bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomised phase III trial of enzalutamide in androgen deprivation therapy (ADT) with radiation therapy for clinically localised, high risk, or node-positive prostate cancer: ENZARAD (ANZUP 1303).
Authors: Williams Scott , Davis Ian D. , Sweeney Christopher , Stockler Martin R. , Martin Andrew James , Hague Wendy , Coskinas Xanthi , Yip Sonia , Tu Emily , Lawrence Nicola Jane , McDermott Ray , Kelly Paul J. , Deignan Olwyn , Hughes Simon , Fonteyne Valerie , Tombal Bertrand F. , Nguyen Paul L. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Published: September 2018

TPS5096

Background: Adjuvant ADT with an LHRH analog (LHRHA) given before, during and after radiotherapy (RT) is standard of care for high risk localised prostate cancer (PC). Enzalutamide is more effective in metastatic disease than conventional non-steroidal anti-androgens (NSAA). We hypothesize that addition of enzalutamide to adjuvant ADT and RT will improve outcomes. The aim is to determine the efficacy of enzalutamide compared with NSAA as part of adjuvant ADT with LHRHA in men planned for RT for localized high risk or node-positive PC. Methods: DESIGN: Open label, randomised, phase 3 trial including ANZ, USA, UK, Ireland and Europe. ENDPOINTS: OS (primary), cause-specific survival, PSA PFS, clinical PFS, time to subsequent hormonal therapy, time to castration-resistant disease (PCWG2 criteria), metastasis free survival, adverse events and HRQOL. Tertiary objectives: identification of prognostic/predictive biomarkers from archival tumour tissue and 4 serial fasting bloods. 800 target participants with 5.5 yrs minimum follow-up. 80% power to detect 33% reduction in the hazard of death assuming 5-year survival rate of 76% amongst controls. TREATMENT: Participants are randomised 1:1 to enzalutamide 160mg daily for 24 months versus conventional NSAA for 6 months. All participants receive LHRHA for 24 months and RT starting after week 16. RT delivered as 78Gy in 39 Fx or 46Gy in 23 Fx plus brachytherapy (nodal RT optional for N0, mandatory for N1). ASSESSMENTS: Baseline, then every 8 weeks until year 2, then 3-4 monthly until year 5, 6-monthly until year 7, then annually. CT/MRI and bone scan at baseline, PSA progression, 6 monthly until re-initiation of ADT, when PCWG2 criteria for CRPC are met and then 3 monthly until evidence of metastases. As of 1st February 2017, 55 of 67 sites open with 398 patients recruited. EORTC sites expected to open from Quarter 1 2017. ENZARAD is an investigator-initiated cooperative group trial led by ANZUP Cancer Trials Group with funds and product from Astellas. ANZUP is supported by Cancer Australia and previously CI NSW. ClinicalTrials.gov: NCT02446444, ANZCTR: ACTRN12614000126617 Clinical trial information: NCT02446444.
Clinical trial in progress: A phase 3 study of maintenance bi-shRNA-furin/GM-CSF-expressing autologous tumor cell vaccine in women with stage IIIb-IV high-grade epithelial ovarian cancer.
Authors: Oh Jonathan , Barve Minal A. , Tewari Devansu , Chan John K. , Grosen Elizabeth , Rocconi Rodney Paul , Stevens Erin Elizabeth , DeMars Leslie Robbins , Ghamande Sharad A. , Coleman Robert L. , Manning Luisa , Wallraven Gladice , Senzer Neil N. , Birkhofer Martin , Nemunaitis John J.
Published: September 2018

TPS5604

Background: Vigil is an immuno-stimulatory autologous cellular therapy, which uses patient tumor cells transfected with a plasmid encoding genes for GM-CSF and furin (to down regulate TGFβ 1&2). In Phase I, systemic immune activation was demonstrated in the majority of patients using an IFNƔ ELISPOT assay. A randomized Phase 2 assessment of Vigil maintenance therapy vs. observation in ovarian cancer demonstrated prolonged relapse free survival (RFS) (Oh J, Barve M, et al. Gynecologic Oncology, 2016; 143: 504–510.). Based on these observations, a Phase 3 study of maintenance Vigil therapy in patients with advanced ovarian cancer was initiated (NCT02346747). Methods: This is a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study of maintenance Vigil in women with Stage IIIb,c or IV high-grade papillary serous/clear cell/ endometrioid ovarian, fallopian tube or primary peritoneal cancer. Patients will have a minimum of 4 and a maximum of 12 Vigil doses manufactured from tumor obtained at primary debulking surgery. Patients must achieve a complete clinical remission following primary surgery and chemotherapy before being randomized 1:1 to receive either monthly intradermal Vigil or placebo. Randomization is stratified by extent of surgical cytoreduction (complete/microscopic vs. macroscopic residual disease) and neoadjuvant vs. adjuvant chemotherapy. The primary objective is to compare RFS of subjects randomized to Vigil vs. placebo, and the key secondary objective is overall survival (OS). The sample size calculation of 222 patients assumes 24 months for accrual and 36 months of follow-up with a median RFS of 19 months from randomization, in the control group. This provides 90% power to detect a hazard ratio (HR) of 0.6 favoring Vigil at the 0.05 level of significance. To date, 61 patients have been randomized and an additional 55 patients are receiving chemotherapy in anticipation of randomization. Tumor tissue is being obtained from approximately 20 patients per month at multiple sites across the U.S. At their last meeting in January, 2017 the independent DSMB recommended that the study continue without change. Clinical trial information: NCT02346747.
A phase 2 study to assess olaparib by homologous recombination deficiency status in patients with platinum-sensitive, relapsed, ovarian, fallopian tube, or primary peritoneal cancer.
Authors: Cadoo Karen Anne , Aghajanian Carol , Fraser Cindy , Milner Alvin , Kolvenbag Geert
Published: September 2018

TPS5606

Background: The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is approved for treatment of patients (pts) with germline BRCA mutations ( BRCAm) and advanced ovarian cancer (OC). BRCA mutations are genetic alterations leading to homologous recombination deficiency (HRD) and tumor susceptibility to DNA-damaging agents, including PARP inhibitors. Loss of genetic heterozygosity, telomeric-allelic imbalance, or large-scale state transitions may identify additional pts who could benefit from PARP inhibitor therapy. Methods: LIGHT is a non-randomized, open-label, phase 2 study to assess the efficacy and safety of olaparib in patient cohorts identified by different HRD genetic tests (NCT02983799). Patients will have platinum-sensitive (progression > 6 mo after the end of the last platinum-based chemotherapy), relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer; ECOG performance status 0–1; and ≥2 prior lines of platinum-based chemotherapy for OC. Key exclusion criteria include prior PARP inhibitor treatment; concomitant use of potent CYP3A4/5 inhibitors or inducers; and symptomatic uncontrolled brain metastases. Patients will be enrolled into 4 cohorts of 30 pts each based upon BRCAm or tumor HRD status determined by genetic test results: germline BRCAm; somatic BRCAm; MyChoice HRD-positive and wildtype BRCAm; MyChoice HRD-negative and wildtype BRCAm. All pts will receive 300 mg olaparib tablets twice daily until disease progression (RECIST v1.1) or unacceptable toxicity. The primary endpoint is investigator-assessed objective response rate (ORR) according to RECIST v1.1 criteria. The maximum precision of the ORR is approximately ±18.7% for 30 pts. Secondary endpoints include duration of response, cancer antigen-125 response rate, disease control rate, progression-free survival, time to any progression, overall survival, and homologous recombination repair gene panel mutation status related to clinical outcome. Planned enrollment of 120 pts at sites in the United States was initiated in December 2016. Clinical trial information: NCT02983799.
A phase II trial of durvalumab (Medi 4736) in advanced endometrial cancer: PHAEDRA.
Authors: Antill Yoland Catherine , Stockler Martin R. , Kok Peey Sei , Robledo Kristy Pamela , Gillies Kim , Stark John , Yip Sonia , Mileshkin Linda R. ,   Australia New Zealand Gynaecological Oncology Group (ANZGOG)
Published: September 2018

TPS5614

Background: Advanced endometrial cancer (EC) progressing after 1 or more lines of chemotherapy is an area of unmet need with objective tumour response rates to subsequent lines of chemotherapy of ≤20%. DNA mismatch repair (MMR) deficiency, seen in approximately 15% of EC, is associated with a high mutational load and in addition, up to 90% of ECs are reported to have PDL1/ PD1 expressions. These factors make immune check point inhibition an ideal target for treatment. Methods: DESIGN: Multicentre phase 2 trial in two cohorts. ELIGIBILITY: Advanced, unresectable endometrial cancer that is either MMR-proficient and progressing after 1-3 lines of chemotherapy, or MMR-deficient and progressing after 0-3 lines of chemotherapy. ENDPOINTS: Objective tumour response rate (OTRR) according to iRECIST (primary) and RECIST 1.1, disease control rates at 16 and 24 weeks, progression free survival, overall survival, duration of OTR and DC, adverse events, health related quality of life. Tertiary correlative objectives: Associations between immunologic (including PD-L1), DNA mismatch repair (MMR) and other genetic characteristics with clinical outcomes; and family history of cancer and referral to familial cancer services. INTERVENTION: Durvalumab 1500 mg intravenously every 28 days until disease progression or prohibitive toxicity. STATISTICS: Total of 70 participants in two cohorts (35 each) will have 90% power to distinguish a difference in observed OTRR of ≥20% versus ≤5% (uninteresting rate) using Simon’s 2-stage minimax design with 10% type 1 error rate and allowing 10% ineligibility and missing data. Durvalumab will be considered worthy of pursuit if 4 or more OTR are observed in the first 32 participants in each cohort (OTRR ≥12.5%). BIOSPECIMENS: Tumour tissue and serial bloods (5 time points) will be collected for translational research. PHAEDRA is an investigator-initiated, cooperative-group trial led by ANZGOG, in collaboration with NHMRC Clinical Trials Centre, University of Sydney. Australian New Zealand Clinical Trials Registry: Clinical trial information: ACTRN12617000106336.
CORALLEEN: A phase 2 clinical trial of chemotherapy or letrozole plus ribociclib as neoadjuvant treatment for postmenopausal patients with luminal B/HER2-negative breast cancer.
Authors: Gavilá Joaquín , Saura Cristina , Oliveira Mafalda , Ortega Vanesa , Lopez Rafael , Ciruelos Eva M. , Gonzalez Xavier , Zaragoza Katrin , Pelaez Rivas Alexandra , de La Pena Lorena , Prat Aleix
Published: September 2018

TPS594

Background: Dysregulation of cyclin D-CDK4/6-Rb pathway is associated with endocrine resistance in hormone receptor–positive (HR+) breast cancer. Recently, a CDK4/6 inhibitor has shown unprecedented efficacy in metastatic disease, leading to its regulatory approval. Several others are currently in clinical development for the management of HR+ breast cancer in the early and advanced settings. However, it is vital to gain insights into the molecular and biological effects of this class of agents and could identify patients who can benefit the most, delaying or avoiding the use of chemotherapy.The neoadjuvant setting provides an ideal scenario to carry out these investigations. Hence, we propose to conduct an exploratory study to evaluate the biological effects and the efficacy of ribociclib in patients with primary luminal B tumors.We hypothesize that the combination of ribociclib plus letrozole may offer clinical benefit in the preoperative setting. Methods: This is a parallel, multicenter, two-arm, randomized exploratory study in postmenopausal women with primary operable HR+/HER2-negative Luminal B breast cancer designed to evaluate the clinical benefit of ribociclib plus letrozole. Eligibility includes stage I-III operable breast cancer, Luminal B by PAM50, ECOG 0-1. They will be randomized 1:1 to receive either six 28-days cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole (2.5mg) or chemotherapy: four cycles of AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 every 21 days) followed by weekly paclitaxel during 12 weeks. Baseline, Day 15 on-treatment, and surgical specimens will be collected for molecular characterization and evaluation of response (decrease in Ki67, change to ROR low disease) The primary endpoint is the rate of Residual Cancer Burden (RCB) per MD Anderson Cancer Center procedures. A rate of RCB 0 and 1 score at surgery, with a rank between 20% to 25% with 47 evaluable patients by group of treatment will offer a precision between 11.5% and 12.4%, respectively (95%CI). Ninety-four patients will be enrolled in 20 sites across Spain.
Phase II study of durvalumab (anti-PD-L1 antibody) in combination with R-CHOP or lenalidomide plus R-CHOP in previously untreated, high-risk diffuse large B-cell lymphoma.
Authors: Nowakowski Grzegorz S. , Kalakonda Nagesh , Truemper Lorenz , Everaus Hele , Fustier Pierre , Jaeger Jonathan , Manzke Oliver , Jäger Ulrich ,   And the MEDI4736-DLBCL-001 Trial Investigators
Published: September 2018

TPS7573

Background: The PD-1/PD-L1 pathway is an important immune checkpoint used by tumor cells and may provide an effective target for enhancing anticancer immune response. In DLBCL, high PD-L1 expression has been identified as a negative prognostic factor for overall survival. Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal Ab that selectively blocks PD-L1 binding to PD-1 and CD80, and preliminary preclinical and clinical activity support the study of durvalumab in high-risk DLBCL subtypes. The primary study objective is to explore the clinical activity of durvalumab with R-CHOP in non-activated B-cell–like (non-ABC) and durvalumab with lenalidomide + R-CHOP (R2-CHOP) in ABC previously untreated DLBCL; secondary objectives are to evaluate safety and identify biomarkers predictive of clinical response. Methods: This is a phase II, two-arm, open-label, global, multicenter study of durvalumab combinations in patients with previously untreated, high-risk DLBCL (MEDI4736-DLBCL-001; EUDRA CT 2015-005173-20; NCT03003520). High risk was defined as Ann Arbor stage III/IV or II with bulky disease (≥7.0 cm), along with intermediate-high/high IPI ≥3 or NCCN-IPI ≥4; patients must also have CD20+ DLBCL, ECOG PS 0-2, and no prior antilymphoma therapy. All patients receive durvalumab + R-CHOP21 in induction cycle 1 simultaneous to cell-of-origin (COO) analysis by gene expression profiling with NanoString technology. Beginning with cycle 2, Arm A (non-ABC) receives durvalumab 1125 mg IV on day 1 with 6 or 8 cycles of R-CHOP21; Arm B (ABC) receives the same durvalumab + R-CHOP21 doses with oral lenalidomide 15 mg/day on days 1-14. Both arms receive durvalumab consolidation 1500 mg IV on day 1 q28d for ≤12 months from induction cycle 1, day 1. The primary endpoint is 2-y progression-free survival (PFS); secondary endpoints include clinical response to treatment in biomarker-defined subpopulations (tumor and peripheral blood) and safety as assessed per NCI CTCAE v4.03 criteria. Exploratory endpoints include PFS at 12 mo, complete response, and PK/PD. Recruitment is ongoing, with a target enrollment of 120 patients. Clinical trial information: NCT03003520.
CheckMate 602: An open-label, randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide and dexamethasone in relapsed/refractory multiple myeloma.
Authors: Lonial Sagar , Richardson Paul G. , Reece Donna Ellen , Mohamed Hesham , Shelat Suresh , San Miguel Jesus
Published: September 2018

TPS8052

Background: Multiple myeloma (MM) cells may evade immune surveillance by suppressing immune responses through the PD-1 pathway, via upregulation of PD-L1.1Nivolumab (nivo), a PD-1 immune checkpoint inhibitor that blocks PD-L1 interaction and disrupts MM-mediated PD-1 signaling, demonstrated modest activity as monotherapy in patients (pts) with relapsed/refractory multiple myeloma (RRMM) in a phase 1b study.2 Pomalidomide, an immunomodulatory drug (IMiD), may sensitize MM cells to PD-1 blockade, and has shown efficacy with dexamethasone (Pd) for RRMM. Elotuzumab (elo), an anti-SLAMF7 monoclonal antibody, directly activates natural killer cells and facilitates antibody-dependent cell-mediated cytotoxicity. Preclinical work suggests PD-1 blockade may enhance elo efficacy3; thus nivo + Pd + elo may increase clinical benefit. Methods: CheckMate 602 (NCT02726581) is a phase 3, open-label, randomized study of efficacy and safety of nivo + Pd (N-Pd) vs Pd in pts with RRMM. Nivo combined with elo + Pd (NE-Pd) will be evaluated in an exploratory arm. Eligible pts must have measurable MM after ≥2 prior lines of therapy (LoTs) that included an IMiD and proteasome inhibitor, each for ≥2 consecutive cycles, alone or combined, and be refractory to their last LoT. Pts with prior elo are eligible. A planned 406 pts will be randomized 3:3:1 to N-Pd, Pd and NE-Pd, stratified by LoT (2 vs 3+) and International Staging System disease stage (I–II vs III). Pts in the Pd arm may cross over to the NE-Pd arm at disease progression. Pts are enrolled at 119 sites in 13 countries. Coprimary endpoints (N-Pd and Pd arms): objective response rate (ORR) and progression-free survival (PFS), assessed by an independent review committee. Secondary endpoints (N-Pd and Pd arms): time to response, duration of response, investigator-assessed ORR and PFS. Exploratory endpoints include ORR and PFS (NE-Pd arm), and safety/tolerability and minimal residual disease status (all arms). 1. Liu et al. Blood 2007;110:296–304 2. Lesokhin et al. JCO 2016;34:2698–704 3. Bezman et al. Haematologica 2016;101:161–2 [S450] Study support: BMS. Writing support: A Gill, Caudex, funded by BMS. Clinical trial information: NCT02726581.
Detect T790M in cell free tumor DNA of Chinese advanced non-small cell lung cancer adenocarcinoma patients by different platforms and evaluate clinical outcomes of T790M positive patients with osimertinib monotherapy.
Authors: Liang Zhiyong , Cheng Ying , Chen Yuan , Liu Weiping , Lu You , Wang Jie , Wu Gang , Ying Jian-Ming , Zhang Xu-Chao , Wu Yi-Long
Published: September 2018

TPS9104

Background: EGFR T790M mutation occurs in approximately 50-60% of non-small cell lung cancer adenocarcinoma (NSCLC) patients with acquired EGFR-TKI resistance, based on tumor re-biopsies using an invasive clinical procedure. Recently, Cell free tumor DNA (ctDNA) has emerged as a specific and sensitive blood-based biomarker and studies have demonstrated ctDNA as a feasible and minimally invasive alternative to tissue biopsy. Data on different technology platforms used for EGFR T790M detection in blood in China is limited. We aim to compare the methods currently available in hospital practise, including cobas EGFR Mutation Test (Roche Molecular Systems), super-ARMS, digital PCR and NGS, to compare each platform and clinically validate each as companion diagnostic to osimertinib. Methods: This is an open-label, multi-center study in 250 locally advanced or metastatic NSCLC patients with documented EGFR sensitizing mutation and progression on previous EGFR-TKI. T790M mutation in plasma ctDNA will be tested by four methods: cobas, super-ARMS, digital PCR and NGS in order to evaluate the concordance, sensitivity and specificity of T790M testing in plasma between the cobas test and the other platforms. T790M positive patients by any of the four platforms will receive osimertinib treatment (administered orally as one 80 mg tablet once a day in ASTRIS study, NCT02474355) and the clinical outcomes (PFS, ORR, OS) will be followed. Patients will continue to receive osimertinib until disease progression (PD), as assessed by investigators. Digital PCR and NGS will be used to monitor the molecular evolution of T790M and C797S in plasma from NSCLC patients during osimertinib treatment. NGS will also be used to explore acquired resistance mechanisms before osimertinib treatment and after PD. 23 of planned 250 patients have been enrolled in the study as of January 2017. Clinical trial information: NCT02997501.
METIS: A phase 3 study of radiosurgery with TTFields for 1-10 brain metastases from NSCLC.
Authors: Mehta Minesh P. , Gondi Vinai , Brown Paul D.
Published: September 2018

TPS9106

Background: Tumor Treating Fields (TTFields) are non-invasive regional anti-mitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and to extend overall survival in newly-diagnosed glioblastoma patients. Methods: 270 patients with 1-10 brain metastases (BM) from NSCLC will be randomized in a ratio of 1:1 to receive stereotactic radio surgery (SRS) followed by either TTFields or supportive care alone. Patients are followed-up every two months until 2nd cerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 2st cerebral progression. Objectives: To test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population. Endpoints: Time to 1st cerebral progression based on the RANO-BM Criteria or neurological death (primary); time to neurocognitive failure based on the following tests: HVLT, COWAT and TMT; overall survival; radiological response rate; quality of life; adverse events severity and frequency (secondary). Main eligibility criteria: Karnofsky performance status (KPS) of 70 or above, 1 inoperable or 2-10 brain lesions amenable to SRS, optimal standard therapy for the extracranial disease, no brain-directed therapy, no signs of significantly increased intracranial pressure, no electronic implantable devices in the brain. Treatment: Continuous TTFields at 150 kHz for at least 18 hours per day will be applied to the brain within 7 days of SRS. The treatment system is a portable medical device allowing normal daily activities. The device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients will receive the best standard of care for their systemic disease. Statistical Considerations: This is a prospective, randomized, multicenter study for 270 patients. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) and has 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. Clinical trial information: NCT02831959.
Phase 1 study to evaluate safety and efficacy of ipilimumab + nivolumab + external beam radiotherapy in patients with metastatic melanoma.
Authors: Postow Michael Andrew , Knox Susan Jane , McCabe Danielle , Macri Mary J. , Schwarzenberger Paul , Ricciardi Toni , Ryan Aileen , Venhaus Ralph Rudolph , Barker Christopher Andrew
Published: September 2018

TPS9591

Background: Immunotherapy (IMT) with checkpoint blocking antibodies has led to progress in metastatic melanoma with 3 FDA-approved drugs, including the combination of ipilimumab (IPI), a CTLA-4 antibody, and nivolumab (NIVO), a PD-1 antibody. Although radiotherapy (RT) is primarily used as local palliative therapy in metastatic melanoma, it also possibly affects systemic antitumor immunity. Preclinical data suggest RT alters the tumor microenvironment and renders tumor cells more susceptible to immunologically-mediated disease regression. These preclinical immunologic effects of RT have been shown to vary by RT dose and fractionation. We are now conducting the first clinical trial in patients to evaluate the triple combination of IPI + NIVO + RT using 2 different dose/fractionation schemes of RT. Methods: This ongoing Phase 1, open-label, multicenter study (NCT02659540) evaluates safety, efficacy, and immunologic effects of IPI + NIVO + RT in 18 patients with unresectable stage IV melanoma. Patients must have 1 melanoma metastasis that can be safely irradiated for palliative purposes and at least 1 measurable lesion that will not be irradiated. Patients receive concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks (Q3W) x 4, followed by NIVO monotherapy (240 mg Q2W), with RT initiated between the first and second doses of IPI + NIVO. In Cohort A, the irradiated metastasis receives a conventionally fractionated low dose of 30 Gy in 10 fractions of 3 Gy each over 2 weeks. If ≤7 of 9 patients (78%) in Cohort A have Grade 3/4 drug- or radiation-related adverse events, safety is deemed acceptable and Cohort B enrollment opens. In Cohort B, the irradiated metastasis receives a hypofractionated high dose of 27 Gy in 3 fractions of 9 Gy each over 2 weeks. The primary endpoint is safety. Secondary endpoints are objective response rate and disease control rate by RECIST and immune-related RECIST measured at Weeks 12 and 18, duration of response, progression-free survival, and overall survival. Exploratory endpoints include correlative studies of immunological effects. Enrollment opened on 05 Aug 2016. As of 31 Dec 2016, 4 patients are enrolled in Cohort A; enrollment is ongoing. Clinical trial information: NCT02659540.
NCI 9922: Phase 2 study of ibrutinib in treatment-refractory distant metastatic cutaneous melanoma (DMCM).
Authors: Moschos Stergios J. , Eroglu Zeynep , Gaughan Elizabeth Mary , Medina Theresa Michelle , Wang Peng , Dees Elizabeth Claire , Cartee Leanne , Arrowood Christy , Carson Craig , Thomas Nancy E , Ollila David W. , Nikolaishvilli-Feinberg Nana , Ivy S. Percy , Harris Pamela Jo , Hurwitz Herbert
Published: September 2018

TPS9592

Background: We have previously shown that the IL-2 inducible kinase (ITK) is highly expressed in primary melanomas compared with nevi due to promoter hypomethylation (Conway PCMR 2011). We have also shown using 2-color immunofluorescence (2CIF) that ITK protein expression is increased even more in metastatic compared to primary melanomas (S100+) and that molecular targeting (shRNA) or pharmacologic inhibition of ITK (BI 10N) in various melanoma cell lines, various melanoma xenografts and an immunocompetent melanoma mouse model suppresses cell proliferation and retards tumor growth without inducing cell death (Carson CCR 2015). We have also shown by intracellular stain of peripheral blood mononuclear cells (PBMC) that ITK is expressed in PBMC obtained from patients (pts) treated with MAPK or CTLA-4 inhibitors. Other groups have shown that ITK and BTK are expressed in Th2 cells, myeloid-derived suppressor cells, and tumor-associated macrophages. We have also shown that ibrutinib suppresses proliferation of various melanoma cell lines in low nM concentrations depending on tumoral expression of ITK. We hypothesize that targeting DMCM with ibrutinib alone will induce antitumor responses and/or prolong survival if DMCM expresses high levels of melanoma-associated ITK by 2CIF (S100/ITK). Methods: This is an open-label, single-arm, multicenter, phase II study of DMCM refractory to or ineligible for PD-1 and MAPK inhibitors. Ibrutinib will be dosed at 840 mg p.o. qd. The null hypothesis is that an ineffective drug will confer a 5% response rate (RR) and 18% 6-month PFS (6m PFS), whereas ibrutinib will confer > = 20% RR and > = 35% 6m PFS (KEYNOTE-002). This trial accrues in two stages; if either the RR and/or 6m PFS endpoint are met after 18 patients, then 14 additional pts will be accrued for a total of 32. The Simon’s design will reject the null hypothesis if > = 4 responses are observed or > = 9 pts have PFS better than 6 months out of 32 patients. All pts are required to have baseline tumor tissue available for analysis of ITK expression by 2CIF. Immune monitoring will be performed on PBMC collected at baseline and various time points during treatment. Trial is currently recruiting pts (NCT02581930). Clinical trial information: NCT02581930.
Multiscale analysis of architecture, cell size and the cell cortex reveals cortical F-actin density and composition are major contributors to mechanical properties during convergent extension
Authors: Shawky Joseph H. , Balakrishnan Uma L. , Stuckenholz Carsten , Davidson Lance A.
Published: September 2018

The large-scale movements that construct complex three-dimensional tissues during development are governed by universal physical principles. Fine-grained control of both mechanical properties and force production is critical to the successful placement of tissues and shaping of organs. Embryos of the frog Xenopus laevis provide a dramatic example of these physical processes, since dorsal tissues increase in Young's modulus by six-fold to 80 Pascal over eight hours as germ layers and the central nervous system are formed. These physical changes coincide with emergence of complex anatomical structures, rounds of cell division, and cytoskeletal remodeling. To understand the contribution of these diverse structures, we adopt the Cellular Solids Model (CSM) to relate bulk stiffness of a solid-foam to the unit-size of individual cells, their microstructural organization, and their material properties. Our results indicate that large scale tissue architecture, and cell size are not likely to influence the bulk mechanical properties of early embryonic or progenitor tissues but that F-actin cortical density and composition of the F-actin cortex play major roles in regulating the physical mechanics of embryonic multicellular tissues.
Variant PRC1 competes with retinoic acid-related signals to repress Meis2 in distal forelimb bud
Authors: Yakushiji-Kaminatsui Nayuta , Kondo Takashi , Hironaka Ken-ichi , Sharif Jafar , Endo Takaho A. , Nakayama Manabu , Masui Osamu , Koseki Yoko , Kondo Kaori , Ohara Osamu , Vidal Miguel , Morishita Yoshihiro , Koseki Haruhiko
Published: September 2018

Suppression of Meis genes in the distal limb bud is required for Proximal-Distal (PD) specification of the forelimb. Polycomb group (PcG) factors play a role in downregulation of retinoic acid (RA)-related signals in the distal forelimb bud, causing Meis repression. It is, however, not known if downregulation of RA-related signals and PcG-mediated proximal genes repression are functionally linked. Here, we reveal that PcG factors and RA-related signals antagonize each other to polarize Meis2 expression along the PD axis. With mathematical modeling and simulation, we propose that PcG factors are required to adjust the threshold for RA-related signaling to regulate Meis2 expression. Finally, we show that a variant Polycomb repressive complex 1 (PRC1), incorporating PCGF3 and PCGF5, represses Meis2 expression in the distal limb bud. Taken together, we reveal a previously unknown link between PcG proteins and downregulation of RA-related signals to mediate the phase transition of Meis2 transcriptional status during forelimb specification.
Effects of both cold and heat stresses on the liver of giant spiny frog Quasipaa spinosa: stress response and histological changes
Authors: Liu Ze-Peng , Gu Wen-Bin , Tu Dan-Dan , Zhu Qi-Hui , Zhou Yi-Lian , Wang Cong , Wang Lan-Zhi , Shu Miao-An
Published: September 2018

Ambient temperature associated stress can affect the normal physiological functions in ectotherms. To assess the effects of cold or heat stress on amphibians, the giant spiny frogs, Quasipaa spinosa, were acclimated at 22 °C followed by being treated at 5 °C or 30 °C for 0, 3, 6, 12, 24 and 48 h, respectively. Histological alterations, apoptotic index, mitochondrial reactive oxygen species (ROS) generation, antioxidant activity indices and stress-response gene expressions in frog livers were subsequently determined. Results showed that many fat droplets appeared after 12 h of heat stress. Percentage of melanomacrophages centres significantly changed during 48 h at both stress conditions. Furthermore, the mitochondrial ROS levels were elevated in a time-dependent manner up to 6 h and 12 h in the cold and heat stress groups, respectively. The activities of superoxide dismutase, glutathione peroxidase and catalase were successively increased along the cold or heat exposure, and most of their gene expression levels showed similar changes at both stress conditions. Most tested HSP genes were sensitive to temperature exposure, and the expression profiles of most apoptosis-related genes was significantly up-regulated at 3 and 48 h under cold and heat stress, respectively. Apoptotic index at 48 h under cold stress was significantly higher than that under heat stress. Notably, lipid droplets, HSP30, HSP70 and HSP110 might be suitable bioindicators of heat stress. The results of these alterations at physiological, biochemical and molecular levels might contribute to a better understanding of the stress response of Q. spinosa and even amphibians under thermal stresses.
No short-term physiological costs of offspring care in a cooperatively breeding bird
Authors: Guindre-Parker Sarah , Rubenstein Dustin R.
Published: September 2018

The cost of reproduction results in a life-history trade-off where investment in current reproduction via costly parental care decreases subsequent fitness. Although this trade-off is thought to occur ubiquitously across animals, there is equivocal evidence that parental care behaviours are costly. A major challenge of studying the cost of parental care has been a lack of consensus over which physiological mechanisms underlie this trade-off. Here we compare four traits believed to mediate the cost of parental care by examining whether glucocorticoids, oxidative stress, immune function, or body condition represent a cost of performing offspring care and shape subsequent fitness. We use a 4-year dataset collected in free-living cooperatively breeding superb starlings (Lamprotornis superbus), a species in which parental and alloparental care effort varies widely among individuals and across years. Our results showed that within-individual change in physiology was unrelated to investment in offspring care, and physiological state during chick-rearing did not predict the likelihood that an individual would breeding in subsequent seasons. Instead, individuals that had elevated baseline corticosterone during incubation performed more nest guarding, suggesting that this hormone may play a preparatory role for investing in offspring care. Together, our results indicate that superb starlings modify their investment in offspring care according to their physiological state during incubation, despite no evidence of a short-term physiological cost of parental or alloparental care. Thus, breeding cooperatively appears to provide individuals with the flexibility to adjust their investment in offspring care and overcome any potential costs of reproduction.
АНАЛИЗ ФОРМИРОВАНИЯ ИМИДЖА ОРГАНИЗАЦИИ-РАБОТОДАТЕЛЯ НА РЫНКЕ ТРУДА КАК ФАКТОРА ПРИВЛЕЧЕНИЯ ПОТЕНЦИАЛЬНЫХ РАБОТНИКОВ
Authors: Yarkova Svetlana Anatolevna , Romantsova Yuliya Dmitrievna , Yakimova Lyubov Dmitrievna , Malakhova Anna Andreevna
Published: September 2018

Имидж компании определяет восприятие, отношение и поведение как нанимаемых сотрудников, так и уже работающих в компании, а также он играет большую роль в укреплении или, наоборот, в разрушении их трудовой лояльности. В статье рассмотрена методика исследования одного из актуальных направлений маркетинга персонала, заключающегося в необходимости формирования положительного и устойчивого имиджа компании-работодателя на рынке труда. Проведен анализ имиджа крупной российской компании, согласно которому выявлены следующие обстоятельства: более низкий уровень сформированности внешнего имиджа работодателя по сравнению с внутренним, наличие различий в восприятии работодателя у текущих и потенциальных работников, а также большое количество негативных отзывов в сети Интернет.В целях повышения привлекательности данной компании для потенциальных работников предложены следующие мероприятия по развитию имиджа: участие представителей организации в тематических выставках и конференциях; организация дней открытых дверей; наполнение сайта организации интересующей потенциальных работников информацией; сотрудничество с кадровыми агентствами; участие в ярмарках вакансий; организация внутренних коммуникаций.Цель – анализ имиджа компании железнодорожной отрасли.Метод или методология проведения работы: в статье использовались эмпирические методы, а также статистические методы анализа.Результаты: определено состояние внешнего и внутреннего имиджа исследуемой компании и предложены мероприятия для его развития.Область применения результатов: полученные результаты целесообразно применять для повышения имиджа в организациях железнодорожной отрасли.
ANALISIS PREDIKSI KEPAILITAN PADA BANK UMUM SWASTA NASIONAL DEVISA YANG TERDAFTAR DI BURSA EFEK INDONESIA TAHUN 2010 – 2013
Authors: Fadhilah Sumaniyatun , Kurniawati Indah
Published: September 2018

The purpose of this study is to assess bankruptcy prediction in the National Private Banks Foreign Exchange listed in Indonesian Stock Exchange. This study uses the size of liquidity ratio of working capital to total assets. This study uses the find were the purposive sampling. The population in this study is the National Private Commercial Bank Foreign Exchange listed on the Indonesian Stock Exchange during the period of the study, namely between 2010 until 2013. The sample amounted to 21 banks during the 4 years that have been selected based on specific criteria. Based on the results of the analysis carried out stating that the National Private Commercial Bank Foreign Exchange listed in Indonesian Stock Exchange in 2010 there were 29 % of banks that are insolvent, 71 % of banks that are in the gray area, and no banks that are in not bankruptcy predictions. In 2011 29 % of banks that are insolvent, 67 % of banks that are in the gray area and 5 % are located on the banks not bankruptcy prediction. In 2012 29 % of banks that are insolvent, 67 % of banks that are in the gray area, and 5 % of banks that are in the prediction of the bank is not bankrup. In 2013 29 % of banks that are in bankruptcy prediction, 71 % of banks that are in the gray area, and there are no banks that are in not bankruptcy predictions. There is no difference in Z-score on bankruptcy prediction National Private Banks Foreign Exchange Listed in Indonesian Stock Exchange between 2010, 2011, 2012, and 2013.
CHARACTERIZATION OF PLUTONIUM DISTRIBUTION IN THO2–PUO2 MIXED OXIDES BY ELECTRON PROBE MICROANALYSIS
Authors: Woods Dawn , Saoudi Mouna , Mayhew Clinton , Ham-Su Rosaura
Published: September 2018

Thoria–plutonia (ThO2–PuO2) pellets with a nominal composition of 9.0 wt% PuO2 were prepared using a fabrication route similar to an industrial process for production of urania–plutonia (UO2–PuO2) mixed oxide fuel. The green fuel pellets were separated into 2 batches and the sintering of each batch was carried out under a reducing atmosphere at 1820 °C or 1750 °C. The distribution of plutonium (Pu) in the sintered pellets was investigated by electron probe microanalysis using X-ray mapping and quantitative point analyses. The results show that the pellet samples consist of Pu-rich agglomerates with Pu content close to that of the mastermix blend and a thorium (Th)-rich matrix. The matrix and the Pu-rich agglomerates are separated by a transition zone with Pu content varying from practically nil to the Pu content of the Pu-rich agglomerates. X-ray maps taken from random regions of the centre of the pellets show different sizes of Pu-rich agglomerates irregularly dispersed in the Th-rich matrix. Image analysis of the Pu X-ray maps indicate that the average diameter of the Pu-rich agglomerates of the material sintered at 1820 °C and 1750 °C were 68 μm and 161 μm, respectively.
Spinal shock in dogs and humans: clinical and comparative findings
Authors: Negrin Arianna , Negrin Livio , Cherubini Giunio Bruto
Published: September 2018

Spinal cord lesion site is mainly localised through correct performance and interpretation of a full neurological examination. Decreased or absent spinal reflexes localises the lesion within that reflex arc (low motor neuron), while intact or increased spinal reflexes indicates a lesion cranial to the reflex arc (upper motor neuron). In acute and severe spinal cord injury, lesion localisation may be compromised by the presence of spinal shock, because in individuals with spinal shock, the clinical presentation shows discrepancy between spinal reflexes and lesion localisation, with loss of segmental spinal reflexes caudally to a lesion, although the intumescence may remain intact. Lack of recognition of spinal shock in these patients could lead to erroneous clinical localisation of the lesion, inappropriate utilisation of diagnostic tests and incorrect reporting of patient prognosis to the owner.
A system under pressure
Authors: Smith Ed , Dasan Sunil
Published: September 2018

Activity levels within emergency medicine, and the pressures experienced by individual clinicians working within the specialty, continue to increase year on year. In 2016–17 there were 18 691 546 attendances at UK emergency departments. Attendance numbers continue to increase annually, patients are becoming older and more unwell, departments are more crowded and as a result, emergency care standard performance figures are deteriorating.

This article describes the impact of this pressure on the staff working within the emergency department and begins to explore the potential for the development of sustainability within the existing and future workforce.
Clinical audit does not work, is quality improvement any better?
Authors: Boyle Adrian , Keep Jeff
Published: September 2018

This article reviews the history of clinical audit and appraises its effectiveness. It discusses why audit can be ineffective in improving care and makes proposals to remove these barriers. The article describes how quality improvement and improvement science may offer a better alternative to traditional audit. It describes how the Royal College of Emergency Medicine is the first specialty society to attempt a national quality improvement programme.
Liquidity Management Mechanisms of Islamic and Conventional Finance: A Shariah Appraisal
Authors: Sheikh Rafiullah  , Dr. Atiquzzafar Khan
Published: September 2018

This paper analyzes liquidity management mechanisms of Islamic and Conventional finance from a Shari'ah perspective. It has been found that, IFIs mainly useSukūkfor the liquidity management purposes. Likewise, IFIs provide their excess liquidity to the liquidity-deficit IFIs throughMudārabahandWakālahbased mechanisms. CommodityMurābahah(based onTawarruq)is another widely used liquidity management instrument but it is criticized by someShari'ahscholars because it involves such transactions that are only used as a subterfuge to obtain ready cash. Conventional liquidity management instruments, on the other hand, are debt-based securities, therefore, are notShari'ahcompliant due to the involvement of Islamically prohibitedRibāandBay' al-Dayn.This paper suggests some Shari'ah compliant liquidity management instruments, such as: (i) an IFI can issue NCDs against a portfolio of bank's assets. (ii) any corporation can issue asset-backedSukūk, which can be used by IFIs for liquidity management purposes; (iii) an IFI can provide acceptance financing facility by means of aMurābahahbased transaction; (iv) a central bank can provide emergency liquidity facility to IFIs on the basis ofSalamtransactions; (v) deposit insurance facility can be provided to the Islamic banking depositors on the basis ofTakāfulprinciples.
Fiber bundle shifting endomicroscopy for high-resolution imaging
Authors: Vyas Khushi , Hughes Michael , Rosa Bruno Gil , Yang Guang-Zhong
Published: September 2018

Flexible endomicroscopes commonly use coherent fiber bundles with high core densities to facilitate high-resolution in vivo imaging during endoscopic and minimally-invasive procedures. However, under-sampling due to the inter-core spacing limits the spatial resolution, making it difficult to resolve smaller cellular features. Here, we report a compact and rapid piezoelectric transducer (PZT) based bundle-shifting endomicroscopy system in which a super-resolution (SR) image is restored from multiple pixelation-limited images by computational means. A miniaturized PZT tube actuates the fiber bundle behind a GRIN micro-lens and a Delaunay triangulation based algorithm reconstructs an enhanced SR image. To enable real-time cellular-level imaging, imaging is performed using a line-scan confocal laser endomicroscope system with a raw frame rate of 120 fps, delivering up to 2 times spatial resolution improvement for a field of view of 350 µm at a net frame rate of 30 fps. The resolution enhancement is confirmed using resolution phantoms and ex vivo fluorescence endomicroscopy imaging of human breast specimens is demonstrated.
Restoration of uterine redox-balance by methanolic extract of Camellia sinensis in arsenicated rats
Authors: Dey Arindam , Chattopadhyay Sandip , Jana Suryashis , Giri Mukul Kumar , Khatun Shamima , Dash Moumita , Perveen Hasina , Maity Moulima
Published: September 2018

Arsenic, an environmental and industrial pollutant causes female reproductive disturbances and female infertility. Several researchers found that the use of Camellia sinensis (CS) (green tea) is effective as an alternative therapeutic strategy in the management of several health ailments. This study explores the role of CS extract against arsenic-induced rat uterine tissue damage. Methanolic extract of CS (10 mg/kg BW) was tested concomitantly in arsenic-treated (10 mg/kg BW) rats for a duration of two-oestrous cycle length (8 days). CS effectively attenuated arsenic-induced antioxidantdepletion and necrosis in uterine tissue. Rats treated with sodium arsenite showed significantlyreduced activities of enzymatic antioxidants like superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in uterine tissue as evidenced by the results of spectrophotometric and electrozymographic analysis. Co-administration of CS significantly reversed the above oxidative stress markers in uterine tissue along with the histopathological changes in ovarian and uterine tissue. Moreover, an increase in the level of transcription factor NF-κB in the uterine tissue in association with reduced serum levels of vitamin B12 and folic acid were mitigated in arsenic fed rats following CS co-administration.
Logistics Tools during Mergers and Acquisitions
Authors: BEREZOVSKIY Eduard Eduardovich , KIZIM Anatolii Aleksandrovich , GAYDUK Vladimir Ivanovich , SEKERIN Vladimir Dmitrievich
Published: September 2018

The article considers basic areas of mergers and acquisitions (M&A) that are peculiar of modern companies based on logistics tools as auxiliary elements when planning various stages of preparing, carrying out and completing the integration or corporation. On this basis modern understanding of the M&A changes both globally and regionally is formed. The article pays special attention to the control over M&A transactions through the efficient implementation of logistics in intercompany processes of various business structures regardless of the scale and sector. It defines modern trends on accelerating M&A transactions in various areas (financial, industrial, energy) based on the extended tools of generally accepted approaches that make it possible to maximize the synergetic effect.