bluuebunny/crossref_metadata_2025 huggingface dataset:
Core principles of Malakit intervention for transferability in other contexts
Authors: Douine Maylis , Lambert Yann , Galindo Muriel Suzanne , Jimeno Maroto Irene , Bardon Teddy , Plessis Lorraine , Mutricy Louise , Bordallo-Miller Jane , Nacher Mathieu , Adenis Antoine , Cairo Hedley , Hiwat Hélène , Vreden Stephen , Carboni Carlotta , Sanna Alice , Suarez-Mutis Martha
Published: June 2024

To eliminate malaria, all populations must be included. For those who are not reached by the health care system, specific interventions must be tailor-made. An innovative Malakit strategy, based on the distribution of self-diagnosis and self-treatment kits, has been evaluated in the Suriname-French Guiana- Amapá (Brazil) region. The results showed effectiveness and good acceptability. The Malakit intervention is complex and has many components. Its transferability requires adaptation to other populations and regions, while retaining the main features of the intervention. This article provides the keys to adapting, implementing and evaluating it in other contexts facing residual malaria in hard-to-reach and/or mobile populations. The process of transferring this intervention includes: diagnosis of the situation (malaria epidemiology, characteristics of the population affected) to define the relevance of the strategy; determination of the stakeholders and the framework of the intervention (research project or public health intervention); adaptation modalities (adaptation of the kit, training, distribution strategy); the role of community health workers and their need for training and supervision. Finally, evaluation needs are specified in relation to prospects for geographical or temporal extension. Malaria elimination is likely to increasingly involve marginalized people due to climate change and displacement of populations. Evaluation of the transferability and effectiveness of the Malakit strategy in new contexts will be essential to increase and refine the evidence of its value, and to decide whether it could be an additional tool in the arsenal recommended in future WHO guidelines.
MDI versus CSII in Chinese adults with type 1 diabetes in a real-world situation: based on propensity score matching method
Authors: Yu Jian , Wang Hong , Zhu Min , Xu Jingjing
Published: June 2024

Background

Compared with multiple daily insulin injections (MDI), continuous subcutaneous insulin infusion (CSII) is significantly more expensive and has not been widely used in Chinese type 1 diabetes mellitus (T1DM) patients. So there are still significant knowledge gaps regarding clinical and patient-reported outcomes in China.

Aims

This study aims to compare the glycated hemoglobin (HbA1C), insulin therapy related quality of life (ITR-QOL), fear of hypoglycemia (FOH) of adult T1DM patients treated with MDI and CSII based on propensity score matching in real-world conditions in China.

Methods

Four hundred twenty adult T1DM patients who were treated with MDI or CSII continuously for more than 12 months in a national metabolic center from June 2021 to June 2023 were selected as the study subjects. Their QOL and FOH were evaluated with Insulin Therapy Related Quality of Life Measure Questionnaire-Chinese version (ITR-QOL-CV) and the Chinese Version Hypoglycemia Fear Survey-Worry Scale (CHFSII-WS), and their HbA1C were collected at the same time. Potential confounding variables between the two groups were matched using propensity score matching.

Results

Of the 420 patients included in the study, 315 were in MDI group and 105 were in CSII group. 102 pairs were successfully matched. After matching, the total score of ITR-QOL-CV scale in CSII group was significantly higher than that in MDI group (87.08 ± 13.53 vs. 80.66 ± 19.25, P = 0.006). Among them, the dimensions of daily life, social life, and psychological state were all statistically different (P < 0.05). The scores of CHFSII-WS (8.33 ± 3.49 vs. 11.77 ± 5.27, P = 0.003) and HbA1C (7.19 ± 1.33% vs. 7.71 ± 1.93%, P = 0.045) in CSII group were lower than those in MDI group.

Conclusions

25.0% of T1DM adults are treated with CSII. Compared with adult T1DM patients treated with MDI, those treated with CSII have higher ITR-QOL, less FoH, and better control of HbA1C in real-world conditions in China. Therefore, regardless of economic factors, CSII is recommended for adult T1DM patients to optimize the therapeutic effect and outcomes.
Profiling the neuroimmune cascade in 3xTg-AD mice exposed to successive mild traumatic brain injuries
Authors: Pybus Alyssa F. , Bitarafan Sara , Brothers Rowan O. , Rohrer Alivia , Khaitan Arushi , Moctezuma Felix Rivera , Udeshi Kareena , Davies Brae , Triplett Sydney , Griffin Martin N. , Dammer Eric B. , Rangaraju Srikant , Buckley Erin M. , Wood Levi B.
Published: June 2024

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (Aβ) plaques, gliosis, and neuronal and functional loss. However, a comprehensive study relating acute changes in immune signaling and glial reactivity to neuronal changes and pathological markers after single and repetitive mTBIs is currently lacking. In the current study, we addressed the question of how repeated injuries affect the brain neuroimmune response in the acute phase of injury (< 24 h) by exposing the 3xTg-AD mouse model of tau and Aβ pathology to successive (1x-5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30 min, 4 h, and 24 h after each injury. We used young adult 2–4 month old 3xTg-AD mice to model the effects of rmTBI in the absence of significant tau and Aβ pathology. We identified pronounced sexual dimorphism in this model, with females eliciting more diverse changes after injury compared to males. Specifically, females showed: (1) a single injury caused a decrease in neuron-enriched genes inversely correlated with inflammatory protein expression and an increase in AD-related genes within 24 h, (2) each injury significantly increased a group of cortical cytokines (IL-1α, IL-1β, IL-2, IL-9, IL-13, IL-17, KC) and MAPK phospho-proteins (phospho-Atf2, phospho-Mek1), several of which co-labeled with neurons and correlated with phospho-tau, and (3) repetitive injury caused increased expression of genes associated with astrocyte reactivity and macrophage-associated immune function. Collectively our data suggest that neurons respond to a single injury within 24 h, while other cell types, including astrocytes, transition to inflammatory phenotypes within days of repetitive injury.
Socio-cultural transformations in modernity and household patterns: a study on local traditions housing and the impact and evolution of vernacular architecture in Yazd, Iran
Authors: Formolly Aimal , Saraei Mohammad Hossain
Published: June 2024

The study investigates the impact of vernacular architecture in Yazd, Iran, focusing on traditional housing and its influence on the socio-physical aspects of homes. The central challenge lies in balancing cultural heritage preservation with the need for modern housing that promotes environmental sustainability and social well-being. Employing a qualitative approach, the study compares four historical houses to four modern homes in Yazd city. Its novelty lies in highlighting the importance of incorporating traditional elements into new developments. The research offers practical recommendations for achieving compatibility between house form and lifestyle, designing spaces for communication and social contact, and integrating cultural continuity with change. Additionally, it emphasizes the importance of considering architectural elements and environmental conditions during residential unit design and planning. The study reveals the negative effects of modernization on residential transformation, particularly in historical areas where rapid construction neglects cultural heritage. It recommends incorporating traditional architectural elements while adapting to current needs to achieve sustainable urban living. This contribution to the discourse on urban development provides nuanced insights into the complex dynamics shaping residential landscapes in the modern era. The study's findings suggest that traditional houses offer essential benefits often missing in modern homes, such as improved well-being, privacy, stability, and a stronger sense of community. This can lead to feelings of alienation, physical discontinuity, and socio-economic inequality in modern developments. The study concludes by recommending a reevaluation of housing dynamics and emphasizes the need for further research comparing traditional and modern houses.
Diffusion Transformer for point cloud registration: digital modeling of cultural heritage
Authors: An Li , Zhou Pengbo , Zhou Mingquan , Wang Yong , Geng Guohua
Published: June 2024

Digital modeling is an essential means for preserving and passing down historical culture within cultural heritage. Point cloud registration technology, by aligning point cloud data captured from multiple perspectives, enhances the accuracy of reconstructing the complex structures of artifacts and buildings and provides a reliable digital foundation for their protection, exhibition, and research. Due to the challenges posed by complex morphology, noise, and missing data when processing cultural heritage data, this paper proposes a point cloud registration method based on the Diffusion Transformer (PointDT). Compared to traditional methods, the Diffusion Transformer can better capture both the global features and local structures of point cloud data, more accurately capturing the geometric and semantic information of the target point cloud, thereby achieving precise digital reconstruction. In this study, we trained our method using indoor datasets such as 3DMatch and large-scale outdoor datasets like KITTI, and validated it on various cultural heritage datasets, including those of the Terracotta Warriors and heritage buildings. The results demonstrate that this method not only significantly improves accuracy but also shows advantages in computational efficiency.
Preliminary study of cyclosporine A/Lifitegrast subconjunctival sustained-release drug membrane in the treatment of dry eyes
Authors: Yang Jie , Chen Miao , Wu Fangyuan , Zuo Jingjing , Ma Huixiang
Published: June 2024

Background

Dry eyes can cause discomfort. To treat dry eye disease, cyclosporine A (CsA) and Lifitegrast are two eye drugs approved by the U.S. Food and Drug Administration (FDA). However, frequent use of eye drops can be challenging and lead to poor compliance, especially in elderly patients. Therefore, this study aimed to develop a drug sustained-release vector and explore its therapeutic effect in animal models of dry eye.

Methods

Firstly, drug membranes loaded with both CsA and Lifitegrast using a carrier called poly(lactate-co-ε-caprolactone) (P(LLA-CL)) were prepared and evaluated for their physicochemical properties, release behavior in vitro, and safety in vivo. Next, a rabbit dry eye model using a 0.1% benzalkonium chloride (BAC) solution was developed and treated by drug-loaded micro membranes. We observed and recorded conjunctival hyperemia, corneal staining, corneal edema, corneal neovascularization, conjunctival goblet cells and hematoxylin and eosin (H&E) staining. Finally, we detected the MUC5AC and MMP-9 by immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA).

Results

The composite film released both CsA and Lifitegrast for at least one month. Compared to the blank membrane group, conjunctival hyperemia, corneal fluorescein staining, corneal edema, corneal neovascularization and conjunctival goblet cells recovered faster in the drug membrane group, and the difference was statistically significant. At the molecular level, the drug membrane group showed an increase in mucin density and a significant anti-inflammatory effect.

Conclusions

The implantation of CsA/Lifitegrast loaded P(LLA-CL) membrane under the subconjunctival of the rabbit eye is safe. The study suggests that this subconjunctival administration could be developed into a minimally invasive delivery system to help patients with dry eye disease who require multiple daily eyedrops but have poor compliance.
From clicks to credits: examining the influence of online engagement and internet addiction on academic performance in Chinese universities
Authors: Jiang Yongzhong , Joshi Dirgha Raj , Khanal Jeevan
Published: June 2024

University students’ engagement in online activities can impact both internet addiction and academic performance. This research aims to investigate these effects among university students. Using data from the "China College Students Longitudinal Survey" conducted by the Chinese Academy of Social Sciences between 2013 and 2018, this study examines the influence of university students’ engagement in online activities. With a sample size of 15,102 university students, we explored the relationship between online activity, internet addiction, and academic performance. Employing stratified random sampling, the study investigates sample characteristics, including gender, study level, time spent online, and experiences accessing websites. Academic performance is assessed through six categories, employing descriptive and inferential statistics such as t-tests, ANOVA, stepwise linear regression, and path analysis. The findings indicate significantly high levels of university students’ engagement in online activities, accompanied by a high prevalence of internet addiction. Key factors determining university students’ engagement, internet addiction, and academic performance include gender, study level, time spent online, and experiences accessing websites beyond the Great Firewall. The study establishes a complex relationship, revealing negative effects of specific online engagements on internet addiction, while the latter influences university students’ engagement. Overall, this research contributes valuable insights into the intricate interplay between online behaviors, addiction, and academic performance among Chinese university students, with implications for educational policies and interventions.
3D-visualization of segmented contacts of directional deep brain stimulation electrodes via registration and fusion of CT and FDCT
Authors: Al-Jaberi Fadil , Moeskes Matthias , Skalej Martin , Fachet Melanie , Hoeschen Christoph
Published: June 2024

Objectives

3D-visualization of the segmented contacts of directional deep brain stimulation (DBS) electrodes is desirable since knowledge about the position of every segmented contact could shorten the timespan for electrode programming. CT cannot yield images fitting that purpose whereas highly resolved flat detector computed tomography (FDCT) can accurately image the inner structure of the electrode. This study aims to demonstrate the applicability of image fusion of highly resolved FDCT and CT to produce highly resolved images that preserve anatomical context for subsequent fusion to preoperative MRI for eventually displaying segmented contactswithin anatomical context in future studies.

Material and methods

Retrospectively collected datasets from 15 patients who underwent bilateral directional DBS electrode implantation were used. Subsequently, after image analysis, a semi-automated 3D-registration of CT and highly resolved FDCT followed by image fusion was performed. The registration accuracy was assessed by computing the target registration error.

Results

Our work demonstrated the feasibility of highly resolved FDCT to visualize segmented electrode contacts in 3D. Semiautomatic image registration to CT was successfully implemented in all cases. Qualitative evaluation by two experts revealed good alignment regarding intracranial osseous structures. Additionally, the average for the mean of the target registration error over all patients, based on the assessments of two raters, was computed to be 4.16 mm.

Conclusion

Our work demonstrated the applicability of image fusion of highly resolved FDCT to CT for a potential workflow regarding subsequent fusion to MRI in the future to put the electrodes in an anatomical context.
Using predatory species and entomopathogenic fungi as alternatives to chemical pesticides in green bean field
Authors: Kamel Hamzah M. , Eid Aziza E. , Nouh Gehan M. , Adly Dalia
Published: June 2024

Background

Green bean, Phaseolus vulgaris L. (Fam.: Leguminosae) is a widely consumed grain legume prized for its edible seeds and pods. It is susceptible to infestations with various pests as insects and mites throughout the growing season. In this study, the efficacy of the predatory species, Chrysoperla carnea (Stephens), Phytoseiulus persimilis Athias-Henriot and the entomopathogenic fungus (EPF) Metarhizium anisopliae (Hypocreales: Clavicipitaceae), as well as conventional pesticides, Mospilan and Vertimec, were evaluated against the most important pests, mainly the whitefly, Bemisia tabaci (Genn.) and the two-spotted spider mite, Tetranychus urticae Koch, infesting the green beans cultivated at two locations Giza and El-Menoufia Governorates in Egypt.

Results

The findings demonstrate that treatments using C. carnea and M. anisopliae effectively reduced the whitefly population, while pesticide treatments were comparatively less effective. In the Giza plots, at the end of the experiments, the use of both M. anisopliae and C. carnea showed high reductions in whitefly population (85.57 and 84.87%), respectively, while in El-Menoufia, C. carnea (97.74%) was the most effective treatment followed by M. anisopliae (90.32%). Pesticide treatment in this case yielded a reduction rate of (22.76 and 59.67%) in Giza and El-Menoufia plots, respectively. However, for spider mite control, P. persimilis proved to be the most effective treatment in Giza and El-Menoufia plots, reducing the spider mite population to 98.44 and 96.14%, respectively. Metarhizium anisopliae treatment also displayed moderate effectiveness, with reduction rates of 75.62 and 75.37% in Giza and El-Menoufia plots, respectively. In comparison, pesticide treatment showed low effectiveness, with reduction rates of only 23.92 and 53.16% in the two locations, respectively.

Conclusion

Applications of the predator, C. carnea and the EPF, M. anisopliae were highly effective in reducing the population of whitefly, while the predator mite P. persimilis proved to be the most effective for controlling the spider mites. Overall, the study suggests that biocontrol agents, such as the predators and the EPF, can be considered as alternatives to synthetic chemical pesticides for controlling pests infesting green beans.
Nutritional effect on lipoproteins and their subfractions in patients with Psoriatic Arthritis: a 12-week randomized trial—the DIETA trial
Authors: Scherer Daniele , Leite Beatriz Figueiredo , Morimoto Melissa Aparecida , Oliveira Thauana Luiza , Klemz Barbara N. Carvalho , Freitas Rosana A. M. Soares , Pappiani Caroline , Damasceno Nágila R. Teixeira , Pinheiro Marcelo de Medeiros
Published: June 2024

Introduction

Patients with psoriatic arthritis have some lipid metabolism changes and higher risk of metabolic syndrome (MetS) and cardiovascular diseases, regardless of traditional risk factors, suggesting that chronic inflammation itself plays a central role concerning the atherosclerosis. However, there is a lack of information regarding atherogenic pattern and lipoprotein subfractions burden in these individuals.

Aim

To evaluate the HDL and LDL-cholesterol plasmatic levels and their subfractions after a nutritional intervention in patients with psoriatic arthritis (PsA).

Methods

This was a randomized, placebo-controlled clinical trial of a 12-week nutritional intervention. PsA patients were randomly assigned to 1-Placebo: 1 g of soybean oil daily, no dietetic intervention; 2-Diet + Supplementation: an individualized diet, supplemented with 604 mg of omega-3 fatty acids, three times a day; and 3-Diet + Placebo: individualized diet + 1 g of soybean oil. The LDL subfractions were classified as non-atherogenic (NAth), atherogenic (Ath) or highly atherogenic (HAth), whereas the HDL subfractions were classified as small, medium, or large particles, according to the current recommendation based on lipoproteins electrophoresis.

Results

A total of 91 patients were included in the study. About 62% of patients (n = 56) had an Ath or HAth profile and the main risk factors associated were male gender, longer skin disease duration and higher BMI. Thirty-two patients (35%) had a high-risk lipoprotein profile despite having LDL plasmatic levels below 100 mg/dL. The 12-week nutritional intervention did not alter the LDL subfractions. However, there were significant improvement of HDL subfractions.

Conclusion

Recognizing the pro-atherogenic subfractions LDL pattern could be a relevant strategy for identifying PsA patients with higher cardiovascular risk, regardless total LDL plasmatic levels and disease activity. In addition, a short-term nutritional intervention based on supervised and individualized diet added to omega-3 fatty acids changed positively the HDLLARGE subfractions, while LDLLARGE subfraction was improved in hypercholesterolemic individuals.

ClinicalTrials.gov identifier: NCT03142503 (http://www.clinicaltrials.gov/).
Standardized observation of temperament in Lebanese toddlers using the laboratory temperament assessment battery (Lab-TAB)
Authors: Shamseddeen W. , Safieddine B. , Mohsen H. , Akoury Dirani L.
Published: June 2024

Background

Temperament is the difference between individuals’ emotional and behavioral responses to diverse external events. It is a complex interplay between genetic and environmental factors. Hence, the need to assess temperament objectively and better understand its impact on developmental and interpersonal outcomes. Measuring temperament in early childhood can be challenging since parents will report their subjective perceptions about their toddlers. While surveys are quick instruments that require less clinical involvement, standardized laboratory assessments secure a relatively high level of objective observation. Since no published studies were conducted in Arab countries, the current research focuses on examining temperament in a sample of twenty mother-toddler dyads using the Laboratory Temperament Assessment Battery (Lab-TAB) locomotor version.

Interrater reliability and validity were assessed. Higher-order temperament components were determined by principal component analysis. T test and one-way ANOVA examined the association between demographics and temperament components.

Results

The retained variables ranged between fair (> 0.43) and good (< 0.98) for all Lab-TAB episodes. Three higher-order temperament components were obtained. Age was significantly negatively correlated with Lab-TAB Fear dimension, r = − .47, p > .05, and Lab-TAB temperament component 3, r = .45, p > .05. Male toddlers (M = .55, SD = 1.055) had significantly higher levels of temperament component 3 compared to female (M = − .45, SD = .718), t(18) = 2.52, p < .05. There was a significant effect of time spent with mother on temperament component 3, F(2,17) = 7.01, p < .05.

Conclusion

After exploring the temperament factor structure, we found that the Lab-TAB locomotor version was a valid tool to be used to observe temperament in toddlers living in Lebanon, a Middle Eastern culture. Some gender significant differences would deserve deeper exploration in future research. A replication of this study would also strengthen its findings.
Preliminary results from FLAGSHP-1: A phase 1 study of ERAS-601 as a monotherapy or in combination with cetuximab in patients (pts) previously treated for advanced chordoma.
Authors: Gounder Mrinal M. , Rosen Ezra , Parikh Aparna Raj , Conley Anthony Paul , Hong David S. , Sheth Siddharth , Mai Nicholas , Sgroe Erica , Mitchell Ryan , Picard Roxana , Brail Les H. , Cote Gregory Michael
Published: June 2024

11522

Background: SHP2 is an oncogenic tyrosine phosphatase that transduces receptor tyrosine kinase signaling in the RAS/MAPK pathway via phosphatase-mediated regulation of guanine nucleotide exchange factors. SHP2 signaling has recently been identified as a genetic dependency for chordoma, a rare tumor type with no approved therapies (1), and preclinical studies with SHP2 inhibitors have demonstrated activity in chordoma models. Methods: As part of the FLAGSHP-1 study, patients (pts) with advanced or metastatic chordoma were enrolled in either the monotherapy or cetuximab combination cohort to assess the safety, tolerability, PK, and preliminary clinical activity of ERAS-601. Chordoma pts previously treated with an EGFR inhibitor were allowed to enroll. Results: As of 31 Oct 2023, a total of 11 pts with previously treated advanced or metastatic chordoma received ERAS-601. Two pts received ERAS-601 as monotherapy: one at 40 mg BID (continuous) and the other at 80 mg TIW (three times a week). An additional 9 pts received the combination of ERAS-601 (40 mg BID 3 weeks on and 1 week off every 28 days [3/1]) in combination with cetuximab (500 mg/m2 Q2W). The treatment-emergent adverse events (TEAEs) occurring in >20% of pts (Grade [Gr] 1-2 unless noted) were: dermatitis acneiform (2 pts-Gr 3), paronychia, dry skin, skin fissures, skin infection (1 pt-Gr. 3), diarrhea, nausea, vomiting, stomatitis, peripheral oedema, fatigue, thrombocytopenia, and AST elevation. No patients discontinued therapy due to TEAEs related to ERAS-601. Out of the 9 pts receiving the combination of ERAS-601 and cetuximab, by RECIST 1.1 there was 1 PR and 8 pts with a best response of SD. Of the 8 pts who had a best response of SD, 7 had some tumor shrinkage. The median time on combination treatment was 5.06 months, with 8 out of 9 pts remaining on the study. Conclusions: The most common toxicities observed for the ERAS-601 + cetuximab combination were dermatologic, which were reversible. Encouraging preliminary activity was seen in advanced, refractory chordoma. 1. Sharifina et al., 2023, Nat. Commun. Clinical trial information: NCT04670679 .
Integrated multi-omics analysis reveals immune landscape of tertiary lymphoid structure in retroperitoneal liposarcoma.
Authors: Tao Ping , Wang Zhenyu , Wang Jiongyuan , Chen Jun , Hong Liang , Ma Lijie , Zhang Yong , Tong Hanxing
Published: June 2024

11563

Background: Retroperitoneal liposarcoma (RPLS) is a rare type of mesenchymal tumor characterized by difficult surgical management, immune desert, poor response to immunotherapy and high local recurrence rate. However, how tertiary lymphoid structures (TLS) dictates complex biological processes such as antitumor immunity remains unknown. Thus, we aimed to investigate the spatio-temporal heterogeneity of TLS formation, maturation, and functional involvement in TIME, and the clinical value of TLS in multiple retrospective RPLS clinical cohorts. Methods: 330 patients were retrospectively enrolled into five independent cohorts from the two largest retroperitoneal tumor research centers in China and the TCGA database. Single-cell RNA sequencing (sc-RNA seq) (n=4) and spatial transcriptome seq (n=2) were performed for the estimation of TIME based on treatment-naive RPLS. Transcriptomic profiles of 309 cases in five cohorts were obtained from the ZSFD, GEO, and TCGA databases. TLS was quantified in three different anatomic subregions (intra-tumor, invasion margin and peri-tumor) and correlated with overall survival (OS) and disease-free survival (DFS) by Cox regression and Kaplan-Meier analysis. Multiplex immunohistochemistry (mIHC) was performed to characterize and validate the spatial composition of TLS in another treatment-naive RPLS cohort (n=16), neoadjuvant chemotherapy (n=12) and neoadjuvant radiotherapy (n=20) RPLS cohorts. Results: The joint scoring system of T and P scores stratified RPLS into four immune classes with different TLS distribution patterns and prognoses (p<0.001). The immune class C-index was significantly higher than the TNM staging system (0.798 vs. 0.62, p=0.005). Importantly, mIHC revealed that regulatory T cells (Tregs) and M2 phenotype tumor-associated macrophages (TAMs) were significantly increased in intra-tumoral TLS in DDLPS compared to WDLPS, showing an immunosuppressive pattern. Strikingly, neoadjuvant chemotherapy and radiotherapy could block this status of immunosuppressive, induced TLS formation and restore the antitumor immune balance with significantly more CD38+IgG+ plasma cells (PCs) in responsive RPLS, whereas non-responsive RPLS deteriorated into a more suppressive one. Sc-RNA Seq and ST analysis further revealed significant intra- and inter-tumoral TIME heterogeneity and identified the underlying transcriptomic programs driving each phenotype. Conclusions: Our study provides a high-resolution map of TIME in treatment-naive and neoadjuvant chemotherapy/radiotherapy RPLS. Effective neoadjuvant chemotherapy and radiotherapy can induce TLS formation and restore the antitumor immune balance in RPLS.
Analyzing the effect of treatment modalities on survival in synovial sarcoma.
Authors: Samuel Maya Mary , Saldhi Prachi , Silberstein Peter T. , Chaddha Jasleen Kaur
Published: June 2024

11570

Background: Synovial sarcoma (SS) is a rare, slow growing, and aggressive soft tissue sarcoma that commonly affects young adults, with a diagnosis at an average age of 30 years. It usually originates near the joints of the extremities and presents as a painless lump. Metastasis to the regional lymph nodes and lungs is common. SS is proposed to be a result of a chromosomal translocation leading to the fusion of SYT and SSX genes. Standard treatment is tumor resection followed by adjuvant therapy. No study has compared the effects of different surgery and adjuvant therapy types on overall survival. This study will compare the effects of various therapeutic modalities on overall survival for patients with SS. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with SS from 2004 to 2020 using histology code 9040 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, and Logistic Regression tests were performed, and data were analyzed using SPSS version 29. Statistical significance was set at α = 0.05. Results: The sample retrieved from NCDB consisted of 2566 patients with SS. Of these 2566 patients, 1962 patients (76.5%) received surgery at the primary site. The receipt of surgery was associated with a marked increase in survival (132.2 months vs. 48.6 months, p<0.001). Out of the surgical patients, 883 patients (45.0%) received a lobectomy, 696 patients (35.5%) received a wedge segmental resection, 21 patients (1.07%) received an extended lobectomy and 1 patient (0.05%) received a hepatectomy. Patients who underwent lobectomy and wedge/segmental resections had improved outcomes compared to patients who received other types of surgery (p<0.001). In addition, 898 patients (45.8%) received adjuvant chemotherapy, 38 patients received adjuvant chemoradiation (1.94%), and 22 patients received adjuvant radiation (1.12%). The receipt of adjuvant chemotherapy was associated with better outcomes than receiving no adjuvant therapy (121.9 months vs. 108.4 months, p<0.001). The receipt of adjuvant chemoradiation was also associated with better outcomes than receiving no adjuvant therapy (132.2 months vs. 108.4 months, p=0.023). The receipt of adjuvant chemotherapy versus adjuvant chemoradiation is not significantly different in regard to overall survival. Conclusions: This study confirms that receiving surgery for SS is associated with markedly increased overall survival. Furthermore, wedge/segmental resections and lobectomies are associated with improved outcomes compared to other types of surgery. Receiving adjuvant therapy is associated with improved outcomes as compared to the receipt of surgery alone. Adjuvant chemotherapy and adjuvant chemoradiation are associated with better outcomes than adjuvant radiation alone. Further studies are needed to understand the factors involved in choosing specific treatment modalities for SS.
A phase II study of an oncolytic herpes simplex virus 2 and an anti-PD-1 antibody in patients with advanced sarcoma.
Authors: Tan Zhichao , Liu Jiayong , Gao Tian , Ding Sijuan , Han Liang , Luo Suxia , Fan Qingxia , Shi Jianhua , Gu Xiangyong , Liu Binlei , Alevizopoulos Nassos , Fan Zhengfu , Huang Jing
Published: June 2024

11571

Background: OH2 is an attenuated oncolytic Herpes Simplex-2 Virus expressing GM-CSF. In a phase I/II open-label clinical trial OH2 was safe and efficacious as monotherapy. When combined with HX008, a humanized anti-PD-1 antibody, OH2 demonstrated a disease control rate of 50% in solid tumors (1). Here, we present the efficacy results observed in a sarcoma-specific expansion cohort of the trial. Methods: Patients refractory to ≥1 prior line of systemic therapy were allocated to a monotherapy group receiving intratumoral OH2 once every 2 weeks and a combination group receiving i.t. OH2 and HX008 (i.v) every 3 weeks. The primary endpoint was best objective response rate (ORR, per RECIST v 1.1). Secondary endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS), duration of response (DOR) and adverse effects (AEs). Results: 26 patients were enrolled in the phase II trial, 7 in the monotherapy group and 19 in the combo group. Median age was 52 years, with 65.4% females. 50% had received ≥3 prior lines of therapy, whereas 30.7% had prior lines of immunotherapy. 25 patients were evaluable for efficacy (1 withdrew). ORR was 0% and 16.7%; DCR 14.3% and 50.0%; median PFS 1.4 and 2.1 months, and median OS 4.5 and 22.3 months, for the monotherapy and combo groups, respectively. In the combo group we observed 1 CR and 2 PRs, in which the DOR was 4.2, 5.6 and 11.1 months (Table). Angiosarcoma and fibrosarcoma patients experienced clinical benefit with durable disease control, with one angiosarcoma patient remaining in study for >1 year. Treatment was well tolerated with most common AEs being grade I and II, including GGT elevation (26.9%), fever (23.1%), neutropenia (19.2%), weight loss (15.4%), LDH elevation (15.4%), and anemia (15.4%). Conclusions: OH2 and HX008 demonstrated goodsafety and encouraging anti-tumor activity in a phase II sarcoma cohort. Further clinical investigation of this combination is warranted. 1. Zhang et al, 2021; PMID: 33837053. [Table: see text]
Prognostic significance of plasma circulating tumor DNA fraction in patients with advanced sarcoma: A French Sarcoma Group study.
Authors: Taleb Sofiane , Brunet Maxime , Belcaid Laila , Bahleda Rastislav , Verret Benjamin , Le Cesne Axel , Peyraud Florent , spalato-Ceruso Mariella , Toulmonde Maud , Italiano Antoine
Published: June 2024

11574

Background: The integration of liquid biopsies into clinical guidelines is revolutionizing the management of late-stage cancer. A notable advancement is the use of broad genomic analysis of circulating tumor DNA (ctDNA) for quantifying tumor fraction (TF). While TF's prognostic relevance in carcinomas has been explored, its significance in sarcomas remains unclear. Methods: This study involved patients with advanced sarcomas from two precision medicine studies (BIP, Institut Bergonié, Bordeaux, France; STING, Gustave Roussy, Villejuif, France) across two French Sarcoma Group sites. All participating patients underwent comprehensive genomic profiling with the FDA approved FoundationOne Liquid CDx assay. TF was measured using single-nucleotide polymorphism-based aneuploidy analysis as previously described (Reichert et al. 2023). Progression-free survival (PFS) and overall survival (OS) were assessed from treatment commencement (PFS) or the date of ctDNA profiling (OS) to disease progression, death, or last patient contact. Univariate analysis examined variables such as age, gender, tumor grade, metastatic sites, performance status (PS), and prior treatment lines. Results: 195 patients (103 males, 92 females) entered the study. The three most frequent histological subtypes were leiomyosarcomas, dedifferentiated liposarcomas, and undifferentiated pleiomorphic sarcomas. Median age was 56 (range 18-91). Thirty patients (15.4%) had high TF (≥ 10%). Among the 189 patients who underwent systemic treatment post-ctDNA profiling, elevated TF correlated with significantly poorer PFS (2.6 vs 4.3 months, p=0.018) and OS (6.7 vs 14.1 months, p=0.005). Multivariate analysis identified TF and ECOG performance status as independent predictors of OS. Conclusions: Plasma ctDNA TF is a practical and independent prognostic biomarker in advanced sarcoma patients. Its integration into treatment paradigms can facilitate precision therapeutic strategies tailored to individual tumor biology.
Identifying optimized assessment of nerve damage during chemotherapy.
Authors: Li Tiffany , Timmins Hannah C , Mahfouz Fawaz Mayez , Mizrahi David , Horvath Lisa , Harrison Michelle L. , Grimison Peter S. , Friedlander Michael , Marx Gavin M. , Boyle Frances M. , Wyld David , Henderson Robert , King Tracy , Baron-Hay Sally E. , Kiernan Matthew C , Rutherford Claudia , Goldstein David , Park Susanna B
Published: June 2024

12016

Background: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a significant and persisting toxicity of anticancer treatments, impacting dose delivery and quality of life. There is a lack of consensus on the optimal method of CIPN assessment in clinical settings. This study compared the validity and responsiveness of patient reported outcome measures (PROMs) against neurological, neurophysiological and sensory assessment approaches of CIPN. Methods: A multi-centre dual study design evaluated patients treated with neurotoxic chemotherapy across two cohorts: patients commencing treatment assessed prospectively and patients who completed treatment assessed cross-sectionally. CIPN was assessed via PROMs (EORTC-CIPN20, FACT/GOG-Ntx, PRO-CTCAE), neurological and neurophysiological assessment (Total Neuropathy Score, sural and tibial compound nerve amplitudes) and sensory functional measures (Grating orientation, Von Frey monofilament and 2-Point discrimination tasks). Convergent and known-groups validity were assessed cross-sectionally following treatment completion and responsiveness was evaluated prospectively during treatment. Neurological, neurophysiological, and sensory outcome measure scores were compared between high and low CIPN symptom reporters. Results: A total of 1,033 patients were recruited, incorporating 1,623 assessments. PROMs demonstrated superior ability to identify CIPN (convergent validity; α = 0.75-0.85, all P < 0.001), to discriminate between CIPN severity (known-groups validity; all P < 0.001) and to detect changes in CIPN development (responsiveness; Cohen’s d = 0.65-0.83) compared to neurological, neurophysiological and sensory assessment approaches. These other measures did not achieve threshold for convergent validity (α < 0.7). and did not demonstrate acceptable responsiveness (Cohen’s d < 0.5). Neurological, neurophysiological, and sensory outcome measures were significantly impaired in patients who were high CIPN symptom reporters compared to low (all P < 0.05). Conclusions: PROMs represent a valid method of CIPN assessment, with preferential measurement properties over other approaches to assessing neuropathy. Adoption of PROMs in clinical practice will allow for accurate representation and early recognition of CIPN, leading to reduced long term morbidity in this key long-term toxicity in cancer survivors.
Impact of protein-energy malnutrition on patients with breast cancer hospitalized for acute decompensated heart failure: Insight from the NIS database 2020.
Authors: Obomanu Elvis , Wattanachayakul Phuuwadith , Jones Colton , Arya Yajur , Syal Arshi , Byfield Karecia , Eidbo Sarah , Ratnani Akshay , Saowapa Sakditad , Polpichai Natchaya , Wannaphut Chalothorn , Casipit Carlo , Casipit Bruce Adrian , Mayo Ryan
Published: June 2024

12030

Background: The breast cancer patient is at risk of acute decompensated heart failure (ADHF) and protein-energy malnutrition (PEM) either from the effects of chemoradiation or primary cancer. There have been several studies on patients with breast cancer and ADHF. However, the exact impact of concurrent PEM on patients with breast cancer admitted for ADHF is unclear. We aim to assess how PEM impacts breast cancer patients admitted with ADHF. Methods: We examined the 2020 US National Inpatient Sample (NIS) to explore how concurrent PEM affects breast cancer patients admitted for ADHF. Participants aged 18 and older were identified using relevant ICD-10 CM codes. A survey multivariate logistic and linear regression analysis was used to calculate the odds ratio (OR) for the outcomes of interest. Results: We identified 30,555 breast cancer patients with ADHF, with a mean age of 77±10 years; 99% were female. Caucasian accounted for 71.4%, followed by Black (17.5%), Mexican American (5%), and Asian (3%). Of these, 6.07% (1854/30,555) had a concurrent PEM diagnosis. In a survey multivariable regression model adjusting for patient and hospital factors, comorbid PEM was significantly associated with prolonged length of stay (β 2.09, 95% CI: 1.68–2.49, P <0.001), increased risk of in-hospital mortality (aOR 2.61, 95% CI: 1.60–4.29, P <0.001), increased risk of cardiogenic shock (aOR 3.17, 95% CI: 1.78–2.59, P< 0.001), anemia (aOR 1.43, 95% CI: 1.14 to 1.80, p 0.002), and total hospital charge $28,285 (95% CI: $21,743–34,827, P< 0.001). Adverse events such as respiratory failure (aOR 1.17, 95% CI 0.91 to 1.50, p 0.212) and DVT (aOR 1.15, 95% CI 0.40 to 3.31, p 0.802) were observed but did not reach statistical significance. Conclusions: Our study demonstrated that comorbid PEM among hospitalized breast cancer patients for ADHF is associated with increased risks of in-hospital mortality, anemia, cardiogenic shock, prolonged length of hospital stays, and total hospital charges. The study also highlights that nutritional status may be a useful prognostic marker in breast cancer patients who are at risk for various cardiovascular morbidities associated with cancer treatment and the primary disease. Additional longitudinal cohort studies are required to improve the understanding of this association.
Impact of palliative care on hospital length of stay and charges in hospitalized patients with cancer at end of life.
Authors: Hsieh Tien-Chan , Zou Guangchen
Published: June 2024

12072

Background: Early palliative care has been shown to enhance the quality of life and survival for cancer patients. However, the economic implications of using palliative care in hospitalized cancer patients remain inconclusive. While palliative care can prevent aggressive interventions in end-of-life patients, it may also prolong hospitalization. Methods: This retrospective study used four years of National Inpatient Sample data (2016-2019) to explore the association between palliative care and hospital length of stay and charges among cancer patients aged 18 and above, hospitalized for at least 7 days and died. Hospital charges were divided by length of stay to derive the average daily charges. Continuous variables, length of stay and average daily charges, were standardized by subtracting means and dividing by standard deviations. We top-coded length of stay and average daily charges at the 99th percentile. Length of stay was also modeled into categories: 7-13, 14-20, 21-27, and 28+ days. A mixed-effects model with individual hospitals as a random effect was employed to account for potential variations in clinical practices and billing at the institutional level. Results: The study included 59,355 distinct cancer hospitalizations, totaling 296,775 weighted hospitalizations. Palliative care utilization was observed in 54.0%, and Do-not-resuscitate (DNR) status was noted in 57.9%. The observed palliative care use and DNR status were most prevalent in the 7-13 days group (56.6% and 61.3%) and least in the 28+ days group (46.9% and 48.8%). 85.2% didn’t receive cardiopulmonary resuscitation (CPR) and that rate was similar across all length of stay groups. In linear mixed-effects models using standardized length of stay, palliative use was associated with shorter length of stay (adjusted Odds Ratio {aOR} 0.89; confidence interval {CI} 0.88-0.90). After adjustment for covariates, DNR was also associated with shorter hospitalization (aOR: 0.81; CI: 0.80-0.82). Receiving CPR had lower adjusted risk for longer hospitalization (aOR: 0.94; CI: 0.93-0.95). In multivariate model, daily charges were inversely correlated to the length of stay (aOR: 0.92; CI: 0.92-0.92). When using average charges per day as dependent variable, palliative care use was associated with less charges (aOR: 0.83; CI: 0.83-0.84). DNR also showed a lower adjusted odds for hospital charges (aOR: 0.89; CI: 0.88-0.89). Receiving CPR had higher adjusted risk of higher charges (aOR: 1.23; CI: 1.22-1.24). Conclusions: The use of palliative care was associated with a shorter length of stay and lower hospital charges per day among cancer patients who died in the hospital after adjusting for covariates. Many of the 46% who died without palliative care could have benefitted from it. Interventions aimed at promoting palliative care services among inpatient cancer patients nearing the end of life might yield economic benefits.
A phase I/II study to evaluate the safety, pharmacokinetics, and efficacy of PRJ1-3024 in patients with advanced solid tumors.
Authors: Zhang Panpan , Qin Yanru , Gong Jifang , Wang Yongsheng , Yang Kunyu , Li Yongsheng , Dai Guanghai , Zhu Ji , Sha Sha , Tong Ming , Liao Xuebin , Shen Lin
Published: June 2024

2590

Background: PRJ1-3024 is a small molecule hematopoietic progenitor kinase 1 (HPK1) inhibitor designed to potentiate T-cell function. It was demonstrated that HPK1 activity suppresses immune functions of a wide range of cells including cluster of differentiation CD4+, CD8+ T cells and dendritic cells (DCs), mediates T-cell dysfunction and is a potential therapeutic target for T-cell-based immunotherapies. These results strongly support inhibitor of HPK1 functioning as a potential cancer immunotherapy agent. Methods: This is a multicenter, open-label study. Primary objective of phase I study is to determine the maximum tolerated dose and recommended Phase 2 dose. Secondary objectives are to evaluate safety, PK, and efficacy of PRJ1-3024. It is dosed orally once daily. Dose-limiting toxicity (DLT) assessment to be completed after 24 days (from the first dose to the end of Cycle 1 continuous 21 medication days). Exploratory analysis of pharmacodynamic targets including multiple cytokines, SLP-76 phosphorylation, cfDNA and IgG typing. Results: As of Dec. 22, 2023, 30 patients were enrolled in 6 dose cohorts: 80, 160, 300, 320, 500, and 700mg. Median age was 59 years (range 36-69). Diagnoses were NSCLC (9), Melanoma (3), TNBC (3), Gastric Cancer (3), HNSCC (3), Esophagus Carcinoma (2), Colon Cancer (2), and other types (5). The most common TEAEs (in ≥2 pts) were diarrhea (12), vomiting (12), nausea (9), proteinuria (8), loss of appetite (6), etc. No DLT events, irAEs or treatment-related deaths occurred in all dose cohorts. 9 subjects reported SAEs, only 2 cases were evaluated to be probably related (6.7%), namely ‘myocardial ischemic’ and ‘acute kidney injury’. 1 melanoma subject achieved sustained PR, had been on treatment for more than 7 months up to now. 4 subjects achieved SD (1 NSCLC, 1 HNSCC, 2 TNBCs). PK and PD assessments will be released in due course. Conclusions: PRJ1-3024 is shown to be well tolerated in Chinese advanced solid tumor patients. Further safety and efficacy results would be presented at the conference. Clinical trial information: NCT05315167 .
A realistic neutrino mixing scheme arising from A4 symmetry
Authors: Dey Manash , Roy Subhankar
Published: June 2024

We propose a unique lepton mixing scheme and its association with an exact hierarchy-philic neutrino mass matrix texture in the light of Type-I+Type-II seesaw mechanism under the framework of

discrete flavour symmetry. The proposed model successfully predicts the normal ordering of neutrino masses and the two Majorana phases. Additionally, the analysis extends to the effective Majorana neutrino mass, in the context of neutrinoless double beta

.