bluuebunny/crossref_metadata_2025 huggingface dataset:
Progesterone regulates tissue non-specific alkaline phosphatase (TNSALP) expression and activity in ovine utero-placental tissues
Authors: Stenhouse Claire , Halloran Katherine M. , Hoskins Emily C. , Moses Robyn M. , Wu Guoyao , Seo Heewon , Johnson Gregory A. , Suva Larry J. , Gaddy Dana , Bazer Fuller W.
Published: July 2024

Background

Tissue non-specific alkaline phosphatase (TNSALP; encoded by the ALPL gene) has a critical role in the postnatal regulation of phosphate homeostasis, yet how TNSALP activity and expression are regulated during pregnancy remain largely unknown. This study tested the hypothesis that progesterone (P4) and/or interferon tau (IFNT) regulate TNSALP activity during pregnancy in sheep.

Methods

In Exp. 1, ewes were bred and received daily intramuscular injections of either corn oil vehicle (CO) or 25 mg progesterone in CO (P4) for the first 8 days of pregnancy and were hysterectomized on either Day 9, 12, or 125 of gestation. In Exp. 2, ewes were fitted with intrauterine catheters on Day 7 of the estrous cycle and received daily intramuscular injections of 50 mg P4 in CO and/or 75 mg progesterone receptor antagonist (RU486) in CO from Days 8 to 15, and twice daily intrauterine injections of either control proteins (CX) or IFNT (25 µg/uterine horn/d) from Days 11 to 15 (treatment groups: P4 + CX; P4 + IFNT; RU486 + P4 + CX; and RU486 + P4 + IFNT) and were hysterectomized on Day 16.

Results

In Exp. 1, endometria from ewes administered P4 had greater expression of ALPL mRNA than ewes administered CO on Day 12. TNSALP activity appeared greater in the epithelia, stratum compactum stroma, and endothelium of the blood vessels in the endometrium and myometrium from ewes administered P4 than ewes administered CO on Day 12. On Day 125, TNSALP activity localized to uterine epithelial and endothelial cells, independent of P4 treatment. TNSALP activity in placentomes appeared greater in P4 treated ewes and was detected in endothelial cells and caruncular tissue in P4 treated but not CO treated ewes. In Exp. 2, endometrial homogenates from ewes administered RU486 + P4 + CX had lower TNSALP activity those for P4 + CX and P4 + IFNT ewes. Immunoreactive TNSALP protein appeared greater in the mid- and deep-glandular epithelia in RU486 + P4 + CX treated ewes as compared to the other treatment groups. Enzymatic activity appeared greater on the apical surface of the deep glandular epithelia in endometria from ewes treated with RU486 + P4 + CX compared to the other treatment groups.

Conclusions

These results suggest that P4, but not IFNT, regulates the expression and activity of TNSALP in utero-placental tissues and has the potential to contribute to the regulation of phosphate availability that is critical for conceptus development during pregnancy.
Association of lipid-lowering drugs with risk of sarcopenia: a drug target mendelian randomization study and meta-analysis
Authors: Li Jiaxin , Zang Chenyang , Lv Hui , Xiao Zheng , Li Peihong , Xiao Bo , Zhou Luo
Published: July 2024

Background

Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain.

Methods

Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums.

Results

Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10− 5) and slower walking pace (OR = 0.918, P = 6.06 × 10− 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10− 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10− 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10− 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10− 6). Meta-analysis further supported the robustness of these causal associations.

Conclusions

Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.
Forecasting and mapping dengue fever epidemics in China: a spatiotemporal analysis
Authors: Ren Hongyan , Xu Nankang
Published: July 2024

Background

Dengue fever (DF) has emerged as a significant public health concern in China. The spatiotemporal patterns and underlying influencing its spread, however, remain elusive. This study aims to identify the factors driving these variations and to assess the city-level risk of DF epidemics in China.

Methods

We analyzed the frequency, intensity, and distribution of DF cases in China from 2003 to 2022 and evaluated 11 natural and socioeconomic factors as potential drivers. Using the random forest (RF) model, we assessed the contributions of these factors to local DF epidemics and predicted the corresponding city-level risk.

Results

Between 2003 and 2022, there was a notable correlation between local and imported DF epidemics in case numbers (r = 0.41, P < 0.01) and affected cities (r = 0.79, P < 0.01). With the increase in the frequency and intensity of imported epidemics, local epidemics have become more severe. Their occurrence has increased from five to eight months per year, with case numbers spanning from 14 to 6641 per month. The spatial distribution of city-level DF epidemics aligns with the geographical divisions defined by the Huhuanyong Line (Hu Line) and Qin Mountain-Huai River Line (Q-H Line) and matched well with the city-level time windows for either mosquito vector activity (83.59%) or DF transmission (95.74%). The RF models achieved a high performance (AUC = 0.92) when considering the time windows. Importantly, they identified imported cases as the primary influencing factor, contributing significantly (24.82%) to local DF epidemics at the city level in the eastern region of the Hu Line (E–H region). Moreover, imported cases were found to have a linear promoting impact on local epidemics, while five climatic and six socioeconomic factors exhibited nonlinear effects (promoting or inhibiting) with varying inflection values. Additionally, this model demonstrated outstanding accuracy (hitting ratio = 95.56%) in predicting the city-level risks of local epidemics in China.

Conclusions

China is experiencing an increasing occurrence of sporadic local DF epidemics driven by an unavoidably higher frequency and intensity of imported DF epidemics. This research offers valuable insights for health authorities to strengthen their intervention capabilities against this disease.

Graphical Abstract
Date estimation of fabrication and repair of Color garments encouragement banner
Authors: Pak Seonghee , An Boyeon , Yun Changsang
Published: July 2024

The Color Garments Encouragement Banner was designated a Korean Heritage in 2014 to recognize it as the most significant object of the color garments encouragement campaign. However, despite its significance, nothing is known about its manufacture. Therefore, this study attempted to analyze the materials of the banners to estimate when they were manufactured and repaired. The investigation of materials on the banner involved visual examination, literature review, microscopy, SEM–EDS, FT-IR, Py-GC–MS, ICP-MS, and LC–MS. The fabric, patch, and threads comprising the artifact were identified as cotton. FT-IR and Py-GC–MS confirmed that the repair patch was a woven blend of polyester and cotton yarns. EDS analysis indicated that the polyester was treated with titanium delustering. ICP-MS detected high concentrations of chromium that were not used in traditional dyeing techniques. The azo and sulfur compounds were identified by LC–MS analysis. The material layered on the grommet patch was thought to be a mixture of Pb, Ti with CaCO3 and BaSO4. Based on the overall results, the production date of the banner was narrowed down to the late 1920s, and the repair date to the mid-1950s. Although the materials used could not be identified owing to the limitations of the applicable analysis. Nonetheless, it is hoped that the analyses conducted in this study can serve as a scientific foundation for dating modern cultural heritage objects with limited handed-down record and historical documentation.
Breaking barriers: shaping global health futures with pilot and feasibility initiative
Authors: Nizar Ambreen , Janus Magdalena
Published: July 2024

In the dynamic landscape of global health, the journey from a new development to its implementation is often fraught with challenges. Yet, it is within the crucible of these challenges that ingenuity flourishes and barriers are transcended. It is with great anticipation and enthusiasm that we introduce our special series, “Breaking barriers: shaping global health futures with pilot and feasibility initiatives.” This series will delve into the evidence surrounding the challenges of conducting health-related studies across diverse regions of the world.
Detectability of intracranial vessel wall atherosclerosis using black-blood spectral CT: a phantom and clinical study
Authors: Zhang Fan , Yao Hui , Langzam Eran , Meng Qinglin , Meng Xiao , van der Geest Rob J. , Luo Chuncai , Zhang Tengyuan , Li Jianyong , Xiong Jianmei , Deng Weiwei , Chen Ke , Zheng Yangrui , Wu Jingping , Cui Fang , Yang Li
Published: July 2024

Background

Computed tomography (CT) is the usual modality for diagnosing stroke, but conventional CT angiography reconstructions have limitations.

Methods

A phantom with tubes of known diameters and wall thickness was scanned for wall detectability, wall thickness, and contrast-to-noise ratio (CNR) on conventional and spectral black-blood (SBB) images. The clinical study included 34 stroke patients. Diagnostic certainty and conspicuity of normal/abnormal intracranial vessels using SBB were compared to conventional. Sensitivity/specificity/accuracy of SBB and conventional were compared for plaque detectability. CNR of the wall/lumen and quantitative comparison of remodeling index, plaque burden, and eccentricity were obtained for SBB imaging and high-resolution magnetic resonance imaging (hrMRI).

Results

The phantom study showed improved detectability of tube walls using SBB (108/108, 100% versus conventional 81/108, 75%, p < 0.001). CNRs were 75.9 ± 62.6 (mean ± standard deviation) for wall/lumen and 22.0 ± 17.1 for wall/water using SBB and 26.4 ± 15.3 and 101.6 ± 62.5 using conventional. Clinical study demonstrated (i) improved certainty and conspicuity of the vessels using SBB versus conventional (certainty, median score 3 versus 0; conspicuity, median score 3 versus 1 (p < 0.001)), (ii) improved sensitivity/specificity/accuracy of plaque (≥ 1.0 mm) detectability (0.944/0.981/0.962 versus 0.239/0.743/0.495) (p < 0.001), (iii) higher wall/lumen CNR of SBB of (78.3 ± 50.4/79.3 ± 96.7) versus hrMRI (18.9 ± 8.4/24.1 ± 14.1) (p < 0.001), and (iv) excellent reproducibility of remodeling index, plaque burden, and eccentricity using SBB versus hrMRI (intraclass correlation coefficient 0.85–0.94).

Conclusions

SBB can enhance the detectability of intracranial plaques with an accuracy similar to that of hrMRI.

Relevance statement

This new spectral black-blood technique for the detection and characterization of intracranial vessel atherosclerotic disease could be a time-saving and cost-effective diagnostic step for clinical stroke patients. It may also facilitate prevention strategies for atherosclerosis.

Key points

• Blooming artifacts can blur vessel wall morphology on conventional CT angiography.

• Spectral black-blood (SBB) images are generated from material decomposition from spectral CT.

• SBB images reduce blooming artifacts and noise and accurately detect small plaques.

Graphical Abstract
Repercussions of microglial efferocytosis on neurodegeneration in Alzheimer’s Disease (AD): a double-edged sword and perplexing factor warranting scrutiny in AD research
Authors: Kanuri SriHarsha
Published: July 2024

Background

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid beta (Aβ) and tau aggregates within the neuronal milieu. To prevent their neurotoxicity, these pathological aggregates will be cleared from the neuronal environment by extracellular, intracellular, and excretory mechanisms. As these compensatory mechanisms become overwhelmed, these left-behind aggregates will instigate neuronal loss via varied downstream signaling events. As a result, neurons undergo cell death through apoptosis and necrosis leading to the accumulation of cellular debris. Timely clearance of this cellular debris is critical, otherwise it can further potentiate neuronal loss by perpetuating pro-inflammatory environment.

Results

Microglial cells migrate and engulf these dead neurons by a process known as canonical efferocytosis. On the other hand, normal living neurons will be cleared by microglial cells through extracellular exposure of phosphatidyl serine (PS) under the pathological influence of Aβ and tau through non-canonical efferocytosis. Canonical efferocytosis should be predominant with the absence of the non-canonical efferocytosis during the physiological conditions. Upregulation of cytokines, and chemokines in AD creates a fertile ground for the amplification of non-canonical efferocytosis in parallel to canonical efferocytosis. The preponderance of the non-canonical over canonical pathways leads to exuberant clearance of stressed and normal living neurons along with dead neurons, thereby leading to exacerbated neuronal loss, brain tissue thinning and severe cognitive disturbances in AD.

Conclusions

Research efforts should be directed to understanding the factors that fine-tune the balance between these clearance processes. Novel therapeutic strategies that reinforce canonical efferocytosis will be beneficial by improving tissue repair, healing, and regeneration in AD.
Horizon picking algorithm using global optimization and coherence measurement in poststacked seismic data
Authors: Mesquita Marcelo Jorge Luz , Cruz João Carlos Ribeiro , Costa Manuel de Jesus dos Santos
Published: July 2024

Accurate horizon recognition within poststack seismic sections is important in seismic interpretation. Horizon picking techniques influence diverse seismic structural analyses and inversion methodologies. Despite encountering challenges such as computational demands and time constraints, the past few years have witnessed the development of numerous 2D and 3D methods. With the progress of modern computing, more robust and efficient techniques, harnessing artificial intelligence, have come to the fore. In this context, we develop an innovative cost-effective algorithm grounded in a global optimization framework. This algorithm combines the very fast simulated annealing method with a set of stability parameters and coherence measurements between neighboring seismic traces, which is used as the objective function. The search is executed on continuous and sequential clusters of seismic traces, with a focus on maximizing coherence amidst the presented events. We evaluate the algorithm’s efficacy by applying it to two distinct input data sets — enveloped and nonenveloped seismic traces. The initial application is to the time-migrated Marmousi data set, a synthetic marine data set originated from a complex geologic sedimentary basin situated in Angola, Africa. Subsequently, we apply the algorithm to depth-migrated land data extracted from a past survey conducted in the Tacutu Basin in northern Brazil. Outcomes arising from the application to 2D synthetic and field data sets underscore the method’s viability as a compelling alternative for seismic horizon picking within the time or depth domain.
Standard atezolizumab leads to severe overexposure in real-world patients with lung cancer: How far could we go in extending dosing intervals and saving money?
Authors: Marolleau Sophie , Mogenet Alice , Boeri Clara , Hamimed Mourad , Ciccolini Joseph , Greillier Laurent
Published: July 2024

3085

Background: Immune checkpoint inhibitors are given as fixed doses, which may lead to drug exposure exceeding the plasma concentrations required for target engagement. If confirmed, this could pave the way for de-escalating treatments without compromising efficacy while reducing drug-costs. Methods: We monitored plasma concentrations of Atezolizumab in 40 real-world patients. A final set of 33 patients with SCLC or NSCLC were available for full PK/PD analysis. Individual PK parameters were derived using a population pharmacokinetics approach. Individual PK parameters allowed to simulate the full concentration-time profiles and to further simulate for each patient the time to reach the target threshold after the first dose of Atezolizumab. In addition, efficacy (RECIST criteria) and immune-related adverse events, (IRAEs, CTCAE grading) were monitored and statistical analysis was performed to search for possible exposure-response relationships. Results: Overall Response Rate was 55% and no severe IRAEs were observed. All patients had Cmin levels significantly above the target threshold on the first cycle of Atezolizumab. The mean Cmax after the first dose on cycle 1 was 426.1 µg/ml and the mean Cmin was 68.5 µg/ml, i.e. 11-time higher than the target threshold associated with target engagement (i.e., 6 µg/ml). The mean AUC at the first cycle was 4763 µg.d/ml. Exposure metrics and PK parameters at baseline and simulated prior RECIST evaluation were tested together with other covariates (i.e. age, sex, smoking, NLR, number of metastatic sites, line of treatment) as possible predictive markers of response or toxicity. None of the parameters related to Atezolizumab pharmacokinetics or exposure levels were associated with efficacy or toxicity, most likely because all patients had plasma levels well above pharmacologically active concentrations. First-line therapy was associated with better response on univariate analysis, but this effect was lost on multivariate analysis. Further simulations based on time required to fall below the efficacy threshold suggest that dosing intervals could be extended from Q7W to Q19W (mean: Q12W). Considering the annual budget for Atezolizumab at our institution, further simulations showed that the annual drug cost could thus be reduced from 2.5 M€ to 0.6 M€ while ensuring that all patients remain above active concentrations. Conclusions: Our study demonstrates in a real-world setting that standard Atezolizumab given as 1200 mg Q3W infusion leads to severe overexposure of the drug. This strong overexposure was not associated with more severe treatment-related toxicities. Finally, our study suggests that PK-guided dosing with Atezolizumab could help customizing the dosing interval while maintaining efficacious trough levels and that Q12W could be an alternate scheduling leading to significant cut in drug costs.
Results of IMPACT 2, a randomized study evaluating molecular profiling and targeted agents in metastatic cancer at MD Anderson Cancer Center.
Authors: Tsimberidou Apostolia Maria , Fu Siqing , Hong David S. , Piha-Paul Sarina A. , Naing Aung , Rodon Ahnert Jordi , Yap Timothy A. , Karp Daniel D. , Dumbrava Ecaterina Elena , Heymach John , Ajani Jaffer A. , Cartwright Carrie , Beck Jennifer , Andersen Clark R. , Kahle Michael , Vining David J. , Ross Jeffrey S. , Chao Calvin Y. , Berry Donald A. , Meric-Bernstam Funda
Published: July 2024

3153

Background: To address the limitations of exploratory studies, we conducted IMPACT2. The primary endpoint was to compare the progression-free survival (PFS) between patients treated with matched targeted therapies (MTT) selected on the basis of tumor molecular alterations and those whose treatment was not selected on the basis of alteration analysis (non-targeted therapy, NTT). Methods: Patients with metastatic cancer and targetable alterations were randomized between the 2 arms when eligibility criteria were met (Part A, 5/2014-4/2017; sponsor, Foundation Medicine). In Part B (3/2019-9/2023; sponsor, Tempus), patients who declined randomization selected the treatment arm ( NCT02152254 ). PFS/OS analysis (Kaplan Meier, Cox model; reference group, comparison, NTT). All cases were presented at weekly Molecular Tumor Board meetings; initial plan, to randomize 300 of 1,362 enrolled patients. Results: Overall, 829 patients (Parts A, 391; B, 438); were enrolled (med. age 59.5 yrs, range 18-84; men 50%; med. No. of prior therapies 3, range 0-17; most common cancers: gastrointestinal 34%, head/neck 13.5%, gynecologic 10%, sarcoma 9.53%; most common genomic alterations RAS 38%, PI3K 31%, FGFR 28%). In Part A, 69 were randomized (MTT, n=35; NTT, n=34); Part B (MTT, n=11, NTT=13; Selected arm: n=16: MTT, n=13; NTT, n=3). Results are shown (Table). MTT group: median PFS by therapy type: FDA approved/off-label, 4.7 months (95% CI, 2.93, 7.1); investigational, 2.6 months (95% CI, 2.27,4.87), combined FDA approved/investigational, 1.7 months (1.7, NR) (p=0.22). Conclusions: Considering the challenges to randomize patients (doi: 10.1038/s41698-022-00317-0), and that the study was underpowered for its original goal, no differences in response, PFS (primary endpoint), or OS was noted between the 2 arms, possibly because of the advanced stage disease and the complexity of tumor biology that cannot be addressed by randomization. Clinical trial information: NCT02152254 . [Table: see text]
A phase 1 study of HRS-1167 (M9466), a highly selective PARP1 inhibitor, in patients (pts) with advanced solid tumors.
Authors: Wu Lingying , Wang Jing , Li Ning , Zhang Jin , Wang Danbo , Jiang Shusuan , Chen Liang , Li Yongsheng , Zou Dongling , Cui Jiuwei , Yan Min , Wang Wei , Zhao Hongwei , Wang Ying , Wang Xiaojia , Liu Funan , Zhang Youzhong , Wang Jing , Zhang Dapeng , Miao Qingqing
Published: July 2024

3154

Background: The use of first-generation dual PARP1/2 inhibitors is limited due to their hematological toxicities and inevitable drug resistance. Given that loss of PARP1 is the primary driver of synthetic lethality in homologous recombination repair (HRR) deficient tumors, and PARP2 is largely associated with hematological toxicities, development of next-generation PARPi with selectivity for PARP1 is warranted. Here, we present results of the dose escalation (D-ESC) and dose expansion (D-EXP) parts of a first-in-human study of HRS-1167 (M9466), a highly selective PARP-1 inhibitor, in pts with advanced solid tumors. Methods: Pts were eligible for the D-ESC part if they had advanced solid tumors that had progressed on standard therapies or for which no standard therapies were available. The D-ESC part began with accelerated titration (30 mg; QD) and then switched to the BOIN design (50, 100, 200, and 300 mg; QD). In the D-EXP part, previously treated pts harboring germline or somatic BRCA1/2, PALB2, or RAD51C/D mutations received HRS-1167 at 50, 100, and 200 mg QD. Prior PARPi was allowed. The primary objectives were to assess the safety and tolerability of HRS-1167. Results: As of Nov 20, 2023, 40 pts were enrolled (median lines of prior treatment, 2 [range, 1–5]; prior PARPi, 15.0%). No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. Grade ≥3 treatment-related adverse events occurred in 12 (30.0%) pts, with the most common being anemia (6 [15.0%]), decreased neutrophil count (5 [12.5%]), and decreased WBC count (5 [12.5%]). Of the 24 pts with HRR mutations who had at least one post-baseline assessment for tumor response, 10 (41.7%) pts had objective responses (8 ovarian cancer, 1 prostate cancer, and 1 pancreatic cancer). PK exposures were approximately dose-proportional. The median Tmax was 1.0–1.5 h, and the mean t1/2 was 10.5–15.0 h following a single dose of HRS-1167 at 30–300 mg. No obvious drug accumulation was observed (Rac, 1.08–1.30 for Cmax; 1.29–1.62 for AUC0-24). Conclusions: HRS-1167 was well-tolerated and exhibited favorable safety and PK profiles in pts with advanced solid tumors, and demonstrated promising anti-tumor activity in pretreated pts with HRR mutations. Clinical trial information: NCT05473624 .
Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: Results from the bladder cohort of the DESTINY-PanTumor02 (DP-02) study.
Authors: Wysocki Piotr Jan , Jung Kyung Hae , Oh Do-Youn , Doroshow Deborah Blythe , Artamonova Elena , Mammatas Lemonitsa , SU Po-Jung , Moiseyenko Vladimir , Penkov Konstantin , Stroyakovskiy Daniil , Bartolome Jorge , Siena Salvatore , Fielding Anitra , Jung Lindsey , Michelini Flavia , Puvvada Soham D. , Makker Vicky
Published: July 2024

4565

Background: In DP-02, T-DXd showed robust responses and clinically meaningful survival outcomes in 267 pretreated pts with HER2-expressing solid tumors; the objective response rate (ORR) by investigator (INV) was 37.1% (95% CI 31.3, 43.2). Here we report subgroup analyses in the bladder cohort (urothelial carcinoma including transitional cell carcinoma of the renal pelvis, ureter, urinary bladder, or urethra), and characterize pts with an objective response (OR). Methods: This open-label, Phase 2 study (NCT04482309) evaluated T-DXd (5.4 mg/kg Q3W) in pts with HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced/metastatic disease after ≥1 systemic treatment (Tx), or without Tx options. The primary endpoint was confirmed ORR by INV. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), and safety. Exploratory endpoints included efficacy outcomes according to HER2 expression. Results: At data cutoff (June 2023), 41 pts with urothelial cancers had received T-DXd (median [m] follow up [range]: 12.65 [0.4–26.8] months); 27 (65.9%) had received ≥2 prior Tx regimens. 16/41 pts (39.0%; 95% CI 24.2, 55.5) had a confirmed OR by INV; 12 responders had received ≥2 prior Tx regimens, 14 had received prior immunotherapy Tx, and 14 had known PD-L1 immune cell status ≥1%. The Table shows efficacy outcomes in all pts and by HER2 expression (central testing). Grade (G) ≥3 drug-related adverse events occurred in 17/41 (41.5%) pts. Adjudicated drug-related interstitial lung disease / pneumonitis occurred in 4/41 (9.8%) pts (n=1 G1; n=3 G2). Conclusions: T-DXd showed clinically meaningful responses in pretreated pts with urothelial cancers, including across HER2 expression levels (IHC 3+ and 2+). Safety was consistent with the known profile. These data support further evaluation of T-DXd as a potential Tx for pretreated pts with HER2-expressing urothelial cancers. Clinical trial information: NCT04482309 . [Table: see text]
Comparison of clinical outcomes of stable disease with confirmed tumor reduction and RECIST partial response for tebentafusp in metastatic uveal melanoma (mUM).
Authors: Ikeguchi Alexandra , Sato Takami , Butler Marcus O. , Carvajal Richard D. , Sacco Joseph J , Shoushtari Alexander Noor , Hassel Jessica Cecile , Nathan Paul D. , Piulats Josep M. , Johnson Douglas Buckner , Luke Jason J. , Espinosa Enrique , Leyvraz Serge , Collins Laura , Edukulla Ramakrishna , Thiyagarajah Piruntha , Hamid Omid
Published: July 2024

9529

Background: Tebentafusp (gp100 x CD3) has demonstrated an overall survival (OS) benefit in mUM. Benefit was observed in patients (pts) who achieved a RECIST v1.1 partial response (PR), stable disease (SD) and even progressive disease (PD) (Nathan 2021). In Phase (Ph) 1, some melanoma pts had SD with tumor reduction > 10% that was confirmed at ≥ 1 subsequent scan (referred to as minor response, MR). In Ph 2, an analysis of MR was pre-specified as an endpoint and presented here. Methods: 127 HLA-A*02:01+ pts with previously treated mUM received weekly intravenous tebentafusp following intra-pt dose escalation of 20mcg Week 1, 30mcg Week 2 and 68mcg Week 3+ (NCT02570308; Carvajal 2022). Radiologic assessments were performed every 8 weeks until week 40, then q12 weeks. Tumor assessment was evaluated by a blinded independent review committee per RECISTv1.1. MR was prospectively defined as RECISTv1.1 best response of SD with reduction in sum of target lesions of -10% to -29% and which was confirmed ≥ 4 weeks later. ctDNA levels were assessed using a targeted mPCR-NGS assay for mutations in 15 genes including mUM oncogenes GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX (Natera). Molecular response was defined as ≥ 0.5 log [68%] ctDNA reduction by week 9. Data cut off: Oct 2022. Median duration of follow-up was 46 months. Results: Of 127 pts, the clinical benefit rate of PR + SD was 50% (64/127). 25% (32/127) had any tumor reduction that was confirmed on ≥ 1 subsequent scan, including 6 PR (ORR 5%) and 26 SD (20%). 8/26 SD (6% of 127) met the pre-defined threshold for MR, most (5/8) had >20% reduction. The median duration of response for PR and MR were 8.7 months and 10.6 months, respectively. The estimated percent of pts with PR and MR remaining in response at Month 20 were 20% and 33%, respectively. 3/6 PR pts were alive ≥ 3 years vs 3/8. 58% of PR + SD pts with evaluable ctDNA had a molecular response (26/45), including 2/4 PRs and 5/5 MRs. Conclusions: This Ph2 UM study prospectively confirmed that a subset of SD patients had tumor reduction over multiple scans. The frequency of minor response was similar to that of PR and had similar durability, OS and ctDNA molecular response. SD with confirmed tumor reduction is an emerging endpoint for the ImmTAC platform and will be studied in other trials (NCT05549297, NCT04262466). Clinical trial information: NCT02570308 .
Long-term overall survival after isolated liver perfusion with melphalan in patients with isolated liver metastases of uveal melanoma (SCANDIUM trial).
Authors: Nelson Axel , Shafazand Amir , All-Eriksson Charlotta , Cahlin Christian , Elander Nils , Helgadottir Hildur , Kiilgaard Jens Folke , Kinhult Sara , Ljuslinder Ingrid , Mattsson Jan Erik , Rizell Magnus , Sternby Eilard Malin , Ullenhag Gustav J. , Nilsson Jonas A , Ny Lars , Lindner Per , Olofsson Bagge Roger
Published: July 2024

9532

Background: Uveal melanoma is a rare subtype of melanoma characterized by frequent metastases to the liver. The median survival for patients with liver metastases is less than one year, and there are few systemic treatment options available, providing only small survival benefits. Patients with liver metastases of uveal melanoma were in the SCANDIUM trial randomized to a one-time treatment with isolated hepatic perfusion (IHP) with high dose melphalan and investigator´s choice. We have previously reported that IHP gave significantly superior response rates and progression-free survival compared to best alternative care Furthermore, the primary endpoint, overall survival (OS) rate at 24 months was numerically higher for the IHP treated group (46.5% vs 29.5%), but the difference was not statistically significant. Here we present extended OS follow-up. Methods: In this randomized, controlled, phase III trial, treatment naïve Swedish patients with isolated liver metastases from uveal melanoma were between 2013 and 2021 randomly assigned in a 1:1 ratio to receive a one-time treatment with IHP or best alternative care (control group). No crossover from the control group to the IHP group was allowed. Results: A total of 87 patients were randomized and assigned to either IHP (43 patients) or control (44 patients). In the IHP group, 41 (89%) patients received IHP. In the control group, the first-line treatment was chemotherapy (49%), immunotherapy (39%) or localized treatment interventions (9%). The overall response rate was 40% in the IHP group, with a median duration of response of 13.7 months (95% CI, 11.6-18.3, n=17). At a minimum follow-up of 36 months, the 3-year OS rate was 18.6% (95% CI, 10.0-34.8%) in the IHP group compared to 9.1% (95% CI, 3.6-23.1%) in the control group (p=0.23, fisher exact test), and the 5-year OS rate was 16.3% (95% CI, 8.3-32.1%) compared to 6.8% (95% CI, 2.3-20.3%). The median OS in the IHP group was 21.4 months (95% CI, 19.0-30.4 months) compared to 17.3 months (95% CI, 13.8-22.3 months) in the control group (p=0.11, log-rank test). Conclusions: This extended analysis from the SCANDIUM trial supports long-term efficacy of a one-time treatment with IHP compared to best alternative care in patients with isolated liver metastases of uveal melanoma. Clinical trial information: NCT01785316 .
Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: Lenvamel, a multicenter retrospective study of the French Group of Skin Cancers.
Authors: Rousset Perrine , Nardin Charlée , Maubec Eve , Heidelberger Valentine , Picard Alexandra , Gérard Emilie , Kramkimel Nora , Steff Maud , Quéreux Gaëlle , Gaudy-Marqueste Caroline , Lesage Candice , Mignard Claire , Jeudy Geraldine , Jouary Thomas , Saint-Jean Mélanie , Baroudjian Barouyr , Archier Elodie , Mortier Laurent , Lebbe Celeste , Montaudie Henri
Published: July 2024

9546

Background: Treatment options for patients (pts) with advanced melanoma who experience resistance to immunotherapy (ICI) +- targeted therapy are lacking. Studies suggest the anti-tumour activity of combined pembrolizumab and lenvatinib in pts progressing on ICI. We report the clinical outcomes of combined lenvatinib and anti-PD-1 in this population. Methods: This French multicenter real-world study was conducted from 09/2020 to 07/2023. The primary endpoint was objective response rate (ORR) according to the RECIST criteria (v.1.1). Secondary endpoints were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS) and duration of response (DOR). Results: Of the 67 pts included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV M1c or M1d disease. Baseline characteristics are presented (Table). Overall ORR was 28.4% (95%CI, 18–41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. ORR was 71.4% (95%CI, 29–96%) for mucosal melanoma, 32,8% (95%CI, 21–46%) for pts pre-treated with anti-PD-1 + anti-CTLA-4, and 31,5% (95%CI, 20–46%) for BRAF wild-type melanoma. Median DOR was 3.1 (IQR, 1.3–4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5–3.7) and 9.8 (95% CI, 5.6–13.9) months respectively. Grade 3–4 TRAEs occurred in 16 pts (24%, no grade 5); common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). Conclusions: Our study demonstrates an interesting response rate and acceptable safety profile of this combination, with manageable toxicities, in an immuno-refractory population with poor prognostic factors. Pts pre-treated with anti-PD-1+ anti-CTLA-4, and those with BRAF wild-type melanoma seemed to benefit more from this strategy. Our study also provides promising data (considering the small sample) for pts with mucosal melanoma. Our data support this treatment option for refractory melanoma, though not yet approved by the health authorities, and highlight the need for new strategies. [Table: see text]
Pembrolizumab (pembro) for locally advanced (LA) or recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC): Long-term results of the phase 2 KEYNOTE-629 study.
Authors: Muñoz Couselo Eva , Hughes Brett Gordon Maxwell , Mortier Laurent , Grob Jean-Jacques , Gutzmer Ralf , Roshdy Osama , Gonzalez Mendoza Rene Lazaro , Schachter Jacob , Arance Ana Maria , Grange Florent , Meyer Nicolas , Joshi Abhishek Jagdish , Billan Salem , Ojavee Sven Erik , Yuan Jianda , Gumuscu Burak , Bratland Åse
Published: July 2024

9554

Background: Pembro monotherapy is approved in certain countries, including the US, for treatment of LA or R/M cSCC based on results from the open-label phase 2 KEYNOTE-629 trial (NCT03284424). Promising antitumor activity was demonstrated with pembro in both the LA and R/M cohorts. ORR (95% CI) was 50.0% (36.1-63.9; 16.7% CRs) in the LA cohort and 35.2% (26.2-45.2; 10.5% CRs) in the R/M cohort. We present data from KEYNOTE-629 with an additional follow-up of 38 mo for LA and R/M cohorts. Methods: Adults with histologically confirmed LA or R/M cSCC, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and ECOG PS 0 or 1 received pembro 200 mg IV every 3 weeks for up to 35 cycles (~2 years). The primary end point was ORR per RECIST v1.1 by BICR. Secondary end points were DOR, DCR (CR + PR + SD ≥12 wks), and PFS per RECIST v1.1 by BICR; OS; and safety. End points were analyzed in pts who received ≥1 dose of pembro. Results: A total of 159 pts were treated with pembro (LA, n = 54; R/M, n = 105). As of September 13, 2023, 33 pts (20.8%) completed treatment and 126 pts (79.2%) discontinued treatment. Median (range) follow-up was 52.4 mo (47.6-56.9) for the LA cohort, 64.7 mo (62.1-69.5) for the R/M cohort, and 63.1 mo (47.6-69.5) in the total population. ORR and DCR are shown in the table. Median DOR (range) was 47.2 mo (1.0+ to 49.9+) in the LA cohort, not reached (NR; 2.7 to 64.2+ mo) in the R/M cohort, and 52.5 mo (1.0+ to 64.2+) in the total population; the proportion of responders with responses ≥12 mo by Kaplan-Meier estimate were 84.8%, 77.8%, and 80.7%, respectively. Median (95% CI) PFS was 14.4 mo (5.5-43.6) in the LA cohort, 5.7 mo (3.1-8.5) in the R/M cohort, and 8.0 mo (5.3-14.4) in the total population; 12-mo rates were 56.7%, 37.3%, and 43.7%, respectively. Median (95% CI) OS was NR (33.3-NR) in the LA cohort, 23.8 mo (13.4-30.9) in the R/M cohort, and 29.8 mo (20.0-42.8) in the total population; 36-mo rates were 62.0%, 39.5%, and 47.0%, respectively. Grade 3-5 treatment-related AEs occurred in 11.3% of pts, and grade 3-5 immune-mediated AEs and infusion reactions occurred in 8.8% of pts. Two pts (1.3%) died due to a treatment-related AE (colitis, cranial nerve disorder). Conclusions: With a median follow-up of more than 5 years, pembro continued to show durable responses in pts with LA or R/M cSCC. No new safety signals were observed. Results from this study continue to support the use of pembro in this pt population. Clinical trial information: NCT03284424 . [Table: see text]
Intracranial outcomes with ipilimumab and nivolumab in melanoma brain metastases following progression on anti-PD-1 therapy.
Authors: Lochrin Sarah E. , Kalvin Hannah L , Smithy James William , Momtaz Parisa , Shoushtari Alexander Noor , Panageas Katherine , Postow Michael A.
Published: July 2024

9555

Background: Ipilimumab + nivolumab (ipi/nivo) is effective for melanoma brain metastases (MBM), but the efficacy of ipi/nivo in MBM in patients (pts) whose melanoma has progressed on anti-PD-1 is unknown. Methods: We conducted a retrospective analysis of pts with progressive MBM who received ipi/nivo at Memorial Sloan Kettering Cancer Center following prior anti-PD-1. Cohort A included pts with ≥1 untreated MBM (≥5mm) without local interventions (such as neurosurgery, radiotherapy). Cohort B included pts who had received local interventions for all MBMs before starting ipi/nivo. The primary endpoint was intracranial (IC) progression free survival (PFS). IC response was assessed based on clinical radiological interpretation for Cohort A. Kaplan-Meier methods were used to estimate time-to-event outcomes. Results: Fifty-seven pts were identified: 28 and 29 in Cohort A and B, respectively. All pts had received prior anti-PD-1, 42% prior ipi, a median of 2 (IQR: 1, 3) prior lines, and 21% (12/57) of pts prior treatment was in the adjuvant setting only. 79% (45/57) of pts had cutaneous, 14% (8/57) acral, 5% (3/57) unknown primary and 2% (1/57) mucosal melanoma. Median age was 64 (IQR: 58, 71) and 55 (IQR: 47, 70) years in Cohort A and B, respectively. Cohort A had median lesion size (largest measurable MBM) of 1.0cm (IQR: 0.60, 2.12), and 64% (18/28) of pts had >5 lesions; Cohort B had a median lesion size 1.5cm (IQR: 1.10, 2.00) and 28% (8/29) of pts had >5 lesions. 14% (8/57) of pts received concurrent steroid (equivalent of ≥dexamethasone 4mg daily) upon starting ipi/nivo, and leptomeningeal disease was present in 14% (4/28) and 7% (2/29) of Cohort A and B, respectively. The IC response rate was 11% (3/28, 2 were complete (CR)) in Cohort A.Both patients with CR were asymptomatic with ≤ 2 lesions and no prior CTLA-4 exposure. Most (20/28, 71%) in Cohort A had best response of progressive disease (PD); all that had a best response of stable disease (SD; 5/28, 18%) sustained that response for less than 6 months. Median IC-PFS was 1.7 (95% CI: 1.3,4.4) and 7.6 (95% CI: 3.6, -) months, and median overall survival (OS) was 6.7 (95% CI: 3.6,10) and 24 (95% CI: 11, -) months in Cohort A and B. 24-month OS was 19% (95% CI: 8.1,45) and 51% (95% CI: 35,75) in Cohort A and B. 30% (8/27) and 66% (19/29) of pts had subsequent systemic therapy, and 48% (13/27) and 52% (15/29) subsequent local therapy in Cohorts A and B. Conclusions: Ipi/nivo has limited efficacy in patients with progressive MBM post-PD-1 therapy in the absence of local therapy. These results highlight the unmet clinical need for more effective therapies to address progressive MBM post-PD-1 therapy, an increasingly relevant clinical scenario particularly in light of the growing use of adjuvant and neoadjuvant anti-PD-1.
Serum multiplex analysis of checkpoint proteins in association with immune-related adverse events in patients with melanoma receiving adjuvant anti-PD-1 therapy.
Authors: Knight Andrew David , Bruno Sabrina , Layding Caroline Jane , Wang Hong , Sander Cindy , Storkus Walter J , Karapetyan Lilit , Kirkwood John M.
Published: July 2024

9588

Background: Immune checkpoint inhibitors have significantly improved melanoma (MEL) patient (PT) outcomes. Immune-related adverse events (irAEs) may cause significant morbidity, rarely including death. Soluble immune checkpoints have been identified as biomarkers of autoimmune activity and potential off-target pathology. Understanding their relationship to pathologic outcomes may assist in the identification of PTs at highest risk of irAEs. Methods: PTs with resectable stage IIB-IV MEL who received adjuvant anti-programmed-death-1 (PD-1) therapy were identified from the University of Pittsburgh’s MEL Center biospecimen repository (N=273). MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel 2 was used to study serum levels of immunomodulatory proteins. Mean pretreatment serum levels in PTs with and without irAEs were compared using a two-sample t-test after performing Box-Cox transformation for non-normally distributed data. Results: Sera from 43 PTs were analyzed. The cohort included 28 (65.1%) male, mean age at diagnosis (62), including MEL stage IIIA = 7 (16.3%), IIIB = 16(37.2%) and IIIC = 20(46.5%). The most common irAEs (n=24, 55.8%) were thyroiditis (n=9, 20.9%), dermatitis (n=8, 18.6%), and adrenal insufficiency (n=9, 21.0%). Multiple irAEs were observed amongst 22 (51.2%) PTs with ≥3 irAEs and 6 (13.9%) with 5 irAEs. Visceral irAEs included Hepatitis (n=3, 7.0%), pneumonitis (n=2, 4.7%), and colitis (n=5, 11.6%). Seven of 8 patients with visceral irAEs required corticosteroids. Siglec-7 (mean 23.4 vs 3.51 pg/mL, p=0.018) and siglec-9 (mean 77.0 vs 33.1 pg/mL, p=0.049) were significantly elevated in the PTs who developed any irAE. After stratifying for each individual irAE, PTs with thyroiditis had elevated Nectin-4 (mean 2785.5 vs 494.7 pg/mL, p<0.001) and serum arginase (mean 2437.5 vs 1383.1 pg/mL, p= 0.046) was elevated in PTs who developed colitis. PTs with hepatitis demonstrated increased galectin-3 (mean 10103.9 vs 9915.3 pg/mL, p=0.045) and decreased levels of CD40L (mean 2869.2 vs 9496.9 pg/mL, p=0.033). In PTs with dermatitis B7-H3 (mean 2503.3 vs 732.4 pg/mL, p=0.009) and MHC class I polypeptide-related sequence B (mean 1598.0 vs 259.1 pg/mL, p=0.048) were elevated. Conclusions: We have demonstrated unique serum checkpoint protein profiles related to specific irAEs in melanoma patients receiving adjuvant anti-PD1. Further studies are warranted to confirm and validate the utility of these irAE predictors during adjuvant anti-PD-1.
HR+/HER2- early breast cancer with a high risk of recurrence: The impact of online education on clinician knowledge, competence, and confidence in utilization of clinical practice guidelines to enhance patient care.
Authors: Patel Urvi , Dorkhom Nabil , Phoenix Victoria , Zhang Cong , Bahra Sukhbir
Published: July 2024

e12515

Background: Clinical practice guidelines drive treatment decision making in HR-positive, HER2-negative early breast cancer with a high risk of recurrence. Understanding is necessary to incorporate the guidelines into practice and improve patient care. To address this gap, two global educational activities were developed that consisted of a 1-hour live streaming virtual meeting with a 45-minute online enduring activity and a 30-minute panel discussion. The objective of this study was to assess the educational impact of the online educational activities. Methods: To assess educational impact a repeated-pairs pre-/post-assessment study design using 6 knowledge/competence questions, in which everyone served as their own control. A paired samples t-test assessed mean differences in the average number of correct responses to the matched pre-/post-assessment questions, and a McNemar’s test assessed significance of improvement across core learning topics from pre- to post-assessment. P values <.05 are statistically significant. Confidence was also assessed using a pre/post confidence question. The activities launched in March 2023 and data was collected till January 2024. Results: 385 oncologists from the US and outside of the US who answered all the pre-/post-assessment questions were included in the analysis. Each assessment question was mapped to an activity learning objective. The learning objectives were grouped into three core topics. All core topics showed a significant improvement in education. Conclusions: These online activities resulted in a significant improvement of oncologists’ knowledge and competence related to the utilization of clinical practice guidelines. Confidence in understanding the implications of the latest guidelines also showed a statistically significant improvement. However, there is still a need for education in a significant percentage of oncologists on this topic. [Table: see text]