bluuebunny/crossref_metadata_2025 huggingface dataset:
STAT3 inhibition for gastroenteropancreatic neuroendocrine tumors: Potential for a new therapeutic target?
Authors: Lopez-Aguiar Alexandra G , Postlewait Lauren McLendon , Zaidi Mohammad , Zhelnin Kristen , Krasinskas Alyssa , Russell Maria C. , Kooby David A. , Cardona Kenneth , El-Rayes Bassel F. , Maithel Shishir
Published: January 2019

340

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascular tumors with similar treatments applied to all sites. The expression of pro-angiogenic factors (STAT3, VEGF, and HIF-1α) and their association with known adverse pathologic factors and disease recurrence after resection is not known. Methods: All pts with non-metastatic primary GEP-NETs who underwent curative-intent resection at a single institution from 2000-2013 were included. Immunohistochemistry was performed for STAT3, VEGF, HIF-1α, Ki-67 index, and CD31 using tissue microarrays made in triplicate by a pathologist blinded to other clinicopathologic variables. STAT3, VEGF, and HIF-1α were categorized into high vs low expression; CD31 was dichotomized at the median value. Primary outcome was 3-yr recurrence-free survival (3-yr RFS); secondary outcomes were correlation of STAT3, VEGF, and HIF-1α expression with Ki-67 index, adverse pathologic factors, and CD31 expression, a marker of microvascular density. Results: Of 265 GEP-NETs resected, 144 had tissue for analysis. STAT3 expression was high in 12 (8%) and low in 132 (92%). VEGF expression was high in 19 (13%) and low in 125 (87%), and HIF-1α was high in 1 (1%) and low in 143 (99%). High STAT3 expression was associated with worse 3-yr RFS compared to low expression (55% vs 84%; p = 0.003). High VEGF expression had a 3-yr RFS of 76% compared to 82% for low expression (p = 0.098); HIF-1α expression was not associated with RFS. Ki-67 ≥3% was associated with worse 3-yr RFS (≥3%: 51% vs < 3%: 84%; p < 0.001), as was the presence of lymphovascular invasion (LVI: 72% vs 95%; p = 0.001) and increased microvascular density per µm2 (CD31 > median: 75% vs CD31 < median: 86%; p = 0.043). High STAT3 expressing tumors were more likely to have a Ki-67≥3% (42% vs 7%; p < 0.001). LVI was present in 82% of high STAT3 tumors compared to only 50% with low STAT3 (p = 0.058). CD31 overexpression was similar between groups (58% vs 49%; p = 0.5). Conclusions: In resected GEP-NETs, high STAT3 expression is associated with an increased Ki-67 index, presence of lymphovascular invasion, and worse 3-yr RFS. STAT3 inhibition may be a novel therapeutic option for patients undergoing resection of high-risk tumors.
Reduction of T-Box 15 gene expression in tumor tissue as a prognostic biomarker for patients with hepatocellular carcinoma.
Authors: Morine Yuji , Utsunomiya Tohru , Imura Satoru , Ikemoto Tetsuya , Iwahashi Shuichi , Saito Yu , Shimada Mitsuo
Published: January 2019

341

Background: Genome-wide analysis is widely applied to detect molecular alterations in tumor and non-tumor tissue during oncogenesis and tumor progression. We analyzed DNA methylation profiles of hepatocellular carcinoma (HCC), which was is the third-highest cause of cancer-related deaths worldwide, and investigated the clinical role of most heyper-methylated gene, encodes T-box 15 (TBX15), which was originally involved in mesodermal differentiation. Methods: We used an Illumina Infinium HumanMethylation450 BeadChip Kit to conduct a genome-wide analysis of DNA methylation of tumor and non-tumor tissue of 15 patients with HCC. Methylation scores for CpG sites were assigned a Beta-value. Another validation set, which comprised 58 patients with HCC who underwent radical resection, was analyzed to investigate the relationships between tumor phenotype, prognosis, and TBX15 mRNA expression. Results: TBX15 was the most hyper-methylated gene (Beta-value in tumor tissue = 0.52 compared with non-tumor tissue), and TBX15 mRNA levels in tumor tissues were significantly lower compared with those of non-tumor tissues (p < 0.0001). When we assigned a cutoff value = 0.5-fold to define differential expression of TBX15 mRNA, low TBX15 expression significantly correlated with higher serum DCP levels, and the overall survival 5-year survival rates of the low-expression group (n = 17) were significantly shorter compared with those of the high-expression group (n = 41) (43.3% vs. 86.2%, p = 0.001). Multivariate analysis identified low TBX15 expression as an independent prognostic factor for overall and disease-free survival. Conclusions: Genome-wide DNA methylation profiling indicates that hypermethylation and reduced expression of TBX15 in tumor tissue represents a potential biomarker for predicting tumor progression and poor survival of patients with HCC.
Relationship between tumor-infiltrating lymphocytes (TIL) and absolute lymphocyte count (ALC) or lymphocyte to neutrophil ratio (LTN) in cholangiocarcinoma (CCA).
Authors: Lim Alexander , Coppola Domenico , Chang Young Doo , Anaya Daniel A. , Kim Dae Won , Kim Richard D.
Published: January 2019

343

Background: Tumor microenvironment is potentially a powerful predictive and prognostic marker of immunotherapy. The presence of CD8 TIL has been suggested as a predictive and prognostic marker of PD-1 inhibitor therapy in several malignancies. However, evaluation of TIL is not always feasible especially during or after immunotherapy. Therefore, easily accessible markers are needed for immune monitoring. In CCA, ALC and LTN in peripheral blood have been reported as prognostic factors. We evaluate the relationship between ALC or LTN and CD8 TILs in CCA. Methods: Formalin-fixed paraffin-embedded tumor samples from 41 patients with resected and histologically verified CCA between 1990 and 2015 were identified and immunohistochemically (IHC) stained with anti-CD8. Absolute lymphocyte and neutrophil count of the patients was obtained within 1 week before surgery. The association between ALC, LTN and CD8+ TIL status was investigated using unpaired Student t test and Spearman rank correlation. Results: The median age was 64 (41-85) with 53% male. 22%, 41% and 37% were stage I, II, and III respectively. In CD8 TIL positive, the average ALC was 1764 and in CD8 TIL negative, the average ALC was 2072. There was no significant difference between the two groups (p = 0.38). No difference of LTN was observed between CD8 TIL positive and negative tumors (0.39 vs 0.38, p = 0.69). The correlation between density of CD8 TILs and ALC or LTN was evaluated. No correlation was observed between CD8 TIL density and ALC (R = 0.02, P = 0.3) or LTN (R = 0.02, P = 0.8). Conclusions: ALC or LTN in peripheral blood may not predict CD8 TIL status in patients with CCA.
Lanreotide for the prolonged control of carcinoid syndrome (CS) in somatostatin analog (SSA)-naïve or experienced patients.
Authors: Wolin Edward M. , Fisher George A. , Liyanage Nilani , Pitman-Lowenthal Susan , Mirakhur Beloo , Pommier Rodney F. , Shaheen Montaser F. , Vinik Aaron
Published: January 2019

347

Background: In the ELECT study, mean percentage of days with rescue octreotide (OCT) use was significantly lower in lanreotide depot/autogel (LAN) 120 mg vs. placebo (PBO) group during 16-week double blind (DB) phase. We examined prospective data on use of subcutaneous (sc) OCT or other medications as rescue during DB and initial open label (IOL) treatment periods of the ELECT trial to evaluate the direct impact of LAN on patients’ relief of CS symptoms for prolonged periods. Methods: Adults with neuroendocrine tumors (NETs) and CS history, with/without prior SSA use, were randomized to 16 weeks DB LAN 120 mg sc or PBO every 4 weeks, followed by a 32-week IOL LAN phase. Prospectively collected data recorded via Interactive Voice (Web) Response System on the use of sc OCT or other rescue medications during screening, DB and IOL treatment periods was analyzed. Results: During the 16-week DB phase, treatment with LAN was associated with less frequent rescue sc OCT use (least squares mean percentage of usage days (MPUD): 33.7% LAN vs. 48.5% PBO; p = 0.02). Through the 32-week LAN IOL period, rescue sc OCT use in the DB LAN group further decreased to 27.1% MPUD. Following crossover from PBO to active treatment, sc rescue OCT MPUD in the DB PBO group decreased from 48.5% to 20.9% during the IOL period. MPUD of other rescue medications at baseline were: 12.9% LAN; 8.3% PBO and no significant decreases were observed with LAN treatment during the DB phase (8.9% LAN vs. 6.3% PBO). MPUD of the DB LAN group remained relatively unchanged through the IOL phase (8.9% LAN DB; 8.8% LAN IOL). Following crossover from PBO to active treatment, the PBO group exhibited a decrease in MPUD of other rescue medications from 6.3% to 3.1% during the IOL period. Stratified by prior SSA therapy cohorts (naïve vs. prior SSA therapy), no apparent differences were observed in the use of sc OCT or other rescue medications between the two cohorts. Trends in MPUD of rescue medications of the individual cohorts were also similar to the overall group. Conclusions: The results of this study demonstrated that LAN is effective for the prolonged control of CS symptoms in SSA-naïve or experienced patients with NETs. Clinical trial information: NCT00774930.
Secondary resectability in locally advanced pancreatic cancer (LAPC) after nab-paclitaxel/gemcitabine- versus FOLFIRINOX-based induction chemotherapy: Interim results of a randomized phase II AIO trial (NEOLAP).
Authors: Kunzmann Volker , Martens Uwe Marc , Alguel Hana , Siveke Jens T. , Goekkurt Eray , Pelzer Uwe , Siegler Gabriele Margareta , Hennes Elke , Waldschmidt Dirk , Jakobs Ralf , Ferenczy Peter , Keller Ralph , Boeck Stefan Hubert , Kullmann Frank , Kapp Markus , Germer Christoph Thomas
Published: January 2019

348

Background: Although there is a strong rationale for downstaging non-resectable pancreatic ductal adenocarcinoma (PDAC) for secondary resections by multi-agent chemotherapy, evidence from prospective randomized studies is missing. Methods: This prospective, randomized, open-label, phase II study aims to assess the activity, safety and feasibility of nab-paclitaxel/gemcitabine (nPG)- and FOLFIRINOX-based induction chemotherapy for patients (pts) with non-resectable PDAC. After two cycles of nPG pts are randomly allocated to receive either two additional cycles of nPG (arm A) or four cycles of FOLFIRINOX (arm B). Secondary resectability is assessed by exploratory laparotomy in all pts with at least stable disease (SD) after induction chemotherapy. The primary endpoint is to compare secondary complete macroscopic resection rates (R0/R1) in both arms. Results: We report the results of a planned interim (futility) analysis for efficacy data after at least 50 patients had completed induction chemotherapy and are evaluable for secondary surgical resection. Of pts who underwent randomization 42 pts were allocated to arm A and 44 pts to arm B, respectively. Disease control rate (DCR) after randomization was 93% in arm A and 89% in arm B. Explorative laparotomy was performed in 55% of randomized pts in arm A and 48% in arm B. Complete macroscopic resection (R0/R1) rate of randomized pts was 24% in arm A and 29% in arm B. For pts who received surgical exploration by laparotomy after completion of induction chemotherapy (n = 44) the complete macroscopic resection (R0/R1) rate was 43% in arm A and 62% in arm B. No new safety signals were identified thus far. Conclusions: nPG- and FOLFIRINOX-based induction chemotherapy approach revealed both effective and feasible in pts with LAPC supporting completion of patient recruitment in this trial. Interim results suggest promising secondary resection rates after multi-agent chemotherapy, especially when secondary resectability is assessed by surgical exploration. Clinical trial information: NCT02125136.
Initial dose of apatinib in Chinese patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction in third- or later-line setting: 500 mg or 850 mg?
Authors: Deng Wenying , Qin Shukui , Li Jin , Wen Lu , Wang Junsheng , Zhang Guifang , Zhong Haijun , Yang Jianwei , Ba Yi , Bai Yuxian , Lin Xiaoyan , Wang Mei , Wang Lin , Liu Likun , He Yifu , Tao Min , Xie Congying , Ye Feng , Wu Xiang-yuan , Jia Tongfu
Published: January 2019

35

Background: A fine balance between maintaining efficacy and reducing toxicity is necessary for drug therapies in many cancers. This study seeks to review the data from phase IV clinical trial of Ahead-G201 to help elucidate the optimal initial dose of apatinib in advanced gastric cancer. Methods: Pts data from the Ahead-G201 study at cut-off date of Jul 10, 2017 were extracted to explore the correlation of apatinib initial dose (500 mg vs 850 mg) with safety and clinical efficacy. Results: 864 of eligible pts received apatinib at an initial dose of 500 mg, and 58 pts received at 850 mg. Dose interruption occurred in 258 pts (33.1%) at 500 mg and in 27 pts (46.5%) at 850 mg. For safety, the most common adverse events (AEs) were proteinuria, hypertension and leukocyte decrease in both groups. Moreover, the incidence of all AEs and grade 3-4 AEs in pts at 500 mg was significantly lower than pts at 850 mg (Table). For efficacy, pts at 500 mg achieved an objective response rate (ORR) of 10.8% and a disease control rate (DCR) of 70.6%, at best response, which were 10.3% and 55.2% in pts at 850 mg. Pts at 500 mg got a significantly longer median progression-free survival (mPFS) and median overall survival (mOS) than pts at 850 mg (PFS, 4.6 mos vs 2.2 mos; OS, 6.8 mos vs 4.0 mos). Multivariate analysis indicated that apatinib treatment at an initial dose of 500 mg was significantly associated with longer mOS in advanced gastric cancer pts (6.8 mos vs 4.0 mos: hazard ratio, 0.5; 95%CI, 0.3 to 0.8), compared to initial dose of 850 mg. Conclusions: Compared to receiving apatinib at initial dose of 850mg, oral administration of apatinib starting from 500 mg seemed to bring more clinical benefit for patients with advanced gastric cancer, whilst with lower toxicities. Clinical trial information: NCT02426034. [Table: see text]
A multi-institutional predicting nomogram for BCLC stage C hepatocellular carcinoma after stereotactic body radiotherapy.
Authors: Huang Wen-Yen , Lin Yu-Ju , Cheng Jason C. , Que Jenny , Lee Mei-Hsuan , Tsai Chiao-Ling , Lo Cheng-Hsiang
Published: January 2019

353

Background: The study aimed to develop a nomogram to predict overall survival (OS) among hepatocellular carcinoma (HCC) patients with BCLC stage C after stereotactic body radiotherapy (SBRT). Methods: Clinical data from the multicenter study consisted of 270 HCC patients with BCLC stage C. The patients underwent SBRT with a median dose of 40 Gy (range: 25-60 Gy) in 2-6 fractions. The model included age, gender, ECOG performance status, etiology (HBV, HCV, and non-B, non-C), number of tumor, tumor size, AFP level, presence of macrovascular invasion, Child-Pugh class, N stage, M stage, sorafinib use, and biologically effective dose. Cox’s proportional hazards models were utilized to estimate regression coefficients of death risk predictors and derive risk scores. The area under receiver operating curve (AUROC) was used to evaluate the performance of the risk models. Results: The median survival was 12.6 months, with 1-year and 2-year OS rates of 51.6% and 30.8%, respectively. Multiple regression showed age (with 5-year increase, HR = 0.89, p = 0.002), ECOG (1 vs. 0, HR = 1.72, p = 0.016; 2 vs. 0, HR = 2.64, p = 0.002), number and size of tumors ( > 5 tumors or > 8 cm vs. ≤5 tumors and ≤ 8 cm, HR = 1.83, p = 0.003; > 5 tumors and > 8cm vs. ≤5 tumors and ≤ 8 cm, HR = 2.04, p = 0.013), macrovascular invasion (yes vs. no, HR = 2.22, p < 0.001), Child-Pugh class (B vs. A, HR = 2.83, p < 0.001), and M stage (1 vs. 0, HR = 2.30, p = 0.001) are statistically significant predictors for OS. All of these significant predictors were included in the risk prediction model. The total risk score of the prediction model ranged from 0 to 48. Each score had its corresponding risk of OS. The AUROC for predicting 1-year OS was 0.820. Conclusions: The nomogram we generated among HCC patients undergoing SBRT had discrimination satisfactory predictability for OS. It can be used to stratify high-risk patients and select appropriate patients for future clinical trials.
Comparisons between intestinal and diffuse gastric cancer in response to apatinib: Data from post-marketing phase IV study.
Authors: Zhang Guifang , Qin Shukui , Li Jin , Deng Wenying , Wen Lu , Wang Junsheng , Zhong Haijun , Jia Tongfu , Yang Jianwei , Ba Yi , Lin Xiaoyan , Wang Mei , Wang Lin , Liu Likun , He Yifu , Tao Min , Xie Congying , Ye Feng , Wu Xiang-yuan , Bai Yuxian
Published: January 2019

36

Background: Intestinal and diffuse gastric cancer are main histological types of gastric cancer, based on Lauren’s classification, which account for 34–47% and 46–57%, respectively. Patients (pts) with intestinal gastric cancer have better prognosis. The present study aimed to compare the safety and efficacy of apatinib between the two intestinal gastric cancer, based on data from post-marketing Phase IV study (Ahead-G201). Methods: The single-arm, open-label, multi-center, Phase IV trial enrolled advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction after failure of ≥2 lines of chemotherapy. Data of pts with intestinal and diffuse gastric cancer were collected and compared. Results: As of 2017/7/10, 96 intestinal and 104 diffuse pts were recruited. Differences in age (64 vs. 55 yrs), gender (male: 77.1% vs. 57.7%) and disease duration ( > 12 months: 71.3% vs. 56.7%) were detected. Between intestinal and diffuse gastric cancer, there was no discrepancy in incidences of adverse events (AEs) (78.1% vs. 73.1%) and Grade ≥3 AEs (41.7% vs. 38.5%). The incidences of typical AEs associated anti-angiogenesis drugs were also comparable (hypertension 26.0% vs. 16.4%; proteinuria 14.6% vs. 20.2%; hand-foot-skin reaction 16.7% vs. 9.6%). No statistical difference was observed in best overall response rate (12.8% vs. 14.3%) and disease control rate (76.0% vs. 64.3%). Survival benefit in pts with intestinal gastric cancer was detected (progression free survival: 5.52 vs. 2.76 months, p = 0.036; overall survival: 8.11 vs. 4.70 months, p = 0.047). However, the multivariable Cox regression model analysis showed that histological type was not independently prognostic factors for survival, indicating that clinical benefit of pts with intestinal gastric cancer was influenced by other factors. Conclusions: Compared with diffuse gastric cancer, pts intestinal gastric cancer have more clinical benefit after treated by apatinib. However, histological type based on the Lauren’s classification was not independently prognostic factors for survival, which needs to be further analyzed, considering the small sample size. Clinical trial information: NCT02426034.
Impact of adjuvant hepatic arterial infusion chemotherapy using high-dose 5-fluorouracil with systemic gemcitabine for resectable pancreatic cancer.
Authors: Nakamura Kota , Akahori Takahiro , Nagai Minako , Nishiwada Satoshi , Nakagawa Kenji , Tanaka Toshihiro , Nishiofuku Hideyuki , Kichikawa Kimihiko , Tamamoto Tetsuro , Hasegawa Masatoshi , Ikeda Naoya , Sho Masayuki
Published: January 2019

360

Background: Despite recent advances in cancer treatment, postoperative recurrence remains an unsolved issue for resectable pancreatic cancer. To prevent hepatic recurrence and prolong postoperative survival, we introduced postoperative adjuvant chemotherapy of high-dose 5-fluorouracil (5-FU) hepatic arterial infusion (HAI) with systemic chemotherapy using gemcitabine in 2006. We retrospectively evaluated the clinical impact of HAI. Methods: A total of 251 patients who underwent pancreatic resection for PC were analyzed. Patients received weekly high-dose 5-FU through the hepatic artery using a port-catheter system (1000 mg/m2 for 5 h) plus concurrent systemic gemcitabine (1000 mg/m2) followed by systemic 3 cycles of gemcitabine or 4 cycles of S-1. Patients were divided into two groups. The patients who completed planned adjuvant chemotherapy of HAI were classified as the completion group (HAI), and the patients who failed to complete HAI or received systemic adjuvant chemotherapy other than HAI were classified as the control group. Results: One hundred thirty-eight patients (55%) completed planned adjuvant chemotherapy of HAI. On the other hand, 28 patients (11%) failed to complete HAI and 85 patients (34%) received systemic adjuvant chemotherapy alone. The reasons for incompletion of HAI were as follows: any recurrence during HAI treatment in 8, poor general condition of patients in 4, hepatic arterial stenosis in 4 and catheter trouble in 3. Initial hepatic metastasis rate was significantly lower in the HAI group than the control group (15.2 vs. 26.3%, p=0.029), and liver metastasis free survival was significantly better in the HAI group than the control group (p=0.001). The HAI group had a better prognosis than the control group (58.1 vs. 26.9M, p < 0.001). Prognostic factor analysis indicated that failure to complete HAI (p < 0.001, HR 1.95), borderline resectable tumor (p = 0.028, HR 1.63), and lymph node metastasis (p = 0.018, HR 1.59) were the independent adverse prognostic factors. Conclusions: Our data demonstrate that HAI can significantly prevent hepatic recurrence and also improve the postoperative prognosis in pancreatic cancer.
Phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma.
Authors: Lee Sunyoung S. , Miller Austin , Krishnamurthi Smitha S. , Estfan Bassam N. , Frazer Andrea , Wang Chong , Iyer Renuka V.
Published: January 2019

364

Background: Sorafenib has been the only FDA-approved medication for inoperable HCC (iHCC) as first line. Agents with better tolerability and potential to improve progression-free-survival (PFS) are needed. Tivozanib (TIVO) is an inhibitor of vascular endothelial growth factor (VEGF) tyrosine kinase, inhibiting angiogenesis critical in HCC. Methods: This is a phase 1b/2 study with HCC patients (pts) having a measurable disease, Child-Pugh class A, and no prior systemic therapy. Phase 1b portion followed a modified 3 + 3 design; phase 2 portion was a two-stage, single arm, un-blinded study. Adverse events were categorized based on CTCAE, and tumor imaging was assessed per RECIST. Results: At 3 centers with IRB approval, 21 eligible pts were enrolled. In phase 1b, 8 pts were enrolled at a starting dose of 1mg once daily q21days with one week off. Upon escalation to 1.5mg, two pts had dose limiting toxicities (DLTs, grade 3 mucositis and hypertension) and came off study without completing the DLT period. The dose of TIVO was de-escalated to 1 mg, and the accrual of remaining patients to phase 2 portion occurred at 1 mg. In a total of 19 pts, median follow up was 16.9 months (mo). The primary endpoint of median PFS was 5.5 mo. Partial response (PR) was seen in 4/19 (21%) and stable disease (SD) in 8/19 (42%): disease control rate was 63%. Overall survival (OS) at 6 and 12 mo was 58% and 25%. Median OS was 7.5 mo. Three pts have remained on TIVO for > 2 years. Viral loads of hepatitis B and C remained stable during the study. Adverse events (AEs) related to TIVO included grade 3 fatigue (15.7%), decreased appetite (5.3%), pulmonary embolism (5.3%), hand-foot syndrome (5.3%), elevated LFT (10.5%), and grade 4 hypertension (5.3%). Conclusions: TIVO is tolerable at 1 mg in iHCC. In few pts, TIVO had deep and durable responses. Biomarker driven studies of TIVO in the context of immunotherapy are warranted. Acknowledgment: We appreciate support from NCCN. Clinical trial information: NCT01835223.
Perioperative and long-term impact of neoadjuvant chemoradiotherapy using full-dose gemcitabine and concurrent radiation for resectable pancreatic cancer.
Authors: Nagai Minako , Akahori Takahiro , Nishiwada Satoshi , Nakagawa Kenji , Nakamura Kota , Tanaka Toshihiro , Nishiofuku Hideyuki , Kichikawa Kimihiko , Tamamoto Tetsuro , Hasegawa Masatoshi , Ikeda Naoya , Sho Masayuki
Published: January 2019

367

Background: Although much attention has been paid to neoadjuvat treatment for pancreatic cancer (PC), its efficacy remains to be established. In this study, we have retrospectively evaluated the impact of neoadjuvant chemoradiotherapy (NACRT) on perioperative and long-term clinical outcome in PC. Methods: One hundred sixty patients who preoperatively received full-dose gemcitabine (1000 mg/m2) with concurrent radiation of 54 Gy between 2006 and 2016 were analyzed. One hundred thirty patients who underwent upfront surgery were served as control. Results: Among the 160 patients treated with NACRT, 153 patients (96%) completed the protocol treatment. The reasons of failure to complete NACRT were drug-induced pneumonia, acute mucosal injury, severe cholangitis and poor performance status (PS). Furthermore 21 (13%) couldn’t undergo pancreatic resection after NACRT because of distant metastasis in 9 patients, tumor progression in 7 and poor PS in 5. The rate of pancreatic fistula was lower and hospital stay was shorter in the NACRT group compared to the control group (P = 0.033, P = 0.002). Furthermore, the rate of lymph node metastasis, R0 resection and pathological stage were favorable in the NACRT group (P < 0.0001, P = 0.006, P < 0.0001). The completion rate of adjuvant chemotherapy was also higher in the NACRT group (P = 0.015). Importantly, patients treated with NACRT had a better prognosis than those without (median survival time: 60.2 vs. 28.5M, P = 0.008). In addition, according to tumor resectability status, patients were classified as R (resectable), BR-P (borderline resectable with venous involvement) and BR-A (borderline resectable with arterial involvement) groups. As a result, patients treated with NACRT had a better prognosis than those without in the R and BR-P groups (58.6 vs. 34.2M, P = 0.013, 62.4 vs. 18.8M, P = 0.015), while NACRT had no significant impact on prognosis in the BR-A group. Conclusions: Neoadjuvant chemoradiotherapy may have a variety of favorable impact in pancreatic cancer treatment. Furthermore, NACRT may improve the prognosis especially in resectable and borderline resectable pancreatic cancer with venous involvement.
Correlation of tissue plasminogen regulators expressed by esophageal adenocarcinoma with VEGF family members.
Authors: Kolesnikov Evgeniy N. , Kit Oleg Ivanovich , Frantsiyants Elena , Bandovkina Valeria A. , Kozlova Larisa S. , Kozhushko Mikhail Anatolievich , Kazieva Tanzila Beksultanovna , Sanamyants Sergey V. , Trifanov Vladimir
Published: January 2019

37

Background: Esophageal cancer is known for its high potential of early lymphogenous metastases. The biological activity of plasminogen (PG) regulators, VEGFs and their receptors controls the growth and differentiation of cells, including malignant ones, the stability of the extracellular matrix, as well as processes of destruction of membranes and extracellular matrix, invasion of malignant cells, angio- and lymphangiogenesis. Our purpose was to study the role of PG regulators in the activation of VEGFs and their receptors in esophageal adenocarcinoma (EA) and its perifocal zone (PZ). Methods: Levels of uPA-Ag, uPA-act; tPA-Ag, tPA-act; PAI-1-Ag and PAI-1-act, VEGF-А, VEGF-R1, VEGF-С and VEGF-R3 were determined by ELISA in surgical specimens of EA (n = 28, st II, G2, T2-3N0-1M0). Statistical analysis was performed using Microsoft Office Excel 2010. Results: Levels of all proteins, except tPA, were higher in tumor (T) tissues than in the resection line (RL, p < 0.01). Protein levels, except uPA-Ag and tPA, in PZ were between levels in T and RL (p < 0.01); uPA-Ag, tPA-Ag and tPA-act were decreased in T and PZ compared with RL (p < 0.01); PAI-1-Ag in T and PZ was higher than in RL by 9.4 and 6.3 times, and PAI-1-act – by 10.7 and 1.9 times. Levels of VEGF-А, VEGF-R1, VEGF-С and VEGF-R3 were increased in T (p < 0.001), and in PZ they were between levels in T and RL (p < 0.001). Strong correlations were registered in EA T between uPA and VEGF-А (r = 86), uPA and VEGF-R1 (r = 81), uPA and VEGF-С (r = 79), uPA and VEGF-R3 (r = 76). A strong correlation between uPA and PAI-1 in T (r = 88) did not exclude PAI-1 biological effects in EA T and its PZ. PZ showed strong correlations between uPA and PAI-1 (r = 87), uPA and VEGF-А (r = 84), uPA and VEGF-С (r = 78). Conclusions: The strong correlations between the activation of uPA, PAI-1, VEGF-А, VEGF-С and their receptors in EA indicate interactions between them, realized both directly and through plasmin. The expression of the studied proteins in T and its PZ, compared to RL, demonstrates the effect of T on the content and activity of uPA, PAI-1, VEGF-A, VEGF-C and their receptors, with the following realization of biological properties that promote the progression of EA.
Three fluoropyrimidine-based regimens in second-line therapy following nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer: Efficacy and tolerance in clinical practice.
Authors: Pointet Anne Laure , Tougeron David , Pernot Simon , Pozet Astrid , Bechade Dominique , Trouilloud Isabelle , Lourenco Nelson , Hautefeuille Vincent , Locher Christophe , Williet Nicolas , Desrame Jérôme , Thirot Bidault Anne , Pezet Denis , Taieb Julien
Published: January 2019

370

Background: Combination of nab-paclitaxel plus gemcitabine (N+G) has recently become a valid first-line treatment (1L) in metastatic pancreatic adenocarcinoma (MPA) in patients (pts) with performance status (PS) of 0,1 or 2, but there is currently no standard second-line treatment (2L) after this new 1L option. We evaluated survival outcomes and tolerability of three usual fluoropyrimidine-based regimens: FOLFOX, FOLFIRI or FOLFIRI.3 (FOLFIRI1/3), and FOLFIRINOX after N+G failure in MPA pts. Methods: We prospectively identified 138 pts from 11 French centers who received 1L N+G for unresectable pancreatic adenocarcinoma. After disease progression or unacceptable toxicity, we excluded pts with locally advanced cancer, or who underwent secondary resection/chemoradiotherapy. Three subgroups of 2L chemotherapy were identified: FOLFOX, FOLFIRI1/3 and FOLFIRINOX regimens. Response was evaluated by RECIST criteria, progression-free survivals (PFS1, PFS2), and overall survival (OS1, OS2) were calculated using Kaplan-Meier method and compared with the Log-rank test. Results: 61 pts with MPA received a 2L. Persistent neuropathy was present in 27% of pts. Median age was 71.7 years [41-83]. PS was 0, 1 or 2. Median 1L duration, number of metastatic sites, PS, CA19.9, albumin, and bilirubin levels, and persistent neuropathy grade were statistically comparable between the 3 subgroups. Median OS for all 2L pts was 6.0 months [4-8]. Third line regimen was used in 32.8% of 2L pts without statistical significance between the subgroups. Main grade 3/4 adverse events reported were thrombocytopenia (18%), anemia (7.7%), neutropenia (21.4%) and nausea (5.4%). No toxic deaths occurred. Conclusions: This study suggests a clinical benefit and a manageable toxicity profile of 2L fluoropyrimidine-based regimens after N+G failure in patients with MPA, in particularly combined with irinotecan.[Table: see text]
Impact of insurance status on survival in neuroendocrine tumors: A multi-institutional Study from the U.S. Neuroendocrine Study Group.
Authors: Marincola Smith Paula , Lopez-Aguiar Alexandra G , Dillhoff Mary , Beal Eliza W , Poultsides George A. , Makris Eleftherios , Rocha Flavio G. , Crown Angelena , Cho Clifford , Beems Megan , Winslow Emily , Rendell Victoria , Krasnick Bradley A. , Fields Ryan , Maithel Shishir , Idrees Kamran
Published: January 2019

371

Background: Insurance status predicts access to medical care in the United States. Previous studies show uninsured and government insured patients have worse outcomes than those with private insurance. However, the impact of insurance status on survival in patients with Gastrointestinal Neuroendocrine Tumors (GI-NETs) is unclear. We evaluate the association between insurance status and survival in patients with GI-NETs. Methods: Our analysis includes 2022 patients who had surgical resection of GI-NETs at 8 institutions in the U.S. Neuroendocrine Study Group. Patients were categorized based on insurance as private (PI), government (GovI) or uninsured (UI). Factors associated with insurance status were assessed by uni- and multi-variate analysis. Primary endpoint was overall survival. Results: Patient demographics between the insurance categories were similar in ECOG performance status and tumor size at presentation. GovI patients had a higher median age than PI or UI (66 vs. 54 vs. 56 years respectively; p<0.01). Uninsured patients were more likely African American (21.5%) or Latino (5%) compared to PI (11.5%, 2%) or GovI (15%, 2%) (p<0.01). The UI group had a higher proportion of patients who underwent no surveillance imaging post-operatively (39%) compared to PI (26%) and GovI patients (26%) but this was not statistically significant (p=0.15). There was no difference in operative intent (curative vs. palliative) between groups (p=0.2). Five-year overall survival was 86% for PI, 82% for GovI, and 73% for UI patients (p<0.01). On multivariate regression analysis, being uninsured was independently associated with reduced survival when controlling for ASA Class, ECOG, race, tumor location, neoadjuvant and adjuvant chemotherapy, Somatostatin analog, or radiation therapy (HR 1.39, p = 0.012). Conclusions: This is the first systematic analysis of insurance status’s association with overall survival in GI-NET patients. Our analysis shows uninsured or government insured patients have shortened survival compared to the privately insured. The disparity is likely underrepresented in this study, as we examined only patients who underwent surgical resection.
Curative intent surgery and associated overall survival variation between elderly and younger patients in the National Cancer Database.
Authors: Anderson Eric , David John , Lo Simon , Nissen Nicholas N. , Hendifar Andrew Eugene , Tuli Richard
Published: January 2019

373

Background: Margin negative oncologic resection drastically improves survival in pancreatic cancer (PC) with low morbidity and mortality rates. Increasing age at the time of surgery may have an impact on overall survival (OS) in PC. We aimed to describe the likelihood of receiving surgery in elderly patients (EP) compared to younger patients and whether this predicted OS. Methods: Non-metastatic PC patients were identified in the National Cancer Database (NCDB). Baseline demographics, clinical, and pathologic factors were compared between patients older (EP) and younger (YP) than age 75. Kaplan-Meier survival methods were used to describe differences in OS. Cox regression methods were performed to describe the impact of multiple variables on OS. Results: From 2004-2014, there were 39,804 PC patients with median age 69 years (range 19-90) and median follow up 47.2 months. Of 12,337 (31.0%) EPs, 2598 (21.1%) underwent surgery, while 9809 of 27467 YPs (35.7%) underwent surgery (p < 0.001). EP were less likely to receive surgery across clinical stages (CS, p < 0.001): CS 1 - 29.5% EP vs. 55.6% YP, CS 2 - 23.4% EP vs. 40.3% YP, CS 3 - 3.1% EP vs. 7.5% YP. EP receiving surgery were more likely to have baseline medical comorbidities (38.8% vs. 35.9%, (p = 0.065) and less likely to receive chemotherapy (47.4% vs. 73.6%, (p < 0.001). Improvement of median OS was seen in EPs undergoing resection (16.9 months vs. 6.4 months, p < 0.001), as well as YP undergoing resection (22.8 vs. 11.2 months, p < 0.001). Multivariate Cox regression revealed that surgical intervention (HR 0.47, 95% CI 0.45-0.48, p < 0.001) and younger age (0.62, 0.60-0.63, p < 0.001) were highly protective. Patient medical comorbidities (1.15, 1.12-1.18, p < 0.001) and T stage (1.38, 1.31-1.44, p < 0.001) predicted poor OS. Conclusions: EPs with PC are less likely to receive definitive surgical resection in the setting of higher or similar medical comorbidities. EPs are also less likely to receive chemotherapy for their non-metastatic disease. In spite of this, surgery portends a significant increase in median OS for these EPs. Given adequate risk stratification and functional assessment, EPs should be strongly considered for surgical resection.
Comparative effectiveness and safety of the implementation of universal public funding of FOLFIRINOX (FFX) and gemcitabine (G) + nab-paclitaxel (GnP) in advanced pancreatic cancer (APC): A population-based study.
Authors: Guo Helen , Beca Jaclyn Marie , Redmond-Misner Ruby , Isaranuwatchai Wanrudee , Qiao Lucy , Earle Craig , Berry Scott R. , Biagi James Joseph , Welch Stephen , Meyers Brandon Matthew , Mittmann Nicole , Coburn Natalie G. , Pardhan Aliya , Arias Jessica , Schwartz Deborah , Gavura Scott , Forbes Leta Marie , McLeod Robin , Kennedy Erin Diane , Chan Kelvin K.
Published: January 2019

375

Background: FFX has been universally publicly funded in Ontario, Canada, for metastatic pancreatic cancer (mPC) and unresectable locally advanced pancreatic cancer (uLAPC) since 11/2011 and 04/2015, respectively. GnP has been publicly funded for uLAPC and mPC (APC) since 04/2015. We examined the real world comparative effectiveness and safety of implementing funding of FFX and GnP for patients with APC. Methods: Patients with APC who received first-line FFX, GnP, or G from 01/2008-03/2016 were identified in CCO’s New Drug Funding Program database and divided into 3 periods: 01/2008-10/2011 (P1), 11/2011-03/2015 (P2), and 04/2015-03/2016 (P3). Data were linked with the Ontario Cancer Registry and others to ascertain demographics, comorbidities, and outcomes. Matching weights of propensity score to simultaneously compare three periods were generated using multinomial logistic regression. Crude and adjusted survival analyses were conducted to assess overall survival (OS) using Kaplan-Meier and weighted Cox regression methods.Weighted negative binomial models were used to estimate rate ratios (RR) for all-cause hospitalization (H) and ED visits. Results: We identified 3696 patients (1250 in P1, 1891 in P2, 555 in P3) (overall mean age 65, female 46%). In P2, 49% received FFX. In P3, 53% received FFX and 35% received GnP. Median OS was 5.7, 7.0, and 7.5 months for P1, P2, and P3, respectively. Median OS for FFX and GnP in mPC were 8.8 and 5.5 months, respectively. OS was improved in P2 vs. P1 (HR = 0.84, 0.78-0.90) and in P3 vs. P2 (HR = 0.82, 0.73-0.92). ED visits were similar compared P2 vs. P1 (RR=1.02, p = 0.75) and P3 vs. P2 (RR=1.04, p = 0.48), and H was reduced in P2 vs. P1 (RR = 0.86, p = 0.01), but similar in P3 vs. P2 (RR = 0.98, p = 0.78). H for febrile neutropenia (FN) was increased in P2 vs. P1 (RR = 2.18, p = 0.04) but not in P3 vs. P2 (RR = 1.32, p = 0.45). Conclusions: Implementation of universal public funding of FFX for mPC improved OS and reduced the rates H overall, but increased FN-related H. Funding of FFX for uLAPC and GnP for APC improved OS without increased in ER and H.
The influence of biliary drainage in patients with advanced pancreatic cancer receiving FOLFIRINOX.
Authors: Ueno Makoto , Yamanaka Takeharu , Ogura Takashi , Yamaguchi Atushi , Mizuno Nobumasa , Ozaka Masato , Ueno Hideki , Uesugi Kazuhiro , Kobayashi Noritoshi , Hayashi Hideyuki , Sudo Kentaro , Okano Naohiro , Horita Yosuke , Kamei Keiko , Hosokawa Takafumi , Henmi Toshiyuki , Kobayashi Marina , Todaka Akiko , Fukutomi Akira
Published: January 2019

378

Background: FOLFIRINOX (FFX) is a standard of care for patients (pts) with advanced pancreatic cancer (APC). In the original FFX report by Conroy (NEJM, 2011), pts with a biliary drainage were limited and the occurrence of cholangitis was not reported. In practice, however, we experience that a certain fraction of APC pts needs a biliary drainage and some of them have an elevated risk of cholangitis or febrile neutropenia (FN) during the course of FFX. We evaluated the influence of biliary drainage on the efficacy and safety of FFX. Methods: We used individual data from nationwide survey of FFX (JASPAC06). The JASPAC06 was a prospective registry of pts with FFX treated in clinical practice and enrolled 399 pts between December 2013 and November 2014 from 27 centers in Japan. We evaluated the associations of OS and PFS, as well as the frequencies of cholangitis and FN, with the use of biliary drainage. We excluded resected cases because an operative method with choledochojejunostomy was unknown. Results: Of 399 pts in the JASPAC06, 319 were eligible for this analysis and 80 resected cases were excluded. The use of biliary drainage was seen in 28% of pts (mainly bile duct stent inserted); primary dose reduction (modified FFX), 67%; previously untreated tumor, 77%; distant metastases, 76%; pancreas head, 47%. The main results are shown in the table. In summary, cholangitis was more frequent in pts with biliary drainage. Grade 3 or higher FN as well as CRP elevation was observed more frequently in pts with biliary drainage. There was no difference in PFS (median PFS, 7.3 vs. 6.5 mo; logrank, p=0.24) and OS (median OS, 12.3 vs. 12.2 mo; p=0.86) between the two groups. Conclusions: Our observation that the frequency of FN and CRP elevation was significantly higher in pts with biliary drainage indicates a higher risk of infection during the FFX treatment by using biliary drainage.[Table: see text]
Neoadjuvant FOLFIRINOX and IMRT concurrent with FDR-gemcitabine in patients with borderline resectable pancreatic cancer (BRPC).
Authors: Tran Nguyen H. , Sahai Vaibhav , Griffith Kent A. , Nathan Hari , Kaza Ravi , Cuneo Kyle Clifford , Sonnenday Christopher J , Cho Clifford , Lawrence Theodore Steven , Zalupski Mark
Published: January 2019

381

Background: Preoperative therapy in BRPC is intended to increase the likelihood of R0 resection although an optimal regimen is yet to be defined. Methods: Patients (pts) with BRPC (NCCNv.2.2010 guidelines) and ECOG PS 0-1 were enrolled in a single-institution, phase II trial (NCT01661088). Pts received FOLFIRINOX x 6, followed by IMRT (50 Gy in 25 fractions) concurrent with FDR-gemcitabine 1 g/m2 on days 1, 8, 22, 29. Two additional FDR-gemcitabine infusions completed pre-operative treatment. Pancreatic protocol CT scans (dual phase, 0.65 mm slices) were performed after 4 infusions of FOLFIRINOX, 3 weeks after IMRT, and at treatment completion. Pts without distant disease were offered surgical exploration. The primary objective was to determine R0 resection rate. Secondary objectives included progression free survival (PFS), overall survival (OS), response rate and safety. Results: A total of 25 pts (64% men) median age 60 years (range 47-77) were enrolled from 11/2011 through 01/2017. Twenty-one (84%) pts completed FOLFIRINOX and 19 (76%) all protocol therapy. Treatment-related grade 3-4 adverse events ( > 10%) included neutropenia (40%), nausea/vomiting (28%), diarrhea (16%) and fatigue (12%). One early death and 1 discontinuation due to toxicity occurred during FOLFIRINOX. Response to pre-op therapy included 11 PR, 9 SD, 3 PD and 2 NE. Of 25 treated pts, 18 (72%) had laparotomy and 13 (52%) underwent resection (all R0). The median PFS and OS were 18.1 (95% CI, 10.6 to 25.1) and 24.2 (95% CI, 12.6 to 40.0) months, respectively. The median OS for R0 resected pts was 37.1 (95% CI, 15.4 – not reached) months. Conclusions: Neoadjuvant therapy with FOLFIRINOX, followed by IMRT with concurrent FDR-gemcitabine in BRPC is feasible and tolerated. While R0 resection rate was not obviously improved, OS of the entire cohort and especially in R0 resected pts was favorable. Clinical trial information: NCT01661088.
Phase 1 studies of 3- and 6-peptide vaccine cocktail derived from GPC3, WDRPUH, and NEIL3 in patients with advanced hepatocellular carcinoma (HCC).
Authors: Ikeda Masafumi , Okusaka Takuji , Ohno Izumi , Mitsunaga Shuichi , Takahashi Hideaki , Kondo Shunsuke , Morizane Chigusa , Furuse Junji
Published: January 2019

387

Background: Glypican 3 (GPC3), WD-Repeat-containing Protein Up-regulated in HCC (WDRPUH), and Nei Endonuclease VIII-Like 3 (NEIL3) are tumor antigens in HCC. We conducted two phase 1 multicenter open-label studies for advanced HCC: one to evaluate the HLA-A*24-restricted 3-epitope peptide vaccine cocktail named ONO-7268MX1 (MX1); the other to evaluate the HLA-A*24 and -A*02-restricted 6-epitope peptide vaccine cocktail named ONO-7268MX2 (MX2). Both vaccines contain epitope peptides derived from GPC3, WDRPUH, and NEIL3. MX1 and MX2 cover most of Japanese HCC patients (pts). Safety is the primary, and efficacy and immunological response are the exploratory objectives. Methods: Pts received SC MX1 or MX2 once weekly. In MX1 study, pts received each of 3 peptides at 0.3 mg (cohort 1), 1 mg (cohort 2), and 3 mg of GPC3, 1.1 mg of WDRPUH and 3 mg of NEIL3 (cohort 3). In MX2 study, pts received each of 6 peptides at 1 mg. Results: In MX1 study, 3, 8, and 7 pts with HLA-A*24 were enrolled to cohort 1, 2, and 3, respectively. In MX2 study, 14 pts (7 with HLA-A*24, 6 with HLA-A*02, and 1 with HLA-A*24/A*02) were enrolled. No dose limiting toxicities were observed in both studies. The most commonly related AEs were Grade 1/2 injection site reaction (erythema, induration, pain, and pruritus), 44.4% (8/18) in MX1 and 78.6% (11/14) in MX2. Grade 3-related AEs occurred only in MX2 study; neutrophil count decreased, white blood cell count decreased, and decreased appetite (each 1 patient). No grade 4-related AEs occurred in both studies. No response (CR or PR) were seen in both studies. In MX1 study, median and mean of PFS [range], median duration of SD were 2.8, 3.4 [0.5-16.8], 3.7 months respectively, in MX2 study those were 1.9 and 2.8 [0.4-8.3], 5.7 respectively. In both studies, some pts showed long disease control (≥6 months). For those pts, each peptide-specific Cytotoxic T Lymphocyte (CTL) responses were shown by the ELISPOT assay. Conclusions: MX1 and MX2 showed good tolerability. Both vaccines induced CTL responses which may be related to antitumor effect. In addition, some pts showed long disease control. These results implied the potential usefulness of these vaccines for the treatment of HCC. Clinical trial information: JapicCTI-121933 and JapicCTI-142477.