bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP-05).
Authors: Unno Michiaki , Motoi Fuyuhiko , Matsuyama Yutaka , Satoi Sohei , Matsumoto Ippei , Aosasa Suefumi , Shirakawa Hirofumi , Wada Keita , Fujii Tsutomu , Yoshitomi Hideyuki , Takahashi Shinichiro , Sho Masayuki , Ueno Hideki , Kosuge Tomoo
Published: January 2019

189

Background: Despite improvements of postoperative adjuvant therapy for resected pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor. A randomized controlled trial has begun to compare neoadjuvant chemotherapy using gemcitabine and S1 (NAC-GS) with upfront surgery (Up-S) for patients with PDAC planned resection. Methods: Patients were enrolled after the diagnosis of resectable PDAC with histological confirmation. They were randomly assigned as either NAC-GS or Up-S. In NAC-GS, gemcitabine was provided at a dose of 1 g/m2 on day 1 and 8 and oral S-1 was administered at a dose of 40 mg/m2 twice daily on 1-14 days. Patients received 2 cycles of this regimen. S-1 adjuvant for 6 months was administered for the patients with curative resection and fully recovered within 10 weeks after surgery in both arms. The primary endpoint for the phase III part was overall survival (OS); secondary endpoints included adverse events, resection rate, recurrence-free survival, residual tumor status, nodal metastases, and tumor marker kinetics. The target sample size required 163 patients (α-error 0.05; power 0.8) in each arm. The trial was conducted by the Health Labor Sciences Research Grant (H22-009) of Japan and registered with the UMIN Clinical Trials Registry as UMIN000009634. Results: From January 2013 to January 2016, 364 patients were enrolled in 57 centers (182 to NAC-GS and 182 to Up-S). Of these, two were excluded because of ineligibility, therefore 182 patients in NAC-GS and 180 in Up-S constituted the ITT analysis-set. The median OS was 36.7 months in NAC-GS and 26.6 months in Up-S; HR 0.72 (95% confidential interval 0.55-0.94; p=0.015 [stratified log-rank test]). Grade 3 or 4 adverse events frequently (72.8%) observed in NAC-GS were leukopenia or neutropenia. However, the resection rate, R0 resection rate, and morbidity of the operation were equivalent in the two groups. There was no perioperative mortality in either group. Conclusions: This phase III study demonstrated the significant survival benefits of NAC-GS treatment. Therefore, the results indicated that neoadjuvant chemotherapy could be a new standard for patients with resectable PDAC. Clinical trial information: UMIN000009634.
Pembrolizumab treatment of advanced neuroendocrine tumors: Results from the phase II KEYNOTE-158 study.
Authors: Strosberg Jonathan R. , Mizuno Nobumasa , Doi Toshihiko , Grande Enrique , Delord Jean-Pierre , Shapira-Frommer Ronnie , Bergsland Emily K. , Shah Manisha H. , Fakih Marwan , Takahashi Shunji , Piha-Paul Sarina Anne , O'Neil Bert , Thomas Sajeve , Lolkema Martijn P. , Wang Jiang Dian , Ibrahim Nageatte , Pruitt Scott K. , Hadoux Julien
Published: January 2019

190

Background: Data from the KEYNOTE-028 study (NCT02054806) suggested that pembrolizumab (pembro) has clinical activity in a subset of patients (pts) with heavily pretreated neuroendocrine tumors (NET). The KEYNOTE-158 study (NCT02628067) is a phase II basket study investigating the antitumor activity of pembro in 10 specific cancer types. An analysis of the 107 pts included in the NET cohort is presented. Methods: Key eligibility criteria for this cohort included well- and moderately-differentiated NET of the lung, appendix, small intestine, colon, rectum, or pancreas; progression on or intolerance to ≥ 1 line of standard therapy; ECOG PS 0 or 1; and provision of a tumor sample for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until progression, intolerable toxicity, or physician or patient decision. Tumor imaging was performed every 9 wks for the first 12 mo, and every 12 wks thereafter. PD-L1 positivity, defined as a combined positive score (CPS) ≥ 1, was evaluated retrospectively by IHC. Primary endpoint was ORR assessed per RECIST v1.1 by independent central radiology review. Secondary endpoints included DOR, PFS, OS, and safety. Results: 107 pts were treated. Median age was 59 (range, 29-80) y, 44.9% had ECOG PS 1, and 67.3% received ≥ 2 prior therapies for advanced disease. 15.9% of enrolled pts had PD-L1+ tumors. As of the January 15, 2018 data cutoff, the median follow-up duration was 18.6 (range, 0.2-22.7) mo. ORR was 3.7% (95% CI, 1.0-9.3), with 0 CR and 4 PR (3 pancreatic and 1 gastrointestinal [unknown primary]). 61 pts had SD as best response. The 4 responses were observed in pts with PD-L1 negative tumors. Median DOR had not been reached (range, 4.1-15.9+), with 3 of 4 responses ongoing after ≥ 9 mo follow-up. Median (95% CI) PFS was 4.1 (3.5-5.4) mo, and the 6-mo PFS rate was 38.2%. Median OS (95% CI) had not been reached (18.8-not reached), and the 6-mo OS rate was 84.6%. Treatment-related AEs occurred in 75.7% of pts, and the most common was fatigue (21.5%). 20.6% of pts had treatment-related grade 3-4 AEs. Conclusions: Pembrolizumab monotherapy showed limited antitumor activity and manageable safety in pts with previously treated advanced NET. Clinical trial information: NCT02628067.
The clinical implication of CD45RA+ naive T cells and CD45RO+ memory T cells in advanced pancreatic cancer: A proxy for tumor biology and outcome prediction.
Authors: Hang Junjie , Wu Lixia , Xu Kequn
Published: January 2019

196

Background: Naive and memory T cells play a pivotal role in solid tumor pathogenesis but their role in pancreatic cancer progression remains elusive. Thus, we aimed to investigate their clinical potential in advanced pancreatic cancer (APC). Methods: Flow cytometry was performed to evaluate the level of peripheral naive and memory T cells from APC patients. Interrelationships between naive, memory T cells and clinicopathological variables were evaluated using pearson’s correlation. The prognostic impact of naive and memory T cells were assessed by Kaplan-Meier analysis and Cox regression. The correlation between naive/memory T cells and tumor progression was investigated by Student’s t test. Results: CD4+ naive/memory ratio showed close correlations with hemoglobin, red blood cell (RBC), absolute neutrophil count (ANC) and platelet while CD8+ naive/memory ratio was correlated with hemoglobin, RBC and CEA. Higher baseline lever of CD4+CD45RO+/CD4+ was correlated with better overall survival (OS) (P = 0.036). Patients with CD4+ naive/memory ratio ≥ 0.36 had a poorer OS than those with CD4+ naive/memory ratio < 0.36 (P = 0.021). In addition, CD4+ naive/memory ratio showed independent prognostic impact (HR 1.427, 95%CI 1.033-1.973, P = 0.031). Furthermore, poorer clinical response was correlated with higher level of CD8+ naive/memory ratio after the third cycle of chemotherapy (P = 0.01). Besides, patients with an low level of CD8+ naive/memory ratio had longer progression-free survival (PFS) (P = 0.028). Conclusions: We propose CD4+ naive/memory ratio as a novel prognostic biomarker for APC. In addition, CD8+ naive/memory ratio can be a candidate marker for predicting PFS and the change of its level may reflect the progression of APC.
Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study.
Authors: Kojima Takashi , Muro Kei , Francois Eric , Hsu Chih-Hung , Moriwaki Toshikazu , Kim Sung-Bae , Lee Se-Hoon , Bennouna Jaafar , Kato Ken , Lin Shen , Qin Shi-Qui , Ferreira Paula , Doi Toshihiko , Adenis Antoine , Enzinger Peter C. , Shah Manish A. , Wang Ruixue , Bhagia Pooja , Kang S. Peter , Metges Jean-Philippe
Published: January 2019

2

Background: Patients with advanced esophageal cancer after first-line chemotherapy (chemo) have a poor prognosis and limited treatment options. We present results of the phase 3 KEYNOTE-181 study of pembrolizumab vs investigator’s choice chemo as second-line therapy for patients (pts) with advanced/metastatic squamous cell carcinoma (SCC) and adenocarcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJ (NCT02564263). Methods: Eligible pts were randomized 1:1 to pembrolizumab 200 mg Q3W for up to 2 years or investigator’s choice chemo of paclitaxel, docetaxel, or irinotecan. Randomization was stratified by histology (SCC vs adenocarcinoma) and region (Asia vs rest of world). Primary end points were OS in the SCC, PD-L1 combined positive score (CPS) ≥10, and ITT populations. Results: 628 pts were randomized including 401 with SCC, and 222 with CPS ≥10. As of October 15, 2018, the median follow-up was 7.1 mo (pembrolizumab) vs 6.9 mo (chemo). Pembrolizumab was superior to chemo for OS in CPS ≥10 (N=222; median 9.3 vs 6.7 mo; HR 0.69; 95% CI 0.52-0.93; P=0.0074). The 12-mo OS rate in pts with CPS ≥10 was 43% vs 20%. There was clinically meaningful improvement in OS with pembrolizumab vs chemo in pts with SCC, but this was not statistically significant per prespecified boundaries (N=401; 8.2 mo vs 7.1 mo; HR 0.78; 95% CI 0.63-0.96; P=0.0095). In the ITT population, while directionally favorable, the difference in OS was not statistically significant (N=628; 7.1 mo vs 7.1 mo; HR 0.89; 95% CI 0.75-1.05; P=0.0560). Fewer pts had any-grade (64% vs 86%) or grade 3-5 (18% vs 41%) drug-related AEs with pembrolizumab vs chemo. Conclusion: Pembrolizumab significantly improved OS compared with chemo as second-line therapy for advanced esophageal cancer with PD-L1 CPS ≥10, with a more favorable safety profile. These data support pembrolizumab as a new second-line standard of care for esophageal cancer with PD-L1 CPS ≥10. The phase 3 KEYNOTE-590 study of pembrolizumab plus chemo as first-line therapy for advanced esophageal cancer is ongoing (NCT03189719). Clinical trial information: NCT02564263.
Phase II trial of SM-88 in patients with metastatic pancreatic cancer: Preliminary results of the first stage.
Authors: Noel Marcus Smith , Wang-Gillam Andrea , Ocean Allyson J. , Chawla Sant P. , Del Priore Giuseppe , Picozzi Vincent J.
Published: January 2019

200

Background: SM-88 (tyrosine derivative [Td], mTOR inhibitor, CYP3a4 inducer and oxidative stress catalyst) is a relatively non-toxic, targeted therapy that utilizes the Warburg Effect in combination with oxidative stress to cause tumor cell death. It is well suited for pancreas cancer because of its ability to penetrate tumors and be tolerated by debilitated patients. Methods: Patients progressed on at least one line of chemotherapy are eligible for either low versus high dose single agent SM-88 in the dose selecting first stage of this trial. The primary endpoint of the study is response rate by BICR (NCT03512756). Results: As of Sept 23, 36 subjects with initial stage II 26%, III 33%, or IV 41%, were randomized between an active Td dose (430 mg/d) and 920 mg/d. Mean age was 64.9 (45.6 - 84.1); BMI 24.2 (16.8 - 36.7); female 45.5%, white 93.1%, black 4.5%; median of 3 prior lines (range 1 - 6); baseline median albumin, neutrophil lymphocyte ratio, alk phos and 19.9 were 3.8 g/dl (2.6 - 9.6), 4 (1 - 141), 179.5 (54 - 661) and 5089 (4 - 651, 696) respectively. The regimen was well tolerated with no treatment related grade 4 or 5 events; 55.6% of treated subjects (20/36) had 94 AEs, with 18.0% (17/94) being at least possibly treatment related, of which three were grade 3 (arthralgia, fatigue and asthenia). CTCs at baseline were detected in 97% (mean 93.1 cells/4 ml) and fell in 69% (11/16) evaluable subjects from 141.4 to a nadir of 30.7/4 ml (median reduction 77% [3% - 97%]). 22.2% (2/9) evaluable subjects showed CA19.9 declines, both of which also showed CTC declines. 83% of subjects have remained on treatment a median of 4.7 wks (1 - 18.7); 6 were eligible for the initial scheduled assessment at 2 months; 3 of 4 evaluable subjects (75%) had RECIST or PET SUV responses. Lesion SUVs decreased an average of 24.1% (8.3 - 35.7%). EORTC QLQ-C30, -PAN26 and correlative assays were obtained including IGF, leptin, genomics, NLR, and others. Conclusions: SM-88 has demonstrated unconfirmed monotherapy efficacy signals with no meaningful toxicity in a preliminary assessment of this ongoing trial. With additional follow up a dose will be selected for expansion Clinical trial information: NCT03512756.
Meta-analysis of OS for pancreatic cancer patients receiving 5FU and oxaliplatin-based therapy after failing first-line gemcitabine-containing therapy.
Authors: Wainberg Zev A. , Feeney Kynan , Lee Myung Ah , Muñoz Martín Andres J. , Cubillo Gracián Antonio , Lonardi Sara , Ryoo Baek-Yeol , Hung Annie , Lin Yong , Bendell Johanna C. , Hecht J. Randolph
Published: January 2019

202

Background: Pancreatic cancer is the 3rd most common cause of cancer-related death in US. After progression on first-line gemcitabine-based therapy, guidelines suggest that 5FU with nanoliposomal irinotecan/irinotecan is the preferred regimen. Oxaliplatin (OXA) is not endorsed as prominently, as conflicting results have emerged on the efficacy of 5FU/OXA. This large variability in efficacy outcomes may be due to the heterogeneity of patient performance status (PS) or other confounding factors. We performed a meta analysis in an attempt to estimate the median (m) OS of patients receiving 5FU/OXA-containing regiments after failing first-line treatment with gemcitabine-containing therapy. Methods: A systematic review of literature and existing meta analyses for second-line treatment of pancreatic cancer was performed. Selection inclusion criteria included: prior gemcitabine treatment, second-line treatment of locally advanced or metastatic pancreatic cancer, 5FU and OXA; exclusion criteria included: oral 5FU (S1), irinotecan, capecitabine/cisplatin, no ECOG disclosure. A Bayesian fixed effect meta analysis was performed for the mOS with PS as predictor. A non-informative prior was used to establish the relationship between mOS and PS. The posterior median of OS and 95% predictive interval (PI) were summarized. Results: Eleven studies (454 patients) met the selection criteria for analysis. Median OS for patients receiving second-line 5FU and OXA-based therapy with ECOG PS 0-1 was 6.2 months (95% PI 5.4, 7.1). Restricting to FOLFOX (6 studies, 258 patients), mOS was 6.3 months (95% PI, 5.4, 7.4). Median OS were comparable to those observed with nanoliposomal irinotecan (NAPOLI-1) where 90% patients had ECOG 0-1. Some of the most frequent ( > 10%) grade 3-4 AEs for 5FU and OXA included neutropenia, thrombocytopenia, anemia, and fatigue, comparable to that reported with irinotecan-based therapy. Conclusions: This meta analysis suggests that after progression on a first-line gemcitabine containing regimen, 5FU and OXA-based therapy (eg. FOLFOX) may be a viable and acceptable treatment for patients with pancreatic cancer with good PS.
CA19-9 decrease and overall survival according to platelet level in patients with metastatic pancreatic cancer.
Authors: Chen Yang , Dai Guanghai
Published: January 2019

203

Background: Several studies have linked a decrease of carbohydrate antigen (CA) 19-9 to lengthened survival in pancreatic cancer. Experimental evidence supported that CA19-9 may be involved in platelet/tumor cell interactions. The object of this study was to correlate a decline in CA19-9 with survival according to platelet level in metastatic pancreatic cancer. Methods: A retrospective analysis of patients with histologically diagnosed metastatic pancreatic cancer was performed. CA19-9 serum concentration and platelet level was measured at baseline and every 6 weeks. Results: Total 174 metastatic pancreatic cancer patients with baseline and week-6 CA19-9 measurements were analyzed. Median follow-up from initial chemotherapy was 29.2 months, and median survival from initial chemotherapy was 6.7 months. Multivariate analyses confirmed an early decrease in CA19-9 concentrations of 25% after two cycles of chemotherapy were associated with a favorable survival compared with patients who did not have a decrease of 25% (HR = 0.56 [95% CI: 0.40-0.78]). The association of CA19-9 decrease with overall survival differed by platelet level ( Pinteraction < 0.001). Multivariable adjusted hazard rations for decrease in CA19-9 of 25% were 0.30 (0.18-0.49) in patients with low platelet level (PLT < 190 × 109/L) and 0.85 (0.53-1.35) in patients with high platelet level (PLT ≥ 190×109/L). Conclusions: In patients with MPC, 25% decrease at week-6 could be an early marker for prognosis. The association of CA19-9 decrease with pancreatic cancer survival is stronger in patients with platelet low tumors than platelet high tumors. Our findings suggest a differential prognostic effect of CA19-9 according to platelet level.
Suggestion of new nomogram including inflammatory marker for predicting invasive carcinoma in intraductal papillary mucinous neoplasm of the pancreas.
Authors: Han In Woong
Published: January 2019

204

Background: Previous studies have analyzed that inflammatory markers, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and advanced lung cancer inflammation index (ALI), associated with the presence of invasive carcinoma in patients with intraductal papillary mucinous neoplasm (IPMN). This study aimed to evaluate the correlation between the inflammatory markers and the invasive carcinoma in IPMN and propose a nomogram including inflammatory markers for predicting invasive IPMN. Methods: From 1995 to 2016, total 468 patients who underwent surgical resection at four institutions for histologically confirmed IPMN and the data were reviewed retrospectively. The patients with history of pancreatitis, other malignancies and without CA19-9 data or lymphocyte counts were excluded, the study cohort consisted of 365 patients. Variables with P < 0.05 in risk factor analysis were included in the nomogram. Results: Of 365 patients, 98 (26.8%) patients had invasive IPMN. In univariate analysis, high body mass index (BMI) ( P = 0.037), pre-operative bilirubin level ( P = 0.001), CA19-9 ( P < 0.001), NLR ( P = 0.019), PLR ( P = 0.002), ALI ( P = 0.001), main duct type (P < 0.001), the presence of solid portion ( P < 0.001) and tumor size (P = 0.086) were identified as risk factors for invasive IPMN. In multivariate analysis, pre-operative bilirubin level (P = 0.003), CA19-9 (P = 0.002), main duct type (P = 0.034) and the presence of solid portion (P < 0.001) were independent predictive markers for invasive IPMN. The nomogram was developed including all factors of risk factor analysis. Conclusions: The inflammatory markers were the risk factors for the presence of IPMN-associated invasive carcinoma. This nomogram may be useful in identifying patients with IPMN at risk of malignancy and for selecting which patients should undergo surgery. Further validation studies are needed to assess the predictive ability of nomogram including inflammatory markers.
The evaluation of the eighth edition of the AJCC/UICC staging system for intrahepatic cholangiocarcinoma: A proposal of a modified new staging system.
Authors: Yamamoto Yusuke , Sugiura Teiichi , Okamura Yukiyasu , Ito Takaaki , Ashida Ryo , Ogi Katsuhisa , Uesaka Katsuhiko
Published: January 2019

206

Background: The objective was to clarify the prognostic impact of the 8th edition of American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) of intrahepatic cholangiocarcinoma (ICC). Methods: ICC patients who underwent hepatectomy for ICC between 2002 and 2016 were enrolled. The survival impact of AJCC/UICC 8th edition was examined. Results: A total of 103 resected patients were enrolled. The 5-year disease-specific survival (DSS) rate was 75.9% in T1a (n = 23), 88.9% in T1b (n = 10), 14.9% in T2 (n = 24), 52.5% in T3 (n = 11), and 15.2% in T4 (n = 35). The DSS was comparable among T2, T3, and T4 (p = 0.345, 0.295). The 5-year DSS was 87.5% in stage IA, 88.9% in IB, 18.1% in II, 66.7% in IIIA, and 15.0% in IIIB. The DSS rates of stage II and stage IIIB were comparable, and the DSS rate of stage II was worse than that of stage IIIB. A multivariate analysis identified multiple tumors (hazard ratio [HR]: 2.821), periductal infiltrating (HR: 2.439), perforation of the visceral peritoneum (HR: 1.850), and vascular invasion (HR: 1.872) as independent prognostic factors that were associated with the DSS. Lymph node metastasis (HR: 1.715) was not an independent prognostic factor. The optimum tumor size with the greatest difference in the DSS was 2 cm (p = 0.014). The new T classification was developed as follows: T1, size ≤ 2 cm without other factors; T2, size > 2 cm without other factors; T3, vascular invasion or perforation of the visceral peritoneum; and T4, multiple tumors or periductal infiltrating. The HR of lymph node metastasis was similar to that of the low-HR factors, so lymph node metastasis was categorized as Stage IIIA. The 5-year DSS was 100% in T1 (n = 7), 76.6% in T2 (n = 28), 45.1% in T3 (n = 28), and 3.4% in T4 (n = 40). There were differences in the DSS between T2 and T3 (p = 0.035) and between T3 and T4 (p = 0.003). The 5-year DSS was 100% in stage I, 85.6% in II, 42.4% in IIIA, and 3.4% in IIIB (Fig. 2d). There were significant differences in the DSS between stage II and IIIA (p = 0.013) and between IIIA and IIIB (p = 0.026). Conclusions: T2, T3, and T4 of AJCC/UICC overlapped with regard to the DSS. The new staging can classify ICC patients with sufficient prognostic differences.
Multiplatform profiling of pancreatic neuroendocrine tumors (PanNETs) identifies novel co-occurring pathogenic alterations and associations with clinicopathologic factors.
Authors: Guan Michelle , Gong Jun , Hendifar Andrew Eugene , Tuli Richard , Placencio-Hickok Veronica , Bender Joseph , Blais Edik Matthew , Petricoin Emanuel
Published: January 2019

211

Background: We correlated genomic, proteomic, and molecular pathway alterations with clinicopathologic factors and identified novel co-occurring pathogenic alterations of potential clinical relevance to PanNET management through multi-omic profiling. Methods: Perthera, Inc. deploys an IRB-approved registry that was utilized in partnership with PanCAN’s “Know Your Tumor” program. PanNETs having undergone molecular profiling for precision matched therapeutic purposes were screened. We performed correlative analyses by pairwise comparisons between pathogenic alterations or altered molecular pathways and clinicopathologic variables. Hierarchical clustering was used to visualize associations. The Kaplan-Meier method was used to estimate overall survival (OS) and survival differences across variables were analyzed by the log-rank test. Results: We included 33 patients with predominantly locally advanced and metastatic PanNETs from 12/2014-1/2018. Chromatin remodeling pathway and MEN1 alterations by next-generation sequencing (NGS) were less associated with having high-grade PanNETs, while MEN1 alterations were also less associated with metastatic disease at diagnosis (all Fisher’s exact two-tailed p ≤ 0.05). Several molecular pathway or pathogenic alterations correlated with worse OS: DNA repair pathway (log-rank p = 0.0022), RB1 alterations by NGS (p = 0.018), and TP53 alterations by NGS (p = 0.01). There were several significant co-occurring alterations (Fisher’s exact p ≤ 0.05): ERCC1 expression by immunohistochemistry (IHC) and DAXX (NGS), RB1 (NGS) and DNA repair pathway (NGS), and TS (IHC) and cyclin-dependent kinase pathway (NGS). Having an altered chromatin remodeling pathway was less associated with having an altered receptor tyrosine kinase (RTK) signaling pathway (Fisher’s exact p ≤ 0.05). Conclusions: We identified several molecular signatures of potential clinical significance for therapeutic targeting and prognostication in PanNETs warranting prospective validation. Our findings are hypothesis generating and can inform larger molecular profiling efforts in PanNETs.
Impact of the distance from the root of the splenic artery to the tumor in patents with the pancreatic body/tail cancer.
Authors: Minagawa Takuya , Okamura Yukiyasu , Sugiura Teiichi , Ito Takaaki , Yamamoto Yusuke , Ashida Ryo , Ogi Katsuhisa , Uesaka Katsuhiko
Published: January 2019

221

Background: The impact of the distance from the root of the splenic artery to the tumor (DST) on prognosis and selection of operative procedures in patients with pancreatic body/tail cancer remains to be unclear. Methods: Between 2008 and 2018, 98 and 17 patients who underwent distal pancreatectomy (DP) and DP with celiac axis resection (DP-CAR) for conventional pancreatic ductal carcinoma were retrospectively analyzed. DST (mm) was measured by preoperative CT scan images. The indications for DP-CAR are the following: tumor involvement of the common hepatic artery and/or the celiac artery or difficulty in keeping surgical margin at the stump of the splenic artery. Results: Patients with DST = 0 had longer operation time ( p = 0.005), greater amount of blood loss ( p= 0.002), and higher morbidity rate ( p= 0.010) than those with DST > 0. The rate of introducing adjuvant chemotherapy in the DST = 0 group was significantly lower than that in the DST > 0 group (50% vs. 82%, p= 0.012). The median survival time (MST) of the DST = 0 group was significantly worse than that of the DST > 0 group (20 vs. 56 months, p< 0.001). In contrast, there was no significant difference of MST between the groups of 0 < DST≤10 and DST > 10 ( p= 0.499). Multivariate analyses revealed that DST = 0 (HR 4.51, p= 0.001), preoperative CA19-9 ≥40 U/mL (HR 2.91, p= 0.032) and preoperative neutrophil-to-lymphocyte ratio ≥2.3 (HR 2.49, p= 0.001) were independent prognostic factors. Regarding to the operative procedures, DP-CAR was performed 12 out of 14 patients with DST = 0, and 5 out of 16 patients with 0 < DST≤10. In the DST = 0 group, DP-CAR presented greater amount of dissected lymph nodes, higher rate of R0 resection, and lower rate of recurrence despite they were not identified statistically significant. In the 0 < DST≤10 group, DP-CAR tended to need longer operative time and higher rate of blood transfusion compared to DP, while there was no difference of prognosis. Conclusions: Multidisciplinary treatment including DP-CAR should be warranted for patients with DST = 0, which was a prognostic indicator. If surgical margin at the root of the splenic artery is secured in patients with DST > 0, DP should be an acceptable procedure.
Sensitivity and specificity of the NETest: A validation study.
Authors: Al-Toubah Taymeyah E. , Cives Mauro , Valone Tiffany , Blue Kirsten , Strosberg Jonathan R.
Published: January 2019

222

Background: Secretory tumor markers traditionally measured in patients with NET, such as chromogranin A, are lacking in sensitivity and specificity, and consequently are of limited clinical utility. The NETest, a novel blood multigene RNA transcript assay, has been found to be highly sensitive and specific. We sought to validate the sensitivity of the NETest in a population consisting of metastatic well-differentiated NETs, and evaluate the specificity of the test in a mixed population of metastatic non-NET GI malignancies and healthy individuals. Methods: 100 individuals consented to be tested, comprising of 49 patients with metastatic well-differentiated NETs of gastroenteropancreatic and lung origin, 25 patients with other gastrointestinal cancers, and 26 healthy individuals. Samples were sent in a blinded fashion to a central laboratory (Wren Laboratories). A NETest value of 0-13% was considered within normal range. Results: Using the ULN of 13%, the sensitivity of the NETest was 98% (CI 89%-100%) with 48 true positive results and one false negative. The overall specificity (in a mixed population of healthy individuals and non-NET cancer patients) was 63% (CI 49%-75%), with 32 true negative and 19 false positive results. Among the 26 healthy individuals the specificity was 81% (CI 62%-92%); among patients with other GI cancers, specificity was 44% (CI 27%-63%). Using an alternate and updated normal range of 0-20%, sensitivity was unchanged (98%), but specificity improved to 100% among healthy patients, and 64% among patients with other cancers. Conclusions: The sensitivity of the NETest is exceptionally high in a population of metastatic well-differentiated NETs. Specificity within a healthy population of patients is exceptionally high when using a normal range of 0-20%, and moderately high when using a normal range of 0-13%. Specificity is lower when evaluating patients with other GI malignancies. Clinical trial information: NCT02948946.
A blood-based assay for diagnosis of early-stage pancreatic cancer.
Authors: Ettrich Thomas Jens , Berger Andreas Wolfgang , Schwerdel Daniel , Reinacher-Schick Anke C. , Uhl Waldemar , Alguel Hana , Friess Helmut , Koenig Alexander , Ghadimi Michael , Gallmeier Eike , Bartsch Detlef K. , Geissler Michael , Staib Ludger , Tannapfel Andrea , Kleger Alexander , Seufferlein Thomas
Published: January 2019

234

Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Biomarker are needed to facilitate early and preferably noninvasive detection of PDAC, which directly may influence patients’ prognosis. Here we aimed to test a new biomarker combination for early PDAC, consisting of thrombospondin-2 (THBS2), CA19-9 and circulating tumor DNA (ctDNA) analysis. Methods: Thirty-nine patients with histologically proven and clearly resectable PDAC (recruited from the NEONAX trial, NCT02047513) were enrolled. Fifteen patients with benign pancreatic disease (intraductal papillary-mucinous neoplasms, IPMN) served as controls. Blood samples were collected prior treatment. KRAS genotyping was performed after isolation of ctDNA from plasma (QIAamp MinElute ccfDNA Kit, Qiagen) by digital droplet PCR ( KRAS Screening Multiplex Kit; QX200 system, both: Bio-Rad). Clinical data and CA 19-9 levels were assessed by ELISA (Roche); THBS2 values were determined by Quantikine ELISA Human Thrombospondin-2 (R&D Systems). Statistical analyses were done by using GraphPad Prism Version 7.00, GraphPad Software, Inc. Results: THBS2 had a c-statistic of 0.73 for all PDAC stages which was comparable to that of CA 19-9 (0.78). The c-statistic was improved to 0.94 by combining CA 19-9, THBS2 and total cfDNA amount. This marker combination performed best for all stages. C-statistics of defined PDAC stages was 0.93, 1.00 and 0.92 for stage I, stage II and stage III, respectively. Of note, the biggest improvement in sensitivity and specificity was seen for stage I PDAC. Here, c-statistic improved from 0.69 or 0.85 for CA 19-9 alone or the combination of CA 19-9 and THBS2, respectively, to 0.93 for the three-marker combination. Conclusions: These data underscore that CA 19-9, THBS2 and cfDNA marker combination constitutes a composite liquid biomarker for non-invasive diagnosis of early-stage PDAC with a remarkable specificity. Larger studies are needed to examine the power of this approach.
Leptomeningeal carcinomatosis in BRCA-mutated pancreatic cancer.
Authors: Slostad Jessica Anne , Hallemeier Christopher Leigh , Bamlet William R , Couch Fergus , McWilliams Robert R.
Published: January 2019

239

Background: Pancreatic adenocarcinoma is a rapidly fatal cancer with 5-year overall survival <5%. 5-10% of pancreatic cancers occur in patients with family history of disease, and 5-27% of these familial cancers are BRCA associated, with defects in Homologous Recombination Repair (HRR). In breast and ovarian cancer, BRCA mutations may be associated with increased risk for brain metastasis (BM). BM is rare in pancreatic cancer, but it is suggested HRR deficient pancreatic cancer patients may have an increased risk for BM/LC. Methods: We analyzed 3030 prospectively identified patients with pancreatic cancer and HHR mutation germline sequencing data (BRCA1/2, ATM, PALB2) from the Mayo Clinic Pancreatic Cancer SPORE Registry. We used clinical databases (2000-2018) to assess the presence of BM or leptomeningeal carcinomatosis (LC). Unconditional logistic regression analysis, with Odds Ratio (OR) and 95% Confidence Interval (CI), assessed the association between HRR gene germline mutation carrier status and any BM. Results: Of 3030 total pancreatic cancer patients, 8 were diagnosed with clinically evident BM/LC (0.26%), confirming the very low incidence of this metastasis site (Table). Of these, all had BM, and 4 also had LC present. No patients had LC diagnosed without BM present. 175/3030 (5.8%) patients had a germline HHR gene mutation. Of these, 1 patient was a BRCA2 carrier (0.57% of HRR deficient patients). 7 /2763 (0.25%) patients without germline HRR mutations had BM or LC (p = 0.44, OR 2.26; 95% CI: 0.27, 18.49). Conclusions: To our knowledge, this is the largest review of BRCA-associated pancreatic cancer patients with BM or LC. The incidence of BM is rare at 0.27%, with LC at 0.14%. Limitations include likely underdiagnosis given short clinical course and lack of availability of somatic HRR gene status. Our study suggests HRR germline carrier patients may have an increased risk of BM/LC development compared to non-carriers. Given rarity, larger studies should be explored. [Table: see text]
Insurance status and hepatocellular carcinoma: A NCDB analysis.
Authors: Ahmed Hibah , Ahmed Aabra , Wolfe Katrina , Silberstein Peter T.
Published: January 2019

240

Background: Typically occurring in patients with chronic liver disease, hepatocellular carcinoma is the most common liver cancer. Our goal was to compare survival of patients with differing insurance types diagnosed with hepatocellular carcinoma identified in the National Cancer Database (NCDB). Methods: We identified 113,159 patients with hepatocellular carcinoma in the NCDB diagnosed between 2004-2014. Patients included were categorized as having no insurance, private insurance, Medicaid, or Medicare were included. Between-insurance survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p < .05 indicated statistical significance. Results: Statistically significant survival differences were indicated between all insurance groups (all adjusted p < 0.05), such that privately insured patients had the highest median survival. The discrepancy in survival between uninsured and privately insured patients was the largest (4.6 months vs. 16.9 months, respectively). Medicaid patients on average had a survival of 9.8 months, while Medicare patients had a median survival of 10.0 months. 19% of uninsured patients presented with stage I hepatocellular carcinoma, whereas 30.3% of privately insured patients presented with stage I hepatocellular carcinoma. More uninsured patients did not have surgery of the primary site compared to privately insured patients (87.7% vs. 70.0%, respectively). Likewise, more privately insured patients had a transplant compared to those with Medicaid, Medicare, or those who were uninsured (13.0% vs. 5.7% vs. 5.0% vs. 1.6%, respectively). Conclusions: Our study shows the discrepancies in survival between patients with differing insurance statuses. Of all insurances, those privately insured had the largest median survival. Median survival and percentage surviving. [Table: see text]
Sorafenib versus transarterial chemoembolization as adjuvant therapies for patients with hepatocellular carcinoma and microvascular invasion.
Authors: Bi Xinyu , Gao Jie , Cai Jianqiang
Published: January 2019

244

Background: Microvascular invasion (MVI) is a risk factor for poor prognosis following curative resection in hepatocellular carcinoma (HCC). Currently, there is no standard of care for patients with HCC and MVI. The present study compared the effectiveness of sorafenib and transarterial chemoembolization (TACE) as adjuvant therapies following hepatic resection in patients with early and intermediate-stage HCC and MVI. Methods: This bi-center retrospective study examined 70 patients with HCC and MVI treated by hepatic resection between June 2009 and March 2018. Twenty-four patients received no postoperative adjuvant therapy (control), 19 received TACE and 27 received sorafenib. Recurrence-free survival (RFS) and overall survival (OS) were compared by the log-rank test. Results: Subjects consisted of 62 males and 8 females, with a median age of 53.5 (range, 28-82) years. The median follow-up was 26.0 (range, 4.1-103.1) months. RFS in the sorafenib group was significantly improved compared with the TACE group (P=0.048), but not with the control group. OS in the sorafenib group was significantly improved compared with both TACE (P=0.015; 2-year OS: 100% vs. 78.6%) and control (P=0.023; 2-year OS: 100% vs. 80.0%) groups. Conclusions: Adjuvant sorafenib following hepatic resection improved OS in patients with HCC and MVI and might be a better choice than adjuvant TACE.
Sunitinib in patients with pancreatic neuroendocrine tumors (panNETs): Exploratory pharmacogenomic analyses.
Authors: Fazio Nicola , Martini Jean-Francois , Croitoru Adina-Emilia , Schenker Michael , Li Sherry , Rosbrook Brad , Fernandez Kathrine C. , Tomasek Jiri , Thiis-Evensen Espen , Kulke Matthew H. , Raymond Eric
Published: January 2019

255

Background: In a phase IV trial (NCT01525550), median progression-free survival (PFS) was 13.2 mo in sunitinib-treated patients (pts) with well-differentiated panNETs. Objective response rate (ORR) was 24.5% and median overall survival (OS) was 37.8 mo. Exploratory analyses evaluated potential associations between single nucleotide polymorphisms (SNP) in genes involved in angiogenesis, protein transport or inflammatory response and clinical outcomes. Methods: Blood samples were genotyped using TaqMan assays for 12 SNPs previously associated with panNET risk, prognosis or drug effect. Associations between SNP and PFS or OS were assessed by comparing genotypes within treatment-naïve (TN), previously treated (PT) and combined groups, and within a genotype between treatment groups, using Kaplan-Meier analysis and Cox proportional hazards models. Fisher’s exact test was used for association between ORR and genotype. PFS and ORR were investigator-assessed. P values displayed are unadjusted and Bonferroni method was used for multiplicity adjustment. Results: 56 pts were genotyped: 25 TN and 31 PT. There were no significant associations between genotype and PFS or OS but there was a trend toward shorter PFS in pts with VEGFR1 rs9554320 C/A versus C/C (hazard ratio [HR] 1.78; 95% confidence interval [CI] 0.83–3.82; p = 0.117) and VEGFR1 rs9582036 A/C versus A/A (HR 1.88; 95% CI 0.9–3.93; p = 0.102). The genotypes G/G of VEGFA rs2010963 (p = 0.041) , G/G of VEGFA rs833068 (p = 0.041) and A/C of VEGFR1 rs9582036 (p = 0.046) showed a trend toward a higher ORR in the PT versus TN group. Genotype T/T of VEGFR2 rs7692791 (p = 0.103) showed a trend toward to a lower ORR in the TN versus PT group. Higher ORR was associated with IL1B rs16944 G/A versus G/G (46.4% vs 4.5%; p = 0.001) in the combined group. Conclusions: Potential associations between ORR and VEGFA rs2010963 and rs833068, VEGFR1 rs9582036 and VEGFR2 rs7692791 were observed. IL1B rs16944 was significantly associated with ORR, consistent with the role of IL1B in panNET etiology and development. Most correlations were not significant after adjustment for multiplicity. Clinical trial information: NCT01525550.
Growth factor signaling in pancreatic neuroendocrine tumor metastases.
Authors: Rheinheimer Brenna , Heimark Ronald , Jie Tun
Published: January 2019

256

Background: Pancreatic neuroendocrine tumors (PanNETs) are among one of the fastest growing cancer diagnoses, yet clinical management for patients with metastatic disease is largely empirically based. Currently, surgical resection remains the only curative option; however, surgical resection of metastatic disease may not be feasible. Preliminary genomic analysis of primary PanNETs revealed a complex mutational landscape with four common oncogenic events; but, critical activation pathways of metastatic lesions have yet to be elucidated. Therefore, pan-genomic analysis of metastatic PanNETs is necessary to understand which genes/pathways are deregulated in PanNET metastases for potential therapeutic exploitation. Methods: We initiated a preliminary genomic sequencing study to evaluate mutations in a set of matched primary and metastatic PanNETs to determine genetic variants involved in metastasis to the liver. De-identified FFPE tumor samples were analyzed from patients who underwent surgical resection without receiving preoperative therapy. DNA was isolated and whole exome sequencing was performed using the Nextera Rapid Capture Exome Kit by Illumina on an Illumina HiSeq 2000/2500. The following criteria were used to define genetic variants: bidirectional, non-synonymous, clean mapping in IGV, ≥ 15X coverage, and an alternate allele frequency of 0.3 ≤ x ≤ 0.7. Results: All metastatic PanNETs were classified as WHO grade G2/G3 based on their KI-67 proliferation index. Each primary PanNET contained an average of 102 genetic variants while liver metastases showed an average of 124 genetic variants. MUFFINN and string analysis revealed that primary PanNETs contained enrichment for mutations involved in the PI3K/Akt and Ras signaling pathways while liver metastases showed enrichment for mutations involved in the MAPK and ErbB signaling pathways. Additionally, two-thirds of liver metastases contained somatic mutations in FGFR3. Conclusions: We have discovered novel pathways that have the potential to regulate pancreatic neuroendocrine tumor metastasis along with an innovative signaling pathway that may sustain metastatic growth and survival as well as exploitation for therapeutic potential.
Whole-exome sequencing in unresectable pancreatic cancer patients with long-term survival.
Authors: Sudo Kentaro , Yokoi Sana , Ohara Osamu , Nakamura Kazuyoshi , Tsujimoto Akiko , Kita Emiri , Hasegawa Yoshinori , Nakayama Manabu , Ishii Hiroshi , Denda Tadamichi , Yamaguchi Taketo
Published: January 2019

260

Background: Advances in technology of genomic sequencing have revealed the mutational landscape of pancreatic cancer. However, little is known with regard to molecular mechanisms underlying clinical diversity in “unresectable” advanced pancreatic cancer. Methods: We performed whole-exome sequencing using frozen cancer tissues prospectively obtained by EUS-FNA from primary tumors before chemotherapy in patients with metastatic or locally advanced pancreatic cancer (n = 35). All patients had pathological confirmation (adenocarcinoma, n = 34; carcinoma, n = 1). Somatic alterations in the cancer genome were compared with clinical outcomes. Results: Seventeen patients had metastatic disease and 18 had locally advanced disease. Thirty-four patients received chemotherapy with or without radiotherapy and one patient was treated with supportive care alone because of rapidly progressive disease. With a median follow-up time of 60.6 months (range 41.9–94.0) for censored cases, the median survival for all patients was 10.8 months. Nine patients survived more than 2 years ( > 6 years, n = 2; > 3 years, n = 3; > 2 years, n = 4), while 11 patients died within 4 months. We show mutational landscape of unresectable advanced pancreatic cancer and identified somatic mutations in known cancer related genes including KRAS (89%), TP53 (71%), SMAD4 (20%), CDKN2A (17%) and ARID1A (14%). We found that ARID1A mutation was mutually exclusive with TP53 mutation except for one tumor and had a significant correlation with survival outcomes. Among 9 patients who survived more than 2 years, 5 patients (56%) had ARID1A somatic mutation, whereas none (0%) had mutations in the remaining 26 patients who died within 2 years ( P = 0.0004). The median overall survival was 47.7 months for 5 patients with ARID1A-mutated tumors and 8.9 months for 30 patients with ARID1A wild-type tumors ( P = 0.0101). Conclusions: This is the first study to perform whole-exome sequencing in unresectable pancreatic cancer patients including very long-term survivors. We found that ARID1A mutations were associated with longer survival.
The effect of hepatic stellate cells on hepatocellular carcinoma progression.
Authors: Iwahashi Shuichi , Shimada Mitsuo , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Saito Yu , Yamada Shinichiro , Rui Feng
Published: January 2019

265

Background: The hepatic stellate cells (HSCs) localize at the space of Disse in the liver and have multiple functions. They are identified as the major contributor to hepatic fibrosis. Some manuscripts mentioned that activated HSCs predicted prognoses of hepatocellular carcinoma. The aim of this study is to investigate the effect of HSCs and the role of IL-6 / Stat3 pathway on HCC progression. Methods: HCC cells (Hep G2 and Huh 7) were co-cultured with HSC (LX2 and Li90). The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44), TGF-b and p-STAT3 of cancer cells were evaluated. Then the IL-6 neutralization was performed during HCC cells and HSCs co-culture. The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44) and p-STAT3 of cancer cells were evaluated. Results: Co-culture with hepatic stellate cell increased cancer cell viability and migration ability. The expression of E-cadherin, EpCAM and CD44 of cancer cells also increased after co-culture with HSCs. The IL-6 expression and secretion of HSCs were elevated by cancer cell stimulation. The over-expressed IL-6 activated STAT3 of cancer cell showed as the level of phosphorylated STAT3 increased. Neutralized IL-6 during co-culture significantly decrease the viability and migration ability of cancer cells. Also, the expression of E-cadherin, EpCAM and CD44 of cancer cells decreased. Conclusions: HSCs might promote HCC progression through IL-6 / STAT3 pathway.
Comprehensive characterization of single circulating rare cells through automated picking and high-throughput mRNA profiling in patients with pancreatic cancer.
Authors: Kim Dong Uk , Lim Min Ji , Cho Yoonkyoung
Published: January 2019

271

Background: Circulating rare cells (CRCs) such as circulating tumor cells (CTCs), tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression. However, there are limited reports characterizing single CRCs comprehensively because of technical limitations including isolation and analysis of rare cells. We aimed to test the feasibility of the automated picking and mRNA profiling platforms of CRCs for evaluating the phenotypic heterogeneity of CRCs and the relationship between clinical outcomes and CRCs in patients with pancreatic cancer. Methods: CRCs were collected from 3ml of whole blood in 4 patients with pancreatic cancer using filter-based lab-on-a-disc platform. The filter membrane was transferred to ALS CellCelector (ALS, Germany) which is picking single nucleated CD45 negative cells to 96-well plate. The single cells were analyzed with the BioMark HD (Fluidigm, USA) which is digital PCR-based mRNA profiling for 48 markers such as epithelial, mesenchymal, stem-like, macrophage, fibroblast, oncogenic and immunogenic markers. Results: CRCs were detected in 3 of 4 patients (75%). Sixty-six-year-old female who had large pancreatic cancer with liver and lung metastasis presented 13 single rare cells including 7 epithelial CTCs with hematopoietic features (CD45 and CD14 positive), 3 mesenchymal CTCs, 2 stem-like CTCs, and 1 CAF. One epithelial CTC with hematopoietic features and one stem-like CTC were detected in 51-year-old male and 61-year-old female with metastatic pancreatic cancer, respectively. There was no CTC in 80-year-old male with localized pancreatic cancer. Conclusions: The automated picking and mRNA profiling platforms showed the feasibility of showing tumor heterogeneity and predicting clinical outcomes in patients with pancreatic cancer.