bluuebunny/crossref_metadata_2025 huggingface dataset:
iPSCs chondrogenic differentiation for personalized regenerative medicine: a literature review
Authors: Ali Eltahir Abdelrazig Mohamed , Smaida Rana , Meyer Morgane , Ou Wenxin , Li Zongjin , Han Zhongchao , Benkirane-Jessel Nadia , Gottenberg Jacques Eric , Hua Guoqiang
Published: June 2024

Cartilage, an important connective tissue, provides structural support to other body tissues, and serves as a cushion against impacts throughout the body. Found at the end of the bones, cartilage decreases friction and averts bone-on-bone contact during joint movement. Therefore, defects of cartilage can result from natural wear and tear, or from traumatic events, such as injuries or sudden changes in direction during sports activities. Overtime, these cartilage defects which do not always produce immediate symptoms, could lead to severe clinical pathologies. The emergence of induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine, providing a promising platform for generating various cell types for therapeutic applications. Thus, chondrocytes differentiated from iPSCs become a promising avenue for non-invasive clinical interventions for cartilage injuries and diseases. In this review, we aim to highlight the current strategies used for in vitro chondrogenic differentiation of iPSCs and to explore their multifaceted applications in disease modeling, drug screening, and personalized regenerative medicine. Achieving abundant functional iPSC-derived chondrocytes requires optimization of culture conditions, incorporating specific growth factors, and precise temporal control. Continual improvements in differentiation methods and integration of emerging genome editing, organoids, and 3D bioprinting technologies will enhance the translational applications of iPSC-derived chondrocytes. Finally, to unlock the benefits for patients suffering from cartilage diseases through iPSCs-derived technologies in chondrogenesis, automatic cell therapy manufacturing systems will not only reduce human intervention and ensure sterile processes within isolator-like platforms to minimize contamination risks, but also provide customized production processes with enhanced scalability and efficiency.

Graphical abstract
Adaptive scheduling-based fine-grained greybox fuzzing for cloud-native applications
Authors: Yang Jiageng , Liu Chuanyi , Fang Binxing
Published: June 2024

Coverage-guided fuzzing is one of the most popular approaches to detect bugs in programs. Existing work has shown that coverage metrics are a crucial factor in guiding fuzzing exploration of targets. A fine-grained coverage metric can help fuzzing to detect more bugs and trigger more execution states. Cloud-native applications that written by Golang play an important role in the modern computing paradigm. However, existing fuzzers for Golang still employ coarse-grained block coverage metrics, and there is no fuzzer specifically for cloud-native applications, which hinders the bug detection in cloud-native applications. Using fine-grained coverage metrics introduces more seeds and even leads to seed explosion, especially in large targets such as cloud-native applications.

Therefore, we employ an accurate edge coverage metric in fuzzer for Golang, which achieves finer test granularity and more accurate coverage information than block coverage metrics. To mitigate the seed explosion problem caused by fine-grained coverage metrics and large target sizes, we propose smart seed selection and adaptive task scheduling algorithms based on a variant of the classical adversarial multi-armed bandit (AMAB) algorithm. Extensive evaluation of our prototype on 16 targets in real-world cloud-native infrastructures shows that our approach detects 233% more bugs than go-fuzz, achieving an average coverage improvement of 100.7%. Our approach effectively mitigates seed explosion by reducing the number of seeds generated by 41% and introduces only 14% performance overhead.
Repercussions of the COVID-19 pandemic on the HIV care continuum and related factors in economically disadvantaged nations: an integrated analysis using mixed-methods systematic review
Authors: Ojukwu Emmanuela , Pashaei Ava , Maia Juliana Cunha , Omobhude Oserekpamen Favour , Tawfik Abdulaziz , Nguyen Yvonne
Published: June 2024

Background

The COVID-19 pandemic affected the self-management and care of people living with HIV, requiring adaptations in the way health services are provided. However, it is unclear how these changes impacted HIV care in low-income countries.

Methods

A systematic review including the current evidence related to changes in HIV care continuum during COVID-19 was conducted through a systematic search in the online databases including CINAHL, OVID-Medline, CAB Direct, and OVID-Embase. A two-step screening process was carried out to include eligible papers and reports according to inclusion criteria.

Results

From the searches we identified 21 total studies published between 2021 and 2024, the studies revealed mostly negative impacts on all stages of the HIV care continuum in low-income countries. There were impacts related to the blocking measures due to COVID-19, fear of contracting the disease, difficulties in providing resources such as income, food and transports, reductions in the provision of care from prevention to viral suppression.

Conclusion

Overall, researchers identified several negative impacts of COVID-19 restrictions on HIV care continuum during pandemic; however, some observations indicated indirect positive impacts on some aspects of HIV care. Decline in HIV care practices during pandemic compared to before pandemic were observed including using preventative methods, counseling and testing, receiving HIV healthcare services, HIV medical appointments, antiretroviral adherence, engagement with treatment, and poor viral suppression. However, in some evidence improvement in ART adherence and PrEP use were observed.
Using proximity loggers in studies of sheep behavior: an estimation of the daily frequency of water consumption
Authors: Abecia José A. , Erden Pelin , Canto Francisco
Published: June 2024

Background

Proximity loggers are a biotelemetry technology used to quantify animal–animal interactions non-invasively. They are small devices can be affixed to a target animal and detects and records if another device is within a certain distance, which can provide unprecedented insights into individual behavior and interactions with other animals or other aspects of the environment. Proximity loggers also can record the duration and distance between the two or more individuals detected, and have been used to study a diverse array of interactions. Studying drinking behavior in sheep is important for several critical reasons, such as improving animal welfare, enhancing productivity, managing resources efficiently, and ensuring sustainable agricultural practices. The objective of this study was to test the capacity for Bluetooth Low Energy proximity loggers to quantify drinking habits in sheep (n = 7 adult females). At all times, they had access to water from two drinking troughs. Animals wore neck collars that contained a mobile logger, and two stationary loggers were placed under the drinking troughs. To store the records downloaded from the stationary loggers, a gateway was placed close to the troughs. The mobile loggers were programmed as beacons to transmit their ID to the stationary loggers, which were programmed as receivers to scan the proximity of the mobile loggers, record the time, the IDs of the mobile loggers, and the received signal strength of the contact with the mobile loggers.

Results

Ewes visited the drinking troughs 2.4 ± 0.5 times per day (rank 1.4–2.9), most frequently (42%) between 0800 and 1000 h, and 84% occurred in the daytime. Mean length of each water intake was 1.72 ± 0.30 min. The cosinor analysis of the distribution of drinking events revealed a significant (P < 0.0001) 24-h circadian rhythm in drinking events, and the acrophase (time of the highest proportion of events) occurred at 1054 h.

Conclusions

Considering that studying water intake in sheep is crucial for optimizing their health, welfare, and management, the proximity loggers were demonstrated to be appropriate for documenting the drinking habits of sheep, and probably, would be suitable for studies of other behaviors that involve approaching other animals or objects.
Extending the theory of planned behavior model to explain people’s behavioral intentions to follow China’s AI generated content law
Authors: Li Jie-Chun , Lin Yi , Yang Yi-Chun
Published: June 2024

AI Generated Content Law was extensively promoted in 2023; hence, it is crucial to uncover factors influencing people’s behavioral intentions to comply with the AI Generated Content Law. This study extends the theory of planned behavior to explore the factors influencing people to follow AI Generated Content Law in China. In addition to the factors in TPB model, such as one’s attitudinal factors, normative factors, and perceived behavioral control, we add another factor-moral obligation to extend the theory of planned behavior model. We used convenient sampling and there were 712 effective samples. Using the statistical software Amos17.0, the result shows that attitude, subjective norms, perceived behavioral control and moral obligation all have positive effects on intentions to follow AI Generated Content Law.
Can watching the World Cup make you mentally healthier? Positive associations between involvement in physical activities and flourishing were mediated by psychological need satisfaction
Authors: Zhou Hui , Hui Bryant Pui Hung , Yang Hong Mian , Wu Anise M. S.
Published: June 2024

Background

The current understanding of the relationship between physical activity involvement and flourishing, as well as the underlying psychological mechanisms, remains limited. Building upon the basic psychological need theory, this study investigates whether and how engaging in physical activities, either as a spectator (e.g., in sports events such as the World Cup) or a participant, explains individual differences in flourishing.

Methods

A total of 1201 Hong Kong-based Chinese adults (Mage = 42.90, SD = 11.40; 54% female) completed an anonymous online survey from the quarter-final to final stages of the 2022 FIFA World Cup in December 2022.

Results

Findings showed that spectator (World Cup) involvement and participant involvement were positively correlated. Moreover, both types of involvements were correlated with flourishing. In addition to the hypothesized positive association with relatedness satisfaction, spectator (World Cup) involvement was also demonstrated significant associations with autonomy and competence satisfaction. Path analysis indicated that associations between physical activities and flourishing were partially mediated by the satisfaction of all three basic psychological needs.

Conclusions

This study is the first to apply the basic psychological need theory in the context of physical activity and supports its relevance in understanding individual differences in flourishing. Different stakeholders are encouraged to recognize the benefits of both spectator and participant involvements in physical activities, which may help them develop supportive strategies (e.g., physical activities with parents, sports events for spectators and participants, and funding for media/communities) in mental health promotion.
Optimization-based convolutional neural model for the classification of white blood cells
Authors: Devi Tulasi Gayatri , Patil Nagamma
Published: June 2024

White blood cells (WBCs) are one of the most significant parts of the human immune system, and they play a crucial role in diagnosing the characteristics of pathologists and blood-related diseases. The characteristics of WBCs are well-defined based on the morphological behavior of their nuclei, and the number and types of WBCs can often determine the presence of diseases or illnesses. Generally, there are different types of WBCs, and the accurate classification of WBCs helps in proper diagnosis and treatment. Although various classification models were developed in the past, they face issues like less classification accuracy, high error rate, and large execution. Hence, a novel classification strategy named the African Buffalo-based Convolutional Neural Model (ABCNM) is proposed to classify the types of WBCs accurately. The proposed strategy commences with collecting WBC sample databases, which are preprocessed and trained into the system for classification. The preprocessing phase removes the noises and training flaws, which helps improve the dataset's quality and consistency. Further, feature extraction is performed to segment the WBCs, and African Buffalo fitness is updated in the classification layer for the correct classification of WBCs. The proposed framework is modeled in Python, and the experimental analysis depicts that it achieved 99.12% accuracy, 98.16% precision, 99% sensitivity, 99.04% specificity, and 99.02% f-measure. Furthermore, a comparative assessment with the existing techniques validated that the proposed strategy obtained better performances than the conventional models.
The simulation of the Indo-Pacific warm pool SST warming trend in CMIP5 and CMIP6
Authors: Bai Wenrong , Liu Hailong , Lin Pengfei , Shen Hongyan
Published: June 2024

This paper evaluates Indo-Pacific warm pool (IPWP) sea surface temperature (SST) warming biases of Coupled Model Intercomparison Project Phase 5 (CMIP5) and CMIP6. The IPWP warming trend in the CMIP5 multi-model ensemble (MME) is closer to observation than in CMIP6 MME, but the IPWP expanding trend is the opposite. There is no qualitative improvement in the simulation of IPWP warming from CMIP5 to CMIP6. In addition, four metrics were used to investigate the performance of Indo-Pacific region warming trends in all models. CMIP6 models perform better than CMIP5 with smaller root mean square error and bias in MME and higher skill scores in MME and top models, which is tightly linked to their better performance in simulating associated physical processes in CMIP6 models. IPWP warming biases are mainly attributed to the combined effects of positive atmospheric process biases and negative ocean dynamics term biases. The positive atmospheric process biases are primarily related to the shortwave radiation and latent heat flux from atmospheric forcing, the latter of which can be attributed to the biases in surface wind fields. Compared with CMIP5 models, the IPWP warming simulated by CMIP6 models is weaker, related to the less robust atmospheric processes and the shallower thermocline anomalies simulated by CMIP6.
Dietary salt intake and kidney function in rural Senegalese populations: a cross-sectional study
Authors: Modou Ndongo , Motoula Latou Lot Nehemie , Maimouna Toure , Dia Amadou Diop , Seck Sidy Mohamed
Published: June 2024

Introduction

High salt intake is a major risk factor for hypertension and its complications such as chronic kidney disease (CKD) and cardiovascular diseases. The present study aimed to determine level of sodium consumption and its relation with kidney function in the rural populations of Ferlo (centre of Senegal).

Subjects and methods

We performed a cross-sectional study including 400 volunteers aged > 18 years. Clinical, biological and dietary data were collected during household visits. Daily sodium intake was measured in the 24 h-urine outpout and CKD was defined as eGFR < 60 ml/min. Linear regression analysis was used to assess association between sodium intake and covariates.

Results

Mean age was 46.42 ± 15.60 and sex-ratio was 1.05. Prevalence of hypertension, CKD and overweight were 21.5, 11.7 and 20.5%, respectively. The median daily salt intake was 11.7 g with interquartile range of 14.8 g. Only 11.25% of participants consumed less than 5 g/day. After multivariate analysis, high salt intake was associated with age > 60 years, overweight and CKD. However, gender and hypertension were not significantly associated with salt intake. Industrial broths (91.5%) and bread (85%) represented the main sources of dietary salt.

Conclusion

This study revealed high levels of daily salt intake contrasting with low potassium intakes in the majority of participants. Participants with CKD, overweight and age > 60 years presented higher salt consumption. Stategies to reduce salt consumption are urgently needed to reduce burden of CKD in rural Senegalese populations.
Use of concept mapping to inform a participatory engagement approach for implementation of evidence-based HPV vaccination strategies in safety-net clinics
Authors: Tsui Jennifer , Shin Michelle , Sloan Kylie , Mackie Thomas I. , Garcia Samantha , Fehrenbacher Anne E. , Crabtree Benjamin F. , Palinkas Lawrence A.
Published: June 2024

Background

Multiple evidence-based strategies (EBS) for promoting HPV vaccination exist. However, adolescent HPV vaccination rates remain below target levels in communities at high risk for HPV-associated cancers and served by safety-net clinics. Participatory engaged approaches are needed to leverage the expertise of community and clinical partners in selecting EBS relevant to their local context. We engaged concept mapping as a method to inform the adoption and adaptation of EBS that seeks to empower implementation partners to prioritize, select, and ultimately implement context-relevant EBS for HPV vaccination.

Methods

Using 38 EBS statements generated from qualitative interviews and national HPV vaccine advocacy sources, we conducted a modified concept mapping activity with partners internal to safety-net clinics and external community members in two study sites of a larger implementation study (Greater Los Angeles and New Jersey), to sort EBS into clusters and rate each EBS by importance and feasibility for increasing HPV vaccination within safety-net clinics. Concept mapping findings (EBS statement ratings, ladder graphs and go-zones) were shared with leaders from a large federally qualified health center (FQHC) system (focusing on three clinic sites), to select and implement EBS over 12 months.

Results

Concept mapping participants (n=23) sorted and rated statements, resulting in an eight-cluster solution: 1) Community education and outreach; 2) Advocacy and policy; 3) Data access/quality improvement monitoring; 4) Provider tracking/audit and feedback; 5) Provider recommendation/communication; 6) Expanding vaccine access; 7) Reducing missed opportunities; and 8) Nurse/staff workflow and training. The FQHC partner then selected to intervene on eight of 17 EBS statements in the “go-zone” for action, with three from “reducing missed opportunities,” two from “nurse/staff workflow and training,” and one each from “provider tracking/audit and feedback,” “provider recommendation/communication,” and “expanding vaccine access,” which the research team addressed through the implementation of three multi-level intervention strategies (e.g., physician communication training, staff training and workflow assessment, audit and feedback of clinic processes).

Conclusions

Concept mapping provided a powerful participatory approach to identify multilevel EBS for HPV vaccination relevant to the local safety-net clinic context, particularly when several strategies exist, and prioritization is necessary. This study demonstrates how a clinic system benefited directly from the ratings and prioritization of EBS by multilevel clinic and community partners within the broader safety-net clinic context to identify and adapt prioritized solutions needed to advance HPV vaccine equity.
Efficacy of imetelstat on red blood cell (RBC)-transfusion independence (TI) in the absence of platelet transfusions or myeloid growth factors in IMerge.
Authors: Zeidan Amer Methqal , Santini Valeria , Platzbecker Uwe , Sekeres Mikkael A. , Savona Michael R. , Fenaux Pierre , Madanat Yazan , Raza Azra , Xia Qi , Sun Libo , Riggs Jennifer , Shah Sheetal , Navada Shyamala Chendeal , Berry Tymara , Komrokji Rami S.
Published: June 2024

6566

Background: In the IMerge trial (NCT02598661) of RBC transfusion-dependent (TD) patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory to or ineligible for erythropoiesis stimulating agents, imetelstat showed significant efficacy vs placebo (PBO) for 8-wk, 24-wk, and 1-y TI endpoints, with neutropenia and thrombocytopenia as the most common adverse events (Platzbecker. Lancet 2024). Supportive care was given to all pts as needed, per investigator discretion. Here we report RBC-TI rates in the absence of platelet transfusions or myeloid growth factor use. Separately, RBC-TI with mean central hemoglobin (Hb) rise of ≥1.5 g/d was assessed in all pts. Methods: Pts were randomized 2:1 to receive imetelstat (n=118) 7.5 mg/kg or PBO (n=60) Q4W IV until disease progression. Primary endpoint was 8-wk RBC-TI; 24-wk RBC-TI was a key secondary endpoint. Primary analysis cutoff was Oct 2022, with Oct 2023 cutoff for 1-y RBC-TI analyses. Results: Overall, 21/118 (18%) pts in the imetelstat group and 1/60 (2%) pts in the PBO group needed platelet transfusions; 41/118 (35%) and 2/60 (3%) pts received myeloid growth factors, respectively. Significantly higher percentages of pts achieved 8-wk, 24-wk, and 1-y RBC-TI with imetelstat vs PBO in the absence of either platelet transfusions or growth factor support (Table). In a separate analysis, 8-wk, 24-wk, and 1-y RBC-TI and concurrent Hb rise of ≥1.5 g/dL with imetelstat vs PBO occurred in 28% vs 2%, 23% vs 0%, and 17% vs 0% of pts, respectively (Table). Among responders, imetelstat increased median central Hb levels compared with PBO: 3.6 g/dL vs 0.8 g/dL for 8-wk, 4.2 g/dL vs 1.1 g/dL for 24-wk, and 5.2 g/dL vs 1.7 g/dL for 1-y RBC-TI. Conclusions: Results from this subanalysis confirm that pts who achieve RBC-TI with imetelstat do so without developing severe neutropenia and thrombocytopenia (functionally defined as needing myeloid growth factors or platelet transfusions, respectively), therefore not negating the clinical benefit of the drug. Imetelstat also led to significant rise in Hb levels in RBC-TI responders, particularly long-term responders. These data further support the efficacy of imetelstat in TD pts with LR-MDS. Clinical trial information: NCT02598661 . [Table: see text]
Trends in the thrombotic complications of myeloproliferative neoplasms: A nationwide analysis.
Authors: Solipuram Divya , Mehta Kathan , Siddappa Malleshappa Sudeep Kumar
Published: June 2024

6581

Background: Thrombotic complications are a well known cause of morbidity and mortality in Philadelphia-negative Myeloproliferative Neoplasms[Polycythemia Vera, Essential thrombocythemia, Primary Myelofibrosis]. Current study evaluated thrombotic events incidence and outcome trends in Myeloproliferative Neoplasms[MPN] from 2012 to 2020. Methods: This is a longitudinal study of thrombotic events in MPN using the Nationwide Inpatient Sample. All patients with a diagnosis of MPN admitted with any thrombotic event including arterial or venous thrombosis were included in the study. Arterial thrombotic events included Myocardial infarction[MI], Ischemic stroke[IS], Transient Ischemic Attack[TIA] while venous thrombotic events included Deep Vein Thrombosis[DVT], Pulmonary Embolism[PE], Budd-Chiari Syndrome[BCS], Portal Vein Thrombosis[PVT]. Thrombosis related inpatient mortality rate, incidence, length of hospital stay, and total hospital charges were calculated. Results: Mortality rate from any thrombotic event overall[arterial plus venous] increased from 2.3% to 2.6% from 2012 to 2020. There was an increase in mortality rates from 2.8% to 3.8% among arterial thrombosis while there was a decrease in venous thrombosis related mortality from 1.7 to 0.4%. Specifically MI and IS related mortality increased from 3.7% to 4.3% and 3% to 4% respectively over the same period. The incidence of any thrombotic event declined from 2 to 1.3 cases/100,000 persons from 2012 to 2020. A similar decline in incidence of arterial, venous events, MI, IS were observed. The mean length of stay decreased from 5.8 days in 2012 to 5.2 days in 2020 among MPN patients with venous thrombosis which was statistically significant. Similar decline was noted in MI patients as well. Though the mean length of stay increased from 7.9 to 9.5 days among MPN patients with IS, this increase was not statistically significant. The mean hospitalization charges for thrombotic events increased from $53,421 in 2012 to $101,598 in 2020 after adjusting for inflation. Similar trends were noted in all types of thrombotic admissions which were all statistically significant. Upon age based stratification of MPN, mortality for those less than 60 years reduced from 2% to 0.3%, while it increased from 4.1 to 5.6% in those more than 60 years from 2012 to 2020. Conclusions: Inpatient mortality from thrombotic events in MPN has shown an increasing trend from 2012 to 2020 though there was a decline in overall incidence of thrombosis during the same period. Despite the decreasing trend in length of stay, the total economic burden of thrombotic complications in MPN is increasing in the US. Specifically the effects were more pronounced in those greater than 60 years. This points to the need for revisiting guidelines regarding thromboprophylaxis in MPN.
A multi-center cohort study Examining risk factors for central nervous system metastases (CNSm) in patients with stage III non-small cell lung cancer (NSCLC) treated with definitive chemoradiation (ChemoRT) followed by durvalumab (Durva).
Authors: Sharp John , Young Philip , Zhao Songzhu , Patel Sandip Pravin , Wei Lai , Li Mingjia , Brownstein Jeremy , Haglund Karl , Palmer Joshua David , Raval Raju R. , Shields Peter G. , He Kai , Kaufman Jacob , Memmott Regan Michelle , Alahmadi Asrar , Carbone David Paul , Otterson Gregory Alan , Presley Carolyn J. , Gentzler Ryan D. , Owen Dwight Hall
Published: June 2024

8076

Background: In the PACIFIC trial, 6.3% of patients with unresectable stage III NSCLC receiving durva after chemoRT developed CNSm. In a single center study, we previously reported real-world incidence of CNSm is higher at 19.8%. Risk factors for development of CNSm post-durva are incompletely understood. Methods: We conducted a multi-center retrospective study of patients with unresectable stage III NSCLC treated with durva after chemoRT from 2018 to 2022 with no CNSm on baseline brain MRI to assess for incidence of CNSm. Patient characteristics were compared between cohorts with and without CNSm to assess for risk factors for CNSm using Fisher’s exact test for categorical variables and two-sample t-test or Wilcoxon Mann-Whitney U-test for continuous variables. Overall survival was compared using log-rank test. Results: Of 193 patients in our study, 32 (16.6%) developed CNSm with median time to CNSm of 6.4 mo (IQR 4.5 - 13.7). Twenty-five (78%) had CNSm within one year. Patients with CNSm had a longer interval between baseline brain MRI and start of durva (median 3.7 mo vs 3.3 mo, p=0.02) and received fewer doses of durva compared to those without CNSm (median 7 vs 12, p=0.03). As some patients received Q2 week and others Q4 week durva, we also compared median durva treatment duration, which was consistent (3.7 mo vs 8.3 mo, p=0.02). There was no association between CNSm and age, sex, histology, T/N stage, PDL1 status, or chemoRT regimen (Table). Patients with CNSm had shorter median survival (19.6 mo vs 36.4 mo, p=0.008). Conclusions: Real-world incidence of CNSm is higher than that seen in PACIFIC. Patients with CNSm received less durva, likely due to early disease progression, and had longer intervals between baseline brain MRI and starting durva. Minimizing treatment delays may improve outcomes. Further research is needed to understand optimal surveillance strategies for CNSm in this patient population. [Table: see text]
Programmed cell death ligand 1 (PD-L1) inhibitors versus programmed cell death 1 (PD-1) inhibitors for the first-line therapy of extensive-stage small cell lung cancer: A propensity score-matched study.
Authors: Tian Yaru , Lu Shuangqing , Sun Yulan , Tang Xiaoyong , Sun Zhuoran , Zhao Ke , Du Guochang , Li Wanjing , Zhu Hui
Published: June 2024

8086

Background: Addition of programmed cell death ligand 1 (PD-L1) inhibitors or programmed cell death 1 (PD-1) inhibitors to etoposide‐platinum (EP) chemotherapy has become the standard first-line regimen for ES-SCLC. The clinical efficacy and safety between the two types of immune checkpoint inhibitors (ICIs) remain controversial. We conduct the retrospective study and propensity score-matched analysis to explore the potential differences between them. Methods: Patients diagnosed with ES-SCLC and treated by EP plus PD-L1 or PD-1 inhibitors at Shandong Cancer Hospital between March 2019 and November 2022 were reviewed retrospectively. According to PD-L1 or PD-1 inhibitors, they were divided into two groups. Propensity score matching (1:1) was performed to balance the baseline characteristics of the two groups. The baseline characteristics and adverse events between the two groups were compared using the chi-squared test. The survival curves of overall survival (OS) and progression-free survival (PFS) were plotted by the Kaplan-Meier method and differences were analyzed by the log-rank test.The primary endpoints were OS and PFS. Results: As a result, 448 patients were analyzed in this study. 264 patients received PD-L1 inhibitors plus EP and 184 received PD-1 inhibitors plus EP. The median follow-up was 17.6 months. The median OS and PFS was 20.4 months and 7.8 months in the overall population. Before propensity score matching, the median OS was 20.1 months in PD-L1 inhibitor plus EP group and 20.7 months in PD-1 inhibitor plus EP group, respectively (HR 1.043, 95%CI 0.776-1.401; p= 0.781). The median PFS was 7.6 months in the PD-L1 inhibitor plus EP group and 8.5 months in PD-1 inhibitor plus EP group (HR 1.099, 95%CI 0.886-1.364; p= 0.390). After propensity score matching, the median OS and PFS were 20.4 months and 7.8months in PD-L1 inhibitor plus EP group, and those were 20.1 months and 8.6 months in PD-1 inhibitor plus EP group. There was no significant difference in OS and PFS between PD-L1 inhibitors plus EP and PD-1 inhibitors plus EP in the matched population (HR 1.104; p= 0.578 and HR 1.072; p= 0.602, respectively). The overall adverse events were comparable in the two groups. Only ≥3 grade neutropenia was more frequent in the PD-L1 inhibitors plus EP group (77.7% vs 69.0%, p= 0.040). Conclusions: In conclusion, the overall efficacy and safety profile was similar between PD-L1 inhibitors and PD-1 inhibitors for the first-line treatment of ES-SCLC.
ARTEMIS-001: Data from a phase 1a/b study of HS-20093 in patients with relapsed small cell lung cancer (SCLC).
Authors: Wang Jie , Duan Jianchun , Sun Yuping , Xing Ligang , Han Liang , Wang Qiming , Wu Lin , Chen Jianhua , Lu Ping , Guo Wei , Wang Haiying , Liu Baogang , Zhang Zhiye , Zhang Junhong , Huang Jianying , Shi Huaqiu , Yang Haiyu , Zhang Guoping , Ning Fangling , Zhu Weiliang
Published: June 2024

8093

Background: SCLC is characterized by a high rate of proliferation and poor prognosis, and new therapies are urgently needed. B7-H3 is highly expressed in SCLC. HS-20093, a B7-H3-targeted antibody-drug conjugate (ADC), demonstrated antitumor activity in advanced solid tumors in the dose escalation part of ARTEMIS-001 study (Jie Wang et al., JCO, 2023) (NCT05276609). Here, we present results on the efficacy and safety of the expansion doses in patients (pts) with SCLC from phase 1a/b. Methods: ARTEMIS-001 study consisted of dose escalation (1a) and expansion (1b) part. Pts were treated with doses of 1.0 to 16.0 mg/kg HS-20093 every 3 weeks in dose escalation, and were treated with doses at 8.0 mg/kg and 10.0 mg/kg randomly in dose expansion. Pts with SCLC were required to have received prior platinum-based standard therapy. B7-H3 expression was retrospectively evaluated by IHC. Results: As of data cutoff November 30th 2023, a total of 56 pts with extensive stage SCLC (ES-SCLC) were enrolled and received ≥1 dose of HS-20093 with doses at 8.0 mg/kg (n=31) or 10.0 mg/kg (n=25). Median prior lines of therapy was 2.0 (range: 1-6). All pts received platinum plus etoposide and 73.2% (41/56) received immunotherapy. Safety profile was consistent with previous reports. The most common grade≥3 treatment-related adverse events (≧10%) were neutropenia, leukopenia, lymphopenia, thrombocytopenia and anemia. Out of 56 pts, 52 pts were efficacy evaluable (8.0 mg/kg: 31 pts; 10.0 mg/kg: 21 pts). HS-20093 showed encouraging efficacy in relapsed ES-SCLC (Table). Tumor shrinkage in target lesions occurred in 96.2% (50/52) pts with a post-baseline scan. Deep response defined as tumor shrinkage ≥50% was obtained in 44.2% (23/52) pts. Median overall survival has not yet reached. Responses were observed regardless of B7-H3 expression. Pharmacokinetic (PK) showed approximately dose-proportional increase in exposure with a half-life of 3-7 days. PK profiles of total antibody and ADC were similar and exposure to payload was considerably low. Conclusions: HS-20093 demonstrated promising antitumor activity and manageable safety in pts with previously-treated SCLC. Phase 3 study is planned to compare the efficacy and safety of HS-20093 with standard-of-care chemotherapy in relapsed SCLC. Clinical trial information: NCT05276609 . [Table: see text]
Survival outcomes of patients with extensive-stage small cell lung cancer who received treatment with atezolizumab in combination with carboplatin and etoposide: A propensity score adjusted cohort study.
Authors: Batah Heya , Adcock Bridget , Lee Monica , Patel Preeyal , Patel Meera , Zureigat Hadil , Hassan Ahmed , Nurse Daniel Paul , Rauf Asad , Tomer Jacqulyn , Hoen Douglas Robert , Hassan Khaled Aref , Pennell Nathan A. , Shapiro Marc A. , Stevenson James , Zabor Emily Craig , Adjei Alex A , Mustafa Ali Moaath Khader
Published: June 2024

8096

Background: Small cell lung cancer (SCLC) is an aggressive type of lung cancer. Most patients (pts) are diagnosed with extensive-stage disease (ES-SCLC). The cornerstone treatment of ES-SCLC has been platinum-based chemotherapy and etoposide. Combining atezolizumab with carboplatin plus etoposide (Carbo-E) improved overall survival (OS) in ES-SCLC pts and became a new standard for first-line treatment. However, there is a paucity of real-world outcomes in ES-SCLC. Herein, we present the largest and longest follow-up retrospective study analyzing atezolizumab in combination with chemotherapy for treatment of ES-SCLC. Methods: We conducted a retrospective study and included all adult pts (≥ 18 years) with ES-SCLC treated at Cleveland Clinic between 1/2010-12/2022. ES-SCLC was defined as stage IIIB or stage IV. We collected treatment regimens and baseline characteristics including age, sex, race, smoking, alcohol intake history, and comorbidities. Responses were assessed using RECIST response criteria. Both OS and progression-free survival (PFS) were calculated from treatment initiation. We used propensity score (PS) weighting and multivariable Cox proportional hazards ratio (CPH) to adjust for baseline confounding. Results: We identified 561 ES-SCLC pts who received treatment, 375 (67%) received Carbo-E and 160 (29%) received Carbo-E + Atezolizumab (Carbo-E-Atezo). The table describes the baseline characteristics of Carbo-E and Carbo-E-Atezo groups. The median follow-up was 30 months (mo) (IQR: 14 - 59). In the Carbo-E arm, 45 patients (12%) received second-line immune therapy (nivolumab +/- ipilimumab or pembrolizumab). On PS-adjusted logistic regression, pts who received Carbo-E-Atezo had a 1.1 odds ratio (95%CI: 0.85-1.43, P>0.05) to respond compared to pts who received Carbo-E. There was no difference in PS-adjusted median OS between pts who received Carbo-E-Atezo (9.2 mo (95%CI: 8.1-11)) vs. Carbo-E (8.4 mo (95%CI: 7.7-9.0)) (log-rank P>0.05). Similarly, there was no difference in adjusted median PFS between pts who received Carbo-E-Atezo (5.9 mo (95%CI: 5.3-6.9)) vs. Carbo-E (5.5 mo (95%CI: 4.7-5.9)) (P>0.05). Using CPH model, the addition of atezolizumab to Carbo-E did not decrease mortality (Hazard Ratio: 0.84, 95%CI: 0.68-1.04, P>0.05). Male gender and increasing age were predictors of worse OS (P<0.05). Conclusions: Among pts with ES-SCLC, the addition of atezolizumab to the standard chemotherapy regimen of Carbo-E showed no significant difference in PFS or OS in our real-world study. [Table: see text]
Efficacy and safety of taletrectinib in patients with advanced or metastatic ROS1+ non–small cell lung cancer: The phase 2 TRUST-I study.
Authors: Li Wei , Xiong Anwen , Yang Nong , Fan Huijie , Yu Qitao , Zhao Yanqiu , Wang Yongsheng , Meng Xue , Wu Jingxun , Wang Ziping , Liu Yunpeng , Wang Xicheng , Qin Xintian , Lu Kaihua , Zhuang Wu , Ren Yizhong , Zhang Xianyu , Yan Bing , Lovly Christine M. , Zhou Caicun
Published: June 2024

8520

Background: Taletrectinib, a highly potent, next-generation, central nervous system–active, selective ROS1 tyrosine kinase inhibitor (TKI), was previously reported to provide high overall and intracranial (IC) response rates, prolonged progression-free survival (PFS), and activity against G2032R with favorable tolerability. We report updated data from the TRUST-I study (NCT04395677), the largest clinical trial to date conducted in patients living with ROS1+ NSCLC. Methods: TRUST-I, a multicenter, single-arm, open-label, pivotal phase 2 study of taletrectinib conducted in China, had 2 cohorts: TKI-naïve and TKI-pretreated. The primary endpoint was objective response rate (ORR) by Independent Review Committee (IRC) per RECIST 1.1. Secondary endpoints included duration of response (DoR), PFS, overall survival (OS), and safety. Results: As of November 2023, 173 patients were enrolled (median age: 55 y; 58% female; 73% never smoked; TKI-naïve: n = 106; TKI-pretreated: n = 67). In TKI-naïve patients, 21% had prior chemotherapy, and 17% had brain metastases; in TKI-pretreated patients, 34% had prior chemotherapy, and 42% had brain metastases. In TKI-naïve patients, the ORR was 91% (95% CI: 83, 95) and IC-ORR was 88% (7/8; 95% CI: 47, 100). In TKI-pretreated patients, the ORR was 52% (95% CI: 40, 65) and IC-ORR was 75% (12/16; 95% CI: 48, 93). In patients with G2032R mutation, 8 of 12 patients (67% [95% CI: 35, 90]) responded. DoR and PFS remain durable, with median follow-up of 23.5 months in TKI-naïve patients and 9.7 months in TKI-pretreated patients (Table). Among all patients (n = 173), the most frequent treatment-emergent adverse events (TEAEs) were AST increase (76%), diarrhea (70%), and ALT increase (68%). Rates of neurologic TEAEs were low (dizziness: 23%; dysgeusia: 10%) and mostly grade 1. Discontinuation (5%) and dose reductions (19%) due to TEAEs were low. Conclusions: With longer follow-up, taletrectinib continues to show high and durable overall responses, robust intracranial and G2032R activity, and a favorable safety profile with a low incidence of neurologic AEs. An additional ongoing pivotal phase 2 study, TRUST-II (NCT04919811), is further evaluating the efficacy and safety of taletrectinib in patients in the US, Europe, and Asia. Clinical trial information: NCT04395677 . [Table: see text]
Efficacy and safety of sigvotatug vedotin, an investigational ADC, in NSCLC: Updated phase 1 results (SGNB6A-001).
Authors: Peters Solange , Hollebecque Antoine , Sehgal Kartik , Lopez Juanita Suzanne , Calvo Emiliano , Dowlati Afshin , Bockorny Bruno , Perez Cesar Augusto , Sanborn Rachel E. , Patnaik Amita , Fontana Elisa , Galvao Vladimir , Kingsley Ed , Patilea-Vrana Gabriela , Wang Tianhua , Knowles Scott , Piha-Paul Sarina A.
Published: June 2024

8521

Background: Integrin beta-6 (IB6), a tumor-associated membrane protein, plays an important role in pathogenesis and invasiveness and its expression correlates with poor outcomes. Sigvotatug vedotin (SV), formerly called SGN-B6A, is an IB6-directed ADC with encouraging activity in NSCLC in the Ph 1 study SGNB6A-001 (NCT04389632) (Hollebecque 2023). Here, we report updated efficacy and safety of SV in NSCLC. Methods: SGNB6A-001 is an open-label, multicenter, Ph 1 study evaluating the safety, pharmacokinetics (PK), and antitumor activity (cORR, DOR, and PFS per RECIST v1.1, and OS) of SV in patients (pts) with advanced solid tumors. Multiple dose regimens were explored during dose escalation (Part A). Dose expansion (Part B) is ongoing with selected regimens in various tumors including NSCLC. Parts C and D will evaluate SV in combination with pembrolizumab in NSCLC and HNSCC. Eligible pts had no therapeutic options (Part A) or had received platinum-based and anti-PD-(L)1 therapy unless contraindicated (Part B) and were dosed with the SV expansion regimens on D1 and D8 in a 21-day cycle (2Q3W; 1.2/1.25 mg/kg total body weight [TBW]) or D1 and D15 in a 28-day cycle (2Q4W; 1.5 mg/kg TBW, 1.8 mg/kg adjusted ideal body weight [AiBW]). Results: As of 01-Dec-2023, 306 pts had received SV; 113 pts with NSCLC received expansion regimens in Parts A and B. Prior lines of therapy and efficacy data for all pts with NSCLC and select subgroups are summarized in the table; cORR was 19.5% (95% CI, 12.6-28.0) in all pts with NSCLC and 32.5% (95% CI, 18.6-49.1) in pts with non-squamous (non-Sq)/taxane-naive NSCLC. Additional time-to-event data will be presented. Rates of TEAEs, ≥G3 TEAEs, SAEs, and TEAEs leading to discontinuation were 98.2%, 46.0%, 33.6%, and 13.3% in pts with NSCLC, and were consistent in all treated pts. The most common ≥G3 TEAEs in pts with NSCLC were dyspnea (9.7%), fatigue (7.1%), and neutropenia (5.3%). One pt with NSCLC had a treatment-related death (pneumonitis). PK variability across weight groups was lowest with 1.8 mg/kg AiBW 2Q4W. Conclusions: SV continues to demonstrate encouraging antitumor activity and a manageable safety profile in pts with NSCLC. Data at 1.8 mg/kg AiBW 2Q4W support initiation of the Ph 3 SGNB6A-002 study in 2/3L NSCLC (NCT06012435) and combination with pembrolizumab in earlier settings. Clinical trial information: NCT04389632 . [Table: see text]
Gene expression correlates of adagrasib response in KRASG12C mutated non-small cell lung cancer (NSCLC).
Authors: Kim Eejung , Tong Xinyuan , Patel Ayushi , Liu Shengwu , Dilly Julien , Hover Laura , Mukhopadhyay Suman , Sherman Fiona , Christensen James G , Olson Peter , Aguirre Andrew , Wong Kwok , Ji Hongbin
Published: June 2024

8529

Background: KRASG12C inhibitors such as adagrasib and sotorasib have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients develop primary or secondary resistance. A biomarker of response to KRASG12C inhibitor is needed for better patient stratification and to understand the resistance mechanism. Methods: We analyzed transcriptional correlates of adagrasib treatment outcome in 68 patients in the KRYSTAL-1 trial, a phase 1/2 clinical trial of adagrasib monotherapy in the second line and beyond treatment for NSCLC. We also treated KRAS-mutated lung cancer mouse models and organoids with a KRAS inhibitor for the long term and characterized the resistant tumors’ transcriptional profile to identify resistance mechanisms. We also performed serial gene expression analysis of KrasG12D mutated lung organoids undergoing squamous transformation to identify transcription factor involved in the resistance process. Results: In patients with lung adenocarcinoma with KRASG12C and STK11/ LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids, treated with KRAS inhibitors adagrasib and MRTX1133, respectively, reveal that tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. We identify TP63 to be a transcription factor whose expression correlated with squamous transformation. The analysis of lineage plasticity program, adagrasib resistant tumors, and p63 regulon revealed KRT6A to be a common biomarker whose expression correlated with overall survival in the KRYSTAL-1 cohort. Conclusions: KRASG12C mutated lung adenocarcinoma patients with a higher expression of squamous cell carcinoma gene expression signature respond poorly to adagrasib treatment. Expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.
Survey of actionable driver mutations KRAS and EGFR in non–small cell lung cancer to evaluate coexisting splicing gene and pathway mutations: A CBioportal database analysis.
Authors: Arter Zhaohui , Nagasaka Misako , Ou Sai-Hong Ignatius
Published: June 2024

8561

Background: Molecularly targeted therapies have advanced treatment for certain cancers, such as lung cancer with specific EGFR or KRAS mutations. However, oftentimes the tumor becomes eventually treatment resistant. This may be partly because cancers driven by EGFR/KRAS mutations may also harbor additional co-occurring genetic alterations. In non-small cell lung cancer (NSCLC), aberrations in RNA splicing pathways have shown substantial implications for tumor behavior and therapeutic responsiveness. Our study focuses on elucidating the interplay between RNA splicing defects and prominent NSCLC mutations. Methods: In this retrospective, cross-sectional study, we analyzed data from 20,719 NSCLC patients enrolled in participating institutions between 2017 and 2022. The data were sourced from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange (version 13.0). EGFR L858R, EGFR E746_750del, KRAS G12C, KRAS G12D and other KRAS G12 mutations cases were identified and individually analyzed to abstract co-occurring RNA splicing genomic alterations. Results: Among 20,719 patients with NSCLC, we identified 1309 patients with EGFR L 858R mutation, 1121 patients with EGFR E746_750del mutation, 2446 with KRAS 12C, 852 with KRAS G12D, 1107 with KRAS G12V, 452 with KRAS G12A, 173 with KRAS G12F, and 109 with KRAS G12S. RBM 10 was the most common co-occurring RNA splicing gene for EGFR L 858R (178, 13.6%), followed by CDK12 (31, 2.3%) and SPEN (27, 2 %). Similarly, the most prevalent co-occurring RNA splicing genes with EGFR E746_750del were RBM 10 (38, 3.4%) and SPEN (23, 2 %). RBM 10 was the most prevalent co-existing RNA splicing gene for KRAS G12C (211, 8.6 %), KRAS G12D (63, 7.4 %), KRAS G12V (80, 7.2%), KRAS G12A (59, 13.1%), KRAS G12F (12, 7.0%), KRAS G12S (11, 10.1%) and KRAS G12R (6, 8%). Conclusions: Our study uncovers a crucial link between EGFR and KRAS mutations in NSCLC and RNA splicing gene dysregulation, particularly involving RBM10. Further research in this field is warranted as targeting RNA splicing, alone or alongside existing targeted inhibitors, could substantially enhance treatment efficacy for EGFR+ or KRAS+ NSCLC patients. [Table: see text]