bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergy of water soluble prodrug triptolide (minnelide) with gemcitabine and nab-paclitaxel in pancreatic cancer.
Authors: Dudeja Vikas , Modi Shrey , Giri Bhuwan , Majumder Kaustav , Banerjee Sulagna , Saluja Ashok 
Published: February 2017

259 Background: Gemcitabine with nab-paclitaxel is the standard of care for metastatic Pancreatic Ductal Adenocarcinoma (PDAC). Addition of nab-paclitaxel to gemcitabine improves the survival of patients with metastatic pancreatic cancer by only 6 weeks while increasing toxicity. Meaningful combinations that reduce the doses while improving efficacy are required. Water soluble prodrug of triptolide (Minnelide) is effective against PDAC in preclinical studies and has demonstrated activity in the ongoing phase I trial. We have evaluated the combination of low dose triptolide prodrug with lowered doses of Abraxane and gemcitabine in PDAC. Methods: Pancreatic cancer cell lines S2-013 and S2-VP10 were xenografted both subcutaneously as well as orthotopically in athymic nude mice. Efficacy of a combination of triptolide prodrug (Minnelide: 0.21mg/kg) with reduced dose of gemcitabine 100mg/kg + Abraxane 10mg/kg (~40% of the clinically effective dose) was evaluated and compared with both standard of care gemcitabine 250mg/kg + Abraxane 25mg/kg as well as reduced dose of gemcitabine + Abraxane in animal models. We also used the immunocompetent model where murine PDAC cell line KPC001 implanted subcutaneously in C57/bl6 mice. Results: In subcutaneous syngeneic model, combination of triptolide prodrug and paclitaxel significantly inhibited tumor growth (tumor volumes expressed as % of Control, Mean±SEM: triptolide prodrug: 75.4±25, paclitaxel: 50.0 ±3, triptolide prodrug + paclitaxel: 11.0 ±1). In metastasis model combination therapy markedly improved survival (median survival in days: Vehicle-13, triptolide prodrug -20, standard of care -45, reduced dose standard of care-30, and Minnelide + reduced dose standard of care (all mice alive at 90 days). Combination of triptolide prodrug and low dose gemcitabine + nab-paclitaxel decreased tumor size, increased survival, reduced metastases and malignant ascites in orthotopic model of PDAC. Conclusions: Triptolide prodrug synergizes with reduced dose standard of care (gemcitabine and nab-paclitaxel) and helps in reducing the doses of these toxic drugs all the while achieving same or better efficacy in animal models of PDAC.
Precision cancer therapy through nanoparticle delivery of siRNA against KRAS.
Authors: Strand Matthew S. , Pan Hua , Grossman Julie G. , Goedegebuure Peter S. , Fleming Timothy , Wickline Samuel A. , Fields Ryan C. 
Published: February 2017

260 Background: Small interfering RNA (siRNA) has potential for highly specific gene manipulation, making it attractive for delivering precision therapy to cancer patients. However, efforts to employ siRNA therapeutically have been limited by its short half-life in circulation, low target tissue specificity, and cellular entrapment within endosomes. We utilized serum-stable, cell-penetrating, and endosomolytic peptide-based nanoparticles (NPs) to overcome these obstacles and deliver siRNA against KRAS to KRAS-mutant human and mouse pancreas and colorectal cancers. Methods: Human and mouse pancreas and colorectal cancer cell lines were tested for NP uptake in vitro utilizing fluorescent siRNAs. Uptake was assessed via fluorescent microscopy and flow cytometry (FC). Mice bearing tumors from these cells were injected IV with the same NP, and uptake was assessed with an in vivo imaging system (IVIS), and FC. Cell lines were treated with KRAS-siRNA NP and KRAS knockdown was assessed by real-time PCR. Results: Mouse and human pancreas and colorectal cancer cell lines took up NP in vitro, with signal detected within > 93% of cells at 24 hours. Tumors from these cells grown in mice were strongly fluorescent after IV injection of fluorescent NP within 2 hours, and until at least 30 hours. FC of a tumor treated with fluorescent NP showed that 86% of tumor cells expressed fluorescent signal 24 hours post-injection. IVIS revealed signal in mouse liver and kidneys, but when assessed by FC, only 17.8% and 13.5% of cells from these tissues were fluorescent, respectively. The brain, heart, lungs, spleen, and pancreas of mice receiving injections were negative. Cancer cell lines exposed to KRAS-siRNA NP for 48 hours express KRAS at levels that are 4.5 to 15.1% of untreated cells. Conclusions: Human and mouse pancreas and colorectal cancers efficiently and specifically take up NP in vitro and in vivo. Selected limitations of siRNA are overcome with this NP delivery system, and NP-packaged siRNA effectively inhibits KRAS. This platform represents a highly specific approach to targeting tumor genes of interest, which may ultimately enable selective knockdown of putative drivers of tumor progression.
Retrospective study of non-mucinous appendiceal adenocarcinomas: Role of systemic chemotherapy and cytoreductive surgery.
Authors: Uemura Marc Isamu , Qiao Wei , Fournier Keith F. , Morris Jeffrey , Mansfield Paul F. , Eng Cathy , Royal Richard Eldon , Wolff Robert A. , Raghav Kanwal Pratap Singh , Overman Michael J. 
Published: February 2017

263 Background: The majority of studies evaluating appendiceal epithelial neoplasms have focused on those with mucinous histology. Few studies have reported on non-mucinous appendiceal adenocarcinomas. We performed the largest single-center study to investigate this histologic subtype, in order to describe the natural history and impact of both cytoreductive surgery (CRS) and systemic chemotherapy. Methods: We retrospectively reviewed 172 pts with non-mucinous appendiceal adenocarcinoma evaluated at the UT-MD Anderson Cancer Center between 1990 and 2015. Patient demographics, tumor characteristics, therapy received, and outcomes were recorded. Response assessment was semi-quantitative (response vs. no response) according to the treating physician. Overall survival (OS) and time to progression (TTP) were calculated using Kaplan Meier product-limit method and survival rates compared using the log rank test. Results: Median age at diagnosis was 52.9 yrs (M:F 1:1). Most pts presented with advanced stage: stage I (1.7%), stage II (32.5%), stage III (14.5%), and stage IV (51.2%). No patient had well-differentiated histology. 56% had moderate and 44% poor histology. Median OS by stage was 90.9m [95% CI: 70.8 to 172.9] for stage II, 52.1m [95% CI: 28.9 to NA] for stage III and 28.3m [95% CI: 22.9 to 31.9] for stage IV, (p < 0.0001). In pts with metastatic disease (n = 128) CRS was attempted in 20 (15.6%) and was complete (CCS 0/1) in 12. The median OS for pts achieving complete CRS was 48.6m. Systemic chemotherapy was administered to 92% (118/128) of metastatic pts. The median TTP was 9.4m [95% CI: 8.0 to 11.5] and semi-quantitative response rate was 54%. The majority of pts received either oxaliplatin-based, 57%, or irinotecan-based, 23%, first-line chemotherapy regimens. No statistical difference in TTP (p = 0.9) or OS (p = 0.07) between different chemotherapies was seen. Conclusions: In contrast to mucinous appendiceal neoplasms, non-mucinous appendiceal adenocarcinomas rarely present with low-grade (well-differentiated) histology. Treatment approaches appear more akin to colorectal cancer with most metastatic pts undergoing systemic chemotherapy and a minority undergoing CRS.
Sarcopenia with modified Glasgow prognostic score as a predictor of long-term survival in patients with gastric cancer.
Authors: Nishi Masaaki , Shimada Mitsuo , Yoshikawa Kozo , Higashijima Jun , Nakao Toshihiro , Kashihara Hideya , Takasu Chie 
Published: February 2017

27 Background: Recent reports suggested that the Glasgow prognostic score (GPS), which is a preoperatively determined inflammation-based score, correlated with long -term survival in several types of cancers. The aim of this study is to create new prognostic index which is superior to modified GPS (mGPS) in gastric cancer. Methods: Seventy five patients with gastric cancer who underwent gastrectomy were enrolled in this study. Prognostic factors were searched for among clinocopathological factors and nutritional- or immune- parameters, including mGPS (J Gastoenterol 2011), neutrophil lymphocyte ratio (NLR), prognostic nutritional index (PNI), or sarcopenia. Cut of value were 3.0: NLR, 40: PNI, respectively. Sarcopenia was assessed by the following CT-based methods (Lancet 2011). Sarcopenia with mGPS (SarcoGPS) were defined as CRP was changed to sarcopenia. Results: The overall survival (OS) rate was significantly lower in mGPS:0 group than in mGPS:1,2 group (p < 0.05). The disease-free survival (DFS) rate didn’t differ in mGPS (N.S). The OS and DFS rate of high NLR group or sarcopenia group were significantly lower than those of low NLR group or non- sarcopenia group (p < 0.05). PNI did not differ significantly both in OS and DFS. SarcoGPS was the poor prognostic factor both in OS and DFS (p < 0.01) Conclusions: SarcoGPS is the new prognostic index, which is superior to mGPS, in gastric cancer.
Molecular prescreening (MP) to treat patients (pts) with advanced pancreatic cancer (PC) in early clinical trials.
Authors: Sauri Tamara , Macarulla Teresa , Cabrera Guadalupe , Verdaguer Helena , Zeron-Medina Jorge , Vivancos Ana , Capdevilla Jaume , Elez Elena , Alsina Maria , Argiles Guillem , Hierro Cinta , Grasselli Julieta , Matos Ignacio , Rodon Jordi , Nuciforo Paolo , Dienstmann Rodrigo , Tabernero Josep 
Published: February 2017

272 Molecular prescreening (MP) to treat advanced pancreatic cancer (PC) patients (pts) in early clinical trials Background: Advanced PC has a dismal prognosis, with conventional therapies having poor impact on disease course. The aim of this study was to investigate the impact of a MP program to identify potentially targetable alterations (PTa) in PC pts eligible for clinical trials with matched targeted therapies. Methods: From Jan 2011 to June 2015, a total of 86 chemorefractory PC pts were referred to MP at the VHIO Phase I Unit. Archived tumor samples were analyzed for selected gene mutations (mut) in using mass spectrometry (MassARRAY, Sequenom) until June 2014 or next-generation sequencing (Amplicon, MiSeq) thereafter. PTEN and PDL1 expression levels were measured with immunohistochemistry. All demographic, treatment and survival data were extracted retrospectively from electronic medical records. Results: Median age was 61 years (range 29-78) and 64% were male. Median treatment lines before MP was 2 (range 1-5). Tissue used for MP was primary tumor in 74% and metastatic lesion in 26%. In total, 29% of the samples did not have enough material for mut analysis. The most common PTa were KRAS mut (20/35 with Sequenom, 57%; 22/26 with Amplicon, 85%; p = 0.02), PTEN low (9/22, 41%), PTEN null (4/22, 18%) and CDKN2A mut (2/26, 8%). RNF43 mut, STK11 mut, BRAF V600E and BRAF G469A were found in one sample each. A total of 30 pts were enrolled in Phase I trials following MP, 10 of them with a direct matched therapy (5 with PI3K pathway inh - PTEN low/null, 3 with PI3K + MEK inhibitor - KRAS mut, 1 anti-PDL1 therapy - PDL1 high, 1 HDM2 inh - TP53 wild-type). Partial response was observed in 1 case (PI3K inh + chemotherapy, PTEN null) and stable disease in additional 4 pts (3 with PI3K inh +/- chemotherapy, PTEN low/null; 1 PI3K + MEK inh, KRASmut). Median time on treatment with matched therapy was 2.5 months (CI95% 1.8 – not reached). Conclusions: Genomic/proteomic characterization of PC is able to identify a subpopulation eligible for matched therapy in early clinical trials, with rare cases presenting a clear treatment benefit. Low recruitment can be linked to lack of enough material for MP, low prevalence of PTa and patient characteristics
Blood neuroendocrine tumor gene cluster analysis to predict somatostatin analog response.
Authors: Kidd Mark S. , Drozdov Ignat , Modlin Irvin Mark 
Published: February 2017

276 Background: Defining therapeutic efficacy in NETs is problematic. We have identified circulating NET transcripts that accurately reflect tumor tissue levels and are sensitive measures of tumor biology. We also identified gene clusters that define NET activity e.g., proliferation. We hypothesized that targeted treatment would alter cluster expression and these could predict treatment response. We evaluated this using somatostatin analogs since they effectively ameliorate symptoms and inhibit tumor growth. Methods: We prospectively evaluated GEP-NETs (n=35) [M:F 12:23; median age: 58 years, small intestine: n=29, pancreas n=3, rectum n=3]. Circulating NET gene expression was assessed (qRT-PCR, normalized gene expression) and imaging (CT/MRI: disease status–RECIST criteria) undertaken. Treatments included: sandostatin (n=32), octreotide (n=2) and pasireotide (n=1); median dose 20mg (range 20-60mg). Gene clusters e.g., proliferation (Ki67, NAP1L1, NOL3, TECPR2) were evaluated as predictive “neoplasia hallmarks” using 2-tailed non-parametric and ROC analyses. Cluster expression is expressed as mean±SEM. Results: Imagery identified25 (71%) patients with stable disease; 10 were progressing. Expression of genes associated with secretory regulation, the “secretome” was significantly down-regulated in the disease-stabilized versus progressive group (2±0.5 vs. 30±25, p<0.001). Individuals with disease progression on SSA therapy exhibited both a significantly elevated proliferation-associated gene cluster (65±15 vs. 16±1, p<0.001) and an epigenetic remodeling cluster (44±6 vs. 32±10, p<0.005). ROC analysis confirmed these accurately identified therapy response (AUC: 0.86-0.97, p<0.0001). Other gene clusters e.g., metabolism (10±1.2 vs. 15.4±3) and apoptosis (1.3±0.2 vs. 1.1±0.8) were not different. Conclusions: SSA therapy alters circulating transcript measurements. Disease stabilization is associated with downregulation of genes linked to tumor secretion while progression is associated with elevation in gene clusters that define tumor proliferation and epigenetic reprogramming. Blood transcript measurements provide an accurate tool to predict the efficacy of SSA therapy.
The Know Your Tumor (KYT) initiative: A national program of multi-omic molecular profiling (MoP) for patients (Pts) with pancreatic cancer (PDA).
Authors: Engebretson Anitra , Brody Jonathan Robert , Rahib Lola , Matrisian Lynn , Hendifar Andrew Eugene , Hoos William Arthur , Mikhail Sameh , Chung Vincent M. , Picozzi Vincent J. , Heartwell Craig , Mason Kimberly , Varieur Katelyn , Madhavan Subha , Petricoin Emanuel , Pishvaian Michael J. 
Published: February 2017

279 Background: There has been a significant increase in the utilization of MoP to facilitate the selection of therapies for pts with advanced cancers. However, coordinated efforts to perform uniform MoP and collect clinical outcomes data have only successfully been executed in limited academic settings. In an effort to “democratize” the availability of MoP for PDA patients in a broad spectrum of clinical settings, The Pancreatic Cancer Action Network (PanCAN) and Perthera initiated the KYT initiative, an academic, industry, and advocacy group collaboration. Methods: PDA pts self-referred to the Patient Central call center at PanCAN. Pts interested in enrolling in an IRB-approved registry trial were then referred to Perthera to facilitate consent, tissue acquisition, and commercial MoP of the pt’s tumor. Test results were reviewed by a team of PDA specialists in the context of the pt’s treatment (tx) history. A report detailing tx options was delivered to the pt’s oncologist. Pts are being actively followed longitudinally to assess physician acceptance of the tx options and to track outcomes. Results: From 06/2014 to 09/2015, 382 pts were enrolled into KYT. Of these, 273 pts from 192 physicians (community and academic) in 38 states were enrolled. Reasons for non-enrollment were: pts no longer interested (67%); pts too ill or not appropriate for KYT (17%); the pt’s physician would not sanction MoP (16%). To date, 162 pt tumor samples have been obtained, and 117 reports delivered. 75% of samples had adequate tissue for genomic profiling (NGS), with 87% of samples harboring a KRAS mutation. Actionable findings (i.e. linked to a specific tx option) identified by NGS included mutations in BRCA2 (5%), PALB2 (1%), ATM (4%); BRAF (2%), PIK3C/PIK3R (7%), STK11 (5%), amplification of ERBB2 (3%), FGFR (2%), PDGFR (2%); and RET fusions (2%). Of the 117 profiles, 43% revealed actionable findings; 58% presented off-label therapy options; and 48% led towards high priority clinical trials. Conclusions: MoP of pts with PDA is feasible irrespective of their geographical location or access to an academic center. Updated information on tx selection and patient outcomes will be provided.
Angiogenesis polymorphisms profile in the prediction of clinical outcome of advanced HCC patients receiving sorafenib: Combined analysis of VEGF and HIF-1α—Final results of the ALICE-2 study.
Authors: Faloppi Luca , Casadei Gardini Andrea , Masi Gianluca , Silvestris Nicola , Loretelli Cristian , Ulivi Paola , Vivaldi Caterina , Bianconi Maristella , Giampieri Riccardo , Bittoni Alessandro , Andrikou Kalliopi , Del Prete Michela , Scartozzi Mario , Cascinu Stefano 
Published: February 2017

280 Background: HIF-1α plays a crucial role in tumour angiogenesis triggering the transcription of several genes including VEGF. The overexpression of HIF-1α in HCC is associated with tumour angiogenesis, invasion, metastasis, treatment resistance and poor prognosis. The therapeutic stronghold of advanced HCC is the TKI sorafenib. In our previous report (ALICE-1 study) SNPs rs2010963 and rs4604006 of VEGF have been shown to predict clinical outcome in HCC patients treated with sorafenib. Methods: 210 patients from a multicentre database were eligible for our analysis. Tumour samples were tested for 8 HIF-1α SNPs. Patients PFS and OS were analysed. Results: At univariate analysis CC > AA+AC of rs1951795, TT > CC+CT of rs10873142, AA+AG > GG of rs12434438 SNPs of HIF-1α were statistically significant for PFS and OS. The extended analysis of VEGF and VEGFR SNPs confirms the results of ALICE-1 study. At multivariate analysis rs12434438 of HIF-1α, rs2010963 of VEGF-A and rs4604006 of VEGF-C have been confirmed as independent factors. At the combined analysis of significant SNPs the presence of 2 favourable alleles of rs2010963 and rs4604006 of VEGF compared to only 1 or to none favourable alleles, identifies three populations with different PFS (respectively: 10.8 vs. 5.6 vs. 3.7 months, p < 0,0001) and OS (respectively: 19.0 vs. 13.5 vs. 7.5 months; p < 0,0001). Furthermore the presence of GG genotype of rs12434438 (HIF-1α) select a population with a particularly poor outcome independently from the clinical effect of the two VEGF SNPs (PFS: 2.6 months, p < 0,0001; OS: 6.6 months, p < 0,0001). Conclusions: This investigation on HIF-1α SNPs, following our previous discoveries on VEGF and VEGFR, may represent a clinical tool to identify patients with favourable response to sorafenib. In the presence of a favourable genotyping, clinicians would administer sorafenib as soon as clinically indicated, instead of delaying it with other treatments. Conversely patients with unfavourable genotyping may not be optimal candidates for sorafenib. These patients should be preferably included in clinical trials exploring new treatment options.
Effect of adjuvant (AD) radiotherapy (RT) on outcomes following pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PDA): A margin-stratified analysis.
Authors: Ocuin Lee Mayer , Miller Jennifer Lee , Zenati Mazen S , Steve Jennifer , Singhi Aatur D. , Burton Steven A. , Bahary Nathan , Bartlett David L , Hogg Melissa Ellen , Zeh Herbert J. , Zureikat Amer H. 
Published: February 2017

311 Background: The role of RT following PD for PDA remains controversial due to ambiguity in the definition of R0/R1 margin status in existing clinical trials. Recent data suggest that increased margin clearance (MC) is associated with improved survival after PD for PDA, however the role of adjuvant radiotherapy (ADRT) in patients with known MC is undefined. We sought to analyze the influence of ADRT on outcomes of PD for PDA based on MC data. Methods: We retrospectively identified 326 patients with MC data (in mm) who underwent PD between 2002-2014. Recurrence-free (RFS) and overall survival (OS) was determined by Kaplan-Meier analysis. Hazard ratios (HR) were calculated by Cox multivariate regression analysis on significant variables. Results: Mean age was 68 yrs and 55% were male. Median follow-up was 21 mos (IQR 12-34 mos). ADRT was administered to 87 patients (27%). Median RFS and OS for the entire cohort was 14 mos and 25 mos. On univariate analysis, ADRT was not associated with improved median RFS (13 vs. 14 mos; p = NS) or OS (23 vs. 27 mos; p = NS), but increasing MC was associated with prolonged median RFS [10 (0mm) vs. 13 (0-1mm) vs. 23 mos ( > 1mm); p < 0.02 for all pairs] and OS [16 (0mm) vs. 23 (0-1mm) vs. 40 mos ( > 1mm); p < 0.01 for all pairs]. After controlling for sex, BMI, neoadjuvant therapy, LVI, PNI, lymph node ratio > 0.2, tumor size > 2.5cm, and adjuvant chemotherapy, increasing MC was independently associated with improved OS [HR 0.680; p = 0.034 (0-1mm); HR 0.451; p < 0.001 ( > 1mm), compared to 0mm]. Patients were subsequently stratified into 3 groups based on MC [0mm (n = 73); 0-1mm (n = 118); > 1mm (n = 135)]. ADRT was administered less frequently to patients with greater MC [0mm (n = 29; 41%); 0-1mm (n = 36; 31%); > 1mm (n = 22; 16%); p < 0.001]. Even when stratified by MC, ADRT was not associated with improved RFS [10 vs. 9 mos (0mm); 13 vs. 12 mos (0-1mm); 21 vs. 23 mos ( > 1mm); p = NS for all pairs] or OS [16 vs. 18 mos (0mm); 24 vs. 23 mos (0-1mm); 33 vs. 42 mos ( > 1mm); p = NS for all pairs]. Conclusions: ADRT is not associated with improved RFS or OS following PD for PDA regardless of MC. The use of RT following PD for PDA should be re-examined.