bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive role of temporal changes in intratumoral metabolic heterogeneity during palliative chemotherapy in advanced pancreatic cancer patients: A prospective cohort study.
Authors: Yoo Shin Hye , Kang Seo Young , Cheon Gi Jeong , Oh Do-Youn , Bang Yung-Jue 
Published: January 2019

311 Background: Metabolic intratumoral heterogeneity (ITH) is known to be related with cancer treatment outcome. However, information on the temporal changes in metabolic ITH during chemotherapy and the correlations between metabolic changes and treatment outcomes in patients with pancreatic cancer (PC) is sparse. We aimed to analyze the temporal changes in metabolic ITH and the predictive role of its changes in advanced PC patients who underwent palliative chemotherapy. Methods: We prospectively enrolled unresectable locally advanced or metastatic PC patients before initiation of first-line palliative chemotherapy. 18F-fluorodeoxyglucose positron emission tomography was performed at baseline (T1) and at the first response follow-up (T2). Standardized uptake values (SUVs), volumetric parameters, and textural features of the primary pancreatic tumor were analyzed. Relationships between the parameters at T1, T2, and changes in the parameters with response to therapy, progression-free survival (PFS), and overall survival (OS) were assessed. Results: Among 63 enrolled patients, the best objective response rate was 25.8% (95% confidence interval [CI], 14.6% to 37.0%). Sixteen (25.8%) patients who obtained partial response were classified as responders and 46 (74.2%) as nonresponders. The median PFS and OS were 7.1 months (95% CI, 5.1 to 9.7 months) and 10.1 months (95% CI, 8.6 to 12.7 months), respectively. Most of the parameters changed significantly during the first-line chemotherapy, in a way of reducing ITH. Metabolic ITH was more profoundly reduced in responders than in nonresponders. Multiple Cox regression analysis identified high baseline compacity ( P = 0.023) and smaller decreases in SUVpeak ( P = 0.007) and entropyGLCM ( P = 0.033) to be independently associated with poor PFS. Patients with a high CA 19-9 ( P = 0.042), high pretreatment SUVpeak ( P = 0.008), and high coefficient of variance at T2 ( P = 0.04) showed worse OS. Conclusions: Reduction in metabolic ITH during palliative chemotherapy in advanced PC patients is associated with response to therapy and might be predictive of PFS and OS.
Neoadjuvant chemotherapy followed by surgery versus upfront surgery in patients with borderline resectable and locally advanced unresectable pancreatic adenocarcinoma.
Authors: Kang Junho , Yoo Changhoon , Shin Sang Hyun , Kim Kyu-Pyo , Jeong Jae Ho , Chang Heung-Moon , Lee Sang Soo , Park Do Hyun , Song Tae Jun , Seo Dong Wan , Lee Sung Koo , Kim Myung-Hwan , Park Jin-hong , Hwang Dae Wook , Song Ki Byung , Lee Jae Hoon , Ryoo Baek-Yeol , Kim Song Cheol 
Published: January 2019

312 Background: Although neoadjuvant chemotherapy (NACT) has been widely investigated, the magnitude of the clinical benefit and the potential risk of NACT followed by surgery compared with upfront surgery remains unclear for patients with locally advanced pancreatic cancer (LAPC). Methods: This retrospective, prospective cohort-based analysis included 135 patients who underwent NACT followed by surgery and 359 patients who received upfront surgery for LAPC between October 2005 and April 2017. Disease-free survival (DFS) and overall survival (OS) from surgery were compared between the two groups. Results: There were no significant differences in gender (male, 53% vs 56%) and age (median 60 vs 61 years) between the NACT followed by surgery group and upfront surgery group. As NACT, gemcitabine-based regimens and FOLFIRINOX were used in 69 (51%) and 66 (49%) patients, respectively. The NACT followed by surgery group showed significantly less advanced T stage (T3–4, 93% vs 99%, p = 0.001) and N stage (N+, 49% vs 71%, p < 0.001) than the upfront surgery group. NACT followed by surgery was significantly associated with better OS (median, 25.4 [18.6–32.2] vs 17.1 [15.5–18.7] months, p = 0.001) and DFS (median, 9.0 [95% CI, 6.8–11.2] vs 7.1 [6.4–7.8] months, p = 0.005) than upfront surgery. These results were consistent in the multivariate analysis for OS (adjusted hazard ratio [aHR], 0.73 [95% CI, 0.56–0.96], p = 0.02) and DFS (aHR, 0.72 [95% CI, 0.56–0.93], p = 0.01). There was no difference in length of hospital stay (median 13 vs 17 days, p = 0.14) for surgery between the two groups, and the NACT followed by surgery group showed a significantly lower incidence of postoperative complication than the upfront surgery group (38% vs 27%, p = 0.03). Conclusions: The present study revealed that NACT followed by surgery may provide survival benefit compared with upfront surgery in LAPC without causing significant safety issues.
Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: Pooled efficacy and safety in Japanese patients across two global randomized phase III studies (REACH-2 and REACH).
Authors: Kudo Masatoshi , Okusaka Takuji , Motomura Kenta , Ohno Izumi , Morimoto Manabu , Seo Satoru , Wada Yoshiyuki , Sato Shinpei , Yamashita Tatsuya , Furukawa Masayuki , Aramaki Takeshi , Nadano Seijin , Ohkawa Kazuyoshi , Fujii Hirofumi , Kudo Toshihiro , Furuse Junji , Takai Hiroki , Homma Gosuke , Yoshikawa Reigetsu , Zhu Andrew X. 
Published: January 2019

320 Background: Ramucirumab (RAM), a human IgG1 monoclonal antibody, inhibits ligand activation of VEGFR2. REACH and REACH-2 were two global, randomized, double-blind, placebo (PBO)-controlled multicenter, phase III studies of RAM versus PBO in patients with HCC after prior sorafenib. REACH-2 confirmed RAM treatment benefit for patients with baseline AFP ≥ 400 ng/mL, consistent with results in a prespecified subgroup of patients in REACH with AFP ≥ 400 ng/mL. Methods: Other than AFP levels, study designs and eligibility for both studies were similar. All patients received RAM (8 mg/kg) I.V. or PBO every 14 days. Pooled analyses were performed to further support the assessments of efficacy and safety in Japanese patients with baseline AFP ≥ 400 ng/mL. Results: In total, 101 Japanese patients were pooled from REACH and REACH-2 (n = 61 RAM; n = 40 PBO). Pooled baseline patient characteristics were balanced between arms including baseline AFP and etiology. As in the individual studies, improvement in OS (median OS 10.78 vs 4.47 mo; HR 0.555; 95% CI 0.348, 0.885; p = .0124) was observed. Improvements in PFS (median PFS 3.88 vs 1.41 mo; HR 0.341; 95% CI 0.212, 0.550; p < .0001), ORR (9.8% vs 2.5%, p = .1285), and disease control rate (67.2% vs 35.0%, p = .0035) were also observed. Consistent with individual study results, hypertension was the only grade 3 or higher adverse events of special interest among ≥ 5% patients that was more frequently observed in the RAM arm (13.1%) compared with the PBO arm (5.0%). Conclusions: Pooled analysis of two phase III trials of RAM as second-line treatment in patients with HCC following first-line sorafenib demonstrated a clinically meaningful benefit with a manageable safety profile in Japanese HCC patients with baseline AFP ≥ 400 ng/mL. Treatment benefits in OS observed in the Japanese subpopulation were consistent with the entire population (median OS 8.1 vs 5.0 mo; HR 0.694; p = .0002. Zhu AX et al., World GI 2018). Further analysis to characterize the Japanese patients compared to the non-Japanese population is planned. Clinical trial information: NCT01140347 (REACH), NCT02435433 (REACH-2).
The role of perioperative systemic therapy in localized pancreatic neuroendocrine tumor.
Authors: Xie Hao , Yadav Siddhartha , Keutgen Xavier , Hobday Timothy J. , Strosberg Jonathan R. , Halfdanarson Thorvardur Ragnar 
Published: January 2019

322 Background: The role of perioperative systemic therapy (PST) is unclear in the management of localized pancreatic neuroendocrine tumor (pNET). We aim to evaluate the benefit of PST compared to surgical resection alone in localized pNET. Methods: We identified patients with stage I–III pNET who underwent curative-intent surgical resection in National Cancer Database from 2006 to 2014. Patients who underwent PST and surgical resection were matched with patients who received surgery alone by propensity score at 1:1 ratio with nearest neighbor method. Factors predicting the use of PST were identified from logistic regression. Survival was estimated with Kaplan-Meier method and compared with Cox proportional hazards regression. Results: 4919 patients were included in this study with median age of 60 years. 1397 (28%) patients had pNET at the head of pancreas. 2708 (55%) patients had pNET at pancreas body and tail. 334 (6.8%) patients received PST. Factors associated with significant more use of PST compared to surgery alone were age < 65 years, low income, community medical facilities, grade 3/4 tumor, tumor at the head of pancreas, T3-4 tumor and N1 tumor. 310 patients in PST group were matched with 310 patients in surgery alone group, with no significant difference for all covariates after match. For those in PST group, 64 (21%) patients received neoadjuvant systemic therapy, 173 (56%) patients received adjuvant systemic therapy, 7 (2.3%) patients received both, and 66 (21%) patients received PST without clear sequence. In the matched cohort, PST group had significantly shorter overall survival (OS) compared to surgery alone group (median OS 91.1 months versus not reached, p = 0.04). This finding was confirmed by multivariable Cox proportional hazards regression in unmatched cohort with HR 1.5 (95% CI 1.2 – 1.9, p = 0.002). Subgroup analysis in patients with grade 3/4 tumor demonstrated PST group has a trend of shorter OS compared to surgery alone group (median OS 34.1 versus 54.4 months, p = 0.1). Conclusions: PST compared to surgery alone is associated with worse OS in patients with localized pNET. This finding suggests that we may use PST in localized pNET with caution in the absence of solid clinical trial data.
Sorafenib versus hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma: A Japanese multi-center large cohort study.
Authors: Ogasawara Sadahisa , Ueshima Kazuomi , Ikeda Masafumi , Yasui Yutaka , Terashima Takeshi , Yamashita Tatsuya , Obi Shuntaro , Sato Shinpei , Aikata Hiroshi , Ohmura Takumi , Kuroda Hidekatsu , Ohki Takamasa , Nagashima Kengo , Kurosaki Masayuki , Chayama Kazuaki , Kaneko Shuichi , Izumi Namiki , Kato Naoya , Kudo Masatoshi , Omata Masao 
Published: January 2019

323 Background: Sorafenib, approved in Japan in 2009, is the first systemic therapy demonstrated to significantly improve overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC). In Japan, hepatic arterial infusion chemotherapy (HAIC), which directly delivers high concentrations of cytotoxic agents to liver tumors, has been offered to patients with advanced HCC since before sorafenib was approved. HAIC is particularly used in patients without extrahepatic metastases (EHM). This study aimed to compare the outcomes of patients with advanced HCC who received HAIC and sorafenib. Methods: Consecutive patients with advanced HCC who received sorafenib or HAIC as the first-line systemic therapy were enrolled from 10 Japanese centers. The statistical analysis plan included pre-defined propensity score matching method and risk factors. All statistical analyses were performed by an independent biostatistician. Results: Between June 2009 and May 2016, 2006 patients were enrolled (sorafenib: 1465 patients, HAIC: 541 patients). The mean OS of patients with macrovascular invasion (MVI) and without EHM was significant longer in the HAIC group compared with the sorafenib group. After propensity score matching, there were 172 patients in each cohort. The OS was 9.1 months for the sorafenib group and 10.1 months for the HAIC group (hazard ratio [HR]: 0.668 [95% CI: 0.475–0.935], P = 0.018). There was no significant difference in OS between patients without both MVI and EHM. After propensity score matching, there were 76 patients in each cohort. The OS was 15.4 months for the sorafenib group and 12.2 months for the HAIC group (hazard ratio [HR]: 1.227 [95% CI: 0.699–2.155], P = 0.475). Conclusions: HAIC might be a potential initial treatment for patients with advanced HCC with MVI (without EHM). Currently, several new drugs appear clinically beneficial for patients with advanced HCC. Although this study only focused on sorafenib as the chemo-agent, additional studies should be conducted to confirm the benefits associated with HAIC in a limited population of patients with advanced HCC.
Results from phase I study of the oncolytic viral immunotherapy agent canerpaturev (C-REV) in combination with gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer.
Authors: Hashimoto Yusuke , Ueno Makoto , Tanaka Maki , Ikeda Masafumi 
Published: January 2019

325 Background: Canerpaturev (C-REV, formerly HF10) is an oncolytic, spontaneous mutant Herpes Simplex Virus type 1, and is one of immunotherapies that combine direct tumor cell killing with immune modulation. The purpose of this study is to determine the recommended dose of C-REV in combination with chemotherapy (Gemcitabine + Nab-paclitaxel; G-nP) in Japanese patients with stage III or IV unresectable pancreatic cancer. We report the safety and antitumor activity data of this study. Methods: This study was a “3 + 3” design with a 2-dose escalation scheme evaluating 2 doses of C-REV. The subjects received C-REV at 1x106 or 1x107 TCID50/mL (up to 2mL, depending on tumor size) intratumorally by EUS-guidance at a 2-week interval in addition to 1000 mg/m2 gemcitabine and 125 mg/m2 nab-paclitaxel by intravenous infusion on days 1, 8, and 15 of a 4-week cycle. The study treatment could continue up to 1 year if eligible for injection. The primary endpoint was Dose Limiting Toxicity (DLT); the secondary endpoints were adverse events (AEs) assessed per NCI CTCAE v4.0, Best Overall Response Rate (BORR) at 16-week by RECIST and progression-free survival. Results: Six patients (pts) were enrolled and treated: 33% (2/6) men, age range 63 to 72 yrs, disease stage 33% III, 66% IV. Of 6 safety evaluable pts, no DLTs were reported. 16% (1/6) pt(s) had C-REV-related ≥ G3 AE, and it was acute pancreatitis (G3). G-nP-related ≥ G3 AEs observed in more than 2 pts were neutropenia (50%), and the majority of ≥ G3 AEs were similar as the AEs previously reported in G-nP therapy. As of 01 Sep 2018, of the 6 efficacy evaluable pts, BORR at 16-week was 66% (4 PR). Disease control rate was 100% (2 SD), and 1 of 2 SD pts continues the study treatment. We will present the updated data. Conclusions: The recommended dose was determined as 1x107 TCID50/mL. The combination of C-REV and the standard chemotherapy demonstrated a favorable benefit/risk profile and encouraging antitumor activity in Japanese patients with unresectable pancreatic cancer. Clinical trial information: NCT03252808.
Adjuvant chemotherapy with or without sequential radiation in resected pancreatic adenocarcinoma: Who will win RTOG 0848?
Authors: Shinde Ashwin , Li Richard , Glaser Scott , Raoof Mustafa , Chung Vincent , Singh Gagandeep , Warner Susanne , Chen Yi-Jen , Amini Arya 
Published: January 2019

334 Background: The current role of adjuvant radiation in the management of resected pancreatic adenocarcinoma (PC) is controversial. A prospective trial, RTOG 0848, is currently in process to determine optimal adjuvant therapy, comparing adjuvant chemotherapy (CT) with or without radiation (RT). We determined outcomes in this population using the National Cancer Database (NCDB). Methods: Patients with non-metastatic PC diagnosed from 2004 to 2015 were identified from the NCDB. Patients who underwent surgery and adjuvant chemotherapy were included. Patients who received RT were only included if RT began at least 4 months after CT, to emulate RTOG 0848 schema. A 6 month landmark analysis was performed. Overall survival (OS) was compared using log-rank Kaplan-Meier for univariate analysis (UVA), and Cox proportional hazards for multivariate analysis (MVA). Logistic regression was used to determine predictors of RT utilization and generate propensity scores. Results: We identified 16075 patients. Median follow-up was 30 months, 37 months for survivors. Patients received sequential RT in 9.5% of cases. On UVA, sequential RT demonstrated OS benefit compared to adjuvant chemotherapy alone (3-year OS 44.6% vs 35.3%, p < 0.001). RT utilization was more likely with diagnosis after 2010, age ≤ 65 years, private insurance, higher income, ≤ 10 miles to treatment facility, treatment in the northeast, node positive disease, positive margins, and head of pancreas primary. On MVA, benefit to RT on OS was maintained (HR 0.68, 95% CI 0.63-0.73, p < 0.001). Other factors that improved OS included diagnosis after 2010, no comorbidity, non-government insurance, higher income, and treatment at academic facility. Factors that predicted for worse OS included increasing pathologic tumor and nodal staging, positive margins, and CA 19-9 above a cut-off of 90. After propensity-adjustment, OS benefit was maintained for RT (HR 0.68, p < 0.001). Conclusions: In a large national database analysis, sequential RT improves survival in patients who receive at least 4 months of adjuvant chemotherapy following upfront resection for pancreatic adenocarcinoma. The results of RTOG 0848 are awaited to confirm these findings.
Combined immune checkpoint inhibition (ICI) with tremelimumab and durvalumab in patients with advanced hepatocellular carcinoma (HCC) or biliary tract carcinomas (BTC).
Authors: Floudas Charalampos S. , Xie Changqing , Brar Gagandeep , Morelli Maria Pia , Fioravanti Suzanne , Walker Melissa , Mabry-Hrones Donna , Wood Brad J. , Levy Elliot B , Krishnasamy Venkatesh P , Greten Tim F. 
Published: January 2019

336 Background: Prognosis in advanced HCC and BTC is unfavorable, and 5-year overall survival (OS) rate is less than 20% and 10%, respectively. Single agent ICI in HCC has response rates (RR) of 20%, while early data in BTC reported 17.4% RR. Dual ICI has increased RR in other malignancies. The purpose of this study was to explore the efficacy of the combination of anti-CTLA4 (tremelimumab) with anti-PD-L1 (durvalumab) in advanced HCC and BTC. Methods: Eligible patients with advanced HCC or BTC who had received (or refused) at least one prior therapy, received monthly tremelimumab 75 mg in combination with durvalumab 1500 mg for 4 doses followed by monthly durvalumab 1500 mg monotherapy until progression of disease or unacceptable toxicity. Response was assessed with CT scan every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint is 6-month progression free survival (PFS). Results: Twenty-two patients were enrolled, 10 with advanced HCC and 12 with advanced BTC. Male to female ratio was 14:8, with median age of 62.5 years (range 19-80). Grade 3/4 treatment-related AEs included lymphocytopenia, hyponatremia, bullous dermatitis, maculopapular rash, mucositis, hypophosphatemia, anaphylaxis, dyspnea, pleural effusion, and pain. Twenty patients were evaluable for response analysis. Two patients (2/10, 20%) achieved a confirmed partial response (both with HCC, lasting 6.9 and 17.6 months), while 9 patients (4 [40%] with HCC and 5 [41.7%] with BTC) had stable disease, with the longest duration of 9.3 months (in an HCC patient). Disease control rate is 60% in HCC and 41.7% in BTC, respectively. In this small pilot cohort, median PFS was 3.1 months (95% CI 0.8 to 4.6 months) and median OS was 5.45 months (95% CI 4.60 to 8.3 months) among BTC patients, while HCC patients median PFS was 7.8 months (95% CI 2.6 to 10.6 months) and median OS was 15.9 (95% CI 7.1 to 16.3 months). Conclusions: Combined ICI with tremelimumab and durvalumab is well tolerated and demonstrates promising activity in patients with advanced HCC and BTC. Clinical trial information: NCT02821754.
The association of novel recurrent in-frame gene fusions with prognosis of diffuse gastric cancer.
Authors: Kim Hark K. 
Published: January 2019

34 Background: Among the two histologic subtype of gastric cancer (GC), diffuse gastric cancer (DGC) is increasingly being considered distinct from intestinal type gastric cancer (IGC). Despite the relative importance of DGC, few whole transcriptomic analyses have been performed for this histological subtype. We therefore conducted an RNA-sequencing study to search for novel driver fusions in DGC. Methods: We conducted a whole transcriptomic and targeted RNA sequencing study of 384 Korean DGCs to identify gene fusions that may be novel prognostic markers or therapeutic targets. Targeted DNA sequencing and SNP6.0 array analyses were conducted in parallel. Results: Whole transcriptomic analyses were conducted in 80 discovery dataset tumors collected from young patients with DGC who had not been treated with chemotherapy or radiation. Twenty-five in-frame fusions were associated with DGC, four of which were recurrent in 384 DGCs based on targeted RNA sequencing and RT-PCR sequencing analyses. Three of the four recurrent fusions contained a RhoGAP domain in their 3’ partner genes. Patients with one of these three fusions have a significantly worse prognosis than those without (HR, 2.8 [95% CI, 1.5‒5.3]). The fusion that harbored a PAP2 domain in the 3’ partner gene was also identified as recurrent and poor prognostic in-frame fusions. Overall, RhoGAP and PAP2 domain-containing fusions were present in 7.5% of DGCs, but not in adjacent normal tissue, and clearly defined the worst prognosis subgroup. Their prognostic impact (adjusted HR 4.1 [95% CI, 2.1‒7.9]) was higher than, and independent of, chromosomal instability (CIN) and CDH1 mutation, which we previously identified as the strongest adverse prognostic genomic abnormalities in DGCs (adjusted HRs, 2.5 (1.5‒4.4) and 2.4 (1.3‒4.4), respectively). Our comprehensive in-frame fusion screen also identified several clinically-actionable fusions amenable to ALK or FGFR inhibition, which had not been previously associated with gastric cancer. Conclusions: Our findings may provide novel genomic insights guiding future personalized strategies for managing DGCs, given the strong prognostic impact of RhoGAP and PAP2 domain-containing gene fusions.