Historical Benchmark Research Articles

Spatial Memory of Notable Hurricane Tracks and Their Geophysical Hazards

Previous research has shown that people use a benchmark hurricane as part of their preparation and evacuation decision-making process. While hurricanes are a common occurrence along the Gulf Coast, research on personal memories of past storms is lacking. Particularly, how well do people remember the track and geophysical hazards (wind speed, storm surge, and total rainfall) of past storms? The accurate or inaccurate recollection and perception of previous storm details can influence personal responses to future storms, such as the decision to evacuate or take other life-saving actions. Survey responses of residents in Alabama and Mississippi were studied to determine if people were accurately able to recall a notable storm’s name when seeing an image of the storm’s track. Those who were able to identify the storm by its track were also asked if they could remember the storm’s maximum reported rainfall, maximum sustained winds, and storm surge at landfall. Results showed that there were statistically significant differences between the levels of accurate recall for different storms, with Hurricanes Katrina and Michael having the most correct responses. Regardless of the storm, most people struggled to remember geophysical hazards. The results of this study are important as they can inform broadcast meteorologists and emergency managers on forecast elements of the storm to better emphasize in future communication in comparison to the actual values from historical benchmark storms.

HexaLCSeg: A historical benchmark dataset from Hexagon satellite images for land cover segmentation [Software and Data Sets

HexaLCSeg: A historical benchmark dataset from Hexagon satellite images for land cover segmentation [Software and Data Sets

Single-Institution Experience of Larotrectinib Therapy for Patients With NTRK Fusion-Positive Thyroid Carcinoma.

The real world efficacy and tolerabiltiy of NTRK inhibitor larotrectinib has not yet been reported in the literature although trial data has shown promising results. We report a retrospective analysis of patients with thyroid cancer harboring NTRK fusions who underwent treatment with larotrectinib. A single-institution, retrospective case series of patients with NTRK fusion-positive thyroid cancers treated with neurotrophic tyrosine receptor kinase (NTRK) inhibitors from January 1, 2007, to January 1, 2023, was performed. This study was conducted at a single academic tertiary referral center. Patients with confirmed NTRK-fusion thyroid cancer who received larotrectinib were included. Larotrectinib was administered in accordance with clinical judgment from oncology providers. The primary end point was progression-free survival (PFS). Eight patients with NTRK fusion-positive thyroid cancer treated with larotrectinib were identified: 4 with papillary thyroid cancer (PTC) (50%), 3 with poorly differentiated thyroid cancer (PDTC) (38%), and 1 with anaplastic thyroid cancer (ATC) (12%). The median PFS (mPFS) for all patients was 24.7 months (95% CI, 11.3-38.1). mPFS in PTC was higher than PDTC (34.6 months [24.7-48.7 months] vs 17.5 [7.1-21.1 months]; P = .017). The median overall survival (OS) was 43.8 months (29.8-56.8 months) overall. The single patient with ATC had a PFS and OS of 23 months. Two patients remained on treatment/alive at data cutoff, with a duration of response of 33.5 months and a median follow-up of 52 months. Patients achieved 1 complete response (12%), 6 partial responses (75%), and 1 stable disease (12%). In this single-institution cohort of patients with NTRK fusion-positive thyroid cancer, NTRK inhibition led to an mPFS of 25 months, with survival surpassing historic benchmarks for ATC and PDTC.

The MUSIC Critical Benchmark and Nuclear Data

The Measurement of Uranium Subcritical and Critical (MUSIC) experiment was a series of measurements of critical and subcritical configurations of bare highly enriched uranium. The goal was to compare measurement methods, analysis techniques, and simulation methods across regimes of criticality and to provide high-quality validation of 235U nuclear data. A benchmark evaluation of the two critical configurations of the MUSIC experiments will soon be published in the release of the International Criticality Safety Benchmark Evaluation Project Handbook. The recent execution of the experiment aids in proper quantification of model simplifications and all uncertainties associated with the experiment. Historical benchmark evaluations are heavily relied on for uranium nuclear data validation despite the fact that the same level of documentation and comparable uncertainty analysis may not be present. The MUSIC evaluation is less likely to include “unknown unknowns” that could impede accurately modeling the system. Presented are both highly detailed and very simplified models, which represent the experimental configurations accurately, aiding the users of the benchmark for nuclear data or transport code validation. The sensitivities of k eff to nuclear data and nuclear data–related uncertainties are very similar between this experiment and previous bare uranium sphere experiments. In addition, the nuclear data uncertainties to any nuclides other than 235 U are small. For all these reasons, the recently evaluated MUSIC benchmark critical configurations could prove very useful for 235 U nuclear data validation. Currently, major libraries have good agreement with the experimental results, within 200 pcm for all nuclear data libraries, and within one standard deviation of the experimental result for most. Suggested nuclear data adjustments based on MUSIC and Lady Godiva are also presented, with posterior improvements to both the agreement in k eff and the uncertainty associated with the nuclear data.

Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn

BackgroundIn early-onset severe hemolytic disease of the fetus and newborn (HDFN), transplacental transfer of maternal antierythrocyte IgG alloantibodies causes fetal anemia that leads to the use of high-risk intrauterine transfusions in order to avoid fetal hydrops and fetal death. Nipocalimab, an anti–neonatal Fc receptor blocker, inhibits transplacental IgG transfer and lowers maternal IgG levels.MethodsIn an international, open-label, single-group, phase 2 study, we assessed treatment with intravenous nipocalimab (30 or 45 mg per kilogram of body weight per week) administered from 14 to 35 weeks’ gestation in participants with pregnancies at high risk for recurrent early-onset severe HDFN. The primary end point was live birth at 32 weeks’ gestation or later without intrauterine transfusions as assessed against a historical benchmark (0%; clinically meaningful difference, 10%).ResultsLive birth at 32 weeks’ gestation or later without intrauterine transfusions occurred in 7 of 13 pregnancies (54%; 95% confidence interval, 25 to 81) in the study. No cases of fetal hydrops occurred, and 6 participants (46%) did not receive any antenatal or neonatal transfusions. Six fetuses received an intrauterine transfusion: five fetuses at 24 weeks’ gestation or later and one fetus before fetal loss at 22 weeks and 5 days’ gestation. Live birth occurred in 12 pregnancies. The median gestational age at delivery was 36 weeks and 4 days. Of the 12 live-born infants, 1 received one exchange transfusion and one simple transfusion and 5 received only simple transfusions. Treatment-related decreases in the alloantibody titer and IgG level were observed in maternal samples and cord blood. No unusual maternal or pediatric infections were observed. Serious adverse events were consistent with HDFN, pregnancy, or prematurity.ConclusionsNipocalimab treatment delayed or prevented fetal anemia or intrauterine transfusions, as compared with the historical benchmark, in pregnancies at high risk for early-onset severe HDFN. (Funded by Janssen Research and Development; UNITY ClinicalTrials.gov number, NCT03842189.)

Randomized Phase II Trial of Immunotherapy-Based Total Neoadjuvant Therapy for Proficient Mismatch Repair or Microsatellite Stable Locally Advanced Rectal Cancer (TORCH).

PURPOSETo assess whether the integration of PD-1 inhibitor with total neoadjuvant therapy (iTNT) can lead to an improvement in complete responses (CRs) and favors a watch-and-wait (WW) strategy in patients with proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC).PATIENTS AND METHODSWe conducted a prospective, multicenter, randomized, open-label, phase II trial using a pick-the-winner design. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma were randomly assigned to group A for short-course radiotherapy (SCRT) followed by six cycles of consolidation immunochemotherapy with capecitabine and oxaliplatin and toripalimab or to group B for two cycles of induction immunochemotherapy followed by SCRT and the rest four doses. Either total mesorectal excision or WW was applied on the basis of tumor response. The primary end point was CR which included pathological CR (pCR) after surgery and clinical CR (cCR) if WW was applicable, with hypothesis of an increased CR of 40% after iTNT compared with historical data of 25% after conventional TNT.RESULTSOf the 130 patients enrolled, 121 pMMR/MSS patients were evaluable (62 in group A and 59 in group B). At a median follow-up of 19 months, CR was achieved at 56.5% in group A and 54.2% in group B. Both groups fulfilled the predefined statistical hypothesis (P < .001). Both groups reported a pCR rate of 50%. Respectively, 15 patients in each group underwent WW and remained disease free. The most frequent grade 3 to 4 toxicities were thrombocytopenia and neutropenia. Patients in group A had higher rate of cCR (43.5% v 35.6%) at restaging and lower rate of grade 3 to 4 thrombocytopenia (24.2% v 33.9%) during neoadjuvant treatment.CONCLUSIONThe iTNT regimens remarkably improved CR rates in pMMR/MSS LARC compared with historical benchmark with acceptable toxicity. Up-front SCRT followed by immunochemotherapy was selected for future definitive study.

Increasing disturbance frequency undermines coral reef recovery

AbstractClimate‐driven alterations to disturbance regimes are increasingly disrupting patterns of recovery in many biomes. Here, we examine the impact of disturbance and subsequent level of recovery in live hard coral cover on the Great Barrier Reef (GBR) across the last three decades. We demonstrate that a preexisting pattern of infrequent disturbances of limited spatial extent has changed to larger and more frequent disturbances, dominated by marine heatwaves and severe tropical cyclones. We detected an increase in the impact (measured as coral loss) across 265 individual disturbance impacts on 131 reefs in a 36‐year dataset (1985–2022). Additionally, the number of survey reefs impacted by disturbance has increased each decade from 6% in the 1980s to 44% in the 2010s, as has the frequency of mass coral bleaching across the GBR, which has increased between 19% and 28% per year, and cyclones (3%–5% per year), resulting in less time for recovery. Of the 265 disturbance impacts we recorded, complete recovery to the highest levels of coral cover recorded earlier in this study (the “historical benchmark”) occurred only 62 (23%) times. Of the 23% of disturbance impacts that resulted in complete recovery to historical benchmarks, 34/62 recovered to their benchmark in 2021 or 2022. Complete recovery was more likely when the historical benchmark was &lt;25% live hard coral cover. The lack of recovery was attributed to recovery time windows becoming shorter due to increases in the frequency of cyclones and of thermal stress events that result in mass coral bleaching episodes. These results confirm that climate change is contributing to ecosystem‐wide changes in the ability of coral reefs to recover.

Characterizing the multisectoral impacts of future global hydrologic variability

There is significant uncertainty in how global water supply will evolve in the future, due to uncertain climate, socioeconomic, and land use change drivers and variability of hydrologic processes. It is critical to characterize the potential impacts of uncertainty in future water supply given its importance for food and energy production. In this work, we introduce a framework that integrates stochastic hydrology and human-environmental systems to characterize uncertainty in future water supply and its multisector impacts. We develop a global stochastic watershed model and demonstrate that this model can generate a large ensemble of realizations of basin-scale runoff with global coverage that preserves the mean, variance, and spatial correlation of a historical benchmark. We couple this model with a well-known human-environmental systems model to explore the impacts of runoff variability on the water and agricultural sectors across spatial scales. We find that the impacts of future hydrologic variability vary across sectors and regions. Impacts are felt most strongly in the water and agricultural sectors for basins that are expected to have unsustainable water use in the future, such as the Indus River basin. For this basin, we find that the variability in future irrigation water withdrawals and irrigated cropland increase over time due to uncertainty in renewable water supply. We also use the Indus basin to show how our stochastic ensemble can be leveraged to explore the global multisector consequences of local extreme runoff conditions. This work introduces a novel technique to explore the propagation of future hydrologic variability across human and natural systems and spatial scales.

Maddison‐style estimates of the evolution of the world economy: A new 2023 update

AbstractThis paper surveys the literature on historical national accounting, discusses the importance of relative income benchmarks for, in particular, historical income estimates, and presents an update of long run global economic development with a new version of the Maddison Project Database (MPD). As benchmarks are central to methodologies for global income comparisons over time, and therefore vital to MPD, we analyze the consequences and biases of three benchmarks, the 1990 benchmark, the 2011 benchmark and the multiple benchmark method following the recent Penn World Tables (PWT) methodology, for pre‐1940 income estimates. We develop a methodology to determine which benchmark in combination with time series produces the best anchor for the historical income estimates in the MPD. We conclude that the best way forward for the Maddison Project is to stick to the original 1990 benchmark, yet with two important changes. First, we integrate the 2011 benchmark for the post‐1990 period, and second, we fine tune the dataset for the pre‐1940 period by integrating a new historical benchmark for the US/UK comparison in 1909. By integrating more benchmarks, the MPD moves closer to a multiple benchmark approach as developed by the PWT.

The Spiral of Tillaux: dead on accurate; a cadaveric study

ABSTRACT Introduction The Spiral of Tillaux describes the historically accepted insertion distances of the medial rectus, inferior rectus, lateral rectus, and superior rectus from the limbus: 5.5 mm, 6.5 mm, 6.9 mm, and 7.7 mm, respectively. The corneal diameters are historically accepted to be 11.7 mm horizontally and 10.6 mm vertically in adults. We investigated the variability of the insertion distances of the extraocular rectus muscles from the limbus as well as the corneal diameters using eyes from human cadavers and compared our measurements to these historically accepted measurements. Methods A sample of 60 eyes were included. For each eye, a 360 peritomy was conducted and the conjunctiva bluntly dissected to view the sclera. Muscle hooks were utilized to isolate the extraocular rectus muscles. Calipers were used to measure the insertion distances of the rectus muscles as well as the corneal diameters. Results The mean rectus muscle insertions distances from the limbus were medial 5.28 mm, inferior 5.72 mm, lateral 6.40 mm, and superior 6.78 mm. These insertion distances were shorter than the historical benchmarks (p < .01). However, observed maximum distances of the rectus muscles were all greater than the historically accepted benchmarks, with the medial, inferior, lateral, and superior rectus muscles being 6.4 mm, 7.3 mm, 7.4 mm, and 7.8 m from the limbus, respectively. The mean width and height of the cornea were 11.7 mm and 10.7 mm, respectively, and similar to the expected ranges. Conclusion This study concludes that variability does exist from the historically accepted Spiral of Tillaux measurements. In addition, significant variation exists between male and female rectus muscle insertions. However, we did confirm that the rectus muscles followed the same spiral pattern described by the Spiral of Tillaux and concluded that the corneal diameters are consistent with previously accepted values.

Size thresholds for repair of abdominal aortic aneurysms warrant reconsideration

BackgroundThe historical size threshold for abdominal aortic aneurysm (AAA) repair is widely accepted to be 5.5 cm for men and 5.0 cm for women. However, contemporary AAA rupture risks may be lower than historical benchmarks, which has implications for when AAAs should be repaired. Our objective was to use contemporary AAA rupture rates to inform optimal size thresholds for AAA repair. MethodsWe used a Markov chain analysis to estimate life expectancy for patients with AAA. The primary outcome was AAA-related mortality. We estimated survival using Social Security Administration life tables and published contemporary AAA rupture estimates. For those undergoing repair, we modified survival estimates using data from the Vascular Quality Initiative and Medicare on complications, late rupture, and open conversion. We used this model to estimate the AAA repair size threshold that minimizes AAA-related mortality for 60-year-old average-health men and women. We performed a sensitivity analysis of poor-health patients and 70- and 80-year-old base cases. ResultsThe annual risk of all-cause mortality under surveillance for a 60-year-old woman presenting with a 5.0 cm AAA using repair thresholds of 5.5 cm, 6.0 cm, 6.5 cm, and 7.0 cm was 1.7%, 2.3%, 2.7%, and 2.8%, respectively. The corresponding risk for a man was 2.3%, 2.9%, 3.3%, and 3.4% for the same repair thresholds, respectively. For a 60-year-old average-health woman, an AAA repair size of 6.1 cm was the optimal threshold to minimize AAA-related mortality. Life expectancy varied by <2 months for repair at sizes from 5.7 cm to 7.1 cm. For a 60-year-old average-health man, an AAA repair size of 6.9 cm was the optimal threshold to minimize AAA-related mortality. Life expectancy varied by <2 months for repair at sizes from 6.0 cm to 7.4 cm. Women in poor health, at various age strata, had optimal AAA repair size thresholds that were >6.5 cm, whereas men in poor health, at all ages, had optimal repair size thresholds that were >8.0 cm. ConclusionsThe optimal threshold for AAA repair is more nuanced than a discrete size. Specifically, there appears to be a range of AAA sizes for which repair is reasonable to minmized AAA-related mortality. Notably, they all are greater than current guideline recommendations. These findings would suggest that contemporary AAA size thresholds for repair should be reconsidered.

Factors affecting Accountable Care Organizations' decisions to remain in or exit the Medicare Shared Savings Program following Pathways to Success.

The Medicare Shared Savings Program (MSSP) is an alternative payment model launched in 2012, creating Accountable Care Organizations (ACOs) to improve quality and lower costs for Traditional Medicare patients. Most MSSP participants were expected to shift from bearing no financial risk to a 2-sided risk model (ie, bonus if spending reduced below historical benchmarks, penalty if not), yet fewer than 20% did. Therefore, in 2019, the Centers for Medicare and Medicaid Services launched the Pathways to Success program, which required shifting to a 2-sided model within 12 months. For the first time, more ACOs exited than entered the MSSP. To understand these participation decisions, we conducted qualitative interviews with ACO leaders. Pathways caused ACOs to reassess their potential shared savings vs losses, particularly in light of benchmarking methodology changes; reconsider perceived nonrevenue benefits; and reassess participation in the MSSP vs other programs. As ACOs, particularly those assuming downside risk, have contained costs and enhanced care quality, policymakers should strive to improve MSSP enrollment rates in downside-risk models through strategies that allow ACOs to achieve shared savings and deliver accountable care.

Complimentary Computational Cues for Water Electrocatalysis: A DFT and ML Perspective

AbstractHeterogenous electrocatalysis continues to witness propagating interest in a plethora of non‐limiting electrochemical fields. Of which, water electrolysis has moved from lab‐scale systems to commercial electrolyzers albeit high dependence on historic benchmark noble‐metal based catalysts is still the status quo. Notwithstanding, advances in material groups such as single‐atom catalysts, perovskites, high‐entropy alloys, among others continue to see an increased interest toward utilization in next‐generation electrolyzers. To that end, progress in electrocatalyst discovery techniques is revolutionized through synergistically combining density functional theory (DFT) and machine learning (ML) techniques. The success of ML herein depends on numerous interlinked factors such as the algorithm employed, data availability and accuracy, with descriptors being critical to encapsulate physicochemical perspectives. Historic utilization of ML frameworks in areas other than materials discovery has left a lack of standardization toward appropriating suitable methods of high‐throughput DFT, ML approaches, and feature engineering that bridge the gap between activity‐structure‐electronic relationships. This review outlines needed considerations toward DFT calculations, important criteria during filtering out screened surfaces, and synergistic approaches toward utilizing theoretical and/or experimental datasets for formulating effective ML frameworks. Persisting challenges, perspectives, and recommendations thereof are highlighted to expedite and generalize future work pertaining to high‐volume water electrocatalysis discovery.

Establishment and Feasibility of an Immediate Lymphatic Reconstruction Program in a Community Health System.

Breast cancer-related lymphedema (BCRL) remains a significant post-surgical complication of breast cancer treatment. Immediate lymphatic reconstruction (ILR) at the time of axillary lymph node dissection (ALND) has shown promise in preventing BCRL. While the primary literature supporting ILR comes from academic institutions, the majority of breast cancer care in the USA occurs in the community setting. This study evaluated a preventative lymphedema program performing ILR at a community health system. A prospective database including all patients who underwent ALND with concurrently attempted ILR from 2019 to 2021 was retrospectively reviewed. The historical benchmark lymphedema rate was calculated through retrospective review of electronic medical records for all patients who underwent ALND without ILR from 2011 to 2021. Ninety patients underwent ALND with ILR, of which ILR was successful in 69 (76.7%). ILR was more likely to be aborted in smokers (p < 0.05) and those with fewer lymphatic channels (p < 0.05) or a higher body mass index (BMI) (p = 0.08). Patients with successful versus aborted ILR had lower lymphedema rates (10.9% versus 66.7%, p < 0.01) and improved Disability of the Arm, Shoulder, and Hand (DASH) scores (8.7 versus 19.8, p = 0.25), and lower lymphedema rates than the historical benchmark (10.9% versus 50.2%, p < 0.01). Among patients with successful ILR, older patients were more likely to develop lymphedema (p < 0.05). Successful ILR after ALND significantly reduced the lymphedema rate when compared with patients with aborted ILR and our institution's historical benchmark. Our experience supports the efficacy of ILR and highlights the feasibility of ILR within a community health system.

Twenty years crystal growth of solar silicon: My serendipity journey

The past two decades have been a transformative era for solar silicon crystal growth, especially in the competition between multi-crystalline silicon (Multi-Si) and mono-crystalline silicon (Mono-Si). As a critical sector of the solar photovoltaic (PV) industry, the demand for this crucial material has surged exponentially, expanding over a thousand-fold. This remarkable increase has led to an accumulative deployment of silicon solar panels, which now approach a striking terawatt (TW), capturing over 95 % of the global PV market share. Furthermore, the rapid advancements in crystal growth technology during this period have set an unprecedented historical benchmark. This paper reviewed our early effort in the hot-zone design of Czochralski (CZ) solar silicon and then discussed its recent advancements. In between, the small-grain high-performance multi-crystalline silicon (HPM-Si), which we proposed, and the mono-like silicon (ML-Si) were briefly introduced. Because of the much better ingot quality and growth yield, HPM-Si became the mainstream until 2018. Its market share peaked at more than 70 % in 2017 but slid down quickly and was replaced by CZ silicon due to the emergence of diamond wire sawing (DWS); the CZ silicon was easier to cut, and its kerf loss was much less. Since then, the CZ ingot size has also started to increase quickly. The wafer size increased from 156 mm × 156 mm (M0) to 217 mm × 217 mm (M12+) in a few recent years; the increase in wafer area was almost doubled. Nowadays, the market share of CZ mono-Si is over 80 %.

An Observational Study of Outcomes Associated with Virtual Pain Management Programmes Based on Acceptance and Commitment Therapy Implemented During the COVID-19 Pandemic.

In response to COVID-19, virtual, group-based interdisciplinary pain management programmes (PMPs) were rapidly implemented. This included implementing different intensities and formats of virtual PMPs to address a range of patient needs and complexity. This observational study investigated outcomes associated with virtual high and low intensity and pre-neuromodulation PMPs based on Acceptance and Commitment Therapy (ACT) as part of routine care during the pandemic. Depending on patients' needs, participants completed a virtual high- or low-intensity PMP, or a virtual PMP in preparation for neuromodulation, from June 2020 to June 2022. Participants completed standardized measures of pain intensity and interference, work and social adjustment, depression, and pain acceptance before and after treatment. Data from 2018 and 2019 for in-person residential (n=561), outpatient (n=123), and pre-neuromodulation (n=207) PMPs were also examined to provide an historical benchmark of performance. The virtual high-intensity PMP (n=294) showed significant improvements on all variables, with small effects. There were significant improvements with small effects for pain interference, depression, and acceptance for the virtual pre-neuromodulation PMP (n=129). No statistically significant improvements were observed for the virtual low intensity PMP (n=90). The improvements associated with pre-pandemic in-person PMPs were generally larger relative to the virtual PMPs of comparable intensity delivered during the pandemic. These data provide preliminary support for the potential benefits of high, but not low, intensity virtual ACT-based PMPs, including in the context of neuromodulation. Research is needed to maximize the impact of virtual PMPs and match patients with the most appropriate delivery format.

Increasing Impact of Spain on the Equity Markets of Brazil, Chile and Mexico During the Neoliberal Reforms of the 1990s

Purpose: The article examines stock index price responses in Brazil, Chile, and Mexico to those in the US, Spain, and four European countries during three sub-periods surrounding the neoliberal reforms of the 1990s: 1988 to 1994, 1995 to 1998, and 1999 to 2004. Design/methodology/approach: The methodology is empirical and uses time series analysis, in particular impulse response functions (IRFs) derived using vector autoregression (VAR) models. Main Findings: It finds that equity markets became more interconnected as countries opened to international trade and capital flows and that there was an increasing impact of Spain on Latin American equity markets. Stronger economic linkages (more trade and foreign direct investment) between Spain and these countries, especially in Brazil, seem to explain increased equity market interconnectedness. Research limitations/implications: The study limitations are, in general, the same that apply to the VAR methodology, and in particular, to missing control variables or to possible bias in the selection of the subsample periods used as historical benchmarks. Originality/value: To our knowledge, no other work showed that there was an increasing impact of Spain on Latin American equity markets during the neoliberal reform period by using IRFs and VAR models.

PEPN1924, a phase 2 study of trastuzumab deruxtecan (DS-8201a, T-DXd) in adolescents and young adults with recurrent HER2+ osteosarcoma: A children’s oncology group pediatric early-phase clinical Trial Network study.

11527 Background: Overall survival for patients (pts) with recurrent, unresectable osteosarcoma (OS) remains poor, and event free survival (EFS) based on historical benchmarks has been used to determine efficacy of investigational agents. HER2, a transmembrane receptor with kinase activity involved in cell signaling through the RAS pathway, is expressed in OS. T-DXd is a HER2 targeting antibody linked to DXd with preclinical in vitro studies demonstrating activity in OS correlating with the presence of HER2 expression. We report results of a Phase 2 study of T-DXd in adolescents and young adults with HER2 positive relapsed, unresectable OS. Methods: Pts (12-39 yrs) with relapsed, unresectable OS were eligible for screening. The most recent available tissue sample was centrally evaluated for HER2 expression by immunohistochemistry. Pts with greater than 10% of OS cells with cytoplasmic or membranous HER2 expression of any intensity were eligible to receive T-DXd at 5.4mg/kg IV every 3 wks for up to 2 yrs. The proportion of pts with an EFS at 24 wks was the primary endpoint estimated using a 9+15 Simon’s optimal two-stage design assuming an unacceptable response rate of 12%, acceptable response rate of 40%, 5% type 1 error, and 90% power. Results: 50 pts were screened for HER2, and 41 samples met the membranous or cytoplasmic HER2 expression inclusion criteria. A single pt had an assay failure and 8 pts had tumor samples with less than 10% HER2+ cells. Nine eligible pts were enrolled (7 male) between April 15th and November 11th of 2021 and received T-DXd. 2 pts were &lt; 18 yrs old and the median age was 19.3 years. Seven pts received 2 cycles and had progressive disease (PD) at the first evaluation. A single pt withdrew consent before the first evaluation. The final pt was event free at wk 24, meeting the protocol specified criteria for a response. With a single pt having more than 24 wks of stable disease (SD) of the 9 planned in the first stage, this study did not meet criteria to progress to stage 2. The estimated response rate is 11.1% (1-sided 95% CI LB: 0.6%). The single responder with SD for 12 cycles had 15% HER2 positive OS cells and the remaining pts had 30-100% HER2 staining. A single cycle 1 DLT of thrombocytopenia (GR4) was observed. No unexpected or at least possibly or greater related AE’s were observed. Grade 3-4 at least possibly related AE’s occurred in 3 of 9 patients and included nausea, vomiting, tumor hemorrhage, cytopenias (n = 3), wound infection, and hypertension. Conclusions: T-DXd did not demonstrate sufficient response to expand enrollment to the planned second stage in pts with OS. None of the pts had significant HER2 membranous staining which may account for the limited efficacy. No new toxicities were observed. Further correlative studies including PK, anti-T-DXd analyses and circulating tumor DNA are ongoing. Clinical trial information: NCT04616560 .

Safety and feasibility of JAK inhibitor ruxolitinib in newly-diagnosed high-grade gliomas (CRUX): Final toxicity report.

2060 Background: Dysregulation of the JAK/STAT pathway in newly-diagnosed high-grade gliomas (nHGG) is linked to enhanced survival and proliferation of tumor cells. Ruxolitinib, a small molecule inhibitor of JAK1, JAK2, and JAK3, limits glioma growth in preclinical models. This concept was explored in a phase I trial (NCT03514069), whose final report on toxicity is presented here. Methods: This non-randomized prospective study included 60 WHO Grade 3-4 nHGG patients who received standard of care (SOC) therapy along with ruxolitinib in a 3+3 dose-escalation design; level 1 of 10 mg BID, level 2 of 15 mg BID, level 3 of 20 mg BID, level -1 of 5 mg BID. The primary study objective was the determination of the maximum tolerated dose (MTD) of ruxolitinib in combination with chemoradiation. The secondary objective was the determination of safety, overall survival (OS), and progression-free survival (PFS). The exploratory aims were to investigate relationships between clinical outcomes and genomic signatures. Results: 60 patients were enrolled, with a median age of 60.5 years (range 22-78). 23 (38%) patients were female and 37 (62%) were male. 29 (48%) were MGMT unmethylated and received ruxolitinib with radiation of 60 Gy over 6 weeks. 31 (52%) patients were MGMT methylated and received ruxolitinib with 75 mg/m2 of temozolomide (TMZ) with radiation of 60 Gy over 6 weeks. The 1-year OS rate was 77% for all GBM patients; 62% for arm 1 (unmethylated MGMT) and 93% for arm 2 (methylated MGMT). Median OS for arm 1 was 18.1 months (10.1, NA) and was not reached for arm 2. MTD for both cohorts was 20 mg BID. No dose-limiting toxicities were observed. Toxicities attributable to study medications included four grade 4 AEs including seizure, respiratory distress, somnolence, and thromboembolic event along with 14 grade 3 adverse events (AEs), including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and meningitis. Conclusions: Ruxolitinib therapy is safe and feasible in combination with TMZ and radiation. Efficacy of ruxolitinib plus SOC appears promising compared to historical benchmarks for both MGMT methylated and MGMT unmethylated cohorts. A randomized phase 2 trial is planned. Clinical trial information: NCT03514069 .

Abstract CT223: Long-term survival follow-up of tebentafusp in previously treated metastatic uveal melanoma (mUM)

Abstract Background: Tebentafusp, a bispecific (gp100 x CD3) ImmTAC, is approved for adult HLA-A*02:01+ patients with unresectable or metastatic uveal melanoma (mUM). In the Ph2 IMCgp100-102 study of pts with previously treated mUM (NCT02570308), tebentafusp demonstrated a median OS of 16.8 months and 1-year OS of 61% after a minimum 2 yrs of follow-up, nearly double the historical observed rates.12, Here we present the final analysis of OS of the Ph2 IMCgp100-102 study. Methods: 127 HLA-A*02:01+ 2L+ pts with mUM were dosed weekly with intravenous tebentafusp following intra-patient dose escalation of 20mcg dose 1, 30mcg dose 2 and 68mcg dose 3+. Primary objective was overall response rate and secondary objectives included safety and OS. OS was estimated by Kaplan-Meier method. Survival for ctDNA evaluable patients was assessed. Analyses are based on a 17 Oct 2022 database lock. Results: With a median follow-up of 46 months, median OS was 16.8 (95% CI: 12.3-21.3) months, consistent with previous reports. Estimated 1-yr, 2-yr, 3-yr and 4-yr OS rates were 61%, 36%, 21% and 11%, respectively. ctDNA clearance by week 9 (n=12) was associated with 100% 1-yr, 73% 2-yr, 45% 3-yr and 23% 4-yr survival. OS for patients with poor prognostic factors compared favorably relative to historical benchmarks (Table 1). Mean and median duration of treatment was 9.9 and 5.6 months. Majority of pts who received a subsequent line of therapy received immunotherapy (48/72; 67%) followed by liver-directed therapy (14/72; 19%). No new safety signals were identified. Conclusions: This study provides the longest follow-up of OS for a soluble TCR therapeutic to date. Tebentafusp continued to show unprecedented survival benefit for 2L+ mUM pts, including the poorest prognostic groups, with estimated OS rates that remain nearly double the historical rates observed in this population at a median follow-up of ~4 years. Early ctDNA clearance was associated with indication of survival benefit. 1. Carvajal et al. Nat Med 2022 2. Sacco et al. J Immunother Canc 2021 Table 1. OS in Ph2 IMCgp100-102 versus historical benchmarks Ph2 IMCgp100-102 Historical benchmarks*,† Population 1-yr 2-yr 3-yr 1-yr 2-yr 3-yr Overall 2L+ 61% 36% 21% 37% 15% 9% Subgroups Age ≥ 65 yrs 51% 31% 25% 38% 12% 6% LDH &amp;gt; ULN 44% 22% 11% 23% 8% 3% Baseline largest liver lesion ≥ 3cm 52% 26% 14% 32% 11% 4% *OS benchmark for 2L+ patients calculated from Rantala et al 2019 †OS benchmarks for pt subgroups (all lines of therapy) estimated from digitized OS curves presented in Khoja et al. 2019 Citation Format: Joseph J. Sacco, Richard D. Carvajal, Marcus O. Butler, Alexander N. Shoushtari, Jessica C. Hassel, Alexandra Ikeguchi, Leonel Hernandez-Aya, Paul Nathan, Omid Hamid, Josep M. Piulats, Matthew Rioth, Douglas B. Johnson, Jason J. Luke, Erique Espinosa, Serge Leyvraz, Laura Collins, Chris Holland, Michelle L. McCully, Takami Sato. Long-term survival follow-up of tebentafusp in previously treated metastatic uveal melanoma (mUM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT223.