bluuebunny/crossref_metadata_2025 huggingface dataset:
Interim results from PURE-01: A phase 2, open-label study of neoadjuvant pembrolizumab (pembro) before radical cystectomy for muscle-invasive urothelial bladder carcinoma (MIUC).
Authors: Necchi Andrea , Briganti Alberto , Raggi Daniele , Giannatempo Patrizia , Mariani Luigi , Messina Antonella , Anichini Andrea , Calareso Giuseppina , Crippa Flavio , Catanzaro Mario , Fossati Nicola , Gandaglia Giorgio , Salonia Andrea , Salvioni Roberto , Montorsi Francesco
Published: February 2018

TPS533

Background: MIUC is an aggressive disease and > 40% of patients (pts) will develop recurrence after radical cystectomy (RC). Despite cisplatin-based neoadjuvant chemotherapy yields Level 1 evidence, it is administered in a minority of pts worldwide. Pembro is an EMA and FDA-approved standard therapy for metastatic UC after platinum failure or for cisplatin-ineligible pts. Our hypothesis was that pembro, given neoadjuvantly, could downstage MIUC and reduce recurrence. Methods: PURE-01 (NCT02736266) is an open-label, single-arm, phase 2 study to evaluate the activity, medical and surgical safety, and immune modulatory effects of pembro administered as a short window-of-opportunity course of therapy preceding RC. Eligibility criteria included: T2-T4aN0 stage, and residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence). The study includes cisplatin eligible- and ineligible pts. Pts receive 3 cycles of pembro 200mg 3 weekly before RC (planned < 3 weeks of the last dose). Computed tomography (CT) scan, FDG-PET/CT scan, and bladder multiparametric magnetic resonance imaging (mpMRI) are done during screening and before RC. Radiologically non responders to pembro (per investigator decision; i.e., study failures) are given 3 additional courses of dose-dense MVAC chemotherapy. After RC, pts are managed according to local guidelines (adjuvant chemotherapy vs observation). Further anti PD-1/PD-L1 therapy will not be given post-operatively. Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be included in the ITT analysis. The H1 is pT0 ≥20% and H0 pT0≤10%. In a 2-stage design, 90 pts overall will be accrued (80% power and a 2-sided test of significance at the 10% level). A first interim analysis for safety is planned after 18 patients enrolled and treated (by December 1st, 2017). Activity results and early translational findings (immune-cell profiling) will be added, and may be regarded to as first data of preoperative immunotherapy before major surgery. Clinical trial information: NCT02736266.
PECULIAR: An open label, multicenter, single-arm, phase 2 study of neoadjuvant pembrolizumab (PEM) and epacadostat (EPA), preceding radical cystectomy (Cy), for patients (pts) with muscle-invasive urothelial bladder cancer (MIUBC).
Authors: Necchi Andrea , Mariani Luigi , Anichini Andrea , Messina Antonella , Giannatempo Patrizia , Raggi Daniele , Briganti Alberto , Montorsi Francesco
Published: February 2018

TPS534

Background: MIUBC is a systemic disease and > 40% of pts develop recurrence after Cy. Despite neoadjuvant chemotherapy yields Level 1 evidence, it is underutilized worldwide and a small survival improvement is deemed over Cy alone. PEM (MK-3475) is the standard-of-care for second-line metastatic UC and is being evaluated as single-agent neoadjuvant therapy for MIUBC (NCT02736266). EPA, an anti-IDO1 agent, combined with PEM, safely improved the response-rate in metastatic UC. Our hypothesis is that PEM+EPA, given neoadjuvantly, could further improve downstaging MIUBC. Methods: Pts with T2-T4a N0 UC with residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence), regardless of cisplatin eligibility, will receive 3 cycles of PEM 200mg intravenously, q3 weekly. EPA will be orally taken at the dose of 100 mg BID, from d1 until 10 days before Cy. Cy should be performed within 3 weeks of the last PEM dose. Computed tomography (CT) scan, 18FDG-PET/CT scan, and multiparametric bladder MRI (mpMRI) will be done during screening and before Cy to stage and evaluate response. After Cy, pts will be managed according to EAU guidelines. Adjuvant anti PD-1 therapy is not allowed. PD-L1 status will be assessed on TURB specimen (Dako, clone 22C3), relying on the combined positivity score (CPS, 10% cutoff). Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be includes in the ITT analysis. The H1 is pT0≥20% and H0 pT0≤10%. A 2-stage design will be used to estimate the number of pts required. Out of 90 pts overall, with the first stage of 49 pts, ≥6 pT0 will be required in the first stage, and ≥13 pT0 in the whole study population (80% power and a 2-sided test of significance at the 10% level). Correlative research on tissue/blood samples will include immune-cell profiling, cytokine assessment, gene expression analyses and next-generation sequencing (FoundationOne). Radiologic findings from mpMRI will be associated with pathologic response (EudraCT number 2017-002379-24). Clinical trial information: 2017-002379-24.
A phase II trial of risk-adapted treatment for muscle invasive bladder cancer after neoadjuvant accelerated MVAC.
Authors: Geynisman Daniel M. , Abbosh Philip , Zibelman Matthew R. , Feldman Rebecca , McConkey David James , Hahn Noah M. , Bivalacqua Trinity , Trabulsi Edouard John , Lallas Costas D. , Hoffman-Censits Jean H. , Viterbo Rosalia , Horwitz Eric M. , Churilla Thomas M. , Alpaugh R. Katherine , Greenberg Richard E. , Smaldone Marc C. , Uzzo Robert , Chen David , Kutikov Alexander , Plimack Elizabeth R.
Published: February 2018

TPS537

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy (Cx) or chemoradiation (CRT) is the standard of care for urothelial carcinoma (UC) pts with muscle invasive bladder cancer (MIBC). Both Cx and CRT carry potential short and long-term toxicity and quality of life implications. Recent work has shown that mutations in DNA damage repair/response genes are predictive of pathologic downstaging after NAC at the time of Cx, with those pts achieving pT0 disease demonstrating excellent long-term survival (Van Allen et al. Cancer Discov. 2014; Plimack et al. Eur Urol. 2015; Liu et al. JAMA Oncol. 2016; Teo et al. CCR. 2017). Sparing pts Cx or CRT after NAC without compromising oncologic outcomes would improve quality of life and decrease morbidity. Methods: A phase II, parallel arm, multi-institutional clinical trial (NCT02710734) is being conducted to evaluate a risk-adapted approach to treatment of MIBC. Pts with cT2-T3N0M0 UC of the bladder, ECOG PS 0-1 and CrCl≥50 mL/min, undergo NAC with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin. Simultaneously, the pre-NAC TURBT specimen is submitted for deep sequencing to identify variants in a panel of cancer-relevant genes (Caris Life Sciences, Phoenix, AZ). Those with an alteration in ATM, RB1, FANCC or ERCC2 and no clinical evidence of disease by restaging TUR and imaging post-NAC will begin a pre-defined active surveillance regimen that includes urinary cytological, cystoscopic, and radiographic evaluations. The remaining pts will undergo bladder-directed therapy at the discretion of the pt and clinician applying either intravesical therapy ( < cT2 post-NAC), CRT or Cx (≤cT2 post-NAC) or Cx (≥cT3 post-NAC). The primary objective is metastasis-free survival (MFS) at 2 years for all enrolled and evaluable pts. The trial has a non-inferiority design with a 14% margin between risk-adapted treatment (MFS = 78%) and standard-of-care (MFS = 64%) with a sample size of 70 pts, 82% power and a type I error of 0.045. Key secondary and translational objectives: assess the rate of UC recurrence in active surveillance pts; validate biomarkers of response to NAC; evaluate urinary biomarkers consistent with persistent UC. Clinical trial information: NCT02710734.
A phase 3b safety study of fixed-dose durvalumab + tremelimumab or durvalumab monotherapy in advanced solid malignancies (STRONG): Urothelial and non-urothelial urinary tract carcinoma module A.
Authors: Sonpavde Guru , Peters Solange , Nordquist Luke T. , Kato Terufumi , Miranda Paulo Andre , Wang Qin , Socinski Mark A.
Published: February 2018

TPS538

Background: Despite initial high response rates to current SoC first-line chemotherapy, most patients with locally advanced or metastatic urothelial carcinoma (UC) eventually experience disease progression. With no defined SoC second-line therapies, prognosis remains poor. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 binding to programmed cell death-1 and CD80. Most current Phase 3 trials of durvalumab were initiated using weight-based dosing (mg/kg) regimens. STRONG (NCT03084471), a Phase 3b safety study of durvalumab alone or in combination with the anti-CTLA-4 agent tremelimumab is being conducted to expand understanding of the safety of fixed dosing in patients with advanced solid tumors. Module A of the study is enrolling patients with UC and non-urothelial carcinoma of the urinary tract (any histology) for treatment with durvalumab in the second-line setting post-chemotherapy. Other study modules will include durvalumab + tremelimumab combination arms. Methods: This is an open-label, multicenter study. Module A will enroll approximately 1200 patients to receive durvalumab monotherapy 1,500 mg i.v. q4w until disease progression or unacceptable toxicity. The study opened for enrolment on 17 April 2017 and is expected to be completed within 5 years. Patients must have histologically or cytologically confirmed disease that has progressed during or after nonplatinum or platinum-based chemotherapy either for metastatic disease or progressive disease less than 12 months after adjuvant or neo-adjuvant chemotherapy, and ECOG performance status 0–2. The primary objective is to assess the safety of durvalumab in terms of incidence, severity, nature, seriousness, intervention, outcome and causality (including immune-relatedness) of adverse events of special interest (AESIs). Secondary objectives include additional assessment of safety and tolerability, the frequency of treatment interruption and discontinuation, and overall survival. Clinical trial information: NCT03084471.
A study of intravesical bacillus Calmette-Guerin (BCG) in combination with ALT-803 in patients with non-muscle invasive bladder cancer.
Authors: Rosser Charles Joel , Chamie Karim , Rock Amy , Ferguson Lydia , Wong Hing C.
Published: February 2018

TPS545

Background: The current standard of care for patients with high risk NMIBC is a transurethral resection of the bladder tumor (TURBT) or biopsy followed by a 6-week induction course of intravesical BCG treatment and supplementary maintenance instillations every 3 months thereafter (Lamm 2000). While clinical response is significantly improved with BCG treatment, 50% of patients are still expected to recur within the first 12 months (Sfakianos 2014). Thus, the pursuit of novel agents to prevent progression and recurrence of NMIBC remains critical. This clinical trial evaluates the safety and efficacy of ALT-803, an IL-15 superagonist, plus BCG in BCG-naïve NMIBC patients. Methods: Patients with high-risk NMIBC (any high-grade disease, T1, or CIS) who are BCG naïve, will be randomized and enrolled into one of two study arms to be treated with either ALT-803 plus BCG or BCG alone. Patients will receive treatment via a urinary catheter in the bladder, weekly for 6 consecutive weeks during induction. A response assessment will be performed at Week 12: Patients with no disease or low-grade Ta disease will receive a maintenance course of therapy (3 weekly instillations of either ALT-803 plus BCG or BCG alone). Presence of Ta will require a TURBT procedure. Patients with presence of high-grade Ta, CIS or low-grade T1 disease will receive a re-induction course of therapy (6 weekly instillations of either ALT-803 plus BCG or BCG alone). Presence of Ta/T1 will require a TURBT procedure. Patients with high-grade T1 or greater disease (including disease progression) will be considered a treatment failure. Patients with no disease or low-grade Ta disease at months 6, 12, and 18 are eligible for maintenance treatment according to their assigned randomization. Patients with presence of disease greater than low-grade Ta will be considered a treatment failure. The primary endpoint of the study is the proportion of patients receiving ALT-803 plus BCG who are responders by Month 12 or earlier. Responders are defined as patients who experience a complete response (CIS patients) or no disease recurrence (defined as reappearance of high-risk disease). Enrollment is underway. Clinical trial information: NCT02138734.
A phase I/II study of sitravatinib (MGCD-516) plus nivolumab in patients (pts) with metastatic clear-cell renal cell carcinoma (ccRCC) that progressed on prior VEGF-targeted therapy.
Authors: Msaouel Pavlos , Thall Peter F. , Yuan Ying , Chen Isan , Tannir Nizar M.
Published: February 2018

TPS708

Background: Sitravatinib is a potent oral tyrosine kinase inhibitor that targets multiple receptor tyrosine kinase pathways including the vascular endothelial growth factor (VEGF), c-MET, and the Tyro3, Axl, and MER family. These pathways can allow tumor cells to escape immune surveillance despite immune checkpoint therapy. We therefore hypothesized that combining sitravatinib with the anti-PD1 antibody nivolumab will enhance antitumor immune responses in pts with ccRCC. The present study is designed to determine the optimal dose for this combination using efficacy and toxicity as co-primary outcomes. Methods: This phase I/II trial uses the sequentially adaptive late-onset EffTox design (Jin et al. J Am Stat Assoc 2014), which accounts for potential late-onset toxicities induced by immunotherapy, and allows dose-finding based on both the efficacy and toxicity of each successive dose. Eligible pts have metastatic ccRCC that progressed on prior VEGF-targeted therapy. Each pt receives initially a pre-specified daily oral dose, among 4 dose levels (60mg, 80 mg, 120 mg, 150 mg), of sitravatinib monotherapy for 2 weeks to allow the drug to reach a pharmacokinetic steady state. Nivolumab is then added at the dose of 240 mg intravenously every 2 weeks. A maximum of 60 pts will be treated in up to 20 cohorts of 3 pts each. Tumor biopsies and peripheral blood are collected to assess changes in tumor microenvironment and immune markers at 4 different time points: 1) at baseline, up to 14 days prior to initiation of sitravatinib, 2) following 2 weeks of sitravatinib monotherapy, 3) after 2 infusions of nivolumab in combination with sitravatinib, and 4) at disease progression. The primary endpoint is optimal dose of sitravatinib based on toxicity (by week 12) and disease control rate (at week 6). Secondary endpoints include objective response rate, progression-free survival, and overall survival. At deadline for abstract submission, 4 pts have been treated on this study. Clinical trial information: NCT03015740.
Single-arm phase ib/II study of durvalumab and guadecitabine in advanced kidney cancer (NCT03308396).
Authors: Yentz Sarah Elizabeth , Reimers Melissa Andrea , Joshi Monika , Zakharia Yousef , Gupta Shilpa , Singer Eric A. , Daignault Stephanie , Zou Weiping , Musapatika Dana , Alva Ajjai Shivaram
Published: February 2018

TPS711

Background: Checkpoint inhibitor immunotherapy directed at PD1/PDL1 has shown clinical efficacy in advanced clear cell Renal Cell Cancer (ccRCC). However, only a minority of patients respond to anti-PD1 monotherapy. There is an urgent unmet need to improve response rates including through rational combinations to reverse immune evasion by tumors. The chemokines CXCL9 and CXCL10 in the tumor micro-environment are chemo-attractants for activated NK and Th1 cells and are critical for anti-tumor immunity. Preclinical data from our group showed hypermethylation induced silencing of CXCL9/10 signaling is an important tumor immune evasion mechanism. In RCC cell lines (A-498, HTB-46 and CRL-1611), hypomethylating agents increased CXCL9/10. In mouse xenograft models, combination therapy with a hypomethylating agent and checkpoint inhibitors led to higher levels of CXCL 9/10, reversal of immune evasion and potent tumor regression. We hypothesized that the combination of guadecitabine (hypomethylating agent) with durvalumab (anti-PDL1 antibody) would increase T lymphocyte infiltration into RCC tumors including those that are immunologically ‘cold’ and result be effective in 1st and 2nd line RCC. Methods: The study is a single arm, multi-site, phase 1b/2 trial through the Big Ten Cancer Research Consortium of Guadecitabine (starting dose of 60 mg/m2/dose subcutaneously on days 1-5) with Durvalumab (1500 mg IV on day 8) in 28-day cycles in pts with metastatic ccRCC. Cohort 1 (N = 36) will consist of pts naïve to checkpoint inhibitor immunotherapy and 0-1 prior therapies. Cohort 2 (N = 16) will include pts who did not respond to prior anti-PD-1/PD-L1 therapy. The primary endpoint is objective response rate by RECIST 1.1 in cohort 1. Statistical analysis will use a binomial exact test to compare the ORR proportion in patients treated in Cohort 1 with the combination compared to an expected proportion of 25% with anti-PDL1 alone. The extensive correlative objectives include serial evaluation of serum CXCL9/10 levels and LINE-1 methylation status as well as tumor infiltrating lymphocytes profiling, PD-L1 expression, tumor mutational burden and NGS on mandatory baseline and optional biopsies at progression. Clinical trial information: NCT03308396.
Phase 3, randomized, double-blind trial of pembrolizumab in the adjuvant treatment of renal cell carcinoma (RCC): KEYNOTE-564.
Authors: Quinn David I. , Zhang Tian , Gurney Howard , Doshi Gurjyot K. , Cobb Patrick Wayne , Parnis Francis , Lee Jae-Lyun , Park Se Hoon , Semenov Andrey , Chang Wayne Yen-Hwa , Powles Thomas , Wan Shuyan (Sabrina) , Poehlein Christian Heinrich , Choueiri Toni K.
Published: February 2018

TPS712

Background: Most patients with intermediate- to high-risk advanced renal cell carcinoma (RCC) will progress within 3 years following nephrectomy. Novel treatments in the adjuvant setting are needed to prevent disease recurrence in these higher-risk patients. Upregulation of the programmed death 1 (PD-1) pathway is associated with more aggressive disease and poor prognosis. PD-1 inhibitors have demonstrated activity in metastatic RCC, and PD-1 may represent a novel therapeutic target in the adjuvant setting. Pembrolizumab, a PD-1 inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Methods: KEYNOTE-564 (NCT03142334) is a randomized, double-blind, placebo-controlled phase 3 trial designed to evaluate the efficacy and safety of pembrolizumab as adjuvant therapy in patients with RCC. Eligibility criteria include age ≥18 years; intermediate- to high-risk (T2 grade 4, T3), high-risk (T4, T), or M1 NED RCC with a clear cell component; no prior systemic therapy for advanced RCC; disease free following complete or partial nephrectomy (and metastasectomy in patients with M1 NED) with negative surgical margins; Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1; and provision of a tumor sample for biomarker analyses. Patients will be randomly assigned (1:1) to pembrolizumab 200 mg administered intravenously every 3 weeks or placebo. Randomization will be stratified by metastasis stage (M0 vs M1 NED); within the M0 group, randomization will be further stratified by ECOG PS (0 vs 1) and region (US vs rest of world). Treatment will continue until disease recurrence, unacceptable toxicity, or the completion of 17 cycles (~1 year). Imaging will be performed every 12 weeks. The primary end point is disease-free survival (DFS) per investigator assessment. The key secondary end point is overall survival (OS). Other secondary objectives include safety, disease recurrence-specific survival, DFS and OS according to PD-L1 expression status, and patient-reported outcomes. Biomarkers that may be associated with response will be evaluated as an exploratory objective. Enrollment is ongoing and will continue until ~950 patients are enrolled. Clinical trial information: NCT03142334.
MDSC clinical assay for cancer detection and monitoring in renal cell carcinoma.
Authors: Basu Arnab , Kollengode Kanthi Athreya , Danenberg Genevieve , Manoli Hugh , Rafatnia Ali , Chakravartty Eesha , Epstein Alan L. , Pinski Jacek K.
Published: February 2018

TPS713

Background: Human Myeloid Derived Suppressor Cells (MDSCs) have gained recognition as a significant population of cells that arise in cancer patients to mediate immune tolerance. Some studies have shown MDSC concentrations to be associated with overall survival and response to therapy in renal cell carcinoma. MDSCs comprise a heterogenous population that are yet to be fully characterized. We have identified a set of biomarkers uniquely expressed by the suppressive human MDSC phenotype and have developed an assay targeted to these markers. MDSCs are potentially a relatively cheap and easily performed screening and monitoring tool in cancers. This study will examine how a proprietary clinical assay works in detecting and monitoring MDSCs in blood and urine samples from patients with localized or metastatic renal cell cancer. Methods: The pilot research trial will enroll 63 subjects in a 1:1:1 ratio in three groups, normal controls over age 40 without evidence of any malignancy, patients with metastatic disease and localized renal cell carcinoma prior to nephrectomy. This sample size provides 80% power to detect a 1SD difference in MDSC concentrations in these groups on an F test. Blood and urine samples will be drawn at baseline and at 4 months for comparison. The percent CD33+ HLA-DRlow HIF1a+, CD33+ HLADRlow C/EBPb+, CD11b+ HLA-DRlow HIF1a+, and CD11b+ HLA-DRlow C/EBPb+cells as a fraction of PBMC will be determined. Primary Outcome Measures will be 1. Change in MDSC levels in patients with known localized renal cell carcinoma who undergo surgical treatment. 2. Change in MDSC level in patients with known metastatic renal cell carcinoma who initiate systemic treatment and 3. The direction and magnitude of the changes compared with radiographically assessed tumor burden. Secondary outcome measures are to assess MDSC level measurements in urine cytology analysis at baseline and after treatment to determine whether the two tests correlate in any of the 3 groups of patients defined in this study. Conclusion: This pilot study will examine if a MDSC clinical assay works in detecting and monitoring MDSCs. Recruitment is open to patients at the USC Cancer center and LAC+USC medical center. Clinical trial information: NCT02664883.
Ιταλικός κινηματογραφικός νεορεαλισμός και ελληνική μεταπολεμική πεζογραφία: Νεορεαλιστική γραφή στο Άνθρωποι και σπίτια του Αντρέα Φραγκιά.
Authors: Φραγκούλη Νάντια Αυγερινός
Published: February 2018

The years 1951-1961 mark the reception of Italian neorealist cinema in Greece with the production of films influenced by neorealism and the discussion of the nature of neorealism by Greek film critics. The novel Anthropi ke spitia [Of Houses and Men] by Adreas Fragkias, published in 1955, four years after the first viewing of De Sica’s Bicycle Thief in Greece, shows significant similarities to the themes and style of the Italian neorealist cinema. Discussing unemployment as a crucial problem of post-war Greek society Anthropi ke spitia presents the life in a poor urban neighbourhood in a series of seemingly random episodes that B. Klaras in his review of the book called ‘cinematic tableaux’. Most importantly, however, it seems that Fragkias’ novel explores the boundaries and the style of realism in post-war literature in a way that resonates the aesthetic principles of the Italian neorealistic films.
Ο ποιητής ως προφήτης και ως πιερότος στην ποίηση του Ρώμου Φιλύρα: Οι επιβιώσεις της ρομαντικής ιδεολογίας
Authors: Ζένιου Σίμος
Published: February 2018

This article argues that Romos Philyras adopts the persona of the Pierrot in the work of Romos Philyras in order to critically appropriate the romantic topos of the poet as prophet. Whereas many symbolist and modernist poets have resource to the figure of the pierrot precisely in order to oppose and demystify high romanticist ideology, I demonstrate that Philyras conjoins the two personae —prophet and pierrot. Employing methodological insights from phenomenological approaches to lyric poetry and enriching them with emphasis on formal and prosodic features, I propose a reading of Philyras’s “Pierrot” (1922) that argues against an anthropomorphizing understanding of the relationship between lyric I and the puppet-pierrot. I highlight instead that for Philyras it is precisely the lack of self-consciousness and self-reflective discourse that is the shared ground between the two personae. Contextualizing my reading with pertinent texts from the European tradition (Heinrich von Kleist, Henri-Louis Bergson), I pursue the relationship between anti-humanism and poetic prophecy in Philyras’s prose work in order to throw in relief the forceful and violent character of the visionary experience.
Physical Activity Research in Intellectual Disability: A Scoping Review Using the Behavioral Epidemiological Framework
Authors: Pitchford E. Andrew , Dixon-Ibarra Alicia , Hauck Janet L.
Published: February 2018

Through a scoping review, the current state of physical activity research in people with intellectual disability was examined. A search of publications between 2000 and 2014 retrieved 362 articles that met inclusion criteria. Eligible studies were coded according to the Behavioral Epidemiological Framework. Of the articles identified, 48% examined associations between physical activity and health outcomes, 9% developed or tested methodology to measure physical activity, 34% examined factors that influence physical activity, 8% evaluated interventions to change physical activity, and 1% examined the dissemination of physical activity/health promotion programming. The categories with lower proportions of studies represent the need for greater population-specific research in physical activity measurement, interventional designs, and translational programs.
Liquid Profiling of Circulating Tumor DNA in Plasma of Melanoma Patients for Companion Diagnostics and Monitoring of BRAF Inhibitor Therapy
Authors: Haselmann Verena , Gebhardt Christoffer , Brechtel Ingrid , Duda Angelika , Czerwinski Claudia , Sucker Antje , Holland-Letz Tim , Utikal Jochen , Schadendorf Dirk , Neumaier Michael
Published: February 2018

BACKGROUND

The current standard for determining eligibility of patients with metastatic melanoma for BRAF-targeted therapy is tissue-based testing of BRAF mutations. As patients are rarely rebiopsied, detection in blood might be advantageous by enabling a comprehensive assessment of tumor mutational status in real time and thereby representing a noninvasive biomarker for monitoring BRAF therapy.

METHODS

In all, 634 stage I to IV melanoma patients were enrolled at 2 centers, and 1406 plasma samples were prospectively collected. Patients were assigned to 3 separate study cohorts: study 1 for assessment of circulating tumor DNA (ctDNA) as part of companion diagnostics, study 2 for assessment of ctDNA for patients with low tumor burden and for follow-up, and study 3 for monitoring of resistance to BRAF inhibitor (BRAFi) or mitogen-activated protein kinase inhibitor therapy.

RESULTS

Overall, a high degree of concordance between plasma and tissue testing results was observed at 90.9% (study 1) and 90.1% (study 2), respectively. Interestingly, discrepant results were in some cases associated with nonresponse to BRAFi (n = 3) or a secondary BRAF-mutant malignancy (n = 5). Importantly, ctDNA results correlated with the clinical course of disease in 95.7% and with response to treatment. Significantly, the detection of BRAF mutant ctDNA preceded relapse assessed by Response Evaluation Criteria in Solid Tumors, and was more specific than serum S100 and lactate dehydrogenase.

CONCLUSIONS

Blood-based testing compares favorably with standard-of-care tissue-based BRAF mutation testing. Importantly, blood-based BRAF testing correlates with the clinical course, even for early-stage patients, and may be used to predict response to treatment, recurrence, and resistance before radioimaging under BRAFi therapy, thereby enabling considerable improvements in patient treatment.
Análise da viabilidade técnica da incorporação de agregados reciclados em concreto
Authors: Fonseca Thales Daniel dos Santos , Ribeiro Junior Leopoldo Uberto , Barbosa Luciano Floriano
Published: February 2018

Os resíduos da construção civil causam grande impacto ambiental, pois são gerados em grande volume e contaminam recursos naturais, porém ele apresenta grande capacidade de reciclagem, possibilitando sua reinserção no ciclo da construção civil, pela substituição dos agregados naturais por reciclados. Este trabalho tem como objetivo, comparar a resistência de concretos com substituição de agregados reciclados nos teores de 15%, 30% e 100%, por meio do ensaio de compressão axial. A execução da pesquisa se dividiu, principalmente, em caracterização física dos agregados, dosagem dos traços de concreto pelo método do American Concrete Institute e o ensaio de compressão axial. A resistência à compressão aos 28 dias do concreto 100% reciclado e do concreto 100% natural se mostraram semelhantes, sendo 30,8 e 32,71 MPa, respectivamente, afirmando que a incorporação de agregados reciclados em novos concretos é viável.
Study of Neuropilin-1/Cd304 Expression in Leukemogenesis
Authors: Allam Ahmed A. , Aziz Shereen P. , Mostafa Ali Elsayed
Published: February 2018

Neuropilins are transmembrane glycoproteins that act as receptors for vascular endothelial growth factors (VEGF) and are involved in the process of tumor angiogenesis. Its importance in hematological malignancies such as acute leukemia (AL) remains to be elucidated. The aim of this study was to evaluate the significance of neuropilin-1 expression in acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) patients by flowcytometry and the difference between both groups of acute leukemia. Bone marrow aspirates of 52 patients with acute leukemia, 29 patients with de novo AML and 23 ALL patients were examined in this study. 15 subjects with non-hematological malignancy serving as the control group were also included. Neuropilin-1 expression by flow cytometry showed a highly significant increase in de novo AML and ALL patients with a mean of 37.9 Â± 20.92% and 32.33Â±19.8%, respectively, compared to control groupâs mean of 11.51 Â± 3.04% (p= 0.001, 0.006). There were no statistically significanct difference between ALL and AML patients (p= 0.76). Neuropilin-1 surface expression by flowcytometry showed a significant positive correlation with total leukocyte count, bone marrow blast percentage, CD45 and CD14 and negative correlation with hemoglobin level, RBCs count in AML patients. In ALL patients, positive significant correlations were found with bone marrow blast percentage and negative correlation with hemoglobin level, RBCs count. Neuropilin-1expression was detected significantly in acute leukemias and it is related to the disease severity.
Iqaluktutiaq Voices: Local Perspectives about the Importance of Muskoxen, Contemporary and Traditional Use and Practices + Supplementary Appendices S1–S5 (See Article Tools)
Authors: Tomaselli Matilde , Gerlach S. Craig , Kutz Susan J. , Checkley Sylvia L. , Iqaluktutiaq The Community of
Published: February 2018

Understanding human-wildlife relationships and interactions is crucial to implementing policies and practices related to wildlife and public health that are locally relevant and adapted to local communities and needs. With the goal of informing a community-based participatory muskox health surveillance system in the community of Iqaluktutiaq (Cambridge Bay) on Victoria Island, Nunavut, Canada, we explored the importance of muskoxen for community residents, their relevance for local food security, and the relationships and interactions between Iqaluktutiamiut and muskoxen. We investigated these themes through individual interviews of 30 community members identified as muskox experts by local organizations. Results were finalized and refined with 26 interviewees in feedback sessions. For Iqaluktutiaq residents, muskoxen have nutritional, economic, sociocultural, and environmental importance. The decline of muskoxen documented locally has a multidimensional impact on the community, with negative effects on all the domains explored, from food security to the integrity of the cultural system. Descriptions of subsistence and commercial harvesting and butchering practices are an asset for the successful implementation of participatory muskox health surveillance activities (e.g., hunter-based sampling), as well as for interpretation of derived data (e.g., local knowledge on muskox diseases). Knowledge of specific harvesting practices that might increase exposure to zoonotic agents is also relevant for designing targeted strategies to mitigate public health risks. This research underlines how careful examination of the human-wildlife context through local perspectives can benefit wildlife health surveillance, public health, and wildlife co-management outcomes.
Assessing Sea Ice Trafficability in a Changing Arctic
Authors: Dammann Dyre O. , Eicken Hajo , Mahoney Andrew R. , Meyer Franz J. , Betcher Sarah
Published: February 2018

Arctic sea ice has undergone rapid changes during the last few decades, with negative implications for over-ice travel and on-ice operations, which benefit from services provided by the sea ice. A Parameter-based Trafficability Hierarchy (PATH) is presented here as a framework for developing quantitative assessment strategies that can guide planning and execution of operations on or near sea ice and quantify the impacts of recent changes on ice use. A PATH assessment has been completed for three case studies in Arctic Alaska. These cases, which correspond to a range of different icescapes and ice uses, identify and quantify different parameters linked to trafficability and safe operations. For ice road applications, PATH was used to determine an ice thickness compensation factor, a factor increasing the minimal thickness threshold for operations, to help translate sporadic auger ice thickness measurements along the Kotzebue–Kiana community ice road into an envelope for safe operations. A compensation factor as high as 1.5 was found to be necessary to ensure safety because of the high local thickness variability that is currently a concern for ice road operators. A PATH assessment of ice roughness for ice trail routing at Utqiaġvik draws on satellite remote sensing and is relevant for over-ice travel in general, including escape, evacuation, and rescue. We compared the routing of local snowmobile trails with Synthetic Aperture Radar (SAR) data products to identify specific ranges of ice conditions, roughness, and topography favored for ice trail construction. The same combination of data sources was used to identify potentially beneficial trail routes. Finally, an ice stability and safety assessment was completed for ice road construction and maintenance by industry near the Northstar Island oil production facility. We evaluated small-scale ice displacement data obtained from SAR interferometry to infer internal ice strain and stress and used these data in assessing the potential for fractures to reduce load-bearing capacity.
What Are Case Studies Good For? A Response to Commentaries by McMullen and Karlin
Authors: Hamburg Sam R.
Published: February 2018

I am grateful to Linda McMullen (2018) and Robert Karlin (2018), for their commentaries on my case studies of Margie and Amie (Hamburg, 2018). Although case studies do not permit strong claims regarding treatment efficacy, they allow strong claims for the plausibility that treatments are efficacious. From a pragmatic standpoint, that is sufficient to justify proposing the treatments to other practitioners to be tried and tested by them, thereby ultimately contributing to the sum total of psychotherapy craft knowledge. On the topic of the placebo effect, the perspectives of researchers and clinicians, based as they are on different kinds of knowledge, can differ to the point of irreconcilability. What have hitherto been characterized as non-specific contributors to treatment outcome might better be classified as specific factors yet to be identified.
Gender Differences in Sexual and Reproductive Health Protective and Risk Factors of Batswana Adolescents: Implications for Parent and Adolescent Interventions
Authors: Sun Christina J. , Seloilwe Esther S. , Magowe Mabel , Dithole Kefalotse S. , Miller Kim S. , St. Lawrence Janet S.
Published: February 2018

Adolescents in sub-Saharan Africa and in Botswana in particular continue to bear the brunt of the HIV epidemic. This analysis assessed gender differences among theory-based sexual and reproductive health protective and risk factors in a cross-sectional sample of 228 Batswana adolescents. Incongruence between preferred and actual sources of sexual information and several important gender differences in parent-adolescent relationships, psychosocial influences, and adolescent sexual behaviors were identified. Parents were the fourth most common source of information about sex; yet, over three-quarters of adolescents preferred to have parents teach them about sex. Boys reported more positive relationships with their parents and girls reported more positive attitudes toward transactional sex. Both boys and girls reported similarly low levels of parental monitoring, parental communication, and parental responsiveness, all of which are important protective factors. These findings suggest interventions should address these gender differences and consider offering parallel interventions for adolescents and their parents in Botswana.
Condomless Anal Intercourse by Partner Type Among Chinese Men Who Have Sex With Men in Tianjin
Authors: Zhou Ning , Bauermeister José , Guo Wei , Yu Maohe , Yang Jie , Zheng Minna , Guo Yan , Gong Hui , Gao Yongjun , Jiang Gueohong
Published: February 2018

HIV prevalence and incidence is high among men who have sex with men (MSM) in China, underscoring the need to support and optimize HIV risk reduction strategies for this population. We sought to estimate the prevalence of condomless anal sex among MSM living in Tianjin, China. We recruited 595 HIV-negative MSM living in Tianjin to participate in a HIV study between 2013 and 2014. Data were collected after a voluntary counseling and testing session through a face-to-face survey. We used multivariable logistic regressions to examine the association between sociodemographic characteristics and HIV risk correlates and MSM's likelihood of engaging in condomless anal intercourse with main and casual partners in the prior 6 months. Results are presented. HIV risk reduction efforts should be developed to be sensitive and responsive to the unique experiences of Chinese MSM. We discuss opportunities for future work, including the development HIV risk reduction interventions.
Making Histories
Authors: Duffett Rachel , Roper Michael
Published: February 2018

This article reflects upon a Heritage Lottery–funded project devised by Britain’s leading practitioner of reminiscence arts, Age Exchange. “Meeting in No Man’s Land” explored the different family legacies of the First World War by bringing together the British and German descendants of its veterans.1 The project process had many similarities to the practice of oral history, but there were also significant differences. This article considers the shared territory of the two methodologies while at the same time acknowledging the uniqueness of Age Exchange’s approach to the making of histories.
“The Discourse We All Need So Seriously”
Authors: Hawkins Callie
Published: February 2018

On the evening after the 2016 presidential election, President Lincoln’s Cottage, a historic site and museum in Washington, DC, opened its doors for an Evening of Reflection. The Cottage has made a habit of rapidly responding to issues facing its community, and the event on November 9 would not have been possible, nor would it have been successful, if not for years of community building and public outreach through exhibits, programs, and online engagement. As a result, when community members needed a place to which to turn in a time of national division, they came to the Cottage.
Disparities in incidence and mortality of pancreatic cancer in the world
Authors: Khani Yousef , Arabsalmani Masoumeh , Pakzad Reza , Ghoncheh Mahshid , Mohammadian-Hafshejani Abdollah , Salehiniya Hamid
Published: February 2018

Background: Pancreatic cancer (PC) is as the twelfth most frequent cancer and the seventh most important cause of mortality by reason of cancer in the world. Being informed about the incidence and mortality of this cancer and the potential role of development is useful in health policy. The aim of this research is investigating disparities in the incidence and mortality of PC in the world countries in the year 2012.

Methods: This study was an ecologic study in the World for assessing the correlation between Human Development Index (HDI) and its details (Gross national income (GNI) per capita, average years of schooling and life expectancy at birth) with age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) of PC.

Results: In total, 337872 new cases of PC occurred in 2012 around the world , that 178116 and 159711 cases take happen in men and women respectively, also at the same year 330391 deaths of PC occurred ,that 173,827 and 156564 cases were in men and women. In assessment the relationship between HDI and ASIR and ASMR of PC there is significant positive correlation equal to 0.767 (p <0.001) between HDI and ASIR of PC, and a significant positive correlation equal to 0.776 (p <0.001) between HDI and ASMR of PC.

Conclusion: The incidence and mortality of PC has a significant positive correlation with the Human Development Index.
Cross-Linguistic Influence in L3 Spanish and Relationship between Language Proficiency and Type of Lexical Errors/Međujezični Utjecaji između Španjolskog J3, Engleskog J2 i Hrvatskog J1 te Veze između Jezičnog Umijeća i Vrste Leksičkih Pogrešaka
Authors: Peric Barbara , Novak Mijic Sonja
Published: February 2018

Abstract This study is focused on lexical cross-linguistic influences in Spanish third language (L3) acquisition. Participants are learners with Croatian first language (L1) and English second language (L2). The study investigates the relationship between L3 proficiency and types of lexical errors. Our hypotheses are focused on two main points: type of language transfer can be related to formal similarity of certain features or language components and to L2 proficiency as well and therefore English L2 will be the main source in both - transfer of form and transfer of meaning and the type of lexical errors is changed with the higher level of proficiency. Calques are more frequent, and code-switching is reduced (Celaya, 2006, 2008). There were 50 participants in this research and all of them are second and third year students of the American College of Management and Technology. Our hypotheses were confirmed on the basis of the error analysis in the compositions of the second and third year students. Key words:  Calques; formal similarity; transfer of form; transfer of meaning    Međujezični utjecaji između španjolskog J3, engleskog J2 i hrvatskog J1 te veze između jezičnog umijeća i vrste leksičkih pogrešaka Sažetak U središtu pozornosti ovog istraživanja su leksički međujezični utjecaji prilikom usvajanja španjolskog jezika kao trećeg stranog jezika kod učenika kojima je hrvatski jezik prvi/ materinski jezik, a engleski drugi jezik.  U ovom radu smo također proučavali veze između jezičnog umijeća u trećem jeziku i vrste leksičkih pogrešaka. Cilj našeg istraživanja je istražiti hrvatske i engleske međujezične utjecaje, a naše pretpostavke su usmjerene na dvije glavne točke: vrsta promatranog jezičnog prijenosa može biti povezana s formalnom sličnosti između određenih značajki ili komponenti jezika te će tako engleski jezik kao J2 biti preferirani izvor leksičkoga prijenosa te da se proizvodnja kalkova povećava kako učenici postaju kompetentniji u trećem jeziku. Istraživanje je provedeno na uzorku od 50 ispitanika. Svi ispitanici su studenti druge i treće godine na Američkoj visokoj školi za menadžment i tehnologiju. Metodom analize pogrešaka analizirani su završni pismeni radovi te potvrđene naše pretpostavke. Ključne riječi:  formalna sličnost;  kalkovi; prijenos forme; prijenos značenja
Structure of Motor Abilities of Pre-School Children before and After Kinesiology Treatment
Authors: Mandić Danimir , Martinović Dragan , Pelemiš Vladan
Published: February 2018

The research included the sample of 114 pre-school children age 6 and 7, with average values of height (TV=123.23cm±5.43) and weight (TT=24.53kg±2.71), divided into two groups: (E) experimental (n=55) which had an additional programme of kinesiological activities lasting for 12 weeks and (K) control group (n=59), which apart from regular activities in physical education classes in the kindergarten did not have a programme of kinesiology activities. The aim of the research was to determine latent structure of motor abilities before and after the treatment of kinesiological activities, and determining compatibility of factor saturation. Correlation was done by Pearson correlation coefficient, and determination of the structure of motor activities was done by factor analysis and by the method of major components with bent promax rotation of isolated main components. Tucker index of saturation factor was used for determining compatibility of isolated factors. Results of the research point at the fact that initial and final measuring of both tested groups, two-dimensional structure of motor abilities consisting of coordination and strength, which could most appropriately be defined as one meaning the general motor factor. Congruence between isolated factors in E and K groups gained in initial and final measuring, show that there are no differences in structure of isolated factors. It can be concluded that motor functioning of children is still under mechanism of structuring movement, so after treatments of kinesiology activities, there are still the same factors, and quality changes in structure of motor abilities are not achieved in the tested age.
effects of levodopa on gait in Parkinson’s disease
Authors: Schaaf Emily C.
Published: February 2018

This literature review aimed to explore the effects of levodopa on gait in Parkinson’s disease. Understanding the degree of and fluctuations in spatiotemporal, kinematic and kinetic gait variables over the course of the levodopa cycle aids clinicians in determining the effectiveness of treatment. A literature search was carried out between August 2015 and October 2015. Databases were searched and abstracts were read for suitability. Appropriate articles were read in full and their reference lists were checked for further relevant titles. The evidence suggests during the ‘off’ phase of the levodopa cycle, the Parkinson’s disease gait is considerably slower, shuffling and flexed compared to that of healthy age match controls. During the ‘on’ phase, spatiotemporal, kinematic and kinetic gait parameters appear to improve compared to the ‘off’ phase, although the improvements are still less than that of healthy matched controls. The effects of levodopa on Parkinson’s disease gait are dependent on the stage of the medication cycle. Further research is needed to evaluate the effects of levodopa on gait in functionally relevant settings.