Combined Scheduling Research Articles

Neurofilaments As Serum Biomarkers of Brentuximabvedotin-Induced Peripheral Neurotoxicity in CD30 + Lymphoma Patients: A Prospective Single-Center Study

Introduction: Brentuximab vedotin (Bv) is increasingly being used for the treatment of CD30+ lymphomas, being Bv-induced peripheral neurotoxicity (BvPN) one of the greatest concerns for treating physicians. The mechanisms of BvPN are still partially known, and currently, no biomarker to predict this side effect and its severity is available. Neurofilament (NfL) is a neuron specific protein; high levels can be detected in peripheral blood with ongoing neuronal damage. It can be useful to quantify the extend of chemotherapy induced peripheral neurotoxicity due to axonal injury but its role in early detecting and predicting severity of BvPN is unknown. The objective of this study is to determine the association between pNfL and BvPN in lymphoma patients receiving Bv. Methods: This is anobservational prospective study that includes patients treated with Bv as a single drug (n=12, 30%) or in combination with other chemotherapy agents (n=28, 70%), being neurotoxic chemotherapy drugs in 15 out of 28 (53,5%). Patients were recruited from January 2021 to June 2023. All patients were assessed using the Total Neuropathy Score (TNS), which measures the severity of peripheral nerve damage (higher values equals worse neuropathy) and the Common Toxicity Criteria for Adverse Events toxicity scale at the following timepoints: before, periodically (every 1-2 cycles), and at three, six and twelve months after the end of Bv-based treatment. Nerve conduction studies (NCS) in upper and lower limbs before and after Bv-based treatment were performed. Serial pNfL were collected at the same timepoints and quantified using the SIMOA technique. Changes in pNfL were correlated with clinical data, depending on the degree of BvPN. Results: Fortypatients are included in the present analysis, with a predominance of males (n=22, 55%) and a median age of 47.5 [21-81] years. The majority of patients had Hodgkin lymphoma (HL, n=25, 62.5%), followed by mycosis fungoides (n=8, 20%) and peripheral T-cell lymphoma (n=7, 17.5%). Of the whole series, 85% of patients developed some degree of BvPN (55% grade 1, 30% grade 2). Baseline pNfL level was normal [15.09 ± 11.90 pg/mL] in most of the patients (n=35, 87.5%). and, as expected, they were correlated with age (r= 0.482, p=0.002) and the amplitude of the left (r= -0.408, p=0.048) and right (r= -0.380, p=0.061) sural (sensory) nerves. pNfL levels early increased with Bv-based therapy and rapidly decreased within the follow-up period (Figure). When completing half of the planned Bv-based therapy, the total increase in pNfL was significantly higher in those receiving combination schedules including other neurotoxic agents (40.07 vs 21.81 pg/mL, p<0.001), without differences according to BvPN development (p=0.7). At the end of treatment, no differences in pNfL were observed with regards to BVPN severity: No BVPN: 52.71±39.77 pg/mL; grade 1: 61.22 ±21.36 pg/mL, and grade 2: 55.46 ± 45.80 pg/mL. In all patients, TNS scores increased during treatment and decreased within the follow-up period (see Figure). Conclusion: NfL is a sensitive blood biomarker that dynamically responds to Bv-based therapy. Our results suggest that additional mechanisms beyond the axonal damage may be associated with BvPN. The present study provides new insights into the pathophysiology of BvPN.

1735. Impact of Children Universal Pneumococcal Vaccination (PCV7v/PCV13v) on Pneumococcal Invasive Disease Hospitalizations in a Private General Hospital, Uruguay

Abstract Background In 2008 Uruguay included pneumococcal conjugate vaccine (PCV) 7valent in children´s vaccination program (2+1). In 2010 PCV13 replaced PCV7. Since 2015, adults at risk of invasive pneumococcal disease (IPD) may receive 23 valent polysaccharide vaccine (PV23) or combined schedule PCV13+PV23. Objective: to assess the impact of this strategy on IPD hospitalization. Methods Rates per 10,000 discharges (Confidence Interval 95 %), diseases and serotypes (ST) are described before PCV7 vaccination (2006-2007), the year of vaccine implementation (2008), early after implementation (2009-2015) and late after implementation (2016-2022), the last 3 years during COVID-19 pandemic. Results In 2006-2022 were 33 IPD cases in children and 88 in adults over 15 years old. Children´s hospitalization median annual rates were as follow 2006-2007: 50 (25-75); 2008: 18,5 (-2-39); 2009-2015: 8,5 (3-14); 2016-2022: 4 (0-8); percentages of rate reduction were 82,5% and 92% (p< 0.0000). In adults 2006-2007: 17 (10-25); 2008: 13,4 (4,62-22,1); 2009-2015: 6,6 (4,4-9); 2016-2022: 6 (3,5-8,5); percentages of rate reduction were 63,5% and 66 % (p= 0,0001). Pneumococcal pneumonia (PP) was the most frequent disease in children 22/33 (66,6%), followed by bacteremia 8/32. PP was also in adults 68/88 (77.2,7%), followed by meningitis (7/88). One non vaccinated child died in 2008. Case fatality rate in adults was 9% (8/88), 3 died in 2006-2007, 2 in 2009-20215 and 3 in 2016-2022. 24 different ST were isolated in adults. Most frequent ST were 12F(15), 7F(11), 1(8), 8(7), 3(6) and 5(6). PCV13 would cover 38/88 (43%). A significant decline in PCV13 serotypes (PCV13-ST) was observed comparing the period prior PCV 17/22 (77%) with the late period 8/24 (34%) (p< 0.0000). 15 different ST were isolated in children: 26 PCV13-ST. 16 prior 2008: most frequent ST 1(5), 14(4), 3(2) and 5(2). In 2009-2022 13 hospitalizations; PCV13-ST: 1(2), 19A(2), 14(1), 6B< (1), 9V(1), 3(1) and non PCV13-ST: 7B/C(1), 24F(1), 13(1), 15A(1), 15B(1). A significant decline of PCV13-ST was observed comparing the period prior PCV (15/16, 94%) with the late period (2/4, 50 %) (p< 0.0000). Conclusion There was a reduction in children’s discharge rates and in adults´ probably due to herd effect. Adult vaccination will improve individual immunization. Disclosures María Catalina Pírez, Pediatrician, Pediatric infectologist, microbiologist Professor of pediatric, Degree V, Merck, Pfizer: Expert Testimony|Merck, Pfizer: Honoraria

Measuring route diversity in spatial and spatial-temporal public transport networks

Route diversity is a pivotal metric for evaluating the redundancy of transportation networks, a fundamental aspect of system resilience. This study provides a comprehensive exploration of route diversity in multimodal public transport systems, specifically considering the unique characteristics of bus networks. Our research introduces a two-pronged approach to measuring route diversity within spatial public transport networks, delving into service-based and infrastructure-based perspectives. The former assesses redundancy against transit service disruptions by factoring in transit line overlaps, while the latter evaluates redundancy against infrastructure-related interruptions by considering overlapping road segments on which transit lines rely. In addition, the study advances by modelling public transport systems as multilayer spatial-temporal networks, integrating time-variable service frequency and travel time uncertainty, which enables us to derive route diversity for origin-destination (O-D) pairs across different time periods.We present a case study of the multimodal public transport network in Jiading District, Shanghai, revealing a power-law distribution of the route diversity. The results unveil O-D pairs with lower route diversity, underscoring their lack of resilience against various disturbances. Lower service-based route diversity suggests the necessity of enhancing service frequency and bolstering cross-line combined transit scheduling, while lower infrastructure-based route diversity could warrant the design of road-diversified transit lines, especially within bus corridors. Besides, relative route diversity between the two indices highlights specific O-D pairs with notable disparities in service and infrastructure redundancy. This difference is correlated with the distance between O-D pairs and the road network's configuration. This analysis underscores the method's potential to offer more relevant insights to public transport planners and operators for adjusting transit lines and schedules through a resilience-focused lens.

A Phase I/II Single Arm Study of Belantamab Mafodotin, Carfilzomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: Planned Interim Analysis of Safety and Efficacy. Amarc 19-02 Belacard Study

Introduction Belantamab Mafodotin (Belamaf, B), a first in class anti-B-cell maturation antigen (BCMA) antibody-drug conjugate, is efficacious in triple-class exposed, relapsed and refractory multiple myeloma (RRMM). Combination therapy with carfilzomib and dexamethasone (Kd) is potentially synergistic through different anti-myeloma mechanisms of action. We report here a planned interim analysis of safety and responses after the first two cycles of combination therapy. Methods BelaCarD is an ongoing, single-arm, multicentre phase I/II study evaluating 8-weekly B dosing schedule in combination with Kd in patients (pts) with RRMM after 1-3 lines of therapy. B (2.5mg/kg) was administered intravenously (IV) on day (D)1 of every second 28D cycle; K 70mg/m2 IV D1 (20mg/m2 on C1D1), D8 and D15 of every cycle and dexamethasone 40mg weekly (20mg/m2 for pts >75 years). Treatment was continued until disease progression. Corneal adverse events (AEs) were graded as per the keratopathy and visual acuity (KVA) scale and all other AEs as per CTCAEv5. Confidence interval coefficients for response rates (RR) were adjusted using an alpha-spending function. The primary objective is progression free survival (PFS). Results As of 13 th July 2023, 65 pts (67% male) of the intended 70 have been enrolled. 55 pts (62% male) received minimum 2 cycles of B-Kd and were included in the protocol-specified interim analysis. The median age was 69.7 years (48-81); 18 pts (33%) had high-risk cytogenetics either at diagnosis or screening. ISS stage I, II, III occurred in 47.3%, 23.6% and 10% respectively. 25.5%, 38.2% and 34.6% pts had 1, 2 and 3 prior lines of therapy respectively including (exposed/refractory) bortezomib (90.9%/42%), K (3.6%/50%), lenalidomide (52.7%/44.8%), pomalidomide (5.5%/33%), anti-CD38 monoclonal Ab (mAb) (30.9%/52.9%), autologous stem cell transplant (ASCT) (41.8%). The median number of cycles received was 9 (2-27). Treatment-related AEs were reported in 93% of pts (Gr3 60%, Gr4 13%); most frequent were (all grade, Gr3, Gr4): blurred vision (40%, 7.3%, 0%), nausea/vomiting (29.1%, 3.6%, 0%), insomnia (23.6%, 10.9%, 0%), thrombocytopenia (23.6%, 10.9%, 5.5%). Ocular AEs occurred in 42 (79.2%) out of 53 evaluable pts including decline in best corrected visual acuity (BCVA) (total 77.2%, Gr1 9.4%, Gr2 33.9%, Gr3 33.9%) and keratopathy (K) (total 75.4%, Gr1 5.6%, Gr2 22.6%, Gr3 47.2%). Median time to reach worst-grade BCVA and K was 106 (25-309) and 76.5 (25-231) days respectively. Median time to return to Gr ≤1 BCVA and K was 61 (28-322) and 94 (30-326) days respectively. Ten pts had B-related SAEs (Gr 1/2 n=2, Gr 3 n=6, Gr 4 n=1, one pt died of sepsis). A second treatment-related death was due to pneumonia. Six pts discontinued therapy due to treatment-related AE including 4 due to B (corneal toxicity n=2, sepsis n=1, proteinuria n=1). Overall RR and ≥ VGPR by end of cycle 2 were 80% (97%CI: 65.3 - 90.5) and 40% (97%CI: 25.5 - 55.9) respectively. At estimated median potential follow-up of 13 months (4-38), the preliminary estimate of PFS at 24m was 56.1%. Conclusion B-Kd with an extended B schedule demonstrates a manageable safety profile. The preliminary efficacy data is encouraging with deep responses observed after only 2 cycles of therapy. Recruitment is close to completion with the main analysis to be conducted once all pts have completed the 12-month assessment. Acknowledgement: pts, their families and participating AMaRC members and sites as well as the support of GSK and funding support from the Victorian Cancer Agency.

Trial in Progress: A Phase 1b Single-Arm, Open-Label Study of Emavusertib (CA-4948) in Combination with Azacitidine and Venetoclax in Acute Myeloid Leukemia Patients in Complete Response with Measurable Residual Disease

Background Emavusertib is a novel potent oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Inhibition of these onco-proteins may induce remission thereby addressing a critical unmet need for novel therapies in acute myeloid leukemia (AML). Clinical studies with emavusertib monotherapy have demonstrated a significant reduction in AML blasts with clinical and molecular responses, including patients with relapsed or refractory AML, previously treated with an HMA and/or FLT3 inhibitors (Metzeler 2022). Azacitidine + venetoclax (aza+ven) has been approved in newly diagnosed, unfit patients with AML. In the VIALE-A study, composite complete response (CRc) (CR, CRh, or CRi) in the absence of measurable residual disease (MRD) of <1 residual blast/1000 leukocytes (MRD negative [MRD−]) resulted in longer duration of response (DOR), event-free survival, and overall survival (OS), and better HSCT outcome compared with patients who achieved CRc but were MRD+ (Pratz, 2022). In pre-clinical studies, emavusertib in combination with aza+ven demonstrated synergistic antileukemic effects in AML cell lines, including azacitidine- or venetoclax-resistant cell lines. Adding emavusertib to aza+ven in MRD+ patients at the time of CR may convert MRD status without adding significant toxicity and confirm that emavusertib can be safely added to aza+ven as a potential new regimen in front-line therapy. Study Design: This is a single-arm, open-label Phase 1b trial evaluating safety and tolerability, PK, and conversion of MRD status with emavusertib as an add-on agent to aza+ven in AML patients who achieved CR or CRh with MRD+ based on local testing (EU CT Number 2023-505828-58-00). The primary objective of the study is to determine a safe and tolerable dosing schedule for the triple combination. Secondary objectives include MRD conversion rate, DOR, OS, and pharmacokinetics. The study will enroll approximately 24 patients at 5 to 10 sites globally. Patients will have received azacitidine and venetoclax as first line therapy and achieved CR or CRh after 1-6 cycles of aza/ven. If MRD status remains positive, emavusertib will be added to the existing well tolerated aza+ven regimen. The starting emavusertib dose is 200 mg BID for 7 days per cycle of 28 days. If well tolerated, duration of emavusertib treatment will be extended to 14 and 21, respectively; no intra-patient change of emavusertib dosing duration is planned. The patients will continue triple treatment (emavusertib+aza+ven) until consent withdrawal, disease progression, intolerable toxicity, or not achieving MRD- within 6 cycles of triple treatment. In this Phase 1b trial, MRD can be evaluated by local testing of bone marrow. Key exclusion criteria include residual toxicities and significant comorbidities.

Intelligent Resource Allocation Using an Artificial Ecosystem Optimizer with Deep Learning on UAV Networks

An Unmanned Aerial Vehicle (UAV)-based cellular network over a millimeter wave (mmWave) frequency band addresses the necessities of flexible coverage and high data rate in the next-generation network. But, the use of a wide range of antennas and higher propagation loss in mmWave networks results in high power utilization and UAVs are limited by low-capacity onboard batteries. To cut down the energy cost of UAV-aided mmWave networks, Energy Harvesting (EH) is a promising solution. But, it is a challenge to sustain strong connectivity in UAV-based terrestrial cellular networks due to the random nature of renewable energy. With this motivation, this article introduces an intelligent resource allocation using an artificial ecosystem optimizer with a deep learning (IRA-AEODL) technique on UAV networks. The presented IRA-AEODL technique aims to effectually allot the resources in wireless UAV networks. In this case, the IRA-AEODL technique focuses on the maximization of system utility over all users, combined user association, energy scheduling, and trajectory design. To optimally allocate the UAV policies, the stacked sparse autoencoder (SSAE) model is used in the UAV networks. For the hyperparameter tuning process, the AEO algorithm is used for enhancing the performance of the SSAE model. The experimental results of the IRA-AEODL technique are examined under different aspects and the outcomes stated the improved performance of the IRA-AEODL approach over recent state of art approaches.

Combined Optimization of Maintenance Works and Crews in Railway Networks

This study develops optimal maintenance schedules for train lines, a critical endeavor ensuring the safety, efficiency, and reliability of railway networks. The study addresses the combined scheduling problem of maintenance works and crews on the railway networks. The baseline scheduling model is initially established with the primary objective of allocating maintenance tasks efficiently while adhering to pertinent constraints, encompassing task grouping and cost minimization. Subsequently, this baseline model is enhanced through the integration of crew scheduling, wherein work crews are strategically assigned to execute predefined tasks, thereby facilitating effective workload distribution. The combined maintenance work and crew scheduling problem is mathematically formulated as a binary linear programming model, enabling the attainment of globally optimal solutions. Comparing the outcomes of our enhanced model, which incorporates both maintenance works and crew schedules, with the baseline model that solely addresses maintenance works, we reveal that task grouping in accordance with predefined conditions leads to reduced overall costs by minimizing maintenance duration during various periods. Additionally, the judicious distribution of workload among the crews ensures comprehensive coverage of all essential tasks. These findings underscore the significance of our proposed approach in enhancing the operational efficacy and economic viability of railway maintenance scheduling, thereby offering valuable insights for practical implementation and future research endeavors.

Massive Multi-Source Joint Outbound and Benefit Distribution Model Based on Cooperative Game

In light of the challenges posed by the widespread distribution of new energy sources in China and their distance from load centers, the power system must effectively integrate both new energy and thermal power transmission. To address this issue, we propose a dynamic coordinated scheduling model that combines wind, photovoltaic, and thermal power to optimize the profit of the energy complementary delivery system. Additionally, we present an improved ant lion optimization algorithm to investigate the coordinated scheduling and benefit distribution of these three power sources. This paper introduces a cooperative mode for benefit distribution and utilizes an enhanced Shapley value method to allocate the benefits of joint operation among the three parties. The distribution of benefits is based on the contribution of each party to the joint proceeds, considering the profit levels of joint outbound and independent outbound modes. Through our analysis, we demonstrate that the upgraded ant lion optimization algorithm facilitates finding the global optimal solution more effectively within the feasible zone. Furthermore, our suggested three-party combined scheduling model and profit-sharing approach are shown to be superior and feasible.

Alternative Best Effort (ABE) for Service Differentiation: Trading Loss Versus Delay

The idea of an Alternative Best Effort (ABE) per-hop behaviour (PHB) emerged about 20 years ago. It provides a low-delay traffic class in the Internet at the expense of more packet loss than Best Effort (BE). Therefore, ABE is better suited than BE for loss-tolerant but delay-sensitive applications. Furthermore, ABE traffic should not degrade the service for BE traffic in terms of packet loss and delay. Therefore, Internet service providers may leave the choice of using BE or ABE to their customers as they achieve service differentiation without compromising other traffic. In this work, we revisit ABE and pursue the fundamental question whether an ABE service is technically feasible, how its service would look like and interact with existing transport protocols? We present a novel scheduler called Deadlines, Saved Credits, and Decay (DSCD) for combined scheduling of BE and ABE traffic. It allows to control ABE’s delay advantage over BE and copes with varying bandwidth. We provide an implementation of DSCD in the Linux network stack and demonstrate its efficiency. A side product of the implementation is an efficient approximation of the exponential function in the kernel and a bandwidth estimation method that even works at moderate link utilization. We study DSCD in a semi-virtualized testbed with real networking stacks to understand implications for transport protocols in a BE/ABE Internet. The study analyzes ABE’s impact on loss and delay under various conditions and gives recommendations for configuration.

Unit Combination Scheduling Method Considering System Frequency Dynamic Constraints under High Wind Power Share

Power systems with a high wind power share are characterized by low rotational inertia and weak frequency regulation, which can easily lead to frequency safety problems. Providing virtual inertia for large-scale wind turbines to participate in frequency regulation is a solution, but virtual inertia is related to wind power output prediction. Due to wind power prediction errors, the system inertia is reduced and there is even a risk of instability. In this regard, this article proposes a unit commitment model that takes into account the constraints of sharp changes in frequency caused by wind power prediction errors. First, the expressions of the equivalent inertia, adjustment coefficient, and other frequency influence parameters of the frequency aggregation model for a high proportion wind power system are derived, revealing the mechanism of the influence of wind power prediction power and synchronous machine start stop status on the frequency modulation characteristics of the system. Second, the time domain expression of the system frequency after the disturbance is calculated by the segment linearization method, and the linear expressions of “frequency drop speed and frequency nadir” constraints are derived to meet the demand of frequency regulation in each stage of the system. Finally, a two-stage robust optimization model based on a wind power fuzzy set is constructed by combining the effects of wind power errors on power fluctuation and frequency regulation capability. The proposed model is solved through affine decision rules to reduce its complexity. The simulation results show that the proposed model and method can effectively improve the frequency response characteristics and increase the operational reliability of high-share wind power systems.

Similar additive effects of doxorubicin in combination with photon or proton irradiation in soft tissue sarcoma models.

High-precision radiotherapy with proton beams is frequently used in the management of aggressive soft tissue sarcoma (STS) and is often combined with doxorubicin (Dox), the first-line chemotherapy for STS. However, current treatment approaches continue to result in high local recurrence rates often occurring within the treatment field. This strongly indicates the need of optimized treatment protocols taking the vast heterogeneity of STS into account, thereby fostering personalized treatment approaches. Here, we used preclinical STS models to investigate the radiation response following photon (X) or proton (H) irradiation alone and in combination with different treatment schedules of Dox. As preclinical models, fibrosarcoma (HT-1080), undifferentiated pleiomorphic sarcoma (GCT), and embryonal rhabdomyosarcoma (RD) cell lines were used; the latter two are mutated for TP53. The cellular response regarding clonogenic survival, apoptosis, cell-cycle distribution, proliferation, viability, morphology, and motility was investigated. The different STS cell types revealed a dose-dependent radiation response with reduced survival, proliferation, viability, and motility whereas G2/M phase arrest as well as apoptosis were induced. RD cells showed the most radiosensitive phenotype; the linear quadratic model fit could not be applied. In combined treatment schedules, Dox showed the highest efficiency when applied after or before and after radiation; Dox treatment only before radiation was less efficient. GCT cells were the most chemoresistant cell line in this study most probably due to their TP53 mutation status. Interestingly, similar additive effects could be observed for X or H irradiation in combination with Dox treatment. However, the additive effects were determined more frequently for X than for H irradiation. Thus, further investigations are needed to specify alternative drug therapies that display superior efficacy when combined with H therapy.

Chemoradiotherapy Combined with Brachytherapy for the Definitive Treatment of Esophageal Carcinoma.

This study aims to investigate the effect of dose escalation with brachytherapy (BT) as an addition to definitive chemoradiotherapy (CRT) on local control and survival in esophageal cancer. From 2001 to 2020, 183 patients with locally limited or locally advanced esophageal cancer received definitive CRT with or without brachytherapy in a two-center study. External-beam radiotherapy was delivered at 50.4 Gy in 1.8 Gy daily fractions, followed by a sequential boost to the primary tumor of 9 Gy in 1.8 Gy daily fractions if indicated. Intraluminal high dose rate (HDR) Ir-192 brachytherapy was performed on 71 patients at 10 Gy in two fractions, with one fraction per week. The combined systemic therapy schedules used included 5-fluorouracil/cisplatin or 5-fluorouracil alone. Cisplatin was not administered in patients receiving brachytherapy. The median local progression-free survival was significantly extended in the BT group (18.7 vs. 6.0 months; p < 0.0001), and the median local control was also significantly prolonged (30.5 vs. 11.3 months, p = 0.008). Overall survival (OS) significantly increased in the BT group (median OS 22.7 vs. 9.1 months, p < 0.0001). No significant difference in the overall rate of acute toxicities was observed; however, the rate of acute esophagitis was significantly higher in the BT group (94.4% vs. 81.2%). Likewise, the overall rate of late toxicities (43.7% vs. 18.8%) was significantly higher in the BT group, including the rate of esophageal stenosis (22.5% vs. 9.8%). There was no difference in the occurrence of life-threatening or lethal late toxicities (grades 4 and 5). Brachytherapy, after chemoradiation with single-agent 5-FU, represents a safe and effective alternative for dose escalation in the definitive treatment of esophageal cancer.

Exploring the optimal therapeutic management of stage ypIA pancreatic ductal adenocarcinoma patients in the era of primary chemotherapy

BackgroundData on the proper post-surgical chemotherapy (PSC) in pancreatic ductal adenocarcinoma (PDAC) patients already treated with neoadjuvant therapy (NAT) are lacking, especially for stage ypIA. Aim and MethodsWe retrospectively analyzed ypT1N0M0 (ypIA) PDAC patients resected after NAT between 2015 and 2020 at our Institution. Primary endpoint was median disease free-survival (DFS) according to PSC treatment. ResultsSeventy-five out of 363 patients achieved a pathological ypIA after NAT (20.6%) and 72 were analyzed. Among the study population 34 patients (47%) were treated with NAT ≤4 months and 38 (53%) >4 months. After surgery, 10 patients (14%) received PSC using the same multidrug NAT regimen (Group A); 35 (49%) received PSC with a different regimen (Group B), with either single agents in 24 patients (68.5%) or combination schedules in 11 (31.5%); 27 patients (14%) did not receive any PSC (Group C). DFS was longer in group A and C as opposed to group B (p = 0.006). ConclusionPatients affected by ypIA PDAC treated with a proper multi-agent chemotherapy for more than 4 months show an improved DFS, regardless of the peri‑operative or totally pre-surgical administration of treatment.

Nivolumab plus ipilimumab in metastatic melanoma: a critical appraisal focused on specific subpopulations.

The development of immune checkpoint inhibitors has revolutionized the landscape of treatment of advanced melanoma in recent years. Based on the efficacy results of the phase III CheckMate 067 trial, nivolumab in combination with ipilimumab is one of the first-line standard options for advanced melanoma along with pembrolizumab, nivolumab, and, recently, nivolumab plus relatlimab. Counterbalancing its efficacy, nivolumab plus ipilimumab is associated with severe immune-related toxicity. This article will review the efficacy and safety of the nivolumab plus ipilimumab combination in advanced melanoma across phase I, II, and III clinical trials that evaluated this approach. We also explore the benefit of the combination schedule across different subgroups of patients and possible predictive biomarkers for efficacy outcomes in order to elucidate which patients could be the best candidates for combination or single-agent therapy. Patients with BRAF-mutant tumours, asymptomatic brain metastases, or PD-L1-negative status appear to reach better survival outcomes with the combination relative to single-agent immunotherapy.

Phase 1/1b study of SY-5609, a selective and potent CDK7 inhibitor, in advanced solid tumors and in 2L/3L pancreatic ductal adenocarcinoma (PDAC) in combination with gemcitabine +/- nab-paclitaxel.

3080 Background: SY-5609 is an oral, highly selective and potent noncovalent inhibitor of CDK7, a key regulator of cell cycle progression and transcription. In this Phase 1 FIH study (NCT04247126), the single agent (SA) continuous daily dosing (CDD) regimen maximum tolerated dose (MTD) was 3 mg/day. Subsequently, enhanced tolerability was demonstrated using an intermittent 7 day on/7 day off (7/7) schedule at higher dose levels (Sharma 2021). SY-5609 preclinical data and early clinical activity provided the rationale for evaluating SY-5609 + gemcitabine (gem) +/- nab-paclitaxel (np) in PDAC. Herein, we present data from the ongoing SA dose escalation and SY-5609 + gem +/- nab-paclitaxel (np) safety lead-ins (SLIs). Methods: The 7/7 schedule was used to further evaluate SA escalation in pts with select solid tumors. In the PDAC combination SLIs, SY-5609, starting with a dose of 4 mg, is escalated using the 7/7 schedule in combination with biweekly gem (1000 mg/m2) +/- np (125 mg/m2). Evaluations included safety, clinical activity (RECIST v1.1), PK, and induction of peripheral blood PD marker POLR2A (Papadopoulos 2020). Results: As of 13 Jan 2023, 87 pts have been enrolled (70 SA, 14 SY-5609 + gem, 3 SY-5609 + gem/np), including 30 pts across the 4, 5, 6, 7, and 10 mg SA 7/7 cohorts included in the safety summary. MTD for the 7/7 schedule has not been reached. The 15 mg SA cohort is now enrolling. Most SA 7/7 AEs were low-grade; AEs included (&gt;20%) nausea, diarrhea, fatigue, anorexia, and thrombocytopenia. No new safety signals were observed in the SY-5609 4 mg and 5 mg + gem and SY-5609 4 mg + gem/np cohorts; 1 pt (SY-5609 5 mg + gem) had a DLT of Gr3 diarrhea. The 10 mg + gem cohort is now enrolling. Most SY-5609 + gem +/- np AEs were low grade. AEs in the SLIs were consistent with the safety profile of either SY-5609 or gem +/- np and included (&gt;20%) fatigue, anorexia, nausea, abdominal pain, and constipation. In the SA cohorts (response-evaluable, n=29), 100% (3/3) of pts in the 10 mg 7/7 cohort had stable disease (SD) as the best response, compared to 19% (5/26) SD rate in 4 to 7 mg SA 7/7 cohorts. Disease control rate in the combination SLIs (response-evaluable, n=11) was 45% (5/11), including 1 confirmed partial response (4 mg + gem) in a patient with liver metastases who had a reduction in CA 19-9 from 60,357 U/mL to 968 U/mL, and SD in 4 pts (3 in 5 mg + gem, 1 in 4 mg + gem/np). SA and SLI PK data support an emerging exposure-activity relationship. POLR2A PD marker data from SA and SLI cohorts correlate with exposure. Conclusions: To date, intermittent dosing of SY-5609 on the 7/7 schedule has acceptable tolerability alone and in combination with gem +/- np. Encouraging preliminary clinical activity and the emerging exposure-activity relationship supports the ongoing escalation of SY-5609 in SA and combination SLI cohorts; updated results will be presented. Clinical trial information: NCT04247126 .

Tolerability and preliminary activity of the potent, selective, oral CDK7 inhibitor SY-5609 in combination with fulvestrant in patients with advanced hormone receptor-positive (HR+), HER2- breast cancer (BC).

3081 Background: SY-5609 is an oral, reversible, potent, and selective inhibitor of CDK7, a key regulator of transcription and cell cycle, currently under investigation in a Phase 1 study in patients (pts) with select advanced solid tumors (NCT04247126). Single agent (SA) dose escalation is ongoing, using a 7 days on/7 days off (7/7) dosing schedule that optimized tolerability (Sharma 2021) and showed a correlation of antitumor activity with higher exposures. SY-5609 may address multiple CDK4/6 inhibitor resistance mechanisms and potentiates SERD activity in CDK4/6 inhibitor-resistant xenograft models (Johannessen 2019). In this Phase 1 study, it was combined with the SERD fulvestrant in advanced HR+, HER2- BC pts who are refractory to CDK4/6 inhibitor + hormonal therapy. Methods: Evaluation of SY-5609 + fulvestrant began with a SY-5609 dose that had cleared the SA dose-limiting toxicity (DLT) evaluation period. SY-5609 was dosed once daily at 3 mg or 4 mg on a 21 days on/7 days off (21/7), 5 days on/2 days off (5/2), or 7/7 schedule and was escalated using a 3+3 design, guided by safety and reports of Cycle 1 qualifying safety events (QSEs), which matched SA DLT criteria. Fulvestrant was dosed at the approved dose/schedule. Safety and tolerability of SY-5609 + fulvestrant and SY-5609 PK were secondary objectives. Exploratory objectives included preliminary antitumor activity (RECIST v1.1.). Results: As of 12 Oct 2022, 14 pts (median age 63; range 46 - 83) received SY-5609 at 3 mg on a 21/7 schedule (n=8) or at 4 mg on a 5/2 (n=5) or 7/7 (n=1) schedule in combination with fulvestrant. Pts had advanced disease, including 79% with liver lesions, and a median of 5.5 (range 2 - 12) prior therapies; 100% had prior hormonal therapy, including 71% who received prior fulvestrant. The majority of adverse events (AEs) were low-grade and reversible. Related AEs (≥10%) included nausea, diarrhea, fatigue, thrombocytopenia, and hot flush. Related ≥Grade 3 AEs were reported in 3 pts (21%), including 1 QSE of Grade 3 thrombocytopenia at 4 mg 5/2. The highest tolerated dose in combination with fulvestrant was not reached. Stable disease (SD) was observed in 5/12 (42%) evaluable pts. SD with tumor shrinkage and/or SD &gt;6 months was observed in 4 pts previously treated with fulvestrant and in pts with liver lesions and/or TP53 mutations. SY-5609 exposure in combination with fulvestrant appeared comparable to SA at Day 1. Conclusions: SY-5609 + fulvestrant has an acceptable safety profile consistent with SA SY-5609 or fulvestrant. The mechanistic rationale for CDK7 inhibition in HR+, HER2- BC and the tolerability and encouraging early activity in this heavily pretreated population support future investigation of SY-5609 in combination with SERDs, including defining the maximum tolerated combination dose using the 7/7 SY-5609 schedule. Clinical trial information: NCT04247126 .

A combined priority scheduling method for distributed machine learning

Algorithms and frameworks for distributed machine learning have been widely used in numerous artificial intelligence engineering applications. A cloud platform provides a large number of resources at a lower cost and is a more convenient method for such applications. With the rapid development of containerization, native cloud combinations based on Docker and Kubernetes have provided effective resource support for distributed machine learning. However, native Kubernetes does not provide efficient priority or fair resource scheduling strategies for distributed machine learning in computationally intensive and time-consuming jobs, which easily leads to resource deadlock, resource waste, and low job execution efficiency. Therefore, to utilize the execution order between multiple jobs in distributed machine learning as well as the dependencies between multiple tasks for the same job, considering intra- and inter-group scheduling priorities, a combined priority scheduling method is proposed for distributed machine learning based on Kubernetes and Volcano. Considering the user priority, task priority, longest wait time, task parallelism, and affinity and non-affinity between the parameter server and worker nodes, a combined priority scheduling model of inter- and intra-job priority is proposed, which is mapped into a scheduling strategy of inter- and intra-group priorities of pods, enabling the efficient scheduling and training of distributed machine learning. The experiment results show that the proposed method achieves preferential resource allocation for urgent, high parallelism, and high-priority jobs with high-priority users and improves the job execution efficiency. The affinity and anti-affinity settings among pods reduce the time of information interaction between the parameter server and worker nodes to a certain extent, thereby improving the job completion efficiency. This group scheduling strategy alleviates the problems of resource deadlock and waste caused by insufficient resources in cloud computing.

A simulation and scheduling method for analyzing the peak time capacity of the dual-robot in-line stocker

ABSTRACT The automated material handling system (AMHS) plays a central role in realising smart manufacturing by providing manufacturing facilities with flexible, fast, and precise controls. This paper investigates a new type of AMHS known as the in-line stocker, which not only moves unit loads in manufacturing facilities under processing, similar to the automated-guided vehicle but also stores them on shelves, similar to the automated storage and retrieval system, which can reduce material handling space requirements. However, the traffic rate is very high inside an in-line stocker, and two robots are used along the single lane, which is the dual-robot in-line stocker (DRIS). This paper develops an analytical model to estimate the capacity of the DRIS based on a combined simulation and scheduling method. The simulation analysis shows that the model can be used not only to estimate the precise capacity of a DRIS but also to optimise its operating parameters.

A Phase 1/2 Multicenter Randomized Trial of Local Ablation plus Toripalimab versus Toripalimab Alone for Previously Treated Unresectable Hepatocellular Carcinoma.

To assess the safety and efficacy of local ablation plus PD-1 inhibitor toripalimab in previously treated unresectable hepatocellular carcinoma (HCC). In the multicenter, two-stage, and randomized phase 1/2 trial, patients were randomly assigned to receive toripalimab alone (240 mg, every 3 weeks), subtotal local ablation followed by toripalimab starting on post-ablation day 3 (Schedule D3), or on post-ablation day 14 (Schedule D14). The first endpoint of stage 1 was to determine which combination schedule could continue and progression-free survival (PFS) as the primary endpoint for stage 1/2. A total of 146 patients were recruited. During stage 1, Schedule D3 achieved numerically higher objective response rate (ORR) than Schedule D14 for non-ablation lesions (37.5% vs. 31.3%), and was chosen for stage 2 evaluation. For the entire cohort of both stages, patients with Schedule D3 had a significantly higher ORR than with toripalimab alone (33.8% vs. 16.9%; P = 0.027). Moreover, patients with Schedule D3 had improved median PFS (7.1 vs. 3.8 months; P < 0.001) and median overall survival (18.4 vs. 13.2 months; P = 0.005), as compared with toripalimab alone. In addition, six (9%) patients with toripalimab, eight (12%) with Schedule D3, and 4 (25%) with Schedule D14 developed grade 3 or 4 adverse events, and one patient (2%) with Schedule D3 manifested grade 5 treatment-related pneumonitis. In patients with previously treated unresectable HCC, subtotal ablation plus toripalimab improved the clinical efficacy as compared with toripalimab alone, with an acceptable safety profile.

Multi-objective combined dispatching optimization of pumped storage and thermal power

To realize precise and stable power grid dispatching, it is urgent to realize the combined scheduling of Pumped Storage and Thermal Power (PSTP). Considering some factors in the power system, a multi-objective combined optimization model of PSTP is proposed in this paper. Then, this paper proposes an improved multi-objective optimization algorithm base on deep reinforcement learning to solve the above model. Finally, this paper analyzes the advantages and disadvantages of the proposed multi-objective optimization model and finds that the model proposed in this paper sacrifices certain economic benefits but can reduce the system’s fluctuation and improve the power system’s reliability.