Historical Benchmark Research Articles

Technical note: Unsupervised classification of ozone profiles in UKESM1

Abstract. The vertical distribution of ozone in the atmosphere, which features complex spatial and temporal variability set by a balance of production, loss, and advection, is relevant for both surface air pollution and climate via its role in radiative forcing. At present, the way in which regions of coherent ozone structure are defined relies on somewhat arbitrarily drawn boundaries. Here we consider a more general, data-driven method for defining coherent regimes of ozone structure. We apply an unsupervised classification technique called Gaussian mixture modeling (GMM), which represents the underlying distribution of ozone profiles as a linear combination of multi-dimensional Gaussian functions. In doing so, GMM identifies coherent groups or subpopulations of the ozone profile distribution. As a proof-of-concept study, we apply GMM to ozone profiles from three subsets of the UKESM1 coupled climate model runs carried out for CMIP6: specifically, the seasonal mean of a historical subset (2009–2014) and two subsets from two different future climate projections (i.e., SSP1-2.6 and SSP5-8.5). Despite not being given any spatiotemporal information, GMM identifies several spatially coherent regions of ozone structure. Using a combination of statistical guidance and post hoc judgment, we select a six-class representation of global ozone, consisting of two tropical classes and four mid-to-high-latitude classes. The tropical classes feature a relatively high-altitude tropopause, while the higher-latitude classes feature a lower-altitude tropopause and low values of tropospheric ozone, as expected based on broad patterns observed in the atmosphere. Both of the future projections feature lower ozone concentrations at 850 hPa than the historical benchmark, with signatures of ozone hole recovery. We find that the area occupied by the tropical classes is expanded in both future projections, which are most prominent during austral summer. Our results suggest that GMM may be a useful method for identifying coherent ozone regimes, particularly in the context of model analysis.

A data-driven framing of player and team performance in U.S. Women's soccer.

In establishing historical benchmarks for success on the pitch and striving to achieve parity off it, the United States Women's National Team (USWNT) and the National Women's Soccer League (NWSL) have long served as standard bearers for professional women's soccer around the globe. However, off-field dilemmas and incessant juxtapositions to men's soccer frequently overshadow the elements that make U.S. women's soccer unique; that is, in the quest to expose and rid the women's game of blatant misconduct, discriminatory practices, and negative stereotypes, relatively little attention has been devoted to performance features that separate the U.S. women's soccer product from its competition. Because many of the issues hindering the progress of women's soccer are rooted in media and managerial practices that marginalize or ignore its positive traits, a need exists for analyses that will properly identify its innate characteristics and competitive advantages so that media members, managers, and fans can accurately frame their perceptions of women competing in the sport. To this end, we collected reliable samples of public event data from 560 professional soccer matches and used ANOVAs and t-tests to identify the characteristics that distinguish U.S. women's soccer from other professional leagues and teams. In doing so, we showed that the USWNT tends to shoot from more opportune areas and press opponents at a higher rate, and that the NWSL has recently been matched in quality across certain performance metrics by England's FA Women's Super League.

Abstract OT2-16-01: ONCX-NAV-G201: A phase 2, basket study of navicixizumab monotherapy or in combination with chemotherapy in patients with select advanced solid tumors: Triple-negative breast cancer cohort (trial in progress)

Abstract Objective: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors. Cohort C will enroll triple-negative breast cancer (TNBC) patients. Background: Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aberrant NOTCH signaling is associated with chemotherapy resistance, tumor plasticity, enhanced metastatic potential, promotion of a cancer stem cell phenotype, and immune evasion. In TNBC, aberrant NOTCH expression is associated with poor prognosis, making targeting of this pathway an attractive therapeutic strategy. Additionally, NOTCH may mediate resistance to angiogenesis inhibition. While VEGF inhibitors are approved for the treatment of multiple solid tumors, observed anti-tumor activity is limited in breast cancer. Pre-clinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway targeting. We postulate that navicixizumab will demonstrate anticancer efficacy against TNBC. Methods: Eligible TNBC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 4 prior lines of standard therapy for metastatic disease, including immunotherapy (for PD-L1 positive TNBC patients), and sacituzumab govitecan. TNBC is defined as ER and PR < 1%, and HER2-negative (IHC 0, 1+, or 2+ and negative fluorescence in situ hybridization [FISH]). Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap™ ExTra with the Xerna TME Panel™ to classify patient samples into one of four tumor microenvironment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each TNBC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort C1) or in combination with paclitaxel (80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle) (Cohort C2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of < 5% and a 20% PFS rate at 4 months, with targets of 15% and 40% respectively considered promising for this study. Interim efficacy assessments will be at 10-patient increments following the time patients have had at least 1 post-baseline scan. Cohort continuation and future evaluation decisions will be guided by the boundaries identified by a sequential monitoring procedure. Secondary efficacy endpoints include overall survival, time to response, disease control rate, duration of response, and the relationship between antitumor activity of navicixizumab and Xerna TME Panel™ biomarker subtypes. Citation Format: Amelia B. Zelnak, Heinz-Josef Lenz, Kerry Culm, Lukas Makris, Valerie Chamberlain Santos, Hagop Youssoufian, Colleen Mockbee, Kathy D. Miller. ONCX-NAV-G201: A phase 2, basket study of navicixizumab monotherapy or in combination with chemotherapy in patients with select advanced solid tumors: Triple-negative breast cancer cohort (trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-01.

Abstract Number: LBA16 Does Intracranial Hemorrhage Associated with Tenecteplase Occur Exclusively Within the Stroke Burden?

Introduction As IV tenecteplase (TNK) is becoming an alternative to IV alteplase in acute ischemic stroke (AIS), establishing the incidence of intracranial hemorrhage (ICH) complications is important. Given the higher fibrin specificity of TNK as compared to alteplase, our aim was to distinguish hemorrhage within the stroke burden versus spontaneous ICH in patients with AIS with TNK‐associated ICH. Methods Retrospective chart review of patients presenting from February 2020 to January 2022 with anterior circulation AIS to our comprehensive stroke center who received TNK was performed to evaluate for associated ICH. ECASS‐3 criteria was used to define hemorrhagic transformation and ICH score was used for primary, spontaneous ICH. Fisher exact test statistic was used to evaluate for significant differences in ASPECTS score, medium versus versus large vessel occlusion, angiographic recanalization, IV eptifibatide use, pre‐morbid antiplatelet use, and association with symptomatic versus asymptomatic hemorrhage. A benchmark less than 5% symptomatic ICH incidence was set based on historical alteplase rates within our network. Social science statistics software was used for data analysis. Results Out of 77 subjects who received TNK, 20.7% (n = 16) developed ICH, 9.1% (n = 7) of which were symptomatic ICH with a temporally‐related increase in NIHSS of at least 4 or greater. Seven subjects (43.75%) were male. Mean age was 73.38 (95% CI 65.92, 80.83). Median initial NIHSS was 16, 95% CI [11.74, 21.51]. Median ASPECTS was 9, 95% CI [8.74, 9.89]. Two subjects developed spontaneous, primary ICH (n = 1 symptomatic ICH, n = 1 non‐symptomatic ICH) in the absence of hemorrhagic transformation of ischemic stroke. No significant difference between subjects with asymptomatic hemorrhage versus symptomatic hemorrhage was found when comparing ASPECTS > = 7 versus < 7 (Fisher value = 1), angiographic recanalization (Fisher value = 1), use of IV eptifibatide (Fisher value = 1), pre‐morbid antiplatelet use (Fisher value = 0.13), or medium vessel occlusion (Fisher value = ‐0.63). Conclusions Expected rates of hemorrhagic transformation were higher in tenecteplase than our historical benchmark rate for alteplase. Spontaneous hemorrhage unrelated to ischemic stroke area were seen in 2 subjects without known hematological disorders. Larger, prospective studies are needed to validate safety of tenecteplase in real world settings.

ONCX-NAV-G201: A phase 2 basket study of navicixizumab monotherapy or in combination with chemotherapy in patients with select advanced solid tumors—Colorectal Cancer Cohort (trial in progress).

TPS263 Background: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors (NCT05453825). Cohort A will enroll colorectal cancer (CRC) patients. Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aggressive CRC remains difficult to treat owing to the aberrant activation of oncogenic signaling pathways including the NOTCH pathway. Preclinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway inhibition. We postulate that navicixizumab will demonstrate anticancer efficacy against CRC. Methods: Eligible CRC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 3 prior lines of standard therapy for metastatic disease, including an anti-VEGF monoclonal antibody. Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap ExTra with the Xerna TME Panel where patient samples will be classified into one of four tumor microenviroment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each CRC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort A1) or in combination with irinotecan (180 mg/m2 on Days 1 and 15 of a 28-day cycle, Cohort A2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of <5% and a 25% PFS rate at 4 months, with targets of 15% and 50% respectively considered promising for this study. Interim efficacy assessments will be at 10-patient increments following the time patients have had at least 1 post-baseline scan. Cohort continuation and future evaluation decisions will be guided by the boundaries identified by a sequential monitoring procedure. Secondary efficacy endpoints include overall survival, time to response, disease control rate, duration of response, and the relationship between antitumor activity of navicixizumab and Xerna TME Panel biomarker subtypes. Clinical trial information: NCT05453825 .

Phase 2 study of AV-GBM-1 (a tumor-initiating cell targeted dendritic cell vaccine) in newly diagnosed Glioblastoma patients: safety and efficacy assessment

BackgroundVaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival.MethodsFresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration.ResultsSuccess rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%.ConclusionsAV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted.Trial registrationNCT, NCT03400917, Registered 10 January 2018,

Real World Effectiveness of "7 + 3" Intensive Chemotherapy Vs Venetoclax and Hypomethylating Agent for Initial Therapy in Adult Acute Myeloid Leukemia

Introduction Initial treatment selection for older adults with AML remains challenging. Historically, clinicians and patients had to choose between intensive chemotherapy (7 + 3), low intensity therapy or best supportive care. Approval of venetoclax and a hypomethylating agent (ven/HMA, NCT02993523) for those ≥75 years or with major comorbidities has offered higher response rates and improved survival vs. low intensity therapy. Use has expanded to other groups like younger patients with high risk disease or patients with "borderline" induction fitness. Prospective comparisons have yet to complete, so we examined retrospective outcomes for older patients receiving either 7 + 3 or ven/HMA as initial therapy. Methods We included patients from both the University of Pennsylvania ("HUP", n=187) and the Flatiron Health electronic health record derived, de-identified database with incident AML diagnosed between January 2017 and 2021, and 7 + 3 (7 days of cytarabine and 3 days of anthracycline) or ven/HMA (azacitadine or decitabine) as initial therapy (n=621). Only patients presumably eligible for 7 + 3 were included (age 60-75, estimated glomerular filtration rate > 30 mL/min, alanine transaminase, aspartate transaminase, bilirubin < 1.5x upper limit of normal (ULN), no history of systolic heart failure). Primary endpoint of overall survival (OS) had 80% power for hazard ratio (HR) 0.74 with alpha 0.05. OS was analyzed by Kaplan-Meier method and compared using log-rank test. Pre-planned sensitivity analyses included multiple imputation (MI) with inverse-probability of treatment weighting (IPTW) to address missingness and balance baseline covariates. Results 305 patients received 7 + 3 and 503 received ven/HMA. Baseline covariates showed ven/HMA patients were older, sicker and had worse disease biology (table 1). Underscoring this imbalance in age and comorbidity, allogeneic transplant rates were 31% vs 16% for 7 + 3 and ven/HMA respectively (p<0.0005). More than 40% of initial 7 + 3 patients received second-line ven/HMA while less than 10% of ven/HMA patients received second line 7 + 3 or CPX-351. In unadjusted analysis, median OS (mOS) was 14 months for all patients and 22 months for 7 + 3 versus 10 months for ven/HMA (HR 0.52, 95% confidence interval CI 0.41-0.67, p-value <0.005, Fig 1). No subset had statistically significant higher OS with ven/HMA compared to 7 and 3; in multi-variate analysis controlling for all covariates with univariate p-value < 0.20 induction choice did not affect overall survival (limited to complete cases n=229, HR 0.72, p-value 0.21). Missing values in the HUP dataset were <5% for all baseline covariates; Flatiron dataset missing values ranged from 0-40% for covariates (e.g., sex and baseline LDH respectively). After balancing covariates and adjustment for missing values, survival remained superior in the 7+3 group (HR 0.71, p-value 0.026, 95% CI 0.53-0.94) (absolute standardized differences for all baseline variables were below 0.10). Regarding safety, early mortality was higher for ven/HMA (13% vs 6%, p=0.003). However, rates of febrile neutropenia and culture positive infection were higher for 7 + 3. Length of stay, including any admission prior to next cycle, was longer for 7 + 3 in the HUP cohort (among patients admitted for induction: average 25 days for ven/HMA vs 34 days for 7 and 3 p=0.0012; an additional 20% of ven/HMA patients were managed entirely outpatient). Conclusion In this large, multi-center real word study, of patients presumed to be eligible for either approach we found superior outcomes for 7 + 3. However, there was significant confounding by indication and imbalance between the groups. Adjusting for these differences, OS was still higher for 7 + 3 (p=0.026). In this real world dataset, the 7 + 3 cohort outperformed historical benchmarks (e.g., NCT02085408) in OS and early mortality, perhaps reflecting improved later lines of therapy and patient selection. Given the significant confounding by indication, uneven cross-over and greater lab-based AEs/longer length of stays for intensive chemotherapy, prospective studies (such as NCT04801797) must confirm superiority of intensive chemotherapy. Careful attention to factors predictive of response to non-7 + 3 based therapy may be as important as the characterization of side effects, quality of life and impact on allotransplant to select optimal therapies for all adult AML patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pseudospectral Approach to the Shape Optimization of Beams Under Buckling Constraints

In this article, a direct transcription approach to the minimization of the volume of elastic straight beams undergoing plane deformation and subject to buckling loads is presented. In particular, the so-called pseudospectral method is employed, where state variables are approximated by Lagrange interpolating polynomials and static equations are collocated at Legendre-Gauss-Radau nonuniform mesh points. The resulting shape optimization problems are thus transcribed into constrained nonlinear programming problems, which in turn are solved by developed routines. Historical benchmark and academic problems such as simply supported beams subject to a concentrated compressing force, compressed and rotating cantilever beams and simply supported beams under a non-conservative follower distributed load are revisited and numerically solved under the conditions of plane deformation theory. Numerical solutions are discussed and compared to those obtained by the shooting method, which is largely employed for these problems, emphasizing how the proposed method could forecast optimal cross sectional area distributions within a unified fashion and without resorting to accurate guesses beforehand.

CTIM-16. PHASE 1 TRIAL OF RUXOLITINIB, TEMOZOLOMIDE, AND RADIATION IN HIGH-GRADE GLIOMAS

Abstract BACKGROUND Ruxolitinib is a small molecule inhibitor of JAK1 (Janus kinase 1) and JAK2 and JAK3. Dysregulation of the JAK/STAT pathway is associated with increased proliferation and survival of malignant cells. Preclinical evidence supporting inhibition of the JAK-STAT pathway arrogated glioma growth led to the design of this trial. METHODS Newly diagnosed patients with unmethylated MGMT HGG (arm 1) received ruxolitinib and 60 Gy radiation for 6 weeks over 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 was 10 mg twice daily, level 2 (15 mg twice daily), level 3 (20 mg twice daily), and level -1 was 5 mg twice daily. Patients with methylated MGMT HGG (arm 2) received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method and compared using the log-rank test. RESULTS 60 HGG were treated in the study and there was no dose-limiting toxicity. Survival data was calculated for 37 GBM patients. The OS for arm 1 was 18.17 months (10.15, NA) and was not reached for arm 2. The 1-year OS was 0.77 for all GBM patients, was 0.62 for arm 1 (unmethylated MGMT) and 0.93 for arm 2 (unmethylated MGMT). CONCLUSIONS A dose of 20 mg twice daily of ruxolitinib is safe with radiation and temozolomide. Preliminary survival data appears promising compared to the historical benchmarks for both the methylated MGMT and unmethylated MGMT groups. Genomic markers of response will be presented. A randomized phase 2 trial is planned.

Integrated evidence-based extent of occurrence for North American bison (Bison bison) since 1500CE and before.

Following the near extinction of bison (Bison bison) from its historic range across North America in the late 19th century, novel bison conservation efforts in the early 20th century catalyzed a popular widespread conservation movement to protect and restore bison among other species and places. Since Allen's initial delineation (1876) of the historic distribution of North American bison, subsequent attempts have been hampered by knowledge gaps about bison distribution and abundance prior to and following colonial arrival and settlement. For the first time, we applied a multidisciplinary approach to assemble a comprehensive, integrated geographic database and meta-analysis of bison occurrence over the last 200,000years, with particular emphasis on the 450years before present. We combined paleontology, archaeology, and historical ecology data for our database, which totaled 6438 observations. We derived the observations from existing online databases, published literature, and first-hand exploration journal entries. To illustrate the conservative maximum historical extent of occurrence of bison, we created a concave hull using observations occurring over the last 450years (n=3379 observations), which is the broadly accepted historical benchmark at 1500CE covering 59% of the North American continent. Although this distribution represents a historic extent of occurrence-merely delineating the maximum margins of the near-continental distribution-it does not replace a density-based approach reconstructing potential historical range distributions, which identifies core and marginal ranges. However, we envision the observations contained in this database will contribute to further research in the increasingly evidence-based disciplines of bison ecology, evolution, rewilding, management, and conservation. There are no copyright or proprietary restrictions on these data, and this data paper should be cited when the data are reused.

Patient-Level Disease Burden as a Predictor of In-Field Failures in Patients Undergoing Bridging Radiotherapy for CD19-Directed Chimeric Antigen Receptor (CAR) T-Cell Therapy for Recurrent/Refractory Large B-Cell Lymphomas

<h3>Purpose/Objective(s)</h3> Radiation therapy (RT) is a safe and effective treatment strategy in bridging patients with relapsed/refractory large B-cell lymphomas (R/R LBCL) to CAR T-cell therapy. However, the optimal implementation of bridging RT (bRT) remains poorly understood, particularly in respect to achieving durable local control (LC) and improving patient outcomes. We sought to identify factors associated with lesion LC and patient survival in patients treated with bRT. <h3>Materials/Methods</h3> Performed a retrospective analysis of R/R LBCL patients receiving CAR T-cell infusion at our institution between 12/2017 and 6/2021. Clinical outcomes were compared with our previously published cohort of 63 unirradiated (nonRT) patients. Categorical results were compared using Fisher's exact test. Time-to-event analysis was estimated using Kaplan-Meier method and compared with log-rank. <h3>Results</h3> Forty-five patients underwent bRT prior to CART. Compared with our previous nonRT cohort, bRT patients had substantially worse disease burden as measured by median metabolic tumor volume (MTV) (463 v. 186cc), the presence of any lesion ≥ 5 cm (87 v. 67%), and the presence of any necrotic lesion (50 v. 28%). Despite the worse prognosis, we observed similar DFS when compared to the prior lower-risk, nonRT cohort (12-month DFS 46 v. 51%). Nearly half of bRT patients maintained a complete and durable response at a median follow-up of 11.6 months. Furthermore, bRT patients experienced fewer local only failures (n=2/22, 9%) compared to our nonRT cohort (n=13/26, 36%; p = 0.03). A trend towards decreased any local failure (64% vs 86%) and an increased distant only failure (36% vs. 14%; both p = 0.06) was observed in our bRT cohort compared to our historical benchmark. Forty patients with 98 irradiated lesions underwent lesion-level analysis. Patients received bRT to a median of 2 lesions (range 1-9) with a median EQ2D (a/b=10) dose of 31.2Gy. In-field progression was observed in 11/40 (28%) of patients and 23/98 (24%) of lesions. In-field progression was strongly correlated within patients with multiple irradiated lesions, with 83% exhibiting uniform outcomes across all treated lesions (i.e., either all local control or failure among irradiated lesions). At the patient level, the presence of any in-field progression was strongly correlated with total disease burden using both the previously reported MTV threshold of 150cc (9 v 34%) and the bRT cohort's median MTV of 463cc (14 v. 42%; both p < 0.05). <h3>Conclusion</h3> Patients receiving bRT prior to CAR T-cell therapy for R/R LBCL with high MTV appear to exhibit comparable outcomes to patients with far lower disease burden who did not undergo irradiation, supporting a potential role of bRT in high-risk patients to improve clinical outcomes. In-field progression of irradiated lesions occurred in a quarter of bRT patients and is strongly correlated with total disease burden. Future prospective trials are needed to optimize RT strategies to improve outcomes in patients undergoing CART therapy.

Improving the genuine progress indicator to measure comparable net welfare: U.S. and California, 1995–2017

This paper argues that important improvements in the Genuine Progress Indicator (GPI) can be made by directly calculating the loss of natural resources, the benefits of leisure, and adjusting for inequality using a global norm, rather than using local, historical benchmarks. Local benchmarking is an obstacle to the standardisation and comparability of the GPI. We provide alternative methods for the five components that have used benchmarking in the standard GPI. We present empirical estimates for the GPI of the United States and California over the period 1995 through 2017, calculated with and without the alternative methods. Using our alternative methods, we show that some differences between the GPI of CA and the U.S. are artefacts of the benchmark methods. Implementing the alternative methods narrows the gap between the CA and the U.S. GPI as it reduces the U.S. environmental costs, and removes the artificial differential between CA and the U.S. in the cost of inequality. However, we find that the GPI provides insight into net welfare not reflected in GDP, both with and without the benchmarking methods. Overall, we suggest that the GPI can be significantly improved with these high priority revisions without changing the fundamental approach or theoretical framework.

Understanding leveraged ETFs’ compounding effect

PurposePrior literature has shown that, theoretically, holding-period returns of a leveraged exchange-traded fund (LETF) are generally negatively affected by the volatility of the underlying benchmark’s daily returns, particularly for long holding periods. However, recent empirical studies simulate LETFs’ returns using historical benchmark returns and report results that are not entirely consistent with the theoretical predictions, leading to the possibility that the distribution of real-world returns may have certain characteristics that influence the outcomes. In this paper, the authors examine how asymmetric volatility affects LETFs’ performance and provide detailed explanations for the behavior of the performance of LETFs under different market conditions.Design/methodology/approachThe authors conduct simulation analyses on a +3x LETF and a −3x LETF based on historical S&P 500 stock index returns, with asymmetric volatility incorporated into the model.FindingsBy incorporating the asymmetric volatility effect, the simulation results suggest that, contrary to the theoretical predictions, higher volatility does not always lead to more negative impact on LETFs’ performance. Rather, the performance depends on the market conditions under which high volatility occurs. The findings therefore help reconcile prior theoretical predictions with reported empirical findings.Originality/valueThe analysis adds to the literature by incorporating the asymmetric volatility effect of stock returns in studying LETFs’ performance. The authors also provide detailed explanations for the behavior of LETFs’ returns and compounding effect under different market conditions, thus providing contexts to prior empirical results.

Economic evaluation of asset pricing models under predictability

This paper performs an out-of-sample comparison of linear factor asset pricing models from an economic perspective under predictability. I assess the economic value added of several factor models when a Bayesian investor is faced with a portfolio allocation problem whereby each model imposes cross-sectional restrictions on the parameters of a predictive stock return regression. The empirical framework explicitly accounts for investor skepticism about the model, i.e., mispricing uncertainty. Despite vast statistical work on in-sample model comparison for the new-generation asset-pricing models, their out-of-sample performance cannot beat a simple benchmark on a wide range of tests from an economic perspective. This is consistent with thus extends the conclusion for the first-generation of factor models. An exceptional case of factor models yielding significant economic gains is observed when evaluating industry portfolios at the shortest horizon (1-month). In this case, I find that the q5 model of Hou et al. (2021) and the behavioral factor model of Stambaugh and Yuan (2017) outperform the historical benchmark in several cases.

Virtual Geritalk: Does Intensive Virtual Communication Skills Training Improve Use of Serious Illness Communication Skills?

Background: The COVID-19 pandemic presented a unique opportunity to adapt in-person communication skills training to a virtual format. Objective: Examine use of serious illness communication skills by learners after participating in an intensive virtual communication skills training. Design: Prospective cohort study. Setting/Subjects: Icahn School of Medicine at Mount Sinai, Clinical Fellows. Measurements: Family Meeting Communication Assessment Tool (FAMCAT) assessed fundamental and advanced communication skills. Results: As compared to a historical benchmark obtained after a prior in-person course, the virtual course showed equivalent or better use of communication skills across fundamental skills and advanced skills. Conclusions: Our findings suggest that a virtual communication skills training is associated with the use of serious illness communication skills in the clinical setting by learners.

Phase 2 study of anti-disialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma: A report from the Children's Oncology Group

PurposeNovel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes. MethodsAOST1421 was a single-arm Phase 2 study for patients with recurrent pulmonary osteosarcoma in complete surgical remission. Patients received up to five cycles of dinutuximab (70 mg/m2/cycle) with granulocyte-macrophage colony-stimulating factor (GM-CSF). Two different dinutuximab infusion schedules were studied: 35 mg/m2/day over 20 h (2 days) and 17.5 mg/m2/day over 10 h (4 days). Primary end point was DCR, defined as a proportion of patients event free at 12 months from enrolment. The historical benchmark was 12-month DCR of 20% (95% CI 10–34%). Dinutuximab would be considered effective if ≥ 16/39 patients remained event free. Secondary objectives included toxicity evaluation and pharmacokinetics. ResultsThirty-nine eligible patients were included in the outcome analysis. Dinutuximab did not demonstrate evidence of efficacy as 11/39 patients remained event free for a DCR of 28.2% (95% CI 15–44.9%). One of 136 administered therapy cycles met criteria for unacceptable toxicity when a patient experienced sudden death of unknown cause. Other ≥ Grade 3 toxicities included pain, diarrhoea, hypoxia, and hypotension. Pharmacokinetic parameters were similar in the two schedules. ConclusionsThe combination of dinutuximab with GM-CSF did not significantly improve DCR in recurrent osteosarcoma. Dinutuximab toxicity and pharmacokinetics in adolescent and young adult osteosarcoma patients were similar to younger patients. Other strategies for targeting GD2 in osteosarcoma are being developed.

How to improve the estimation of intra-firm prices for financial and tax reporting during economic downturns

In this article, we propose an approach that can be employed to estimate prices in intra-group trade at times of economic turmoil, and to improve financial, management, and tax reporting by using current macroeconomic data to adjust historic benchmarks. We explored the use of a predictive model, that employs macroeconomic data, and in particular changes in GDP, to predict company profitability and arm’s length profit ranges. The results of our analysis show that there are correlations between changes in GDP and changes in certain P&L items of companies operating in Europe. While the relation might or might not be explained by a causal/inference model (Granger causality), it may have a practical use: to predict changes in the profitability of companies when company data are not available in real time (Shmueli, 2010).

P1351: CHARACTERIZING ALLOGENEIC STEM CELL TRANSPLANTATION SAFETY IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES AFTER PEMBROLIZUMAB THERAPY

Background: Although allogeneic stem cell transplantation (allo-SCT) and programmed cell death 1 (PD-1) blockade have separately shown efficacy in some lymphoid malignancies, the safety of allo-SCT after anti–PD-1 therapy in these patients remains a high clinical interest. Aims: We present data from an analysis from 4 KEYNOTE phase 1-3 studies to describe predetermined complications in patients who received allo-SCT following pembrolizumab therapy. Methods: The analysis included patients from the KEYNOTE-013 (NCT01953692, n=20), KEYNOTE-087 (NCT02453594, n=31), KEYNOTE-170 (NCT02576990, n=5), and KEYNOTE-204 (NCT02684292, n=14) trials who have a known allo-SCT transplantation date received within 2 years of the last dose of study pembrolizumab. Descriptive statistics were used for predefined post–allo-SCT complications of interest. The cumulative incidence of acute grade 2-4 graft-versus-host disease (GVHD), acute grade 3-4 GVHD, and chronic GVHD was estimated. The corresponding competing risk events were death without acute grade 2-4 GVHD, death without acute grade 3-4 GVHD, and death without chronic GVHD, respectively. The cumulative incidence of post–allo-SCT transplant-related mortality (TRM) was estimated with relapse as a competing risk. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Seventy patients were included in the analysis. Median age was 30 y (range, 18-65), 57 (81.4%) had classical Hodgkin lymphoma (cHL), and the rest had non-Hodgkin lymphoma. 69 of 70 (98.6%) patients received pembrolizumab monotherapy; 1 patient received pembrolizumab + lenalidomide. Median duration on study treatment was 5.3 months (range, 0.7-29.6) and median time from last pembrolizumab dose to first allo-SCT was 4.6 months (range, 1-20). Before transplantation, 49 patients (70.0%) had intervening anticancer regimen; 34 (48.6%) had active disease, 31 patients (44.3%) were in remission at time of transplant, and 5 patients (7.1%) had unknown disease status. Overall, 55 patients (78.6%) developed GVHD (acute, 38; chronic, 17). The estimated 6-month post–allo-SCT cumulative incidence was 0.41 (95% CI, 0.30-0.53) for grade II-IV acute GVHD and 0.20 (95% CI, 0.12-0.30) for grade III-IV acute GVHD; 1 year post–allo-SCT was 0.21 (95% CI, 0.12-0.31) for chronic GVHD. Other predetermined complications, including critical illness, immune-mediated adverse events, pulmonary complications, and veno-occlusive liver disease, occurred in 32 patients (45.7%). After a median follow-up (defined as the time from allo-SCT to data cutoff) of 40.1 months (range, 5.1-71.2), the post–allo-SCT median PFS was not reached (NR) (95% CI, 14.5-NR) and the 30-month post–allo-SCT PFS rate was 56.8% (95% CI, 42.9-68.5) (Figure A); median OS was NR (95% CI, NR-NR) and the OS rate at 12 months was 82.2% (Figure B). The estimated post–allo-SCT cumulative incidence for TRM at 6 months was 0.09 (95% CI, 0.03-0.17) and for relapse at 26 months was 0.27 (95% CI, 0.16-0.38). PFS and OS outcomes were comparable in the subgroup of patients with cHL. Image:Summary/Conclusion: The incidence of GVHD in this population is comparable to historical data (40%-80% and 30%-70%, respectively). The incidence of severe acute GVHD may be higher than a typical modern allo-SCT series, although TRM was low. The observed PFS and OS outcomes compare favorably to historical benchmarks (2-year PFS ranging from 45%-48%; 1-year OS >80%). Altogether, this analysis lends confidence that allo-SCT is feasible for patients with lymphoid malignancies after PD-1 blockade.

БЕНЧМАРКИНГ КАК ВАЖНЫЙ МЕТОД ДЛЯ РАЗВИТИЯ СИСТЕМЫ ЗДРАВООХРАНЕНИЯ НА МОДЕЛИ ПРОФИЛЯ «ДЕТСКАЯ ОНКОЛОГИЯ И ГЕМАТОЛОГИЯ»

The national medical research centers (NMRCs) play an important role in managing the quality of healthcare system and evaluating its resources within the supervised profiles in Russia. The lack of controlling resources within NMRCs limit the possibility for improving the efficiency of healthcare in supervised profiles. The electronic benchmarking system could’ve become such a tool for the controlling over medical organizations (MO). It would allow evaluating the activities of MO (for example, comparing the activities of the analyzed MO with the reference MO, or dynamics of changes in MO - historical benchmarking), finding and implementing the most effective methods for organization of work of MO and improving the quality of medical care provided to patients. The authors of the article describe the experience of development and implementation of benchmarking system in MO of the “Children's Oncology and Hematology” profile. Based on the initial results of the analysis, the following issues were identified: 1) absence of nutritive support algorithms (in 90 % of MO analyzed); 2) absence of children patient register for oncology and hematology (61 % of MO analyzed); 3) inability to organize radiation therapy service (55 % of MO analyzed); 4) deficit of surgeon operators in the field of “pediatric oncology” (42 % of MO analyzed); 5) absence of capacity for isolation of immunocompromised patients within intensive care units (39 % of MO analyzed). Thus, after analyzing with the use of electronic benchmarking tools, the primary problematics can be shown therefore the key problems requiring corrective measures by the MO management can be distinguished. The further dynamic assessment also allows evaluating of the effectiveness of the ‘work on bugs’ done.

A practical algorithm for VMAT optimization using column generation techniques.

As a challenging but important optimization problem, the inverse planning for volumetric modulated arc therapy (VMAT) has attracted much research attention. The column generation (CG) type method is so far one of the most effective solution schemes. However, it often relies on simplifications leading to significant gaps between the output and the actual feasible plan. This paper presents a novel column generation (NCG) approach to push the planning results substantially closer topractice. The proposed NCG algorithm is equipped with multiple new quality-enhancing and computation-facilitating modules as below: (1) Flexible constraints are enabled on both dose rates and treatment time to adapt to machine capabilities as well as planner's preferences, respectively; (2) a cross-control-point intermediate aperture simulation is incorporated to better conform to the underlying physics; (3) new pricing and pruning subroutines are adopted to achieve better optimization outputs. To evaluate the effectiveness of this NCG, five VMAT plans, that is, three prostate cases and two head-and-neck cases, were computed using proposed NCG. The planning results were compared with those yielded by a historical benchmark planningscheme. The NCG generated plans of significantly better quality than the benchmark planning algorithm. For prostate cases, NCG plans satisfied all planning target volume (PTV) criteria whereas CG plans failed on D10% criteria of PTVs for over 9 Gy or more on all cases. For head-and-neck cases, again, NCG plans satisfied all PTVs criteria while CG plans failed on D10% criteria of PTVs for over 3 Gy or more on all cases as well as the max dose criteria of both cord and brain stem for over 13 Gy on one case. Moreover, the pruning scheme was found to be effective in enhancing the optimizationquality. The proposed NCG inherits the computational advantages of the traditional CG, while capturing a more realistic characterization of the machine capability and underlying physics. The output solutions of the NCG are substantially closer to practicalimplementation.