bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recombinant growth/differentiation factor-5 enhances cell proliferation and tendogenic differentiation of human periodontal ligament stem cells in vitro.
Authors: Xia Dengsheng , Sumita Yoshinori , Tran Simon 
Published: March 2020

e22191 Background: To investigate the function of growth/differentiation factor-5 (GDF-5) on cell proliferation and tendogenic differentiation of human periodontal ligment stem cells (PDLSCs) in vitro. Methods: PDLSCs were obtained from human healthy periodontal ligaments of wisdom teeth. Immunofluorescence cytochemistry was used to detect the characters of mesenchymal stem cells (MSCs) in PDLSCs. Recombinant mouse GDF-5 (rmGDF-5) protein was used to stimulate the PDLSCs. Tetrazolium reduction assay was carried out for cell proliferation. Alkaline phosphatase (ALP) activity was measured by ALP activity assay and ALP staining. Real-time RT-PCR was performed to detect the gene expressions of aggrecan (ACAN), collagen, type III (COL3), scleraxis (SCX), decorin (DCN), tenomodulin (TNMD) and tenascin C (TNC) in PDLSCs after stimulated by rmGDF-5 protein. Results: 5.6% STRO-1 positive cells was detected in primary PDLSCs. The cell proliferation of PDLSCs was enhanced by rmGDF-5 in a dose-dependent manner at 0, 20, 100 and 500 ng/ml of concentration. The special markers of tendogenic differention, ACAN, COL3, SCX and TNMD were up-regulated at mRNA level after rmGDF-5 treatment for 1, 2 or 3 weeks, and the 20 ng/ml was the more effective than 100 ng/ml and 500 ng/ml for rmGDF-5 in PDLSCs. The expressions of TNC and DCN were increased at 4 or 8 hours after 20, 50 and 100 ng/m rmGDF-5 treatment. The ALP activity results showed that ALP activities were decreased paralleled with increased rmGDF-5 concentration. Conclusions: The rmGDF-5 could promote the cell proliferation and tendogenic differentiation of PDLSCs in vitro.
“Druggable” alterations detected by ion torrent in metastasis colorectal cancer patients.
Authors: Fang Weijia , Radovich Milan , Zhou Anwu , Zheng Yulong , Zhao Peng , Huang Wenying , Mao Chenyu , Zheng Yi , Jia Yankai , Zheng Shusen 
Published: March 2020

e22192 Background: The frequency and poor prognosis of metastasis colorectal cancer (mCRC) emphasizes the need of better markers for both treatment and prognosis. Here we describe an approach of identifying somatic variants in exonic regions of key cancer genes. Methods: Formalin-fixed paraffin embedded (FFPE) tissues biopsied from mCRC patients were collected. DNA was extracted and sequenced on the Ion Torrrent Personal Genome Machine.For targeted amplification, we used the Ion AmpliSeq Cancer Panel which is designed to detect 739 mutations in 604 loci from 46 oncogenes and tumor suppressor genes with as little as 10ng of input DNA.Sequencing results were then analyzed using the Ampliseq Variant Caller plug-in within Ion Torrent Suite Software. Ingenuity Pathway Software was used to do pathway analysis. Cox regression was tested regarding the potential relationship between the alteration numbers and the clinical factors including response rate, disease free survival and overall survival, etc. Results: Among 10 specimens, we identified 66 genetic alterations in 24 genes after excluding the germline mutations according the dbSNP database. 41% of those alterations were also present in the COSMIC database (Catalogue of Somatic Mutations in Cancer). No clinical factor was found to be significantly associated with the alteration numbers by univariate analysis. Notably, there are 11 genes including the expected APC, BRAF, KRAS, PIK3CA and TP53 that were mutated in at least 2 samples. Pathway analysis identified “Colorectal Cancer Metastasis Signaling” as the top mutated canonical pathway. This analysis further revealed mutated genes in the classic signal pathways of Wnt, PI3K/AKT, and TGF-beta/SMAD as significantly present. Interestingly, 90% of specimens harbored at least one “druggable” alteration (range from 1 ~ 6)that has been linked to a target treatment or is currently being investigated in clinical trials. Those pairs of drug and targeted genes are vemurafenib to BRAF; cetuximab to EGFR; palifermin to FGFR2; pazopanib to FGFR3; AEE 788 to KDR and BEZ235 to PIK3CA. Conclusions: DNA deep sequencing of key cancer related genes enables identification of “druggable” mutations for individual colorectal cancer patients.
In vivo optical pathology of paclitaxel efficacy on the peritoneal metastatic xenografts of gastric cancer using multiphoton microscopy.
Authors: Tanaka Koji , Shimura Tadanobu , Okigami Masato , Toiyama Yuji , Morimoto Yuhki , Kitajima Takahito , Kondo Satoru , Kawamura Mikio , Saigusa Susumu , Okugawa Yoshinaga , Ohi Masaki , Inoue Yasuhiro , Uchida Keiichi , Araki Toshimitsu , Mohri Yasuhiko , Mizoguchi Akira , Kusunoki Masato 
Published: March 2020

e22205 Background: Peritoneal metastasis shows an extremely poor prognosis in patients with gastric cancer. Clinically, the tumor response to chemotherapeutics depends on anatomical location of metastasis. Metastatic tumor xenografts have been shown to be more resistant to chemotherapy than subcutaneous non-metastatic tumor xenografts in preclinical murine model. We have reported a method of in vivo optical pathology using multiphoton microscopy (MPM) in colorectal liver metastatic tumor xenograft model. Aim: We established a method of time-series in vivo optical pathology of peritoneal metastatic xenografts of gastric cancer using MPM. Then, we imaged and evaluated paclitaxel efficacy in the tumor microenvironment with regard to both tumor cell itself and intravascular change in tumor vessels. Methods: Red fluorescent protein (RFP) expressing human gastric cancer cell line (NUGC4) was inoculated into the peritoneal cavity of green fluorescent protein (GFP) expressing nude mice. Paclitaxel (10 mg/kg) was administered three times a week for more than three weeks. Intravital MPM was performed before and after paclitaxel treatment for the exteriorized peritoneal metastatic lesion in the same living mouse. Results: Four to six weeks later, RFP-NUGC4 cells formed macroscopic peritoneal metastases. Red-colored cancer cells and green-colored surrounding stroma with tumor vessels were clearly imaged at the cellular level (in vivooptical pathology). Their cross-sectional images were obtained from the tissue surface to the area of depth of 200 μm (z-stacks imaging). After paclitaxel treatment, tumor cell fragmentation, condensation, swelling and intracellular vacuoles were observed. Within the tumor vessels, platelet aggregation and platelet adhesion to endothelial cells were observed. Conclusions: In vivo optical pathology using MPM provides histopathological information about three-dimensional tissue microarchitecture without tissue shrinkage by fixation and tissue destruction by microtome-sectioning. Our method may become a powerful tool to evaluate the tumor response to new chemotherapeutics on ‘metastatic site’ in preclinical tumor xenograft model.
Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study.
Authors: Hammel Pascal , Huguet Florence , Van Laethem Jean-Luc , Goldstein David , Glimelius Bengt , Artru Pascal , Borbath Ivan , Bouche Olivier , Shannon Jenny , André Thierry , Mineur Laurent , Chibaudel Benoist , Bonnetain Franck , Louvet Christophe 
Published: March 2020

LBA4003 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
A phase III randomized trial of chemoimmunotherapy comprising gemcitabine and capecitabine with or without telomerase vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer.
Authors: Middleton Gary William , Valle Juan W. , Wadsley Jonathan , Propper David , Coxon Fareeda Y. , Ross Paul J. , Madhusudan Srinivasan , Roques Tom , Cunningham David , Corrie Philippa , Greenhalf William , Shaw Victoria , Cox Trevor F. , Silcocks Paul , Nanson Gemma , Neoptolemos John P. 
Published: March 2020

LBA4004 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
A phase II study of oral ENMD-2076 administered to patients (pts) with advanced soft tissue sarcoma (STS).
Authors: Loong Herbert H. F. , Blackstein Martin E. , Gupta Abha A. , Hogg David , Mackay Helen , Dhani Neesha C. , Oza Amit M. , Moore Malcolm J. , Razak Albiruni R.A. 
Published: March 2020

TPS10593 Background: The use of angiogenic and Aurora kinase inhibitors has been shown to abrogate tumour growth in STS. ENMD-2076 is an oral Aurora A and angiogenic kinase inhibitor that has demonstrated single-agent activity in sarcoma cell lines. Prior phase I dose escalation study has determined the maximum tolerated dose of ENMD-2076 to be 160mg/m2, with a recommended starting dose of 275mg/day. In that study, one patient with STS experienced durable stable disease (21 months). Primary Objective: To determine the activity of ENMD-2076 in advanced STS (with ≤1 prior line of therapy) as defined by 6-month progression-free survival rate (PFSR). Secondary Objectives: (i) To determine the safety and tolerability of ENMD-2076, (ii) To determine the objective response rate (ORR) as per RECIST criteria and duration of response, (iii) To perform exploratory analysis of factors associated with survival. Study Design and Methodology: This is a single-center, open-labeled phase II study of ENMD-2076 in advanced STS. Pts are commenced on 275 mg daily dose on a 28 day cycle. Treatment-emergent adverse events will be assessed by the NCI-CTCAE (4.0). Radiographic or clinical tumour measurements will occur every 2 cycles. Sample Size Justification: It is assumed that ENMD-2076 shall be deemed non-efficacious in this population if the true 6- month PFSR probability is <15% (p0), whilst a 6-month PFSR probability >40% will be considered positive for activity. This translates to a minimum of 21 evaluable subjects required in the study, within which ≥6 patients need to have shown lack of progression at 6 months in order for this study to be considered positive. This design has a significance level of 10% and power of 90%. Methods: PFSR at 6-months will be estimated using the Kaplan-Meier method. ORR will be estimated and 2-sided 95% exact binomial confidence interval will be provided. Study Progress: At deadline for abstract submission, 3 patients have been enrolled onto this study. Clinical trial information: NCT01719744.
Phase II study of ruxolitinib in patients with pStat3+ breast cancer.
Authors: Lin Nancy U. , Gelman Rebecca Sue , Brock Jane E. , Bardia Aditya , Mayer Erica L. , Overmoyer Beth , Wang Vivian , Iannone Marie , Krop Ian E. , Polyak Kornelia , Winer Eric P. 
Published: March 2020

TPS1134 Background: Multiple lines of evidence implicate the IL-6/JAK2/Stat3 signaling pathway in metastatic progression and therapeutic resistance in breast cancer (Marotta et al, JCI2011; Britschgi et al, Cancer Cell 2012). Ruxolitinib, an oral inhibitor of JAK1 and JAK2, is approved for the treatment of intermediate or high-risk myelofibrosis, but has not been extensively tested in solid tumors. Methods: Pts with triple-negative breast cancer or inflammatory breast cancer of any subtype are eligible for prescreening of archival tumor tissue for pStat3 expression by immunohistochemistry. Pts with high (Cohort A; T-score >5) or low (Cohort B; T-score 3-4) pStat3 expression, measurable disease, adequate organ function, ECOG PS 0-2, and progression through > 1 line of prior therapy may proceed to receive ruxolitinib, 25 mg orally twice daily. Staging studies are performed at baseline (BL) and every 8 weeks (wk). Baseline tumor biopsy is required for pts who have accessible disease, with an optional biopsy at progression. Blood for IL-6, CRP, and circulating tumor cells are collected at BL, Wk 4, and off-treatment. Patient reported outcomes including EORTC QLQ C-30 and the M.D. Anderson Symptom Inventory are collected at BL, Wk 4, Wk 8, and off-treatment. Statistical Considerations: The primary endpoint of this open-label phase 2 trial is objective response by RECIST 1.1. The study is designed to distinguish between a response rate of 5% versus 20% in each cohort, separately. If > 2 responses out of 21 pts are observed in the first stage of Cohort A, a further 20 pts will be entered on that cohort; the agent will be deemed worthy of further study if > 5 of the total 41 pts achieve an objective response (power 0.90, type I error 0.046). Cohort B will open to accrual if Cohort A passes the first stage. If > 2 responses out of 21 pts are observed in the first stage of Cohort B, a further 20 patients will be entered into Cohort B, and the agent will be deemed worthy of further study if > 5 of the total 41 pts achieve an objective response (power 0.90, type I error 0.046). Study Status: A total of 85 patients have consented for prescreening of tumor tissue. As of January 3, 2013, 5 of a planned 41 patients with high pStat3 IHC scores have been treated with ruxolitinib, and accrual is ongoing. Clinical trial information: NCT01562873.
A phase I study of the BCR-ABL tyrosine kinase inhibitor nilotinib and cetuximab in patients with solid tumors that can be treated with cetuximab.
Authors: Smaglo Brandon George , Wang Hongkun , Steadman Kenneth , Murray Joseph , Pishvaian Michael , He Aiwu Ruth , Hwang Jimmy J. , Subramaniam Deepa Suresh , Deeken John F. , Weiner Louis M. 
Published: March 2020

TPS2624 Background: Therapeutic blockade of Epidermal Growth Factor Receptor (EGFR) signaling with the monoclonal antibody cetuximab is clinically effective in the treatment of patients with metastatic squamous cell carcinoma of the head and neck or KRAS wildtype colorectal cancer. However, these patients eventually become resistant to this therapy. An exploration of the EGFR signaling network using an EGFR network-focused small interfering RNA library identified potential regulators of resistance to EGFR-targeted therapies. The ABL1 gene was identified as a central node to target in this complex genomic pathway. In a preclinical EGFR-expressing cancer cell line model, targeting c-abl, the gene product of ABL1, using nilotinib was found to be highly synergistic in decreasing cell survival when combined with anti-EGFR targeted therapy. Methods: We have initiated an open-label Phase I study for patients who progressed after standard therapies for metastatic KRAS wildtype colorectal cancer or metastatic head and neck squamous cell carcinoma. Enrolled patients must have adequate performance status and organ function. Treatment consists of cetuximab 400 mg/m2 on day 1, then 250 mg/m2 once weekly, and nilotinib twice daily, starting on day 1, according to a traditional 3+3 dose escalation, from 200mg to 300mg BID. Patients are restaged every 2 cycles (every 8 weeks). The primary endpoint is the maximum tolerated dose (MTD) of nilotinib when used in conjunction with cetuximab. Secondary endpoints are clinical benefit rate (defined as rates of stable disease, partial response, and complete response) and response rate. Additionally, biopsies of metastases obtained prior to and after initiation of therapy will be used to establish primary tumor cell cultures using conditional cellular reprogramming to permit the dynamic study of signaling and drug sensitivity through an evaluation of evidence of a drug effect on EGFR signaling and on Antibody-Dependent Cell-Mediated Cytotoxicity. An additional 10 colorectal cancer patients will be treated as an expansion cohort at the MTD. This expansion cohort data may be used to plan a Phase II trial in the future.
FGFR: Proof-of-concept study of AZD4547 in patients with FGFR1 or FGFR2 amplified tumours.
Authors: Smyth Elizabeth Catherine , Turner Nicholas C. , Popat Sanjay , Morgan Shethah , Owen Kate , Gillbanks Angela , Jain Vikram Kumar , Cunningham David 
Published: March 2020

TPS2626 Background: Genetic modifications of the FGFR family of transmembrane tyrosine kinase growth factor receptors are described in a range of cancers. Amplification of FGFR2 is detected in up to 10% of oesophagogastric cancers where it is associated with poor prognosis. FGFR1 amplification has also been demonstrated in 10% of breast cancers, is more common in luminal B ER positive tumors, and is also associated with inferior survival outcomes. Finally, FGFR1 amplification has been described in up to 22% of squamous cell lung cancers. AZD4547 is a potent and selective inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases. Preclinically, AZD4547 potently inhibits growth in FGFR amplified gastric and lung cancer cell lines and induces dose dependent tumor growth inhibition and regression in FGFR amplified tumour xenograft and patient derived explant models. Methods: This is an open label, phase II non-randomised multi-centre study to assess the efficacy of AZD4547 monotherapy and resulting molecular changes in serial biopsies in pts with previously treated FGFR1 amplified advanced breast cancer, FGFR2 amplified advanced oesophagogastric cancer, or FGFR1 amplified advanced squamous lung cancer. Eligibility include centrally verified FGFR amplified tumour (ratio >2.2), PS=0-2, ability to comply with the collection of tumor biopsies (mandatory at baseline and on days 10-14), calcium and phosphate within normal limits, measurable disease (RECIST 1.1), and no history of significant eye disease. Pts may be prescreened for FGFR amplification on archival tissue while undergoing first line or adjuvant chemotherapy. Sixteen pts will be enrolled per cohort. All pts will receive AZD4547 80mg bd on a two week on, one week off schedule. The primary endpoint is correlation between change in pERK in pretreatment and day 10-14 biopsy and change in tumour diameter on week 8 CT. Secondary endpoints include ORR, DCR and PFS. Multiple exploratory translational endpoints are also planned. The study is currently open at the Royal Marsden Hospital and will open at 15 selected UK cancer centres. This study is sponsored by the Royal Marsden Hospital, funded by AstraZeneca and has been adopted to the UK National Cancer Research Network (NCRN) portfolio. Clinical trial information: 2011-003718-18.
A phase I dose-escalation study evaluating the effects of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with select relapsed or refractory hematologic malignancies.
Authors: Lesokhin Alexander M. , Gutierrez Martin , Halwani Ahmad Sami , Ansell Stephen Maxted , Armand Philippe , Borrello Ivan , Segota Zdenka E , Cohen Adam D. , Talpaz Moshe , Cattry Deepika , Turner Tracy , Mezes Maria , Hartman Christina , Gupta Ashok Kumar , Kim Su Young , Wigginton Jon M. , Timmerman John 
Published: March 2020

TPS3113 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported with various hematologic malignancies and may prevent the host immune response from exerting an antitumor effect on the malignant cells. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, has demonstrated antitumor activity in pts with solid tumors including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. We hypothesized that nivolumab could also mediate antitumor activity in pts with hematologic malignancies, a significant area of unmet medical need. We describe a phase I study to evaluate the effects of nivolumab in pts with select hematologic malignancies. Methods: This open-label, two-part study will enroll approximately 100 pts. During dose escalation, successive cohorts of pts with relapsed or refractory hematologic malignancies will be treated using a 6+3 escalation design. Pts will receive 1 or 3 mg/kg nivolumab IV every 2 weeks (wks) (the first dose will be followed by a 3-wk evaluation period), for 2 years, with the potential for an additional year of therapy for pts who progress during the follow-up period. Subsequently, 5 tumor-specific cohorts of 16 pts will be enrolled at the maximum tolerated dose (MTD) for multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia. Response will be assessed at wks 4, 8, 16, 24, and every 16 wks thereafter. The primary study objective is to establish dose limiting toxicities, the MTD, and the recommended phase II nivolumab dose. Secondary objectives are to characterize nivolumab pharmacokinetics, immunogenicity, preliminary antitumor activity, and the potential association between PD-L1 expression on tumor cells and clinical efficacy. Exploratory objectives include investigation of the immunoregulatory effects of nivolumab in peripheral blood, bone marrow, and/or tumor. Pts are currently being enrolled at 3 mg/kg. Clinical trial information: NCT01592370.
Biomarker correlation to clinical response in phase I/II trials of the adjuvant breast cancer vaccine neuvax (nelipepimut-S or E75).
Authors: Berry John S. , Trappey Alfred F , Sears Alan K. , Vreeland Timothy J , Clifton Guy T. , Hale Diane F. , Patil Ritesh , Holmes Jarrod P. , Ponniah Sathibalan , Mittendorf Elizabeth Ann , Peoples George Earl , Van Echo David C. 
Published: March 2020

TPS3126 Background: We completed phase I/II clinical trials with NeuVax (nelipepimut-S), a HLA-A2/A3-restricted, HER2-derived peptide vaccine. The vaccine was administered in the adjuvant setting to prevent recurrence in breast cancer patients rendered disease-free with standard-of-care therapy. Here, we examine the relationship between in vitro immunologic response (IR) and clinical recurrence (CR) after 5-year follow-up. Methods: The phase I/II trials were performed as dose-escalation/schedule-optimization trials enrolling node positive and high-risk, node-negative patients (pts) with tumors expressing any level of HER2 (IHC 1+,2+,or 3+). HLA-A2/A3+ pts were enrolled in the vaccine group (VG) while HLA-A2/A3- pts were followed prospectively as an untreated control group (CG). The VG was given 4-6 monthly intradermal inoculations of nelipepimut-S+GMCSF (immunoadjuvant) during the primary vaccine series (PVS). In vitro IR was assessed for E75-specific, cytotoxic T lymphocyte clonal expansion by HLA-A2:IgG dimer assay and expressed as mean dimer index (mdi) at baseline, after PVS (R6), and six months after the PVS. HER2 under-expression was defined as an IHC 1/2, and a FISH < 2.2. VG and CG pts were followed for CR over 60 months. P-values were calculated using the Fisher’s exact test. Results: Of the 195 pts enrolled, 8 withdrew, leaving 187 evaluable pts; 108 in the VG and 79 in the CG. R6 dimer assays were available for 86 pts in the VG. The mean R6 dimer in the VG is 0.63 mdi+.08. Of the 30 pts with an R6 dimer above the mean, only one recurred, compared to eight of the 56 below the mean (p=.09). The difference between baseline and maximum mdi was available in 56 HER2 under-expressing VG pts. Of the 26 pts above the mean difference (1.08 mdi +.17), one recurred, compared to six CR in the 30 pts below the mean (p=.06). There were no CR in pts with HER2 under expression with a mean difference ranked in the top third. Conclusions: In prospective, completed phase I/II trials of NeuVax (nelipepimut-S), patients who exhibit robust in vitro IR have lower recurrence rates. This finding suggests that nelipepimut-specific CTL clonal expansion is a valid biomarker for CR in pts treated with NeuVax. Clinical trial information: NCT00841399.