bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of cytoreductive nephrectomy and survival in the immune checkpoint inhibitor era.
Authors: Miccio Joseph , Ma Sung Jun , Oladeru Oluwadamilola Temilade , Yang Daniel X. , Peters Gabrielle W. , Jethwa Krishan , Park Henry S. , Hurwitz Michael E. , Leapman Michael , Sprenkle Preston , Nguyen Paul , Yu James , Johung Kimberly
Published: February 2020

748

Background: Cytoreductive nephrectomy (CN) for patients (pts) with metastatic renal cell carcinoma (mRCC) improved overall survival (OS) in the interferon (IFN) era, but the benefit of CN in the immune checkpoint inhibitor (ICI) era is unknown. Methods: We identified pts with mRCC receiving immunotherapy (IT) from 2004-2015 in the National Cancer Database (NCDB). Pts with partial nephrectomy or ablation were excluded. The ICI era was defined as 2013-2015 based on a high-profile publication in 2012 demonstrating efficacy of ICI in mRCC and the IFN era was defined as 2004-2005 due to FDA approval of sorafenib in 12/2005. Pts receiving CN with TKI were excluded, as prior NCDB study showed an OS benefit to CN in contrast to the results of the CARMENA trial. Univariable (UVA) and multivariable (MVA) associates with OS during each era were identified using Cox regression analysis including age, sex, race, income, insurance, treatment facility type, treatment location, clinical T stage (cT), clinical N stage (cN), histology, Fuhrman grade (FG), other metastectomy, and CN. Results: There was a 65% decline in mRCC pts receiving IT from 2005 to 2006 (end of the IFN era), which remained low (11% rise from 2006-2012) until a 93% rise from 2012 to 2013 (start of the ICI era). 128 of 422 (30.3%) pts in the IFN era received CN compared to 218 of 526 (41.4%) patients in the ICI era, p<0.001. Pts in each era were balanced with respect to median age, race, income, location, cT, and histology, but the ICI era had higher proportions of pts with private insurance, treatment at an academic center, N0 disease, FG 3-4, and other metastatectomy (p<0.05). Most pts with CN in the ICI era had IT after CN (89.9%); this was not coded in the IFN era. In the IFN era, CN compared to IT alone was associated with improved OS on UVA (HR 0.59, 95% CI 0.47-0.73, p<0.001) and MVA (HR 0.62, 95% CI 0.47-0.83, p=0.001). In the ICI era, CN compared to IT alone was associated with improved OS on UVA (HR 0.63, 95% CI 0.49-0.81, p<0.001) but not on MVA (0.82, 95% CI 0.58-1.14, p=0.234). Conclusions: Despite increased utilization of CN for US pts with mRCC treated with IT during the ICI era, the lack of OS benefit in recent years suggests a need for prospective reevaluation of the value CN and its timing with ICI.
Impact of oncological versus nononcological on survival outcomes in African Americans with renal cell carcinoma.
Authors: Meagher Margaret Frances , Bradshaw Aaron , Patil Dattatraya H , Saito Kazutaka , Cotta Brittney , Yasuda Yosuke , Eldefrawy Ahmed , Fujii Yasuhisa , Master Viraj A. , Derweesh Ithaar
Published: February 2020

749

Background: African-Americans have an increased incidence of renal tumors of lower oncological potential when compared to other ethno-racial groups. Yet, survival outcomes are similar. We investigated the impact of African-American race on overall survival, oncological and functional outcomes, and non-cancer mortality. Methods: Multi-institutional (Emory, TMDU, UCSD) retrospective analysis of patients who underwent partial or radical nephrectomy between 1998-2018. Primary outcome was overall survival (OS). Secondary outcomes were non-cancer mortality (NCM), recurrence free survival (RFS), and eGFR decline. Multivariable logistic regression (MVA) was used to analyze OS, NCM, and RFS, and estimated glomerular filtration rate (eGFR)<45 and <30 ml/min/1.73m2. Results: 3632 patients were grouped into African American (AA, n=531) and Non-African American (NAA, n=3101). No difference was noted between groups with respect to mean tumor size (p=0.31). NAA had a higher proportion of metastases at presentation (9.9% vs. 7.0%, p=0.04). AA race was an independent risk factor for functional decline to de novo eGFR <45 (OR=1.43, p=0.04) and de novo eGFR<30 (OR 2.01, p<0.001). MVA for worsened NCM demonstrated AA race (OR=1.63, p=0.02), increasing age (OR=1.05, p<0.001), male sex (OR=1.56, p=0.01), and hypertension (OR=1.73, p=0.001) to be independent risk factors. Significant factors on MVA for worsened OS included increasing age (OR=1.03, p<0.001), radical nephrectomy (OR=1.47, p=0.01), increasing tumor size (OR=1.11, p<0.001), hypertension (OR=2.63, p<0.001), high tumor grade (OR=1.97, p<0.001), and post-operative eGFR <45 (OR=1.50, p=0.01). MVA for worsening RFS demonstrated high tumor grade (OR=2.04, p<0.001) and increasing clinical tumor size (OR=1.15, p<0.001) to be independent factors. Conclusions: African Americans undergoing surgical management for RCC appear to have similar OS and RFS, but poorer NCM than non-African American patients. The cause of these disparities is multi-faceted but likely is associated with functional decline. Nephron-sparing management when feasible and appropriate should be considered in African-Americans presenting with renal cortical tumors.
Baseline lymphocyte to monocyte ratio (LMR) and systemic inflammation index (SII) as prognostic factors in metastatic renal cell carcinoma (mRCC) patients treated with nivolumab: Preliminary results of the Meet-URO 15 (I-BIO-REC) study.
Authors: Rebuzzi Sara Elena , Buti Sebastiano , Sbrana Andrea , Procopio Giuseppe , De Giorgi Ugo , Vitale Maria Giuseppa , Massari Francesco , Santini Daniele , Cavo Alessia , Banna Giuseppe Luigi , Soraru' Mariella , Cortellini Alessio , Messina Marco , Martelli Valentino , Mollica Veronica , Stellato Marco , Lipari Helga , Catalano Fabio , Signori Alessio , Fornarini Giuseppe
Published: February 2020

751

Background: Biomarkers to select mRCC patients most likely to benefit to immune-checkpoint inhibitors are still needed. The ongoing retrospective multicentre Meet-URO 15 (I-BIO-REC) study evaluates the prognostic role of peripheral blood cells in mRCC patients treated with nivolumab. Methods:The primary endpoint of the study was median overall survival (mOS) according to baseline neutrophil to lymphocyte ratio (NLR), but here preliminary analyses on baseline LMR and SII (secondary endpoints) are reported. LMR was defined as the ratio of lymphocyte to monocyte (cutoff = 3) and SII as platelet x neutrophil/lymphocyte (cutoff = 1375). Results: From May 2016 to January 2019 189 patients started nivolumab as 2nd (62%), 3rd (25%) and > 3rd (13%) line. Median age was 69 years, 67% were male and 87% had clear cell histology. Baseline IMDC group was favorable in 26%, intermediate in 63% and poor in 11%. Lymph-nodes, visceral and bone metastases were present in 55%, 92% and 37%. mOS and progression-free survival (PFS) were 30.5 months and 9.5 months. Overall response rate (ORR) and disease control rate (DCR) were 28% and 57%. LMR was available in 150 patients: LMR ≥ 3 (44%) correlated with statistically significant longer OS [NR vs 26.8 months, HR 0.50 (0.29-0.88); p = 0.016] but not PFS (10.3 vs 9.9 months, HR 0.87 (0.58-1.31); p = 0.5) with similar ORR (34% vs 33%) and DCR (60% vs 63%) compared to LMR < 3. SII was available in 162 patients. SII < 1375 (82%) correlated with statistically significant longer PFS [11.5 vs 3.4 months; HR 2.16 (1.36-3.43), p = 0.001] and OS [NR vs 9.5 months; HR 3.87 (2.21-6.78), p < 0.001] with higher ORR (35% vs 20%) and DCR (65% vs 40%) compared to SII ≥ 1375. Univariate and multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation between SII with PFS and OS, but not for LMR. Conclusions: Preliminary analyses of our study showed a prognostic role of baseline SII, while it is uncertain for LMR in mRCC patients treated with nivolumab.
Improving IMDC criteria in patients with metastatic renal cell carcinoma through the addition of initial metastatic site in bone, brain, and liver.
Authors: Di Nunno Vincenzo , Massari Francesco , Guida Annalisa , Alves Costa Silva Carolina , Derosa Lisa , Mollica Veronica , Colomba Emeline , Escudier Bernard , Albiges Laurence
Published: February 2020

754

Background: IMDC criteria are largely adopted to estimate patient prognosis. In a retrospective study we assessed that the addition of first site of metastases in brain bone and liver (bbl) metastases as variable improves prognostic stratification of patients (pts) with metastatic renal cell carcinoma (mRCC). We performed a validation study in an external cohort of patients with mRCC. Methods: All consecutive mRCC pts treated at a single institute and included in the local IGReCC database. All pts received at least one line of targeted therapy or ICIs. Primary outcome was OS from first line start. Univariate and multivariate analysis (cox regression model) were performed. Bootstrap was also carried out for validation. Results: 1073 mRCC pts were analysed (808 with known IMDC score). Of 13 initial variables considered for prognostic model, the presence of bbl as first site/s of metastases plus the 6 variables included in IMDC resulted as statistically significant factors associated with OS (table). By including this new parameter we developed a 7-variables based score (IMDC-7). Patients with 0, 1-2 and≥3 positive variable/s were considered as good, intermediate and poor risk patients respectively. 56 (22%) pts moved from good (IMDC) to intermediate (IMDC-7) and 66 (15.4%) pts moved from intermediate (IMDC) to poor (IMDC-7) group (table). Final bias corrected concordance c-index was 0.69 and 0.71 in overall cohort and in pts treated with ICI (n=241). Conclusions: The addition of bbl primary metastases to the others IMDC variables improves prognostic predictive power of the model.[Table: see text]
Recurrence of surgically resected chromophobe renal cell carcinoma: Recommendations for follow-up.
Authors: Vanaclocha Saiz Leyre , Neves Joana B. , Marchetti Marta , Barod Ravi , Patki Prasad , Mumtaz Faiz , Dabestani Saeed , Tran Maxine Gia Binh , Bex Axel
Published: February 2020

755

Background: Post-operative follow-up protocols for renal cell carcinoma (RCC) are based on outcomes of the clear cell subtype and often rely on variables not applicable to chromophobe RCC (chRCC), such as Fuhrman nuclear grading. We aimed to evaluate predictors of recurrence to guide follow-up regimes in the context of chRCC. Methods: Combined retrospective analysis of non-metastatic surgical cases with a final diagnosis of chRCC from an institutional database at a UK tertiary high-volume centre (June/2013 to March/2019) and from the international collaborative database RECUR (12 institutes across 8 European countries; 2006 to 2011). TNM risk group, tumour size, histopathological features, cancer specific survival (CSS) and recurrence free survival (RFS) were analysed. Kaplan Meier plots and Cox regression analysis were performed to determine factors associated with recurrence (local or distant). Results: 295 cases were identified (57.3% male, median age 60). After a median follow up of 58 months, 17 (5.8%) recurrences were observed, the majority of which were distant recurrences (n = 13). CSS was 96.3%. Tumours staged ≥pT2b (HR 13.7; 95%CI 3 to 63.1; p = 0.001), with coagulative necrosis (HR 3.9; 95%CI 1.3 to 11.1; p = 0.012) and sarcomatoid differentiation (HR 33; 95%CI 8.1 to 134.6.1; p = 0.000) were more likely to recur during follow-up. Only two cases of pT1a lesions had local recurrence, both after a positive surgical margin. All patients with early recurrences ( < 18 months after surgery; n = 6) had tumours staged ≥pT2b with coagulative necrosis; sarcomatoid differentiation was also present in 3 cases. Conclusions: Recurrence of surgically resected chRCC is not common. For patients with pT1 lesions, negative margins, no coagulative necrosis or sarcomatoid features, prognosis is excellent. Follow up can be curtailed to avoid excess radiation exposure and patient anxiety.
Predicting long-term results with circulating tumor cells in patients with de novo androgen sensitive prostate cancer treated with hTERT peptides vaccine.
Authors: Lilleby Wolfgang , Guldvik Ingrid Jenny , Hole Knut H. , Olaussen Richard , Mills Ian G. , Stensvold Andreas , Seierstad Therese , Tran Phuoc T. , Inderberg Else Marit
Published: February 2020

98

Background: Androgen deprivation, radiotherapy and chemotherapy improves survival in advanced prostate cancer (PC), but many patients still progress and experience toxicity from treatment. We investigated the clinical utility of a medical wire, collecting circulating tumor cells (CTCs) from a peripheral vein, to predict oncologic outcomes prior to treatment with a hTERT peptide vaccine. Methods: Twenty-three patients with advanced PC with non-visceral spread and unselected HLA-type were eligible. One patient progressed before initiation of the vaccination (median FU 60 months). The hTERT peptides vaccine schedule started one week after inclusion with a total of 13 vaccinations (N=22). Patients with no signs of deterioration during the vaccine schedule received image-guided radiation to the prostate (2Gy/37f, n=20). Vaccine response was evaluated by T-cell proliferation assay. CTCs were enriched from the peripheral blood using EpCAM as antibody (CellCollector, Gilupi, Potsdam, Germany). Kaplan-Meier outcome curves were constructed for prostate cancer-specific survival (PCSS) and overall survival with stratification by immune response, CTCs (no/yes), PSA and comparison of patient subsets using the log-rank test. Results: Median age of the cohort was 67 years (range 51-78 years).The mean time from CellCollector after ADT to start vaccine was 2,95 months (SD+-1,78 months). The mean yield of CTCs was 3 cells (range 0 - 22). The detection of CTCs showed an inverse trend towards immune response (p=0.07). None of the patients with a positive CellCollector finding and a PSA below ≤0.2 (n=9) had died of prostate cancer during the observation period of 5 years, patients with no CTCS and a PSA >0.2 (n=14) had an estimated median PCSS of 39 months (log-rank test 0=0.007, Fig. 1). The overall survival analysis showed that 6 out of 9 patients with CTCs compared to 5 out of 14 patients in the CTCs negative group were alive at 5 years FU (log-rank-test=0.159). Conclusions: Patients with a de novo diagnozed metastatic prostate cancer and a positive CTC burden do better when subsequently treated with the hTERT vaccine than those with a negative CTC finding. Clinical trial information: NCT01784913.
Phase 0 study to assess [111In]-DOTA-h11B6 to target human kallikrein-2 (hk2) in men with metastatic castration-resistant prostate cancer.
Authors: Morris Michael J. , O' Donoghue Joseph A. , Chetty Dushen , Russell Mike , Zulch Emma , Avadhani Anjali Narayan , Divgi Chaitanya R. , Pandit-Taskar Neeta
Published: February 2020

TPS249

Background: Human kallikrein-2 (hk2) is a member of the kallikrein family, is produced by prostatic epithelium, has 80% DNA sequence homology with PSA, is both circulating and bound to prostatic tissue, and is highly expressed even in high grade tumors. hK2 holds the promise of serving as a new therapeutic target for radiopharmaceuticals in prostate cancer. h11B6 is a humanized antibody directed to an epitope found on the catalytically active form of hK2, which is permanently internalized after binding. This is a first-in-human trial of [111In]-DOTA-h11B6 to determine the radio-immunotherapeutic potential of targeting hK2 with nanomolar affinity. The trial will determine the most favorable antibody mass as well as assess tumor targeting. Methods: To determine the optimal antibody mass, two cohorts of patients will be studied. All patients will receive 2 mg of [111In]-labeled h11B6. The first cohort consists of escalating amounts of antibody mass in 2-6 patients: 2, 10 and 20 mg total antibody respectively. Patients will undergo serial whole-body images for up to a week, along with assessments of serum clearance kinetics and normal organ residence time. The lowest mass amount of antibody that demonstrates favorable biodistribution and evidence of radioactivity accumulation in tumor will be used for the second cohort. Up to 6 patients will be studied in the second cohort, which will focus on assessment of antibody tumor targeting. Following this optimization and targeting imaging trial, a phase 1 dose-escalation radioimmunotherapy trial may be performed. Clinical trial information: NCT04116164.
Targeting resistant prostate cancer with ATR and PARP inhibition (TRAP trial): A phase II study.
Authors: Reichert Zachery R. , Daignault Stephanie , Teply Benjamin A. , Devitt Michael Edward , Heath Elisabeth I.
Published: February 2020

TPS254

Background: Inhibition of poly(ADP-ribose) polymerase (PARP) shows promise in prostate cancer, but is limited to the ~20% of men with defects in genes encoding for DNA repair proteins BRCA1, BRCA2 or ATM (homologous recombination defect positive, HRD+). The effect is modest for HRD+ patients with a progression free survival of ~7 months. Pharmacologically simulating genetic DNA repair defects may expand who benefits to homologous recombination defect negative (HRD-) patients and improve HRD+ response. The ataxia telangiectasia and Rad3-related protein (ATR) is ideal with its roles in cell cycle regulation, replication fork resolution and both single and double strand break repair. Preclinical studies on HRD-/HRD+ cell lines support this. We hypothesize co-inhibition of ATR and PARP will respond regardless of HRD status. Methods: TRAP is a prospective, multi-institutional, phase 2 clinical trial testing AZD6738 combined with olaparib in HRD+ and HRD- mCRPC patients. Primary endpoint is the response rate (RR) by RECIST radiographic response or PSA decline ≥50% in 35 HRD- patients, with a secondary objective of RR in 12 HRD+ patients. HRD+ is mono/biallelic loss of ATM or biallelic loss of BRCA1/2. Tissue based sequencing is done unless completed prior in mCRPC, known BRCA germline loss, treating provider deems biopsy unsafe or biopsy fails. Those unable or failing biopsy are designated as HRD-, but BRCA1/2 and ATM are tested via circulating tumor DNA in a commercial test. Eligible patients must progress after ≥1 line of mCRPC therapy. Progression on a second generation anti-androgen (e.g. apalutamide), abiraterone or within 6 months of docetaxel in hormone sensitive disease are eligible. Treatment entails 160 mg PO daily of AZD6738 on days 1-7 and 300 mg PO BID of olaparib on days 1-28 of a 28-day cycle. Statistical analysis will provide RR with 95% binomial confidence intervals. Analysis of tumor specimens, circulating tumor cells and DNA will be performed for predictors of response and acquired resistance. The study is at four sites in the US, participates in the Prostate Cancer Clinical Trials Consortium, LLC, is managed by the University of Michigan and funded by AstraZeneca. Clinical trial information: NCT03787680.
A phase Ib/IIa study of rucaparib (PARP inhibitor) combined with nivolumab in metastatic castrate-resistant prostate cancer.
Authors: Patnaik Akash , Duttagupta Priyanka , Chaudagar Kiranj , Alter Raanan , Hieromnimon Hanna , Szmulewitz Russell Zelig , Fleming Gini F. , Stadler Walter Michael
Published: February 2020

TPS270

Background: Immune checkpoint blockade (ICB) therapies have had a major impact across a wide range of cancers. However, only subsets of patients across all malignancies benefit from ICB. In particular, metastatic castrate-resistant prostate cancers (mCRPC) have shown very limited responses to ICB. While there is ongoing work to identify predictive biomarkers to ICB responsiveness, early preclinical data from our group suggests that targeting fundamental DNA repair pathways could markedly increase the fraction of patients responsive to immunotherapeutic interventions. Based on these preclinical studies, we are conducting an investigator-initiated Phase Ib/IIa co-clinical trial of rucaparib and nivolumab singly and in combination, in mCRPC patients. Methods: Patients are randomized to one of three arms – rucaparib, nivolumab, or both drugs in combination for 4 weeks. Metastatic biopsy samples are collected at baseline and after 4 weeks on treatment, after which all arms switch to combination therapy. The primary objective is to assess feasibility of the combination, and to elucidate changes in T cell infiltration by RNA-seq analysis using established T-cell non-inflamed and inflamed gene signatures. Secondary objectives are to assess changes in immune cell infiltration via flow cytometry, multiplex IHC, transparent tissue tomography (3D mapping) and single-cell RNA-seq. We will correlate changes in the metastatic tumor microenvironment (TME) at baseline and following 4 weeks of treatment, with genomic alterations and clinical responses. We have currently enrolled 12 patients to the study, and collected pre- and 4 week on-treatment biopsies. This study utilizes novel emerging technologies for in-depth TME analysis that will unravel the impact of PARP inhibition, singly and in combination with PD-1 blockade, on specific immune subsets within the TME. The correlative analyses will also lead to the discovery of novel biomarkers of response/resistance, and suggest additional immuno-oncology combinations for specific genomic subsets of mCRPC. Clinical trial information: NCT03572478.
Intraoperative application of platelet-rich plasma to the neurovascular bundles during radical prostatectomy: A prospective clinical trial.
Authors: Joshi Vidhu B. , Juvet Tristan , Nichols Paige E. , Boorjian Stephen A. , Karnes Jeffrey , Tollefson Matthew K. , Gettman Matthew
Published: February 2020

TPS380

Background: Radical prostatectomy (RP) is the most common surgical treatment for prostate cancer (PC). Yet even with nerve-sparing RP (NS-RP), a significant proportion of men experience transient or permanent erectile dysfunction (ED) partially due to intraoperative neurovascular bundle (NVB) damage from thermal or mechanical trauma. Studies have shown that platelet released growth factors counteract trauma and facilitate healing. We evaluate the use of platelet rich plasma (PRP) to facilitate early nerve healing and decrease ED after NS-RP. Methods: A prospective, open label, 20 subject human trial evaluating intraoperative topical NVB PRP application was approved by the IRB and FDA under an Investigational Device Exemption (IDE 16915) for the investigational use of an approved blood separation device. Men aged 50-60 with newly diagnosed, localized PC and normal preoperative sexual and urinary function, defined as a Sexual Health Inventory for Men (SHIM) score of >19 and an answer of “none” on question 5 of the Expanded Prostate Cancer Index Composite (EPIC) are eligible. Intraoperatively, a 10ml PRP product is created from a 180 mL sample of the patient’s whole blood using the Angel Concentrated Platelet Rich Plasma System (Cytomedix, Inc., Gaithersburg, MD USA). PRP is applied via mechanical transfer to the NVB after completion of the vesicourethral anastomosis. The primary endpoint is the safety and tolerability of PRP on the NVB after NS-RP. Secondary endpoints include feasibility of intraoperative PRP application and longitudinal assessment of erectile function and urinary continence by questionnaire administration at 3, 6, 9, 12 and 18 months after NS-RP. Clinical trial information: NCT02957149.
INTACT: Phase III randomized trial of concurrent chemoradiotherapy with or without atezolizumab in localized muscle invasive bladder cancer—SWOG/NRG1806.
Authors: Singh Parminder , Tangen Cathy , Efstathiou Jason A. , Lerner Seth P. , Jhavar Sameer G. , Hahn Noah M. , Costello Brian Addis , Sridhar Srikala S. , Du Weliang , Meeks Joshua J. , Faltas Bishoy Morris , Grivas Petros , Feng Felix Y , Chen Ronald C. , Morgans Alicia K. , Gupta Amit , Bangs Richard Carlton , Winter Kathryn A. , Vogelzang Nicholas J. , Thompson Ian Murchie
Published: February 2020

TPS586

Background: Chemoradiotherapy(CRT) is a SOC for patients with muscle invasive bladder cancer (MIBC) who refuse or are not fit for radical cystectomy. Radiotherapy and chemotherapy are known to increases the PD-L1 expression in bladder cancer. Based on these observations, we hypothesized that addition of atezolizumab to CRT will increase its efficacy. Methods: This is a randomized phase III trial testing CRT with and without atezolizumab for 6 months in 475 patients with MIBC. Pts will be stratified on performance status (0-1 vs. 2); clinical stage (T2 vs T3/T4a, chemotherapy(cisplatin vs 5FU+mitomycin vs gemcitabine); and radiation field (bladder only vs small pelvis). Patients will undergo biopsy 18 week from registration. If they have residual disease they will be taken off protocol treatment and can proceed with alternative SOC option including radical cystectomy. Patients will be followed for 5 years. The primary end point of the study is bladder intact event –free survival (BIEFS). The event is comprised of: recurrence or residual muscle-invasive bladder cancer at 18 weeks or later, clinical evidence of nodal or metastatic disease, radical cystectomy, or death due to any cause. This composite endpoint is reflective of the intent of bladder preservation strategy with radical cystectomy included as one of the outcomes. Secondary end points include overall survival, modified event free survival, pathologic response at 18 weeks, metastasis free survival, cancer specific survival, rate of salvage cystectomy, rate of adverse event and QOL & PRO end points. The expected 3 year BIEFS for the control arm is 52%. The study leadership concluded that a 12% improvement in this endpoint is meaningful for this patient population. With a sample size of 475 patients the study has 85% power to detect the improvement from 52% to 64% in the BIEFS at 3 years (hazard ratio=0.68). The study team will perform translational studies evaluating tumor tissue, whole blood and urine for molecular and immunologic markers of immune response and response to RT. Successful completion of this trial could lead to a new treatment paradigm for patients with muscle invasive bladder cancer. Clinical trial information: NCT03775265.
PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring FGFR3 alterations.
Authors: Pal Sumanta K. , Daneshmand Siamak , Matin Surena F. , Loriot Yohann , Sridhar Srikala S. , Grivas Petros , Gupta Shilpa , Sonpavde Guru , Fleming Mark T. , Lerner Seth P. , Berman Craig , Rearden Jessica , Ye Yining , Takkele Hiywot , Moran Susan , Bellmunt Joaquim
Published: February 2020

TPS600

Background: Radical surgery ± cisplatin‐based (neo)adjuvant therapy (NAT) is the mainstay of treatment for invasive urothelial carcinoma of the upper urinary tract (UTUC) or bladder (UBC), but recurrence rates are high. Furthermore, many patients (pts) are unable to receive NAT because of cisplatin ineligibility. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of UBC, and may constitute a potential candidate for targeted therapy. Infigratinib (BGJ398), a selective FGFR1–3 inhibitor, has shown promising clinical activity and tolerability in pts with advanced urothelial carcinoma having FGFR3 alterations [Pal et al. Cancer Discov 2018]. PROOF 302 has been designed to investigate the efficacy and safety of infigratinib versus placebo as adjuvant therapy in pts with high-risk invasive urothelial carcinoma and FGFR3 alterations. Methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase III study of approx. 218 pts. Adults with high-risk invasive UTUC or UBC with FGFR3 genetic alterations (i.e. mutations, gene fusions or translocations) who are ≤120 days following surgical resection and ineligible for cisplatin-based adjuvant chemotherapy or with residual disease after cisplatin- based NAT are eligible. Those who received non cisplatin-based NAT are eligible if they have residual disease and are ineligible for adjuvant cisplatin. Pts receive oral infigratinib 125 mg or placebo (1:1 ratio) once daily on days 1–21 every 28 days for up to 52 weeks or until disease recurrence, unacceptable toxicity or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: DFS including intraluminal low-risk recurrence; metastasis-free survival; overall survival; DFS (per investigator); safety and tolerability. Exploratory endpoints include: quality of life; pharmacokinetics; cell-free DNA (cfDNA) and/or RNA for resistance mechanisms. The study will involve approximately 120 centers worldwide. Enrollment is expected to begin in January 2020. Trial registration: EudraCT 2019-003248-63. Clinical trial information: EudraCT 2019-003248-63.
Human Capital As a Factor of Effective Digitalization of the Economy
Authors: Zubova E.
Published: February 2020

The main trend of corporations today is the departure of business and production in digital, which leads to the transformation of demand in regional labor markets in the direction of IT professionals. First of all, specialists capable of leading innovative projects in the field of high technologies are becoming in demand today. These specialists are not afraid of the digital sphere. They know how to launch a new product and how to increase its sales. Programmers-developers of new software are extremely actual today. Humanity’s need for technology is endless. The article analyzes the current dynamics of indicators of human capital development and its innovative activity in the modern Russian economy.
‘Sometimes you just need someone to guide you through the maze’ – Improving cardiac care services in the North of England: suggestions from a patient-led project
Authors: Goodfellow Julie , Stark Cathy , Mackersie Ian , Mackersie Vera
Published: February 2020

Cardiomyopathy is a disease of the heart muscle, thought to affect around 160 000 people in the UK. It is often inherited and can be life-changing, with symptoms including tiredness, breathlessness and palpitations. The role of the patient in NHS care is no longer that of a passive recipient of care. There is an expectation that patients will be engaged in their own health, care and treatment. Initiatives exist where patients are encouraged to become involved in the design, planning and delivery of services. A patient-led service improvement project was designed and carried out by members of a local Cardiomyopathy UK support group, in order to capture the experiences of people affected by cardiomyopathy as they journeyed through the healthcare system in the North of England. This has enabled an evaluation of service provision, highlighting examples of good practice and areas for improvement. A total of 21 people, both patients and family members, shared their story through in-depth interviews. The overall picture that emerged was of a group of people deeply affected by a diagnosis of cardiomyopathy, who had experienced both positive and negative aspects of a healthcare system that does not appear to fully understand cardiomyopathy or the impact the condition has on the lives of patients and carers. The project highlighted a need for information and support at key times on a patient's journey through cardiomyopathy—at diagnosis, on discharge from hospital, when dealing with a device, when issues around family screening arise, or when the condition changes in some way. Many respondents had experienced a lack of information and support at these key times and communication between patients and health professionals was sometimes inadequate.
Exploring outcomes of public health nurse-facilitated breastfeeding support groups
Authors: Hanafin Sinead
Published: February 2020

Breastfeeding groups have been identified in national and international policy as an important support mechanism for increasing breastfeeding duration. The aim of this study was to estimate the value of public health nurse- (PHN) facilitated breastfeeding group support. The study was informed by methodology used to calculate a social return on investment (SROI). Data were collected from primary and secondary stakeholders using focus group, joint and individual interviews. Mothers reported improved mental health and increased duration of breastfeeding, and PHNs reported being more knowledgeable about breastfeeding, being able to offer a better service and experiencing higher job satisfaction. PHNs who did not facilitate groups but whose clients attended reported reduced workload and improvements in access to information. Family and friends reported more positive attitudes to breastfeeding. PHN-facilitated breastfeeding groups have benefits for mothers, PHNs and for society; therefore, a more systematised and geographically equitable approach to their implementation in Ireland should be promoted.
Development of indanones and isatins as non-cytotoxic inhibitors of cholinesterases
Authors: Gießel Josephine M. , Loesche Anne , Hoenke Sophie , Serbian Immo , Al-Harrasi Ahmed , Csuk Rene
Published: February 2020

A small library of indanone-amides and substituted isatin derivatives has been prepared; these compounds have been investigated for their ability to act as inhibitors for the enzymes acetyl- and butyrylcholinesterase (AChE, BChE). Several of them were moderate inhibitors for AChE and not cytotoxic for a variety of human tumor cell lines as well as for non-malignant mouse fibroblasts. In this library consisting of 49 derivatives, 5,7-dibromo-4-iodoisatin was shown to be a good mixed-type inhibitor for AChE (K­i = 2.52 ± 0.61 µM and Ki´ = 11.74 ± 1.31 µM) but this compound also acted as a dual inhibitor for BChE (Ki = 4.49 ± 0.32 µM and Ki´ = 6.56 ± 0.57 µM). Interestingly, N-hexyl-1-oxo-2,3-dihydro-1H-indene-2-carboxamide was cytotoxic especially for MCF-7 breast adenocarcinoma cells (EC50 = 4.28 ± 0.5 µM).
Monuments d’homenatge, carrers i places dedicades a sir Alexandre Fleming a Catalunya.
Authors: BRUGUERA i CORTADA Miquel
Published: February 2020

MONUMENTS OF TRIBUTE AND STREETS AND PUBLIC SQUARES DEDICATED TO SIR ALEXANDER FLEMING IN CATALONIA: We describe the monuments of tribute in the form of statues or name plates dedicated to Dr. Alexander Fleming in Catalonia, as well as the number of thoroughfare, streets and public squares, which bear his name in the Catalan towns, as manifestations of affection and admiration in our country for the discoverer of penicillin. The frequency of these physical demonstrations of tribute is compared to that in other countries, such as England and Italy.
Modeling electromagnetic resonators using quasinormal modes
Authors: Kristensen Philip Trøst , Herrmann Kathrin , Intravaia Francesco , Busch Kurt
Published: February 2020

We present a biorthogonal approach for modeling the response of localized electromagnetic resonators using quasinormal modes, which represent the natural, dissipative eigenmodes of the system with complex frequencies. For many problems of interest in optics and nanophotonics, the quasinormal modes constitute a powerful modeling tool, and the biorthogonal approach provides a coherent, precise, and accessible derivation of the associated theory, enabling an illustrative connection between different modeling approaches that exist in the literature.
Deep-ultraviolet aperiodic-oscillation emission of AlGaN films
Authors: Zhu Yanming , Zheng Wei , Ran Junxue , Huang Feng
Published: February 2020

In this Letter, we describe an aperiodic-oscillation emission phenomenon originating from the Fabry–Perot effect in the deep-ultraviolet backscattering fluorescence spectrum of the

c

-plane AlGaN film, which is related to the dispersion of its ordinary refractive index near the band edge. Based on this fluorescence spectrum, the ordinary refractive index of the AlGaN film near the band edge could be directly obtained. Certainly, by means of variable angle spectroscopic ellipsometry, the ordinary refractive index of the AlGaN film could be also achieved. Comparing the results obtained by both methods, we discovered that the refractive indices are quite similar, which suggests that the aperiodic-oscillation fluorescence spectrum is also a reliable approach to capture the refractive index of anisotropic optical films.
Superconducting nanowire multi-photon detectors enabled by current reservoirs
Authors: Zou Kai , Meng Yun , Wang Zhao , Hu Xiaolong
Published: February 2020

Single-photon detectors are ubiquitous devices in quantum-photonic-based communication, computation, metrology, and sensing. In these applications,

N

-fold coincidence photon counting is often needed, for example, to characterize entanglement. However,

N

-fold coincidence photon counting typically requires

N

individual single-photon detectors and associated bias and readout electronics, and these resources could become prohibitive if

N

goes large and the detectors need to work at cryogenic temperatures. Here, to break this limit on

N

, we propose a device architecture based on

N

cascaded photosensitive superconducting nanowires and one wider nanowire that functions as a current reservoir. We show that by strategically designing the device, the network of these superconducting nanowires can work in a synergic manner as an

n

-photon detector, where

n

can be from 1 to

N

, depending on the bias conditions. We therefore name the devices of this type superconducting nanowire multi-photon detectors (SNMPDs). In addition to its simple one-port bias and readout circuitry, the coincidences are counted internally in the detector, eliminating the need for external multi-channel, time-correlated pulse counters. We believe that the SNMPDs proposed in this work could open avenues towards conveniently measuring high-order temporal correlations of light and characterizing multi-photon entanglement.
Particle-in-cell Simulation Concerning Heat-flux Mitigation Using Electromagnetic Fields
Authors: Lüskow K. F. , Kemnitz S. , Bandelow G. , Duras J. , Kahnfeld D. , Schneider R. , Konigorski D.
Published: February 2020

The Particle-in-Cell (PIC) method was used to study heat flux mitigation experiments with argon. In the experiment it was shown that a magnetic field allows to reduce the heat flux towards a target. PIC is well-suited for plasma simulation, giving the chance to get a better basic understanding of the underlying physics. The simulation demonstrates the importance of a self-consistent neutral-plasma description to understand the effect of heat flux reduction.
Hydrolysis of PLA-like Plasma Polymer Films with Varying Degree of Crosslinking
Authors: Kolarova Raskova Z. , Kousal J. , Stloukal P. , Krtous Z.
Published: February 2020

Poly-lactide acid (PLA) based biodegradable films are of interest for packaging materials or bioapplications. Plasma-assisted vacuum evaporation technique uses oligomers released during thermal decomposition of source polymer as precursors for plasma polymerization. Conventionally prepared PLA with mw = 10000 g/mol was used as a source polymer. Films were prepared at various RF (13.56 MHz) plasma powers (0-20 W) in order to vary the amount of crosslinking in the film.

Swelling and hydrolysis of films were monitored in real time using spectroscopic ellipsometry. The concentration profile of products of hydrolysis was measured by liquid-chromatography (LC-MS). FTIR, XPS and SEM analyses were used for monitoring of film composition and surface characterization. Molecular weights of source polymer and of the plasma polymer were determined by gel-permeation chromatography (GPC). Possibility to prepare PLA-like plasma polymer films with controlled degradability by hydrolysis was demonstrated.
Prediksi Akumulasi Sedimen Berdasarkan Survei Batimetri dan Hidrodinamika di Pesisir Teluk Mandeh, Kabupaten Pesisir Selatan, Sumatera Barat
Authors: Rahmawan Guntur Adhi , Wisha Ulung Jantama , Gemilang Wisnu Arya , Ilham Ilham , Husrin Semeidi
Published: February 2020

Mandeh Bay is a semi-enclosed water area that there are two main estuaries, Mandeh and Nyalo River estuary. Sedimentation issue has been gotten worse due to the massive development in coastal area. This study aims to determine the sediment accumulation within Mandeh bay and its distribution patterns. The measurement of sedimentation rate applied in the Mandeh and Nyalo Estuaries. Oceanography parameters (tides and currents) recorded for 30 days measurement. The thickness of sediment accumulation was predicted by applying single beam echosounder dual frequency. The calculation of sediment volume was done using frustum formula grid 10 x10 meters. Flow model approach was also simulated to depict the distribution pattern of sediment. The thickness of sediment accumulation categorized into five spatial categories that are 0-0,3m, 0,4-0,6m, 0,7-0,9,1-1,2m, and 1,3-1,5m. The sedimentation rate in Mandeh estuary ranged from 60,85 up to 62,16 g.m-2.day-1, while in Nyalo estuary is approximately 48,86 g.m-2.day-1. The tidal current speed that is weak ranged from 0-0,05 m/s induces the sediment accumulation which mainly occurs during the neap tidal conditions. The thickness of sediment accumulation which is more than one meter identified around Mandeh River estuary and several areas near Carocok Tarusan Port where the sediment intake takes place and due to the weak current feature, it causes the increase of sedimentation in this region.  Teluk mandeh merupakan kawasan teluk semi tertutup yang mempunyai 2 muara sungai besar yaitu sungai Mandeh dan sungai Nyalo. Masalah sedimentasi menjadi semakin parah karena pengembangan wilayah pesisir yang masif. Tujuan dari penelitian ini adalah untuk mengetahui ketebalan akumulasi sedimen di dalam Teluk Mandeh dan pola distribusinya. Pengukuran laju sedimentasi dilakukan pada dua fokus area yakni muara Sungai Mandeh dan Sungai Nyalo. Pengukuran parameter oseanografi (arus dan pasang surut) dilakukan selama 30 hari pengukuran. Ketebalan akumulasi sedimen diukur menggunakan alat Single Beam Echosounder Dual Frekuensi. Perhitungan volume sedimen dihitung dengan rumus frustum grid 10x10 meter. Simulasi flow model juga dilakukan untuk mengetahui pola distribusi sedimen. Sebaran ketebalan sedimen yang dibagi dalam 5 kategori spasial yakni 0-0,3m, 0,4-0,6m, 0,7-0,9,1-1,2m, dan 1,3-1,5m. Laju sedimentasi di muara Sungai Mandeh berkisar antara 60,85 sampai 62,16 g.m-2.hari-1 dan di muara Sungai Nyalo rata-rata 48,86 g.m-2.hari-1. Kecepatan arus pasang surut yang cukup lemah berkisar antara 0-0,05 m/s menyebabkan potensi akumulasi sedimen akan berlangsung terutama saat kondisi perbani. Sedimen dengan ketebalan lebih dari 1 meter teridentifikasi di sekitar Sungai Mandeh dan beberapa Kawasan Pelabuhan Carocok Tarusan dimana asupan sedimen mendominasi. Karena karakteristik arus yang lemah, sedimentasi meningkat diwilayah ini.
The Issue of Immunity of Private Actors Exercising Public Authority and the New Paradigm of International Law
Authors: Oddenino Alberto , Bonetto Diego
Published: February 2020

1. The changing image and structure of international law – 2. The exercise of public authority through delegation – 3. The question of state immunity in the context of hybridisation between public and private – 4. The content of the activity as a paradigm to guide the extension of state immunity – 5. The issue of limiting the immunity of delegated non state actors – 6. Conclusions
High strength paper from high yield pulps by means of hot-pressing
Authors: Joelsson Tove , Pettersson Gunilla , Norgren Sven , Svedberg Anna , Höglund Hans , Engstrand Per
Published: February 2020

The hypothesis is that it should be possible to modify papermaking conditions in line with the softening properties of high yield pulp fibres and achieve similar strength properties to conventional chemical pulp based paper. We therefore investigated the rheological and physical properties of high yield pulp based papers during hot-pressing. Our results confirm that increased temperature combined with sufficient pressure enables permanent densification by softening of lignin, producing very high tensile strength. This treatment also significantly improved the wet tensile strength in comparison to bleached kraft pulp without using wet strength agents. The high yield pulps used here were spruce based thermomechanical pulp, chemi-thermomechanical pulp, and high temperature chemi-thermomechanical pulp, and birch-aspen based neutral sulphite semi chemical pulp, with spruce-pine based bleached kraft pulp as reference. Rapid Köhten sheets of150g/m2150\hspace{0.1667em}\text{g}/{\text{m}^{2}}and 50 % dryness were hot-pressed in a cylinder-press at 20–200 °C, 7 MPa, and 1 m/min. The mechanical properties showed great improvements in these high yield pulp papers, with tensile index increased to 75 kNm/kg and compression strength index to 45 kNm/kg; levels close to and better than bleached kraft. Wet strength increased to 16 Nm/g compared to 5 Nm/g for bleached kraft.
Why We Must Talk About Institutional Corruption to Understand Wrongdoing in the Health Sector Comment on "We Need to Talk About Corruption in Health Systems"
Authors: Fotaki Marianna
Published: February 2020

While various forms of corruption are common in many health systems around the world, defining wrongdoing in terms of legality and the use of public office for private gain obstructs our understanding of its nature and intractability. To address this, I suggest, we must not only break the silence about the extent of wrongdoing in the health sector, but also talk differently about corruption in general, and corruption in healthcare specifically. I propose adopting the notion of institutional corruption (IC) developed by Thompson and Lessig, as divergence from the original purpose of the institution, which may not be illegal but may nevertheless cause harm to people who depend on it by creating perverse dependencies and compelling individuals to act against its core purpose. Such work is much needed to provide in-depth accounts of how external political and legislative pressures enable corruption in healthcare systems. I also argue for bringing together insights from various research domains and levels of analysis to capture why and how corruption becomes systemic, deeply embedded, and intractable.
A Decomposition of Life Expectancy and Life Disparity: Comparison Between Hong Kong and Japan
Authors: Zheng Yan , Chen Mengni , Yip Paul SF
Published: February 2020

Background: Life expectancy and life disparity are 2 useful indicators to assess the health condition of a society. Both Hong Kong and Japan have one of the longest life expectancies in the world. Recently, Hong Kong has overtaken Japan and topped the life expectancy rankings. However, whether Hong Kong has also outperformed Japan in life disparity is still unknown. Methods: Decomposition analyses have been conducted to evaluate age-specific contributions to the changes in life expectancy and life disparity for each of the populations. Furthermore, the differences between the 2 populations were examined over the period 1977-2016. Results: Reduction in mortality of the adult and the old age groups contributes most to the increase in life expectancy for the study period. Hong Kong has a higher life disparity than Japan, and due to the great improvement in reducing premature deaths, the Hong Kong-Japan gap has been narrowing. However, in recent years, further reduction in mortality of the oldest elderly in Hong Kong has actually contributed to the increase in its disparity, thus widening its gap with Japan again. Conclusion: Increasing dominant influence of "saving lives at late ages" is very likely to cause the reemergence of increasing life disparity in these 2 long-lived populations.