bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjuvant chemotherapy (AC) for stage III colorectal cancer (CRC) in the elderly: An Irish experience.
Authors: Harrold Emily , Greally Megan , Peters Niamh , Sui Jane Sze Yin , McCaffrey John 
Published: February 2020

54 Background: Since 2004 6 months of adjuvant Oxaliplatin containing regimens (OCR) has been standard of care for Stage III CRC despite cumulative neurotoxicity. The IDEA collaboration evaluated 3 versus 6 months of OCR in high/low risk pts with regard to peripheral neuropathy (PN) and efficacy.The median pt age was 64; individual studies included pts ≤85. Methods: This study is part of a retrospective review of the clinicopathological records of consecutive CRC pts referred to the multi-disciplinary CRC team at an Irish tertiary referral centre from 2002-2018. We recorded pt characteristics, Rx received and outcomes. Overall Survival (OS) was assessed using Kaplan-Meier analysis. Results: 869 pts were identified; 37% (328) female. 63% (551/869) < 70 and 37% (318/869) ≥ 70. Median OS for < 70 cohort was 31.5 months versus 19 months in ≥ 70 cohort (p < 0.0001).Stage distribution in < 70: ≥70 cohorts was Stage II 14%( 79/551):20% (63/318), Stage III 47% (260/55):46% (142/318) and Stage IV 38% (207/551):34% (111/318). In < 70 Stage III cohort 7% (37/551) pts received no AC, 42%(230/551) received FOLFOX, 3%(16/551) received FLOX or XELOX, 7%(38/551) received 5FU/LEU. 32%(78/246) of pts < 70 developed PN with persistence at 6 months in 18%(44/256). In ≥ 70 Stage III cohort 58%(83/142) did not received AC. 23%(32/142) received an OCR and 16%(23/142) received 5FU/LEU; there was a statistically significant survival difference with an OCR. 47% (15/32) of pts ≥70 receiving OCR developed PN which persisted at 6 months in 28% (9/32). In < 70 cohort there was no significant survival difference in the IDEA-trial-defined low risk group between 12 versus < 12 FOLFOX. There was a numerical survival difference in the < 70 high risk group between 12 versus < 12 FOLFOX; this was not statistically significant. In the ≥70 age group there was no survival difference in either IDEA risk groups for 12 versus < 12 FOLFOX. Conclusions: > 50% of Stage III CRC patients ≥ 70 did not receive AC. OCRs were associated with a significant OS improvement but with higher PN than in < 70 cohort and higher persistence at 6 months. Irrespective of IDEA-defined risk groups,there was no statistically significant survival difference for Stage III CRC ≥70 receiving 12 versus < 12 FOLFOX.
Capecitabine and cisplatin as a second-line chemotherapy for patients with advanced biliary tract cancer.
Authors: Shin Kabsoo , Lee In Seok , Hong Tae Ho , Kim Joori , Lee Myung Ah 
Published: February 2020

543 Background: Few data are available on second-line chemotherapy for patients with advanced biliary tract cancer. We retrospectively analyzed the efficacy and safety of capecitabine and cisplatin combination as second-line chemotherapy for advanced biliary tract cancer. Methods: Between Mar, 2014 and Dec, 2018, advanced BTC patients who received second-line capecitabine and cisplatin after the failure of the gemcitabine-platinum combination were analyzed. Progression‐free survival (PFS) and overall survival (OS) were estimated with the Kaplan‐Meier method. Cox models were used for multivariate analyses. Results: Of total 40 patients, male: female was 24(60%) to 16(40%), and the median age was 68 years old (range: 45-77) . As primary tumor site, 8(20%) was intrahepatic, 16(40%) was extrahepatic and 16(40%) was gallbladder. Initially metastatic disease was 22(55%), and recurrent disease after curative surgery was 17(42.5%) and locally advanced unresectable disease was 1(2.5%). 30(75%) patients had ECOG performance status of 0-1. The mean number of the chemotherapy cycles was 3.3 ± 2.0. Objective response rates and stable disease were 12.5% and 25%, respectively. Median PFS and median OS from the beginning of the capcitabine and cisplatin combination were 2.8 and 7.0 months, respectively. Grade 3-4 adverse event were neutropenia (n = 7, 17.5%), anemia(n = 3, 7.5%), hand-foot syndrome (n = 3, 7.5%), nausea and vomiting(n = 2, 5%), peripheral neuropathy (n = 2, 5%) and mucositis(n = 1, 2.5%). And there was no treatment related death. Conclusions: This study showed the possible survival benefit of capecitabine and cisplatin combination as second-line chemotherapy for advanced biliary tract cancer.
Pattern of progression in advanced HCC treated with ramucirumab/placebo: Results from two randomized phase III trials (REACH/REACH-2).
Authors: Reig Maria , Galle Peter R. , Kudo Masatoshi , Finn Richard S. , Llovet Josep M. , Schelman William R. , Liang Kun , Wang Chunxiao , Widau Ryan C. , Abada Paolo , Zhu Andrew X. 
Published: February 2020

544 Background: REACH (NCT01140347) and REACH-2 (NCT02435433) studied ramucirumab (RAM) in pts with advanced hepatocellular carcinoma (HCC) following sorafenib; REACH-2 enrolled pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL, and met its primary endpoint of overall survival (OS) for RAM vs placebo. This post-hoc analysis examined radiological progression patterns (RPP) incidence every 6 weeks per RECIST v1.1, and if RPP were related to OS and post-progression survival (PPS). Methods: Pts with advanced HCC, Child-Pugh A, and ECOG PS 0-1 with prior sorafenib were randomized (REACH 1:1; REACH-2 2:1) to receive RAM 8 mg/kg or placebo Q2W. Among pts with ≥1 RPP (new extrahepatic lesion [NEH], new intrahepatic lesion [NIH], extrahepatic growth [EHG], or intrahepatic growth [IHG]), results were analyzed by trial and for pooled individual patient data of REACH-2 and REACH (AFP ≥400 ng/mL). Cox models evaluated treatment effect of RPP on OS, and prognostic implications of RPP on OS (adjusting baseline ECOG PS, AFP, macrovascular invasion, arm) and on PPS (adjusting ECOG PS, AFP at progression). Results: RPP incidence in the pooled population was: NEH 39%; NIH 24%; EHG 39%; IHG 37%. When examining NEH vs other RPP, PPS was worse among those with NEH in REACH (HR 2.33, 95% CI 1.51, 3.60), REACH-2 (HR 1.49, 95% CI 0.72, 3.08), and the pooled data (HR 1.75, 95% CI 1.12, 2.74). Use of post-discontinuation therapy may have influenced results. OS was also significantly reduced in those with NEH across studies (Table). RAM provided OS benefit in the pooled population, including pts with NEH (HR 0.56, 95% CI 0.39, 0.80). Conclusions: Acknowledging limitations of post-randomization RPP analysis, the emergence of NEH on RAM or placebo may be an independent poor prognostic factor for PPS. The impact of RAM on OS was consistent across all RPP subgroups. Clinical trial information: NCT01140347 and NCT02435433. [Table: see text]
Exploring the genomic landscape of hepatobiliary cancers to establish a novel molecular subtype classification.
Authors: Scholer Anthony Joseph , Garland-Kledzik Mary , Ghosh Debopyria , Santamaria-Barria Juan , Khader Adam , Orozco Javier , Goldfarb Melanie , Marzese Diego M. 
Published: February 2020

562 Background: The current understanding of the genomic landscape of hepatobiliary cancer (HBC) is limited. Recent genomic and epigenomic studies have demonstrated that various cancers of different tissue origins can have similar molecular phenotypes. Therefore, the aim of this study is to evaluate the genomic alterations of HBCs as a first step towards creating a novel molecular subtype classification. Methods: A multidimensional analysis of next-generation sequencing for the genomic landscape of HBCs was conducted using mutational data from the AACR-Genomics Evidence Neoplasia Information Exchange database (v. 5.0). From 61 gene mutation platforms, we found 42 genes common to all HBC cases. Associations between histomolecular characteristics of HBCs (hepatocellular (HCC), cholangiocarcinoma (CCA), and gallbladder carcinoma (GBC)) with gene mutations (classified by COSMIC CENSUS) were analyzed using Pearson’s χ2 test. Results: A total of 1,017 alterations were identified in 61 genes (516 missense variant, 157 gene amplifications, 101 inactivating mutations, 106 truncating mutations, 84 upstream gene variants, 37 gene homozygous deletions, 16 gene rearrangements) in 329 patients: 115 (35%) CCA, 87 (26.4%) GBC, and 127 (38.6%) HCC. The majority 77.8% (256) of tumors harbored at least two mutations and 38.9% (128) had at least one alteration, with GBC having a higher average number of alterations (3.28) than HCC (3.23) and CCA (2.49) However, HCCs had the higher maximum number of alterations compared to CCA and GBC (p < 0.05). The ten genes most frequently altered across all the HBCs were TP53, TERT, CTNNB1, KRAS, ARID1A, CDKN2A, IDH1, PIK3CA, MYC, and SMAD4 with disparities in the distribution of genes altered repeatedly observed (p < 0.001). IDH1 mutations were associated with CCA, CTNNB1 and TERT mutations with HCC, and TP53 mutations with both HCC and GBC. Conclusions: HBC subtypes appear to have unique mutational landscapes, but also significant overlap of genetic signatures. Therefore, further exploratory genetic and epigenomic research is needed to develop a histomolecular classification algorithm that can be used for prognostic and therapeutic stratification of these cancers.
Hepatocyte-derived intrahepatic cholangiocarcinoma requires Yap and Sox9: A clinical and preclinical analysis.
Authors: Monga Satdarshan , Ko Sungjin , Molina Laura , Tao Junyan , Singhi Aatur D. , Bell Aaron 
Published: February 2020

582 Background: Intrahepatic cholangiocarcinoma (ICC) is a liver tumor of increasing incidence and devastating prognosis. WGS and WES have identified numerous molecular pathways and fusions in ICC. Recent studies have also suggested hepatocyte as a cell source in a subset of ICCs, especially those associated with chronic liver insult such as non-alcoholic steatohepatitis (NASH) or primary sclerosing cholangitis (PSC). Methods: Since co-expression of myristoylated AKT (myrAKT) & Notch intracellular domain (NICD) in hepatocytes using sleeping beauty transposon/transposase-based hydrodynamic tail vein injection (SB-HTVI) lead to ICC, we initiated a comprehensive analysis of mechanism of ICC development in patients and in this preclinical model. Results: Over 90% of CC samples exhibited high levels of nuclear SOX9 & YAP, in addition to a significant positivity for pAKT in ICCs as compared to extrahepatic CC. We also identified upregulation of p-AKT, SOX9 & YAP in hepatocytes of patients with PSC and NASH. This was also seen in many murine models of cholestatic injury and NASH. While co-expression of myrAKT+NICD led to hepatocyte-derived ICC, conditional deletion of either Yap or Sox9 significantly delayed and almost completely abrogated ICC development. While Yap deletion impaired the initial HC-to-BEC fate conversion, Sox9 elimination had no such effect on reprograming. Interestingly, following deletion of either Yap or Sox9 we observed a few AKT/NICD-driven ICC tumors expressing either Sox9 or Yap but not both. This also occurred in a small subset of human CC tumors which may be Sox9+Yap- (4%) or Sox9-Yap+ (3.7%), showing that deletion of Yap or Sox9 is not sufficient to completely abrogate ICC development. We finally demonstrated that conditional deletion of both Yap & Sox9 completely blocked development of ICC tumors in the myrAKT+NICD model. Conclusions: Thus, we show that cholestatic injury or NASH in humans and mice induces hepatocyte-to-cholangiocyte reprograming to increase the risk of ICC development. We also provide evidence for critical but distinct roles of Yap and Sox9 in ICC development and demonstrate the therapeutic potential of targeting these factors for treatment of subsets of ICC.
Evaluation of the current treatment strategies for pancreatic neuroendocrine tumors.
Authors: Meredith Kenneth Lee , Maramara Taylor , Blinn Paige , Huston Jamie , Shridhar Ravi 
Published: February 2020

611 Background: The management of pancreatic neuroendocrine tumors (PNET) varies between observation (O), pancreatic resection (PR) and enucleation (E). Currently, size, grade and location are used to determine which treatment strategy may be employed. We sought to evaluate each strategy and further clarify the role for surgery. Methods: Utilizing the National Cancer Database we identified patients with pancreatic neuroendocrine tumors. Tumors were stratified based upon size <1cm, 1-2cm and >2 cm. Mann-Whitney U and Kruskal were used to compare continuous variables and Pearson’s Chi-square test was used to compare categorical variables. Unadjusted survival analyses were performed using the Kaplan-Meier method. Multivariate analysis (MVA) was performed to identify predictors of survival. All statistical tests were two-sided and p<0.05 was considered significant. Results: We identified 17,921 patients. (<1cm, 1214, 1-2cm, 4325, and >2cm, 12,382) with a median age of 61.5 (18-90). Males more often presented with tumors >2cm, 56% vs 44%, <0.001. Tumors >2cm were more likely to be poorly differentiated (PD), p<0.001, have node positive disease, p<0.001 and less likely to undergo R0 resection, p<0.001. Tumors <1cm and well differentiated (WD) the median and overall 5-year survival in the O group was not reached (NR) (77%) vs 142.6 months (87%) in the surgery groups, p<0.04; in the 1-2 cm WD group 95.7 months and 60% vs NR and 94%, p<0.001. Similarly in the PD tumors <1cm the median and overall survival was 32.9 months and 24% in the O vs NR and 81%, p<001; in the 1-2 cm group 14.8 months and 19% vs NR and 73%, p<0.001. There were no differences in survival in patients undergoing PR or E, p=0.09. MVA revealed age, grade, Charleson Deyo score, tumor size, tumor location, and surgery (PR or E) were all independent predictors of survival. Conclusions: While observation is currently an acceptable option for the management of small <1cm WD PNET, we found an improvement in survival in the patients undergoing surgery. Additionally, 1-2 cm PNET benefited from the surgical approach. Enucleation and pancreatic resection did not differ in overall survival. Surgery for PNET should be considered as the first line treatment of these patients.
Exploring telotristat ethyl’s antiproliferative effects in patients with carcinoid syndrome (TELEACE): A real-world observational study.
Authors: Morse Michael , Liu Eric , Joish Vijay N. , Huynh Lynn , Cheng Mu , Totev Todor , Duh Mei S. , Lapuerta Pablo , Metz David C. 
Published: February 2020

618 Background: Serotonin may have proliferative effects on neuroendocrine tumors (NETs). Inhibition of tryptophan hydroxylase (TPH), with resulting reduction of serotonin, may impact tumor size and growth (TG) in patients with NETs. We investigated the effects of TPH inhibitor telotristat ethyl (TE) on TG among patients receiving TE in clinical practice. Methods: A chart review study of 200 patients who had initiated TE was conducted. All patients had ≥2 radiological scans in the past 12 months prior to TE initiation and ≥1 scan post-TE initiation. Data were collected via a secure online portal. Descriptive statistics summarized physician and patient characteristics, and documented background NET treatment (i.e., somatostatin analog [SSA] and/or non-SSA). Longitudinal analyses of TG were assessed using a generalized linear regression model after controlling for documented background NET treatment and time since first scan. Results: Most physicians (71/114) were community-based oncologists. On average, patients were 61 ± 10 years old when initiating TE, 57% male, and 74% white; 61% had well-differentiated tumor with 61% of gastrointestinal origin. Patients received TE for an average of 12.0 ± 7.3 months and 82% (n = 163) were still receiving TE treatment at the time of data collection. The mean time from first scan to TE initiation was 5.6 ± 4.7 months and from TE initiation to last scan was 7.2 ± 6.3 months. Significant mean reductions in tumor size, after TE initiation, of 0.6 cm (p = 0.006) and TG of 8.5% (p = 0.045) were observed. Documented background NET treatment prior to initiating TE and time since first scan were not significant predictors of TG reduction. Results were consistent in a subset (n = 65) of patients who had no change in documented background NET treatment before and after initiating TE (mean reductions in tumor size 0.6 cm, p = 0.044 and TG 8.1%, p = 0.203). Conclusions: Treatment with TE may impact TG in patients with NETs. Prospective clinical studies are warranted to further examine the antiproliferative effects of TE.
Incidence and survival patterns of pancreatic neuroendocrine tumors over the last two decades: A SEER database analysis.
Authors: Sonbol Mohamad Bassam , Mazza Gina L. , Starr Jason Scott , Hobday Timothy J. , Halfdanarson Thorvardur Ragnar 
Published: February 2020

629 Background: Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms with outcome varying by stage, grade, and clinical presentation. We present an analysis of the epidemiology and prognosis of patients (pts) with PNETs over the last two decades using a large population-based database. Methods: Using 2000-2016 data from the SEER 18 registry, we identified pts with PNETs using a combination of ICD-O-3 and histology codes. Age-adjusted incidence rates were calculated using SEER*Stat 8.3.5. Using SAS 9.4, overall survival (OS) was analyzed using the Kaplan–Meier method, and prognostic factors were investigated using a multivariate Cox proportional hazards model. Results: We identified 8,944 pts with PNETs. Annual incidence rates increased over the study period from 0.27 to 1.00 per 100,000. This was largely explained by a significant increase in number of pts diagnosed with localized disease in recent years (2012-2016). Median OS (mOS) for the entire cohort was 68 months (95% CI 64-73) and 5-year OS rates in localized, regional, and metastatic disease were 83%, 67%, and 28%, respectively. There was a significant improvement in OS for pts diagnosed between 2009-2016 (mOS 85 months) compared to those diagnosed between 2000-2008 (mOS 46 months) (HR 0.66; p < .001). In addition, pts with grade I/II metastatic disease who underwent surgery experienced significantly longer OS (mOS 84 months) compared to those who did not undergo surgery (mOS 18 months) (HR 0.31; p < .001). In the multivariate analysis, more recent diagnosis, younger age, female sex, surgery, early stage, and lower grade favorably predicted OS. On the other hand, functional status and race did not predict OS. Conclusions: There has been a steady increase in the incidence of PNETs with notable stage migration as most patients are diagnosed in early stages of disease in recent years. Additionally, this increase in incidence is accompanied by a significant improvement in survival across different disease stages.
Causes of death following neuroendocrine tumors diagnosis: A United States population-based analysis.
Authors: Saad Anas M. , Halfdanarson Thorvardur Ragnar , Sonbol Mohamad Bassam 
Published: February 2020

630 Background: Neuroendocrine tumors (NET) are heterogeneous in terms of prognosis based on location, grade, and stage. In this study we report causes of deaths (COD) in patients with NET. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) Program to query data of NET patients diagnosed between 2000 and 2016 and report COD following NET diagnosis. Results: We reviewed 94,399 NET cases of which 38,692 died during the follow-up period. The highest number of deaths (5,721) occurred within less than a year following grade 3 (G3) NET diagnosis while most deaths in grade 1/2 (G1/G2) cases occurred within 1-5 years of diagnosis (1,889 and 987, respectively). During the first year of diagnosis, most deaths were from NETs (73%), followed by other cancers (11.2%) and cardiac diseases (CD) (4.6%). As time passed, NET deaths decreased to be responsible for 24.3% of deaths after > 10 years of diagnosis, while other cancers (14%) and CD (19.7%) became more common. When dividing NET cases by grade, NETs were responsible for 42.8%, 63.4%, and 81.2% of deaths in G1, G2, and G3, respectively, while other cancers were responsible for 16.2%, 11.8%, and 7.2% of deaths, respectively and CDs were responsible for 12.3%, 7.2%, and 3.2% of deaths, respectively. For G1 localized NET: non-NET cancers (22.2%) was the most common COD followed by NET (19.7 %) and CD (16.8%). For G2 localized NET, NET was COD in 31.1% of cases followed by non-NET cancers (22.4%) and CD (13.8%). In metastatic disease, NET was the most common COD regardless of grade. Conclusions: In G1 and G2 localized NET, deaths were mostly secondary to non-NET causes. Therefore, counseling patients regarding survivorship with cancer-screening and focusing on prevention from non-cancer deaths is important. On the other hand, NET is responsible for most deaths in metastatic NET regardless of grade. Further advances in systemic therapies are needed to improve the outcomes of advanced disease.
Randomized Phase III Study of FOLFOX Alone and with Pegilodecakin as Second-line Therapy in Patients with Metastatic Pancreatic Cancer (SEQUOIA).
Authors: Hecht J. Randolph , Lonardi Sara , Bendell Johanna C. , Sim Hao-Wen , Macarulla Teresa , Lopez Charles D. , Van Cutsem Eric , Martin Andres J. Munoz , Park Joon Oh , Greil Richard , Lin Yong , Rao Sujata , Ryoo Baek-Yeol 
Published: February 2020

637 Background: Effective therapies are limited for advanced metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) who have progressed after 1st line gemcitabine-based chemotherapy (Gem). FOLFOX has clinical benefit in Gem-refractory PDAC pts. A phase 1 trial demonstrated promising activity with pegilodecakin (PEG; pegylated IL-10) and FOLFOX in Gem-refractory PDAC pts, providing rationale for the phase 3 trial (SEQUOIA; NCT02923921). Methods: SEQUOIA is a randomized phase 3 study of FOLFOX alone or with PEG in Gem-refractory PDAC pts. Pts were randomized 1:1, excluding pts with prior surgery and radiation, and received FOLFOX ( dI-Leucovorin [400 mg/m2], oxaliplatin [85 mg/m2] followed by bolus 5-FU [400 mg/m2], and a 46-48 hr infusion of 5-FU [2400 mg/m2]) on day 1 of a 14-day cycle up to 12 cycles. PEG + FOLFOX arm received PEG (0.4 mg/d if ≤80kg and 0.8mg/d if > 80 kg) on Days 1-5 then Days 8-12 + FOLFOX. Pts could continue PEG monotherapy (0.8mg/d if ≤ 80 kg and 1.6 mg/d if > 80 kg) after FOLFOX discontinuation. Primary objective was OS. Secondary objectives included PFS, ORR per RECIST 1.1, and safety. Assuming OS HR of 0.74, the study was powered to 85% at 2-sided α = 0.05 with ~566 pts to detect superiority of PEG + FOLFOX. Results: As of Sept 9, 2019, 567 pts were randomized to PEG + FOLFOX (283) or FOLFOX (284). The majority (94.7%) had 1st line Gem+nab paclitaxel. The mOS was similar between FOLFOX + PEG arm [5.8 months] and FOLFOX arm [6.3 months] with HR = 1.045 (95% CI [0.863, 1.265], p = 0.6565). No statistical difference was observed for PFS, mPFS was 2.1 months in both arms with HR = 0.981, (95% CI [0.808, 1.190], p = 0.8144). ORR was 4.6% on the PEG+FOLFOX arm and 5.6% on the FOLFOX arm. Grade ≥3 adverse events that were 5% higher on the PEG+FOLFOX arm included thrombocytopenia (25.2% vs. 3.6%), anemia (16.2% vs. 4.0%), neutropenia (29.5% vs. 22.7%), and fatigue (17.6% vs. 10.8%). Conclusions: The addition of PEG to FOLFOX did not improve efficacy (OS, PFS, ORR) in advanced PDAC pts who have progressed after 1st line Gem-containing therapy. Safety findings were consistent with previous data observed from PEG + chemotherapy; toxicity was manageable and tolerable. Clinical trial information: NCT02923921.