bluuebunny/crossref_metadata_2025_split huggingface dataset:
Precision delivery of RAS-inhibiting siRNA to pancreatic cancer via peptide-based nanoparticles.
Authors: Strand Matthew S. , Pan Hua , Krasnick Bradley , Zhang Xiuli , Goedegebuure Peter S. , Fleming Timothy , DeNardo David G , Gillanders William E. , Hawkins William G. , Wickline Samuel A. , Fields Ryan C. 
Published: March 2017

287 Background: Greater than 95% of pancreatic adenocarcinomas (PDACs) are driven by KRAS activation; yet, despite decades of work, no RAS inhibitors have reached the clinic. Furthermore, the delivery of therapeutic agents of any kind to PDAC has been hindered by the extensive desmoplasia that accompanies these tumors. Herein, we show that serum-stable and pH-sensing nanoparticles (NPs) are taken up by PDAC cells, can deliver KRAS-specific siRNA into the cytoplasm and inhibit KRAS expression, thereby causing cell death. We go on to use a spontaneous model of pancreas cancer to show that this system can effectively deliver siRNA to stroma-rich tumors. Methods: The murine PDAC cell line KP1 was tested for NP uptake in vitro utilizing fluorescent siRNA NPs (fNPs) in combination with confocal microscopy and flow cytometry. KP1 cells were treated with KRAS-siRNA NP, and KRAS expression and cell viability were assessed with RT-PCR and CellTiter-Glo, respectively. Mice bearing subcutaneous KP1 tumors and KPPC mice with spontaneous PDAC were injected with fNP, and tumor fluorescence was assessed using an in vivo imaging system and fluorescence microscopy. Results: KP1 cells take up fNP in vitro, with > 99% of cells positive for fluorescent signal at 24 hours. Treatment with KRAS-siRNA NP of KP1 cells reduced KRAS expression by 69% (see Figure) and reduced cell viability by 45% compared to untreated and scramble-siRNA treated controls. Gemcitabine demonstrated an additive effect with anti-KRAS therapy. Tumors from KP1 cells grown in mice, and tumors from KPPC mice, were strongly fluorescent 24 hours after IV injection of fNP. Fluorescence microscopy showed successful delivery of fNP to tumors. Conclusions: Our NP system can precisely deliver siRNA to KP1 cells and spontaneous PDAC, overcoming the predominant stromal component in these tumors. KRAS-siRNA delivery downregulates KRAS expression, leading to cell death. This represents a novel treatment for PDAC. Furthermore, with its ability to deliver siRNA into the tumor microenvironment and suppress a known oncogene, this platform could be used to target other putative drivers of tumor progression across various cancer types.
Serum HER2 level during chemotherapy as a biomarker for advanced gastric cancer.
Authors: Saito Mayuko , Arimura Yoshiaki , Yamashita Kentaro , Suzuki Kazuya , Adachi Takeya , Kaneto Hiroyuki , Yawata Atsushi , Nakachi Kohei , Okuda Hiroyuki , Yoshimoto Mitsuru , Tanuma Tokuma , Hamamoto Yasuo , Nakase Hiroshi 
Published: March 2017

29 Background: Recent studies showed that serum HER2 levels correlated with tissue HER2 status in gastric cancer. The aim of this prospective study (UMIN000006442, 000006445) was to investigate changes in serum HER2 levels and tissue HER2 status during chemotherapy for advanced gastric cancer (AGC). Methods: Chemotherapy (Capecitabine and cisplatin) with and without trastuzumab was administered to patients with HER2-positive and HER2-negative AGC, respectively. Serum HER2 level was measured using chemiluminescense immunoassay (CLIA) at 4 points: at the initial diagnosis, after two cycles of chemotherapy, at the initial evaluation of tumor response, and at the time of progression. If possible, second biopsy was performed at progression to compare tissue HER2 status before and after chemotherapy. Results: Thirty-three patients (14 HER2-positive and 19 HER2-negative) with a median age of 67 years (range 51-80) were recruited. The median baseline serum HER2 level of the HER2-positive group was significantly higher than that of the HER2-negative group (p = 0.038, 12.0 ng/ml (range 6.5-148.0) and 8.2 ng/ml (4.5-27.2), respectively). A Decrease in serum HER2 level was correlated with tumor response in the HER2-positive group while it was not in the HER2-negative group. Tissue samples at the time of progression were obtained in 6 out of 19 HER2-negative cases. Of these, serum HER2 level elevated at progression in 4 cases, and tissue HER2 status has turned to positive at tumor progression in one case. In the HER2-positive group, tissue samples at tumor progression were obtained in 2 cases, and both showed HER2-positive result, same as the initial diagnosis. Conclusions: Serum HER2 could be useful as a response indicator in HER2-positive AGC. Tissue HER2 status may change from negative to positive over time and serum HER2 has a possibility to predict it. Further studies are needed to confirm these findings. Clinical trial information: UMIN000006442,000006445.
Characteristics of long-term survivors in a randomized phase III trial (NAPOLI-1) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan (nal-IRI; MM-398) + 5-FU/LV.
Authors: Wang-Gillam Andrea , Li Chung-Pin , Bodoky Gyorgy , Dean Andrew , Lee Kyung-Hun , Cunningham David , Hubner Richard , Siveke Jens T. , Braiteh Fadi S. , Pipas J. Marc , Belanger Bruce , de Jong Floris , Mody Purvi D. , Chen Li-Tzong , Von Hoff Daniel D. 
Published: March 2017

293 Background: nal-IRI, a liposomal formulation of irinotecan, plus 5-FU/LV is approved in the United States and Taiwan for patients (pts) with mPDAC previously treated with gemcitabine-based therapy. Primary analysis of the NAPOLI-1 trial (NCT01494506) showed that nal-IRI+5-FU/LV significantly improved median overall survival vs 5-FU/LV (6.1 vs 4.2 months; HR, 0.67; 95% CI, 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). Herein we report baseline characteristics of pts surviving ≥1 year (data cutoff, Nov 2015). Methods: This analysis includes 117 pts assigned to treatment with nal-IRI 70 mg/m2 (free base) + 5-FU/LV 2400/400 mg/m2 q2w, and 119 pts assigned to treatment with 5-FU/LV 2000/200 mg/m2weekly for weeks 1-4 q6w. Results: A total of 29 (25%) pts in the nal-IRI+5-FU/LV arm and 17 (14%) in the 5-FU/LV arm survived ≥1 year. These pts typically had better performance status, lower CA19-9 (U/mL) levels, and were less likely to have liver metastases at baseline, compared with the overall population (Table). For long-term survivors in the nal-IRI+5-FU/LV arm, a higher proportion of pts had neutrophil-to-lymphocyte ratio (NLR) >5, a marker of poor prognosis, suggesting that higher NLR may potentially be predictive of survival outcome with nal-IRI+5-FU/LV. Conclusions: More pts receiving nal-IRI+5-FU/LV versus 5-FU/LV were alive beyond 1 year. The most prominent prognostic markers of survival ≥1 year included lower CA19-9, KPS ≥90 and absence of liver metastases. These analyses may be limited by small sample sizes. Clinical trial information: NCT01494506. [Table: see text]
Phase IB trial of ADI-PEG 20 (A) plus nab-paclitaxel (nab-P) and gemcitabine (gem) in patients with advanced pancreatic cancer (PC).
Authors: Lowery Maeve Aine , Harding James J. , Yu Kenneth H. , Kelsen David Paul , Bomalaski John S. , Glassman Danielle C. , Covington Christina M. , Brenner Robin , Hollywood Ellen , Barba Adalberto , Johnston Amanda , Liu Kay Chia-Wei , Capanu Marinela , Abou-Alfa Ghassan K. , O'Reilly Eileen Mary 
Published: March 2017

295 Background: ADI-PEG 20 (A) is a pegylated form of arginine depleting enzyme, arginine deaminase. Normal cells synthesise arginine using the enzyme argininosuccinate synthetase (ASS). A selectively targets malignant cells which lack ASS. A has shown encouraging pre clinical activity as monotherapy in PC, and synergistic activity with gem and taxanes. Methods: Eligibility: Metastatic PC, up to one line of prior treatment (dose escalation cohort:ct) no prior treatment (expansion ct), ECOG 0-1.Treatment: gem 1,000 mg/m2, nab-P 125mg/m2 3 out of 4 weeks, A 18 mg IM weekly (ct 1), A 36mg weekly (ct 2 and expansion ct). Primary endpoint: determine MTD of A in combination with nab-P and gem. Statistical plan: Single arm, non-randomized, open-label, phase IB, standard 3 + 3 dose escalation with expansion ct of 9 patients at MTD. Secondary endpoints: progression-free survival (PFS), response rate, overall survival (OS), safety, tolerability, blood and archival tumor analyses for ASS expression and immunogenicity. Pts treated at MTD and on expansion cohort were eligible for primary and secondary endpoints. Results: Between 11/14 and 09/15, 18 pts enrolled. 4 pts (22%) had 1 prior line of therapy. Toxicity attributable to A was limited to grade 1 rash/erythema at injection site (n = 3). Cohort 2 was expanded to 6 pts due to DLT of elevated LFTs, no further DLTs observed. ≥ grade 3 toxicity attributable to gem and/or nab-P included elevation in AST/ALT, hematologic toxicity, fatigue, diarrhea, neutropenic fever, alopecia as expected. No A related grade 3-5 toxicities were observed. Response: 6 pts (40%) PR, including one previously treated pt, 8 pts (53%) stable disease (SD), 1 pt inevaluable. Two pts continue on study, median PFS 6.5 months (95% CI 5.3 – 15.2), median OS 11.3 months (95% CI 4.9- . ). Eight of 15 pts treated at MTD received 2nd-line chemotherapy at progression. Five of 11 archival tumors samples tested for ASS1 expression by IHC were deficient. Conclusions: A was well tolerated in combination with gem and nab-P. Activity was observed in treated and untreated pts, and in pts with ASS deficient and proficient tumors; synergy of A with cytotoxics may be independent of ASS status and future investigation in an unselected population is warranted. Clinical trial information: NCT02101580.
Profiling of small intestine neuroendocrine tumors to reveal characteristic miRNAs detectable in plasma.
Authors: Bowden Michaela , Zhou Chensheng Willa , Zhang Sui , Brais Lauren K. , Rossi Ashley , Naudin Laurent , Thiagalingam Arunthi , Sicinska Ewa , Kulke Matthew H. 
Published: March 2017

299 Background: Current blood-based biomarkers for neuroendocrine tumors are limited. We performed a multi-stage study to identify characteristic circulating miRNAs in patients with advanced small intestine neuroendocrine tumors, and to assess associations between miRNA levels and survival. Methods: Using a 742-miRNA panel, we identified candidate miRNAs similarly expressed in 19 small intestine neuroendocrine tumors and matched plasma samples. We refined our panel in an independent cohort of plasma samples from 40 patients with advanced small intestine NET and 40 controls, and validated this panel in a second cohort of 120 patients and 120 controls. Results: miRNA profiling of 19 tumors and matched plasma samples revealed 31 candidate miRNAs similarly expressed in both tissue and plasma. We evaluated expression of these 31 candidate miRNAs in 40 independent cases and 40 normal controls, and identified 4 miRNAs (miR-21-5p, miR-22-3p, miR-29b-3p, and miR-150-5p) that were differently expressed in cases and controls (p < 0.05). We validated these 4 miRNAs in a separate, larger panel of 120 cases and 120 controls. High circulating levels of miR-22-3p (p < 0.0001), high levels of miR 21-5p, and low levels of miR-150-5p (p = 0.027) were associated with the presence of advanced small intestine NET. While levels of 29b-3p were lower in cases than in controls in both the initial cohort and the validation cohort, the difference in the validation cohort did not reach statistical significance. We further found that high levels of circulating miR-21-5p, high levels of circulating miR-22-3p and low levels of circulating miR-150-5p were each independently associated with shorter overall survival. A combined analysis using all three markers was highly prognostic for survival (HR 0.47, 95% CI 0.27-0.82). Conclusions: Our study suggests that elevated circulating levels of miR-21-5p and miR-22-3p and low levels of miR-150-5p are characteristic in patients with advanced small intestine neuroendocrine tumors, and further suggests that levels of these miRNAs are associated with overall survival.
Overcoming erlotinib resistance with STAT3 inhibition in pancreatic cancer.
Authors: Salzberg Matthew Philip , Merchant Nipun B. 
Published: March 2017

304 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a major therapeutic challenge. Cytotoxic chemotherapy remains the standard approach in PDAC, but results in minimal survival benefit for patients, highlighting a desperate need for novel treatment strategies. Epidermal growth factor receptor (EGFR) is overexpressed in 25-90% of PDACs and has been shown to be an adverse prognostic marker for survival, making it a rational target. To date, the combination of the EGFR tyrosine kinase inhibitor, erlotinib, with gemcitabine remains the only approved targeted therapy based on a significant, yet modest, improved overall survival when compared to gemcitabine alone in a phase III clinical trial. We have previously shown that constitutively activated signal transducer and activator of transcription 3 (STAT3) signaling is a biomarker of resistance to both gemcitabine and erlotinib. Therefore, we hypothesized that combined STAT3 and EGFR inhibition would overcome resistance to erlotinib and gemcitabine in PDAC. Methods: Human pancreatic cancer cell lines MiaPaca2 ( KRASG12C ; TP53mut ; EGFRwt) or BxPC-3 ( KRASwt ; TP53mut ; EGFRwt) were treated in a dose dependent manner with erlotinib in the presence or absence of gemcitabine. PDAC cells were additionally treated with EC50doses of a STAT3 inhibitor (AZD1480), erlotinib, and/or gemcitabine. Lysates were then collected and western blot analysis was performed to detect total and phosphorylated extracellular signal regulated kinase (ERK) or STAT3. Results: EGFR inhibition with erlotinib, with or without gemcitabine, results in decreased ERK activation, however, causes an increased activation of STAT3 signaling in both MiaPaca2 and BxPC-3 cells. Combined STAT3 and EGFR inhibition results in sustained attenuation of both phosphorylated ERK and STAT3 levels. Conclusions: Our study demonstrates that activated STAT3 signaling appears to be a mechanism of resistance to erlotinib and gemicitabine treatment in PDAC. Combining STAT3 inhibition with EGFR inhibition overcomes this resistance.
Analysis of prior malignancies in patients with cholangiocarcinoma.
Authors: Boucher Taryn Mary , Kemeny Nancy E. , Chou Joanne F. , Capanu Marinela , Lowery Maeve Aine , Cercek Andrea 
Published: March 2017

305 Background: Cholangiocarcinomas account for approximately 3% of gastrointestinal tumors. Our aim was to analyze types of prior malignancies in patients (pts) with cholangiocarcinoma, with a special interest in pts with prior breast cancer. Methods: An IRB waiver was obtained to retrospectively review female pts who presented with an initial diagnosis of cholangiocarcinoma to Memorial Sloan Kettering Cancer Center between January 2000 and August 2015. Results: Medical records of 804 female pts were reviewed. After excluding pts with limited records or without biopsy-proven cholangiocarcinoma, a total of 625 pts were analyzed. Of 625 pts with cholangiocarcinoma, 506 (81%) were intrahepatic (ICC), 85 (14%) hilar, 24 (4%) extrahepatic and 10 (2%) mixed ICC and hepatocellular carcinoma or rare variant. The median age at cholangiocarcinoma diagnosis was 63 years [range: 16-97 years] and 82.7% were white. Of the 625 pts, 105 (17%) had a history of another cancer: 44 (7.04%) breast, 9 (1.44%) colon, 9 (1.44%) melanoma and 5 (0.8%) ovarian. The remaining 38 pts with various prior cancers were grouped as Other. There was no association between the site of cholangiocarcinoma (intrahepatic versus extrahepatic) and type of prior cancer (p = 0.26). In pts with a prior cancer (n = 105), the median time from diagnosis of prior cancer to cholangiocarcinoma was 76 months [range: 2-624 months], which did not differ among types of prior malignancies (p = 0.25). The interval between diagnosis of breast cancer and cholangiocarcinoma was 82 months [range 4-526 months]. In pts with prior breast cancer, 21 (48%) received radiation and 25 (57%) received chemotherapy for their breast cancer. In 22 pts who had ER/PR testing, 16 were ER positive and 15 were PR positive. In 17 pts who had HER2 testing, 4 were HER2 positive. Conclusions: In 625 female pts with cholangiocarcinoma, 17% had a history of another cancer, with 44 (7%) having a history of breast cancer. The apparent increase in proportions of prior breast cancer compared to other cancers should be investigated further. An analysis of tumor mutations (MSK-IMPACT) and germline mutations in pts with cholangiocarcinoma and a history of breast cancer is underway to determine a potential association of molecular factors.
ATM as a biomarker for DNA damage repair deficiency in pancreatic ductal adenocarcinoma.
Authors: Golan Talia , Halparin Sharon , Stossel Chani , Raitses-Gurevich Maria , Atias Dikla , Buzhor Ella , Cohen Keren , Borshtein Roni , Schvimer Michael , Berger Raanan 
Published: March 2017

308 Background: Approximately 15% of PDAC tumors display DNA damage repair (DDR) deficiency. Germline BRCA (gBRCA) mutation serves as a robust biomarker for the DDR deficiency. A subset of patients displays a similar clinical phenotype but lack the gBRCA mutation. Identification of these BRCA-like subset of patients remains a challenge and an alternative approach may include DDR functional assays. Here we suggest loss of the ATM protein as one of the biomarkers for the identification of the DDR deficiency signature in PDAC. Methods: Patients were identified from the Sheba pancreatic cancer database based on strong family/personal history of BRCA- associated cancers or a durable response to platinum containing regimens ( ≥ 6 month) or harboring germline/somatic mutations in the DNA repair pathway (excluding gBRCA mutation). Archival FFPE blocks of primary tumors/metastatic lesions were used to explore ATM protein expression by IHC. Nuclear staining was regarded as positive. Tumor infiltrating lymphocytes served as an internal positive control. ATM loss was defined as less than10% neoplastic nuclear staining at any intensity in the presence of positive lymphocytes staining. Results: We identified 53 patients with DDR deficiency phenotype between 2014-2016 from the Sheba PDAC database (n = 250). Median age at diagnosis was 65 years (46-81) and the majority were female (62%). 47% were diagnosed at stage I/II and 53% stage IV. In the subgroup of patients with DDR deficiency phenotype, 55% displayed a family history of BRCA-associated cancers, 19% had a personal history of malignancy and23% had known mutation in DNA repair pathway. 23/53 identified subjects have been analyzed to date. We identified 52% loss of ATM in the analyzed group (n = 23). Conclusions: Loss of ATM in an unselected PDAC population is 12% (H. Kim et al, 2014). Our data demonstrate that 52% of the highly selected subgroup of PDAC patients (DDR deficiency phenotype) was found to have loss of ATM protein expression, suggesting it to be one of the biomarker for DDR signature. Identification of these patients, based on ATM protein expression profile may lead to personalized treatment options.
The efficacy of stratifying patients with laparoscopic gastrectomy at age, body mass index and preoperative serum C-reactive protein level for predicting an incidence ratio of postoperative complications.
Authors: Amada En , Takeuchi Hiroya , Nakamura Rieko , Suda Koichi , Wada Norihito , Kawakubo Hirofumi , Kitagawa Yuko 
Published: March 2017

31 Background: Wide variety of Predictive factors (PF) of postoperative complications (PC) in patients with gastric cancer(GC) that have undergone laparoscopic gastrectomy(LG) has been reported. The aim of this study is to devise simple PF for PC for LG that can estimate risk of PC preoperatively. Methods: Two hundred and ninety-eight patients that have been underwent curative LG against GC during May 2012 to March 2016 were enrolled. Patients’ characteristics, preoperative (pre-) laboratory data, operative information and pathological factors were analyzed. Also PC with Clavien-Dindo classification Grade (CD)≥II (PC≥II), pancreatic fistula (PF), intraabdominal abscess (IA), pneumonia (PN) and anastomotic leakage (AL) with CD≥III were examined. Results: Patients with pStage I, II, III and IV was 83%, 11%, 5.6% and 0.4%, respectively. Patients with PC≥II, PF or IA, PN and AL was 17.4%, 5%, 1% and 2.3%, respectively. Patients with PC≥II were significantly elder (p=0.01) and had higher pre-serum-C-reactive protein level (CRP) (p=0.02). Also, patients with AL had significantly higher Body Mass Index (BMI) (p=0.04). We devised “ABC score” by Age, BMI and CRP. It is defined as a number of factors in age, BMI and CRP that are higher than cutoff value of 66 years’ old, 23 kg/m2 and 0.04 mg/dL, respectively. Patients with ABCs 0, 1, 2, and 3 were 26%, 33%, 34% and 7%, respectively. Patients with ABCs 3 had significant high risk of PC≥II and AL (HR 2.8, p=0.03 and HR 9.9, p=0.004, respectively). Also we found higher ABCs has higher risk of AL (HR1.2, p=0.07 for ABCs 2 and HR2.2, p=0.04 for ABCs 3). Conclusions: ABCs can be a PF for PC in patients with LG. Especially it may evaluate an incidence ratio of AL.
Phase I study of gemcitabine (G), dasatinib (D), and erlotinib (E) in advanced pancreatic carcinoma (PC).
Authors: Cardin Dana Backlund , Goff Laura Williams , Chan Emily , Whisenant Jennifer , Arlinghaus Lori R. , Yankeelov Thomas , Koyama Tatsuki , Berlin Jordan , Merchant Nipun B. 
Published: March 2017

315 Background: The combination of E with G remains the only approved targeted therapy for PC based on significant, yet modest, improved overall survival when compared to G alone in a phase III clinical trial. We have shown previously that adding the Src inhibitor D with E and G resulted in synergistic attenuation of tumor growth in vivo. The purpose of this study was to assess the safety of D given with E and G. Methods: This investigator-initiated study used 3+3 dose-escalation to determine the maximum tolerated dose in advanced PC patients (pts). Dose escalation started at 70 mg daily of D, 100 mg daily of E, and G on days 1, 8, and 15 (800 mg/m2) of a 28-day cycle. Diffusion-weighted MRI (DW-MRI) measurements (ADC) were collected prior to and at four weeks in a subset of pts (n=3). Results: Nineteen pts were enrolled. One pt experienced a DLT at the starting dose (L0); however, given the side effects observed in the first two pts, D was reduced to 50 mg (L-1). At L-1, one DLT was observed in 1/6 pts and the dose was re-escalated to L0. Zero DLTs were observed in the next four pts at L0 thus D was escalated to 100 mg (L1). Seven pts were treated at L1 as one pt was not evaluable for safety. In this cohort, 1/6 pts experienced a DLT. Although L1 was tolerable, dose escalation was stopped as it was felt L1was within the therapeutic window and escalation would enhance toxicity with minimal benefit. Most frequent toxicities (%) were anemia (89), elevated aspartate aminotransferase (79), fatigue (79), nausea (79), elevated alanine aminotransferase (74), lymphopenia (74), leukopenia (74), neutropenia (63), and thrombocytopenia (63), most Gr1/2. Zero responses were observed, but disease stabilization (SD) occurred in 9/13 (69%). Median duration of SD was 4 months, and median OS was 7.7 mos. At the time of data cutoff, two pts are still alive and in follow-up. Increase in ADC on MRI reflected a decrease in tumor cellularity suggesting therapeutic benefit; disease assessment at 8 weeks was SD. Conclusions: The most tolerable dose was determined to be 70 mg of D, 100 mg of E, and 800 mg/m2 of G. Clinical activity of this combination was observed as SD occurred in 69% of pts. DW-MRI could be a promising technique to assess clinical benefit early during the course of therapy. Clinical trial information: NCT01660971.