bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of survival and objective response (OR) in patients with hepatocellular carcinoma in a phase III study of lenvatinib (REFLECT).
Authors: Kudo Masatoshi , Finn Richard S. , Qin Shukui , Han Kwang-Hyub , Ikeda Kenji , Cheng Ann-Lii , Piscaglia Fabio , Ueshima Kazuomi , Aikata Hiroshi , Vogel Arndt , Lopez Carlos , Pracht Marc , Meng Zhiqiang , Daniele Bruno , Park Joong-Won , Palmer Daniel H. , Dutcus Corina E. , Tamai Toshiyuki , Saito Kenichi , Lencioni Riccardo 
Published: January 2019

186 Background: In REFLECT, Lenvatinib (LEN) demonstrated treatment effect on overall survival (OS) by statistical confirmation of noninferiority to sorafenib (SOR). OR rates for LEN versus SOR were: 24% versus 9% by investigator review and 41% versus 12% by independent review (Kudo et al 2018). Since the relationship between OR and OS in phase III HCC studies is unclear, we explored the relationship between OR and OS in REFLECT. Methods: OR assessed by investigators per mRECIST were used to analyze the association between OR and OS of pts treated with LEN or SOR. The median OS of responders (CR or PR) was compared to that of nonresponders (SD, PD, or UNK/NE) irrespective of treatment. Landmark analyses were performed by OR status at several fixed time points as sensitivity analyses, and the effect on OS was evaluated by Cox regression with OR as a time-dependent covariate, with other prognostic factors. Results: Median OS was 22.4 months for responders and 11.4 months for nonresponders. Hazard ratios (HR) of landmark analyses at 2, 4, and 6 months were 0.75 (95% CI, 0.57–0.98), 0.72 (95% CI, 0.56–0.92), and 0.73 (95% CI, 0.57–0.93). Independent predictors of OS based on unstratified Cox regression are in the table. Conclusions: In REFLECT, OR was an independent predictor of OS in pts with HCC regardless of treatment. The results indicate this correlation is worth further investigation. Clinical trial information: NCT01761266. [Table: see text]
Determination of O-6-methylguanine-DNA methyltransferase by immunochemistry and pyrosequencing as a predictive factor of response to temozolomide in pancreatic neuroendocrine tumors.
Authors: Escala Roberto , Navarro L Miguel , Del Carmen Martínez Sofía , Malmierca Gonzalez Sandra I , Ayuso Martín-Romo Julia , Cigarral García Belén , García Muñoz María , Casado Elía Diego , Barrios Collado Beatriz , Claros Ampuero Juncal , Escalera Martín Elena , Cruz-Hernández Juan J. 
Published: January 2019

195 Background: Temozolomide (TMZ) is an alkylating agent that has shown good results in the treatment of neuroendocrine and central nervous system (CNS) tumors. The loss of O-6-methylguanine-DNA methyltransferase (MGMT) expression by pyrosequencing (PSQ) is a predictive factor of response to treatment with TMZ in high-grade gliomas. However, its predictive value in pancreatic neuroendocrine tumors (pNET) is controversial, and there is no consensus on how to best assess MGMT. The aim was to evaluate the objective response rate in pNET according to the state of MGMT, assessed by PSQ for evaluation of promoter methylation and immunohistochemistry (IHC). Methods: Patients with pNET who were treated with TMZ at the center between 2008 and 2017 were studied retrospectively. Ten patients were included in the study. A deficiency of MGMT was determined by IHC and MGMT promoter methylation by PSQ. For IHC, the cut-off was 10%, defined as negative < 10% of tumor cells positive in the tumor tissue. For the PSQ, the cut-off was 8%, defined as methylated who presented > 8%. Results: A deficiency of MGMT was detected in five patients (50%) by IHC. An MGMT promoter methylation by PSQ was observed in three patients (30%). The IHC results were consistent with PSQ results in only six patients (60%); one patient with methylated MGMT had positive IHC, and three patients had unmethylated MGMT by PSQ unmethylated, IHC negative. PSQ had a high positive predictive value of response because the three patients with MGMT promoter methylation by PSQ presented objective responses (OR). Nevertheless, a low negative predictive power (57%) was observed because three of seven patients with unmethylated MGMT presented OR. Of the five patients with MGMT deficiency by IHC, four (80%) presented OR, suggesting positive predictive value of 80%; however, it also presented a low negative predictive power of 60%. Conclusions: Despite having 100% of the patients with MGMT promoter methylation showing OR in this series, the low negative predictive power suggests that the absence of MGMT deficiency by IHC or MGMT unmethylated by PSQ does not contraindicate the use of TMZ in pNET treatment.
Baseline and longitudinal quantification of lean muscle mass using routine CT measurements prior to resection for pancreatic adenocarcinoma.
Authors: Oberstein Paul Eliezer , Rosario Vilma , Guo Xiaotao , Zhao Binsheng , Genkinger Jeanine M , Kluger Michael D. , Chabot John A. 
Published: January 2019

198 Background: When compared to healthy populations subjects are defined as sarcopenic if they have severe loss of lean muscle mass (LMM). Sarcopenia is associated with poor outcomes in some studies of pancreatic cancer (PDA) but the prevelance remains uncertain in resected patients and there is little data about changes in LMM during neoadjuvant chemotherapy. Muscle mass can be reliably quantified in cancer patients using routine imaging. We analyzed a large cohort of patients undergoing surgery at a high-volume center to quantify LMM at baseline and with treatment, and to determine the association of sarcopenia with tumor histology and outcomes. Methods: We analyzed subjects undergoing surgery for PDA at the Pancreas Center at Columbia University from 2011-2014. We utilized CT scans to measure cross sectional area of muscle at the L3 vertebral body (LMM in cm2) and used height to define a smooth muscle index (SMI-cm/m). Sarcopenia was determined based on SMI < 38.9 for females and < 55.4 for males. In subjects undergoing neoadjuvant chemotherapy, SMI was also calculated on post therapy scans. We collected information on clinical and pathological variables and performed statistical analyses utilizing SAS 9.4 software. Results: Among subjects with available imaging (n = 106) sarcopenia rates at initial staging were high whether they were immediately resectable (52%) or locally advanced (63%). Rates of sarcopenia were higher in males than females (77 vs 38%, p < 0.001). Sarcopenic status was not correlated with survival, tumor stage or grade but was associated with age, gender, and BMI. Among locally advanced subjects who proceeded to surgery after neoadjuvant chemotherapy (n = 40) there was no change in SMI or incidence of sarcopenia following treatment (median 171 days). Conclusions: Sarcopenia is highly prevalent at diagnosis in subjects undergoing surgery for PDA but was not associated with survival, tumor grade or stage in this cohort. Subjects who successfully completed neoadjuvant treatment did not experience significant loss in LMM despite extensive treatment suggesting that lack of change in LMM may assist in predicting favorable response to neoadjuvant therapy in PDA.
Enhancements in pancreatic protocol CT as a prognostic indicator in pancreatic cancer.
Authors: Park Jaewon , Cho In Kuk , Lee Jong-Chan , Lee Jongchan , Kim Young Hoon , Kim Jaihwan , Hwang Jin-Hyeok 
Published: January 2019

216 Background: Pancreatic protocol CT (pCT) is widely used to evaluate stage and resectability of pancreatic ductal adenocarcinoma (PDAC). Recent studies show that CT enhancement patterns are related to the patient’s prognosis in several cancers, however it is not well described that pCT enhancement has prognostic effect in resectable PDAC so far. We aimed to show correlaton between pCT enhancements and prognosis in resectable PDAC. Methods: We retrospectively enrolled 159 patients (median age, 67.8 years) who underwent pCT before curative resection in Seoul National University Bundang Hospital between January 2010 and December 2015, with final pathological diagnosis of PDAC. CT enhancement ratio (CTER) of each primary lesion was calculated as proportional difference between maximum Houndsfield Unit (HU) of pancreatic phase (PP) image and maximum HU of non-contrast image; [(max HU of PP) - (max HU of non-contrast)] / (max HU of non-contrast). Patients were classified into two groups, based on CTER. Kaplan–Meier analysis and Cox proportional hazards models were used to correlate CTER with overall survival (OS) and recurrence free survival (RFS). Results: Median overall survival was 22.0 months during a median follow-up period of 18.5 months. Based on CTER with cut-off value of 1.8, higher (CTER ≥ 1.8) group (N = 43) was compared with lower (CTER < 1.8) group (N = 116) in terms of OS and RFS. Lower group showed significantly shorter median OS (18.5 months versus 39.3 months, P < 0.001) and median RFS (9.9 months versus 21.5 months, P = 0.006) than those of higher group. Multivariate regression analysis showed that lower group had shorter OS (HR 1.70; CI 1.01-2.85, P = 0.044) and RFS (HR 1.84; CI 1.10-3.06, P = 0.019). Conclusions: Our study suggests that lower enhancement in pancreatic phase of pCT is related to poor prognosis in PDAC. Therefore, active surveillance would be required in resected PDAC patients with CTER less than 1.8.
Comparison of biomarkers among 34855 GI cancer samples shows heterogeneity of tumor types.
Authors: Dawood Shaheenah S. 
Published: January 2019

217 Background: Recent data indicate that biomarker driven use of targeted therapy and I/O-therapy among patients with GI cancer is associated with improved outcome. The presence of biomarkers varies broadly between different GI tumor types, highlighting the importance of comprehensive molecular profiling. To analyze the presence of various alterations in GI cancer samples of a large database, comparing congruency between various tumor types. Methods: A retrospective data analysis of 34855 GI cancer patients profiled at CARIS Life Sciences obtained from Jan 1, 2010 till Sep 14, 2018 was performed. GI tumors were classified as CRC, esophageal/gastric/GIST, small intestine, pancreatic/hepatobiliary/liver. Technologies used to analyze the biomarkers: IHC for PD-L1, MMR and Her2, and DNA-NGS for EGFR, BRAF, KRAS, NRAS, MET-CNV, TMB, MSI, POLE and BRCA1/2. Results: Median age was 61 range (18-89 years). 51.5% was CRC (n=18047), 15.5 % was esophageal/Gastric/GIST (n=5470), 3% was small intestinal cancer (n=886) and 30% was pancreatic/hepatobiliary/liver cancer (n=10452). Information on biomarkers was available from 2931 cases for MET amplification to 28536 for RAS mutation. Overall, the most common finding was a pathogenic RAS-mutation in 7650 cases (26.81%), the rarest one was a mutation in EGFR in 12 cases (0.06%). Higher rate of HER2 amplification was observed among pts with esophageal/gastric/GIST tumors (6.5%) in comparison to tumors at other GI sites ( ~1.5%). High TMB was seen among patient with CRC and small intestine tumors (~7%) while it was lowest among pancreatic cancer (1.8%). Compared to other GI sites lower MSI /MMR deficiency rates were observed in pancreatic /hepatobiliary tumors, significantly higher PD-L1 positivity was observed in gastrooesophageal cancer types, increased MET-amplifications in gastrooesophageal and small intestinal cancer types and lower RAS-mutation rate in gastrooesophageal cancer. Conclusions: Molecular profiling analyzing druggable biomarkers can help identify patients with increased likelihood for benefit from immune-checkpoint-inhibitors and targeted therapies. Further investigations are needed to evaluate the different findings in various GI cancer types.
Circulating calprotectin, innate inflammatory protein, was decreased under disease control during first-line chemotherapy for advanced pancreatic cancer.
Authors: Shibuki Taro , Mitsunaga Shuichi , Kan Motoyasu , Kimura Gen , Umemoto Kumiko , Watanabe Kazuo , Sasaki Mitsuhito , Takahashi Hideaki , Hashimoto Yusuke , Imaoka Hiroshi , Ohno Izumi , Ikeda Masafumi 
Published: January 2019

218 Background: There is increasing evidence of a close link between inflammation and disease control in pancreatic ductal adenocarcinoma (PDAC). Damaged-associated molecular patterns (DAMPs) were inducers of inflammation in the innate immune system and were detected in PDAC tissue in recent reports. Calprotectin, one of DAMPs, is recognized as a potential mediator of the process of disease control in various tumors. In this study, circulating calprotectin is characterized on disease control in patients with 1st line chemotherapy for advanced PDAC. Methods: Patients with treatment-naïve advanced PDAC were enrolled in this study. Patients with obvious infectious conditions were excluded. Serum levels of calprotectin and pro-inflammatory cytokines including interleukin-6 (IL-6) were measured at baseline and at one or two months later after the start of 1st line chemotherapy. Disease control rate (DCR) was evaluated on the Response Evaluation Criteria in Solid Tumors ver. 1.1. Results: A total of 73 patients were evaluated. DCRs of gemcitabine group (GEM) (n = 57) and the patients with modified FOLFIRINOX or GEM + nab-paclitaxel (mFFX/GN) (n = 16) were 52.6% and 75.0%,respectively. In comparison of baseline-and-after data, circulating calprotectin levels were significantly decreased under disease control in GEM (baseline vs. after: 2.9 vs. 2.3 ng/ml in median, p = 0.084) and GN/mFFX (2.7 vs. 0.5 ng/ml, p = 0.024. IL-6 was decreased in GN/mFFX (9.1 vs. 5.9 pg/ml; p= 0.095) but not in GEM (4.3 vs. 3.1　pg/ml; p = 0.303). There were no obvious changes under non-disease control in calprotectin (baseline vs. after: 6.2 vs. 5.9 ng/ml in GEM, 5.1 vs. 4.5 ng/ml in mFFX/GN) and IL-6 (16.5 vs. 25.6 pg/ml in GEM, 3.1 vs. 4.7 pg/ml in mFFX/GN). Conclusions: DCR relateda decrease of circulating calprotectin levelduring 1st line chemotherapy for advanced PDAC. Innate immune system plays a role in the chemotherapeutic efficacy in advanced PDAC.
Gastric cancer staging in the era of neoadjuvant therapy and its prognostic implications.
Authors: Kim Gina , Friedmann Patricia , Muscarella Peter , McAuliffe John Christopher , In Haejin 
Published: January 2019

22 Background: Increasingly patients are undergoing neoadjuvant therapy for gastric cancer. The relationship between stage-based prognostic information available prior to treatment (cStage), after surgery (ypStage), and difference between cStage and ypStage (delta) remains unclear. We aim to describe the relationship between cStage and ypStage as relates to survival for gastric cancer patients. Methods: Data from the National Cancer Data Base (NCDB) from 2004-2015 was used for the analysis. Patients with gastric adenocarcinoma who received neoadjuvant therapy then underwent surgery were included. Kaplan Meier curves were used to model survival. Harrell’s C-statistics obtained from Cox Regression models were reported. Results: 9,959 patients met our inclusion criteria. Increases in cStage, ypStage and delta (ypStage-cStage) were associated with worse survival. Median overall survivals for cStages 1-4 were: 53.8, 39.5, 29.2, 20.9 months (logrank test, p<0.0001). Median survivals for ypStage 0-4 were: 95.4, 89.7, 36.9, 23.4, 16.0 months (logrank test, p<0.0001). Survival was further stratified by delta. A representative table comparing cStage 2 and ypStage 2 is shown below. A cox regression model with cStage as predictor of survival yielded a Harrell’s C-statistic of 0.555; when delta was added to the model, the C-statistic increased to 0.638. Separately, a Cox-regression model with ypStage as predictor yielded a C-statistic of 0.632; when delta was added to this model, the C-statistic increased negligibly to 0.638. Conclusions: Prognostic accuracy using cStage prior to treatment improved when tumor responsiveness was considered while this was not the case for ypStage. Pre-surgical prognostic information should be provided with a caveat that treatment response will influence survival. Post-surgery, the clinical stage is less relevant and ypStage can be used alone in providing prognostic information. [Table: see text]
The gastric cancer survivorship experience: A global perspective.
Authors: Raymond Martha Ann , Lustig Craig 
Published: January 2019

24 Background: The World Health Organization estimates 1.03 million new gastric cancer cases will be diagnosed in 2018. Globally, gastric cancer is the 5th most common cancer and the 3rd most common cause of cancer death. Our study explores the gastric cancer survivorship experience throughout the care continuum. Methods: The Ruesch Center for the Cure of Gastrointestinal Cancers and the GI Cancers Alliance developed a global gastric cancer advocacy initiative (December 2017) to better understand the patient experience. As convener, we facilitated numerous meetings with international advocacy organizations; healthcare professionals; patients and caregivers to gain a global perspective. Based on our goal to help improve patient outcomes, our initiative included analysis to support: efforts to increase earlier detection; provide access to best treatment protocols including clinical trials; enhanced patient education and patient-centered communication. A key element of our research began with a global patient survey, focus groups and interviews. Results: 521 gastric cancer patients (54% female 46% male) participated in the international survey (April-May 2018). 49% indicated a ‘poor’ quality of life; 91% indicated survivorship care gaps; 42% were Stage 4. North and South America, Europe, Asia, and Australia were represented. Follow-up interviews and focus groups (July-September 2018) provided valuable insight and a greater understanding of the patient profile. Conclusions: Additional educational and supportive services are needed to meet patient unmet needs. We will continue providing key stakeholder platforms to address patient concerns; create meaningful and relevant patient education; continue outreach leading to increased patient empowerment; convene and work with global partners improving patient quality of life to ultimately achieve better patient outcomes.
Incidence patterns of neuroendocrine neoplasms in California.
Authors: Paciorek Alan , Shih Brandon , McKinley Meg , Cheng Iona , Zhang Li , Mulvey Claire , Griffin Ann , Van Loon Katherine , Bergsland Emily K. 
Published: January 2019

242 Background: Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors that typically account for < 5% of tumors arising in any organ site. Both the low incidence and heterogeneity contribute to the paucity of epidemiologic data regarding risk factors. However, evidence suggests that incidence rates in the U.S. are rising. We aimed to further characterize the burden of NENs in California. Methods: Using data from the California Cancer Registry (CCR), we identified all newly diagnosed NENs arising from pulmonary (including SCLC) and gastrointestinal (GI) sites from 1992-2015. We estimated age-adjusted incidence rates (AIR) standardized to the 2000 U.S. census population. We calculated annual percent change (APC) in AIRs using Joinpoint regression and compared AIRs by sex, race-ethnicity, primary tumor site, and county of residence categorized as urban, suburban or rural using SEER∗Stat. Results: From 1992-2015, 97,398 NENs were reported, with 40,099 GI (not lung or bronchus). Overall AIR was 12.5 per 100,000 person-years. Most NENs were of pulmonary (AIR 7.6) or colorectal (AIR 1.3) origin. Females had lower AIR with IR ratio (IRR) vs. males (0.80 95% CI 0.79-0.81). However, females had higher rates of gastric (IRR 1.22 95% CI 1.12-1.32) and appendiceal (IRR 1.19 95% CI 1.07-1.33) primaries vs. males. Compared to non-Hispanic (NH) whites, NH blacks had an IRR of 1.06 (95% CI 1.03-1.09), Asian/Pacific Islanders had an IRR of 0.46 (95% CI 0.45-0.48), and Hispanics had an IRR of 0.57 (95% CI 0.56-0.58). For all NEN subtypes, we estimated lower rates for residents of urban counties (IRR 0.83 95% CI 0.80-0.86) and suburban counties (IRR 0.94 95% CI 0.90-0.97) vs. rural counties. However for GI NENs, we estimated higher rates for residents of suburban counties (IRR 1.11 95% CI 1.03-1.18) and urban counties (IRR 1.10 95% CI 1.03-1.18) vs. rural counties. We found that rates of pulmonary NENs decreased since 1992 (APC -2.6), but rates increased in colorectal (APC 3.9) and all other GI primaries (all APCs ≥ 2.8). Conclusions: Based on these results we conclude that incidence rates for GI NENs reported to CCR steadily increased from 1992-2015. Residence in a suburban or urban county was associated with increased incidence of GI NENs. Additional analyses are ongoing.
A systematic review and network meta-analysis of adjuvant therapy for curatively resected biliary tract cancers.
Authors: Kish Maxine , Chan Kelvin K. , Perry Kaitlyn , Ko Yoo-Joung 
Published: January 2019

247 Background: Although recently completed randomized controlled trials (RCTs) have added high-quality data regarding adjuvant therapy in curatively resected biliary tract cancer (BTC), there is still no standard approach to manage these patients. We conducted a systematic review and network meta-analysis to compare the efficacy of adjuvant therapy regimens in curatively resected BTC to help guide clinical decision making and the design of future prospective trials. Methods: We conducted a systematic review of published studies and abstracts up to and including June 2018. Studies were included if they were phase III RCTs on patients with histologically proven BTC receiving adjuvant chemotherapy after a complete surgical resection (R0 or R1). BTCs included gallbladder cancer, intrahepatic and extrahepatic cholangiocarcinoma. The endpoints of interest were overall survival (OS) and relapse-free survival (RFS). Network meta-analysis methods were used for indirect comparison between adjuvant therapy regimens. Results: Five RCTs were included in the qualitative synthesis and three RCTs (BILCAP, PRODIGE 12-ACCORD 18 and BCAT) included sufficient data to be included in the meta-analysis. Results from the indirect comparison demonstrated no significant difference in OS between any of the adjuvant therapy regimens, however there was a trend that favoured adjuvant therapy with capecitabine over gemcitabine or gemcitabine plus oxaliplatin (GEMOX), with hazard ratios (HRs) of 0.82 (95% CI, 0.53-1.27) and 0.86 (95% CI, 0.56-1.34), respectively. Similarly there was no significant improvement in RFS with capecitabine compared to gemcitabine or GEMOX with HRs of 0.82 (95% CI, 0.53-1.27) and 0.86 (95% CI, 0.56-1.34), respectively. Conclusions: Although capecitabine is considered to be standard of care in the adjuvant setting based on a single randomized phase III study, in this indirect comparison, we did not find a statistically significant improvement in OS or RFS with capecitabine compared to GEMOX or gemcitabine. Further prospective trials comparing adjuvant therapies to capecitabine are warranted.