients of GI origin only (Singh, ASCO-GI 2016). In addition, HRQoL was maintained with no statistically or clinically relevant differences in patients receiving EVE compared to PBO in the full sample (Pavel, ASCO 2016) and in patients with NET of GI origin (Pavel, NANETS 2016). Complementary analyses are presented to assess treatment effect on HRQoL in the subpopulation of patients with NET of GI origin. Methods: HRQoL was measured with FACT-G, a 27-item validated questionnaire with 4 domains: physical (PWB), social/family (SWB), emotional (EWB), and functional wellbeing (FWB). FACT-G was completed at baseline and every 8 weeks until month 12, then every 12 weeks until study drug discontinuation. Linear mixed models (LMM) were fitted to analyze mean FACT-G total (scale: 0 – 108) and subscale scores over time. A responder analysis in terms of cumulative distribution functions (CDF) of patients mean change from baseline across the entire study period was also conducted. Results: The subgroup of patients with NET of GI origin included 211 patients (141 on EVE and 70 on PBO) with NET of ileum, rectum, jejunum, stomach, duodenum, colon, caecum, appendix, or cancer of unknown primary (CUP), generally known as GI origin. In LMM, FACT-G total score at week 8 was 79.9 (95% CI: 77.7, 81.1) for EVE and 79.9 (95% CI: 77.0, 82.8) for PBO, declining to 77.1 (95% CI: 73.9, 80.4) and 78.7 (95% CI: 73.4, 83.9) at week 48. At each time point, differences in mean scores between treatment arms were lower than the minimally important difference (MID) of 7 points. Differences in mean subscale scores between treatment arms also did not exceed the MID (3 points). CDF plots showed no differences in distributions for the FACT-G total score (p = 0.9348). Conclusions: In addition to PFS benefits, HRQoL is maintained in patients with NET of GI origin receiving EVE despite usual toxicities of active cancer treatment. Clinical trial information: NCT01524783.
Prognostic value of CD8+CD45RO+ tumor-infiltrating lymphocytes (TIL) and PD-L1 in cholangiocarcinoma.
Authors: Kim Dae Won , Coppola Domenico , Chang Young , Kim Richard D.
Published: March 2017

286

Background: Cholangiocarcinoma is a malignancy arising from the epithelial cells of the biliary tract with poor prognosis. TILs and PD-L1 have a prognostic impact in various solid tumors. We aimed to investigate TILs and PD-L1 expression and their clinical relevance in cholangiocarcinoma. Methods: Formalin-fixed paraffin-embedded tumor samples from 41 patients with resected and histologically verified cholangiocarcinoma between 1990 and 2015 were identified and immunohistochemically (IHC) stained with anti-CD8, anti-CD45RO and the anti-PDL1 mouse IgG1 (clone 5H1; Thompson) antibodies. Stained tumor samples were reviewed and enumerated by a GI pathologist. PD-L1 positivity was defined ≥ 5% of tumor cells with a minimum of 100 evaluable tumor cells. The association between expression of PDL1, CD8 or CD45RO and survival was investigated using Kaplan-Meier survival and COX proportional hazard regression analyses. Results: The median age of patients was 64 (41-85) with 53% male. 22%, 41% and 37% were stage I, II and III, respectively. CD8 was positive in 16 (39%), CD8CD45RO (memory CD8 cells) was positive in 5 (12%), and PD-L1 was positive in 19 (46%). With a median follow-up of 21.4 months, tumors with CD8+CD45RO+ TIL has better cancer specific survival (median: unreached vs 41.2mo, HR = 0.27, 95% CI: 0.09-0.83, P = 0.023) and overall survival (median: unreached vs 21.4mo, HR = 0.34, 95%CI: 0.14-0.82, P = 0.016) than CD45RO-. The expression of CD8 alone or PD-L1 in tumor was not associated with prognosis. Multivariate analysis showed that CD8+CD45RO+ TIL (HR = 0.13, 95% CI: 0.02-0.99, P = 0.049) as well as stage, adjuvant treatment and R0 resection (microscopically margin-negative) were independent predictors of OS. Conclusions: Presence of CD8 memory T cells (CD8+CD45RO+) in tumor microenvironment was associated with significant better clinical outcome, and the expression of PD-L1 on cholangiocarcinoma cells may suggest a potential therapeutic target of antiPD-L1 antibody therapy in cholangiocarcinoma.
Association of elevated alpha-1 antitrypsin with advanced clinicopathologic features of hepatocellular carcinoma.
Authors: Abdel-Wahab Reham , Hassan Manal , Wolff Robert A. , Lacin Sahin , Al-Shamsi Humaid Obaid , Raghav Kanwal Pratap Singh , Shalaby Ahmed S , Yao James C. , Kaseb Ahmed Omar
Published: March 2017

289

Background: Alpha-1 Antitrypsin (A1AT) is a circulating liver derived protease inhibitor. There is an evolving evidence that elevated level of A1AT stimulate tumor cell proliferation, and invasion in different cancers. Despite A1AT well-known involvement in hepatic fibrosis, its role in hepatocellular carcinoma (HCC) pathogenesis is not well characterized. The current study aimed to investigate the association between A1AT and clinicopathologic features and prognosis of patients with HCC. Methods: Between 2001 and 2014, total of 766 HCC patients from MD Anderson Cancer Center were enrolled. Under IRB approval, baseline patients’ clinical characteristics were retrieved from medical records. The normal level of plasma A1AT was defined based on the Mayo clinic reference value (1 – 1.9 mg/ml). Survival analysis included Kaplan Meier statistic and Cox regression analysis. Multivariate Hazard Ratio (HR) and 95% Confidence interval (CI) were estimated to determine the independent effect of A1AT on HCC prognosis. Results: The mean and standard deviation of plasma A1AT level was 2.7 ± 0.98 mg/mL. All patients were categorized into 2 groups: group 1 (N = 156) with normal serum level ( ≤ 1.9) and group 2 (N = 610) with higher values ( > 1.9). Median survival (months), 95% CI were 24.4 (18.02 – 30.7) and 11.6 (9.6 – 13.6) in group 1 and 2 respectively, (P < .0001). Patients in group 2 experienced poor clinical characteristics than group 1. The estimated multivariate HR (95% CI) for A1AT is 1.4 (1.1 – 1.7) after adjustment for age, sex, race, cirrhosis, AFP, TNM staging, and treatment exposure. Conclusions: High plasma level of A1AT is associated with higher α-feto protein, advanced TNM and Barcelona clinic liver cancer (BCLC) staging and poor survival of HCC patients. Recent preliminary studies suggested that changes in glycosylaion of production of A1AT by HCC cells correlates with the microenvironment inflammatory and proteolytic activities, which are probably linked to advanced clinicopathologic features and poorer survival. Future excremental studies are warranted to understand the mechanistic pathways of potential A1AT involvement in HCC initiation and progression.
Next-generation sequencing (NGS) in pancreatic neuroendocrine tumors (panNETs): Defining differentiation and grade genetically.
Authors: Raj Nitya Prabhakar , Klimstra David , Shah Ronak , Osoba Muyinat , Alexander Derek , Reidy Diane Lauren
Published: March 2017

291

Background: Advances in tumor sequencing technology have improved our understanding of the genetic basis of panNETs. Whole exome sequencing of well differentiated (WD) panNETs demonstrated changes in chromatin remodeling genes; in poorly differentiated (PD) neuroendocrine carcinomas, changes along the TP53/RB signaling pathways have been observed. We sought to validate these observations in clinical practice. Methods: This prospective study (NCT01775072) used the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) assay to do NGS on panNETs in the routine practice setting. MSK-IMPACT is an assay providing full exon coverage of 410 cancer related genes, detecting base substitutions, small indels, copy number changes, and select gene rearrangements. Results: Results are available in 89 tumor samples from 78 patients (mean patient age 53, 58% female); 31 tumors (35%) low grade, 35 tumors (39%) intermediate grade, and 23 tumors (26%) high grade; 5 patients (6%) with PD tumors and 73 patients (94%) with WD tumors. Changes in chromatin remodeling genes were observed only in WD tumors; DAXX alterations in 24 tumors (27%), ATRX alterations in 15 tumors (17%), and SETD2 alterations in 10 tumors (11%). RB1 alterations were identified in 3 tumors (3%); all of these tumors were PD/high grade. TP53 alterations were seen in 9 tumors (10%); 4/9 tumors (44%) PD/high grade, 3/9 tumors (33%) WD/intermediate grade, 2/9 tumors (22%) WD/low grade. All WD, TP53-altered tumors also had DAXX/ATRX changes. Conclusions: In line with prior work, using an institutional NGS assay, we demonstrated tumor differentiation and grade genetically. Changes in chromatin remodeling genes were exclusive to WD tumors. Only PD tumors had RB1 changes. While TP53 was altered in both WD and PD tumors, TP53-altered WD tumors also harbored changes in the chromatin remodeling genes.
Combined treatment with TLR7/8 agonists and carbon ion radiation induces local and abscopal immune responses in gastrointestinal tumor models.
Authors: Huber Peter E , Nicolay Nils H , Lopez Ramon
Published: March 2017

292

Background: Radiotherapy is a mainstay of local tumor treatment for rectal and pancreatic carcinoma. Radiation has local and abscopal immunological effects, and may beneficially be combined with immune therapies. Photon radiotherapy can favorably be combined with a TLR7/8 agonist to induce strong immune responses in gastrointestinal tumors in mice. Here we investigated carbon ion particle radiation, which has superior physical radiation dose precision and a higher relative anti-tumor effect strength (relative biological effect, RBE, compared with photons), because it was unclear if carbon ions can also favorably be combined with immunotherapies such as TLR agonists. Methods: Therefore we investigated the effects of 3M-011, a TLR7/8 agonist (that was systemically given), and carbon ions in vivo in gastrointestinal tumors in mice in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro, cytotoxicity assays were applied to identify the immune cell populations involved in the therapy-induced immune reaction. The tumor specific T cell immune reaction was demonstrated by ELISPOT assays. Results: We found that the carbon ions and the TLR7/8 agonist 3M-011 induced strong immune responses in s.c. and orthotopic colorectal and pancreatic cancer models in mice. The TLR agonist dramatically enhanced the carbon ion effects in both local and distant antitumor activity. Depletion experiments showed that NK and CD8 T cells mediated the cytotoxic effects of the TLR agonist and in vivo depletion of CD11c+cells using a transgenic mouse carrying the diphteria toxin receptor showed that DCs are the necessary cell population inducing the detected antitumor immunity for monotherapies and combination treatment. Conclusions: Our findings suggest that TLR7/8 agonists are potent adjuvants not only to photon radiotherapy but also to particle radiation with carbon ions, and that the combination induced local and relevant systemic immune responses. In conclusion our preclinical proof of concept data supports the notion that TLR7/8 agonists may be favorably combined with particle radiation to treat GI tumors including pancreatic and rectal cancer.
Multivariate assessment of SPARC expression in resected pancreatic ductal adenocarcinoma to identify subgroups that are sensitive to adjuvant gemcitabine.
Authors: Kalloger Steve , Karasinska Joanna , Wong Hui-li , Renouf Daniel John , Schaeffer David F.
Published: March 2017

297

Background: Secreted Protein, Acid, Cysteine-Rich (SPARC) has recently been postulated as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). The clinical trial findings investigating SPARC expression and nab-paclitaxel sensitivity have been discordant. This study aims to develop an integrated component based approach to the quantification of SPARC in PDAC to identify discrete predictive subgroups in a cohort of resected patients treated with an gemcitabine (GEM) or subjected to post-surgical observation. Methods: Immunohistochemical quantification of SPARC was performed on the epithelial and stromal compartments of resected PDAC on 219 patient samples on a tissue-microarray. The staining was assessed by the generation of H-Scores. The resultant scores were subjected to unsupervised hierarchical clustering. The maximum number of clusters was determined through an a priori decision that no cluster could be composed of less than 15% of the cohort. Univariable disease specific survival (DSS) analysis was performed with the Kaplan-Meier method to examine the cluster specific survival profiles with regard to gemcitabine sensitivity. Results: Mean age was 67 [38-88] with 56% being male. Most of the cohort had advanced disease with pT3 = 95% and pN1 = 72%. Lymphovascular and perinueural invasion were found in 58% and 93% of the cohort respectively. Clusters ranging in size from 35 to 76 cases were derived and represented the four-biomarker combinations of Low/Low, Low/High, High/High, and High/Low for the epithelial and stromal components respectively. None of the clinico-pathologic variables were significantly enriched in the clusters. Assessment of the predictive ability of the 4 clusters demonstrated that only one cluster (High/High) representing 76 (35%) patients in this cohort was sensitive to adjuvant GEM (p = 0.0067). Conclusions: This study shows that there is enhanced value in a combinatorial approach to the examination of SPARC in the stromal and epithelial components of PDAC where we have discovered that co-expression in both the epithelial and stromal components is significantly associated with sensitivity to adjuvant GEM.
Analysis of tissue and circulating tumor DNA by next-generation sequencing of hepatocellular carcinoma.
Authors: Ikeda Sadakatsu , Lim Jordan S , Kurzrock Razelle
Published: March 2017

298

Background: Hepatocellular carcinoma (HCC) has limited treatment options. Molecular analysis of its mutational landscape may enable the discovery of new treatment option.However, biopsy is not routinely performed in HCC and involves risks. The utility of analyzing cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is not established. Methods: We performed 32 ctDNA NGS and 10 tissue NGS analyses in 26 patients with advanced HCC (January 2015 – October 2015). ctDNA analysis (54 to 70 genes) was performed using Guardant 360, which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations. The mutant allele fraction for detected alterations was calculated relative to wild type in ctDNA. Tissue NGS was performed using Foundation One or Molecular Health. The study ws conducted in accordance with UCSD Moores Cancer Center Institutional Review Board requirements. Results: Among 32 ctDNA NGS, at least one genomic alteration (excluding variants of uncertain significance (VUS)) was discerned in 27 samples (84.3%) (average = 2.1 alterations per patient [range, 0-5]) with a median mutant allele fraction of 0.92% (range, 0.06% - 40.57%). Ten patients had both ctDNA NGS and tissue NGS. The median time difference between the date of tissue and ctDNA NGS testing was 450 days (range, 29 – 876 days), possibly reflecting the challenge with doing a second tissue biopsy at the time of relapse. The most commonly mutated gene was TP53 (16 samples, 50.0%), followed by CTNNB1 (8 samples, 25.0%), ARID1A (6 samples, 18.6%), EGFR (4 samples, 12.5%) and MYC (4 samples, 12.5%). Amplification was observed in 11 genes, including CDK4, CDK6, CCNE1, EGFR, ERBB2, FGFR1, KRAS, and MYC. No fusions or indels were observed. At least one potentially actionable alteration was observed in 20 of the 26 patients (76.9%). In two patients treated on the basis of the ctDNA alterations alone, a response was seen. Conclusions: ctDNA profiling is feasible in advanced HCC, and may provide a tissue biopsy-free alternative in these difficult-to-biopsy patients. Further study of clinical validity and utility is ongoing.
Preclinical study of c-Met inhibitor as an adjuvant treatment for hepatocellular carcinoma with macroscopic portal vein invasion.
Authors: Kokudo Takashi , Inagaki Yoshinori , Hasegawa Kiyoshi , Shirata Chikara , Amikura Katsumi , Takahashi Amane , Kaneko Junichi , Akamatsu Nobuhisa , Arita Junichi , Sakamoto Yoshihiro , Sakamoto Hirohiko , Kokudo Norihiro
Published: March 2017

301

Background: Patients with advanced hepatocellular carcinoma (HCC) demonstrating a macroscopic portal vein tumor thrombus (PVTT) have been reported to have an extremely poor prognosis. Palliative sorafenib is the only recommended treatment option. Methods: We statistically compared the patient characteristics and surgical outcomes in HCC patients with PVTT. Among 1,611 hepatic resections, 105 cases of PVTT were identified. Microarray analysis was performed in three patients to identify gene expression changes in PVTT compared with those in the principal tumor, and the changes were validated in 20 human HCC tissues with PVTT. The human HCC cell lines HuH-7 and SKHep-1 were used for this experimental study. A subcutaneously transplanted xenograft model was employed for the in vivo study. The c-Met inhibitor SU11274 was used in both in vitro and in vivoanalyses. Results: The median survival time in patients with PVTT was 2.01 years, while that in patients without PVTT was 6.43 years; the median time to recurrence was 0.31 and 1.61 years, respectively. Microarray analysis revealed 36 genes related to PVTT. Immunohistochemistry analysis revealed that compared with the principal tumor, E-cadherin (a key regulator of cancer metastatic potential) significantly decreased in PVTT in all 20 patients. The c-Met inhibitor elevated the E-cadherin expression level in HCC cells both in vitro and in vivo. This inhibitor induced sheet formation and attenuated the migration of HCC cells. Conclusions: Although liver resection provides acceptable overall survival for patients with PVTT, the recurrence rate remains high. The c-Met inhibitor exhibits an anti-metastatic effect in vitro and in vivo and may be useful as an adjuvant treatment for PVTT.
Genetic difference between multicentric carcinogenesis and intrahepatic metastasis of multiple hepatocellular carcinoma.
Authors: Midorikawa Yutaka , Yamamoto Shogo , Tatsuno Kenji , Ueda Hiroki , Tsuji Shingo , Nagae Genta , Takayama Tadatoshi , Aburatani Hiroyuki
Published: March 2017

307

Background: Multiple hepatocellular carcinoma (HCC) is categorized into 2 types; multicentric carcinogeneis (MC) and intrahepatic metastasis (IM). Although discrimination of the types of multiple HCC is of clinical importance, it is difficult to determine it correctly even after histological diagnosis. Methods: In order to classify multiple HCC into MC and IM, we compared pairs of multiple HCC and matched non-tumoral liver samples from 22 patients who were clinically diagnosed MC and 8 patients with IM with regard to molecular aberrations using next generation sequencer. Results: Exome sequence showed that among the 22 patients with clinical MC, 7 patients were genetically determined as having IM (gIM) because of the concordance of mutations, while all the patients with clinical IM were as having MC (gMC). In 15 patients with gIM, 125 mutations (90.6%) per patient were common, which were consistent with the result of a pair of primary HCC, and only a few passenger mutations were different between IM specimens suggesting that IM pairs developed from the common ancestor. On the other hand, 138 somatic mutations per tumor, and no common somatic mutations were identified in the 15 patients with gMC. Clinically, vascular invasion was significantly frequent in gIM group ( P = 0.007). On the other hand, after a median follow-up of 2.56 years (range; 0.27−6.32 years), the median overall survivals were 3.7 years (95%CI, 1.26–6.14) and 3.37 years (2.02−6.32, P = 0.712) in the patients with IM and MC, respectively. The 3-year rates of overall survival were 71.7% and 65.1% in the two groups, respectively. Conclusions: Taken together, genetic comparison of mutations in a pair of HCCs makes it possible to classify MC and IM, which is available to make treatment plan for multiple HCC patients.
Subgroup analyses of a phase 1/2 study of lenvatinib (E7080), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC).
Authors: Ikeda Masafumi , Ikeda Kenji , Kudo Masatoshi , Osaki Yukio , Okusaka Takuji , Tamai Toshiyuki , Suzuki Takuya , Hisai Takashi , Miyagishi Hideaki , Okita Kiwamu , Kumada Hiromitsu
Published: March 2017

309

Background: Lenvatinib is an oral tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT. A phase 1/2 trial in pts (n = 46) with advanced HCC and Child-Pugh score A treated with lenvatinib 12 mg once daily showed a median overall survival (OS) of 18.7 months, and a median time to progression (TTP) of 12.8 months by investigator review and 7.4 months by independent radiologic review (IRR). Objective response rate was 37.0% as assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Based on these results, a phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib is ongoing. Here, we report subgroup analyses of the phase 2 part of this study. Methods: Subgroups were retrospectively analyzed by Barcelona clinic liver cancer (BCLC) staging, disease etiology, prior therapy for advanced HCC (including sorafenib), and baseline Alpha-fetoprotein (AFP) levels. Efficacy endpoints including OS and TTP by IRR were assessed for each subgroup. TTP based on mRECIST and OS were assessed from the date of study registration to progressive disease and to death, respectively. Results: Median TTP and OS for each of the relevant subgroups of baseline characteristics are shown in the table. Conclusions: Pts with advanced HCC treated with lenvatinib showed similar TTP regardless of subgroup. Although the number of patients was limited, lenvatinib treatment shows promising efficacy even in patients with hepatitis B virus. Clinical trial information: NCT00946153. [Table: see text]
Clinical utilization of targetable molecular results in pancreatic cancer: Longer-term outcomes from the Individualized Molecular Pancreatic Cancer Therapy (IMPACT) trial.
Authors: Chantrill Lorraine A. , Nagrial Adnan , Johns Amber , McKay Skye , Gill Anthony J. , Pavlakis Nick , Grimison Peter S. , Asghari Gholamreza , Waddell Nicola , Chou Angela , Chin Venessa T. , Sebastian Lucille T , Verghis Jaclyn , Yip Sonia , Sjoquist Katrin Marie , Simes John , Biankin Andrew
Published: March 2017

314

Background: The IMPaCT trial screened patients with advanced pancreas cancer for molecular targets and aimed to test molecularly guided therapy in a pilot randomized study, but closed in December 2015 having delivered personalized treatment to only 1 patient. A follow up analysis of the screened cohort provides insight into the clinical utilisation of targetable molecular results in pancreas cancer. Methods: IMPaCT screened for 3 genetic phenotypes matched to precision treatment: Her2 amplification (trastuzamab + gemcitabine), KRAS wildtype (erlotinib + gemcitabine) and DNA damage repair pathway defects (platinum-based). Previously recruited primary resected APGI participants known to be alive were also screened for these targets. The initial pilot protocol included randomisation, but after amendment in early 2015, became a single-arm study allowing one cycle of gemcitabine + nab-paclitaxel during screening. Results: A total of 101 potential patients were screened. This was enriched for patients with known targets where sequence data was available from primary pancreatectomy. 23 had one of the 3 molecular targets in this enriched population (4 Her2 amplified, 16 KRAS wt, 2 BRCA2, 1 ATM). The prospectively recruited de novo metastatic cohort (n = 63) had an actionable mutation detection rate of 14.3%. Of the 23 patients identified, 3 received personalised treatment off study, 1 on study, 3 are currently alive without recurrence, 1 is monitored for suspected recurrence, 2 developed second primary malignancies, 10 died or progressed prior to result and 3 decided not to use personalised treatment. The identification of a molecular target did not significantly affect overall survival. Conclusions: Although actionable molecular targets were detected, recruitment rates on the IMPaCT trial were low (1%). Follow up illustrates that these molecular results were incorporated into clinical care off trial or still have the potential to be utilised in another 6.9% of the cohort. Further follow up is planned for long term outcomes. Clinical trial information: ACTRN12612000777897.
Homologous recombination deficiency (HRD) in patients with pancreatic cancer (PC) and response to chemotherapy.
Authors: Shahda Safi , Timms Kirsten , Ibrahim Ashley , Reid Julia E. , Cramer Harvey M , Radovich Milan , Ibrahim Sulfikar , Allen Brian , O'Neil Bert H.
Published: March 2017

317

Background: Mutations or copy number abnormalities of genes involved in homologous recombination occur in PC. DNA-based measures of HRD have been developed and may help identify tumors with better response to DNA damaging agents. This study aimed to describe the mutation and HRD status of PC and determine their association with treatment response and outcome. Methods: This was a retrospective analysis of tumor samples from patients treated at Indiana University for locally advanced or metastatic PC. Patients were included if they received gemcitabine/nab-paclitaxel or FOLFIRINOX and had adequate follow up to assess survival and response to therapy. Tumor analysis generated a 3-biomarker (LOH, TAI, LST) HRD score and mutation data for 45 genes. Results: Ninety-one samples met inclusion criteria, 78 (15 FFPE and 63 FNA) generated mutation data. HRD analysis was successful for 57; the primary cause of failure low tumor %. The final analysis set consisted of 78 samples with mutation status, including 57 with HRD scores (range= 5 -61 (median=18,)). Six BRCA1/ 2 mutations were detected, 5 had high HRD scores, with 4 in the top decile (p=0.011). Other DNA repair gene mutations ( ATM=3, ATR=1, BRIP1=1 and FANCI=1) were detected, but most retained one functional allele and were not associated with HRD score. There was no statistically significant correlation between HRD score and response to FOLFIRINOX (OR per interquartile range = 1.40, p=0.32 adjusted for treatment). HRD score was not associated with PFS or OS. For FOLFIRINOX, median survival times for low vs. high HRD (dichotomized at the median) were 5.3 vs. 9.4 months PFS (p=0.049) and OS 12.3 vs. 11.3 months (p=0.89). For gemcitabine/nab-paclitaxel, mPFS was 6.1 vs. 4.6 months (p=0.88), and mOS was 14.4 vs. 11.4 months (p=0.29). Conclusions: Mutations in DNA repair genes occur in PC, and HRD scores can be generated in the majority of cases. HRD score was not significantly associated with higher response rate or prolonged survival in relation to FOLFIRINOX in this small non-randomized retrospective cohort. Larger studies to examine the association of mutations in DNA repair genes and HRD may be needed to detect significant associations.
Preoperative vascular grading in patients undergoing surgery for pancreatic cancer: Does radiologic arterial or venous involvement predict margin status?
Authors: Reddy Sanjay S. , Karachristos Andreas , Ruth Karen , Hoffman John Parker
Published: March 2017

319

Background: The use of neoadjuvant therapy has been widely used for borderline resectable pancreatic cancer (BLRPC). Controversy exists on the definition of BLRPC, and because of this, we examined the association of vascular involvement and margin status in patients who had initial resection. Methods: Records of 137 patients who had surgery for resectable or BLRPC were collected. Included were radiologist grading of venous/arterial involvement based on preoperative imaging. For patients with both staging recorded, we categorized vascular involvement as none, arterial only, venous only, or both. We examined the association of vascular involvement and margin status using Chi-square tests, and logistic regression. Results: Of 137 patients, all underwent surgery first. 85% had a Whipple without vascular resection, and 13% with. Of 134 patients with Ishikawa staging, there were 63% stage I, 17% stage II, 11% stage III, and 9% stage IV. Of 96 patients with arterial staging, there were 74% stage i, 16% stage ii, and 10% stage iii. Of 93 patients with both Ishikawa and arterial staging recorded, 61% had no vascular involvement, 7% arterial, 14% venous, and 17% had both. Ishikawa stage I-IV was associated with a positive SMA margin, and was seen in 14%, 44%, 53%, and 58%, respectively (p < 0.001). However, for arterial staging the association was weaker, and for arterial stages i-iii, a positive SMA margin was seen in 20%, 40%, and 40%, respectively (p = 0.06). Therefore, Ishikawa staging was more predicative of arterial involvement. Higher Ishikawa staging was associated with increased positive SMV margins; 5%, 26%, 33%, respectively (p < 0.001), while preoperative arterial staging was not predictive (p = 0.63). In logistic regression for any positive margin, only venous staging was significant in predicting a positive margin. Conclusions: The use of imaging in predicting positive margins is more accurate when using a venous grading system as opposed to an arterial one. With a more standard approach of designating degree of vein involvement, and better preoperative imaging, further studies will be needed to substantiate these findings.
Predictive factors of residual tumor for the patients with non-curative resection after endoscopic submucosal dissection for early gastric cancer.
Authors: Sunagawa Hideki , Kinoshita Takahiro , Kaito Akio , Kaneko Kazuhiro
Published: March 2017

32

Background: Endoscopic submucosal dissection (ESD) is commonly performed for the patients who diagnosed with early gastric cancer. Although additional gastrectomy is recommended for the patients with non-curative ESD in the points of potential risk of residual tumor, many cases have neither lymph node (LN) metastasis nor local residual tumor in surgical specimens. Clinically, it can be difficult to decide whether to perform additional surgery according to patients’ conditions. This study aimed to analyze the clinicopathological features of patients who underwent additional gastrectomy as well as to detect the predictive factors for residual tumor after non-curative ESD. Methods: The patients who underwent additional gastrectomy after non-curative ESD in our institution from January 2005 to August 2016 were retrospectively reviewed. The incidence rates of LN metastasis or local residual tumor were calculated, and furthermore the predictive factors for these outcomes were estimated. Results: 211 patients were enrolled in this study. Pathological examination after additional surgery revealed LN metastasis in 18 patients (8.5%) and local residual tumor in 26 patients (12.3%). Multivariable analysis revealed that lymphatic invasion ( p< 0.0001, odds ratio = 15.6), vascular invasion ( p= 0.042, odds ratio = 3.92) and macroscopic findings (flat/elevated type) ( p= 0.03, odds ratio = 3.53) are predictors for lymph node metastasis. All of the patients without LN metastasis revealed no lymphovascular invasion. Positive vertical margin ( p= 0.0045, odds ratio = 4.17) and horizontal margin ( p= 0.0002, odds ratio = 6.6) were predictors for local residual tumor. Conclusions: The risk of residual tumor can be estimated based on histopathology of ESD. Patients without lymphovascular invasion appear to be a low risk subpopulation for LN metastasis.
Association of hyaluronan accumulation with clinical-pathologic features in pancreatic ductal adenocarcinomas.
Authors: Larson Brent K , Pan Dana , Khanuja Jasleen , Patel Rishi , Zhou Jenny , Osipov Arsen , Guindi Maha , Müller Thomas , Li Quanlin , Jiang Ping , Tuli Richard , Hendifar Andrew Eugene
Published: March 2017

322

Background: Pancreatic ductal adenocarcinoma (PDA) is characterized by marked stromal fibrosis and hyaluronan (HA) accumulation. Degradation of stromal HA using PEGylated recombinant human hyaluronidase (PEGPH20) in combination with anti-cancer therapeutics has demonstrated increased efficacy in preclinical models. This study used an exploratory prototype HA assay to assess HA and to explore the association of HA status with clinical and pathological variables. Methods: Sixty-four PDA samples from 49 patients treated with gemcitabine and nab-paclitaxel were stained for HA using a prototype histochemical binding assay. The tumor extracellular matrix staining for HA at any intensity above background as a proportion of the total tumor surface area was recorded. Cases were categorized as HA-high (HA score of ≥50%) or HA-low (HA score of <50%). Subgroup analyses were also performed in paired pre- and post-chemotherapy samples. Results: Twenty-six of 49 (53%) patients were determined to be HA-high. HA-high status was significantly associated with pN1 (positive node) status (p<0.001) and well/moderate differentiation (p<0.001). No correlation of HA status was observed with sex, race, primary tumor location, pT (tumor) stage, lymph-vascular invasion, pathologic stage, or initial CA19-9 levels. No trend in HA status was observed comparing pre- and post-chemotherapy specimens (n=5). Conclusions: HA status was significantly associated with nodal stage and grade.