bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental study on the seismic behavior of precast concrete column with grouted corrugated sleeves and debonded longitudinal reinforcements
Authors: Chen Jun , Zhao Chenhui , Ding Faxing , Xiang Ping
Published: July 2019

The seismic performance and the influence of debonded longitudinal reinforcements at the footing on the precast concrete columns connected with the embedded grouted corrugated sleeve were investigated experimentally in this research. Low cyclic loading tests were carried out on eight bending columns and four shear columns, considering the designed parameters of the partial debonding of the longitudinal reinforcements above the column–foundation interface, the axial load index, and the strength of the stirrups. Experimental results indicate that the partial debonding of the longitudinal reinforcements heavily influenced the damage spreading of the bending columns, but does not affect the damages of the shear columns. Compared to the columns without debonded longitudinal reinforcements, the seismic behaviors in terms of the ductility and energy dissipation can be improved clearly by the partial debonding of the longitudinal reinforcements for bending columns, but there was no clear improvement for shear columns. In addition, with the decrease of the axial load index or the increase of the strength of the stirrups, the seismic behaviors of the precast columns with the partial debonding of the longitudinal reinforcements are improved largely.
Experimental investigation of the protective effect of wind barriers on high-speed railway bridge in inland strong wind area
Authors: Ren Wanmin , Duan Qingsong , Ma Cunming , Liao Haili , Li Qiusheng
Published: July 2019

This study aims to investigate the wind protective effect of wind barriers on the Lanzhou–Xinjiang high-speed railway using wind tunnel tests. Wind barriers with different heights and porosities were analyzed. Two girders, that is, a box-girder and a trough-girder, each with 1:30 and 1:8 scales were experimentally investigated. The results suggest that the protective effect of the wind barrier with a height of 4 m and porosity of 20% is better than the others. The influence of wind barriers on the aerodynamic characteristics of train vehicles and girders must be analyzed simultaneously. The aerostatic force coefficients of trains are approximately the same at different scales, and the Reynolds number effect could be neglected.
Unemployment among young people and mental health: A systematic review
Authors: Bartelink Vicky H. M. , Zay Ya Kyaw , Guldbrandsson Karin , Bremberg Sven
Published: July 2019

Aim: The aim of this systematic review is to obtain a better understanding of the association between unemployment among young people and mental health. Methods: After screening the title and abstract of 794 articles drawn from four electronic databases, 52 articles remained for full-text reading. Of these, 20 studies met the inclusion criteria and were assessed on methodological quality. All steps were performed independently by two reviewers. Finally, a total of 17 articles were included in the systematic review. Results: Analysis of cross-sectional studies ( N = 5) showed an association between unemployment among young people and mental health. An effect of unemployment on mental health was found when considering cohort studies ( N = 12) that did not control for confounders (7/7). When controlling for confounders except mental health at baseline, this effect decreased in most studies leading to mixed results, although the majority (6/8) still found an effect. However, when taking mental health at baseline into account as one of the confounders, only a minority of studies (3/8) found a significant effect of unemployment on mental health. Conclusions: This systematic review showed an association between unemployment among young people and mental health. However, whether there is a causal relationship is less clear. More evidence from, for example, natural experiments and longitudinal studies that control for confounding variables, especially mental health at baseline, is required to better understand the association and potential causation between unemployment among young people and mental health.
The high-resolution mass spectrometry study of the protein composition of amyloid-like urine aggregates associated with preeclampsia
Authors: Sergeeva Victoria A , Zakharova Natalia V , Bugrova Anna E , Starodubtseva Natalia L , Indeykina Maria I , Kononikhin Alexey S , Frankevich Vladimir E , Nikolaev Eugene N
Published: July 2019

The study of protein misfolding and post-translational processing abnormalities is a promising diagnostic approach for socially significant pathologies associated with the accumulation of abnormal forms of proteins. Recently, it was shown that amyloid-like aggregates can be observed in the urine of pregnant women with preeclampsia, which is the most severe hypertensive complication that can lead to fateful outcomes. The protein composition of urine aggregates may clarify the molecular mechanisms underlying the pathology and has not yet been studied in detail. Using a proteomic approach based on high-resolution mass spectrometry, we studied the protein composition of amyloid-like structures that aggregate in the presence of Congo red azo-dye in the urine of pregnant women with preeclampsia. Fragments of β-sheets of α-1-antitrypsin, complement 3, haptoglobin, ceruloplasmin, and trypstatin were identified as most likely targets for Congo red binding.
Validation Study of the Family Involvement Questionnaire–Elementary Version With Families in Belize
Authors: Garbacz S. Andrew , Hall Garret J. , Young Kaitlyn , Lee Yen , Youngblom Rachel K. , Houlihan Daniel D.
Published: July 2019

The purpose of this study was to examine the factor structure of the Family Involvement Questionnaire–Elementary Version with families in Belize. Participants were 185 primary caregivers of children in primary education settings in Belize. Caregivers were given the Family Involvement Questionnaire–Elementary Version to measure their educational involvement in their children’s schooling. Findings indicated the factor structure of the Family Involvement Questionnaire–Elementary Version in Belize was not congruent with the factor structures with samples from the United States and New Zealand. Exploratory factor analysis suggested a five-factor solution: (a) home-school communication, (b) home expectations and monitoring, (c) educational support, (d) school and community involvement, and (e) school attendance. In light of similar measurement studies in the literature, these data indicate that family educational involvement varies across geographic and cultural contexts. This suggests that interventions and policies to improve education outcomes via family involvement ought to consider the unique structure of families’ involvement in the educational system.
Mobile edge computing resource allocation: A joint Stackelberg game and matching strategy
Authors: Guo Shaoyong , Hu Xing , Dong Gangsong , Li Wencui , Qiu Xuesong
Published: July 2019

Mobile edge computing has attracted great interests in the popularity of fifth-generation (5G) networks and Internet of Things. It aims to supply low-latency and high-interaction services for delay-sensitive applications. Utilizing mobile edge computing with Smart Home, which is one of the most important fields of Internet of Things, is a method to satisfy users’ demand for higher computing power and storage capacity. However, due to limited computing resource, how to improve efficiency of resource allocation is a challenge. In this article, we propose a hierarchical architecture in Smart Home with mobile edge computing, providing low-latency services and promoting edge process for smart devices. Based on that, a Stackelberg Game is designed in order to allocate computing resource to devices efficiently. Then, one-to-many matching is established to handle resource allocation problems. It is proved that the allocation strategy can optimize the utility of mobile edge computing server and improve allocating efficiency. Simulation results show the effectiveness of the proposed strategy compared with schemes based on auction game, and present performance with different changing system parameters.
Cognition-based hybrid path planning for autonomous underwater vehicle target following
Authors: Ming Li Yue , Hai Huang , Yang Xu , Guocheng Zhang , Jiyong Li , Hongde Qin
Published: July 2019

Intelligent path planning is one of the key techniques for autonomous underwater vehicles for the purpose of target detection, environmental survey and so on. In order to realize automatic motion plan, an intelligent cognitive architecture for autonomous underwater vehicle motion planning has been proposed to realize complicated target detection and mobile target following in the disturbance environment. A novel adaptive ant colony optimization and particle swarm optimization fusion-based fuzzy rules optimization algorithm has been proposed to generate optimized fuzzy rules. Through this optimization algorithm, the preliminary fuzzy rules can be optimized to realize intelligent motion planning for complicated operation tasks. Experiments of channel following for wall detection and mobile target following in the oceanic environment have verified the validity of path planning method in the implementation of detection and operation tasks.
To believe or not to believe? How voice and accent information in speech alter listener impressions of trust
Authors: Jiang Xiaoming , Gossack-Keenan Kira , Pell Marc D
Published: July 2019

Our decision to believe what another person says can be influenced by vocally expressed confidence in speech and by whether the speaker–listener are members of the same social group. The dynamic effects of these two information sources on neurocognitive processes that promote believability impressions from vocal cues are unclear. Here, English Canadian listeners were presented personal statements ( She has access to the building) produced in a confident or doubtful voice by speakers of their own dialect (in-group) or speakers from two different “out-groups” (regional or foreign-accented English). Participants rated how believable the speaker is for each statement and event-related potentials (ERPs) were analysed from utterance onset. Believability decisions were modulated by both the speaker’s vocal confidence level and their perceived in-group status. For in-group speakers, ERP effects revealed an early differentiation of vocally expressed confidence (i.e., N100, P200), highlighting the motivational significance of doubtful voices for drawing believability inferences. These early effects on vocal confidence perception were qualitatively different or absent when speakers had an accent; evaluating out-group voices was associated with increased demands on contextual integration and re-analysis of a non-native representation of believability (i.e., increased N400, late negativity response). Accent intelligibility and experience with particular out-group accents each influenced how vocal confidence was processed for out-group speakers. The N100 amplitude was sensitive to out-group attitudes and predicted actual believability decisions for certain out-group speakers. We propose a neurocognitive model in which vocal identity information (social categorization) dynamically influences how vocal expressions are decoded and used to derive social inferences during person perception.
Utility of 3-(thiophen-2-yl)prop-2-enoyl isothiocyanate in heterocyclic synthesis
Authors: El-Sayed Amira A , Atta-Allah Saad R , Hemdan Magdy M
Published: July 2019

Convenient syntheses of quinazoline, benzothiazole, thiadiazole, imidazole, and thiourea derivatives starting from 3-(thiophen-2-yl)prop-2-enoyl isothiocyanate are described. The structures of the synthesized compounds are confirmed from their microanalytical and spectral data. Some of the products are examined for their antibacterial activity against Gram-positive and Gram-negative bacteria and fungi.
Positive fluid balance and mortality in adult patients treated with extracorporeal membrane oxygenation: A retrospective study
Authors: Fong Ka Man , Au Shek Yin , Ng George Wing Yiu , Leung Anne Kit Hung
Published: July 2019

Background

Intravenous fluid is important for resuscitation and maintenance of circuit flow in patients with extracorporeal membrane oxygenation, but fluid overload is widely recognized as detrimental in critically ill patients. This study aimed to evaluate the association between positive fluid balance and outcomes in adult patients treated with extracorporeal membrane oxygenation.

Methods

This was a retrospective observational study of a tertiary hospital from October 2010 to January 2018. Patients aged ≥18 years who received extracorporeal membrane oxygenation for ≥48 h were included. The fluid balance was determined as the difference between fluid intake and fluid output, and the cumulative fluid balance was calculated as the sum of these values on the preceding days. The primary outcome was hospital mortality.

Results

Of the 123 included extracorporeal membrane oxygenation episodes, 79 were venovenous extracorporeal membrane oxygenation. The hospital mortality rate was 31.7%. Seventy-eight patients underwent continuous renal replacement therapy during their extracorporeal membrane oxygenation course. Non-survivors had a greater cumulative fluid balance (p≤0.001) and a lower cumulative fluid output (p = 0.006) than survivors on day 7. Fluid intake was not significantly different between survivors and non-survivors (p = 0.583). In the multivariate analysis, the cumulative fluid balance (per litre) on day 7, but not on day 3, was associated with increased hospital mortality (adjusted OR: 1.17, 95% CI: 1.06–1.29, p = 0.001).

Conclusions

In adult patients treated with extracorporeal membrane oxygenation, a higher positive cumulative fluid balance on day 7 was associated with increased hospital mortality. The association between positive fluid balance and mortality was mainly influenced by lower fluid output rather than an increase in fluid intake.
Anaphylaxis
Authors: Hendon-John Lewis
Published: July 2019

Anaphylaxis is a surprisingly common condition, with 1-in-300 people in the UK expected to have at least one episode in their lifetime. It is a condition that can occur rapidly in an otherwise healthy individual, with potentially fatal consequences. Primary care clinicians may be involved in all stages of management from immediate recognition and emergency treatment, to provision of repeat prescriptions and organisation of long-term follow up. It is, therefore, important that GPs understand the implications and management of anaphylaxis.
Computed Tomography–Mediated Registration of Trapeziometacarpal Articular Cartilage Using Intraarticular Optical Coherence Tomography and Cryomicrotome Imaging: A Cadaver Study
Authors: Cernohorsky Paul , Strackee Simon D. , Streekstra Geert J. , van den Wijngaard Jeroen P. , Spaan Jos A. E. , Siebes Maria , van Leeuwen Ton G. , de Bruin Daniel M.
Published: July 2019

Objective

Accurate, high-resolution imaging of articular cartilage thickness is an important clinical challenge in patients with osteoarthritis, especially in small joints. In this study, computed tomography (CT) mediated catheter-based optical coherence tomography (OCT) was utilized to create a digital reconstruction of the articular surface of the trapeziometacarpal (TMC) joint and to assess cartilage thickness in comparison to cryomicrotome data.

Design

Using needle-based introduction of the OCT probe, the articular surface of the TMC joint of 5 cadaver wrists was scanned in different probe positions with matching CT scans to record the intraarticular probe trajectory. Subsequently and based on the acquired CT data, 3-dimensional realignment of the OCT data to the curved intraarticular trajectory was performed for all probe positions. The scanned TMC joints were processed using a cryomicrotome imaging system. Finally, cartilage thickness measurements between OCT and cryomicrotome data were compared.

Results

Successful visualization of TMC articular cartilage was performed using OCT. The CT-mediated registration yielded a digital reconstruction of the articular surface on which thickness measurements could be performed. A near-perfect agreement between OCT and cryomicrotome thickness measurements was found ( r2 = 0.989).

Conclusion

The proposed approach enables 3D reconstruction of the TMC articular surface with subsequent accurate cartilage thickness measurements, encouraging the development of intraarticular cartilage OCT for future (clinical) application.
Novel therapy in Acute myeloid leukemia (AML): moving toward targeted approaches
Authors: Winer Eric S. , Stone Richard M.
Published: July 2019

Acute myeloid leukemia (AML) is a heterogenous and complex disease characterized by rapid cellular proliferation, an aggressive clinical course, and generally high mortality. While progress has been made in the understanding of the genetic and molecular biology of the disease, the standard of care for patients had only changed minimally over the past 40 years. Recently, rapid movement of potentially useful agents from bench to bedside has translated into new therapies either recently approved or in clinical trials. These therapies include improved chemotherapies, mutationally targeted inhibitors, pro-apoptotic agents, microenvironment targeting molecules, cell cycle checkpoint inhibitors, and epigenetic regulators. Furthermore, advances in immunotherapy employ monoclonal and bispecific antibodies, chimeric antigen receptor (CAR) T cells, checkpoint inhibitors, and vaccines provide an alternative pathway for AML treatment. In this review, we discuss the recent results of completed or ongoing clinical trials with these novel therapeutic agents in AML.
Rabbit palatum-derived mesenchymal progenitor cells tri-lineage differentiation on 2D substrates and 3D printed constructs
Authors: Kim Dong Hwan , Kim Bo Young , Kim Dong Hyun , Hur Jin , Baek Chung-Hwan
Published: July 2019

Hard palate, developed by embryo neural crest stem cells, is a tissue with strong regenerative abilities. It is considered an abundant source of progenitor cells, forming various mesenchymal tissues. Rabbits are more suitable models than murine animals for regenerative preclinical study of the head and neck, owing to their larger size. However, there are no reports of the existence or characteristics of neural crest stem cells in the hard palate of rabbits. In this study, we demonstrate for the first time the presence of nestin-, Sox2-, and p75-positive neural crest stem cells obtained from the hard palate of rabbits and the properties of these cells. Flow cytometry analysis revealed that CD29, CD44, and CD81 were positive; and CD11b, CD34, and CD90 were negative on the ex vivo expanded palatal progenitor cells. Finally, we differentiated them into cells of mesenchymal lineages (bone, cartilage, and fat) in vitro, and in three-dimensional fabricated polycaprolactone and polycaprolactone–tricalcium phosphate scaffolds. Taken together, our data showed the existence of rabbit palatum-derived mesenchymal progenitor cells, and successful fabrication of progenitor cell-loaded biodegradable scaffold using three-dimensional printing. This study will open avenues for new tissue engineering strategies for cell therapy using three-dimensional printing with scaffolds for reconstruction of head and neck defects.
Quadriceps Tendon Graft Anatomy in the Skeletally Immature Patient
Authors: Shea Kevin G. , Burlile Jessica F. , Richmond Connor G. , Ellis Henry B. , Wilson Philip L. , Fabricant Peter D. , Mayer Stephanie , Stavinoha Tyler , Troyer Stockton , Dingel Aleksei B. , Ganley Theodore J.
Published: July 2019

Background:

The quadriceps tendon (QT) is increasingly considered for primary and revision anterior cruciate ligament reconstruction in skeletally immature patients, as it may be harvested as a purely soft tissue graft with considerable tissue volume. Because of distinct rectus tendon (RT) separation from the QT complex, the potential for RT retraction exists and could lead to QT weakness after QT graft harvest.

Purpose:

To describe the anatomy of the pediatric QT and clarify decussation of the RT and QT to avoid the risk of delayed RT retraction and QT weakness after QT graft harvest.

Study Design:

Descriptive epidemiology study.

Methods:

Nine cadaveric knee specimens (aged 4-11 years) underwent gross dissection. Coronal-plane width and depth of the QT were measured at intervals proximal to the superior pole of the patella at distances of 0.0, 0.5, 1.0, and 1.5 times the length of the patella. The distance was measured from the superior patellar pole to the point of RT separation from the remainder of the deeper/posterior QT.

Results:

The median patellar length was 28 mm (interquartile range, 26-37 mm). The coronal-plane width of the QT was larger superficially/anteriorly when closest to the patella but wider when measured deeper/posteriorly as the tendon extended proximally. The median distance between the superior pole of the patella and RT separation from the QT was 0.95 times the patellar length. The distance to widening of the deeper/posterior aspect of the QT was 1.14 times the patellar length proximal to the patella.

Conclusion:

The RT begins a distinct separation from the QT above the superior pole of the patella at a median of 0.95 times the patellar length in skeletally immature specimens. The deeper/posterior aspect of the QT begins to increase in coronal-plane width proximally after a distance of 1.14 times the patellar length above the knee, while the superficial/anterior aspect of the tendon continues to narrow. Awareness of the separation of the RT from the QT, and the coronal-plane width variation aspects of the QT proximally, is important for surgeons utilizing the QT as a graft to avoid inadvertent release of the RT from the rest of the QT complex.
Can a Different Formulation of Vitamin D3 Allow Savings? An Analysis From an Italian Regional Perspective
Authors: Sanò Mario , Dutto Patrizia , D’Anna Stefano , Rognoni Carla
Published: July 2019

Vitamin D3 reported in Italy in 2017 the net expenditure of almost €180 million, reaching the first place for consumption and the third place for conventional pharmaceutical spending. The aim of the study was to evaluate whether a shift of vitamin D3 prescriptions toward 100 000 IU formulation, less costly, could allow savings from the health-care perspective. An approach promoting the prescription of this formulation has been applied in a local health authority (ASL CN2) in Piedmont Region (Italy) starting from 2015. The retail pharmaceutical market and the consumption of vitamin D3 has been analyzed from year 2014 to 2017 in order to evaluate differences in expenditures. Despite an increase in consumption, the introduction of the new formulation enabled ASL CN2 to save about €280 000 in 2017 considering the regional average expenditure per 1000 inhabitants as a reference. If Piedmont Region had presented an average expenditure in line with that of ASL CN2, the annual regional savings would have exceeded €7 million in 2017 alone. A shift of vitamin D3 prescriptions toward 100 000 IU formulations would allow reducing costs from the payer perspective. Savings may be used to contain public pharmaceutical expenditure or can be allocated to fund other health-care technologies and services.
Correction to: Detection and classification of social media-based extremist affiliations using sentiment analysis techniques
Authors: Ahmad Shakeel , Asghar Muhammad Zubair , Alotaibi Fahad M. , Awan Irfanullah
Published: July 2019

In the original publication of this article [1], the Acknowledgements and Funding section in Declarations need to be revised.
Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study
Authors: Hillmen Peter , Rawstron Andy C. , Brock Kristian , Muñoz-Vicente Samuel , Yates Francesca J. , Bishop Rebecca , Boucher Rebecca , MacDonald Donald , Fegan Christopher , McCaig Alison , Schuh Anna , Pettitt Andrew , Gribben John G. , Patten Piers E.M. , Devereux Stephen , Bloor Adrian , Fox Christopher P. , Forconi Francesco , Munir Talha
Published: July 2019

PURPOSE

The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy.

PATIENTS AND METHODS

CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival.

RESULTS

In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events.

CONCLUSION

The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL.
Final analysis of nelipepimut-S plus GM-CSF with trastuzumab versus trastuzumab alone to prevent recurrences in high-risk, HER2 low-expressing breast cancer: A prospective, randomized, blinded, multicenter phase IIb trial.
Authors: Hickerson Annelies , Clifton G. Travis , Hale Diane F. , Peace Kaitlin M. , Holmes Jarrod P. , Vreeland Timothy J. , Litton Jennifer Keating , Murthy Rashmi Krishna , Lukas Jason Jerome , Mittendorf Elizabeth A. , Peoples George Earl
Published: July 2019

1

Background: Preclinical data shows synergism between trastuzumab (Tz) and HER2-targeted vaccines. We evaluated adjvuant nelipepimut-S (NPS) + GM-CSF with Tz compared to Tz with GM-CSF alone in HER2 low-expressing (LE) breast cancer (BC) patients (pts) to prevent recurrences. After a planned interim analysis showed benefit in triple negative BC (TNBC) pts, the decision was made to close the trial with guidance from the independent DSMB. Here, we report the final analysis of the trial with 7 months (mo) of added follow-up (f/u). Methods: The phase 2b trial enrolled clinically disease-free BC pts after standard therapy. Pts were HLA-A2, A3, A24, and/or A26+, had HER2-LE (IHC 1-2+, FISH non-amplified) BC and were node positive and/or TNBC. Pts were randomized to placebo with GM-CSF(control group, CG) or NPS with GM-CSF (vaccine group, VG), while all received Tz Q3wk for 1 year. GM-CSF or NPS + GM-CSF were given q3wks x 6 starting with the 3rd Tz dose, and boosters every 6 months x 4. Safety was assessed and pts were followed clinically for recurrences. The primary outcome was DFS at 24 mo. Results: 589 pts were screened at 26 sites. 275 pts were enrolled and randomized (VG:136, CG:139). There were no clinicopathologic differences between groups. Concurrent Tz and NPS was safe with no added overall or cardiac toxicity compared to CG and no grade 4/5 toxicities. In the ITT analysis (median f/u 25.7 mo), the estimated DFS was favorable but did not reach significance in the VG compared with the CG (HR 0.62, 95% CI: 0.31-1.25, p = 0.18). In the TNBC pts, the VG had statistically improved DFS compared to the CG (HR 0.26, 95% CI: 0.08-0.81, p = 0.013). Conclusions: The combination of NPS with Tz is safe with no added toxicity compared to Tz alone, even after prolonged exposure (25.7 mo). In this final analysis, there was a trend towards benefit in the ITT population that improved since the interim analysis with added f/u. The significant benefit seen at interim in the TNBC pts continued to strengthen in the VG group. These findings could position the NPS + Tz combination as an adjuvant therapy for early-stage TNBC and warrant further study. Clinical trial information: NCT01570036.
Evaluation of PQ500, a 500-plasma protein blood panel in NSCLC subjects using high-throughput MRM mass spectrometry.
Authors: Dupuis Nicholas , Muller Sebastian , Treiber Tobias , Escher Claudia
Published: July 2019

110

Background: Monitoring of circulating proteins in cancer subjects can provide insight into the host response to the tumor. Recent studies have demonstrated the utility of circulating proteins for early detection, differential diagnosis, and predicting response to therapy. Although the utility is clear, standardization of measurement methods across a large number of proteins from plasma has remained challenging. Here, we evaluate the detection of proteins from a > 500-protein plasma panel assembled from stable-isotope standard (SIS) peptides and measured in a high-throughput MRM workflow. Methods: Plasma samples from subjects with Stage III-IV non-small cell lung cancer (n = 15), Stage IV pancreatic cancer (n = 6) and healthy donors (n = 15) were prepared for analysis. Prior to analysis, a panel of SIS peptides covering 582 plasma proteins (804 peptides), was spiked into each sample enabling absolute quantification of detectable peptide species. All samples were analyzed using a capillary flow liquid chromatography (5 µl/min) with a one-hour gradient coupled to a Thermo Scientific TSQ Altis triple quadrupole mass spectrometer. Protein data was extracted and quantified for statistical analysis using SpectroDive (Biognosys). Results: Across all samples, 607 peptides representing 411 proteins were quantified at least once, with an average of 300 proteins quantified per sample. From triplicate analyses, the median CV across all proteins was 5.3%. Statistical testing identified 42 significantly regulated proteins (36 up- and 6 down-regulated; q-value > 0.05 and log2 fold change > 0.58). Key species that were strongly dysregulated in cancer samples included: c-reactive protein (CRP), serum amyloid a (SAA1/SAA2), complement C9, S100A8/S100A9, and leucine rich glycoprotein 1 (LRG1). Conclusions: PQ500 is a comprehensive blood-focused multiplexed biomarker panel that enables absolute quantification of plasma proteins. The dysregulated proteins identified in this study highlight that the PQ500 can monitor the host immune response through multiple pathways. Accurate monitoring these proteins offers the possibility to define molecular based markers with clinical and diagnostic utility.
Galectins role as predictive markers for anti-PD-1-based immunotherapy in non-small cell lung cancer.
Authors: Capalbo Carlo , Filetti Marco , Scafetta Giorgia , Marchetti Paolo , Bartolazzi Armando
Published: July 2019

111

Background: Checkpoint inhibitor-based immunotherapy is opening a promising scenario in oncology with objective responses registered in several tumors. However reliable predictive markers of tumor responsiveness are still lacking. These markers need to be urgently identified for a better selection of patients candidate to immunotherapy. In NSCLC setting, the pleiotropic molecules Galectin 1 and 3 regulate apoptosis and tumor immune-escape and are in the right position to play as predictive marker in anti-PD1 based immunotherapy. Methods: 27 consecutive patients with non small cell lung cancer (NSCLC) stage IV, treatment-naive, selected on the basis of PD-L1 tumor proportion score (TPS) ≥ 50 % were considered for immunotherapy with anti PD-1 antibodies as a first-line treatment. Patients assessments were conducted at baseline and after 3 cycles of therapy (week 12) and classified according to immune-related response criteria (iRECIST). Immunohistochemical analysis was performed on primary tumor biopsies before treatment in order to evaluate Gal-1 and Gal-3 expression both in cancer cells and tumor interstitium. Tumors were grouped in 2 different classes depending on the expression level of these molecules. Results: In our preliminary data there seems to be a strong correlation between the responses to anti-PD-1 treatment and a low-intermediate expression of intratumoral Gal-3 and interstitial Gal-1. In fact, all patients in the intratumoral Gal-3 low-intermediate expression group had an excellent response to immunotherapic treatment (10/10 patients), while 15/17 patients with high intracellular Gal-3 expression had clinical and radiographic progression of the disease after only three cycles of treatment, despite the high expression of PD-L1. In contrast, 8/11 patients with a low-intermediate interstitial expression of Gal-1 had an excellent response to treatment, whereas in the group with high interstitial expression of Gal-1, the response rate was drastically lower (5/15 patients). Conclusions: The expression of interstitial Gal-1 protein and intratumoral Gal-3 protein appear to be a good candidates as predictive markers of response to immunotherapy.
Clinical and molecular characteristics of responders versus non-responders to immune checkpoint inhibitors (ICI) in NSCLC.
Authors: Shah Arpeet , Padda Sukhmani K. , Neal Joel W.
Published: July 2019

114

Background: Evidence from randomized clinical trials and retrospective studies has shown that tumors with specific driver mutations may be less likely to respond to ICI; the optimal timing of ICI is unknown in this population. In this analysis, we evaluated the characteristics of responders to ICI compared to non-responders, with emphasis on the role of driver mutations. Methods: We retrospectively collected clinical characteristics and outcomes for patients who received ICI for NSCLC at Stanford University between April 2015 and August 2016. Patients were classified as responders if time on ICI was 180 days or more, and as non-responders if less than 180 days. Outcomes included radiographic improvement while on ICI, survival from diagnosis, and survival from ICI initiation. Results: Data were available for 84 patients, with median follow-up of 31 months. 18 patients were deemed responders (21%); 66 were deemed non-responders (79%). Of the patients who underwent genomic testing, 13% (2/15) of responders had mutations in EGFR/ALK/ROS1, compared to 32% (17/49) of non-responders (p = 0.195). Within the responders, 89% (16/18) had an associated radiographic improvement, compared to 11% (7/66) of non-responders (p < 0.0001). Patients with mutations in EGFR/ALK/ROS1 had a median overall survival of 46 months from diagnosis, compared to 26 months in those without these mutations (p = 0.08). Patients with mutations in EGFR/ALK/ROS1 had a median survival of 4.9 months from ICI initiation, compared to 7.0 months in those without (p = 0.45). Conclusions: Patients receiving ICI for 180 days or more had a significantly higher rate of radiographic improvement, suggesting that time on therapy appears to be a surrogate endpoint of clinical benefit. While there was not a statistically significant smaller number of responders with EGFR/ALK/ROS1, there appeared to be clinically meaningful lower response rate in these patients. This was likely limited by sample size; expansion of the sample size is planned. There was a trend to overall survival benefit in patients with driver mutations, likely driven by targeted therapy as there were no statistical differences in survival from time of ICI initiation.
Tumor mutational burden (TMB): Assessment of inter- and intra-tumor heterogeneity.
Authors: Conroy Jeffrey M. , Pabla Sarabjot , Glenn Sean T. , Nesline Mary , Burgher Blake , Lenzo Felicia L. , Papanicolau-Sengos Antonios , Gardner Mark , Morrison Carl
Published: July 2019

27

Background: As an emerging biomarker, a high TMB is associated with response to immune checkpoint inhibitors. The tissue selected for molecular analysis could be critical for accurate TMB assessment and therapeutic selection. We evaluated TMB and the tumor specimen tested to determine the extent tissue selection has on TMB analysis. Methods: TMB profiling was performed on 73 cases representing 8 tumor types. 8 patients with multiple specimens from the same surgical event were evaluated for intra-tumor heterogeneity, and 20 patients with specimens from multiple surgical events spanning up to seven years were tested for inter-tumor heterogeneity. Two to six specimens, including primary, recurrent and metastatic cases, were evaluated per patient. For each patient, TMB values within and between tumors were assessed for concordance using a clinically relevant TMB-high cutoff of ≥ 10 mutations/Mb. Results: TMB values ranged from 0 – 58, with 7 cases scored as TMB-high. One patient with a primary skin melanoma and a lung metastasis biopsied after 34 months was concordant for TMB-high. For 19 patients (76%), all samples were concordant for TMB-low. For intratumor testing, 2 of 8 (25%) patients had discordant specimens (crossed the TMB-cutoff). The first patient had 4 intra-tumor CRC samples with TMB values of 10.6, 10.7, 9.7 and 9.7. The second patient had 5 intra-tumor pancreatic samples with TMB values of 10.7, 4.4, 6.2, 8.8, 7.9. Of the patients with 20 inter-tumor samples, 2 patients (each with melanoma) had discordant TMB-high calls. One had a lymph node metastasis TMB of 12.3 and a liver metastasis collected five months later with a reduced TMB of 0.9. In contrast, the second discordant melanoma patient had a peritoneum metastasis with an elevated TMB of 11.4 collected 14 months after a mesentery metastasis with a TMB of 8.7. Conclusions: TMB variation within tumors and between tumors from different surgical events occurs equally and in 17% of patients. This clinical tumor heterogeneity on the inter- or intra-tumor level may limit the utility and the application of TMB at a cutoff of 10. A careful analysis of tissues to enrich for neoplastic cells may improve assay sensitivity and increase analytical accuracy at this precise cut point.
Randomized, open-label, perioperative phase II study evaluating nivolumab alone versus nivolumab plus ipilimumab in patients with resectable HCC.
Authors: Kaseb Ahmed Omar , Carmagnani Pestana Roberto , Vence Luis M. , Blando Jorge M. , Singh Shalini , Ikoma Naruhiko , Vauthey Jean-Nicolas , Allison James Patrick , Sharma Padmanee
Published: July 2019

52

Background: In HCC, surgical resection is associated with high recurrence rate, and no effective neoadjuvant or adjuvant therapies currently exist. On the basis of previous reports on the efficacy and safety of anti–PD-1 (nivolumab) and anti–CTLA-4 (ipilimumab) antibodies against HCC, we initiated a randomized pilot trial of perioperative immunotherapy for resectable HCC. Methods: This is a randomized, phase II pilot trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as peri-operative treatment for patients (pt) with HCC who are eligible for surgical resection. Pt are given nivolumab 240 mg every 2 weeks (wk) for a total of 6 wk. Pt in Arm B are treated concurrently with ipilimumab 1 mg/kg every 6 wk. Surgical resection occurs within 4 weeks after last cycle of therapy. Pt continue adjuvant immunotherapy for up to 2 years after resection. Primary objective is the safety and tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, complete response rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood. Results: 9 pt were enrolled at the time of first interim analysis, and 8 pt were evaluable (5 in Arm A, 3 in Arm B). Most pt (78%) were 60-69 yo, and males (78%). 5 pt were HCV-positive and 1 had chronic hepatitis B infection. 7 pt proceeded with resection as planned; surgery was aborted for 1 pt due to frozen abdomen from previous surgery. Pathologic complete response (pCR) was observed in 3/8 pt – 2 in Arm A and 1 Arm B (37.5% pCR). 2 pt in Arm B and 1 in Arm A experienced grade 3 or higher toxicity. No grade 4 or higher toxicity were observed. Immune analysis of the first case with a pCR in Arm B demonstrated that clinical response correlated with an increase in CD8+ T cell infiltration, notably an increase in two effector T cell clusters. Conclusions: We report a pCR rate of 37.5% in the first interim analysis of a phase II pilot trial of perioperative immunotherapy for resectable HCC. Treatment was safe and surgical resection was not delayed. The study is ongoing and results may contribute to a paradigm shift in the perioperative treatment of HCC. Clinical trial information: NCT03222076.
Planning for survivorship after checkpoint inhibitors: A multidisicplinary education initiative.
Authors: Perloff Tara , Dawkins Monique , Hurd Mary , Wang Jennifer , Hallmeyer Sigrun
Published: July 2019

98

Background: Survivorship care plans are a key piece of coordinated, patient-centered care delivery. As with other cancer treatment modalities, patients with metastatic disease who achieve durable benefit with immunotherapy (IO) treatment may experience late physical and psychosocial effects which can negatively impact quality of life. An online education program was created to educate the multidisciplinary cancer care team on the nuances related to survivorship for patients who are treated with checkpoint inhibitors. Methods: A medical oncologist, oncology nurse, oncology social worker and patient developed a curriculum to identify challenges and solutions for survivorship care planning, prepare care teams for nuances related to survivorship for IO patients, and optimize coordination and communication between the care team and the patient. In June 2018, a live-online 1-hour webcast that included a panel discussion with presentation slides, participant polling, and live ‘ask the panel’ questions was produced and made available on-demand. Results: A total of 149 learners viewed the webcast; 86 of these learners participated in the live webinar and 63 watched on-demand. To date, an estimated 590 patients per month are impacted by this education. Learners were actively engaged for an average of 35 minutes (out of 52 minutes). Most learners indicated specializing in oncology (49%), were practicing physicians (39%), and saw 1-10 new patients on an IO therapy each week (59%) in a hospital-based setting (42%). Due to the education provided, learners reported improvements in their ability to identify challenges and solutions for IO survivorship care planning (97%) and handle nuances related to survivorship for patients on cancer immunotherapies (88%). Learners also demonstrated improved comprehension via case study by identifying the most common, concerning side-effect for a high-risk melanoma patient treated with ipilimumab and nivolumab. Conclusions: Continued refinement of care coordination practices related to survivorship is recommended to improve the long-term management of patients who are treated with checkpoint inhibitors.
Randomized open-label study of M7824 versus pembrolizumab as first-line (1L) treatment in patients with PD-L1 expressing advanced non-small cell lung cancer (NSCLC).
Authors: Ahn Myung-Ju , Barlesi Fabrice , Felip Enriqueta , Garon Edward B. , Martin Claudio Marcelo , Mok Tony S. K. , Vokes Everett E. , Ojalvo Laureen S. , Koenig Andre , Dussault Isabelle , Paz-Ares Luis G.
Published: July 2019

TPS127

Background: Transforming growth factor β (TGF- β) promotes tumor progression via immune- and non–immune-related processes. M7824 is an innovative first-in-class bifunctional fusion protein composed of 2 extracellular domains of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody against PD-L1. Targeting these independent and complementary pathways may restore and enhance antitumor responses. An expansion cohort of the study of patients with advanced NSCLC (n=80) treated with M7824 in the second-line setting presented at ESMO 2018 showed an objective response rate of 86% in the subgroup with high PD-L1 tumor expression at the recommended phase 2 dose (1200 mg intravenously [IV] every 2 weeks [Q2W]). Observed data support the hypothesis that M7824 may be superior to other PD-(L)1 inhibitors, including pembrolizumab, for the treatment of NSCLC. Based on the promising antitumor activity and manageable safety profile, this study will evaluate M7824 treatment in patients with advanced NSCLC in the 1L setting. Methods: Here we present a global, randomized trial comparing M7824 vs pembrolizumab in the 1L treatment of patients with metastatic NSCLC with high PD-L1 expression levels. Patients in this study must have a histologically confirmed diagnosis of advanced NSCLC with high PD-L1 expression on tumor cells (defined as either ≥80% by the Dako 73-10 pharmDx kit or ≥50% by the Dako 22C3 pharmDx kit since both assays are expected to select a similar patient population at their respective cut-offs). ECOG performance status must be 0 or 1. Patients must not have received prior systemic treatment for advanced NSCLC. Patients with tumors with actionable mutations (for which targeted therapy is locally approved) are not eligible. Patients will receive 1200 mg Q2W or pembrolizumab 200 mg Q3W as an IV infusion until confirmed disease progression, unacceptable toxicity, or trial withdrawal. Dual primary endpoints are progression-free survival and best overall response; key secondary endpoints include overall survival, duration of response, and safety. Estimated enrollment is 300 patients. Clinical trial information: NCT02517398, NCT03631706 .
Love, Lebanese Style
Authors: Allouche Sabiha
Published: July 2019

This article draws on a year of fieldwork conducted in Lebanon to highlight the paradoxical entanglement of power with romantic love in Lebanon, evident in the intricate gendered, aged, classed, and sect-related negotiations that accompany courtship periods. In addition, the article highlights the inclusive and relational qualities that external kin relations conduce. Kin approval ought not be seen as either/or divisive/conditional. For many of the couples interviewed, kin relations constitute an arena in which they can disseminate their affective bond. Such analysis is threefold. In addition to embracing the multiple subjectivity of the interlocutors, it moves beyond the standard political-economic approach that generally informs marriage studies in the Middle East and dismantles monolithic perceptions of Middle Eastern kin networks.