bluuebunny/crossref_metadata_2025 huggingface dataset:
Rotational stability and refractive outcomes of a new hydrophobic acrylic toric intraocular lens
Authors: Schartmüller Daniel , Lisy Marcus , Mahnert Nikolaus , Schranz Markus , Danzinger Victor , Schwarzenbacher Luca , Pieh Stefan , Abela-Formanek Claudette , Leydolt Christina , Menapace Rupert
Published: July 2024

Purpose

To assess rotational stability and refractive outcomes of a new toric hydrophobic acrylic intraocular lens (IOL).

Design

Single-center, prospective, interventional clinical trial.

Methods

A total of 130 eyes of 82 patients with age-related cataract and total corneal astigmatism of greater than 1.0 diopters (D) received a hydrophobic acrylic toric IOL Clareon CNW0T3-9. Baseline measurement for rotational stability evaluation was performed at the end of surgery (EOS), with the patient still supine on the operating table, using non-movable vessels as reference landmarks. Postoperative retroillumination pictures were taken at 1 h, 1 week, 1 month and 4–6 months postoperatively. Subjective manifest refraction was assessed at the 6 months follow-up visit.

Results

Final results were obtained in 126 eyes of 80 patients. Mean absolute rotation from EOS to 6 months was 1.33 ± 2.00 [0.01, 19.80] degrees. Rotational stability values from EOS to 1 h, 1 h to 1 week, 1 week to 1 month and 1 month to 6 months were 0.86 ± 0.82 [0.00, 3.90], 1.06 ± 1.94 [0.00, 19.45], 0.47 ± 0.42 [0.00, 2.03] and 0.38 ± 0.40 [0.00, 2.56] degrees. Mean preoperative corneal astigmatism was 1.78 ± 0.83 [1.00, 4.76] D which changed to a mean postoperative refractive astigmatism of 0.33 ± 0.27 [0.00, 1.25] D at 6 months.

Conclusion

The Clareon toric IOL presented very good rotational stability with a mean absolute rotation below 1.4° from EOS to 6 months. Only two IOLs rotated more than 5° with none of them requiring repositioning surgery. Refractive outcomes were satisfying with a mean residual refractive astigmatism below 0.50 D.

Trial registration

Registered at Clinicaltrials.gov NCT03803852; on May 17, 2022.
Eldercare or childcare: intergenerational distribution in Chinese families facing care deficits
Authors: Zhong Xiaohui , Peng Minggang
Published: July 2024

In the face of an aging population and declining birth rates, urban Chinese families are grappling with a new challenge of simultaneously caring for both elderly parents and children. This study employs a three-generational analytical framework and a mixed research method to examine the intergenerational distribution of care resources and its consequences for urban Chinese families. The findings reveal intergenerational competition for care resources within families, with a general tendency to prioritize children and only respond to crisis situations for elderly parents; this leads to a care deficit for older individuals. Furthermore, social care resources are ineffective in bridging this care gap, thereby inducing anxiety within families as they strive to balance the care needs of both elderly parents and children. The study argues that insufficient support from care policies exacerbates the resource squeeze on the elderly side by the children’s side within families, which calls for enhancing the policy support system to help families balance eldercare, childcare, and work commitments.
Experimental and statistical investigation on the dielectric breakdown of magneto nanofluids for power applications
Authors: Rizwan Md , Khan Suhaib Ahmad , Khan M. Rizwan , Khan Asfar Ali
Published: July 2024

The insulating oil serves the dual purpose of providing insulation and cooling within transformers. This investigation aims to explore the impact of various nanoparticles on the dielectric breakdown voltage (BDV) of dielectric oils. The study examines the effect of the concentration of magnetic nanoparticles on the dielectric breakdown voltage of insulating oils. Nanoparticles such as iron (II, III) oxide (Fe3O4), cobalt (II, III) oxide (CO3O4), and ferrous phosphide (Fe3P) were utilized to create nanofluids with carrier mediums consisting of mineral oil and synthetic ester oil. BDV determination was conducted using a VDE and S–S electrode system according to IEC 60156 standards. Nanofluid were prepared using a two-step method, and their concentrations ranged from 0.01 g/L, 0.02 g/L, and 0.04 g/L in base oils. Twelve iterations were conducted for each prepared nanofluid, and breakdown voltage measurements were recorded. The results indicate a noteworthy enhancement in the breakdown voltage of nanofluids. The statistical analysis was performed on the dielectric property of nanofluid samples for better breakdown accuracy. The maximum enhancement at specific nanoparticle concentrations was shown by each nanofluid. The results show that under the S–S electrode configuration, the greatest overall enhancement was observed for Fe3P in mineral oil, with an enhancement of 70.05%, and Fe3O4 in synthetic ester oil, with an enhancement of 46.29%.
Tuck-in tenon patch graft for giant full-thickness macular holes
Authors: Saleh Maher , Koman Chiatse Ellalie
Published: July 2024

Purpose

To report the results of using autologous Tenon patch grafts for managing giant full-thickness macular holes (FTMHs) when other alternatives are not applicable.

Methods

The same surgical technique was performed in all three cases. Briefly, a small fragment of Tenon’s tissue was collected. The graft was introduced through a 23G trocar and released over the macular hole under a bubble of PFCL. The patch is delicately pushed towards the edges of the hole to slide underneath. The PFCL bubble is then actively aspirated next to the optic disc. Tamponade with gas or silicone oil is subsequently injected, with care taken to minimize fluid turbulence during the procedure.

Results

The outcomes of autologous Tenon patch grafts in three giant FTMHs are reported. In the first case, silicone oil tamponade was injected, in the second, C2F6 gas was injected. And in the third case, that of a woman with advanced glaucoma, no tamponade was left in the eye. No adverse effects were observed during or after the procedures. Closure of the macular hole and functional improvement were documented during the follow-up period in all three cases.

Conclusion

With a follow-up of up to 6 months, the Tenon patch graft appeared to be a promising technique for managing complex cases of FTMH. Additional studies to investigate long-term outcomes and determine the most appropriate indications are warranted.
Mutual capacity building model for adaptation (MCB-MA): a seven-step procedure for bidirectional learning and support during intervention adaptation
Authors: Jack Helen E. , Giusto Ali , Rose Alexandra L. , Mwamuka Rukudzo , Brown Imani , Bere Tarisai , Verhey Ruth , Wainberg Milton , Myers Bronwyn , Kohrt Brandon , Wingood Gina , DiClemente Ralph , Magidson Jessica F.
Published: July 2024

Global health reciprocal innovation emphasizes the movement of technologies or interventions between high- and low-income countries to address a shared public health problem, in contrast to unidirectional models of “development aid” or “reverse innovation”. Evidence-based interventions are frequently adapted from the setting in which they were developed and applied in a new setting, presenting an opportunity for learning and partnership across high- and low-income contexts. However, few clear procedures exist to guide researchers and implementers on how to incorporate equitable and learning-oriented approaches into intervention adaptation across settings. We integrated theories from pedagogy, implementation science, and public health with examples from experience adapting behavioral health interventions across diverse settings to develop a procedure for a bidirectional, equitable process of intervention adaptation across high- and low-income contexts. The Mutual capacity building model for adaptation (MCB-MA) is made up of seven steps: 1) Exploring: A dialogue about the scope of the proposed adaptation and situational appraisal in the new setting; 2) Developing a shared vision: Agreeing on common goals for the adaptation; 3) Formalizing: Developing agreements around resource and data sharing; 4) Sharing complementary expertise: Group originating the intervention supporting the adapting group to learn about the intervention and develop adaptations, while gleaning new strategies for intervention implementation from the adapting group; 5) Reciprocal training: Originating and adapting groups collaborate to train the individuals who will be implementing the adapted intervention; 6) Mutual feedback: Originating and adapting groups share data and feedback on the outcomes of the adapted intervention and lessons learned; and 7) Consideration of next steps: Discuss future collaborations. This evidence-informed procedure may provide researchers with specific actions to approach the often ambiguous and challenging task of equitable partnership building. These steps can be used alongside existing intervention adaptation models, which guide the adaptation of the intervention itself.
A mixed methods evaluation of patient perspectives on the implementation of an electronic health record-integrated patient-reported symptom and needs monitoring program in cancer care
Authors: Lyleroehr Madison J. , Webster Kimberly A. , Perry Laura M. , Patten Elijah A. , Cantoral Jackelyn , Smith Justin D. , Cella David , Penedo Frank J. , Garcia Sofia F.
Published: July 2024

Background

As cancer centers have increased focus on patient-centered, evidenced-based care, implementing efficient programs that facilitate effective patient-clinician communication remains critical. We implemented an electronic health record-integrated patient-reported symptom and needs monitoring program (‘cPRO’ for cancer patient-reported outcomes). To aid evaluation of cPRO implementation, we asked patients receiving care in one of three geographical regions of an academic healthcare system about their experiences.

Methods

Using a sequential mixed-methods approach, we collected feedback in two waves. Wave 1 included virtual focus groups and interviews with patients who had completed cPRO. In Wave 2, we administered a structured survey to systematically examine Wave 1 themes. All participants had a diagnosed malignancy and received at least 2 invitations to complete cPRO. We used rapid and traditional qualitative methods to analyze Wave 1 data and focused on identifying facilitators and barriers to cPRO implementation. Wave 2 data were analyzed descriptively.

Results

Participants (n = 180) were on average 62.9 years old; were majority female, White, non-Hispanic, and married; and represented various cancer types and phases of treatment. Wave 1 participants (n = 37) identified facilitators, including cPRO’s perceived value and favorable usability, and barriers, including confusion about cPRO’s purpose and various considerations for responding. High levels of clinician engagement with, and patient education on, cPRO were described as facilitators while low levels were described as barriers. Wave 2 (n = 143) data demonstrated high endorsement rates of cPRO’s usability on domains such as navigability (91.6%), comprehensibility (98.7%), and relevance (82.4%). Wave 2 data also indicated low rates of understanding cPRO’s purpose (56.7%), education from care teams about cPRO (22.5%), and discussing results of cPRO with care teams (16.3%).

Conclusions

While patients reported high value and ease of use when completing cPRO, they also reported areas of confusion, emphasizing the importance of patient education on the purpose and use of cPRO and clinician engagement to sustain participation. These results guided successful implementation changes and will inform future improvements.
Re-examining the factor structure of the Insomnia Severity Index (ISI) and defining the meaningful within-individual change (MWIC) for subjects with insomnia disorder in two phase III clinical trials of the efficacy of lemborexant
Authors: Lenderking William R. , Savva Yulia , Atkinson Mark J. , Campbell Renee , Chabot Isabelle , Moline Margaret , Meier Genevieve , Morin Charles M.
Published: July 2024

Background

The Insomnia Severity Index (ISI) is a widely used measure of insomnia severity. Various ISI research findings suggest different factor solutions and meaningful within-individual change (MWIC) to detect treatment response in patients with insomnia. This study examined an ISI factor solution and psychometric indices to define MWIC in a robust patient sample from clinical trial settings.

Methods

We endeavored to improve upon previous validation of ISI by examining structural components of confirmatory factor analysis (CFA) models using two large, placebo-controlled clinical trials of lemborexant for insomnia. Using the best-fitting two-factor solution, we evaluated anchor-based, distribution-based and receiver operating characteristic (ROC) curve methods to derive an estimate of the MWIC.

Results

The model structure for the 7-item scale proposed in other research did not fit the observed data from our two lemborexant clinical trials (N = 1956) as well as a two-factor solution based on 6 items did. Using triangulation of anchor-based, distribution-based, and ROC methods, we determined that a 5-point reduction using 6 items best represented a clinically meaningful improvement in individuals with insomnia in our patient sample.

Conclusions

A 6-item two-factor scale had better psychometric properties than the 7-item scale in this patient sample. On the 6-item scale, a reduction of 5 points in the ISI total score represented the MWIC. Generalizability of the proposed MWIC may be limited to patient populations with similar demographic and clinical characteristics.
Ginger (Zingiber officinale) attenuates the neurotoxicity in rats induced by organophosphate pesticide
Authors: Keshav Poonam , Goyal Deepak Kumar , Singh Santosh
Published: July 2024

Background

We are exposed to different chemicals in various ways in our daily life, and these can be toxic at minute concentrations. The pesticides used for different purposes are also toxic and may pose threat to life by inducing oxidative stress. Dichlorvos (DDVP) is an organophosphate pesticide used for various purposes and is also reported to be toxic. In this study, the neurotoxicity of DDVP exposure was studied. The role of ginger, Zingiber officinale (ZO), was also evaluated against the neurotoxic effects of DDVP. Forty-eight Wistar rats of both the sexes were used in this study. The rats were exposed to DDVP and post-treatment with ZO was given. The oxidative stress in terms of lipid peroxidation (LPO), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) levels were estimated after exposure and treatment.

Results

DDVP resulted in oxidative stress, evidenced by enhanced LPO level. The simultaneous reductions in other non-enzymatic and enzymatic antioxidants were reported. The post-treatment with ZO led to a reduction in oxidative stress in rat brains. The levels of SOD, CAT, GSH, GR, and GPx were increased whereas declined levels of LPO were reported after treatment.

Conclusion

Hence, ginger can help mitigate the pesticide toxicity through the up-regulation of antioxidant levels.
Impact of Streptomyces on sesame plants under Macrophomina phaseolina infestation
Authors: Amin M. M. , Abd-Elbaky A. A.
Published: July 2024

Background

Sesame is an ancient oil crop that has been cultivated for centuries. It is an important source worldwide for food, industry and edible oil. Sesame plants are attacked by many pathogens during different stages of growth. Macrophomina phaseolina is considerable one of the most dangerous fungi that attacks sesame plants during their different growth stages. The impact of Streptomyces violaceoruber and Streptomyces hirsutus in comparison with Topsin-M fungicide on damping-off and charcoal rot caused by M. phaseolina and also on the growth of sesame plants was studied.

Results

In general, S. hirsutus was effective more than S. violaceoruber. S. hirsutus reduced the linear growth of M. phaseolina in vitro by 70.83%, while reduction with S. violaceoruber reached 53.89%. S. hirsutus isolate reduced pre-, post-emergence damping-off, and charcoal rot incidence by 58.3, 56.6, and 50%, under greenhouse conditions, in 2021 growing season, while the percentage reduction of disease was 43, 56.4, and 71.2% for 2021 and 2022 growing seasons, respectively, under field conditions at Fayoum Governorate, Egypt. Streptomyces treatments increased concentration of nitrogen, phosphorus, and potassium (NPK) in plant leaves, seed yield, and seed oil concentration more than Topsin-M treatment and untreated plants.

Conclusions

S. violaceoruber and S. hirsutus have proven that they can be used to combat soil-borne diseases, as well as improve growth parameters and increase yields.
Isolation, identification, biological characteristics, and pathogenicity of an entomogenous fungus against the Egyptian mealybug, Icerya aegyptiaca (J.) (Hemiptera: Monophlebidae)
Authors: Wei Yanhua , He Jingchao , Liang Chaopeng , Cheng Dongmei
Published: July 2024

Background

In this study, an entomogenous, fungus was isolated from the Egyptian mealybug, Icerya aegyptiaca (J.) (Hemiptera: Monophlebidae) on the parasol leaf tree, Macaranga tanarius, in China where evaluated as a biocontrol fungus to reduce the population of the target insect. The strain was identified as Aspergillus parasiticus by morphological and phylogenetic analysisand named ZHKUAP1. The biological characteristics, pathogenicity, and field control effect of the strain were determined.

Results

The most suitable medium for the mycelial growth of strain ZHKUAP1 was PPDA medium, with an optimum temperature of 30 °C and pH 7, in addition to glucose and peptone as carbon and nitrogen sources. The optimum sporulation conditions were the PPDA medium at 30 °C and pH 6, using the soluble starch and beef extract as carbon and nitrogen sources. The mycelial growth and spore production of strain ZHKUAP1 were stopped at 70 °C and above, indicating that it was not resistant to high temperatures. High concentrations of spore suspension, against young insect age, resulted high corrected mortality, as well as decreased the median lethal time. When the spore concentration was 1 × 108 cfu/ml, the corrected mortality of the second nymph was 88.33%, and the LT50 was 0.66 day. After 10 days of inoculation, the LC50 of the second instar nymph was the smallest, reaching 4.07 × 104 cfu/ml. On the 10th day of the field experiment, the corrected mortality was 76.45%, indicating that the A. parasiticus strain ZHKUAP1 had strong pathogenicity on I. aegyptiaca population.

Conclusions

The indoor toxicity of the strain to I. aegyptiaca was determined, and the field control effect of the pathogen was explored on this basis. The results have important application prospects in the biological control of I. aegyptiaca.
Direct numerical simulation of supersonic boundary layer transition induced by gap-type roughness
Authors: Liu Hongkang , Peng Kehui , Zhao Yatian , Yu Qian , Kong Zhiqiang , Chen Jianqiang
Published: July 2024

The transition of the supersonic boundary layer induced by roughness is a highly intricate process. Gaining a profound understanding of the transition phenomena and mechanisms is crucial for accurate prediction and control. In this study, to delve into the flow mechanisms of a transition in a supersonic boundary layer induced by the medium gap-type roughness, direct numerical simulation is employed to capture and analyze the transition process. Research indicates that as the flow over the flat plate passes the gap, the spanwise convergence effect leads to the formation of both upper and lower counter-rotating vortex pairs. As the flow progresses, these counter-rotating vortex pairs in the central region exhibit attenuation, with streamwise vortices developing on both sides. At a certain downstream distance, the boundary layer becomes unstable, triggering the formation of streamwise vortex legs. These streamwise vortex legs undergo further evolution, transforming into hairpin vortices and leg-buffer vortices. The formation of the central low-speed zone downstream of the roughness element is mainly attributed to the lift-up effect of the low-speed flow propelled by the central counter-rotating vortex pairs. The low-speed streaks on both sides are primarily influenced by the streamwise vortices. Through a meticulous analysis of the turbulent kinetic energy distribution and its generation mechanisms during the transition phase, this study infers that the primary sources of turbulent kinetic energy are the hairpin vortices, leg-buffer vortices, and their consequent secondary vortices. Combined with modal analysis, the study further elucidates the generation and breakdown of hairpin and leg-buffer vortices.
An assessment of workability, mechanical and durability properties of high-strength concrete incorporating nano-silica and recycled E-waste materials
Authors: Hinge Pawan , Shende Tushar , Ralegaonkar Rahul , Nandurkar Bhupesh , Raut Sanjay , Kamath Muralidhar , Tantri Adithya , Naganna Sujay Raghavendra
Published: July 2024

Background

Presently, the proper disposal of E-waste is a major challenge for all nations. Portland cement and aggregates continue to play a major role in the construction industry's operations. Meanwhile, natural resources like gravel (aggregates) are becoming scarce. Thus, E-waste is now offering the building industry a chance to replace traditional aggregates. The main goal of the current study is to determine the highest amount of E-waste that may be replaced with 10-mm coarse aggregates with a nano-silica associated ternary blend in M-60 grade high-strength concrete while still maintaining the designed concrete's mechanical, durability, microstructural and workability characteristics.

Results

When compared to normal concrete, concrete with 15% E-waste replacement maintained the design-required compressive, flexural and tensile strength properties. When the E-waste plastic component percentage is considerably high (15–30%), there is a significant decremental performance regarding the mechanical properties and the decremental rate is found to be in the range of 13–23%. Even the microstructure characteristics of concrete validate the mechanical performance of concrete. Nevertheless, the durability characteristics of E-waste incorporated concrete were found to be promising.

Conclusions

The overall outcome of the study recommends 15% as the optimal replacement percentage of E-waste for conventional concrete, and it is recommended to adopt for real-time practices.
CFD modeling of orthogonal wave-current interactions in a rectangular numerical wave basin
Authors: Wei Kai , Hu Kaiyu
Published: July 2024

Sea-crossing bridges are subject to long-term simultaneous wave and current loadings throughout thier life cycle. The wave-current interaction makes the hydrodynamic load calculation difficult and challenging, especially in simulating the noncollinear wave-current interactions between waves and currents due to potential disturbances such as wall reflections within the observational zone. Therefore, in this study, a numerical flume was built based on the Reynolds time-average (RANS) equation and k-ε turbulence model using the computational fluid dynamics (CFD) software Flow-3D to investigate noncollinear wave-current interaction numerical simulation methods. The collinear wave-current interactions were then numerically simulated using the inflow boundary and mass source wave generation method, and the developed numerical flume was validated with experimental results based on a large-scale wave-current flume. Furthermore, a three-dimensional numerical simulation of complex noncollinear wave-current interactions was developed. The developed rectangular numerical basin based on the collinear wave-current flume was validated with theoretical results regarding wavelength variations in a noncollinear wave-current interaction field. Finally, the effective observation zone of orthogonal wave-current interactions was explored. This study is important for advancing bridge hydrodynamic research into noncollinear wave-current interactions.
Impacts of micro- and nanoplastics on early-life health: a roadmap towards risk assessment
Authors: Christopher Emily A. , Christopher-de Vries Yvette , Devadoss Anitha , Mandemaker Laurens D.B. , van Boxel Jeske , Copsey Helena M. , Dusza Hanna M. , Legler Juliette , Meirer Florian , Muncke Jane , Nawrot Tim S. , Saenen Nelly D. , Scholz-Böttcher Barbara M. , Tran Lang , Weckhuysen Bert M. , Zou Runyu , Zimmermann Lisa , Galea Karen S. , Vermeulen Roel , Boyles Matthew S. P.
Published: July 2024

Micro- and nanoplastics (MNPs) are ubiquitous environmental pollutants representing a concern for human health. MNPs have been detected in human placentas, indicating that during pregnancy maternal exposure may lead to placental transfer and foetal exposure, with potential for adverse effects on early-life development. However, a comprehensive risk assessment (RA) framework, specific to early-life is lacking. Here, we propose a novel roadmap to assist the development of an early-life health RA of MNPs. This roadmap is designed based on established chemical, mixture, particle, and MNP assessment strategies aligned with standard RA components (problem formulation, hazard identification, hazard characterisation, exposure assessment, risk characterisation). We systematically work through these stages to identify what is needed to progress a RA for the early-life impacts of MNPs, including what information is missing, and what may be used in the interim. While challenges such as complex physicochemical properties of MNPs, limited toxicity data at relevant exposure levels, and uncertainties related to characterising complex exposures have been described elsewhere, our work discusses how these challenges specifically impact early-life stages such as the significance of MNP presence in biological samples and factors influencing bioaccumulation and placental transfer. Additionally, we introduce the development of new technology readiness levels for methods used in the detection of MNPs in complex matrices. Importantly, this review integrates a broad scope of relevant information into one comprehensive document, providing a unified resource. We highlight specific requirements and areas for targeted research, including the development of dose-response relationships specific to early-life stages and novel strategies for assessing bioaccumulation and placental transfer of MNPs. By addressing these gaps, our roadmap aims to advance the development of a robust framework, ultimately enhancing the understanding and mitigation of risks associated with early-life exposure to MNPs.
Diffusion models for multidimensional seismic noise attenuation and superresolution
Authors: Xiao Yuan , Li Kewen , Dou Yimin , Li Wentao , Yang Zhixuan , Zhu Xinyuan
Published: July 2024

Seismic data quality proves pivotal to its interpretation, necessitating the reduction of noise and enhancement of resolution. Traditional and deep-learning-based solutions have achieved varying degrees of success on low-dimensional seismic data. We develop a deep generative solution for high-dimensional seismic data denoising and superresolution through the innovative application of denoising diffusion probabilistic models (DDPMs), which we refer to as MD Diffusion. MD Diffusion treats degraded seismic data as a conditional prior that guides the generative process, enhancing the capability to recover data from complex noise. By iteratively training an implicit probability model, we achieve a sampling speed 10 times faster than the original DDPM. Extensive training allows us to explicitly model complex seismic data distributions in synthetic data sets to transfer this knowledge to the process of recovering field data with unknown noise levels, thereby attenuating the noise and enhancing the resolution in an unsupervised manner. Quantitative metrics and qualitative results for 3D synthetic and field data demonstrate that MD Diffusion exhibits superior performance in high-dimensional seismic data denoising and superresolution compared with the UNet and seismic superresolution methods, especially in enhancing thin-layer structures and preserving fault features, and indicates the potential for application to higher-dimensional data.
A phase I study of highly potent oral ATR inhibitor (ATRi) tuvusertib plus oral PARP inhibitor (PARPi) niraparib in patients with solid tumors.
Authors: Yap Timothy A. , Plummer Elizabeth Ruth , Tolcher Anthony W. , Szucs Zoltan , Gounaris Ioannis , Locatelli Giuseppe , Enderlin Marta , Hicking Christine , Kaur Mukker Jatinder , De Bono Johann S.
Published: July 2024

3018

Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase and poly-ADP ribose polymerases (PARPs) are crucial components in the DNA damage response (DDR). Combining tuvusertib and niraparib may synergistically enhance synthetic lethality and increase apoptosis. Part B1 of the DDRiver Solid Tumors 301 study (NCT04170153) assessed this combination. Methods: Part B1 of this open-label multicenter dose-escalation phase Ib trial enrolled unselected patients with metastatic or locally advanced unresectable solid tumors refractory to standard treatment. The primary objective was to determine safety (including maximum tolerable dose and recommended dose(s) for expansion [RDE]). Secondary and tertiary objectives included determination of the pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of different dosing regimens of tuvusertib plus niraparib. Multiple continuous and intermittent schedules were explored with tuvusertib doses ranging from 90–180 mg once-daily (QD) and niraparib doses from 100–200 mg QD. A partial ordering continual reassessment method was used to identify the RDEs. Results: As of 02 January 2024, 43 patients had been enrolled (all with baseline body weight <77kg or platelet count <150,000/mm3); 13 patients remained on treatment. Ten (26.3%) patients had dose-limiting toxicities (DLTs). The most common DLT was grade 3 anemia requiring blood transfusion (n=4; 10.5%); the most frequent grade ≥3 treatment-emergent adverse events were anemia (n=18; 41.9%), platelet count decrease (n=6; 14.0%) and fatigue (n=4; 9.3%). The PK of tuvusertib when combined with niraparib was consistent with that of tuvusertib monotherapy, suggesting a lack of any clinically meaningful mutual drug–drug interactions. Dose-dependent ɣ-H2AX inhibition (proximal PD marker) was observed at tuvusertib doses ≥130 mg QD. Preliminary efficacy data show 5 (15.6%) responses (3 confirmed) by RECIST v1.1 in 32 evaluable patients: 2 in patients with epithelial ovarian cancer (EOC; 1 with BRCA1-mutant [ BRCA1m] PARPi-resistant EOC, 1 with BRCA-wild type homologous recombination deficiency-positive EOC) and 1 each in patients with non-small cell lung cancer, estrogen receptor-positive HER2-negative BRCA1m breast cancer, and BRCA1m PARPi-resistant pancreatic cancer. Tuvusertib 180 mg QD and niraparib 100 mg QD or tuvusertib 90 mg QD and niraparib 200 mg QD, both given in a 1 week on/1 week off schedule, were identified as RDEs. Conclusions: The combination of tuvusertib plus niraparib, each administered on a 1 week on/1 week off schedule, has a manageable safety profile and is suitable for further investigation. A combination study in patients with PARPi-resistant EOC is planned. Clinical trial information: NCT04170153 .
YL202/BNT326, a HER3-targeted ADC, in patients with locally advanced or metastatic non-small cell lung cancer and breast cancer: Preliminary results from a first-in-human phase I trial.
Authors: Cheng Ying , Zhang Xiaochen , Liu Jian , Huang Zhangzhou , Lv Dongqing , Zhang Yiping , Wang Xiaojia , Chaudhry Arvind , Amin Harshad , Damodaran Senthil , Patel Shiven B. , Assad Hadeel , Lee Arielle Shebay , Zhao Hui , Bai Jinyun , Xue Tongtong , Chin Steve
Published: July 2024

3034

Background: YL202/BNT326 is a novel ADC consisting of an anti-HER3 IgG1 monoclonal antibody linked to 8 molecules of YL0010014, a novel topoisomerase I inhibitor, via a tripeptide linker. We report preliminary safety and efficacy results from a phase I trial of YL202/BNT326. Methods: This multinational trial is recruiting patients (pts) with locally advanced/metastatic non-small cell lung cancer (NSCLC) with an EGFR-activating mutation who were previously treated with 3rd generation TKI and platinum-based chemotherapy, and pts with unresectable, locally advanced or metastatic, HR-positive and HER2-negative (IHC 0,1+,2+/ISH-) breast cancer (BC) who were previously treated with CDK4/6 inhibitor and at least one line of chemotherapy. YL202/BNT326 was given at 6 dose levels (DLs, Q3W, iv) in a BOIN dose escalation (D-ESC) scheme, followed by cohort backfill(BF) at selected doses. Primary endpoints are safety and tolerability (dose-limiting toxicities [DLTs] and adverse events [AEs]). Secondary endpoints include pharmacokinetics [PK] and efficacy per RECIST v1.1(ORR, DCR, BOR). Results: At data cutoff (4 Feb 2024), 52 pts were enrolled in D-ESC and BF (39 NSCLC, 13 BC). One DLT (grade 3 febrile neutropenia) occurred during D-ESC at the highest dose. Most common TRAEs (>20%, all grade / ≥ G3) were anemia (71%/20%), white blood cell count decreased (67%/31%), neutrophil count decreased (63%/29%), nausea (52%/0%), decreased appetite (42%/4%), lymphocyte count decreased (37%/23%), platelet count decreased (37%/10%), vomiting (37%/0%), dry mouth (25%/0%), fatigue (25%/0%), stomatitis (23%/2%), alopecia (21%/0%). Interstitial pneumonia occurred in 1 (2%) pt after COVID-19 infection. PK exposure was increased through dose escalation, with low systemic exposure of payload and no accumulation of YL202/BTN326 upon repeated administration. In 46 pts with at least 1 tumor assessment were evaluable for efficacy. Of the non-evaluable pts, 5 are on treatment pending first tumor assessment and 1 discontinued treatment prior to first assessment. In DL3 to DL5 dose range, ORR was 41.0% (95%CI, 25.6, 57.9), DCR was 94.9% (95%CI, 82.7, 99.4) across all tumor types; and the ORR in BC pts was 54.5% (95%CI, 23.4, 83.3), DCR was 100% (95%CI, 71.5, 100.0). Conclusions: YL202/BNT326 demonstrated encouraging efficacy in heavily pretreated locally advanced/ metastatic NSCLC and BC. The safety profile showed adequate safety and tolerability. Clinical trial information: NCT05653752 . [Table: see text]
Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study.
Authors: Park John J. , Gao Bo , Beecroft Claire , Wilkinson Kate Jessica , Parsonson Andrew , Zhang Karl , Yan Xiangyun , Wang Ni
Published: July 2024

3038

Background: JSKN003 is a biparatopic HER2-directed ADC conjugated to a topoisomerase I inhibitor with an average DAR 4. Preclinical studies showed that JSKN003 had a good serum stability and strong anti-tumor activity. Hence JSKN003 could be effective in HER2 expressing tumors with a potentially broader therapeutic window. Methods: JSKN003-101 is a first-in-human, dose-escalation and -expansion study in Australian pts with advanced solid tumors. Pts (ECOG 0-1) with histologically documented HER2-expressing (HER2-positive defined as IHC 2+ or 2+/ISH+, HER2 low defined as IHC 1+ pr 2+/ISH-) or HER2-mutation by local testing who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, tolerability, MTD or RP2D, PK, and preliminary antitumor activity. Here the results from dose-escalation part were reported. Results: As of 15 Dec 2023, 32 pts were enrolled and received JSKN003 across 7 dose levels (1.0-8.4 mg/kg, Q3W). Among the 32 pts, 9 were IHC 1+, 16 were IHC 2+, and 7 were IHC 3+. Most pts (22/32, 68.8%) received ≥ 3 prior lines of therapy. The median duration of treatment was 15.8 (range, 6-54) weeks, and 19 pts (59.4%) remain on treatment. TRAEs occurred in 27 pts (84.4%) and 2 pts (6.3%) in 4.2mg/kg and 7.3mg/kg experienced grade 3 TRAE (anemia and fatigue); the most common TRAEs were diarrhea (62.5%) and nausea (50.0%), which were all grade 1-2. Only 1 pt experienced ILD/pneumonia (7.3mg/kg, grade 2). To date, no DLT events were found yet, and no TRAE led to death or treatment discontinuation. MTD has not been reached in 8.4 mg/kg. Following a single dose, exposures (Cmax and AUC) of JSKN003 and released TOP1i increased proportionally over a dose range of 4.2 mg/kg to 8.4 mg/kg. T1/2 of JSKN003 is approximately 5-6 days for 6.3 mg/kg and higher doses and increases with dose escalation. Accumulation of JSKN003 was minimal within the range of 1.1-1.5. The exposure of released payload was significantly lower than JSKN003 ADC, demonstrating the stability of the JSKN003 in circulation. All pts had at least one post-baseline tumor assessment. 16 pts achieved PR per RECIST 1.1 by investigator. Thus, ORR and DCR was 50.0% (95%CI: 31.9%, 68.1%) and 90.6% (95%CI: 75.0%, 98.0%), respectively. The ORR in pts with IHC 1+, 2+ and 3+ was 55.6% (5/9), 37.5% (6/16), and 71.4% (5/7), respectively. As for the efficacy of the HER2-positive and HER2-low breast cancer, the ORR was 80% (4/5) and 40.0% (4/10), respectively. Conclusions: JSKN003 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2 expressed tumors. As of the cut-off date, no DLT was observed, MTD has not been reached yet. Clinical trial information: NCT05494918 .
Subclonal mutational signatures in breast cancer brain metastases.
Authors: Varuzza Muriele Bertagna , Winata Helena , Patel Yash , Mootor Mohammed Faizal Eeman , Souza Cristiano de Padua , Boutros Paul Christopher , Silveira Marcia Maria Chiquitelli Marques
Published: July 2024

e13108

Background: Breast cancer is the leading cause of cancer-related deaths among women in Brazil and the cancer type with highest incidence. When diagnosed at early stages, it has an overall five-year survival rate of up to 90%. However, in advanced stages, survival rate is reduced to about 24%, and 90% of women in stage IV die of metastatic complications. Brain is one of the most common metastatic sites in breast cancer patients, and even though it is a site with poor prognosis, the mutational profile of brain tumors is poorly described in the literature. Therefore, we understand that the identification of this profile may contribute to elucidate mechanisms associated with tumor progression. The aim of this study was to reconstruct the subclonal evolution of breast cancer metastases in the brain. Methods: To carry out this study, the whole exome was accessed through Next Generation Sequencing (NGS) using the Illumina platform in DNA samples extracted from buffy coat cryopreserved and paraffin material of breast tumors and paired brain metastases (n=10). The median read coverage was 68x. DNA was aligned to a Human Reference Genome using the Burrows–Wheeler Aligner, Genome Analysis Toolkit was used for germline short variants calling, and Mutect2 and MuSE were used for variant calling with somatic character (SNVs and INDELs). FACETS was used for assessing the somatic DNA copy number (Copy Number Aberrations). PyClone-VI tool was used for the subclonal reconstruction and to infer the phylogeny it was considered the mutation loci, Cancer Cell Fraction (CCF) and clustering assignments, using R Statistical Environment and Stats, Argparse, and Devtools packages. Results: We identified the mutational signature in these patients with subclonal and clonal mutations that segregated in approximately two clusters with a median between ten and forty variants related with tumor progression process. Conclusions: These findings show a set of variants with driver potential for breast cancer brain metastasis, bringing new perspectives in identifying mechanisms associated with disease progression.
Survival analysis of brain metastases secondary to breast cancer: A single-center experience.
Authors: Chun Brie , Oyogoa Emmanuella , Kaempf Andy , Levy Julia , Padilla Lazos Thalia , Rounsavill Teyhana , Nguyen Mai-Loan , Stefanik Fiona , Eichten Victoria , Kornachuk Tana , Duong Jessica , Goodyear Shaun M. , Zimmer Alexandra Dos Santos
Published: July 2024

e13111

Background: Brain metastasis (BM) contributes to substantial morbidity and mortality for breast cancer (BCa) patients (pts). Advances in systemic therapies have improved survival following BM diagnosis; however, other factors such as age, timing of BM development, and molecular features may also affect outcomes. Here we characterize the overall survival (OS) of pts with BM secondary to BCa treated at our institution with the aim of identifying predictors that can used to improve treatment and management. Methods: In an electronic medical record of “brain metastasis” and “breast cancer”, we identified pts aged >18 years treated between 2015 and 2022. All cases were manually reviewed by ≥2 reviewers. Cases with second metastatic (met) solid tumors, hematologic malignancies, or insufficient data were excluded. Only cases with intraparenchymal and/or leptomeningeal disease attributed to met BCa were included. Kaplan-Meier estimation and Cox regression were applied to OS. Results: Of 344 cases reviewed, 229 (1 male) were appropriate for inclusion. The median age at BM diagnosis (dx) was 58 years. 28% underwent surgical resection and 81% received radiation treatment for BM. With a median follow-up of 5 years, 82% of pts died and median OS (mOS) following BM dx was 14 months (95% CI: 9-19). Among 208 pts without de novo BM, time to BM development (mTBM) from primary BCa varied by subtype: mTBM (IQR) HR+HER2- of 6.4 years (3.9-10.5), HR+HER2+ of 3.5 years (2.0-9.1), HR-HER2+ of 2.1 years (1.2-3.1), TNBC of 2.4 years (1.1-4.9). mOS varied by BCa subtype (table, log-rank p=0.029). 41 cases had de novo met disease (met dx ≤2 months of BCa dx) with 21 (9%) having de novo BM. HER2+ BCa and shorter mTBM were associated with longer mOS (table). Pts with BM dx in 2nd or later met relapse vs. earlier BM (de novo or 1st met relapse), OS HR was 1.67 (95% CI: 1.24-2.25; p=0.001). OS did not vary by age at BM diagnosis. Conclusions: Our findings build on prior work showing differential BM survival by subtype. We observe significantly shorter post-BM survival among pts who develop BM after a second or later line of met treatment. Ongoing work will expand our database and explore molecular features of resected brain tumors. [Table: see text]
A cross-sectional study of synchronous liver metastasis in patients with gastric cancer.
Authors: Zhang Haijun , Wang Tingya
Published: July 2024

e16015

Background: The specific organ microenvironment can promote the colonization of tumor cells. However, lack of research shed light on the liver microenvironment in synchronous liver metastasis in patients with gastric cancer (synGCLM). With the epidemic of hepatitis B virus (HBV) infection in China, we aim to explore the influence of hepatitis B surface antigen (HBsAg) on the risk of synGCLM. Methods: It was a cross-sectional study that enrolled 858 cases of newly diagnosed gastric cancer (GC). SynGCLM confirmed by biopsy or imaging evaluation reported by two senior radiologists. HBsAg-positive was defined as the detection of serum HBsAg more than 10 IU/mL. The prevalence of synGCLM was compared between patients with HBsAg (HBsAg+) and those without HBsAg (HBsAg-). The risk factors for synGCLM were analyzed by univariate and multivariate logistic regression analyses. Especially in the HBsAg+ GC patients, aspartate aminotransferase to platelet ratio index (APRI), liver fibrosis-4 index (FIB-4) levels and hepatitis B e antigen (HBeAg) status were further analyzed. Results: The prevalence of synGCLM of the HBsAg+ group was 16.7%, higher compared to 7.0% of the HBsAg- group, which was of statistical significance (p = 0.014). Multivariate logistic regression analysis demonstrated that HBsAg (Odds ratio (OR) = 3.359, p = 0.008), the elevated level of carcinoembryonic antigen (CEA) (OR = 3.775, p < 0.001), alpha-fetoprotein (AFP) (OR = 6.204, p < 0.001), γ-glutamyltransferase (GGT) (OR = 5.081, p < 0.001), alkaline phosphatase (ALP) (OR = 3.968, p = 0.002) and age (OR = 1.028, p = 0.033) were risk factors for synGCLM. Among the HBsAg+ patients, both ARPI and FIB-4 were statistically higher in the patients with synGCLM (synGCLM+) compared to those without synGCLM (synGCLM-) (ARPI: p = 0.045; FIB-4: p = 0.047); HBeAg positivity was detected in 20.0% of synGCLM+ patients compared to 6.0% of synGCLM- patients, but the difference was of no significance (p = 0.190). Conclusions: HBV infection is a risk factor for synGCLM whereas elevated ARPI and FIB-4 may be pro-metastatic especially among the HBsAg+ GC patients. Age, preoperative CEA, AFP, GGT and ALP levels are associated with increased risk of synGCLM.
Fruquintinib combined with sintilimab and SOX as conversion therapy for unresectable locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (GC/GEJC): A single-arm, open-label, phase 2 clinical trial.
Authors: Ma Fei , Luo Suxia , Zhang Bin , Ma Qi , Ji Sheqing , Zhang Zhandong , Zhang Yonglei , Yang Wei , Peng Liangqun , Guo Dandan , Ren Jinjun , Zhang Yuan , Su Yueyue , Li Jing , Liu Wentao , Huang Jinxi , Yuan Weiwei
Published: July 2024

e16021

Background: The evidence of conversion therapy for unresectable GC/GEJC is limited. Fruquintinib is an oral, highly selective VEGFR 1/2/3 inhibitor that has synergistic antitumor effects when combined with ICIs/chemotherapy. This study was conducted to evaluate the efficacy and safety of fruquintinib combined with sintilimab and SOX as a conversion therapy in patients (pts) with initially unresectable locally advanced or metastatic GC/GEJC. Methods: Eligible pts received 3 to 6 cycles of fruquintinib (4mg/d, po, qd, d1-14) combined with sintilimab (200mg, iv, d1), oxaliplatin (130 mg/m2, iv, d1) and S-1 (40-60mg based on BSA, po, bid, d1-14) every 3 weeks. One more cycle of sintilimab plus SOX was given before resection. Radiographic assessments were performed every 3 cycles and MDTs were employed to determine surgical feasibility. Primary endpoint was R0 resection rate. Secondary endpoints included pathological response, ORR, PFS, OS, and safety. Results: From May 2022 to December 2023, 34 pts (29 males/5 females) with a median age of 62 years (range: 43–76), 71% ECOG PS1, 59% GEJC were enrolled. The unresectable factors included liver metastasis 15% (5/34), peritoneal metastasis 6% (2/34), para-aortic lymph node metastasis 3% (1/34), extensive or bulky lymph nodes 53% (18/34), and local progression 38% (13/34). Five pts had more than one unresectable factors. The ORR and DCR of 29 pts who had at least one preoperative assessment were 65.5% (19 PR) and 96.6%, respectively. Among the 18 pts who had completed surgical conversion, all of them had R0 resection (100%), 2 pts (11.1%) achieved pathological complete response (pCR), and 1 pt reached AJCC-TRG1. The pathological response rate (pRR) according to JCGC (≥ Grade 1b) was 100% (18/18). Additionally, downstaging to pN0 was achieved in 13 pts (72.2%). During preoperative treatment, treatment-emergent adverse events (TEAEs) occurred in 85.3% (29/34) pts, and most events were grade 1–2. Grade 3 TEAEs included 2 cases of neutrophil count decreased, and 1 case of each (platelet count decreased, anemia, diarrhea, and immune-related pneumonitis). No severe surgery-related complication was observed. Conclusions: Fruquintinib combined with sintilimab and SOX as a conversion therapy strategy shown acceptable toxicity in unresectable GC/GEJC and induced very high R0 resection, pathological response, and downstaging rate. The study is ongoing, more data will be disclosed in the future. Clinical trial information: NCT05177068 .