Sequential Line Research Articles

The cytotoxic effects of green synthesized AgCl2 nanoparticles on gastric cancer (AGS) cells

In recent years, with the development of nanotechnology, the use of various metal nanoparticles has become widespread specifically in the treatment of cancer. Furthermore, the application of silver nanoparticles (AgNPs) should not be denied in this respect. AgNPs hold great potential in the field of cancer biology and because of their anti-microbial activities they are vastly used in diverse clinical applications. AgNPs possess some physical and chemical features including heterogeneity in size, shape, and capping material. Moreover, their novel cytotoxic characteristics against mammalian cells makes them more applicable in tumor therapy and acting as anti-cancer agents. AgNPs have great potential in tumor diagnosis as well as treatment (Zhao et al., 2022; Păduraru et al., 2022; Patil et al., 2021). Gastric cancer is the fifth most common cancer with more than 1 million people newly diagnosed worldwide each year. Despite its worldwide decline in incidence and mortality over the past 5 decades, gastric cancer remains the third leading cause of cancer-related death (Sexton et al., 2020; Thrift and El-Serag, 2020) Gastric cancer is diagnosed histologically after endoscopic biopsy and staged using CT, endoscopic ultrasound, PET, and laparoscopy. The main treatment for early gastric cancer is endoscopic resection. Non-early operable gastric cancer is treated with surgery, which should include D2 lymphadenectomy (including lymph node stations in the perigastric mesentery and along the celiac arterial branches). Perioperative or adjuvant chemotherapy improves survival in patients with stage 1B or higher cancers. Advanced gastric cancer is treated with sequential lines of chemotherapy, starting with a platinum and fluoropyrimidine doublet in the first line; median survival is less than 1 year. Metastatic gastric cancer remains a non-curative disease. Palliative chemotherapy has been demonstrated to prolong survival without quality of life compromise. Many single-agents and combinations have been confirmed to be active in the treatment of metastatic disease. In the setting of metastatic or inoperable gastric cancer, the current evidence shows that chemotherapy improves survival in comparison to best supportive care and that combination chemotherapy is superior to monotherapy in terms of survival, response rate and symptom control. Although there are no internationally accepted standard regimens, in Europe, ECF (epirubicin, cisplatin, fluorouracil) has been considered the reference regimen; in the US cisplatin-fluoropyrimidine combinations are mainly used, while in Japan, cisplatin with S1 has become the standard. It has also been suggested that immunochemotherapy may improve survival of patients with curatively resected gastric cancer. Targeted therapies licensed to treat gastric cancer include trastuzumab (HER2-positive patients first line), ramucirumab (anti-angiogenic second line), and nivolumab or pembrolizumab (anti-PD-1 third line). Gastrointestinal symptoms are the most notable side effects of chemotherapeutic drugs (Kim et al., 2013; Janunger et al., 2001; Choi et al., 2018; Sastre et al., 2006; Zhou et al., 2017). Many recent studies have shown that green synthesized silver nanoparticles (AgNPs) can have cytotoxic effects on different cancer cells (Yesilot and Aydin, 2019). The biosynthesized AgNPs using the leaves extracts of Hemichroa pentandra showed considerable antioxidant activity and excellent anti-cancer activity against breast cancer cells (Punathil, 2018). Biosynthesized AgNPs from the leaf extract of Ochradenus arabicus can have suppressive effects against the human breast cancer cells (Al-kawmani et al., 2020). Also, green synthesized silver nanoparticles using Teucrium polium leaf extract exhibited significant anticancer activity against MNK45 human gastric cancer cell line (Hashemi et al., 2020). In this study we investigated the cytotoxic effects of green synthesized AgCl2 nanoparticles on gastric cancer (AGS) cells. Onopordum acanthium extract was used to synthesize AgCl2 nanoparticles. Onopordum acanthium has been applied traditionally as bactericide and antitumor agent (Al-Snafi, 2020). Gastric cancer cells were purchased from Pasteur Institute of Iran and cultured in growth medium until they reached 80-90% confluence. The cells were then treated with different concentrations (1.5625, 3.125, 6.25, 12.5, 25 and 50 μg/ml) of AgCl2 nanoparticle for 24 hours. The cytotoxic effect of AgCl2 nanoparticles was assessed using MTT assay method. The results showed that viability of AGS cells did not significantly change 24 hours after treatment with 1.5625 μg/ml of green synthesized AgCl2 nanoparticles compared to the control group; However, the viability in AGS cells significantly decreased when treated with 3.125, 6.25, 12.5, 25 and 50 μg/ml of green synthesized AgCl2 nanoparticles compared to control group. There cytotoxic effect was more in groups treated with 6.25, 12.5, and 25 than groups treated with 3.125, 6.25, and 12.5 μg/ml of green synthesized AgCl2, respectively. There was not significant difference between cell viability of group treated with 25 and 50 μg/ml of green synthesized AgCl2.Conclusion: Our results show that green synthesized AgCl2 nanoparticles have cytotoxic effects against gastric cancer (AGS) cells in vitro.

Tandem hemodialysis and DFPP: Procedure, safety and cost-effectiveness in patients requiring chronic hemodialysis and lipid apheresis.

Certain patients require simultaneous lipoprotein apheresis (LA) and intermittent hemodialysis (HD). Instead of undergoing 2 consecutive treatment sessions, a double filtration plasmapheresis (DFPP) and HD tandem procedure could be offered to reduce treatment times and costs. Our study evaluated the performance, safety and cost of this tandem procedure. Three patients underwent 168 HD and DFPP tandem sessions in a tertiary center from August 2018 to November 2020, using a Fresenius 5008 generator for HD and an InfomedHF440 for DFPP. The system's efficacy was assessed by lipid subtraction performance for DFPP. Efficacy of 2 blood line connection configurations (parallel or sequential) was compared in terms of Kt/V and matched against an HD control session for each patient. Clinical and biological safety and the differential cost between tandem and consecutive procedures were evaluated. Throughout the tandem sessions, DFPP lasted 85 to 120 minutes, overlapping the 240-minute HD. Blood flow for HD and Kt/V were significantly lower during the tandem procedure with a parallel configuration compared to sequential or control paired HD. DFPP efficacy was comparable between all groups: over 60% reduction in cholesterol and over 50% for triglycerides. Symptomatic hypotension depended on the patients, not the procedure. The tandem procedure revealed an acceptable benefit-cost ratio. HD-DFPP tandem with a sequential blood line connecting system (derivation installed on the HD venous line) is effective and well-tolerated with a good cost-benefit ratio. Tandem reduces hospitalization and treatment session times and can be offered to patients requiring simultaneous HD and DFPP.

Therapy options for metastatic triple negative breast cancer

Metastatic triple-negative breast cancer remains the most unfavourable among all breast cancer subtypes from the prognostic point of view. Despite the active introduction into practice of combinations of cytostatics with immunotherapeutic agents, as well as PARP inhibitors, sequential lines of chemotherapy with the median overall survival which does not exceed 15 months remains the main method of treating patients in this group. This breast cancer subtype is characterized by a rapid development of drug resistance at the early stages of systemic treatment and a predominantly visceral progression, which determines a low life expectancy in patients. The combination of capecitabine and ixabepilone has proved to be effective in the treatment of tumours that are resistant to taxanes and anthracyclines. The use of this combination is characterized by an acceptable and controlled toxicity profile. This article presents a clinical case of therapy with a combination of ixabepilone and capecitabine of a patient with breast cancer progression during the previous therapy of taxanes, a platinum-based doublet chemotherapy and eribulin. This approach, together with symptomatic laparocentesis and pleurodesis, allowed for overall survival exceeding 45 months with the preservation of a satisfactory functional status of the patient.

Androgen receptor genomic alterations and treatment resistance in metastatic prostate cancer

Genomic alterations to the androgen receptor (AR) are common in metastatic castration-resistant prostate cancer (mCRPC). AR copy number amplifications, ligand-binding domain missense mutations, and intronic structural rearrangements can all drive resistance to approved AR pathway inhibitors and their detection via tissue or liquid biopsy is linked to clinical outcomes. With an increasingly crowded treatment landscape, there is hope that AR genomic alterations can act as prognostic and/or predictive biomarkers to guide patient management. In this review, we evaluate the current evidence for AR genomic alterations as clinical biomarkers in mCRPC, focusing on correlative studies that have used plasma circulating tumor DNAto characterize AR genotype. We highlight data that demonstrates the complexity of AR genotype within individual patients, and suggest that future studies should account for cancer clonal heterogeneity and variable tumor content in liquid biopsy samples. Given the potential for cooccurrence of multiple AR genomic alterations in the same or competing subclones of a patient, it is distinctly challenging to attribute blanket clinical significance to any individual alteration. This challenge is further complicated by the varied treatment exposures in contemporary patients, and the fact that AR genotype continues to evolve in the mCRPC setting across sequential lines of systemic therapy. As treatment access and liquid biopsy technology continues to improve, we posit that real-time measures of AR biology are likely to play a key role in emerging precision oncology strategies for metastatic prostate cancer.

Clinical experience of using the radium-223 in patients with bone metastasis of castration-resistant prostate cancer

Background. Prostate cancer is one of the actual problems of modern oncology. The incidence of prostate cancer is steadily increasing despite of popularization of screening and early diagnostics. It is worth to highlight separately the castration-resistant prostate cancer which develops on the average 2 years after surgical or medicinal castration. For the patients with metastatic castration-resistant prostate cancer (mCRPC) the main purpose of treatment is increasing of overall survival while maintaining the quality of life. Currently there are several treatment options for mCRPC: chemotherapy, inhibitors of androgen receptor pathway,systemic alfa-radiotherapy, PARP-inhibitorsfor homologousrecombination DNA repair deficiency. Using of several sequential lines of mCRPC therapy leads to maintaining the patients’ quality of life and increasing its duration. Systemic alfa-radiotherapy is using since 2013 – the first is radium-223 which was approved by Food and Drug Administration according the results of the phase III trial ALSYMPCA. In Russian Federation radium-223 was approved in 2016.Objective: to evaluate the efficiency and safety oftherapy with radium-223 as well as pain response at patients with mCRPC.Materials and methods. 67 patients were included in this analysis who received radium-223 therapy at Scientific Research Institute of Tomsk National Research Medical Center of Russian Academy of Sciences and Tomsk Regional Oncology Dispensary.Results and conclusion. Radium-223 has demonstrated its efficiency for mCRPC patients with good safety profile and positive pain response and maintaining the QoL.

Chemorefractory Gastric Cancer: The Evolving Terrain of Third-Line Therapy and Beyond.

Simple SummaryGastric and gastro-oesophageal junction cancers (GC) are the fourth cause of cancer-related deaths, representing an international problem which needs a proper assessment. Beyond being an aggressive disease, which rapidly progress to different lines of treatment, patients suffering GC normally present a non-depreciable number of symptoms that make them especially fragile. In this context, sequential treatment lines with few toxic adverse events have been associated to an increased survival. A satisfactory GC therapy comprise at least three lines of treatment including chemotherapy and immunotherapy and/or targeted agents when indicated.Gastric and gastro-oesophageal junction cancer (GC) represent a global healthcare problem being the fifth most common tumour type and the fourth cause of cancer mortality. Extremely poor median survival of approximately 10 months is normally reported within advanced GC patients, mainly secondary to two factors, i.e., the fragility of these patients and the aggressiveness of this disease. In this context, the correct treatment of GC patients requires not only a multidisciplinary team with special attention to palliative and nutritional care but also a close follow-up with regular monitoring of disease symptoms and tumour evaluation. Sequential treatment lines with few toxic adverse events have emerged as the best therapeutic approach, and a third line of therapy could further improve survival and quality of life of GC patients. Chemotherapy, immunotherapy, and targeted agents -when indicated- constitute the treatment armamentarium of these patients. In this review, we discuss treatment options in the refractory setting as well as novel approaches to overcome the poor prognosis of GC.

Abstract P5-13-35: Mechanisms of CDK4/6 inhibitor resistance in hormone receptor positive metastatic breast cancer: Single institution retrospective analysis

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are the standard of care for hormone receptor positive (HR+) metastatic breast cancer (MBC). Mechanisms of intrinsic and acquired resistances have been proposed but are poorly understood in the real-world setting. The current study aims to study the association of genomic biomarkers and CDK 4/6i resistance mechanisms utilizing genomic data acquired through routine clinical practice. Methods: Tumor genomic data from patients with HR+ MBC who received FDA-approved CDK4/6i (palbociclib, ribociclib, and abemaciclib) were obtained by chart review. Progression free survival (PFS) was determined from the first day of treatment until date of disease progression. Patients were divided by number of lines of treatment (first line vs. ≥ 2 lines of therapy) and subcategorized into early progressors (< 6 months PFS), intermediate progressors (6-24 months PFS for first line and 6-9 months PFS for ≥ 2 lines of therapy), and late progressors (>24 months PFS for first line and > 9 months PFS for ≥ 2 lines of therapy). Genomic alterations from next-generation sequencing (NGS) were analyzed with PFS. PFS stratified by first vs. >2 lines of treatment were performed using a Cox proportional hazards model with hazard ratios and 95% confidence intervals reported. Results: Among 795 patients with HR+ MBC treated with CDK 4/6i between 2015 and 2020 including 673 patients from a main campus and 122 patients from community sites, a total of 131 patients had genomic data available for the analysis. The obtaining rate of genomic data was 18% (122 out of 673 patients) from the main campus and 7% (9 out of 122 patients) from community sites. Seventy-one patients were treated with CDK4/6i as the first line of MBC, and 60 were treated as second or sequential lines. 35 patients had early progression, 40 patients had intermediate progression, 44 patients had late progression, and 12 patients were indeterminate. The distribution of genomic alterations was not significantly different between each group. The genomic alterations that were associated with impaired PFS were ZNF703(hazard ratio, HR 2.1, N=13), ERBB2 (HR 1.9, N=12), MDM2 (HR 3.3, N=6), PALB2 (HR 3.8, N=5), ARFRP1 (HR 3.1, N=4), FRS1 (HR 2.9, N=4), IRS2 (HR 6.9, N=2), and JAK2 (HR 6, N=2). RNA seq analysis is currently underway. Conclusion: Tumor genomic tests are not routinely performed for patients with HR+ MBC, particularly less performed from community practices. In this single institution retrospective analysis, we identified genomic alterations, such as ZNF703, ERBB2, PALB2, and MDM2, as potential resistance mechanisms of CDK4/6i. Tumor genomics through standard clinical practice are essential to understand resistance mechanisms to CDK4/6i. Citation Format: Jin Sun Lee, Susan Yost, Yujie Cui, Paul Frankel, Sierra Min Li, Yate-Ching Yuan, Denise Morse, Judy Wong-Toh, Linda Bosserman, Joanne Mortimer, Yuan Yuan. Mechanisms of CDK4/6 inhibitor resistance in hormone receptor positive metastatic breast cancer: Single institution retrospective analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-35.

Optimization for sequential communication line attack in interdependent power-communication network

In this paper, we construct a novel model to study cascading failures that occur in the interdependent power-communication network. Based on this model, we employ the Q-learning algorithm to search for the optimal attack sequence against the lines in the communication network with the aim to bring the most destructive damage to the power grid. The effectiveness of the deduced optimal attack sequence is validated through numerical simulations, in which the IEEE-39 bus test system is used as the power grid and the Barabási–Albert (BA) scale-free network is modeled as the communication network. It is found that in the interdependent power-communication network, large-scale failure in the power grid can be caused by attacking only a small fraction of lines in the communication network. In addition, under the same number of attack actions, the attack sequence resulted from Q-learning algorithm is more destructive than random attack sequence and the attack sequence based on traditional complex network characteristics. Furthermore, according to the analysis of simulation results, we identify the most vulnerable lines in the communication network and propose the corresponding protection strategy. The proposed protection strategy proves to be able to effectively reduce the number of independent optimal attack sequences that the attacker can launch and improve the robustness of the whole network.

Overview of Adverse Outcome Pathways and Current Applications on Nanomaterials.

Nanomaterials (NMs) have important and useful applications in chemical industry, electronics, pharmaceuticals, food and others. Their rapid proliferation presents a dilemma to regulators regarding hazard identification and increased concerns for public health.The Adverse Outcome Pathways (AOPs) are innovative central elements of a toxicological knowledge framework, developed for supporting chemical risk assessment based on mechanistic reasoning. AOPs describe a sequence of causally linked events at different levels of biological organisation, triggered by exposure to a stressor (like chemicals or NMs) leading to an adverse health effect in humans or wildlife. The integrative analysis of the cellular and molecular mechanisms of nanotoxicity towards the identification of connected adverse outcomes drives a sequential line - an AOP landscape definition. Each defined AOP is available for crossing data, linking known and unknown landscapes, reducing the reliance on animal studies, associated costs and ethical issues. NMs have unique properties, with specific associated toxicological challenges, which may represent unknown AOP landscapes.In this chapter, an overview of AOPs as important novel strategic tools in nanotoxicology is presented, highlighting the current applications in hazard identification and human health risk assessment.

Molecular Genetics of Pre-B Acute Lymphoblastic Leukemia Sister Cell Lines during Disease Progression.

For many years, immortalized tumor cell lines have been used as reliable tools to understand the function of oncogenes and tumor suppressor genes. Today, we know that tumors can comprise subclones with common and with subclone-specific genetic alterations. We sequenced DNA and RNA of sequential sister cell lines obtained from patients with pre-B acute lymphoblastic leukemia at different phases of the disease. All five pairs of cell lines carry alterations that are typical for this disease: loss of tumor suppressors (CDKN2A, CDKN2B), expression of fusion genes (ETV6-RUNX1, BCR-ABL1, MEF2D-BCL9) or of genes targeted by point mutations (KRAS A146T, NRAS G12C, PAX5 R38H). MEF2D-BCL9 and PAX R38H mutations in cell lines have hitherto been undescribed, suggesting that YCUB-4 (MEF2D-BCL9), PC-53 (PAX R38H) and their sister cell lines will be useful models to elucidate the function of these genes. All aberrations mentioned above occur in both sister cell lines, demonstrating that the sisters derive from a common ancestor. However, we also found mutations that are specific for one sister cell line only, pointing to individual subclones of the primary tumor as originating cells. Our data show that sequential sister cell lines can be used to study the clonal development of tumors and to elucidate the function of common and clone-specific mutations.

Hydrogen Absorption and Desorption Behavior on Aluminum-Coated Hot-Stamped Boron Steel during Hot Press Forming and Automotive Manufacturing Processes.

Our study mainly focused on diffusible hydrogen in aluminum–silicon-coated hot-stamped boron steel during a hot press forming process and in pre-treatment sequential lines of the automotive manufacturing process using a thermal desorption spectroscopy (TDS) technique. First, in the hot stamping procedure, as the soaking time increased in the heating furnace at a specific dew point when austenitizing, a high concentration of diffusible hydrogen was absorbed into the hot-stamped boron steel. Based on the TDS analysis of hydrogen absorbed from hot stamping, the activation energy value of hydrogen trapping in 1.8 GPa grade steel is lower than that of 1.5 GPa grade steel. This means that diffusible hydrogen can be more easily diffused into defective sites of the microstructure at a higher level of the tensile strength grade. Second, in sequential pre-treatment lines of the automotive manufacturing process, additional hydrogen did not flow into the surface, and an electro-deposition process, including a baking procedure, was effective in removing diffusible hydrogen, which was similar to the residual hydrogen of the as-received state (i.e., initial cold rolled blank). Based on these results, the hydrogen absorption was facilitated during hot press forming, but the hydrogen was sequentially desorbed during automotive sequential lines on aluminum-coated hot-stamped steel parts.

NPM1 Mutations Do Not Retain a Favorable Prognostic Impact in Adults with Advanced Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)

NPM1 Mutations Do Not Retain a Favorable Prognostic Impact in Adults with Advanced Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)

Sequential Line Searchを利用した振動触覚イコライザシステム

Sequential Line Searchを利用した振動触覚イコライザシステム

Clinical case of the use of oral metronomic vinorelbin in patient with metastatic Her2 negative breast cancer

Endocrine therapy in combination with inhibitors of cyclin-dependent kinases 4/6 in first lines is the current standard of treatment of metastatic ER positive Her2 negative breast cancer. After progression on several lines of endocrine therapy according to current principles we apply sequential lines of monochemotherapy. If possible non-toxic agents are prefered in order to maintain high quality of life. The special role in this context may play oral agents, when regular visits in clinic and intravenous injection are not needed. The efficacy of oral vinorelbine is well explored, unfortunately the standard dosage regimen сan have quite high especially hematologic toxicity. The metronomic dosing regimen is believed to be as effective as the standard, but is less toxic. In addition, the anti-angiogenic properties of the metronomic mode are described. Taking into account the increasing use of combination of endocrine therapy with CDK4/6 inhibitors in first treatment lines, it is extremely important to study the efficacy and tolerability of various regimens and drugs after progression on combined endocrine therapy. In this article, we represent a clinical case of the use of oral vinorelbine in the metronomic mode in the patient after progression on combination of fulvestrant and palbociclib. Long-term disease control with satisfactory quality of life has been demonstrated.

Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition.

Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance. We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA). Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the AR gene, with an average 50% increase in AR copy number, changes in AR mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements. Our data show that the dominant AR genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.

PCN231 Humanistic and Economic Burden in Patients with Chronic Myeloid Leukemia – A Review of the Literature

Introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML) but an unmet need still exists in patients receiving later lines of therapy. A review was conducted to understand the published evidence on the humanistic and economic burden associated with CML. Literature search of English publications from the last 20 years (2001-2020) was performed in Embase® and Medline® databases. Studies reporting health related quality of life (HRQoL), symptom burden and costs associated with CML patients were included. Twenty-one studies reported humanistic burden, ten studies reported economic burden and two studies reported both humanistic together with economic burden. SF-36 and EORTC QLQ-C30 were the two most commonly used instruments assessing Quality of life (QoL). Physical function was one of the most severely impacted domain with females presenting with worse HRQoL profile than males. Fatigue, musculoskeletal pain, and disturbed sleep were the most frequently reported symptoms. Primary drivers of increased cost burden associated with treatment failure in later lines of therapies were medical services such as inpatient, emergency room, ambulatory and laboratory tests. In USA, average 1 year cost post TKI failure (adjusted to 2012 USD) for patients who failed first-line treatment was $78,677, which increased to $99,624 for patients who failed second-line treatment and was highest for patients failing third-line therapy ($181,029). Patients in later line of TKI therapies had significantly higher resource utilizations. CML patients had significantly impaired HRQoL across all lines of therapies accompanied by increased symptom burden. Economic burden post-TKI failure increases with each sequential line of therapy. Results from the literature suggest the need for treatments that address long-term outcomes including reduced treatment resistance and improved Qol. This will further reduce the economic burden associated with the treatment of CML in later lines of therapy.

A Simulation Model of Construction Projects Executed in Random Conditions with the Overlapping Construction Works

Reducing the duration of construction works requires additional organizational measures, such as selecting construction methods that assure a shorter realization time, engaging additional resources, working overtime, or allowing construction works to be performed simultaneously in the same working units. The simultaneous work of crews may affect the quality of works and the efficiency of construction processes. This article presents a simulation model aimed at assessing the impact of the overlap period on the extension of the working time of the crews and the reduction of a repetitive project’s duration in random conditions. The purpose of simulation studies is to provide construction managers with guidelines when deciding on the dates of starting the sequential technological process lines realized by specialized working crews, for sustainable scheduling and organization of construction projects.

POS1034 RESPONSE TO SEQUENTIAL LINES OF BIOLOGICAL THERAPY IN PSORIATIC ARTHRITIS: A SINGLE CENTRE COHORT STUDY

Background:Biologic interventions using highly specific immuno-modulatory biologic disease-modifying anti-rheumatic drugs (bDMARDs) represent a rapidly developing therapeutic approach to the treatment of Psoriatic Arthritis (PsA). However, despite high rates of response, adverse events, primary and secondary inefficacy are common, and multiple sequential lines of bDMARDs are often required. Data on drug persistence, as a surrogate for response, from national registries indicates switching has become accepted routine practice. One third of patients will fail or discontinue their first biologic with a significant proportion switching on to a 3rd biologic or higher.1-4 Due to a lack of evidence on the response to sequential therapies, individual patients may not have further lines routinely funded after three bDMARDs in the UK. While limiting lines of therapy remains a UK concern, many countries with rationed healthcare systems follow the UK model of drug usage.Objectives:To describe the response to sequential lines of bDMARD therapy prescribed in routine care in a UK single centre cohort.Methods:A retrospective sample of patients with PsA who fulfilled CASPAR criteria and had received at least one bDMARD were taken from the Bath longitudinal cohort for inclusion in the study. Clinical and laboratory variables that constitute physician and patient-reported outcome measures were collected at baseline and after a median (range) follow-up of 3 months (2-5) into their respective therapy line in accordance with the National Institute for Health and Care Excellence (NICE) rules. The mean change with a 95% confidence interval (CI) was used to report the difference between the baseline and follow-up measures. All patients provided consent to use their data collected during routine care, and ethical approval by the local committee was granted.Results:The patients mean age was 57.7 (SD 12.2) with a median (range) disease duration of 14.4 years (9.7 – 23.2). Data was available for 194 patients commencing 1st line bDMARD, 106 (2nd line), 93 (3rd line), 33 (4th line), 12 (5th line), and 9 (6th line and higher) from a total of 759 patients in the cohort. Mean tender and swollen joint count at baseline 1st bDMARD was 7 (SD 4.7) and 22 (SD 14.0), pain visual analogue scale 50 (SD 27.6) and PASI 1.3 (SD 2.2). Reasons for changing biological therapies include lack or loss of efficacy, intolerance, side effects, and comorbidities. Mean levels of joint disease at drug initiation did not diminish with subsequent lines of therapy. Clinical and patient reported outcomes by line of therapy are reported in Figure 1. Clinical responses were greatest to first line bDMARD, however clinically relevant DAPSA improvements were seen up to 5th line. Absolute levels of psoriasis in the cohort were low, however improvement in PASI was achieved across all lines of therapy. Patient and Physician Global Assessments (1-5 on Likert scale) and the Pain Visual analogue score (VAS on 1-10 Likert scale) showed a similar trend with greatest improvement to first line treatment across all lines of therapy.Conclusion:In this study we report the clinical response to sequential lines of bDMARD therapy for active PsA in routine clinical practice. Clinical response was greatest to the first line bDMARD but overall improvement in DAPSA, PASI or pain response did not appear to diminish up to 5th line. Further study in larger cohorts is required to confirm this finding and build on our understanding of clinical response to sequential lines of bDMARD therapy.

VEdge_Detector: automated coastal vegetation edge detection using a convolutional neural network

ABSTRACT Coastal communities, land covers, and intertidal habitats are vulnerable receptors of erosion, flooding or both in combination. This vulnerability is likely to increase with sea level rise and greater storminess over future decadal-scale time periods. The accurate, rapid, and wide-scale determination of shoreline position, and its migration, is therefore imperative for future coastal risk adaptation and management. This paper develops and applies an automated tool, VEdge_Detector, to extract the coastal vegetation line from high spatial resolution (Planet’s 3 to 5 m) remote-sensing imagery, training a very deep convolutional neural network (holistically nested edge detection), to predict sequential vegetation line locations on annual to decadal timescales. Red, green, and near-infrared (RG-NIR) was found to be the optimum image spectral band combination during neural network training and validation. The VEdge_Detector outputs were compared with vegetation lines derived from ground-referenced positional measurements and manually digitized aerial photographs, which were used to ascertain a mean distance error of <6 m (two image pixels) and >84% producer accuracy (P A) at six out of the seven sites. Extracting vegetation lines from Planet imagery of the rapidly retreating cliffed coastline at Covehithe, Suffolk, United Kingdom, has identified a landward retreat rate >3 m year−1 (2010–2020). Plausible vegetation lines were successfully retrieved from images in The Netherlands and Australia, which were not used to train the neural network, although significant areas of exposed rocky coastline proved to be less well recovered by VEdge_Detector. The method therefore promises the possibility of generalizing to estimate retreat of sandy coastlines from Planet imagery in otherwise data-poor areas, which lack ground-referenced measurements. Vegetation line outputs derived from VEdge_Detector are produced rapidly and efficiently compared to more traditional non-automated methods. These outputs also have the potential to inform upon a range of future coastal risk management decisions, incorporating future shoreline change.

Anakinra for patients with COVID-19: a meta-analysis of non-randomized cohort studies.

IntroductionSevere COVID-19 cases have a detrimental hyper-inflammatory host response and different cytokine-blocking biologic agents were explored to improve outcomes. Anakinra blocks the activity of both IL-1α and IL‑1β and is approved for different autoinflammatory disorders, but it is used off-label for conditions characterized by an excess of cytokine production. Several studies on anakinra in COVID-19 patients reported positive effects. We performed a meta-analysis of all published evidence on the use of anakinra in COVID19 to investigate its effect on survival and need for mechanical ventilation. MethodsWe searched for any study performed on adult patients with acute hypoxemic failure related to 2019-nCoV infection, receiving anakinra versus any comparator. Primary endpoint was mortality at the longest available follow-up. Adverse effects, need for mechanical ventilation and discharge at home with no limitations were also analysed. ResultsFour observational studies involving 184 patients were included. Overall mortality of patients treated with anakinra was significantly lower than mortality in the control group (95% CI 0.14-0.48, p<0.0001). Moreover, patients treated with anakinra had a significantly lower risk of need for mechanical ventilation than controls (95% CI 0.250.74, p=0.002). No difference in adverse events and discharge at home with no limitations was observed. The Trial Sequential Analysis z-cumulative line reached the monitoring boundary for benefit and the required sample size. ConclusionsAdministration of anakinra in COVID-19 patients was safe and might be associated with reductions in both mortality and need for mechanical ventilation. Randomized clinical trials are warranted to confirm these findings.