bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of atezolizumab plus chemotherapy after progression on single-agent PD-1 or PD-L1 inhibitor in cisplatin ineligible patients with advanced urothelial carcinoma HCRN GU17-295.
Authors: Adra Nabil , Hauke Ralph J. , Kaimakliotis Hristos Z. , Gulati Shuchi , Hashemi Neda , Pili Roberto
Published: February 2020

TPS587

Background: Patients (pts) with cisplatin ineligible metastatic urothelial carcinoma (mUC) who progress after first-line PD1/PDL1 inhibition have limited treatment options. The concept of maintenance therapy with targeted agents and adding onto it at time of progression is a proven effective strategy. Preclinical data indicate that carboplatin+gemcitabine have immunomodulatory effect to potentially augment immune response. We hypothesize that in pts with cisplatin ineligible mUC, the use of atezolizumab+chemotherapy after progression on single-agent PD1/PDL1 inhibitor will result in clinical benefit. Methods: Multi-center, single arm, open label phase 2 trial of atezolizumab+carboplatin+gemcitabine in pts with cisplatin ineligible mUC. Eligible pts are adults with mUC (mixed histology allowed) who progressed after first line PD1/PDL1 inhibitor. Pts should be cisplatin ineligible based on consensus criteria. Neoadjuvant/adjuvant chemotherapy completed ≥12 months prior to enrollment is allowed. Treatment with atezolizumab will continue until disease progression or unacceptable toxicity while carboplatin+gemcitabine can be stopped after 4-6 cycles. Primary objective is progression-free survival per RECIST and secondary objectives are overall response rate, clinical benefit rate, and overall survival (OS). Exploratory endpoints include to compare OS of atezolizumab+carboplatin+gemcitabine in this trial compared to a virtual control arm of carboplatin+gemcitabine in mUC after progression on first-line PD1/PDL1 inhibitors. Other exploratory endpoints include to compare PD-L1 status at time of diagnosis and at time of enrollment (after progression on PD1/PDL1 inhibitor). Using an alternate hypothesis that atezolizumab+carboplatin+gemcitabine will have a median PFS of 9 months compared to historical control of 5 months with a platinum regimen in 2nd line setting, we plan to enroll 33 patients. This study is currently enrolling pts. A protocol amendment is under way that will allow pts with prior platinum-based chemotherapy to enroll on this trial. Clinical trial information: NCT03737123.
Tislelizumab plus cisplatin/carboplatin and gemcitabine versus placebo plus cisplatin/carboplatin and gemcitabine in Chinese patients with advanced urothelial carcinoma: A phase III trial in progress.
Authors: BI Feng , Li Han-Zhong , Zhu Shaoxing , Zou Qing , Tang Jia , Zhang Wei , Ye Dingwei
Published: February 2020

TPS588

Background: Platinum-based chemotherapy is standard first-line treatment for patients with advanced urothelial carcinoma (UC). Checkpoint inhibitors (ie, anti-PD-1 antibodies) are first-line treatment options for cisplatin-ineligible patients. Combining anti-PD-1 treatment with chemotherapy may have synergistic effects and has demonstrated antitumor activity in a variety of tumor types. Tislelizumab, an investigational monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports showed tislelizumab, as a single agent or combined with chemotherapy, was generally well tolerated and had antitumor activity in patients with advanced UC. Methods: This phase 3, randomized, double-blind, placebo-controlled study (NCT03967977) will compare the efficacy and safety/tolerability of tislelizumab vs placebo, both in combination with cisplatin/carboplatin and gemcitabine. Adult Chinese patients (n≈420) with histologically confirmed, inoperable, locally advanced/metastatic UC who are eligible for (but have not received) systemic anticancer therapy for advanced UC, therapies targeting PD-1/L1, or other antibody/drug targeting T-cell costimulation or checkpoint pathways, will be randomized 1:1 to receive tislelizumab (200 mg Q3W) or placebo (Q3W) plus gemcitabine (1000 mg/m2 administered on Day 1 and 8 of each 3-week cycle) and cisplatin (70 mg/m2) or carboplatin (AUC 4.5) administered on Day 1 or 2 of each 3-week cycle. Patients must provide a fresh biopsy or archival tissue for central assessment of PD-L1 expression. Overall survival (OS) is the primary endpoint. Investigator-assessed overall response rate (RECIST v1.1), duration of response, progression-free survival, and OS rates at Year 1 and 2 are secondary endpoints. Safety/tolerability, assessed by monitoring incidence and severity of adverse events, and health-related quality-of-life measures will also be evaluated. Clinical trial information: NCT03967977.
FIDES-02, a phase Ib/II study of derazantinib (DZB) as monotherapy and combination therapy with atezolizumab (A) in patients with surgically unresectable or metastaticurothelial cancer (UC) and FGFR genetic aberrations.
Authors: Chaudhry Arvind , Sternberg Cora N. , De Santis Maria , Bellmunt Joaquim , Necchi Andrea , Powles Thomas , Cantero Frederique , Marszewska Michalina , Grzyb Michal , McSheehy Paul , Braun Stephan , Siefker-Radtke Arlene O.
Published: February 2020

TPS590

Background: Deregulation of the FGFR signaling pathway is implicated in various cancers. In UC, FGFR genetic aberrations include FGFR1/2/3 mutations (M) and, less commonly, fusions (F), while the role of amplifications warrants further research. Prognosis of UC patients is overall poor and treatment options are limited. DZB is an oral small-molecule FGFR1/2/3 and CSF1R kinase inhibitor, which demonstrated promising antitumor activity in preclinical studies, including FGFR-driven patient-derived xenograft models. Preclinical data show that DZB reduced CSF1-stimulated CSF1R phosphorylation in macrophages, with a maximal effect similar to the CSF1R inhibitor BLZ945, suggesting DZB could have an effect on tumor-associated macrophage regulation. Thus, DZB+A (PD-L1 immune-checkpoint blockade [ICB]) is a rationale combination for immunogenic tumors like UC. FIDES-02 is a multicenter, multicohort open-label Phase 1b/2 study evaluating the effect of DZB as monotherapy and DZB+A combination. Methods: The study evaluates 300 mg DZB p.o. daily or DZB+A (1200 mg i.v.) in UC patients with FGFR1-3 M/F per liquid or tissue biopsy-based NGS. Cohort 1 (C1) enrolls pts after one or more standard chemotherapy ± ICB regimens (Phase 2; treatment: DZB); C2 enrolls patients with any advanced solid tumor, any FGFR status, any prior treatment (Phase 1b; for RP2D of DZB+A); C3 enrolls first-line patients with cisplatin-ineligible, PD-L1-low UC (Phase 2; DZB v DZB+A); C4 enrolls UC patients resistant to FGFR inhibitor treatment (Phase 2; DZB v DZB+A). Treatment will continue until disease progression, intolerance, withdrawal of informed consent, or death. Using Simon’s two-stage designs, objective response rate (per RECIST 1.1 central review) is the primary endpoint to assess the antitumor activity of DZB or DZB+A in Ph2. Main secondary objectives include evaluation of median PFS, duration of response, safety profile, HR-QoL (incl., QLQ C30, FACT-Bl, EQ-5D), and symptom response from baseline. The study was initiated in July 2019 and C1 (N=71) and C2 (N=24) are currently open for enrollment. Clinical trial information: NCT04045613.
Phase Ib/II umbrella trial to evaluate the safety and efficacy of multiple 2L cancer immunotherapy (CIT) combinations in advanced/metastatic urothelial carcinoma (mUC): MORPHEUS-mUC.
Authors: Drakaki Alexandra , Rezazadeh Kalebasty Arash , Lee Jae-Lyun , Martin-Liberal Juan , Kim Miso , Shin Sang Joon , Shi Jane , Mariathasan Sanjeev , Ci Bo , Degaonkar Viraj , Williams Patrick , Cha Edward , Maltzman Julia , Powles Thomas
Published: February 2020

TPS591

Background: Although CIT has efficacy against multiple cancers, only subsets of patients (pts) have durable responses with monotherapy. CIT combination treatment (tx) targets multiple immune-evasion mechanisms and may thus be more likely to improve outcomes. However, a large number of potential combinations need to be tested to identify effective combinations. The MORPHEUS platform comprises multiple global, open-label, randomized Phase Ib/II trials to identify early efficacy signals and safety of tx combinations in pts with different cancers. MORPHEUS-mUC is a randomized study of 6 CIT combinations compared with a single CIT control in pts with locally advanced UC/mUC who progressed during or after a platinum-containing regimen. The PD-L1 inhibitor atezolizumab will be combined with agents targeting different mechanisms (via nectin-4, PARP, CD47, CD38, DPP-4 and IL-6R) to simultaneously enhance immune cell priming and activation, tumor infiltration and/or recognition of tumor cells. To accelerate the clinical development of novel combinations, MORPHEUS has the flexibility, via amendment, to allow for the modification of eligibility criteria or the opening of new tx arms to replace arms that demonstrate no signs of clinical activity/unacceptable toxicity. Methods: MORPHEUS-mUC (NCT03869190) has 2 stages. In Stage 1, approximately 130-305 pts with histologically documented, locally advanced inoperable UC/mUC will be randomized to atezolizumab monotherapy (control) or experimental arms: atezolizumab + either enfortumab vedotin, niraparib, magrolimab (Hu5F9-G4), isatuximab, linagliptin or tocilizumab. Safety will be monitored for potential overlapping toxicities. Stage 2 arms will be atezolizumab + either enfortumab vedotin or linagliptin arms, unless these combinations show no activity in Stage 1. Eligible pts who experience unacceptable toxicity or loss of clinical benefit in Stage 1 may enroll in Stage 2 within 3 months. The primary study endpoint is investigator-assessed ORR per RECIST 1.1; secondary endpoints include PFS, OS, DOR, DCR and safety. Biomarkers will also be explored. Clinical trial information: NCT03869190.
Study EV-103: New cohorts testing enfortumab vedotin alone or in combination with pembrolizumab in muscle invasive urothelial cancer.
Authors: Hoimes Christopher J. , Rosenberg Jonathan E. , Petrylak Daniel Peter , Carret Anne-Sophie , Sasse Carolyn , Chaney Marya F. , Flaig Thomas W.
Published: February 2020

TPS595

Background: Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle invasive urothelial cancer (MIUC) before radical cystectomy (RC) and lymph node dissection in cisplatin-eligible patients (pts). However, many pts are cisplatin-ineligible and while PD-1/PD-L1 inhibitors have had encouraging results in this population, they are not approved for MIUC; new therapies are needed. Enfortumab vedotin (EV), an investigational antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in urothelial cancer. In a phase 2 study, EV monotherapy had a confirmed ORR of 44% in 125 heavily pre-treated metastatic urothelial cancer (mUC) pts (Rosenberg JCO 2019). In the present study, an initial analysis of EV combined with the PD-1 inhibitor, pembrolizumab (P) had a confirmed ORR of 71% in 45 cisplatin-ineligible mUC pts in the first-line setting (Hoimes ESMO 2019). These results suggest that EV and EV+P may be suitable for research in MIUC. Methods: Study EV-103 (NCT03288545) mUC cohorts were described previously (Hoimes ASCO 2019). Sequential cohorts were added to test EV alone (Cohort H, n = 20) and EV+P (Cohort J, n = 20) as neoadjuvant therapy in cisplatin-ineligible pts (stage cT2-T4a, N0, M0) with treatment naive MIUC. Eligible pts are ECOG 0-2, have CrCl ≥30 mL/min, and are medically fit for and scheduled for RC. Cohort H pts receive 3 cycles of EV (1.25 mg/kg) on Days 1 and 8 of each 3-week cycle. Cohort J pts receive 3 cycles of EV as described for Cohort H plus P on Day 1 of each cycle. Following EV or EV+P, pts undergo their scheduled RC. Pathological complete response (pCR) rate per local pathology review is the primary endpoint of the MIUC cohorts. Secondary endpoints include assessment of pCR and pathological response (PaR) rate per central pathology review, PaR per local pathology review, PFS and investigator assessed disease-free survival per RECIST v1.1, OS, and assessment of safety and tolerability, including planned surgeries delayed due to treatment-related adverse events. The ongoing study opened Oct 2017 and was amended to include MIUC cohorts Aug 2019. Clinical trial information: NCT03288545.
NEXT: A phase II, open-label study of nivolumab adjuvant to chemoradiation in patients (pts) with localized muscle invasive bladder cancer.
Authors: Gupta Sumati , Maughan Benjamin Louis , Dechet Christopher B. , Lowrance William Thomas , O Neil Brock , Kokeny Kristine E. , Lloyd Shane , Tward Jonathan David , Boucher Kenneth M. , Agarwal Neeraj
Published: February 2020

TPS605

Background: In pts with localized muscle invasive bladder cancer (MIBC), trimodality bladder preserving therapy (TMT), with transurethral resection of bladder tumor, radio-sensitizing chemotherapy and definitive radiation, has up to a 50% risk of local and systemic relapse during the 2-year post treatment phase. We hypothesize that by inhibiting immune checkpoints, chemo-radiation induced tumor specific immune response will be enhanced both locally and abscopally, resulting in better failure-free survival (FFS). In the NEXT trial, we evaluate the efficacy of nivolumab after completion of the TMT in this setting. Methods: Pts with localized MIBC who have completed standard TMT are eligible. Pts receive nivolumab 480 mg intravenously every 4 weeks for up to 12 doses. Treatment with nivolumab begins within 90 days of completion of TMT. Subjects undergo surveillance cystoscopic and scan based assessments on study. Archived tumor tissue at baseline and at relapse is obtained for correlative studies. The primary endpoint is 2-year FFS. Secondary endpoints include FFS at 2 years in patients with intact bladder, rate of radical cystectomy (RC), cystoscopic local control, distant FFS in patients with intact bladder and those that undergo RC, overall survival, toxicity and quality of life. Exploratory endpoints include to characterize changes in immune cell subsets that can be correlated with clinical outcome and to assess the correlation of response to PD-L1 expression in pretreatment tumor tissue in the study subjects. The planned sample size for this single arm, open label trial is 28 pts. Kaplan-Meier methods will be used to plot survival endpoints and cystoscopic local control rates. Exact binomial methods will be used to provide 6 months, 1-year and 2-year estimates for these endpoints. The sample size justification is based on the maximum width of a two-sided 95% binomial confidence interval for 2 year FFS. With 28 evaluable subjects, a 95% exact binomial confidence interval, estimated using the method of Clopper-Pearson, will extend no more than 20% from the observed FFS. Clinical trial information: NCT03171025.
A pilot study of tazemetostat and MK-3475 (pembrolizumab) in advanced urothelial carcinoma (ETCTN 10183).
Authors: Meeks Joshua J. , Shilatifard Ali , Miller Stephen D. , Morgans Alicia K. , VanderWeele David James , Kocherginsky Masha , Hussain Maha H. A.
Published: February 2020

TPS607

Background: Few patients with metastatic urothelial carcinoma (UC) achieve a durable response despite early stabilization with chemotherapy or immunotherapy. Mutations in the COMPASS-related proteins KMT2D, KMT2C, and KDM6A are found in 66% of patients with UC, suggesting disruption of histone regulation may be an acquired mechanism of tumor viability. Using a carcinogen-derived mouse model of UC in which 80% of animals have alterations in Kmt2d, Kmt2d or both, we found regression of tumors when treated an enzymatic inhibitor of EZH2 (Tazemetostat). In vivo administration of Tazemetostat enhanced the immune response with more necrosis when combined with an anti-PD1 antibody. Therefore, we hypothesized that treatment of UC with an Tazemetostat may further improve the activity of immunotherapy as only 21% of cisplatin refractory (KN45) and 24% of cisplatin ineligible (KN52) patients achieve an objective response. We hypothesized that restoration of the epigenetic imbalance, combined with immunotherapy may improve survival in patients with metastatic UC. Methods: ETCTN10183 (NCT03854474) is a Phase I/II trial evaluating the efficacy of Tazemetostat at 800 mg BID + Pembrolizumab 200 mg IV every 3 weeks in patients with either cisplatin-refractory (Cohort A) or cisplatin-ineligible (Cohort B) metastatic UC. The safety lead-in portion of the trial will follow a “3+3” design with one dose de-escalation level (800mg or 600mg BID Tazemetostat) and will enroll 6-12 patients to establish the recommended phase II dose (RP2D) of Tazemetostat. All DLTs will be reviewed and if tolerated, two dose expansion cohorts will be initiated and will include 24 patients with 12 in each cohort (cisplatin refractory and ineligible). The primary objectives are to identify the RP2D of Tazemetostat in combination with Pembrolizumab, and secondary objectives are to determine the objective disease response in patients with either cisplatin-refractory or unresponsive UC per RECIST criteria, safety, tolerability and progression-free survival. Translational objectives include evaluation of tumor mutations in COMPASS genes, total mutation burden, T cell infiltration, TCR clonality, tumor subtyping and PD-L1 expression. Clinical trial information: NCT03854474.
PROSPER: Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).
Authors: Harshman Lauren Christine , Puligandla Maneka , Allaf Mohamad E. , McDermott David F. , Drake Charles G. , Signoretti Sabina , Cella David , Gupta Rajan T. , Shuch Brian M. , Lara Primo , Kapoor Anil , Heng Daniel Yick Chin , Leibovich Bradley , Michaelson M. Dror , Choueiri Toni K. , Master Viraj A. , Jewett Michael A.S. , Maskens Deb , Haas Naomi B. , Carducci Michael Anthony ,   On behalf of the PROSPER RCC Investigators
Published: February 2020

TPS765

Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of October 18, 2019, 317 patients have been enrolled. Clinical trial information: NCT03055013.
A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk.
Authors: Choueiri Toni K. , Albiges Laurence , Powles Thomas , Scheffold Christian , Wang Fong , Motzer Robert J.
Published: February 2020

TPS767

Background: C inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER), and may promote an immune-permissive tumor environment, resulting in enhanced response to immune checkpoint inhibitors. C has shown preliminary clinical activity and tolerability in combination with the PD-1 inhibitor N and as part of a triplet combination with N and the CTLA-4 inhibitor I in pts with aRCC (Nadal et al. ASCO 2018). C is approved for pts with aRCC, and N+I is approved as a combination therapy in pts with previously untreated aRCC of intermediate or poor risk. We present the study design of a phase 3 trial of C+N+I vs N+I in previously untreated pts with aRCC of IMDC intermediate or poor risk (NCT03937219). Methods: This randomized, double-blind, controlled phase 3 study evaluates the efficacy and safety of C+N+I vs N+I in previously untreated pts with IMDC intermediate or poor risk aRCC. Eligible pts are randomized 1:1 to receive C+N+I or N+I in combination with placebo, stratified by IMDC prognostic score and geographic region. Pts receive C (40 mg oral QD) + N (3 mg/kg IV Q3W) x 4 doses + I (1 mg/kg IV Q3W) x 4 doses, followed by C (40 mg oral QD) + N (480 mg IV flat dose Q4W). Control pts receive C-matched placebo and the same treatment regimen for N+I as the experimental arm. N will be administered for a maximum of 2 years. Eligibility criteria include histologically confirmed metastatic or aRCC with a clear cell component, intermediate or poor risk RCC per IMDC criteria, measurable disease per RECIST 1.1, KPS ≥70%, adequate organ and marrow function and age ≥18 years. Exclusion criteria include prior systemic therapy for aRCC and uncontrolled significant illnesses. The primary endpoint is PFS per RECIST 1.1 by BICR; the secondary endpoint is OS. Additional endpoints include ORR, safety, correlation of biomarkers with outcomes, and pharmacokinetics of C in combination with N+I. The first patient was enrolled in June 2019 and enrollment is ongoing. Clinical trial information: NCT03937219.
Higher Circulating Adiponectin Concentrations Predict Incident Cancer in Type 2 Diabetes – The Adiponectin Paradox
Authors: Lee Chi Ho , Lui David T W , Cheung Chloe Y Y , Fong Carol H Y , Yuen Michele M A , Chow Wing Sun , Woo Yu Cho , Xu Aimin , Lam Karen S L
Published: February 2020

Introduction

Despite the beneficial cardiometabolic effects of adiponectin demonstrated in preclinical studies, paradoxically higher circulating adiponectin concentrations have been found in epidemiological studies to be associated with incident cardiovascular events, renal outcomes, and mortality in patients with diabetes. On the other hand, diabetes is also associated with an increased risk of cancer. Here, we investigated prospectively the association between circulating adiponectin concentrations and incident cancer using a cohort of exclusively individuals with type 2 diabetes.

Materials and Methods

Baseline serum adiponectin concentrations were measured in 5658 participants recruited from the Hong Kong West Diabetes Registry. The associations of circulating adiponectin concentrations with incident cancer and cancer-related deaths were evaluated using multivariable Cox regression analysis, with hazard ratio (HR) for adiponectin referring to the respective risk per doubling of serum adiponectin concentration.

Results

Over a median-follow up of 6.5 years, 7.53% and 3% of participants developed cancer and had cancer-related deaths, respectively. Serum adiponectin concentrations were significantly higher in those who had incident cancer (9.8 μg/mL vs 9.1 μg/mL, P < 0.001) and cancer-related deaths (11.5 μg/mL vs 9.3 μg/mL, P < 0.001) compared with those without. Moreover, in multivariable analyses, serum adiponectin concentration was independently associated with both incident cancer (hazard ratio, 1.19; 95% confidence interval, 1.05–1.35; P = 0.006) and cancer-related deaths (hazard ratio, 1.23; 95% confidence interval, 1.03–1.47; P = 0.024).

Conclusions

Higher serum adiponectin concentration was independently associated with incident cancer and cancer-related deaths in type 2 diabetes, indicating that adiponectin paradox can be observed in another major diabetic complication in addition to cardiovascular and kidney diseases.
Bone Metastases in Medullary Thyroid Carcinoma: High Morbidity and Poor Prognosis Associated With Osteolytic Morphology
Authors: Vogel Theresa , Wendler Julia , Frank-Raue Karin , Kreissl Michael C , Spitzweg Christine , Fassnacht Martin , Raue Friedhelm , Kroiss Matthias
Published: February 2020

Context

The clinical relevance of bone metastases (BM) in advanced medullary thyroid carcinoma (MTC) is poorly described.

Objective

The objectives of this work are to describe the prevalence of BM, frequency of skeletal related events (SREs), and impact of BM morphology and SREs on prognosis, and to assess the role of antiresorptive treatment (ART).

Design

A retrospective cohort study was conducted.

Setting

This study was conducted at 4 German referral centers.

Patients

A total of 1060 MTC patients were included.

Main Outcome Measure

Main outcome measures include descriptive statistics, overall survival (OS) by the Kaplan-Meier method, and risk factors by Cox proportional hazards modeling.

Results

A total of 120 of 416 patients (29%) with metastatic MTC had BM, of which 97% had concurrent nonosseous metastases. BM occurred 2.1 years (median, range –0.1 to 20.6 years) after initial diagnosis, were multifocal in 79%, and were located preferentially in the spine (86%) and pelvis (60%). BM morphology was osteolytic in 32%, osteoblastic in 25%, and mixed in 22% of cases (unknown: 21%). Within a median observation period of 26.6 months (range, 0-188 months) after BM diagnosis, 47% of patients experienced one or more SREs (bone radiation 50%, pathological fractures 32%), of which 42% occurred in osteolytic and 17% in osteoblastic BM (P = .047). Presence of osteolytic metastases (hazard ratio 3.85, 95% CI 1.52-9.77, P = .005) but not occurrence of SREs was associated with impaired OS. Among the 36 patients who received ART (no ART: n = 71), SREs were significantly less frequent than in untreated patients (P = .04).

Conclusion

BM are common in metastatic MTC and most often with an osteolytic morphology and an unfavorable prognosis. The majority of SREs occur in osteolytic metastases and may be prevented by ART.
Normocalcemic Hyperparathyroidism: Study of its Prevalence and Natural History
Authors: Schini Marian , Jacques Richard M , Oakes Eleanor , Peel Nicola F A , Walsh Jennifer S , Eastell Richard
Published: February 2020

Context

Normocalcemic hyperparathyroidism (NPHPT) is characterized by persistently normal calcium levels and elevated parathyroid hormone (PTH) values, after excluding other causes of secondary hyperparathyroidism. The prevalence of the disease varies greatly and the data on the natural history of this disease are sparse and inconclusive.

Objectives

The objectives of this study are to describe the prevalence of NPHPT and its natural history in a referral population and to compare the variability of serum calcium with a group of patients with primary hyperparathyroidism (PHPT).

Design

A retrospective study was conducted over 5 years.

Setting

The setting for this study was a metabolic bone referral center.

Patients

A total of 6280 patients were referred for a bone mineral density measurement (BMD).

Main Outcome Measures

The prevalence and natural history of NPHPT and variability of calcium were the main outcome measures.

Results

We identified NPHPT patients using data from the day of the BMD measurement. We excluded patients with low estimated glomerular filtration rate (eGFR) or vitamin D, or with no measurements available. Based on the evaluation of their medical files, we identified 11 patients with NPHPT (prevalence 0.18%). Only 4 patients had consistent normocalcemia throughout their follow-up, with only 2 also having consistently high PTH. None had consistently normal eGFR or vitamin D.

Intermittent hypercalcemia was present in 7 of the 11 NPHPT patients. The mean adjusted calcium was found to be significantly lower in the NPHPT group compared with the PHPT group but higher than the control group. PTH was similar for NPHPT and PHPT. These 2 groups had similar variability in serum calcium.

Conclusions

NPHPT patients often have episodes of hypercalcemia. We believe that NPHPT is a mild form of PHPT.
Corticotropin-releasing factor protects against ammonia neurotoxicity in isolated larval zebrafish brains
Authors: Williams Tegan A. , Bernier Nicholas J.
Published: February 2020

The physiological roles of corticotropin-releasing factor (CRF) have recently been extended to cytoprotection. Here, to determine whether CRF is neuroprotective in fish, the effects of CRF against high environmental ammonia (HEA)-mediated neurogenic impairment and cell death were investigated in zebrafish. In vivo, exposure of 1 day post-fertilization (dpf) embryos to HEA only reduced the expression of the determined neuron marker neurod1. In contrast, in 5 dpf larvae, HEA increased the expression of nes and sox2, neural progenitor cell markers, and reduced the expression of neurog1, gfap and mbpa, proneuronal cell, radial glia and oligodendrocyte markers, respectively, and neurod1. The N-methyl-d-aspartate (NMDA) receptor inhibitor MK801 rescued the HEA-induced reduction in neurod1 in 5 dpf larvae but did not affect the HEA-induced transcriptional changes in other neural cell types, suggesting that hyperactivation of NMDA receptors specifically contributes to the deleterious effects of HEA in determined neurons. As observed in vivo, HEA exposure elicited marked changes in the expression of cell type-specific markers in isolated 5 dpf larval brains. The addition of CRF reversed the in vitro effects of HEA on neurod1 expression and prevented an HEA-induced increase in cell death. Finally, the protective effects of CRF against HEA-mediated neurogenic impairment and cell death were prevented by the CRF type 1 receptor selective antagonist antalarmin. Together, these results provide novel evidence that HEA has developmental time- and cell type-specific neurotoxic effects, that NMDA receptor hyperactivation contributes to HEA-mediated impairment of determined neurons, and that CRF has neuroprotective properties in the larval zebrafish brain.
On Bilevel Optimization with Inexact Follower
Authors: Zare M. Hosein , Prokopyev Oleg A. , Sauré Denis
Published: February 2020

Traditionally, in the bilevel optimization framework, a leader chooses her actions by solving an upper-level problem, assuming that a follower chooses an optimal reaction by solving a lower-level problem. However, in many settings, the lower-level problems might be nontrivial, thus requiring the use of tailored algorithms for their solution. More importantly, in practice, such problems might be inexactly solved by heuristics and approximation algorithms. Motivated by this consideration, we study a broad class of bilevel optimization problems where the follower might not optimally react to the leader’s actions. In particular, we present a modeling framework in which the leader considers that the follower might use one of a number of known algorithms to solve the lower-level problem, either approximately or heuristically. Thus, the leader can hedge against the follower’s use of suboptimal solutions. We provide algorithmic implementations of the framework for a class of nonlinear bilevel knapsack problem (BKP), and we illustrate the potential impact of incorporating this realistic feature through numerical experiments in the context of defender-attacker problems.
A Review of Probabilistic Opinion Pooling Algorithms with Application to Insider Threat Detection
Authors: Beekman Jared A. , Woodaman Ronald F. A. , Buede Dennis M.
Published: February 2020

We retrospectively explore the effectiveness of various probabilistic opinion pools against a set of insider threat detection modeling data from a recently completed, multiyear, sponsored research effort. We explored four opinion pools: the linear opinion pool (likely the most popular), the beta-transformed linear opinion pool, the geometric opinion pool, and a multiplicative method based on odds called Bordley’s formula. The data for our study came from our recent work in the inference of insider threats for our research sponsor. In this work, we created a multimodeling inference enterprise modeling (MIEM) process to either predict threats within a population or, given the threats, predict how well the enterprise system can detect those threats. As part of larger research challenges designed by the research sponsor, we applied the MIEM process quarterly to respond to a sequence of varying challenge problems (CPs). Via MIEM, we developed multiple, independent computation forecast models. These models generated certainty intervals to answer CP questions. These intervals were fused into a single interval for each question via an expert panel prior to submission. The sponsors scored the responses against ground truth. In this paper, we (a) ask which pooling functions work best on these data and consider why, and (b) compare this performance to the actual submissions to determine if one of the pooling functions performed better than our judgment-based fusion.
Dynamic speckle analysis with coarse quantization of the raw data
Authors: Stoykova Elena , Nazarova Dimana , Nedelchev Lian , Ivanov Branimir , Blagoeva Blaga , Oh Kwan-Jung , Park Joongki
Published: February 2020

Analysis of dynamic speckle formed on the surface of diffusely reflecting objects under laser illumination is a non-contact method for inspection of speed of processes. The paper deals with intensity-based implementation of the method that relies on statistical processing of correlated in time sequences of speckle images. A two-dimensional activity map is built for each sequence to visualize regions of different speed on the object surface at a given instant. A great number of images is required to track a process in time. We propose data compression by coarse quantization of the raw speckle data. Efficacy of quantization is analyzed by simulation and experiment for low- and high-contrast speckle patterns with bell-shaped and long-tailed distributions of intensity, respectively. Non-uniform quantization is proposed for long-tailed speckle intensity distributions. Decreasing the bit depth from 8 to 4 causes no change in the probability density function of the activity estimate.
Determination of the NOAA-20 VIIRS screen transmittance functions with both the yaw maneuver and regular on-orbit calibration data
Authors: Lei Ning , Xiong Xiaoxiong
Published: February 2020

The Visible Infrared Imaging Radiometer Suite (VIIRS) aboard the NOAA-20 satellite regularly performs on-orbit radiometric calibration of its reflective solar bands (RSBs) through observations of an onboard sunlit solar diffuser (SD). The incident sunlight passes through an attenuation screen (the SD screen) and then scatters off the SD to provide a radiance source for the calibration. The on-orbit change of the SD’s bidirectional reflectance distribution function (BRDF), referred to as the

H

-factor, is determined by an onboard solar diffuser stability monitor (SDSM) whose eight detectors alternately observe the Sun through another attenuation screen (the SDSM screen) and the sunlit SD. The products of the SD screen transmittance and the BRDF at the mission start for both the SDSM and RSBs and the SDSM screen effective transmittance were measured prelaunch. Large unrealistic undulations in the retrieved

H

-factor were seen when using the prelaunch screen functions. To improve the accuracy of the retrieved

H

-factor, shortly after the satellite launch, 15 yaw maneuvers were performed to further characterize the screens. Although significantly improved, the

H

-factor derived using the screen functions determined from the yaw maneuver data still has large unrealistic undulations, revealing that the solar azimuth angular step size of the yaw maneuvers is too large. In this paper, we add high-quality regular on-orbit SD calibration data to the yaw maneuver data to further improve the relative product of the SD screen effective transmittance and the BRDF at the mission start for the SDSM and the SDSM screen relative effective transmittance. The

H

-factor time series derived from the newly determined screen transmittance functions is much smoother than that derived from using only the yaw maneuver data and thus considerably improves the radiometric calibration accuracy.
Integration of MEMS IR detectors with MIR waveguides for sensing applications
Authors: Yazici Mahmut Sami , Dong Bowei , Hasan Dihan , Sun Fujun , Lee Chengkuo
Published: February 2020

Waveguides have been utilized for label-free and miniaturized mid-infrared gas sensors that operate on the evanescent field absorption principle. For integrated systems, photodetectors based on the photocarrier generation principle are previously integrated with waveguides. However, due to the thermal excitation of carriers at room temperature, they suffer from large dark currents and noise in the long-wavelength region. In this paper, we introduce the integration of a MEMS-based broadband infrared thermopile sensor with mid-infrared waveguides via flip-chip bonding technology and demonstrate a proof-of-concept gas (N2O) sensor working at 3.9 µm. A photonic device with input and output grating couplers designed at 3.72 µm was fabricated on a silicon-on-insulator (SOI) platform and integrated with a bare thermopile chip on its output side via flip-chip bonding in order to realize an integrated photonic platform for a myriad range of sensing applications. A responsivity of 69 mV/W was measured at 3.72 µm for an 11 mm waveguide. A second device designed at 3.9 µm has a 1800 ppm resolution for N2O sensing.
Large-range, continuously tunable perfect absorbers based on Dirac semimetals
Authors: Shi Xinwei , Fang Panpan , Zhai Xiang , Li Hongjian , Wang Lingling
Published: February 2020

Plasmonic metamaterials enable manipulation of light at subwavelength scales and exhibit unique optical functionalities. However, the realization of high-performance, large-range, and dynamically tunable optical absorbers based on plasmonic metamaterials remains challenging. Here, we propose and demonstrate a continuously tunable absorbers consisting of a zigzag array of bulk Dirac semimetals (BDS) meta-atoms and a metal reflector spaced by insulator layers. This structure exhibits a collective resonance formed by the electric dipole modes polarized along the long axis of each individual meta-atom, which allows us to precisely control this resonance frequency by fine-tuning the unit cell geometry and the Fermi energy levels of the BDS. In addition, the related physical mechanism behind this complete absorption can explained by employing coupled-mode theory (CMT) and mode-expansion theory (MET). Our results may arouse the investigations of the tunable metamaterials device based on the BDS.
Large positive and negative Goos-Hänchen shifts near the surface plasmon resonance in subwavelength grating
Authors: Petrov Nikolai I. , Danilov Viktor A. , Popov Vladimir V. , Usievich Boris A.
Published: February 2020

Diffraction of light of a visible spectral range by subwavelength metal gratings has been investigated experimentally and theoretically using rigorous electromagnetic calculations. It has been demonstrated that an effect of surface plasmon resonance (SPR), at which total absorption of light by metal grating can be observed, occurs under certain conditions. Large positive and negative Goos-Hänchen (GH) shifts occur near the SPR. It has been shown that the reflected beam is split into two parts, the relative powers of which depend on the incident beam width and the grating depth. The dependence of the GH shifts on the grating period and grating depth has been investigated for different incident beam widths. The high sensitivity of the GH shift on the incident angle of a light beam near the SPR has been demonstrated.
Universality, spectrality, proximity: The cinematic faces of Europe's other
Authors: Pantev Boris
Published: February 2020

For a number of scholars, the crisis of European identity is a result of the asymmetry between Europe's universal normative claims and its particular ethnic, cultural and racial contexts. This asymmetry is epitomized by the EU's failure to ratify its legally binding constitution. For others, the same asymmetry constitutes the very condition of being a European. Those envision Europeanness beyond its regulative idea as the ethical injunction of a promise to 'the other'. This article probes the validity of each of these arguments by juxtaposing two groups of films. Gianfraco Rosi's Fire at Sea (2016) and Ai Weiwei's Human Flow (2017) remain committed to the idea of human rights as a universal norm, an idea whose most prominent advocate is Jürgen Habermas. As an alternative to this view, Guido Hendrikx's Stranger in Paradise (2016) and Christian Petzold's Transit (2018) are taken to demonstrate what Jacques Derrida describes as 'hospitality' and 'spectrality'. Based on this analysis, the paper finds both models inadequate to hold together the irreconcilable modalities of the political and the ethical. To address this deficiency, it revisits Levinas' account of 'justice beyond the face' to propose an extension of the ethical view of Europeanness into the spheres of international law and public institutions.
Laju Pertumbuhan dan Pertumbuhan Mutlak Karang Lunak Cladiella sp. pada Substrat yang Berbeda
Authors: Fitriani Diah Putri , Zainuri Muhammad , Nugraha Wahyu Andy
Published: February 2020

Soft corals have a soft textured skeletal like tiny spikes made of calcium carbonate present in their tissues. In general, soft corals are attached to hard substrates in the bottom of the waters. This study aims to determine the survival rate, relative and absolute growth rate, and comparison of soft coral growth rates on different substrates. The survival rate obtained was 100%, or 20 soft coral fragments lived until the end of the study. The growth rate and absolute growth of soft coral is relatively varied due to environmental and water quality, with the highest growth rate and absolute growth found in rubble substrate. week and 2,875 cm / week. There was no significant difference in growth rate of soft coral Cladiella sp. on the different substrate. In transplantation or soft coral cultivation activities, the selection of substrates becomes very important, and it is recommended to use rubble or dead coral substrates. Karang lunak mempunyai tekstur  kerangka yang lunak berupa duri-duri kecil dari kalsium karbonat yang ada dalam jaringan tubuhnya. Pada umumnya karang lunak melekat pada substrat yang keras di dasar perairan. Penelitian ini bertujuan untuk mengetahui tingkat kelangsungan hidup, laju pertumbuhan relatif dan mutlak, dan perbandingan laju pertumbuhan karang lunak pada substrat yang berbeda. Tingkat kelangsungan hidup yang didapatkan yaitu 100 % atau 20 fragmen karang lunak dapat hidup sampai akhir penelitian. Laju pertumbuhan karang lunak relatif bervariasi karena pengaruh lingkungan dan kualitas air. Laju pertumbuhan dan pertumbuhan mutlak karang lunak Cladiella sp. relatif bervariasi karena pengaruh perbedaan substrat yang berbeda, dengan laju pertumbuhan dan pertumbuhan mutlak tertinggi ditemukan pada substrat rubble. Tidak ada perbedaan yang nyata pada laju pertumbuhan karang lunak Cladiella sp. pada substrat yang berbeda. Pada kegiatan transplantasi ataupun budidaya karang lunak, pemilihan substrat menjadi sangat penting, dan disarankan untuk menggunakan substrat rubble atau karang mati.
ParPaRaw
Authors: Stehle Elias , Jacobsen Hans-Arno
Published: February 2020

Parsing is essential for a wide range of use cases, such as stream processing, bulk loading, and in-situ querying of raw data. Yet, the compute-intense step often constitutes a major bottleneck in the data ingestion pipeline, since parsing of inputs that require more involved parsing rules is challenging to parallelise. This work proposes a massively parallel algorithm for parsing delimiter-separated data formats on GPUs. Other than the state-of-the-art, the proposed approach does not require an initial sequential pass over the input to determine a thread's parsing context. That is, how a thread, beginning somewhere in the middle of the input, should interpret a certain symbol (e.g., whether to interpret a comma as a delimiter or as part of a larger string enclosed in double-quotes). Instead of tailoring the approach to a single format, we are able to perform a massively parallel finite state machine (FSM) simulation, which is more flexible and powerful, supporting more expressive parsing rules with general applicability. Achieving a parsing rate of as much as 14.2 GB/s, our experimental evaluation on a GPU with 3 584 cores shows that the presented approach is able to scale to thousands of cores and beyond. With an end-to-end streaming approach, we are able to exploit the full-duplex capabilities of the PCIe bus and hide latency from data transfers. Considering the end-to-end performance, the algorithm parses 4.8 GB in as little as 0.44 seconds, including data transfers.
Simultaneous Impacts of Fe3O4{\text{Fe}_{3}}{\text{O}_{4}} Particles and Thermal Radiation on Natural Convection of Non-Newtonian Flow Between Two Vertical Flat Plates Using ADM
Authors: Gabli Ameur , Kezzar Mohamed , Zighed Lilia , Sari Mohamed Rafik , Tabet Ismail
Published: February 2020

The main aim of this research work is to show the simultaneous effects of ferro-particles (

Fe

3

O

4

{\text{Fe}_{3}}{\text{O}_{4}}

) and thermal radiation on the natural convection of non-Newtonian nanofluid flow between two vertical flat plates. The studied nanofluid is created by dispersing ferro-particles (

Fe

3

O

4

{\text{Fe}_{3}}{\text{O}_{4}}

) in sodium alginate (SA), which is considered as a non-Newtonian base fluid. Resolution of the resulting set of coupled non-linear second order differential equations characterizing dynamic and thermal distributions (velocity/temperature) is ensured via the Adomian decomposition method (ADM). Thereafter the obtained ADM results are compared to the Runge–Kutta–Feldberg based shooting data. In this investigation, a parametric study was conducted showing the influence of varying physical parameters, such as volumic fraction of

Fe

3

O

4

{\text{Fe}_{3}}{\text{O}_{4}}

nanoparticles, Eckert number (

E

c

{E_{c}}

) and thermal radiation parameter (N), on the velocity distribution, the skin friction coefficient, the heat transfer rate and the temperature distribution. Results obtained also show the advantages of ferro-particles over other types of standard nanoparticles. On the other hand, this investigation demonstrates the accuracy of the adopted analytical ADM technique.