bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful treatment of cortical visual impairment in children using anti-amblyopia treatment despite the absence of amblyopia: a case report
Authors: Sica Attilio , Michieletto Paola , Pensiero Stefano , Barbi Egidio
Published: July 2024

Background

Cortical visual impairment (CVI) is a verifiable visual dysfunction that cannot be attributed to disorders of the anterior visual pathways or any potentially co-occurring ocular impairment. Given the limited knowledge on the most effective interventions for visual impairment resulting from CVI, this case report provides valuable insights into an example of successful implementation of anti-amblyopia therapy in a patient with CVI.

Case presentation

This case report presents a 5-year-old girl with CVI secondary to hypoxic-ischemic injury, resulting in visual impairment, dyspraxia, and abnormal visual evoked potential testing. The girl did not suffer from amblyopia, there was no evidence of relevant refractive errors or strabismus, so visual pathway damage was the cause of her visual deficit. Nevertheless, the patient underwent anti-amblyopia therapy and showed significant improvement in visual acuity after 12 months of treatment. The improvement, resulting from visual stimulation, was due to a good functional recovery by a better usage of the damaged visual pathways. The therapy included prescribing corrective glasses and implementing secondary occlusion of the better eye for 4 months, which was protracted for another 4 months, leading to further improvements in visual acuity.

Conclusions

The case report shows that addressing even minor refractive errors and implementing anti-amblyopia therapy can significantly improve vision in children with CVI, even without co-existing amblyopia. It also highlights the importance of early intervention and multidisciplinary rehabilitation in children with CVI, focusing on motor and cognitive skills. Additionally, it emphasizes the need for further research to establish evidence-based practice standards for improving vision in children with CVI.
Comparison of D2 vs D3 lymph node dissection for RIght COloN cancer (RICON): study protocol for an international multicenter open-label randomized controlled trial
Authors: Balaban Vladimir , Mutyk Mikhail , Bondarenko Nikolay , Zolotukhin Stanislav , Sovpel Oleg , Sovpel Igor , Zykov Dmitriy , Rublevskiy Igor , Klochkov Mikhail , Prado Alfredo Ponce , He Mingze , Tsarkov Petr
Published: July 2024

Background

Colon cancer is a global health concern, ranking fifth in both new diagnoses and deaths among tumors worldwide. Surgical intervention remains the primary treatment for localized cases, with a historical evolution marked by a focus on short-term outcomes. While Japan pioneered radical tumor removal with a systematic categorization of lymph nodes (D1, D2, D3), the dissemination of Japanese practices to the West was delayed until 90th of last century. Discrepancies between Japanese D3 dissection and the CME with CVL principle persist, with variations in longitudinal margins and recommended procedures. Non-randomized trials indicate the superiority of D3 over D2, but a consensus is lacking.

Methods

This prospective, international, multicenter, randomized controlled trial employs a two-arm, parallel-group, open-label design to rigorously compare the 5-year overall survival outcomes between D2 and D3 lymph node dissection in stage II-III right colon cancer. Building on prior studies, the trial aims to address existing knowledge gaps and provide a comprehensive evaluation of the outcomes associated with D3 dissection. The study population comprises patients with right colon cancer, ensuring a focused investigation into the specific context of this disease. The trial design emphasizes its global scope and collaboration across multiple centers, enhancing the generalizability of the findings.

Discussion

This study’s primary objective is to elucidate the potential superiority in 5-year overall survival benefits of D3 lymph node dissection compared to the conventional D2 approach in patients with stage II-III right colon cancer. By examining this specific subset of patients, the research aims to contribute valuable insights into optimizing surgical strategies for improved long-term outcomes. The trial’s international and multicenter nature enhances its applicability across diverse populations. The outcomes of this study may inform future guidelines and contribute to the ongoing discourse surrounding the standardization of colon cancer surgery, particularly in the context of right colon cancer.

Trial registration

ClinicalTrials.gov NCT03200834. Registered on June 27, 2017.
Case report: two novel PPARG pathogenic variants associated with type 3 familial partial lipodystrophy in Brazil
Authors: da Silva Monique Alvares , Soares Reivla Marques Vasconcelos , de Oliveira Filho Antônio Fernandes , Campos Leonardo René Santos , de Lima Josivan Gomes , de Melo Campos Julliane Tamara Araújo
Published: July 2024

Introduction and aim

Type 3 Familial Partial Lipodystrophy (FPLD3) is a rare metabolic disease related to pathogenic PPARG gene variants. FPLD3 is characterized by a loss of fatty tissue in the upper and lower limbs, hips, and face. FPLD3 pathophysiology is usually associated with metabolic comorbidities such as type 2 diabetes, insulin resistance, hypertriglyceridemia, and liver dysfunction. Here, we clinically and molecularly characterized FPLD3 patients harboring novel PPARG pathogenic variants.

Materials and methods

Lipodystrophy-suspected patients were recruited by clinicians from an Endocrinology Reference Center. Clinical evaluation was performed, biological samples were collected for biochemical analysis, and DNA sequencing was performed to define the pathogenic variants associated with the lipodystrophic phenotype found in our clinically diagnosed FPLD subjects. Bioinformatics predictions were conducted to characterize the novel mutated PPARγ proteins.

Results

We clinically described FPLD patients harboring two novel heterozygous PPARG variants in Brazil. Case 1 had the c.533T > C variant, which promotes the substitution of leucine to proline in position 178 (p.Leu178Pro), and cases 2 and 3 had the c.641 C > T variant, which results in the substitution of proline to leucine in the position 214 (p.Pro214Leu) at the PPARγ2 protein. These variants result in substantial conformational changes in the PPARγ2 protein.

Conclusion

Two novel PPARG pathogenic variants related to FPLD3 were identified in a Brazilian FPLD cohort. These data will provide new epidemiologic data concerning FPLD3 and help understand the genotype-phenotype relationships related to the PPARG gene.
No beneficial effect of aerobic whole-body electromyostimulation on lower limbs strength and power – a randomized controlled trial
Authors: Krause Anne , Centner Christoph , Walther Moritz , Memmert Daniel , Walser Nicolas , Ritzmann Ramona
Published: July 2024

Background

Applying whole-body electromyostimulation (wbEMS) to voluntary activation of the muscle is known to impact motor unit recruitment. Thus, wbEMS as an additional training stimulus enhances force-related capacities. This study aimed to evaluate the mono- and multiarticular strength adaptations to a running intervention with wbEMS compared to running without wbEMS.

Methods

In a randomized controlled trial (RCT), 59 healthy participants (32 female/ 27 male, 41 ± 7 years) with minor running experience conducted an eight-week running intervention (2x/ week à 20 min) with a wbEMS suit (EG) or without wbEMS (control group, CG). Maximal isokinetic knee extensor and flexor strength and jump height during countermovement jumps were recorded prior and after the intervention to assess maximal strength and power.

Results

Following eight weeks of running, maximal isokinetic knee extension torque decreased significantly over time for both interventions (EG $$\Delta$$
Δ
-4%, CG $$\Delta$$
Δ
-4%; F(1, 44.14) = 5.96, p = 0.02, $${\upeta }$$
η
= 0.12). No changes were observed for flexion torque (F(1, 43.20) = 3.93, p = 0.05, $${\upeta }$$
η
= 0.08) or jump height (F(1, 43.04) = 0.32, p = 0.57, $${\upeta }$$
η
 = 0.01).

Conclusions

The outcomes indicate that there is no additional effect over neuromuscular function adaptations with the inclusion of wbEMS during running training. Knee extensor strength is even slightly reduced which supports the principle of training specificity in regards to strength adaptation. We conclude that strength improvements cannot be achieved by running with wbEMS.

Trial registration

German Clinical Trials Register, ID DRKS00026827, date 10/26/21.
Quantitative assessment of preoperative brain development in pediatric congenital heart disease patients by synthetic MRI
Authors: Xu Shengfang , Ma Zihan , Zhang Jinlong , Wang Shaoyu , Ge Xin , Yue Songhong , Li Xinyi , Qian Jifang , Zhu Dalin , Liu Guangyao , Zhang Jing
Published: July 2024

Objectives

This study investigated the quantitative assessment and application of Synthetic MRI (SyMRI) for preoperative brain development in children with congenital heart disease (CHD).

Methods

Forty-three CHD patients aged 2–24 months were prospectively included in the observation group, and 43 healthy infants were included in the control group. The SyMRI scans were processed by postprocessing software to obtain T1, T2, and PD maps. The values of T1, T2, and PD in different brain regions were compared with the scores of the five ability areas of the Gesell Development Scale by Pearson correlation analysis.

Results

In the observation group, the T1 values of the posterior limb of the internal capsule (PLIC), Optic radiation (PTR), cerebral peduncle, centrum semiovale, occipital white matter, temporal white matter, and dentate nucleus were greater than those in the control group. In the observation group, the T2 values of the PLIC, PTR, frontal white matter, occipital white matter, temporal white matter, and dentate nucleus were greater than those in the control group. Pearson correlation analysis revealed that the observation group had significantly lower Development Scale scores. In the observation group, the T2 value of the splenium of the corpus callosum was significantly positively correlated with the personal social behavior score. The AUCs for diagnosing preoperative brain developmental abnormalities in children with CHD using T1 values of the temporal white matter and dentate nucleus were both greater than 0.60.

Conclusions

Quantitative assessment using SyMRI can aid in the early detection of preoperative brain development abnormalities in children with CHD.

Critical relevance statement

T1 and T2 relaxation values from SyMRI can be considered as a quantitative imaging marker to detect abnormalities, allowing for early clinical evaluation and timely intervention, thereby reducing neurodevelopmental disorders in these children.

Key Points

T1 and T2 relaxation values by SyMRI are related to myelin development.

Evaluated development quotient markers were lower in the observation compared to the control group.

SyMRI can act as a reference indicator for brain development in CHD children.

Graphical Abstract
Research progress and prospects of benefit-risk assessment methods for umbilical cord mesenchymal stem cell transplantation in the clinical treatment of spinal cord injury
Authors: Shen Ruoqi , Lu Yubao , Cai Chaoyang , Wang Ziming , Zhao Jiayu , Wu Yingjie , Zhang Yinian , Yang Yang
Published: July 2024

Over the past decade, we have witnessed the development of cell transplantation as a new strategy for repairing spinal cord injury (SCI). However, due to the complexity of the central nervous system (CNS), achieving successful clinical translation remains a significant challenge. Human umbilical cord mesenchymal stem cells (hUMSCs) possess distinct advantages, such as easy collection, lack of ethical concerns, high self-renewal ability, multilineage differentiation potential, and immunomodulatory properties. hUMSCs are promising for regenerating the injured spinal cord to a significant extent. At the same time, for advancing SCI treatment, the appropriate benefit and risk evaluation methods play a pivotal role in determining the clinical applicability of treatment plans. Hence, this study discusses the advantages and risks of hUMSCs in SCI treatment across four dimensions—comprehensive evaluation of motor and sensory function, imaging, electrophysiology, and autonomic nervous system (ANS) function—aiming to improve the rationality of relevant clinical research and the feasibility of clinical translation.
Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes
Authors: Puertas-Neyra Kevin , Coco-Martin Rosa M. , Hernandez-Rodriguez Leticia A. , Gobelli Dino , Garcia-Ferrer Yenisey , Palma-Vecino Raicel , Tellería Juan José , Simarro Maria , de la Fuente Miguel A. , Fernandez-Bueno Ivan
Published: July 2024

Background

Inherited retinal dystrophies (IRD) are one of the main causes of incurable blindness worldwide. IRD are caused by mutations in genes that encode essential proteins for the retina, leading to photoreceptor degeneration and loss of visual function. IRD generates an enormous global financial burden due to the lack of understanding of a significant part of its pathophysiology, molecular diagnosis, and the near absence of non-palliative treatment options. Patient-derived induced pluripotent stem cells (iPSC) for IRD seem to be an excellent option for addressing these questions, serving as exceptional tools for in-depth studies of IRD pathophysiology and testing new therapeutic approaches.

Methods

From a cohort of 8 patients with PROM1-related IRD, we identified 3 patients carrying the same variant (c.1354dupT) but expressing three different IRD phenotypes: Cone and rod dystrophy (CORD), Retinitis pigmentosa (RP), and Stargardt disease type 4 (STGD4). These three target patients, along with one healthy relative from each, underwent comprehensive ophthalmic examinations and their genetic panel study was expanded through clinical exome sequencing (CES). Subsequently, non-integrative patient-derived iPSC were generated and fully characterized. Correction of the c.1354dupT mutation was performed using CRISPR/Cas9, and the genetic restoration of the PROM1 gene was confirmed through flow cytometry and western blotting in the patient-derived iPSC lines.

Results

CES revealed that 2 target patients with the c.1354dupT mutation presented monoallelic variants in genes associated with the complement system or photoreceptor differentiation and peroxisome biogenesis disorders, respectively. The pluripotency and functionality of the patient-derived iPSC lines were confirmed, and the correction of the target mutation fully restored the capability of encoding Prominin-1 (CD133) in the genetically repaired patient-derived iPSC lines.

Conclusions

The c.1354dupT mutation in the PROM1 gene is associated to three distinct AR phenotypes of IRD. This pleotropic effect might be related to the influence of monoallelic variants in other genes associated with retinal dystrophies. However, further evidence needs to be provided. Future experiments should include gene-edited patient-derived iPSC due to its potential as disease modelling tools to elucidate this matter in question.

Graphical Abstract
Impact of a family support intervention on hospitalization costs and hospital readmissions among ICU patients at high risk of death or severe functional impairment
Authors: Andersen Sarah K. , Chang Chung-Chou H. , Arnold Robert M. , Pidro Caroline , Darby Joseph M. , Angus Derek C. , White Douglas B. ,   the Pairing Re-engineered Intensive Care Teams with Nurse-driven Emotional Support, Relationship building (PARTNER) Investigators
Published: July 2024

Background

Patients with advanced critical illness often receive more intensive treatment than they would choose for themselves, which contributes to high health care costs near the end of life. The purpose of this study was to determine whether a family support intervention delivered by the interprofessional ICU team decreases hospitalization costs and hospital readmissions among critically ill patients at high risk of death or severe functional impairment.

Results

We examined index hospitalization costs as well as post-discharge utilization of acute care hospitals, rehabilitation and skilled nursing facilities, and hospice services for the PARTNER trial, a multicenter, stepped-wedge, cluster randomized trial of an interprofessional ICU family support intervention. We determined patients’ total controllable and direct variable costs using a computerized accounting system. We determined post-discharge resource utilization (as defined above) by structured telephone interview at 6-month follow-up. We used multiple variable regression modelling to compare outcomes between groups. Compared to usual care, the PARTNER intervention resulted in significantly lower total controllable costs (geometric mean: $26,529 vs $32,105; log-linear coefficient: − 0.30; 95% CI − 0.49, − 0.11) and direct variable costs ($3912 vs $6034; − 0.33; 95% CI − 0.56, − 0.10). A larger cost reduction occurred for decedents ($20,304 vs. $26,610; − 0.66; 95% CI − 1.01, − 0.31) compared to survivors ($31,353 vs. $35,015; − 0.15; 95% CI − 0.35,0.05). A lower proportion in the intervention arm were re-admitted to an acute care hospital (34.9% vs 45.1%; 0.66; 95% CI 0.56, 0.77) or skilled nursing facility (25.3% vs 31.6%; 0.63; 95% CI 0.47, 0.84).

Conclusions

A family support intervention delivered by the interprofessional ICU team significantly decreased index hospitalization costs and readmission rates over 6-month follow-up.

Trial registration Trial registration number: NCT01844492
Asymptotic stability and bifurcations of a perturbed McMillan map
Authors: Qian Lili , Lu Qiuying , Deng Guifeng
Published: July 2024

This paper presents various bifurcations of the McMillan map under perturbations of its coefficients, such as period-doubling, pitchfork, and hysteresis bifurcation. The associated existence regions are located. Using the quasi-Lyapunov function method, the existence of asymptotically stable fixed point is also demonstrated.
Profiles of child labour: prevalence, activities, contexts, and children’s harm extent in Raya-Kobo and Angot Districts, Ethiopia
Authors: Weldeyesus Mengistu Abate , Alemu Bamlaku Alamirew
Published: July 2024

Using a mixed research design, the overall objective of this study is to investigate the profiles of child labour in Ethiopia’s districts of Raya-Kobo and Angot. The study’s specific objectives are to examine types of activities and prevalence of child labour, to identify the children’s working contexts, and to evaluate the extent of harm children face in workplaces. The study hypothesizes the existence of significant variations in the profiles of child labour (activity types, prevalence rates, settings, and level of harm to children) as a result of several circumstances. While survey methodology was used to collect primary data from 431 randomly selected respondents, desk review and document analysis were also used to gather secondary data. The sampling procedures used include multi-stage purposive and systematic random sampling. Descriptive and inferential (Ordered Probit Regression model) methods of data analysis are utilized to analyze the data. The results of the descriptive analysis demonstrate a high incidence and magnitude of child labour, as well as children’s early entry to work. The regression analysis reveals children’s exposure to high levels of harm at work, which is directly exacerbated by household age, income diversification, land fragmentation, livestock number, shocks, and the predicted value of remittances. Contrarily, access to rural transportation, household heads’ education level, cart ownership, and family size reduce children’s harm extent while working. The study highlights the need to design strategies for age-appropriate work to protect children from hazardous and high-intensity activities, undertake community awareness campaigns about the impact of child labour on children, and strengthen local stakeholders’ capacity. Additionally, connecting rural areas and farmers’ croplands to towns or major routes via repaired or new roads would be beneficial.
Visualization of cecal tumor by near-infrared laparoscopy and intraoperative colonoscopy
Authors: Watanabe Kaori , Takahashi Hiroki , Uehara Shuhei , Kato Akira , Fujii Yoshiaki , Yanagita Takeshi , Suzuki Takuya , Ushigome Hajime , Maeda Yuzo , Ogawa Ryo , Matsuo Yoichi , Mitsui Akira , Takiguchi Shuji
Published: July 2024

Background

In laparoscopic colorectal surgery, accurate localization of a tumor is essential for ensuring an adequate ablative margin. Therefore, a new method, near-infrared laparoscopy combined with intraoperative colonoscopy, was developed for visualizing the contour of a cecal tumor from outside of the bowel. The method was used after it was verified on a model that employed a silicone tube.

Case presentation

The patient was a 77-year-old man with a cecal tumor near the appendiceal orifice. Laparoscopy was used to clamp of the terminal ileum, and a colonoscope was then inserted through the anus to the cecum. The laparoscope in the normal light mode could not be used to identify the cecal tumor. However, a laparoscope in the near-infrared ray mode could clearly visualize the contour of the cecal tumor from outside of the bowel, and the tumor could be safely resected by a stapler. The histopathological diagnosis of the resected specimen was adenocarcinoma with an invasion depth of M and a clear negative margin.

Conclusions

This is the first report of the laparoscopic detection of the contour of a cecal tumor from outside the bowel. This technique is useful and safe for contouring tumors in laparoscopic colorectal surgery and can be used in various surgeries that combine endoscopy and laparoscopy.
Contextualising and challenging under-representation in research in light of Cultural Trauma: a qualitative focus group and interview study
Authors: Fryer Kate , Hutt Isobel , Aminu Habiba , Linton Emma , White Johanna , Reynolds Josie , Mitchell Caroline
Published: July 2024

Background

Although underserved populations— including those from ethnic minority communities and those living in poverty—have worse health and poorer healthcare experiences, most primary care research does not fairly reflect these groups. Patient and public involvement (PPI) is usually embedded within research studies in the United Kingdom (UK), but often fails to represent underserved populations. This study worked with patient and public contributors and local community leaders, situated in a socio-economically deprived and ethnically diverse urban area, to explore under-representation in primary healthcare research.

Methods

We undertook a focus group with a purposive sample of 6 members of a Patient and Public Involvement Group (PPIG), and interviews with 4 community leaders (representing Black, South Asian, Roma and socio-economically deprived communities). An iterative analysis process based on template analysis was used. Focus group 1 was rapidly analysed, and a template created. Findings were presented in focus group 2, and the template further developed. The Cultural Trauma concept was than applied to the template to give a wider theoretical lens. In-depth analysis of focus groups and interviews was then performed based on the template.

Results

Wider societal and historical influences have degraded trust in academic and healthcare institutions within underserved populations. Along with more practical considerations, trust underpins personal motivations to engage with research. Researchers need to invest time and resources in prolonged, mutually beneficial engagement with communities of importance to their research, including sharing power and influence over research priorities. Researcher reflexivity regarding differential power and cultural competencies are crucial. Utilising participatory methodologies including co-production demonstrates a commitment to inclusive study design.

Conclusions

Re-framing evidence-based medicine to be more useful and relevant to underserved populations with the highest burden of ill health is urgently needed. Lack of representation in primary healthcare research reflects wider societal inequalities, to which Cultural Trauma provides a useful lens. However, there are actions that researchers can take to widen representation. This will ultimately help achieve the goal of increased health equity by enhancing scientific rigour and research generalizability.
Prospective evaluation of the diagnostic efficacy of multiparametric MRI clear cell Likelihood Score in small solid renal masses and its predictive value for tumor grade
Authors: Soliman Osama M. , Mousa Amani Ezzat , Zaky Mona , Abdelhamid Abdalla
Published: July 2024

Background

The detection of small renal masses has significantly increased due to the widespread use of cross-sectional imaging in recent years. Among these masses, clear cell renal cell carcinoma (ccRCC) is the most common subtype and progresses quickly, resulting in the advancement of the disease and the development of metastases. In this prospective study, our goal is to assess the effectiveness of multiparametric MRI clear cell Likelihood Score in small solid renal masses and its utility in predicting tumor grade.

Results

In total, 103 patients (mean age 52.5 ± 13.16 years) with small solid renal masses of stage T1a (≤ 4 cm) were identified. Mean tumor size was 3.4 ± 0.6 cm. According to our study results, the clear cell Likelihood Score (ccLS) had sensitivity of 75.6%, specificity of 93.5%, PPV of 88.6%, NPV of 85.3% and accuracy of 86.4% in diagnosing ccRCC using a ccLS threshold of 4 and 5. As regard the assessment of ccLS threshold of 1 or 2 in excluding ccRCC pathological subtype, our study found that out of 29 patients with ccLS 1 or 2, there was only 1 ccRCC case with false result (3% false positive). It was also noted that there is significant relation between Arterial-to-delayed-enhancement-ratio (ADER) value and the grade of the ccRCC. The median interquartile range (IQR) of ADER parameter was statistically significant higher in grade II compared to grade I (Median was 1.6 and 0.9 respectively) and much higher in grade III compared to grades I and II (Median was 2.9) with P value < 0.001.

Conclusion

This ccLS showed promising efficacy in prediction and exclusion of ccRCC subtype. Moreover, it aids in predicting the ccRCC grade.
Near open generalizations of rough sets and their applications
Authors: Salama A. S. , El Atik A. A. , Hussein A. M. , Embaby O. A. , Bondok M. S.
Published: July 2024

Background

The concept of near open sets is a potent tool that empowers researchers to achieve a more encompassing approximation of rough sets, thereby enhancing the accuracy of measurements. The evolution of rough set theory into various generalized forms, based on topological structures, has emerged as a significant approach in the realm of knowledge discovery within databases.

Results

This paper’s primary contribution lies in the introduction of a novel category of generalized near open sets, termed “inverse simply open sets,” within the context of the $$\text{j}$$
j
-neighborhood space. The paper proposes diverse methods for extending the Pawlak’s rough approximations leading to the definition of new approximations in the $$\text{j}$$
j
-neighborhood space. By employing these newly introduced generalizations, we establish fresh connections between two pivotal theories, namely “general topology and rough set theory”. Through a comprehensive investigation, we conduct multiple comparisons between our methodology and classical approaches. Furthermore, we showcase practical applications of these techniques within real-life scenarios, demonstrating their utility in decision-making processes.

Conclusions

We reduced the data’s ambiguity while increasing its accuracy measure. As a result, we may conclude that the proposed approximations were more precise than earlier techniques and contributed to the elimination of data ambiguity in real-world scenarios requiring accurate decisions.
Novel organoid platform for drug screening of patients with breast cancer.
Authors: Shih Shian-Jiun , Zhang Ruobo , Han Yi Chun , Pegram Mark D. , Chang Ying C.
Published: July 2024

e13125

Background: Marketed methods are available for in vitro organoid growth for the purpose of translational science, evaluation of drug efficacy and patient treatment predictivity, but require needle biopsy of the tumor which is invasive to the patient. Non-invasive methods exist for isolating circulating tumor cells (CTC) from blood but require large volumes due to their low frequency (<1 in 105-106 PBMCs). Low CTC recovery limits the number of downstream analyses. To overcome these obstacles, Cellentia is introducing a novel in vitro system called R3CE (Rapid, Reproducible, Rare Cell Expansion), developed by AcroCyte Therapeutics Inc. (Taiwan), to the US market. The advantage of R3CE is that blood is used to generate viable representative cells of the patient’s tumor which can be expanded and banked, thus the number of characterization assays is flexible. The R3CE method allows for extensive drug screening within a rapid timeframe to inform patient treatment. This poster will show drug screening results on organoids derived from blood of breast cancer patients, and R3CE method transfer to Cellentia. Methods: For patient drug screening, 0.5 mL of peripheral blood was drawn from stage IV breast cancer patients. Cells were seeded onto proprietary plates, cultured for several days, passaged and screened for drug resistance or susceptibility to Cisplatin, Paclitaxel, 5-FU, Vinorelbine, and Gemcitabine by assessing the relative viability from luminescent measurements of drug treated organoids normalized to a mock control. For R3CE method transfer, frozen breast cancer organoids were thawed and seeded onto proprietary plates, grown for several days and used in the drug screen as described above. Results: Blood from five breast cancer patients (Patients A-E) were grown into organoids and used for screening drugs listed (Table). Relative viabilities were calculated. A threshold was set at 10% where relative viabilities above or below 10% showed the organoids were resistant (R) or susceptible (S) to killing by the drug candidate, respectively. The results of the R3CE drug test were compared to the clinical (Clin) outcome for each patient (clinical outcome is unknown (U) in some instances) and shown (Table). The drug test and the clinical outcome showed 100% concordance. Cellentia executed drug screening with the same drug panel utilizing frozen breast cancer organoids in the R3CE platform and demonstrated susceptibility in the drug screening. Conclusions: R3CE platform showed promising results as a personalized drug screening tool for breast cancer patients. Frozen breast cancer organoids for drug screening demonstrated successful method transfer to Cellentia. [Table: see text]
Immune checkpoint inhibitor retreatment in second-line treatment of esophageal cancer: A real-world study.
Authors: Kang Yixin , Zhang Dianbao , Mi Youjia , Niu Xiedong , Kang Yuan , Xie Dongjie , Li Wenyao , Zhang Ce , Yang Junqiang , Yao Jun
Published: July 2024

e16034

Background: Immunotherapy combined with chemotherapy has been recommended in several guidelines and consensus for the first-line treatment of advanced esophageal cancer(EC), but it is controversial whether to continue immune checkpoint inhibitors (ICIs) after the progress of first-line immunotherapy. Methods: This was a single-center, retrospective, observational, real-world study to collect general conditions and clinical data of EC patients hospitalized in the First Affiliated Hospital of Henan University of Science and Technology between February 2020 and December 2023. All patients received programmed cell death protein 1 (PD-1) or its ligand (PD-L1) inhibitor combination therapy in the first-line and received at least two cycles of PD-1/PD-L1 inhibitor-based therapy in the second-line setting after progression. We evaluated the efficacy and safety including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), grade 3-5 treatment-related adverse effects (TRAE) and immune-related adverse events (irAEs). We also evaluated the relationship between clinical features and outcomes using univariate and multivariate analyses. Results: We enrolled 214 patients, with a median age 67.9 (47 – 87) years, male sex 66.8%, 201(93.9%) ESCC and 11(5.1%) EAC. In all patients, the mOS and mPFS were 9.6 (95%CI 9.1-10.1) months and 4.4 (95%CI 4.1-4.7) months; The ORR was 33.2%, DCR was 65.9%. 162 (75.7%) patients treated with immunochemotherapy(I+C), 37 (17.3%) patients received immunotherapy combined with anti-angiogenic drugs(I+A) and 15 (7.0%) patients treated with immunotherapy combined with chemotherapy and anti-angiogenic drugs(I+C+A). The mOS were 9.1 (95% CI 8.4 – 9.8) months, 10.0 (95% CI 8.7 – 11.3) months and 11.5 (95% CI 10.7 – 12.3) months, respectively. The mPFS were 4.3m (95%CI 4.0-4.6) months, 4.3 (95%CI 4.0-14.6) months and 6.0 (95%CI 4.2-6.4) months. mPFS and mOS did not have significant difference between these groups. Univariate and multivariate analyses showed that PFS more than 6 months on first-line therapy was an independent prognostic factor for PFS and OS in second-line therapy. The incidence of grade ≥ 3 TRAEs and irAEs were 25.7% and 5.6%. No treatment-related deaths occurred. Conclusions: This real-world data showed PD-1 or PD-L1 inhibitors retreatment might have good efficacy and manageable safety in EC patients who progress after first-line immunochemotherapy. [Table: see text]
Population based assessment of HER-2 and PD-L1 positivity in gastric and gastroesophageal junction adenocarcinomas in a Canadian population.
Authors: Holland Patrick , Rafiq Rumana , Matheson Kara , Dakin-Hache Kelly , Sapp Heidi , Stueck Ashley , Moss Phillip , Thana Myuran , Arnason Thomas , Snow Stephanie Leann
Published: July 2024

e16038

Background: Current standard of care for advanced gastric and gastroesophageal cancers combines systemic chemotherapy with either human epidermal growth factor receptor 2 (HER-2) or programmed death ligand 1 (PD-L1) targeting therapy. New data is emerging that for patients whose tumours are positive for both HER-2 overexpression and have a PD-L1 combined positive score (CPS) >1%, combining all three treatment modalities results in superior outcomes. There is limited international data, and no Canadian data, exploring the frequency of patients who have tumours that are both HER-2 and PD-L1 positive who will be eligible for this novel treatment approach. Objective: To determine the proportion of patients in Nova Scotia with HER-2 positive gastric and GEJ adenocarcinomas who have a PD-L1 CPS score above established clinical thresholds. Methods: A retrospective review of PD-L1 and HER-2 status for all patients diagnosed with gastric and GEJ adenocarcinomas in Nova Scotia between June 3, 2022 and August 13, 2023 was completed. PD-L1 CPS was evaluated using the 28-8 assay and was considered positive if >1%. HER-2 overexpression was evaluated by immunohistochemistry and in cases with equivocal expression, status was based on fluorescence in situ hybridization. Results: Over the study period, 56 cases of gastric and 42 cases of GEJ adenocarcinoma were identified for a total of 98 cases. The median age of the study population was 73 years (range 38 - 91). 73 patients (74%) were male and 25 patients (26%) were female. HER-2 expression was evaluated in 92 cases, and PD-L1 CPS was evaluated in 95 cases. 19 cases (21%) were HER-2 positive and 86 cases (91%) were PD-L1 positive. 17 HER-2 positive cases were also PD-L1 positive (89%). Conclusions: This study provides population level data in a Canadian context on patients with gastric and GEJ adenocarcinoma with respect to HER-2 overexpression and PD-L1 status. This data will be helpful in planning allocation of clinical and financial resources as a new standard of care for these patients is established.
Envafolimab in combination with lenvatinib and albumin paclitaxel for previously treated advanced gastric/gastroesophageal junction adenocarcinoma: Preliminary analysis of a phase II, two-cohort study.
Authors: Zhao Xiaoying , Guo Weijian , Zhu Xiaodong , Feng Wanjing , Huang Mingzhu , Geng Qirong , Zhang Zhe , Sheng Xuedan
Published: July 2024

e16039

Background: The combination of first-line chemotherapy and PD-1 has emerged as a standard treatment, enhancing the efficacy in advanced gastric/gastroesophageal junction (GEJ) cancer. The efficacy of the combination of second-line chemotherapy and PD-1/PD-L1 remains unclear. This study aims to observe the efficacy of Envafolimab plus tyrosine kinase inhibitors (TKIs) and second-line chemotherapy in the treatment of patients with advanced GEJ adenocarcinoma. Methods: This prospective, open-label, phaseⅡ, two cohort study was conducted to assess the efficacy and safety of Envafolimab-based therapy in patients experiencing progression after initial first-line treatment. Eligible patients with HER2-negative, microsatellite stable (MSS), advanced GEJ adenocarcinoma were consecutively enrolled and assigned into cohort A or cohort B, according to whether they received PD-1 inhibitors in the first-line treatment. Patients in both cohorts received Envafolimab (200mg, hypodermic injection, days 1 and 15, Q4W) combined with Lenvatinib (8mg/12mg, po, once a day) and albumin paclitaxel (100mg/m2, IV, days 1, 8 and 15, Q4W, up to 6 cycles) until disease progression, unacceptable toxicity, or patients refusal to continue treatment. The primary endpoint was objective response rate(ORR) per iRECIST v1.1, and the secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. The efficacy and safety data in this analysis were from patients in cohort A who previously failed in first-line chemotherapy and did not receive PD-1 or PD-L1 inhibitors ever. Results: From October 2022 to June 2023, cohort A enrolled 16 patients, and 15 of them were evaluable for efficacy analysis. The average age was 58.87 ±11.81 years, 80% patients were male. 6 patients had been tested for PD-L1 status, of which 1 (16.7%) was positive and 5 (83.3%) were negative. As of Jan29, 2024, the median follow-up was 10.6 months (95%CI = 8.67-12.53), the median number of treatment cycles was 7 cycles (IQR: 5, 8). Based on the iRECIST v1.1, the ORR was 60.00% (90% CI = 35.96%-80.91%), the DCR was 100.00% (90% CI = 81.90%-100.00%). The median PFS (mPFS) was 8.23 months (90% CI =6.27-8.61), and the median OS (mOS) was 10.6 months (90% CI =8.79-12.15). Overall incidences of adverse events (AEs) of any grade was 100%, and 75.00% (n = 12) had ≥ grade 3 AEs during treatment. Most treatment-related adverse events (TRAEs) of grade ≥3 included neutrophil count (56.25%), decreased leukocyte count (37.5%). Conclusions: In patients of advanced gastric cancer who have not previously received PD-1/PD-L1 inhibitors, this second-line combination therapy demonstrates promising preliminary effects. Clinical trial information: NCT06030934 .
Effectiveness and safety of first-line serplulimab in patients with metastatic/locally advanced esophageal carcinoma (EC): A real-world study.
Authors: Zhu Jingni , Sun Changjiang , Ren Yuanyuan , Yu Xinnian , Sun Zijian , Sun Yan
Published: July 2024

e16044

Background: The prognosis of metastatic/locally advanced EC has significantly improved with the development of immune checkpoint inhibitors. Serplulimab has been approved in the treatment of various solid tumors (e.g. esophageal squamous cell carcinoma [ESCC], small cell lung cancer). Considering the lack of real-world evidence, this study aimed to explore the real-world effectiveness and safety of serplulimab as first-line therapy in patients with metastatic/locally advanced EC. Methods: Thismulticenterretrospective study included patients with metastatic/locally advanced EC who received first-line serplulimab-containing therapy from March 2022 to December 2023. The demographic and disease characteristics, chemotherapy regimens selected by physicians, treatment response and adverse events were collected from medical record. The outcomes included progression free survival (PFS), objective response rate (ORR), overall survival (OS), duration of response (DoR), time to treatment discontinuation (TTD) and safety. Results: A total of 57 patients were included, 45 (78.9%) were male with a mean age of 68 years. A majority of patients had ESCC (n=40, 70.2%) and metastatic disease (n=35, 61.4%). The most common chemotherapy regimens combined with serplulimab were paclitaxel plus cisplatin (n=27, 39.1%) and etoposide and platinum (n=13, 23.6%). With a median follow-up of 4.8 month (range: 0.7-19.7), the median PFS was 7.4 months (95% confidence interval [CI]: 3.7-11.1). The ORR and DCR were 22.8% and 96.5% in all patients, respectively. The median DoR and TTD were 4.7 months (95% CI: 4.3-not estimated [NE]) and 13.9 months (95% CI: 3.6-24.1), respectively, while the median OS was not reached (NR). The mPFS was 11.1 months (95% CI: 7.0-NE) in patients with ESCC, which was numerically longer than those with neuroendocrine carcinoma (6.5 months, 95% CI: 5.8-7.3, P=0.052). Other effectiveness outcomes in ESCC are presented in Table. Patients > 65 years had a significant improved mPFS compare to those ≤ 65 years (5.9 vs. 11.1 months, P=0.001). The rate of any grade adverse events (AEs) was 26.3% (n=15), while grade 3 or higher AEs was 10.5% (n=6), thrombocytopenia (7.0%, n=4), myelosuppression and pulmonary infection (both 5.3%, n=3) being the most common. Conclusions: First-line serplulimab combined with chemotherapy demonstrated promising effectiveness and favorable safety profile in patients with metastatic/locally advanced EC, especially in ESCC. The current real-world evidence indicates that serplulimab combined with chemotherapy could provide survival benefit for patients with advanced first-line EC. [Table: see text]
Revolutionizing outcome prediction for immunotherapy with vision transformer-based pathomics signature in esophageal squamous cell cancer.
Authors: Li Butuo , Qin Wenru , Wang Linlin
Published: July 2024

e16049

Background: Immune checkpoint inhibitors (ICIs) has notably enhanced the survival prospects for patients with esophageal squamous cell carcinoma (ESCC), however the clinical benefit was limited to only a small portion of patients. This study aimed to perform a deep learning signature based on H&E-stained pathological specimens for the purpose of identifying effective markers that can accurately predict the clinical benefit of ICIs among patients with ESCC. Methods: ESCC patients receiving PD-1 inhibitors from Shandong Cancer Hospital were included. Whole slide images (WSIs) of H&E-stained histological specimens of included patients were collected, and subsequently randomly allocated into two sets: a training set comprising 70% of the samples, and a validation set consisting of the remaining 30%. The labels of images were defined by the progression-free survival (PFS) with the interval of 4 months. The pretrained ViT model was used for patch-level model training, and all patches were projected into probabilities after linear classifier. Then the most predictive patches were passed to RNN for final patient-level prediction to construct ESCC-pathomics signature (ESCC-PS). Accuracy rate and survival analysis were performed to evaluate the performance of ViT-RNN survival model in validation cohort. Results: 163 ESCC patients receiving PD-1 inhibitors were included for model training. There were 486,188 patches of 1024*1024 pixels from 324 WSI images of H&E-stained histological specimens after image pre-processing. The training cohort consisted of 120 patients with a total of 227 images, while the validation cohort comprised 43 patients and featured 97 images. Notably, both groups exhibited balanced baseline characteristics between them. The ESCC-PS achieved an accuracy of 84.5% in the validation cohort, and could distinguish patients into three risk groups with the median PFS of 2.7, 4.8 and 16.7 months (P < 0.001). The multivariate cox analysis revealed ESCC-PS could act as an independent predictor of survival from PD-1 inhibitors (P < 0.001). A combined signature incorporating ESCC-PS and expression of PD-L1 shows significantly improved accuracy in outcome prediction of PD-1 inhibitors compared to ESCC-PS and PD-L1 anlone, with the area under curve value of 0.952, 0.924, 0.648 for 6-month PFS and C-index of 0.816, 0.806, 0.66, respectively. Conclusions: The outcome supervised pathomics signature based on deep learning has the potential to enable superior prognostic stratification of ESCC patients receiving PD-1 inhibitors, which convert the images pixels to an effective and labour-saving tool to optimize clinical management of ESCC patients.
Immune checkpoint inhibitor plus chemotherapy versus chemotherapy alone in HER2-negative advanced gastric or gastroesophageal junction cancer: A systematic review and meta-analysis of randomized controlled trials.
Authors: Oliveira João Pedro , Silva Isadora Mamede Mendes da , de Liz Caio Dabbous , Maia Melissa , Oliveira Audrey Cabral Ferreira de , Alves Ana Caroline Fonseca
Published: July 2024

e16052

Background: Synergistic effects of immune checkpoint inhibitors (ICI) and chemotherapy (CTX) have been documented, demonstrating promising efficacy across diverse cancer types. This report presents a meta-analysis aimed at assessing the effectiveness and safety profile of ICI plus CTX in patients diagnosed with Human Epidermal Growth Factor Receptor type 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) cancers. Methods: PubMed, EMBASE, Cochrane Central, and ASCO Abstracts databases were systematically searched for randomized controlled trials comparing PD-1 or PD-L1 inhibitors plus CTX with CTX alone in patients diagnosed with HER2-negative gastric or GEJ cancers. The assessed outcomes included Progression-Free Survival (PFS) and Overall Survival (OS), stratified by PD-L1 Combinated Positive Score (CPS) in tumors, as well as any Adverse Events (AE) and Treatment-Related Adverse Events (TRAE) graded as ≥ 3. Statistical analysis employed a random effects model in R version 4.3.2, with heterogeneity assessed using the I2 statistic. Results: We conducted a meta-analysis comprising 6 RCTs involving 5,520 patients, among whom 2,766 received PD-1 or PD-L1 inhibitors in combination with chemotherapy. This combined regimen demonstrated significant improvements in both general PFS (HR 0.73; 95% CI [0.68; 0.78]; p < 0.01) and OS (HR 0.77; 95% CI [0.71; 0.84]; p < 0.01). Specifically, the combination of ICI with CTX exhibited enhanced PFS across various subgroups, including CPS ≥ 5 (HR 0.66; 95% CI [0.59; 0.75]; p < 0.01), CPS ≥ 10 (HR 0.75; 95% CI [0.65; 0.87]; p < 0.01), and CPS ≤ 1 (HR 0.75; 95% CI [0.69; 0.82]; p < 0.01). Median OS similarly reflected this improvement in CPS ≥ 5 (HR 0.71; 95% CI [0.63; 0.81]; p < 0.01) and CPS ≥ 10 (HR 0.66; 95% CI [0.57; 0.75]; p < 0.01) subgroups, albeit not in the CPS ≤ 1 subgroup (HR 0.91; 95% CI [0.77; 1.08]; p = 0.29). Furthermore, no significant differences were observed in the incidence of adverse events (AE) (RR 1.01; 95% CI [0.99; 1.04]; p = 0.221), while grade 3 or more treatment-related adverse events (TRAE) were slightly higher in the ICI plus CTX group (RR 1.15; 95% CI [1.01; 1.32]; p = 0.038). Conclusions: These findings indicate that the combination of ICI with CTX demonstrates superior efficacy compared to CTX alone in HER2-negative gastric or GEJ cancer. However, this efficacy trend is not maintained in patients with PD-L1 CPS ≤ 1 tumors. Moreover, the absence of differences in AE and the slight increase in TRAE in the ICI plus CTX group still further supports the safety profile of this combination therapy.