bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nomogram for predicting overall survival (OS) in patients (pts) treated with liposomal irinotecan (nal-IRI) ± 5-fluorouracil/leucovorin (5-FU/LV) in metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy in NAPOLI-1.
Authors: Wang-Gillam Andrea , Hubner Richard , Mirakhur Beloo , de Jong Floris A , Belanger Bruce , Chen Li-Tzong 
Published: January 2019

459 Background: Results from NAPOLI-1 (NCT01494506), a phase 3 study in pts with mPDAC previously treated with gemcitabine-based therapy, demonstrated an improvement in OS (primary endpoint), progression-free survival, and objective response rate with nal-IRI+5-FU/LV vs 5-FU/LV. The MPACT study reported a nomogram to predict OS using baseline pt variables in previously untreated mPDAC. We conducted an exploratory post hoc analysis of NAPOLI-1 variables to develop a nomogram to predict OS in the post-gemcitabine setting. Methods: In NAPOLI-1, pts were randomized to receive nal-IRI 80 mg/m2 q2w + 5-FU/LV, nal-IRI 100 mg/m2 q3w, or 5-FU/LV. Univariate and multivariate analyses determined factors significantly predictive of OS. A multivariable Cox model was created using these factors to develop a nomogram that assigned points equal to the weighted sum of relative significance of each variable. Predictive accuracy of the nomogram as measured by the concordance index (c-index) was evaluated by internal bootstrap validation. Results: Data from the 417-pt univariate analysis and 399-pt multivariate analysis (18 pts excluded for missing baseline data) were used. Eight of 21 variables were retained in the multivariate analysis (p < 0.01 except BMI [p=0.08]). Conclusions: In NAPOLI-1, predictors of OS were nal-IRI+5-FU/LV treatment, KPS, NLR, albumin level, baseline CA19-9, stage 4 at diagnosis, BMI, and presence of liver metastasis. The nomogram, which will distinguish between risk groups and may aid in clinical decision making, will be presented in the poster. Clinical trial information: NCT01494506. [Table: see text]
Identification and validation of a novel drug target in an organoid model of esophageal cancer.
Authors: Shukla Navika , Salahudeen Ameen Abdulla , de la O Sean , Hart Daniel James , Taylor Gregory , Zhu Junjie , Yuki Kanako , Seoane Jose , Ma Zhicheng , Ding Jie , Han Kyuho , Morgens David , Bassik Michael , Curtis Christina , Kuo Calvin Jay 
Published: January 2019

46 Background: Esophageal squamous cell carcinomas remains a particularly intractable disease due to limited therapeutic options as well as a lack of targeted therapies. The genetic landscape of esophageal squamous cell carcinoma is varied, but a common means of tumorigenesis in squamous cancers are alterations in copy number of putative oncogenic loci that result in upregulated mRNA. Within this subset of loci with copy number alterations, however, it has been difficult to distinguish between driver and passenger mutations using traditional in vitro models. Methods: We functionally screened a data set of amplified “outlier” candidates nominated through a bioinformatics pipeline that scored chromosomal amplifications with linked mRNA overexpression. Screening and validation was performed in a novel three-dimensional organoid model of esophageal squamous cell carcinoma that served as a tabula rasa by virtue of a single p53 null alteration. Results: Functional screening uncovered a novel oncogenic mechanism that serves to drive esophageal squamous cell cancer tumorigenesis both in vitro and in vivo when subcutaneously transplanted into immunodeficient mice. In addition, pharmacologic perturbation of this mechanism resulted in attenuation of the oncogenic phenotype in vitro. Conclusions: We have paired bioinformatics analysis of TCGA data with a p53 null organoid model to functionally validate a novel driver mechanism of esophageal squamous cell carcinoma. Studies are underway to translate these findings and hopefully generate additional therapeutic strategies for esophageal squamous cell carcinoma patients.
Subgroup analysis by measurable metastatic lesion (ML) number and selected lesion locations (LL) at baseline (BL) in NAPOLI-1: A phase III study of liposomal irinotecan (nal-IRI)±5-fluorouracil/leucovorin (5-FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy.
Authors: Siveke Jens T. , Hubner Richard , Macarulla Teresa Mercade , Wang-Gillam Andrea , Dean Andrew Peter , Blanc Jean-Frédéric , Cunningham David , Mirakhur Beloo , Belanger Bruce , de Jong Floris A , Chen Li-Tzong 
Published: January 2019

460 Background: We report a post hoc, exploratory analysis of pts with BL ML number and LL data who received nal-IRI+5-FU/LV, nal-IRI or 5-FU/LV in NAPOLI-1, a pivotal, phase 3 trial (NCT01494506). nal-IRI+5-FU/LV increased median OS (mOS) vs 5-FU/LV (6.1 vs 4.2 mo [HR=0.67; p=0.012]). Methods: ML (1, 2, 3, >3) and LL were recorded (local investigator) at BL. Pts with >1 LL were counted for each location. Results: 354 of 417 ITT pts had measurable BL ML and 1,080 LL were recorded. There was no clear trend in the percentage of pts with KPS ≥80 in 1- >3 ML (range 87%-95%) or LL (range 89%-94%) subgroups. ML 1 (n=81), 2 (n=65) and 3 (n=24) subgroups were small. nal-IRI+5-FU/LV significantly improved mOS vs. 5-FU/LV in pts with 2/>3 ML (n=184/24); nal-IRI+5-FU/LV had numerically higher mOS vs. 5-FU/LV for all LL (Table). nal-IRI+5-FU/LV had favourable median PFS (mPFS) vs. 5-FU/LV in pts with 1–>3 ML (range 2.0-4.2 vs. 1.4-1.9 mo; HR range 0.35-0.88) and for all LL (range 2.8-4.2 vs. 1.4-2.0 mo; HR range 0.39-0.55). Conclusions: Low pt numbers across groups and repeat counting of pts in LL subgroups preclude firm conclusions on treatment efficacy, pending further analyses. Allowing for these limitations, we detected no clear prognostic effect on outcomes of higher BL ML number or LL in NAPOLI-1 ITT pts. nal-IRI+5-FU/LV improved mOS vs. 5-FU/LV in some ML groups and across LL groups; improvement in mPFS vs. 5-FU/LV in the ITT population was maintained in all subgroups. Clinical trial information: NCT01494506. [Table: see text]
Ampullary adenocarcinoma: A single center experience.
Authors: Henry Jason , Iyer Pritish , Garberich Ross , Davis Sarah Lindsey , Lieu Christopher Hanyoung , Meguid Cheryl Lauren , Edil Barish H. , Leong Stephen 
Published: January 2019

462 Background: Ampullary adenocarcinoma (AC) is a rare clinical entity representing only 0.2% of gastrointestinal malignancies. While outcomes are superior compared to other hepatobiliary cancers, mortality remains high. There is limited data to guide clinical decisions regarding adjuvant therapy, largely extrapolated from other hepatobiliary cancers. We evaluated treatment strategies and variables associated with survival in patients with AC. Methods: We retrospectively reviewed 54 consecutive patients with pathologically proven AC between January 2012 and August of 2015. Demographic data, adverse prognostic features and adjuvant treatment patterns were examined using a cox univariate hazard model for predictors of overall survival (OS). There were 5 patients who had metastatic disease on presentation who were included for markers of poor prognosis but excluded from treatment analysis. Results: The average age was 64.7 years with 50% male. Treatment strategy included 40.8% surgery alone, 44.9% adjuvant chemotherapy (CT) and surgery, 14.2% chemoradiation (CRT) and surgery while only 1 patient did not have surgery. Open surgical whipple (n = 28) was most frequent followed by laparoscopic whipple (n = 18) and endoscopic resection (n = 2). The two most common chemotherapeutic agents were single agent gemcitabine (74%) and capecitabine plus oxaliplatin. (7%). At time of last follow-up, 20 (37%) patients had died with a median follow-up of 16.8 months (range 1.9 to 47.4). Older age (HR [95% CI]: 1.05 [1.02, 1.09]; p = 0.002), Stage III (6.75 [1.40, 32.53]; p = 0.017), Stage IV (32.44 [32.44, 216.92]; p < 0.001), N stage 1 (8.52 [2.44, 29.67]; p = 0.014), lymphovascular invasion (LVI) (4.80 [1.54, 15.00]; p = 0.007), and peri-neural invasion (PNI) (3.835 [1.197, 12.29]; p = 0.024) were all associated with poor OS. There was no difference in OS between histologic subtype, surgery type, adjuvant CT or CRT. Conclusions: There was no difference in OS between adjuvant CT or CRT, or between surgical modalities. Despite being administered more frequently in patients with adverse prognostic features including LVI, PNI and advanced stage, adjuvant CT or CRT was equivalent to no adjuvant therapy.
Significance of hypoxia inducible factor-1 expression in liver metastasis of colorectal cancer.
Authors: Wada Yuma , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Iwahashi Shuichi , Saito Yu , Teraoku Hiroki , Ohta Shogo , Higashijima Jun , Shimada Mitsuo 
Published: January 2019

464 Background: In colorectal liver metastasis (CRLM), the difference of tumor malignancy between primary and metastatic lesion has been elucidated. Hypoxia inducible factor-1 (HIF-1) represent tumor malignancy including angiogenesis, tumor growth and epithelial mesenchymal transition (EMT). The aim of this study was to investigate the difference of tumor malignancy between metastatic and primary lesion of CRLM and its impact for patient’s prognosis. Methods: In an initial curative hepatectomy of 75 cases in CRLM, HIF-1 expression in primary and metastatic lesion was evaluated by immunostaining method (Sigma-Aldrich, HPA 001275). Staining score was classified as follows, staining intensity (0: negative, 1: low, 2: medium, 3: high) and staining area (0: 0%, 1: -25%, 2: 26-50%, 3: ≥ 51%), and defined more than 4 points as positive expression. We evaluated the clinicopathological features according to HIF-1 expression. Results: Regarding HIF-1 expression of metastatic site, we divided into the positive group (n = 54) and the negative group (n = 21). There was no difference between metastatic HIF-1 expression and clinicopathological factors. Nevertheless, in overall survival, multivariate analysis revealed that HIF-1 positive in metastasis (HR: 2.850, p = 0.042) and poor differentiation type of primary lesion (HR: 20.873, p = 0.001) were independent prognostic factors. HIF-1 positive and negative patients were 3 year survival of 95.2% and 58.6%, respectively. Also, in disease free survival, HIF-1 positive in metastasis (HR: 2.608, p = 0.004), Synchronous (HR: 1.794, p = 0.049), Grade BC (HR: 2.145, p = 0.008), and lymph node metastasis in primary lesion (HR: 2.070, p = 0.016) was identified. Regarding HIF-1 expression of primary site, we divided into 51 cases of positive group and 24 cases of negative group. There was no relationship to clinicopathological factors as well as HIF-1 expression in metastasis, besides HIF-1 expression of prognosis was not associated. Conclusions: In CRLM, HIF-1 expression in the metastatic lesion is not associated with the primary lesion and may be useful as prognostic marker.
Retrospective comparison of modified FOLFIRINOX with full-dose FOLFIRINOX for advanced pancreatic cancer: A Japanese cancer center experience.
Authors: Ohba Akihiro , Ueno Hideki , Sakamoto Yasunari , Kondo Shunsuke , Morizane Chigusa , Okusaka Takuji 
Published: January 2019

469 Background: Various modified FOLFIRINOX (mFFX) regimens have been reported and widely used in clinical practice. Although there are retrospective studies and single-arm phase 2 studies comparing modified regimens to the full-dose regimen of the historical control group, head-to-head comparisons in the same population are limited. This study aimed to compare mFFX with full-dose FOLFIRINOX (fFFX) in patients with advanced pancreatic cancer (APC). Methods: We reviewed 85 patients with APC who received mFFX (no bolus fluorouracil and irinotecan 150 mg per square) or fFFX as first-line chemotherapy between January 2014 and December 2016. mFFX has been used since January 2016 on the basis of results of a Japanese phase 2 study. The efficacy, safety, and dose reduction pattern were evaluated. Results: A total of 56 eligible patients (26 treated with mFFX and 30 with fFFX) were selected. Baseline characteristics of each group were well-balanced. The median relative dose intensities of oxaliplatin, irinotecan, bolus fluorouracil, and continuous infusion fluorouracil were 68.6%, 78.5%, 0%, and 88.5% in the mFFX group, and 80.5%, 76.5%, 25.6%, and 83.6% in the fFFX group, respectively. Second cycle dose reduction occurred in 38% of the patients in the mFFX group and in 62% of those in the fFFX group. The median overall survival (OS) was 19.0 months in the mFFX group, compared to 13.2 months in the fFFX group (HR 0.60, 95% CI 0.25–1.47, P = 0.27). In a multivariate analysis to adjust for prognostic factors for OS, the hazard ratio for death with mFFX was significant (adjusted HR 0.36, 95% CI 0.14–0.93, P = 0.04). The median progression-free survival was 8.3 months in the mFFX group and 5.9 months in the fFFX group (HR 0.83, 95% CI 0.44–1.54, P = 0.55). The response rate was 35% in the mFFX group versus 30% (P = 0.78) in the fFFX group, respectively. Grade 3 or 4 leucopenia (15% versus 40%), neutropenia (42% versus 70%), febrile neutropenia (8% versus 17%), and nausea (4% versus 13%) were decreased in the mFFX group, but the differences were not statistically significant. Conclusions: mFFX had equivalent or higher efficacy and improved safety compared to fFFX in the same population.
The association of an exosomal form of PD-L1 with immunosuppressive activity and gastric cancer prognosis.
Authors: Fan Yibo , Che Xiaofang , Li Zhi , Qu Xiujuan , Liu Yunpeng 
Published: January 2019

47 Background: The greatest challenge in cancer immunotherapy is to identify efficient predictive biomarkers to select patients for treatment. Though tumor cell membrane PD-L1 has been most anticipated, tumor cell membrane PD-L1 does not correlate with higher response rates and predict for clinical benefit. Subsequently studies showed that the prognostic value of tumor cell membrane PD-L1 in cancer patients remains controversial. In addition to membrane-associated PD-L1, tumor cell also secreted extracellular soluble PD-L1 in the microenvironment. However, even if extracellular soluble PD-L1 was detected, it did not solve the problem mentioned above. In the present study, we discovered another form of PD-L1 in extracellular microenvironment in cancer cells, that is exosomal PD-L1. However, the predictive role and the effect of tumor-derived exosomal PD-L1 is unclear. Methods: We evaluated the prognostic value of exosomal PD-L1 in the plasma of gastric cancer patients by ELISA and the effect of exosomal PD-L1-derived from gastric cancer cell lines by Western blot and Flow cytometry analysis. Results: Exosomal PD-L1 was detected in plasma samples from 69 gastric cancer patients, and exosomal PD-L1 content was significantly associated with T stage (P = 0.012). Overall Survival was significantly lower in the high exosomal PD-L1 group (p = 0.021). Additionally, gastric cancer cells also secreted exosomal PD-L1, with the amounts positively associated with PD-L1 amounts in the corresponding gastric cancer cell lines. Besides, exosomal PD-L1 was more stable and showed stronger immunosuppressive effects in the microenvironment compared with soluble PD-L1. Conclusions: Exosomal PD-L1 might predict the survival in gastric cancer, and induces higher T-cell apoptosis levels compared with soluble PD-L1.
Nano-liposomal irinotecan and 5-FU/LV (N+F) for the treatment of advanced PDAC: Memorial Sloan Kettering (MSK) Single Cancer Center Evaluation.
Authors: Glassman Danielle C. , Desai Avni Mukund , Ku Geoffrey Yuyat , Li Jia , Harding James J. , Varghese Anna M. , O'Reilly Eileen Mary , Yu Kenneth H. 
Published: January 2019

471 Background: Therapy options for advanced pancreatic adenocarcinoma (PDAC) are finite. NAPOLI-1, a phase III randomized trial, demonstrated the efficacy of N+F following progression on gemcitabine (G) based therapy (mPFS 3.1 mo, mOS 6.1 mo). There are limited additional data on the safety and efficacy of N+F following FDA approval in October 2015. We examined the post approval safety, tolerability and effectiveness of N+F in advanced PDAC patients at MSK. Methods: A retrospective chart review was conducted of all patients treated with N+F from Feb 2016 and ending in Aug 2017. Using the EMR and institutional database, information was extracted pertaining to demographics, performance status (ECOG), prior therapies, dose, duration of N+F, adverse events, PFS, OS and treatment response per RECIST. Results:N = 56 identified. Demographics: M/F 29/27, age 68 (range 42-88), prior lines of palliative chemotherapy (0/1/2/3/ > 3, 4/20/21/11). Median PFS was 2.9 months and median OS was 5.3 months. There was a significant difference in PFS, OS and prior lines of therapy between patients who previously progressed on irinotecan (N = 27) versus not (N = 29); PFS = 2.4 v 4.8 mo, p = 0.0154; OS = 3.9 v 8.4 mo, p = 0.0021; 2 v 1 line. ECOG score was not predictive of PFS or OS. There were 19 dose reductions (DR), most frequent reasons: fatigue (42%) and diarrhea (37%). Regarding RECIST: PR = 2 (4%), SD = 19 (34%). 10/43 (23%) experienced > 50% CA 19-9 reduction. Dose reductions were not associated with worse outcomes, in fact, patients with 1 or more DR experienced significantly longer PFS v none (DR 2, not reached; DR 1, 5.2 mo; DR 0, 2.5 mo, p = 0.0185). For the subset who received sequential therapy with G+nab-paclitaxel (P) followed by N+F (N = 25) mOS of 25.4 mo. Conclusions: These data support the safety and efficacy of N+F, re-inforcing results of NAPOLI-1. Patients whose disease previously progressed on irinotecan fared significantly worse than patients who did not, when treated with N+F. N+F appears active even in patients requiring DR. Sequential therapy with G+P followed by N+F demonstrates encouraging mOS. Collectively these findings underscore the utility of N+F in the therapy of advanced PDAC.
Outcomes of locoregional treatment for unifocal progression in widespread metastatic gastroenteropancreatic neuroendocrine tumors.
Authors: Al-Toubah Taymeyah E. , Cives Mauro , Anaya Daniel A. , Soares Heloisa P. , Strosberg Jonathan R. 
Published: January 2019

472 Background: New systemic treatments have improved the therapeutic landscape for patients with progressive, metastatic GEP-NETs. While drugs such as everolimus are appropriate for patients with widespread disease progression, local treatment approaches may be more appropriate for patients with unifocal progression. Surgical resection, radiofrequency ablation (RFA), hepatic arterial embolization (HAE), or radiation, can control discrete sites of progression, allowing patients to continue their existing therapy, and sparing them toxicities of a new systemic treatment. Methods: We reviewed records of patients treated at a large referral center to identify patients seen between 1/2014 and 5/2017 with metastatic GEP-NETs who underwent a local treatment for focal progression. Patients undergoing lobar HAE or cytoreductive hepatic surgery were not included. The primary endpoint was time to new systemic therapy. Secondary endpoints included time to any additional intervention (systemic or local), progression free survival, and side effects of treatment. Results: 59 patients were identified who underwent a form of local treatment for a progressive metastatic tumor in the setting of widespread metastases. 27% underwent resection, 29% RFA, 25% external beam radiation, and 19% selective HAE. With a median follow-up of 17 months, 19 patients (32.2%) eventually progressed to the extent that they received salvage systemic treatment. 6 patients (10.2%) progressed and received further local treatment. Median time to new systemic treatment was 42 months (95% CI, 9.7-74.3 months). Median time to any additional intervention was 21 months (95% CI, 11.4-30.6 months). 4 patients died, all of whom had progressed and received further systemic treatment. Conclusions: We identified a large cohort of patients with metastatic GEP-NETs who underwent a local treatment for unifocal progression in the setting of widespread metastases. Control of local sites of progression enabled the majority of patients to remain on their existing systemic treatment and avoid potential toxicities associated with salvage systemic therapy.
The impact of tumor genomic profile on the effectiveness of adjuvant chemotherapy in resectable intrahepatic cholangiocarcinoma.
Authors: Marcus Rebecca , Lillemoe Heather A. , Abdel-Wahab Reham , Shroff Rachna T. , Javle Milind M. , Aloia Thomas A. 
Published: January 2019

474 Background: The incidence and mortality of ICC is rising in the U.S. While surgical resection currently offers the only potential for cure, the role of adjuvant chemotherapy is not well defined. Tumor genomic profiling is increasingly used to make adjuvant therapy decisions for malignancies. The purpose of this project was to evaluate the correlation between tumor genomic profile and the ability of adjuvant chemotherapy to prevent ICC recurrence after resection. Methods: A retrospective review of 49 patients with ICC undergoing surgical resection and comprehensive tumor genomic profiling was performed. The median age at diagnosis was 56 years (range: 21-72 yrs), 67% were female, and 67% were Caucasian. At resection, 20% had stage I disease, 43% stage II, 29% stage III, and 8% stage IV. Over 90% had moderately or poorly differentiated adenocarcinoma. Clinically relevant genetic mutations (those targeted by anticancer drugs currently on the market or required for entry into a mechanism-driven clinical trial) were evaluated using Foundation Medicine testing. Results: The median recurrence free survival (RFS) for the entire cohort was 9 months (range: 1-55 mo). 59% of patients received adjuvant chemotherapy – 66% gemcitabine-based treatment and 31% capecitabine-based. The most prevalent mutations were FGFR2 (28%), CDKN2A/B (24%), IDH1 (17%), and ARID1A (17%). Median RFS for the adjuvantly treated group was 12 months (range: 3-55 mo), and the presence of any clinically relevant mutation was associated with worse RFS (x vs. y, p = 0.03). IDH1 (30%), BAP1 (25%), and PBRM1 (20%) were most frequently mutated amongst patients who did not receive adjuvant therapy, and their median RFS was 5 months (range: 1-54 mo). Lack of an IDH1 mutation correlated with worse RFS (p = 0.02), while lower stage correlated with improved RFS (p = 0.01). Conclusions: For patients with ICC undergoing resection and adjuvant chemotherapy, the presence of clinically relevant genetic mutations is associated with reduced RFS. To gain further insight into the influence of tumor genomic profile on the effectiveness of adjuvant chemotherapy for this patient population, a multicenter collaborative effort is needed.