bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overall survival (OS) achieved with gemcitabine (G) or gemcitabine-abraxane (GA) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) who received first line modified FOLFIRINOX (m-FFX) palliative chemotherapy.
Authors: Aung Kyaw Lwin , Creighton Sean , Fraser Adriana , Dodd Anna , Moura Shari , Albaba Hamzeh , O'Kane Grainne M. , Hedley David W. , Dhani Neesha C. , Knox Jennifer J. 
Published: September 2018

e15715 Background: The standard second line treatment in advanced PDAC pts after m-FFX first line palliative chemotherapy is not clearly defined. G is the standard 2nd line treatment in Canada and GA can only be prescribed for pts with a private fund or private drug plan that covers the cost of Abraxane. More data is needed to establish OS achieved with 2ndline G or GA. Methods: The OS of PDAC pts treated with G or GA after m-FFX palliative chemotherapy given between 01-Dec-2011 and 30-Nov-2015 at the Princess Margaret Cancer Centre (PM), Toronto, Canada were retrospectively reviewed. OS was calculated from date of commencement of 2ndline treatment until death or date of last oncology follow up. Results: Over the 4-year study period, 132 pts were treated with 1st line palliative m-FFX at PM. Of them, at disease progression, 78 (59%) pts received a 2ndline therapy (50 G, 17 GA, 9 clinical trials, and 2 other). The results including demographics, treatment details and survival outcomes of patients treated with G and GA are summarized in the Table 1. Conclusions: Our results do not support single agent G after m-FFX 1st line palliative chemotherapy as median duration of treatment was too short and OS observed with G in this setting is very much limited. The median duration of treatment on GA and OS achieved with GA seem superior but sample size was too small to make a conclusion. [Table: see text]
Effect of KRAS and P-STAT3 inhibition by SBT-100 on gemcitabine and pancreatic cancer growth in vivo.
Authors: Singh Sunanda , Murillo Genoveva , Singh Avani , Singh Samara , Parihar Meenakshi S , Singh Anjali H , Mehta Rajendra , Parihar Ashutosh S 
Published: September 2018

e15727 Background: Over 90% of pancreatic cancers have KRAS mutations and hyper-expression of P-STAT3 oncoproteins, which if specifically targeted may help treatment of pancreatic cancers. Singh Biotechnology’s proprietary technology engineered SBT-100, a single domain antibody that is bispecific for KRAS & STAT3, which can cross the cell membranes and bind to these intracellular oncoproteins. Combining this targeted therapy with an established chemotherapy, such as gemcitabine, may improve patient’s response to treatment. Methods: Human pancreatic cancer cells (PANC-1 and BX-PC3) were used. Biacore assay demonstrates SBT-100 binding to KRAS, KRAS (G12D), and STAT3. Immunoprecipitation (IP) and western blot analysis confirmed binding to STAT3 by SBT-100. Pancreatic cancer cells were treated at varying doses of SBT-100 ranging from 0µg/ml to 200µg/ml ± gemcitabine, and after 72 hours growth inhibition was determined by a MTT assay. PANC-1 tumors were grown in athymic nude mice, divided into four groups and staged to a range of 100-150mm3 before treatment. Groups were: vehicle only, SBT-100, gemcitabine, and SBT-100 & gemcitabine. Animals received treatments for 14 days, then monitored for 7 days. Results: Biacore study shows SBT-100 binds KRAS with an affinity of 10-9M, KRAS (G12D) with 10-8M, and STAT3 with 10-8M. IP and western blot analysis demonstrates that SBT-100 binds P-STAT3. MTT assay demonstrates SBT-100 inhibits the growth of PANC-1 and BX-PC3 (p < 0.001). In PANC1 cells a combination of SBT-100 & gemcitabine demonstrates synergism in inhibiting growth of PANC-1, even at 1/8th the gemcitabine IC50 concentration. PANC-1 xenograft study demonstrates that combination therapy of SBT-100 & gemcitabine is superior to either SBT-100 or gemcitabine alone. Compared to the vehicle group, SBT-100 & gemcitabine is far superior (p < 0.001) and gives statistically significant suppression of pancreatic cancer growth in vivo. Conclusions: Targeted therapy for KRAS and P-STAT3 expressing tumors with SBT-100 & gemcitabine is synergistic for the treatment of pancreatic cancer. This study suggests that synergism maybe achieved with lower doses of gemcitabine, thereby reducing toxicity in patients.
Retrospective multicenter cohort of nab-paclitaxel plus gemcitabine (NG) after FOLFIRINOX failure in advanced pancreatic cancer (APC): Effectiveness, tolerability, and response markers.
Authors: Vendrell Ines , Ferreira Arlindo Rebelo , Pulido Catarina , Parmanande Anuraj , Ferreira Da Silva Filipa , Barreira João Vasco , Godinho João , Pinto João Moreira , Gago Joaquim , Couto Nuno , Castro Ana , Carvalho Carlos , Passos-Coelho José , Semedo Monica , Pinto Conceição , Costa Luis 
Published: September 2018

e15743 Background: NG is a standard 1st line treatment for APC. Although recommended in 2nd line after FOLFIRINOX, there is little evidence of its efficacy, tolerability and of markers of efficacy. Methods: We performed a multicenter retrospective cohort study, including patients (pts) with APC from 5 centers in Portugal treated with 2nd line NG after 1st line FOLFIRINOX from 01/2013-12/2016. We collected demographic, clinicopathological characteristics and treatment data. We used descriptive statistics, Kaplan-Meier methods and Cox proportional hazards analysis. Results: 30 pts were included; median age was 64 years (range 45–78); the majority had stage IV (90%) disease, an ECOG Performance Status of 0 (76.7%) and had received a median of 8.5 cycles of FOLFIRINOX (range 1–18). A median of 6 cycles of NG were administered (range 1–13). Median progression free survival (PFS) and overall survival (OS) were 6.4 months (CI 95% 3.0-8.5) and 11.4 months (CI 95% 8.4–16.5), respectively, and did not differ by age < 65 or ≥65 (p = 0.87; p = 0.57 respectively). The most frequent toxicity was fatigue (66.6%, any grade). Grade 3-4 events occurred in 40% of pts – thrombocytopenia in 16.7%, neutropenia in 10.0%; anemia, sensorial neuropathy, fatigue and diarrhea each occurred in 3.3% of patients. No febrile neutropenia events or toxic deaths occurred. Median CA 19.9 at the beginning of NG was 1254U/mL (IQR: 207–6775); the median decrease of CA19.9 at 3 months was 45U/mL (IQR:-1373– +174). CA 19.9 variation at 3 months did not correlate with PFS (p = 0.53) or OS (p = 0.09) in multivariate analysis (adjusted for age and stage at diagnosis). Neutrophil to Lymphocyte ratio (NLR) was high ( > 3.0) in 37.5% of patients before 1st line treatment and in 27.6% at the beginning of NG. In multivariate analysis NLR before 1st or 2nd chemotherapy lines were not associated with PFS (p = 0.39; p = 0.14 respectively) or OS (p = 0.44; p = 0.12, respectively). Conclusions: In this cohort of pts with APC, NG was an effective and well tolerated 2nd line regimen after FOLFIRINOX failure, even in pts ≥65 years. Neither CA19.9 variation at 3 months nor NLR were markers of NG clinical benefit.
Use of phenotypic profiling to determine sensitivity of gemcitabine with nab-paclitaxel for front-line treatment of pancreatic cancer.
Authors: Ricigliano Mark , Cooper Brandon , Bartlett Andrew , Yu Kenneth H. 
Published: September 2018

e15749 Background: Standard of care treatment for pancreatic adenocarcinoma (PDAC) consists of FOLFIRINOX (FFX) or gemcitabine with nab-paclitaxel (G/nab-P) in the front-line setting. The decision to use FFX or G/nab-P is a physician choice as there are no standardized assays to guide treatment selection. Here we report the results of a prospective clinical trial to evaluate a blood-based assay to select patients for G/nab-P in the front line setting. The assay was developed on the premise that if two patients have the same genomic profile, they will have the same response to chemotherapy. Methods: In a prospective study, 37 PDAC patients were pre-selected to receive G/nab-P at Memorial Sloan Kettering as a front-line treatment. Circulating tumor and infiltrating cells (CTICs) were isolated from peripheral blood samples using a cell invasion matrix. RNA was isolated and cDNA synthesized for qPCR gene expression. 83 drug transport genes were used as classifiers to create four treatment templates, one each for G/nab-P, GAX, FFX and FOLFOX. Nearest Template Prediction was used to match the genomic profile of the PDAC patient sample to one of the four a priori defined treatment templates. Results: Front-line PFS was correlated to treatment phenotype with G/nab-P (8.6 mos.), GAX (6.7mos.), FFX (5.6 mos.) and FOLFOX (5.0 mos.). Patients with a positive sensitivity (S+) to G/nab-P demonstrated a median PFS of 7.7 mos. vs. 4.7 mos. compared to those with a negative sensitivity (S-) to G/nab-P (p-value = 0.027). Contingency analysis demonstrated sensitivity (78%), specificity (64%), and likelihood ratio (2.139) with p-value = 0.048. Correlation between G/nab-P sensitivity and PFS was significant as measured by linear regression (R2= 0.90, p-value = 0.013). Conclusions: Phenotype profiling for selecting front-line treatment to G/nab-P is feasible in PDAC. Clinical trial information: NCT01474564.
A study of REOLYSIN in combination with pembrolizumab and chemotherapy in patients (pts) with relapsed metastatic adenocarcinoma of the pancreas (MAP).
Authors: Mahalingam Devalingam , Fountzilas Christos , Moseley Jennifer L. , Noronha Nicole , Cheetham Karol , Dzugalo Adrian , Nuovo Gerard , Gutierrez Andres , Arora Sukeshi Patel 
Published: September 2018

e15753 Background: REOLYSIN is an immuno-oncology-reoviral agent that induces an inflamed tumor phenotype secondary to viral infection of cancer cells. In combination with chemotherapy, it achieves 1 & 2 year-survival rates of 46% & 24% in MAP pts, respectively. Tumor analysis from pts showed reovirus protein replication, T-cell infiltration and upregulation of PD-L1. Similarly, the combination of REOLYSIN with anti-PD-1 antibody documented survival benefit in a pre-clinical model. We hypothesized that REOLYSIN in combination with chemo and pembrolizumab in pts with MAP would be clinically efficacious. Methods: A phase 2 study (NCT02620423) enrolled MAP pts who progressed after first line treatment. Pts received REOLYSIN (4.5 x 10 10 TCID 50 IV, D1 & D2), plus pembrolizumab (2mg/kg IV, D8) plus either 1)5-FU (LV (200 mg/m2 /5-FU 200 mg /m2 IV bolus, 5-FU 1200mg/m2 continuous IV infusion D1) or 2) gemcitabine (1000 mg/m2 IV, D1), or 3) irinotecan (125 mg/m2 IV, D1) q3w, until disease progression/unacceptable toxicity. The primary endpoint was safety. Secondary objectives included tumor response & evaluation for reovirus replication/immune analysis. We report results of safety cohort analysis. Results: 11 pts were enrolled with REOLYSIN, pembrolizumab and gem (n = 6), 5-FU (n = 3), or iri (n = 2). Grade 1 or 2 TEAEs occurred in all pts: fever (64%), headache (55%), chills (46%), fatigue (46%), dehydration (27%), and nausea (27%). In one pt (gem arm), transient Gr 2 increased transaminases was reported on two occasions. Grade 3 or 4 TEAEs occurred in 8 pts (73%): abdominal pain, anemia, arthralgias, biliary obstruction, chills, DVT, diarrhea, fever, hyperglycemia, leukopenia, myalgias, nausea, neutropenia, pulmonary emboli, vomiting. Of the 5 efficacy evaluable pts, one had PR (6 m duration) and 2 SD (lasting 126 and 221 days). Seven died secondary to PD. On-treatment biopsy show reovirus infection in cancer cells and immune infiltrates. Conclusions: The combination therapy showed manageable safety profiles and antitumor activity in previously treated MAP pts. Further evaluation of anti-tumor activity of REOLYSIN and anti-PD-1 antibody ± chemotherapy combos is planned. Clinical trial information: NCT02620423.
Impact of intensified chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical routine: A Pan-European study.
Authors: Javed Muhammad Ahsan , Beyer Georg , Le Nha Ngoc Hoa , Vinci Alessio , Wong Helen , Palmer Daniel H. , Morgan Robert , Lamarca Angela , Hubner Richard , Valle Juan W. , Alam Salma , Chowdhury Sumsur , Ma Yuk Ting , Archibugi Livia , Capurso Gabriele , Maisonneuve Patrick , Neesse Albrecht , Sund Malin , Schober Marvin , Krug Sebastian 
Published: September 2018

e15774 Background: Gemcitabine (GEM) based chemotherapy has been the standard of care for patients with metastatic PDAC with marginal effects on overall survival (OS). In recent years, FOLFIRINOX and Nab-paclitaxel (NAB) + GEM regimens have shown significant survival benefits compared to gemcitabine in clinical trial settings. This study aims to investigate the efficacy of FOLFIRINOX and NAB + GEM versus GEM monotherapy and GEM doublet combinations in real-life settings across different European institutions. Methods: Patients from UK, Sweden, Germany, Italy and Hungary with metastatic PDAC receiving palliative chemotherapy between 2012 and 2015 were included in a retrospective multinational study. Kaplan-Meier method was used for survival analysis. Results: Of the 1089 included patients, 576 (52.9%) were male and 170 (15.6%) underwent primary resection before systemic recurrence. GEM monotherapy was the most commonly used regimen (40.0%; n = 436), followed by combination treatments such as GEM + oxaliplatin, GEM + cisplatin, GEM + capecitabine (24.2%; n = 263), FOLFIRINOX (17,5%; n = 191) and NAB + GEM (7.3%; n = 80). Overall, 6-months and 12-months mortality rate was 48.9% and 72.5%, respectively. The median OS in different groups was: FOLFIRINOX 9.0 months (95% CI 7.1-10.9), NAB + GEM 7.0 months (95% CI 5.8-8.2), other GEM doublet combinations 7.0 months (95% CI 6.0-8.0) and GEM monotherapy 5.0 months (95% CI 4.3-5.7). Compared to GEM monotherapy, intensified chemotherapy either with FOLFIRINOX (p = 0.0001), NAB + GEM (p = 0.02) or GEM doublets (p = 0.0001) was associated with significantly improved survival. Comparison of the different combination regimens was as follows: NAB + GEM vs. FOLFIRINOX (OS: 7.0 vs 9.0 months, p = 0.25), NAB + GEM vs. GEM doublets (OS: 7.0 vs. 7.0 months, p = 0.79) and FOLFIRINOX vs. GEM doublets (OS: 9.0 vs. 7.0 months, p = 0.29). Conclusions: The use of FOLFIRIOX and NAB in clinical routine is variable in Europe. GEM based regimens seem to be the preferred standard of care. Compared to GEM monotherapy, combination treatments improved survival. No significant differences amongst combination therapeutic regimens were identified within our cohort.
DNA sequencing of the small bowel adenocarcinomas to identify targetable ErbB2 mutations.
Authors: Adam Liana , Fowler Jerry , Wu Wenhui , Yu Yao , Wang Huamin , San Lucas Francis A , Huff Chad , Kopetz Scott , Scheet Paul , Overman Michael J. 
Published: September 2018

e15800 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy of the digestive tract with limited knowledge about its genetic alterations. Methods: Eighteen tumor and normal matched samples were sequenced using the whole-exome-Illumina platform. Various agnostic analysis methods were used to identify relevant somatic mutations and the results were compared with the available TCGA datasets. To test potential targetable mutations we developed eight patient-derived xenografts (PDX) and three cell lines from freshly-collected primary or metastatic SBA tissues. Two kinase-activating ErbB2 mutations (V842I and Y803H) and one wild-type (wt) ErbB2 (n = 30) PDX models were used to measure the effect of Dacomitinib (Daco) on tumor growth. ErbB2-mutant tumor-derived cell lines were tested for Daco and Lapatinib (Lapa) response in-vitro. Reverse-phase-protein-arrays (RPPA) were used to identify molecular changes. Results: Several unexpected oncogenic mechanisms were suggested by the pattern of somatic mutations across the dataset, including mutations in the Notch and Hippo pathways. In addition, we found 6/18 APC truncating mutations exclusive to mutations in ZNRF3 or RNF43 genes, suggesting that non-APC wnt-activating mechanisms are important in SBA, while considered a minority in CRC. Importantly, 6/18 samples displayed ErbB2 mutations, of which 4 resided in the kinase domain, D769Y, V777L, Y803H and V842I. Nanomolar doses of both Lapa and Daco significantly inhibited ErbB2-mutants’ cell proliferation in-vitro. Target inhibition was confirmed by the RPPA results: EGFR-Y1068, ErbB2-Y1248 and PKCα-S657 dephosphorylation, PCNA reduction and PARP cleavage increase. In-vivo-administered Daco resulted in significant tumor reduction in ErbB2-V841I (39%, p = 0.03) and ErbB2-Y803H (59%, p = 0.03) tumors, and had no anti-tumor effect on wt-ErbB2 tumors. Conclusions: The generation of in-vitro and in-vivo model systems from rare cancers is possible and provides a valuable resource into understanding potentially relevant targetable mutations. Our findings suggest that SBA patients with ErbB2-activating mutations should be considered for clinical trials targeting this alteration.
An exploratory study to investigate the immunomodulatory activity of radiation therapy in combination with pembrolizumab in patients with renal cell cancer.
Authors: Lin Jianqing , Hoffman-Censits Jean H. , Kelly William Kevin , Tuluc Madalina , Shaw Colette , Philipose Sherin , Leiby Benjamin E. , Louie Jennifer , Harshyne Larry , Kean Rhonda , Bar-Ad Voichita , Den Robert Benjamin , Hurwitz Mark , Johnson Jennifer Maria , Hubert Christine , Deshmukh Sandeep , Dicker Adam , Hooper D. Craig , Lu Bo 
Published: September 2018

e16058 Background: Preclinical data suggest there are synergistic effects of radiation therapy (RT) and check point inhibitors in anticancer immunity. The primary objective of this study was to explore the immunomodulatory activity of RT alone or in combination with Pembrolizumab (pembro) in solid tumors including renal cell cancer (RCC) patients (pts). Methods: RCC pts who progressed after at least one front-line therapy were eligible. Pts were treated with either RT (8Gy x 1 or 4Gy x 5) followed by (f/b)pembro or 1 dose pembro f/b RT f/b pembro. Pre- and post RT tumor biopsy was obtained to evaluate PD-L1 expression (assay by QualTeck). Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Treatment response was measured based on modified RECIST criteria. Results: Twelve RCC patients were enrolled including 2 with non-clear cell subtype. One pt was not evaluable since pt quickly deteriorated and was taken off study. As of January 13, 2017, 2 pts are still on active treatment. Two pts had partial response (18%) and were on study for at 54 and 63 weeks. One responder was treated with 8 Gy f/b pembro while 1 was treated with 1 dose pembro f/b RT f/b pembro. Five pts had stable disease of 18 to 45 weeks and 4 pts (36%, non-responders) had progression in 9 weeks. For adverse events, 1 pt developed grade 3 pneumonitis after 10 cycles of pembro (RT to adrenal mets). Grade 3 AEs include Fatigue, Nausea, Hyperglycemia, Lymphopenia, thrombocytopenia and AST elevation (post RT for liver mets). PDL1 expression and tumor infiltrating lymphocytes presence after RT showed various patterns. Preliminary flow cytometry showed persistent higher numbers of monocytes in non-responders comparing with responders. CD4+, CD8+ and NK cells and other markers are under analyzed and the results will be presented. Conclusions: The combination of RT (8Gy or 20Gy) with pembro is feasible and tolerated, and demonstrates clinical activity. The AE profile is similar to single agent pembro. Monocytes, T and NK cell kinetics are being examined. (ClinicalTrials.gov ID: NCT02318771) Clinical trial information: NCT02318771.
Thermo reversible hydrogel based delivery of mitomycin C for treatment of upper tract urothelial carcinoma (UTUC).
Authors: Lin Jeffery Shyh-Jye , Kleinmann Nir , Wirth Gregory J , Matin Surena F. , Mayer Gil , Nativ Ofer , Witjes Alfred , Shvero Asaf , Chamie Karim , Pantuck Allan J. , Smith Angela , Schoenberg Mark , Malchi Nadav , Hakim Gil , Agmon-Gerstein Yael , Jeshurun-Gutshtat Michal , Klein Ifat , Kopelen Helen , Lerner Seth P. 
Published: September 2018

e16089 Background: There is a large unmet need for novel drug delivery systems and effective therapy for UTUC, especially for patients with CKD and anatomic solitary kidneys. A temperature sensitive water-soluble gel formulation of Mitomycin C (MMC) demonstrated increased drug delivery time (4 to 6 hrs) and safety in the pelvicalyceal system of swine and human bladders. We report the efficacy and safety of gel+MMC as primary treatment (tx) of UTUC on a compassionate use basis. Methods: Compassionate use approval was obtained on an individual patient basis from the respective regulatory authorities and IRBs. 22 patients were approved for tx to date from 14 institutions in 4 countries. Tx included 6 weekly instillations instilled via ureteral catheter or percutaneous nephrostomy. Gel volume ranged from 5-20cc and MMC concentration was 2-6 mg/cc. Adverse events were recorded throughout treatment. Ureteroscopy was performed 2-6 weeks following tx completion for response determination. Results: Median age of the cohort was 75 yrs, with 15 males. 18 patients (pts) had low-grade (LG) tumor, 2 high-grade (HG), and 2 indeterminate grade. 16 (73%) completed treatment - 9 pts had a complete response, CR (41%; 59% of those who completed tx), 5 pts had a partial response, PR (23%; 31%), and 2 pts had no response, NR (9.1%, 12.5%). 4 patients could not complete tx due to adverse events (pyelonephritis, acute renal failure, pancytopenia, and unstable cardiac condition), 1 patient was diagnosed with a non-urothelial cancer during treatment, and 1 patient died prior to the third instillation due to suspected pulmonary embolus, determined to be unrelated to treatment with MitoGel. A total of 77 adverse events were recorded with 6 events related to MitoGel and serious (requiring intervention), and 21 events related to treatment and not serious. CR (9) and PR (5) were observed in 14 of 15 evaluable patients completing treatment for LG tumors. Conclusions: This compassionate use program of a thermosensitive gel+MMC for chemoablation of UTUC demonstrates proof of concept for treatment of low-grade tumors. A single arm Phase III multi-center registration trial to treat patients with low-grade renal pelvis tumors has been activated.