True Response Research Articles

Randomized phase II trial of pembrolizumab/lenvatinib (P+L) +/- responder fecal microbiota transplant (R-FMT) in PD-1 relapsed/refractory (R/R) cutaneous melanoma (MEL).

TPS9607 Background: A significant portion of patients (pts) with advanced MEL develop resistance to immune checkpoint inhibitors (ICI). The gut microbiome is a major tumor-extrinsic regulator of ICI response. In mice, gut microbiota modulate therapeutic activity of ICI, and administration of certain gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy in melanoma-bearing mice. In the LEAP-004 trial, P+L produced 21% ORR in PD-1 R/R MEL with Gr3+ TRAE 45.6%. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key species including Actinobacteria and Firmicutes are associated with favorable response. We and others have previously demonstrated that microbiome modulation using R-FMT reversed PD-1 non-response in PD-1 R/R MEL. In PD-1 naïve MEL, healthy donor FMT (hdFMT) augments benefit of PD-1 monotherapy. We hypothesized that intestinal dysbiosis mediates PD-1 resistance in PD-1 R/R MEL, microbiome modulation may reverse TKI toxicity, and that R-FMT may resensitize MEL to PD-1 blockade. Methods: This is an investigator-initiated, randomized, phase II trial of P+L vs. P+L+R-FMT in PD-1 R/R MEL. Pts must have measurable disease per RECIST v1.1, no active CNS metastases (or if present, previously treated and stable on repeat imaging), and no contraindications to FMT administration. R-FMT is derived from non-obese, advanced MEL with durable response (mPFS ≥24 months) following prior PD-1 ICI, with no recent (≤1 month) antibiotic exposure. Donors are screened broadly for infectious agents including SARS-CoV-2 using bookend screening. R-FMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts are randomized 1:1 to either P+L [P 200mg every 3 weeks (Q3W) along with L 20mg orally once daily] or P+L+R-FMT. R-FMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo biopsies at baseline and W8, with optional biopsy at progression. Primary endpoint: ORR assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 20% will be tested versus a one-sided alternative hypothesis of ≥50%. This design has a type I error rate 0.10 and power 0.8 when the true response rate is 0.25. Enrollment has commenced. Clinical trial information: NCT06030037 .

Confidence intervals for mean response times of a open queueing network: calibration approach

Response time is a key factor in the analysis of the different queueing network model properties. This study computes a series of response times using a data-based recurrence relation. The true average response time is determined using the sample averages from those response times. Several confidence intervals are created for the open queueing net- work model’s average response times using the calibration approach. Using a numerical simulation analysis, the accuracy of the various confidence intervals is evaluated. Journal of Statistical Research 2023, Vol 57, No.1-2, pp.69-79

A simulation study: comparing independent component analysis and signal-space projection - source-informed reconstruction for rejecting muscle artifacts evoked by transcranial magnetic stimulation.

The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) allows researchers to explore cortico-cortical connections. To study effective connections, the first few tens of milliseconds of the TMS-evoked potentials are the most critical. Yet, TMS-evoked artifacts complicate the interpretation of early-latency data. Data-processing strategies like independent component analysis (ICA) and the combined signal-space projection-source-informed reconstruction approach (SSP-SIR) are designed to mitigate artifacts, but their objective assessment is challenging because the true neuronal EEG responses under large-amplitude artifacts are generally unknown. Through simulations, we quantified how the spatiotemporal properties of the artifacts affect the cleaning performances of ICA and SSP-SIR. We simulated TMS-induced muscle artifacts and superposed them on pre-processed TMS-EEG data, serving as the ground truth. The simulated muscle artifacts were varied both in terms of their topography and temporal profiles. The signals were then cleaned using ICA and SSP-SIR, and subsequent comparisons were made with the ground truth data. ICA performed better when the artifact time courses were highly variable across the trials, whereas the effectiveness of SSP-SIR depended on the congruence between the artifact and neuronal topographies, with the performance of SSP-SIR being better when difference between topographies was larger. Overall, SSP-SIR performed better than ICA across the tested conditions. Based on these simulations, SSP-SIR appears to be more effective in suppressing TMS-evoked muscle artifacts. These artifacts are shown to be highly time-locked to the TMS pulse and manifest in topographies that differ substantially from the patterns of neuronal potentials. Selecting between ICA and SSP-SIR should be guided by the characteristics of the artifacts. SSP-SIR might be better equipped for suppressing time-locked artifacts, provided that their topographies are sufficiently different from the neuronal potential patterns of interest, and that the SSP-SIR algorithm can successfully find those artifact topographies from the high-pass-filtered data. ICA remains a powerful tool for rejecting artifacts that are not strongly time locked to the TMS pulse.

Ultrafast dephasing in solid-state high harmonic generation: macroscopic origin revealed by real-space dynamics [Invited

Using a fully real-space perspective on high harmonic generation (HHG) in solids, we examine the relationship between microscopic response, macroscopic propagation of this response to the far-field, and the extremely short dephasing times routinely used in the theoretical simulations of experimentally measured solid-state HHG spectra. We find that far-field propagation naturally reduces the contribution to the observed HHG emission from electrons that do not return to the lattice site where they have been injected into the conduction band. We then show that extremely short dephasing times routinely used in microscopic simulations suppress many electron trajectories that contribute to the far-field spectra, leading to significant distortions of the true high harmonic response. We show that a real-space based dephasing mechanism, which preferentially suppresses trajectories that veer too far away from their original lattice site, yields HHG spectra that faithfully retain those trajectories that contribute to the far-field spectra while filtering out those that do not, already at the microscopic level. Our findings emphasize the similarities between atomic and solid-state HHG by highlighting the importance of the intensity-dependent phase of HHG emission and address the longstanding issue regarding the origin of extremely short dephasing times in solid-state HHG.

Applicability of 1D site response analysis to shallow sedimentary basins: A critical evaluation through physics‐based 3D ground motion simulations

AbstractOne‐dimensional site response analysis (1D SRA) remains the standard practice in considering the effect of local soil deposits and predicting site‐specific ground motions, although its range of applicability to realistic seismic wavefields is still in question. In this 1D approach, horizontal and vertical ground shaking are assumed to be induced by vertically propagating shear and compressional waves, respectively. A recent study based on analytical two‐dimensional (2D) plane waves and simple point source earthquake simulations has shown two mechanistic limitations in this 1D modelling technique for general inclined seismic waves, that is, systematic over‐prediction of the vertical motion and wave trapping in the 1D soil column. In this article, we evaluate in detail the applicability of this 1D modelling approach to realistic three‐dimensional (3D) simulated seismic wavefields in shallow sedimentary basins. Linear‐viscoelastic 1D SRA predictions using two types of input motions that are commonly used in practice—rock outcrop and in‐column motions, are compared with the reference true site response results from 3D earthquake simulations in terms of various measures in the frequency and time domain. It is shown that the horizontal motion in the 3D seismic wavefield exhibits dominant shear wave propagation phenomenon, while the vertical motion is a combined effect of compressional and shear waves and can be over‐predicted by the 1D approach when the incident seismic waves are inclined. Direct evidence of the wave refraction process that leads to the vertical motion over‐prediction is provided. 1D SRA with in‐column inputs can yield motions that have significantly longer duration compared to the true 3D site response solution due to trapped waves, casting in doubt the frequent need for increased soil damping in existing site studies to compensate for wave attenuation due to scattering alone. Sensitivity investigation on the increase of soil profile damping by a multiplier Dmul shows Dmul values compatible with those found in the literature for both horizontal and vertical motions. It is shown that the level of Dmul optimized for a best match of the spectral acceleration is dependent on the characteristic of the input motion and a larger Dmul is typically required for the vertical component. In contrast, 1D SRA with outcrop motions predicts motions with shorter significant duration due to its inability to capture the basin‐edge generated surface waves. A suite of ground motion simulations was performed to assess the sensitivity of the observations to the basin geologic structure including the velocity gradient, rock‐basin impedance contrast and basin depth. The analysis results show that the accuracy of the simplified 1D procedure is dependent on the wavefield composition of both the input motions and the true 3D site response solution. While the horizontal motions in shallow sedimentary basins can, to the first order, be reasonably captured by the simplified 1D approach, 1D SRA for the vertical component is in general not reliable and contributions from inclined shear waves should be accounted for in site‐specific evaluation of the vertical design ground motion.

CARLA: Adjusted common average referencing for cortico-cortical evoked potential data

Human brain connectivity can be mapped by single pulse electrical stimulation during intracranial EEG measurements. The raw cortico-cortical evoked potentials (CCEP) are often contaminated by noise. Common average referencing (CAR) removes common noise and preserves response shapes but can introduce bias from responsive channels. We address this issue with an adjusted, adaptive CAR algorithm termed “CAR by Least Anticorrelation (CARLA)”. CARLA was tested on simulated CCEP data and real CCEP data collected from four human participants. In CARLA, the channels are ordered by increasing mean cross-trial covariance, and iteratively added to the common average until anticorrelation between any single channel and all re-referenced channels reaches a minimum, as a measure of shared noise. We simulated CCEP data with true responses in 0–45 of 50 total channels. We quantified CARLA’s error and found that it erroneously included 0 (median) truly responsive channels in the common average with ≤42 responsive channels, and erroneously excluded ≤2.5 (median) unresponsive channels at all responsiveness levels. On real CCEP data, signal quality was quantified with the mean R2 between all pairs of channels, which represents inter-channel dependency and is low for well-referenced data. CARLA re-referencing produced significantly lower mean R2 than standard CAR, CAR using a fixed bottom quartile of channels by covariance, and no re-referencing. CARLA minimizes bias in re-referenced CCEP data by adaptively selecting the optimal subset of non-responsive channels. It showed high specificity and sensitivity on simulated CCEP data and lowered inter-channel dependency compared to CAR on real CCEP data.

Abstract PO1-19-07: A Phase I Study Accessing Immunotherapy Combination of Balstilimab and Ivermectin in Patients with Metastatic Triple Negative Breast Cancer

Abstract Background: Despite recent FDA approval of immune checkpoint inhibitor (ICI) and antibody-drug conjugates (ADCs), therapeutic options for metastatic triple negative breast cancer (mTNBC) remain limited. There is an unmet need to identify novel ICI combinations for improved efficacy. We recently demonstrated that ivermectin induces robust T cell infiltration into breast tumors and turning “cold” tumors “hot” in mouse model of TNBC. Balstilimab is a fully humanized IgG4 anti-PD-1 agent with proven safety and efficacy in metastatic cervical cancer. The current phase I/II trial is designed to test the safety and efficacy of the combination of ivermectin and balstilimab in patients with mTNBC. Methods: Key eligibility criteria include patients with unresectable or metastatic TNBC; progressed on 1-2 prior chemotherapies including an immune checkpoint inhibitor-containing regimen; ECOG 0-1; RECIST 1.1 measurable disease. Eligible patients receive balstilimab 450 mg, IV, on Day 1 and ivermectin (30, 45 or 60 mg po daily), PO, Days 1-3, 8-10, 15-17 of each 21 days cycle till disease progression or intolerance. The primary objection of the phase 1 portion of the study is t determine the recommended phase 2 dose of ivermectin in combination with balstilimab using NCI-CTCAE v5.0. The primary objective of the phase II portion of the study is to determine the efficacy of the combination in mTNBC who are PD-L1 negative using the objective response rate (ORR). Secondary objectives are progression free survival (PFS), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), and patients’ quality of life (QOL) by EORTC QLQ-C30. Peripheral blood, tumor tissue and gut microbiome will be collected for correlative aims include pharmacokinetics, tumor microenvironment ICDs and gut microbiota in association with response to therapy. In the Phase 1 portion, eligible patients will be enrolled to one of three doses using the IQ 3+3 design. In the Phase 2 portion, patients will continue to be accrued to the RP2D (either the MTD or a lower dose depending on clinical judgement considering all the clinical and correlative data available). The Phase 2 portion will be conducted in two stages. In stage 1, a total of 13 PDL1-negative TNBC breast cancer patients will be treated at the RP2D. If there are no responders, the Phase 2 portion will close. With at least one responder, accrual may continue until 25 patients are accrued to the Phase 2 portion. If at least 3 responders are noted in 25 patients, this will be sufficient to consider the combination promising. This rule provides a type I error of 12% for a true response rate of 5%, and a power of 88% for true response rate of 20%. The estimated targeted accrual is 34-41 (Phase 1: 14-16; Phase 2: 20-25). Clinical trial information: NCT05318469 Citation Format: Yuan Yuan, Stephen Shiao, Mourad Tighiouart, Monica Mita, Jin-Sun Bitar, Philomena McAndrew, Park Dorothy, Maryliza El-Masry, Paul Frankel, Peter Lee. A Phase I Study Accessing Immunotherapy Combination of Balstilimab and Ivermectin in Patients with Metastatic Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-07.

Time delays between physiological signals in interpreting the body’s responses to intermittent hypoxia in obstructive sleep apnea

Objective. Intermittent hypoxia, the primary pathology of obstructive sleep apnea (OSA), causes cardiovascular responses resulting in changes in hemodynamic parameters such as stroke volume (SV), blood pressure (BP), and heart rate (HR). However, previous studies have produced very different conclusions, such as suggesting that SV increases or decreases during apnea. A key reason for drawing contrary conclusions from similar measurements may be due to ignoring the time delay in acquiring response signals. By analyzing the signals collected during hypoxia, we aim to establish criteria for determining the delay time between the onset of apnea and the onset of physiological parameter response. Approach. We monitored oxygen saturation (SpO2), transcutaneous oxygen pressure (TcPO2), and hemodynamic parameters SV, HR, and BP, during sleep in 66 patients with different OSA severity to observe body’s response to hypoxia and determine the delay time of above parameters. Data were analyzed using the Kruskal–Wallis test, Quade test, and Spearman test. Main results. We found that simultaneous acquisition of various parameters inevitably involved varying degrees of response delay (7.12–25.60 s). The delay time of hemodynamic parameters was significantly shorter than that of SpO2 and TcPO2 (p< 0.01). OSA severity affected the response delay of SpO2, TcPO2, SV, mean BP, and HR (p < 0.05). SV delay time was negatively correlated with the apnea-hypopnea index (r = −0.4831, p< 0.0001). Significance. The real body response should be determined after removing the effect of delay time, which is the key to solve the problem of drawing contradictory conclusions from similar studies. The methods and important findings presented in this study provide key information for revealing the true response of the cardiovascular system during hypoxia, indicating the importance of proper signal analysis for correctly interpreting the cardiovascular hemodynamic response phenomena and exploring their physiological and pathophysiological mechanisms.

Resolvent analysis of turbulent flow laden with low-inertia particles

We extend the resolvent framework to two-phase flows with low-inertia particles. The particle velocities are modelled using the equilibrium Eulerian model. We analyse the turbulent flow in a vertical pipe with Reynolds number of $5300$ (based on diameter and bulk velocity), for Stokes numbers $St^+=0-1$ , Froude numbers $Fr_z=-4,-0.4,0.4,4$ and $1/Fr_z = 0$ (gravity omitted). The governing equations are written in input–output form and a singular value decomposition is performed on the resolvent operator. As for single-phase flows, the operator is low rank around the critical layer, and the true response can be approximated using one singular vector. Even with a crude forcing model, the formulation can predict physical phenomena observed in Lagrangian simulations, such as particle clustering and gravitational effects. Increasing the Stokes number shifts the predicted concentration spectra to lower wavelengths; this shift also appears in the direct numerical simulation spectra and is due to particle clustering. When gravity is present, there are two critical layers, one for the concentration field, and one for the velocity field. For upward flow, the peak of concentration fluctuations shifts closer to the wall, in agreement with the literature. We explain this with the aid of the different locations of the two critical layers. Finally, the model correctly predicts the interaction of near-wall vortices with particle clusters. Overall, the resolvent operator provides a useful framework to explain and interpret many features observed in Lagrangian simulations. The application of the resolvent framework to higher $St^+$ flows in combination with Lagrangian simulations is also discussed.

Quantifying holistic capacity response and healthcare resilience in tackling COVID-19: Assessment of country capacity by MCDM.

The resilience of a country during the COVID-19 pandemic was determined based in whether it was holistically prepared and responsive. This resilience can only be identified through systematic data collection and analysis. Historical evidence-based response indicators have been proven to mitigate pandemics like COVID-19. However, most databases are outdated, requiring updating, derivation, and explicit interpretation to gain insight into the impact of COVID-19. Outdated databases do not show a country's true preparedness and response capacity, therefore, it undermines pandemic threat. This study uses up-to-date evidence-based pandemic indictors to run a cross-country comparative analysis of COVID-19 preparedness, response capacity, and healthcare resilience. PROMETHEE-a multicriteria decision making (MCDM) technique-is used to quantify the strengths (positive) and weaknesses (negative) of each country's COVID-19 responses, with full ranking (net) from best to least responsive. From 22 countries, South Korea obtained the highest net outranking value of 0.1945, indicating that it was the most resilient, while Mexico had the lowest (-0.1428). Although countries were underprepared, there was a robust response to the pandemic, especially in developing countries. This study demonstrates the performance and response capacity of 22 key countries to resist COVID-19, from which other countries can compare their statutory capacity ranking in order to learn/adopt the evidence-based responses of better performing countries to improve their resilience.

Abstract CT024: A DNA plasmid melanoma cancer vaccine, SCIB1, combined with nivolumab + ipilimumab in patients with advanced unresectable melanoma: Efficacy and safety results from the open-label Phase 2 SCOPE Trial

Abstract Background Targeting melanoma by T cells drives anti-tumor responses. We previously showed that a DNA vaccine, SCIB1, incorporating T cell epitopes from TRP-2/gp100 into an antibody framework to allow Fc targeting of activated dendritic cells, was successfully evaluated as a monotherapy in a phase 1/2 in stage 3/4 melanoma patients. Unresectable melanoma patients showed a 60% ORR and 88% of patients treated with SCIB1 post tumor resection, remained disease free for 5 years [1]. The current SCOPE trial tests the hypothesis that unresectable patients may have an improved response when SCIB1 is combined with checkpoint inhibitors (CPI). Methods Patients were treated with nivolumab with ipilimumab and SCIB1 (8mg) i.m. using needle-free injection at a fixed dosing schedule for a total of 10 doses over 24 months. The CPI therapy was administered i.v. in accordance with their respective SmPC. ORR as measured by RECIST 1.1 in the overall intention-to-treat population was the primary endpoint. The study is designed using Simon's two stage methodology with 80% power when the true response rate is 70% with an overall type I error of 5%. In the first stage, 15 patients will be enrolled and if there are eight or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), further recruitment will be stopped. The null hypothesis will be rejected if 27 or more responses are observed in 43 patients. Results 19 patients received the combination of SCIB1 with nivolumab and ipilimumab. At study entry, all patients were stage IV. 13 patients had reached the first imaging timepoint at 13 weeks, and the objective response rate is 85%. 9/9 responses were confirmed in a subsequent scan. Patients showed a 40-95% reduction in tumor volume between 13 and 25 weeks. Most of the SCIB1-related adverse events were Grade 1/2. Only 1 patient reported a Grade 3 rash. No enhancement of immune-mediated adverse events was observed when SCIB1 was added to nivolumab with ipilimumab. Conclusions SCIB1 in combination with nivolumab and ipilimumab as first line treatment for unresectable melanoma improved the ORR to 85% without an increase in clinically meaningful adverse events. These results if confirmed in a larger patient cohort provide confidence in initiating a randomized registration program in unresectable melanoma patients with the novel DNA plasmid technology Citation Format: Heather Shaw, Poulam Patel, Miranda Payne, Satish Kumar, Martin Highley, Kellati Prasad, Ruth Board, Clare Barlow, Sarah Danson, Robert Miller, Georgia Goodhew, Fayaz Master, Lindy Durrant. A DNA plasmid melanoma cancer vaccine, SCIB1, combined with nivolumab + ipilimumab in patients with advanced unresectable melanoma: Efficacy and safety results from the open-label Phase 2 SCOPE Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT024.

Data-driven dimensionality reduction and causal inference for spatiotemporal climate fields.

We propose a data-driven framework to describe spatiotemporal climate variability in terms of a few entities and their causal linkages. Given a high-dimensional climate field, the methodology first reduces its dimensionality into a set of regionally constrained patterns. Causal relations among such patterns are then inferred in the interventional sense through the fluctuation-response formalism. To distinguish between true and spurious responses, we propose an analytical null model for the fluctuation-dissipation relation, therefore allowing us for uncertainty estimation at a given confidence level. We showcase the methodology on the sea surface temperature field from a state-of-the-art climate model. The usefulness of the proposed framework for spatiotemporal climate data is demonstrated in several ways. First, we focus on the correct identification of known causal relations across tropical basins. Second, we show how the methodology allows us to visualize the cumulative response of the whole system to climate variability in a few selected regions. Finally, each pattern is ranked in terms of its causal strength, quantifying its relative ability to influence the system's dynamics. We argue that the methodology allows us to explore and characterize causal relations in spatiotemporal fields in a rigorous and interpretable way.

A Call to Arms: Proposing the Use of Social Science Methods in Transnational Competition Law

Competition law enforcement is one of the cornerstones of sound business regulation; yet it faces a problem in the transnational context. Whereas transnational commerce seamlessly transcends borders, competition law has jurisdictional roots, lacking a true transnational response. Global frictions due to the enforcement of divergent domestic laws and policies seem inevitable yet are surprisingly rare. We argue this phenomenon cannot be fully explained by a doctrinal analysis of the global efforts towards policy or legal convergence. Instead, the focus should be on the competition law officials who operationalise the law in a transnational context. This ‘human element’ of the inquiry must embrace qualitative research methods, such as ethnographic studies commonly used in legal anthropology, to develop a comprehensive legal analysis in this context.

Numerically assisted calibration procedure of nonlinear in-plane shear properties of unidirectional composite laminae based on off-axis tensile experiments

In this paper, a novel methodology is presented to evaluate the true nonlinear shear response of continuous fiber-reinforced plastic (CFRP) unidirectional laminae. It requires simple off-axis tensile experiments to be conducted and a finite element (FE) representation of them with a material constitutive law capable of handling nonlinearity in shear. Upon successful evaluation of the normal stiffness properties, the shear stress-strain response is derived via numerical calibration of the underlying FE models. The presented approach is also demonstrated by processing the raw data of an extensive material characterization test campaign conducted on a thermoplastic matrix CFRP. The outcome is compared to the conventional methods for shear response derivation using relevant standards such as ASTM D3518 and ASTM D5379. It has been successfully demonstrated that the pseudo-hardening phenomenon obtained from standard shear experiments as a result of fibers aligning with load direction can be eliminated with off-axis specimen tension experiments, thus, the true shear stress versus deformation response can be extracted up to failure. The main purpose of current work is to demonstrate the inconsistency in the available standard methods related to mechanical testing-based derivation of nonlinear in-plane shear behavior of UD plies. In addition, a novel technique is presented to achieve a more accurate prediction of nonlinear shear stress and strain along the entire representative loading range that contributes to more accurate simulations of composite parts up to failure and thus, better strength predictions.

Abstract 3626: Day 21 early bone marrow response does not offer high concordance with response bone marrow in the induction chemotherapy setting of FLT3 mutant acute myeloid leukemia

Abstract Purpose: Day 14 early bone marrow biopsies are routinely initiated to determine need for reinduction chemotherapy, but poorly predict true response and risk overtreatment. Day 21 (D21) bone marrow biopsies have been performed in the context of trials utilizing FLT3-targeted therapies in combination with induction chemotherapy (Stone et al. NEJM 2017). However, the utility of D21 bone marrow responses is not well defined. Methods: We retrospectively identified 26 newly diagnosed FLT3 mutant AML patients who underwent induction chemotherapy with midostaurin and Next Generation Sequencing (NGS) of bone marrow aspirate within a week of diagnosis. Results: 19/26 (73%) of patients had both D21 and response bone marrow biopsy. Of the remaining 7 patients, 4 patients did not have D21 bone marrow, 2 died of unrelated complications prior to response bone marrow, and 1 did not have recovery marrow available for assessment. Our cohort included 13 (50%) men with a median age of 57 years (range, 21 - 73 years). All patients had ECOG of 0 - 1. 96% of cases were de novo AML and 81% had normal cytogenetics. FLT3 ITD mutations were detected in 17 (65%) patients with a median FLT3 ITD ratio of 0.305 (range, 0.03 - 1) and median FLT3 VAF of 23.8% (range, 3.2 - 80.6%). 7 patients (26.9%) underwent additional allogeneic stem cell transplant. In the 19 patients evaluable for analysis, 13/13 (100%) patients with blast % ≤ 5 at D21 achieved a complete response (CR) based on recovery marrow. 4/6 (67%) patients with blast % &amp;gt; 5 at D21 which were considered to have residual disease based on pathology review (median blast % 11 (range, 6 - 17%) ultimately achieved a CR. The 2 patients that did not achieve a CR has a blast % of 29% and 9% on D21 marrow. Thus, the positive predictive value of D21 early bone marrow response corresponding with the response bone marrow was only 33% in our patient cohort. Of the 4 patients that did not have D21 marrow but had recovery marrows available for review, the CR rate was 100%. No other significant differences in initial disease characteristics were seen. There were no differences proportion of co-mutations in NPM1, DNMT3A, TP53, IDH2, and IDH1, and higher FLT3 ITD ratio nor FLT3 VAF corresponded with ability to clear D21 bone marrow. Additionally, there were no differences in minimal residual disease (MRD) and overall survival (OS) between the groups. Conclusions: Our study suggests early bone marrow response in the context of FLT3-mutant disease is not dependent on inherent disease characteristics and does not correspond to overall response to targeted induction chemotherapy. The utility of these marrows in is this population needs to be studied further in a larger cohort to better understand the clinical necessity to avoid unnecessary cost/procedures to patients and even more importantly unnecessary reinductions. Citation Format: Vincent Lok, Su Bin Hahn, Nikesh N. Shah, Daniel A. Kerr, Ivan M. Borrello, Eduardo M. Sotomayor, David M. Swoboda. Day 21 early bone marrow response does not offer high concordance with response bone marrow in the induction chemotherapy setting of FLT3 mutant acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3626.

A generalisation of the method of regression calibration and comparison with Bayesian and frequentist model averaging methods

For many cancer sites low-dose risks are not known and must be extrapolated from those observed in groups exposed at much higher levels of dose. Measurement error can substantially alter the dose–response shape and hence the extrapolated risk. Even in studies with direct measurement of low-dose exposures measurement error could be substantial in relation to the size of the dose estimates and thereby distort population risk estimates. Recently, there has been considerable attention paid to methods of dealing with shared errors, which are common in many datasets, and particularly important in occupational and environmental settings. In this paper we test Bayesian model averaging (BMA) and frequentist model averaging (FMA) methods, the first of these similar to the so-called Bayesian two-dimensional Monte Carlo (2DMC) method, and both fairly recently proposed, against a very newly proposed modification of the regression calibration method, the extended regression calibration (ERC) method, which is particularly suited to studies in which there is a substantial amount of shared error, and in which there may also be curvature in the true dose response. The quasi-2DMC with BMA method performs well when a linear model is assumed, but very poorly when a linear-quadratic model is assumed, with coverage probabilities both for the linear and quadratic dose coefficients that are under 5% when the magnitude of shared Berkson error is large (50%). For the linear model the bias is generally under 10%. However, using a linear-quadratic model it produces substantially biased (by a factor of 10) estimates of both the linear and quadratic coefficients, with the linear coefficient overestimated and the quadratic coefficient underestimated. FMA performs as well as quasi-2DMC with BMA when a linear model is assumed, and generally much better with a linear-quadratic model, although the coverage probability for the quadratic coefficient is uniformly too high. However both linear and quadratic coefficients have pronounced upward bias, particularly when Berkson error is large. By comparison ERC yields coverage probabilities that are too low when shared and unshared Berkson errors are both large (50%), although otherwise it performs well, and coverage is generally better than the quasi-2DMC with BMA or FMA methods, particularly for the linear-quadratic model. The bias of the predicted relative risk at a variety of doses is generally smallest for ERC, and largest for the quasi-2DMC with BMA and FMA methods (apart from unadjusted regression), with standard regression calibration and Monte Carlo maximum likelihood exhibiting bias in predicted relative risk generally somewhat intermediate between ERC and the other two methods. In general ERC performs best in the scenarios presented, and should be the method of choice in situations where there may be substantial shared error, or suspected curvature in the dose response.

A stacking-based ensemble prediction method for multiobjective aerodynamic optimization of high-speed train nose shape

A stacking-based ensemble prediction method is proposed in order to improve the efficiency and accuracy of aerodynamic shape optimization. This can be divided into a two-level model. The first-level model uses various base learners to predict the training dataset and obtain various combinations of predictions. In the second-level model, the meta-learner is trained using various combinations of predictions as inputs and the true response values as outputs. The RMSE and R-Square metrics results show that the performance metrics of the stacked models are significantly better than those of the original surrogate models, except for the stacked RBFNN model. The stacked Kriging model and LSSVR model achieved the best results with RMSE and R-Square index values of 0.0039 and 0.8418 for aerodynamic drag coefficient, respectively. The stacked Kriging model, RBFNN model, and LSSVR model achieved the best results with RMSE and R-Square index values of 0.0024 and 0.76 for aerodynamic lift coefficient, respectively. Four state-of-the-art multiobjective optimization algorithms are used to perform the optimization process. The results of hypervolume and Pareto fronts demonstrate the effectiveness of the selected FDV-NSGAII algorithm. After optimization, the drag and lift coefficients before and after optimization are reduced by 1.9% and 12.7%, respectively.

An extended modal approach for modal parameter identification of structure under the existence of harmonic excitations

The existing operational modal analysis (OMA) methods for the structure subjected to white noise and harmonic combined excitations have some limitations such as easy misjudgment of true and spurious modes and slow identification speed. Through expressing the system response with the extended modal matrix (EMM) and the extended modal response (EMR) vector, a novel operational modal parameter identification approach called the extended modal approach is proposed to obtain structural true modes under the existence of multiple harmonic excitations. The EMRs consist of the true modal responses and the spurious modal responses, and each of the former is random while each of the latter is harmonic. It is also proved theoretically that the EMM can be identified using the power spectrum density transmissibility (PSDT) method. Therefore, the extended modal approach includes three steps: (1) Using the PSDT to identify the EMM; (2) Utilizing the least squares reconstruction method to obtain the EMRs from the underdetermined extended modal equation; (3) Judging each of the EMRs to be true or spurious according to its empirical density function. Structural true modes can be ultimately obtained by removing all spurious modes from the identified results. The new approach is numerically verified through the OMA of two multiple-degree-of-freedom systems and then experimentally verified through the OMA of a test beam. The results in numerical simulation and experiments all show that the extended modal approach can identify accurately and quickly structural true modes under multiple harmonic excitations. Besides, the approach has good robustness against noise contamination.

Enfortumab vedotin (EV) as monotherapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of stage I of a phase 2 trial.

152 Background: EV is an antibody-drug conjugate consisting of a fully human antibody directed against the extracellular domain of Nectin-4, which is conjugated to a microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker. In animal models of prostate cancer, metastatic lesions showed high membranous Nectin-4 expression (PMID: 30767361). We aimed to investigate EV in pts with mCRPC. Methods: This IRB-approved, investigator-initiated, single-arm, single-center, phase 2 study administered EV at 1.25 mg/kg IV on days 1, 8, and 15 of 28 days cycle. Key eligibility criteria: ≥18 years age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, performance status ≤ 1, adequate organ function, prior treatment (Rx) with ≥3 cycles of docetaxel and at least one androgen-receptor pathway inhibitor, received/refused all therapies shown to improve overall survival except cabazitaxel which is exclusionary. Primary objective: To assess antitumor activity of EV as determined by one of the following: 1) objective response by RECIST 1.1 in those with measurable disease, 2) confirmed conversion of circulating tumor cell count (CTC) to &lt;5/7.5 mL blood, 3) PSA decline of ≥ 50%, and 4) stable disease for ≥ 6 months per PCWG3 modified RECIST 1.1. Simon’s two-stage design was used. The null hypothesis (H0) that true response rate (RR) is 25% is tested against a one-sided alternative. In stage I if ≤3 responses were observed of 11 pts, the study will be stopped. Otherwise, 23 additional pts will be accrued (total 34). H0 will be rejected if ≥13 responses are observed in 34 pts (type I error rate 0.046, power 0.854 when true RR is 50%). Results: Herein, we present results of 11 pts treated on stage I of study. All pts were non-Hispanic white with median age of 72 years (range 43-78). Median number of prior systemic therapies in addition to castration: 5 (range 3-8). Median follow-up of the cohort was 9 months (range 1-13). 4/11 had RECIST measurable disease and 7/11 had CTC ≥5 at baseline. Overall 7/11 (64%) pts had protocol-defined response (5/11 PSA 50% responses, 3/4 objective response, 4/7 confirmed CTC response and 2/11 ≥ 6 months on Rx). Of the 9 pts who discontinued Rx, 8 discontinued due to disease progression (1 withdrew consent). Median number of completed cycles were 6 (range: 2-12) and median radiographic progression-free survival was 5.5 months (95% CI 5.3-not reached). Most common grade 3/4 treatment-related adverse events (TRAEs) were anemia, AST increase, dry skin, fatigue, hyperglycemia, rash, leucopenia (1 pt each) and nausea and decrease in neutrophil (2 pts each). 8 pts had dose interruptions and dose reductions. No Grade 5 TRAEs. Conclusions: EV showed promising efficacy and an acceptable safety profile in pts with heavily treated refractory mCRPC. Further enrollment in stage 2 of the trial is ongoing. Clinical trial information: NCT04754191 .

Evaluating Treatment Response in GEJ Adenocarcinoma: The Role of Pretherapeutic and Posttherapeutic Iodine Mapping.

Neoadjuvant therapy regimens have significantly improved the prognosis of GEJ (gastroesophageal junction) cancer; however, there are a significant percentage of patients who benefit from earlier resection or adapted therapy regimens, and the true response rate can only be determined histopathologically. Methods that allow preoperative assessment of response are lacking. The purpose of this retrospective study is to assess the potential of pretherapeutic and posttherapeutic spectral CT iodine density (IoD) in predicting histopathological response to neoadjuvant chemotherapy in patients diagnosed with adenocarcinoma of the GEJ. In this retrospective cohort study, a total of 62 patients with GEJ carcinoma were studied. Patients received a multiphasic CT scan at diagnosis and preoperatively. Iodine-density maps were generated based on spectral CT data. All tumors were histopathologically analyzed, and the tumor regression grade (TRG) according to Becker et al ( Cancer . 2003;98:1521-1530) was determined. Two experienced radiologists blindly placed 5 defined ROIs in the tumor region of highest density, and the maximum value was used for further analysis. Iodine density was normalized to the aortic iodine uptake. In addition, tumor response was assessed according to standard RECIST measurement. After assessing interrater reliability, the correlation of IoD values with treatment response and with histopathologic TRG was evaluated. The normalized ΔIoD (IoD at diagnosis - IoD after neoadjuvant treatment) and the normalized IoD after neoadjuvant treatment correlated significantly with the TRG. For the detection of responders and nonresponders, the receiver operating characteristic (ROC) curve for normalized ΔIoD yielded the highest area under the curve of 0.95 and achieved a sensitivity and specificity of 92.3% and 92.1%, respectively. Iodine density after neoadjuvant treatment achieved an area under the curve of 0.88 and a sensitivity and specificity of 86.8% and 84.6%, respectively (cutoff, 0.266). Iodine density at diagnosis and RECIST did not provide information to distinguish responders from nonresponders. Using the cutoff value for IoD after neoadjuvant treatment, a reliable classification of responders and nonresponders was achieved for both readers in a test set of 11 patients. Intraclass correlation coefficient revealed excellent interrater reliability (intraclass correlation coefficient, >0.9). Lastly, using the cutoff value for normalized ΔIoD as a definition for treatment response, a significantly longer survival of responders was shown. Changes in IoD after neoadjuvant treatment of GEJ cancer may be a potential surrogate for therapy response.