bluuebunny/crossref_metadata_2025 huggingface dataset:
Utilizing two different sustainable and green spectrophotometric approaches using derivative ratio spectra for the determination of a ternary severely overlapped mixture: application to veterinary formulation
Authors: Abdullatif Hind A. , Abdelkawy Mohammed , Kamal Maha , Fahmy Nesma M.
Published: June 2024

Mathematical manipulation technique has proven to be a very powerful tool for efficient processing and handling of highly overlapped spectra. This work introduced two green and sustainable approaches for the successful recovery of the ternary mixture, Tylosin tartarate (TYL), Sulfadimdine (SLD), and Trimethoprim (TRI). The approaches were constructed using three different methods, derivative ratio spectrum zero-crossing method (DRSZ), double divisor ratio spectra derivative method (DDRD), and factorized derivative ratio method coupled with spectrum subtraction (FDRM-SS). The two approaches succeeded in recovering the three drugs (Linearity range achieved were 0.5–5 µg/mL for TYL, 0.3–1.3 µg/mL for SLD, and 0.3–5 µg/mL for TRI), giving convenient standard deviations and satisfactory recovery percentages. The recommended methods have been verified in accordance with (ICH) guidelines. When the results were statistically compared to the official methods, no significant difference was found. Both AGREE—Analytical GREEnness Metric Approach and Software, and White Analytical Chemistry (WAC) RGB model gave scores of 0.93 and 97.2%, respectively, which proved that the approaches were eco-friendly and abiding by the sustainability principles.
Molecular-phylogenetic investigation of trichomonads in dogs and cats reveals a novel Tritrichomonas species
Authors: Tuska-Szalay Barbara , Gilbert Julia , Takács Nóra , Boldogh Sándor A. , Fáy József , Sterczer Ágnes , Psáder Roland , Kontschán Jenő , Izsó Ádám , Hornok Sándor
Published: June 2024

Background

Trichomonosis is a common infection in small animals, mostly manifesting in gastrointestinal symptoms such as diarrhea. Although oral trichomonads are also known, the species found colonizing the large intestine are more frequently detected protozoa.

Methods

In the present study, four wildcats, 94 domestic cats, and 25 dogs, originating from 18 different locations in Hungary, were investigated for the presence of oral and large intestinal trichomonads based on the 18S rRNA gene and ITS2.

Results

All oral swabs were negative by polymerase chain reaction (PCR). However, Tritrichomonas foetus was detected in a high proportion among tested domestic cats (13.8%) and dogs (16%), and Pentatrichomonas hominis only in two domestic cats. In addition, a novel Tritrichomonas genotype was identified in one cat, probably representing a new species that was shown to be phylogenetically most closely related to Tritrichomonas casperi described recently from mice. All positive dogs and half of the positive cats showed symptoms, and among cats, the most frequent breed was the Ragdoll.

Conclusions

With molecular methods, this study evaluated the prevalence of oral and intestinal trichomonads in clinical samples of dogs and cats from Hungary, providing the first evidence of T. foetus in dogs of this region. In contrast to literature data, P. hominis was more prevalent in cats than in dogs. Finally, a hitherto unknown large intestinal Tritrichomonas species (closely related to T. casperi) was shown to be present in a cat, raising two possibilities. First, this novel genotype might have been a rodent-associated pseudoparasite in the relevant cat. Otherwise, the cat was actually infected, thus suggesting the role of a predator–prey link in the evolution of this trichomonad.

Graphical Abstract
Double vertical interrupted suture for optimal adaptation and stabilization of free gingival graft around dental implants: a case report
Authors: Moslemi Neda , Dolatabadi Amirmohammad , Mohseni Salehimonfared Seyedhossein , Goudarzimoghaddam Fatemeh
Published: June 2024

Background

Free gingival graft is commonly used to augment the keratinized mucosa and vestibular depth around dental implants. The proper suturing technique is fundamental to achieve a successful result following free gingival graft. However, there are limited studies that focus on the details of the suturing methods to optimize graft adaptation. The purpose of this technical note is to describe a new suturing technique for optimal approximation and stabilization of free gingival graft around dental implants.

Case presentation

Here, we present a 53-year-old Persian female with peri-implantitis and lack of keratinized mucosa around mandibular implants who was a candidate for free gingival graft. A new suturing technique, double vertical interrupted suture, was conducted in the interimplant areas. In addition, the suspensory cross-mattress sutures were added to ensure the adaptation of the graft over the implants. The proposed suturing technique is useful for soft tissue augmentation around multiple implants with concave or uneven recipient bed.

Conclusion

The present article describes a novel suturing technique for good adaptation and fixation of free gingival graft around dental implants.
Ψ-Bielecki-type norm inequalities for a generalized Sturm–Liouville–Langevin differential equation involving Ψ-Caputo fractional derivative
Authors: Serrai Hacen , Tellab Brahim , Etemad Sina , Avcı İbrahim , Rezapour Shahram
Published: June 2024

The present research work investigates some new results for a fractional generalized Sturm–Liouville–Langevin (FGSLL) equation involving the Ψ-Caputo fractional derivative with a modified argument. We prove the uniqueness of the solution using the Banach contraction principle endowed with a norm of the Ψ-Bielecki-type. Meanwhile, the fixed-point theorems of the Leray–Schauder and Krasnoselskii type associated with the Ψ-Bielecki-type norm are used to derive the existence properties by removing some strong conditions. We use the generalized Gronwall-type inequality to discuss Ulam–Hyers (), generalized Ulam–Hyers (), Ulam–Hyers–Rassias (), and generalized Ulam–Hyers–Rassias () stability of these solutions. Lastly, three examples are provided to show the effectiveness of our main results for different cases of (FGSLL)-problem such as Caputo-type Sturm–Liouville, Caputo-type Langevin, Caputo–Erdélyi–Kober-type Langevin problems.
Co-design workshops with families experiencing multiple and interacting adversities including parental mental health, substance use, domestic violence, and poverty: intervention principles and insights from mothers, fathers, and young people
Authors: Muir Cassey , Kedzior Sophie G. E. , Barrett Simon , McGovern Ruth , Kaner Eileen , Wolfe Ingrid , Forman Julia R. ,   On behalf of the ORACLE consortium
Published: June 2024

Background

Clustering and co-occurring of family adversities, including mental health problems, substance use, domestic violence and abuse, as well as poverty can increase health and behavioural risks for children, which persist throughout the life course. Yet, interventions that acknowledge and account for the complex interactive nature of such risks are limited. This study aimed to develop intervention principles based on reflections from mothers, fathers, and young people who experience multiple and interacting adversities. These principles will show how family members perceive an intervention may bring about positive change and highlight key insights into design and delivery.

Methods

A series of six co-design workshops with mothers, fathers, and young people who experienced multiple and interacting adversities (n = 41) were iteratively conducted across two regions in England (London and North-East) by four researchers. Workshop content and co-design activities were informed by advisory groups. Data from facilitator notes and activities were analysed thematically, resulting in a set of intervention principles.

Results

The intervention principles highlighted that: (1) to reduce isolation and loneliness parents and young people wanted to be connected to services, resources, and peer support networks within their local community, particularly by a knowledgeable and friendly community worker; (2) to address feelings of being misunderstood, parents and young people wanted the development of specialised trauma informed training for practitioners and to have the space to build trusting, gradual, and non-stigmatising relationships with practitioners; and (3) to address the needs and strengths of individual family members, mothers, fathers, and young people wanted separate, tailored, and confidential support.

Conclusions

The current study has important implications for practice in supporting families that experience multiple and interacting adversities. The intervention principles from this study share common characteristics with other intervention models currently on offer in the United Kingdom, including social prescribing, but go beyond these to holistically consider the whole families’ needs, environments, and circumstances. There should be particular focus on the child’s as well as the mothers’ and fathers’ needs, independently of the family unit. Further refinement and piloting of the developing intervention are needed.
Prevalence and correlates of diarrhoea among children under five in selected coastal communities in Ghana
Authors: Bandoh Delia Akosua , Dwomoh Duah , Yirenya-Tawiah Dzidzo , Kenu Ernest , Dzodzomenyo Mawuli
Published: June 2024

Introduction

Diarrhoea is a preventable disease affecting children under five years disproportionately. Globally, thousands of children die from diarrhoea related diseases each year, most deaths occuring in sub-Saharan Africa where Ghana is located. Coastal communities bear the greatest brunt due to poor sanitary conditions. We assess the prevalence of diarrhoea in selected coastal communities along the eastern coast of Ghana.

Methods

We conducted a cross-sectional study in Mumford, Opetekwei, Anyako, Anyauni and Ateteti communities in the Central, Greater Accra and Volta region respectively. We interviewed households with children under five years on the occurrence of diarrhoea and health seeking practices. We also used a checklist to assess the sanitary conditions of the household. Frequencies and proportions were generated. We determined significant differences using modified Poisson regression models at p < 0.05. Results were presented in tables and text.

Results

The prevalence ratio of diarrhoea was 36% (95% CI 33–40%). Most cases were from Anyako community. All interviewed households in Mumford and Opetekwei used improved water sources whiles 94% in Atetetio used improved water sources. Children who were fully vaccinated had 32% lower prevalence of diarrhoea compared to those who were not (aPR: 0.68, 95% CI 0.55–0.84).

Conclusion

Diarrhoea prevalence was high inspite of the reported use of improved water sources and sanitation facilities by majority of households in the communities. Fully vaccinated children had a relatively lower prevalence of diarrhoea compared to children who were not fully vaccinated. We recommend in-depth analysis of the use of water and sanitation facilities in these settings to understand the reasons for the observed diarrhoea prevalence.
Determinants of preventive behavior against Covid-19 in secondary school students based on Health Belief Model (HBM): a structural equations modeling (SEM)
Authors: Jadgal Mohammad Saeed , Karimi Mehrdad , Alizadeh-Siuki Hadi , Salarzehi Fatemeh Kord , Zareipour MoradAli
Published: June 2024

Measures such as education, improving knowledge, attitude and taking preventive action to protect against COVID-19 are vital strategies for prevention. The aim of this study was to determine the predictability of Health Belief Model (HBM) constructs in performing preventive behaviors against COVID-19 among secondary school students in Chabahar, Iran. In this cross-sectional-analytical study, 400 secondary school students of Chabahar city were investigated by simple random sampling. The data collection tool was a questionnaire including demographic characteristics, knowledge, behavior, and Health Belief Model constructs’ questions. Exploratory Factor Analysis (EFA) was used to evaluate the validity of HBM constructs, and the structural equation modeling (SEM) method was used to evaluate the direct and indirect effects of the relationship between knowledge, HBM constructs, and preventive behavior against COVID-19 based on the conceptual model. Based on the results of the structural modeling, the direct effect of knowledge on the constructs of the health belief model was positive and significant (β = 0.34, P-value < 0.001), and on the preventive behavior of students was insignificant (β = 0.12, P-value = 0.07) while the indirect effect of knowledge through increasing the constructs of the HBM on student behavior was positive and significant (β = 0.30, P < 0.001). The relationship between the constructs of the HBM constructs and student behavior was also positive and significant (β = 0.89, P-value < 0.001).Due to the fact that knowledge and HBM structures played a role in predicting the adoption of preventive behavior from COVID-19, it is possible to design appropriate interventions to increase knowledge, sensitivity, perceived severity, and self-efficacy, in order to recover from COVID-19 by adopting preventive behaviors.
Exploring CT pixel and voxel size effect on anatomic modeling in mandibular reconstruction
Authors: Ahmed Maariyah , Garzanich Myra , Melaragno Luigi E. , Nyirjesy Sarah , Windheim Natalia Von , Marquardt Matthew , Luttrull Michael , Quails Nathan , VanKoevering Kyle K.
Published: June 2024

Background

Computer-aided modeling and design (CAM/CAD) of patient anatomy from computed tomography (CT) imaging and 3D printing technology enable the creation of tangible, patient-specific anatomic models that can be used for surgical guidance. These models have been associated with better patient outcomes; however, a lack of CT imaging guidelines risks the capture of unsuitable imaging for patient-specific modeling. This study aims to investigate how CT image pixel size (X-Y) and slice thickness (Z) impact the accuracy of mandibular models.

Methods

Six cadaver heads were CT scanned at varying slice thicknesses and pixel sizes and turned into CAD models of the mandible for each scan. The cadaveric mandibles were then dissected and surface scanned, producing a CAD model of the true anatomy to be used as the gold standard for digital comparison. The root mean square (RMS) value of these comparisons, and the percentage of points that deviated from the true cadaveric anatomy by over 2.00 mm were used to evaluate accuracy. Two-way ANOVA and Tukey-Kramer post-hoc tests were used to determine significant differences in accuracy.

Results

Two-way ANOVA demonstrated significant difference in RMS for slice thickness but not pixel size while post-hoc testing showed a significant difference in pixel size only between pixels of 0.32 mm and 1.32 mm. For slice thickness, post-hoc testing revealed significantly smaller RMS values for scans with slice thicknesses of 0.67 mm, 1.25 mm, and 3.00 mm compared to those with a slice thickness of 5.00 mm. No significant differences were found between 0.67 mm, 1.25 mm, and 3.00 mm slice thicknesses. Results for the percentage of points deviating from cadaveric anatomy greater than 2.00 mm agreed with those for RMS except when comparing pixel sizes of 0.75 mm and 0.818 mm against 1.32 mm in post-hoc testing, which showed a significant difference as well.

Conclusion

This study suggests that slice thickness has a more significant impact on 3D model accuracy than pixel size, providing objective validation for guidelines favoring rigorous standards for slice thickness while recommending isotropic voxels. Additionally, our results indicate that CT scans up to 3.00 mm in slice thickness may provide an adequate 3D model for facial bony anatomy, such as the mandible, depending on the clinical indication.
A mini-review of efficacy, safety, and influence of novel evinacumab on familial hypercholesterolemia
Authors: Olatunji Gbolahan , Kokori Emmanuel , Moradeyo Abdulrahmon Akanmu , Lema Kaleb , Ayo Olanipekun Ridwan , Obasanjo Opabode Muntaqim , Mustapha Mubarak Jolayemi , Stanley Anthony Chidera , Aderinto Nicholas
Published: June 2024

Background

Familial hypercholesterolemia (FH) poses a substantial risk of cardiovascular diseases. The recent approval of evinacumab signifies a breakthrough in FH management. This review synthesizes evidence from diverse clinical trials, examining evinacumab’s efficacy, safety, and broader impact on hypercholesterolemia.

Body

As highlighted by multiple trials, Evinacumab demonstrates robust efficacy in reducing LDL-C levels, particularly in refractory cases. Its sustained impact, evidenced by enduring reductions in LDL-C levels throughout extended treatment periods, positions it as a potential long-term solution. While the safety profile appears favorable, instances of deaths underline the importance of holistic clinical management and ongoing surveillance. The clinical implications are profound, suggesting evinacumab’s potential inclusion in guidelines for managing severe lipid disorders.

Conclusion

Future research directions emphasize inclusivity, diversity, and real-world applications to establish sustained efficacy and safety across diverse populations. Integrating evinacumab into clinical guidelines requires evidence-based recommendations, necessitating collaboration between researchers, clinicians, and guideline developers.
Significance of transthoracic ultra-sonography in early detection of patients with interstitial lung diseases in Aswan University Hospital
Authors: Ahmed Shazly , Sayed Suzan Salama , Gharib Mostafa , Kinawy Sayed Abdelsabour
Published: June 2024

Background

Recently, the diagnosis and follow-up of numerous pulmonary diseases such as pneumothorax, pneumonia, and pleural effusion were easily by use of conventional ultrasound, and the maximum usefulness of transthoracic ultrasonography (TUS) in pulmonary diseases especially diffuse parenchymal lung disease has not been detected yet. This study was conducted to determine the value of transthoracic ultrasonography in patients with interstitial lung disease (ILD). Moreover, the viable correlations of the ultrasound findings with the functional and radiological findings of ILDs had been assessed.

Results

TUS diagnosis was positive in 73 cases, there was a substantial variation between the two groups classified according to ultrasonographic diagnosis regarding age and smoking history (p = 0.003 and 0.013 respectively). All the patients with usual interstitial pneumonia (n = 42) and Indeterminate UIP (n = 49) had positive ultra-sonographic findings [p = 0.041 and 0.001 accordingly]. Regarding pulmonary function tests, there was a considerable variance between both groups regarding FVC, PEF, FEF25-75, FEV1/VC (p = 0.037, 0.029, 0.015, and 0.000 accordingly). The most positive US diagnosis areas were upper lateral, lateral basal, and interscapular areas. There was a weak negative correlation between TUS diagnosis and FVC [r =  − 0.25, p = 0.026].

Conclusion

We concluded the great significant value of TUS in the diagnosis and follow-up of patients with interstitial lung diseases. It had an extremely thoughtful role in the diagnosis of ILD by detection of multiple B-lines distribution emerging from pleura and extending in the entire lung surface. The use of TUS in early detection and follow-up of ILDs reduced the cost.
A novel filtering technique for extracting formation slowness from poorly bonded cased boreholes
Authors: Xu Song , Tang Xiaoming , Zhao Lingling , Zou Zhihui , Chen Xuelian
Published: June 2024

Extracting formation properties from sonic logging data in poorly bonded cased boreholes is crucial. The importance of this task is underscored by the increasing number of cased wells worldwide and instances wherein sonic measurements are omitted before casing the well. Analyzing formation signals from poorly bonded cased boreholes is highly challenging, especially in the case of free-pipe situations wherein the casing is detached from the formation. We develop a new signal processing technique designed specifically for the sonic data in cased wellbores. This method uses the inherent stopbands of the casing waves for filtering, effectively suppressing the casing wave signal. We provide a frequency range template for various casing types to guide signal processing. Our method has been applied to sonic data from a field cased wellbore to evaluate its performance. We determine its capability to enhance formation signals, even in the presence of dominant casing signals, particularly in cases wherein the formation wave velocity is fast and close to the casing wave velocity, thus providing new perspectives and guidance for the processing of sonic data in cased wellbores.
Frequency of comedication of proton pump inhibitors with crystalline dasatinib in chronic myeloid leukemia and effects on TKI-bioavailability.
Authors: Dahlén Torsten , Larfors Gunnar , Lennernäs Hans , Liljebris Charlotta , Von Euler Mikael , Brisander Magnus , Andersson Per , Stenke Leif
Published: June 2024

6561

Background: Tyrosine kinase inhibitors (TKI), including dasatinib, have profoundly improved clinical outcome in chronic myeloid leukemia (CML). However, solubility, bioavailability and systematic exposure of the crystalline formulation of dasatinib (Sprycel) is reduced at higher gastric pH levels. This is problematic for comedication with acid reducing agents as lower bioavailability may reduce clinical response. Methods: We investigated proton pump inhibitor (PPI) and TKI comedication, including dasatinib, in a large real world CML cohort. Furthermore, we assessed the influence of timing of PPI comedication on the absorption and bioavailability of dasatinib. Results: Using the Swedish CML- and Prescribed Drug-Registries, we identified 1,328 chronic phase CML patients, diagnosed 2002-2018. 1,261 (95%) had received specified/known TKI treatment and 685 of those (54%) were prescribed a PPI (ATC-code: “A02BC”) at some point after CML diagnosis. TKIs and PPIs prescribed within 12 months of CML diagnosis were prescribed by different HCPs in 66% of cases (284/432). Of the 388 patients treated with dasatinib, 91 (23.5%) received a concomitant PPI. The PPI prescription rate increased to 53% (204/388) in the dasatinib cohort after dasatinib treatment had ended. Further, we assessed the drug-drug interaction (DDI) in 18 healthy volunteers given crystalline dasatinib (100mg) alone or together with omeprazole (40mg, at steady state) administered 9 hours apart; a time point when a high effect on bioavailability is expected. Compared to dosing with crystalline dasatinib alone, Cmax and AUC0-24 were reduced by 96% and 88% by omeprazole comedication (Table). Conclusions: Despite warnings, comedication with PPI is common among dasatinib treated CML patients. Further, an even larger proportion of patients need PPI co-treatment, which however, cannot fully be administered due to its negative impact on dasatinib pharmacokinetics. Moreover, with an optimized study design, we observed a higher than previously reported negative interaction of PPI comedication on crystalline dasatinib bioavailability. This may compromise clinical efficacy and risk CML disease progression. For patients in need of PPI, selection of a non-crystalline, less pH-sensitive formulation of dasatinib therefore appears more appropriate. Clinical trial information: NCT06145217 . [Table: see text]
Time toxicity for patients receiving oral versus parenteral hypomethylating agents for myelodysplastic syndromes/neoplasms (MDS).
Authors: Epstein Robert S , Zeidan Amer Methqal , Olopoenia Abisola , Costantino Halley , Modi Kushal , Salimi Tehseen , Washington Terri , Krenitsky JoAnn
Published: June 2024

6568

Background: Patients spend substantial time receiving cancer care. Patients with higher-risk MDS treated with hypomethylating agents (HMAs) are generally older and have a median life expectancy of 11–17 months. Patients receiving parenteral treatment for MDS spend significant time in clinics receiving HMA treatment; as such, information on the time burden of treatments (“time toxicity”) is needed to help clinicians guide patients and caregivers with alternative routes of administration. The development of oral HMA therapies offers a strategy that mitigates the time toxicity associated with MDS treatment by increasing the number of “home days” for patients. This study details the time burden among patients with MDS receiving oral HMA therapy versus those receiving intravenous and subcutaneous (IV/SC) HMAs. Methods: This was a retrospective analysis of adult patients with MDS initiating HMA therapy (oral or IV/SC HMA), using the US Cerner Enviza claims database (08/2020–08/2022). Propensity score matching (1:1) was performed on the treatment groups to balance confounding factors; matched cohorts were analyzed (N=158 each). The total direct healthcare encounter days for oral and IV/SC HMA administered patients were evaluated based on the number of healthcare encounter days spent on parenteral HMA administration (0 days for oral HMAs), outpatient, inpatient, and emergency room (ER) visits, and infusion days. Only distinct encounter days were included in the total count; multiple visits in a day were de-duplicated. Mean (SD) healthcare days for oral versus IV/SC HMA groups were calculated for each type of healthcare encounter and summarized. Results: Patients receiving oral HMA incurred a mean total of 15.2 healthcare encounter days compared with 32.8 days for those receiving IV/SC HMAs (Table). Most encounter days for the oral HMA cohort were in the outpatient setting (34.9%) while most encounters for the IV/SC HMA cohort were attributed to receiving parenteral HMA administration (55.5%), followed by inpatient (16.2%) and outpatient visits (14.9%). Conclusions: This study, which is the first report to date of time toxicity in MDS among patients treated with HMA therapy, revealed that patients receiving oral HMA incurred half the time burden of those receiving IV/SC HMAs. Further research is warranted to validate these results in a larger patient cohort and compare these findings with other cancer therapies. [Table: see text]
Overall survival of adebrelimab plus chemotherapy and sequential thoracic radiotherapy as first-line treatment for extensive-stage small cell lung cancer.
Authors: Chen Dawei , Gao Aiqin , Zou Bing , Huang Wei , Shao Qian , Meng Xiangjiao , Zhang Pinliang , Tang Xiaoyong , Hu Xudong , Zhang Yan , Guo Jun , Zhao Wei , Fu Lei , Zhao Changhong , Yuan Jiajia , Yu Jinming , Wang Linlin
Published: June 2024

8014

Background: The phase 3 trial (CAPSTONE-1) showed that adebrelimab (PD-L1 antibody) combined with first-line chemotherapy could prolong overall survival (OS) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC). Previous studies have shown that radiotherapy can enhance the immunogenicity of tumors, indicating the great potential of combining radiotherapy with immunotherapy. The purpose of this study was to explore the efficacy and safety of adebrelimab combined with chemotherapy and sequential thoracic radiotherapy (TRT) as first-line therapy for ES-SCLC. Methods: Key inclusion factors were 18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Pts received 4~6 cycles of adebrelimab (20mg/kg, D1, q3w) combined with EP/EC (etoposide, 100mg/m2, D1-3, q3w and cisplatin, 75mg/m², D1, q3w or carboplatin, AUC = 5, D1, q3w). Pts with response sequentially received adebrelimab combined with consolidate TRT (≥30 Gy in 10 fractions or ≥50 Gy in 25 fractions, involved-field irradiation). Pts then entered the maintenance treatment stage with adebrelimab until disease progression or intolerable side effects. The primary endpoint was OS. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: From October 2020 to April 2023, 67 pts with ES-SCLC were enrolled. Most patients were male (83.6%), current or former smokers (65.7%) with an ECOG performance status of 1 (95.5%). 22 (32.8%) patients were diagnosed with brain metastasis and 21 (31.3%) patients had liver metastasis at baseline. 45 patients received sequential TRT as planned. All patients were included in the safety and efficacy analysis population. At data cutoff (December 22, 2023), the median follow-up duration was 17.7 months. The median OS was 21.4 months (95% CI: 17.2–not reached months). 1-year and 2-year OS rate were 74.1% (95% CI: 63.6-86.4%) and 39.7% (95% CI: 25.5-61.9%). The median PFS was 10.1 months (95% CI: 6.9–15.5 months). The confirmed ORR was 71.6% (95% CI: 59.3-82.0%) and DCR was 89.6% (95% CI: 79.7-95.7%). The most common grade 3 or higher treatment-related adverse events included neutrophil count decreased (41.8%), white blood cell count decreased (19.4%) and lymphocyte count decreased (13.4%). No unexpected adverse events were observed. Conclusions: Adebrelimab plus chemotherapy and sequential TRT as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. Clinical trial information: NCT04562337 .
Multidimensional analysis of B7 homolog 3 (B7-H3) RNA expression in small-cell lung cancer (SCLC) molecular subtypes.
Authors: Gay Carl Michael , Owonikoko Taofeek K. , Byers Lauren Averett , Choudhury Noura J. , Ahmed Sajid , Cain Zachary , Qian Xiaozhong , Brentnall Matthew , Heeke Simon , Poi Ming , Wu Sharon , Rudin Charles M.
Published: June 2024

8088

Background: SCLC is an aggressive cancer with a poor prognosis. B7-H3, a transmembrane protein showing low expression in normal tissues but overexpression in SCLC and other tumors, is a promising target for antibody–drug conjugates. We performed a multidimensional analysis of B7-H3/ CD276 expression in SCLC molecular subtypes (SCLC-A, -N, -P, and -I) and its relationship with expression of other immune-related genes. Methods: Clinical and molecular data for a cohort of patients (pts) with SCLC were derived from a real-world database (Caris Life Sciences, Irving, TX, USA). Tumor RNA expression was used to assign the SCLC molecular subtype derived from non-negative matrix factorization. Programmed death ligand-1 (PD-L1) protein expression was assessed by immunohistochemistry (IHC; antibody 22c3; positive cut-off: tumor proportion score >1%). Demographic, clinical, and molecular data were summarized by SCLC subtype or B7-H3 expression quartile (Q). Spearman’s r evaluated correlations between expression of B7-H3 and other immune-related genes/signatures. Results: The cohort included 1721 pts (52.5% female; 98.9% [434/439] smokers; median age, 67 years [range, 18–90+]). Across the subtypes, B7-H3 expression was high and remarkably consistent ( q>0.05; Table). Other biomarker genes, including DLL3 (q<0.05), had lower and more variable expression. Median (range) B7-H3 expression across all samples was 16.75 (0–68.2) transcripts per million (TPM). Across B7-H3 expression Qs, the proportion of PD-L1-positive pts by IHC was similar (Q1, 39.8%; Q2, 46.5%; Q3, 40.7%; Q4, 39.2%). Median (95% confidence interval) B7-H3 expression was similar between pts with prior immunotherapy ( n=24; 14.43 [11.64–21.17] TPM) and pts without ( n=208; 14.20 [13.00–15.91] TPM); treatment information was not available for the remaining samples in this cohort. B7-H3 expression was not strongly correlated with any other immune-related genes/signatures, although several had moderate correlation ( HAVCR2/ TIM3, r=0.59; PDCD1LG2/ PD-L2, r=0.56; M2 macrophages, r=0.56; CD86, r=0.56). Conclusions: In pts with SCLC, B7-H3 showed high and consistent expression across subgroups defined by molecular subtype or prior immunotherapy. The relative expression of B7-H3 was higher and less variable among molecular subtypes than for other key molecular targets in this tumor type, including DLL3. B7-H3 expression had limited association with PD-L1 expression, supporting a role as a distinct therapeutic target. [Table: see text]
PD-L1 and alternative immune checkpoints (AICs) in non-small cell lung cancer (NSCLC): Insights into the tumor immune microenvironment (TIME) and immunotherapy (IO) outcomes.
Authors: D'Aiello Angelica , Nazari Shayan , Jeon Hyein , Elliott Andrew , Vanderwalde Ari M. , Borghaei Hossein , Liu Stephen V. , Zang Xingxing , Halmos Balazs , Cheng Haiying
Published: June 2024

8531

Background: PD-L1 and recently identified AICs (B7x, B7-H3, and HHLA2) may function as key immune evasion mechanisms in NSCLC and influence IO efficacy. This study explores the expression patterns of PD-L1 and AICs within the TIME and their impact on IO outcomes in NSCLC, including key molecular subtypes. Methods: NSCLC samples (n=27,629) were analyzed (Caris Life Sciences) with NextGen Sequencing on DNA (592 genes or whole exome)/RNA (whole transcriptome). Tumor cell PD-L1 expression (22c3) was assessed by IHC. Gene expression profiles were analyzed for IFN-γ score and QuantiSEQ was used to assess immune cell infiltration in the TIME. Real-world overall survival (rwOS: from time of biopsy to last contact), time on treatment [TOT: from the first pembrolizumab (pembro) treatment to the last], and OS on pembro (OSpem: from pembro start to last contact) were calculated. Mann-Whitney U, X2/Fisher-Exact, and log-rank tests were applied where appropriate. Results: PD-L1 IHC+ NSCLC and cases with high PD-L1 RNA expression had higher IFN-γ score and immune cell fractions (p<0.0001 for both) vs PD-L1 IHC- and low expression, respectively. Additionally, PD-L1 IHC+ NSCLC was associated with (a/w) higher median transcript levels (TPM) of PD-L1 and B7-H3, while PD-L1 IHC- NSCLC was a/w higher TPM of HHLA2 and B7x (p<0.0001 for all). AICs expression varied by molecular subtype, e.g., higher HHLA2/B7x RNA in EGFR mutant vs wild-type (WT) NSCLC. Moreover, PD-L1 IHC+ NSCLC and cases with high PD-L1 RNA and low B7H3 RNA were a/w longer rwOS, OSpem, and TOT; high HHLA2 RNA was a/w longer rwOS and OSpem with similar TOT; and low B7x RNA expression was a/w longer OSpem and TOT with similar rwOS (Table). Conclusions: Both PD-L1 IHC+ NSCLC and cases with high PD-L1 RNA expression are a/w a more inflammatory TIME, and superior survival and IO outcomes. Moreover, consistent with our prior HHLA2 IHC work (PMIDs: 27553831, 29374053), HHLA2 RNA expression was significantly higher in PD-L1 IHC- and EGFR mutant cases. These findings support the potential utility of transcriptomics along with protein expression for assessing novel predictive biomarkers for IO. Furthermore, the distinct expression profiles of AICs identified in our study may represent key subtypes mediating IO response in WT and EGFR mutant NSCLC. [Table: see text]
Molecular profiling across histologies in lung cancer: Time to change WHO nomenclature?
Authors: Russo Alessandro , Javey Manana , Hiemenz Matthew , Kaplan Benjamin G , Yaung Stephanie J. , Huang Richard S.P. , Rolfo Christian Diego
Published: June 2024

8532

Background: Biomarker testing is essential for optimal therapeutic management of Non-Small lung Cancer (NSCLC). However, a not negligible percentage of patients (pts) is not tested in clinical practice for all the relevant actionable biomarkers. Biomarker testing is recommended in lung adenocarcinoma (LUAD), while in tumors with other histologies it is reserved when clinical features indicate a higher probability of an oncogenic driver. Histopathology report and biomarker testing are usually performed sequentially, which is time consuming and delays patient care. Herein we determined the distribution of actionable biomarkers across NSCLC histotypes and other clinic-demographic characteristics. Methods: This is an observational retrospective analysis on histologically confirmed NSCLC cases tested between 2014-2022 using FoundationOne/FoundationOneCDx assay. Histopathologies of all cases were centrally reviewed and confirmed by Board Certified Anatomic Pathologists. Results: 82,328 NSCLC pts were included. Actionable genomic alterations (GA) were found in 35.1% of the cases (Table). LUAD and adenosquamous (ASC) were more commonly associated with actionable GA (45.8% and 40.9%, respectively) as compared with sarcomatoid (29.1%), not otherwise specified (NOS) (27.6%), large cell (LCC) (21.1%), and squamous cell (LUSC) (6.5%) histologies. Sarcomatoid histology had the highest METex14 skipping mutations (muts) frequency (9.9% vs. 2.4% in LUAD). Tumor mutational burden (TMB) ≥10 Mut/Mb was associated with histology (50.9% in LCC, 40.8% in NOS, 39.1% in LUSC, and 36.3% in sarcomatoid vs. 31.2% in LUAD and 29.2% in ASC). Pts with actionable GA usually had a low TMB (80.9%). A significant correlation (p<0.005) between age and actionable GA was reported for BRAF/ ERBB2 muts, ALK/RET/ROS1 rearrangements (RE), and MET amplification. EGFR actionable muts and KRASG12C were more commonly observed in females, whereas no significant correlation between sex and other GA was observed. Finally, genetic ancestry analyses revealed a strong correlation between EGFR actionable muts and South/East Asian and American ancestries, but not for other GA. Conclusions: This is the largest NSCLC dataset analyzed for biomarker distribution across histologies, age, sex and genetic ancestry. This dataset confirms sufficient enough biomarker prevalence across LUAD and ASC carcinoma to be included in WHO nomenclature for lung tumors, and provides reassurance that cases with NOS, LCC and sarcomatoid histologies must be considered for biomarker workup. [Table: see text]
Socioeconomic disparities in survival outcomes of patients with NSCLC with brain metastases: A real-world analysis.
Authors: Bellur Shreyas S , Ahmad Shahzaib , Bhat Vivek , Ganiyani Mohammad Arfat , Ozair Ahmad , Jayram Diya , Khosla Atulya Aman , Podder Vivek , Ahluwalia Manmeet Singh
Published: June 2024

8569

Background: Racial and ethnic disparities have been previously reported in outcomes of metastatic cancer patients. While novel therapies have improved outcomes of NSCLC patients with brain metastases (BM), however, barriers to therapy persist, warranting updated evaluations of socioeconomic disparities in clinical outcomes. Methods: A retrospective cohort study was conducted on patients diagnosed with NSCLC BM in 2018-2020 in the National Cancer Database. Patients were classified as White, Black, American Indian, Aleutian or Pacific Islander (AAPI), or Asian. Sociodemographic and clinical outcomes were analyzed and reported using median overall survival (mOS) (95% CI). Multivariate analyses were performed using Cox proportional hazard models adjusting for sex, race, facility type, and income and reported using hazard ratios for death (HR) (95% CI). Results: 13850 patients with NSCLC BM were included: 81% (N=11123) were White, 14% (N=1914) Black, 0.5% (N=73) AAPI, 3.7% (N=508) Asian. 8% were treated in community cancer centers (CCC) and 39% in comprehensive CCCs (CCCC). 55% were Medicare-insured and 30% had annual income >$74063. Compared to White, Asian patients had significantly better mOS of 29.1 months (24.57-36.5). Compared to non-Hispanic, Hispanic patients had significantly better mOS at 18.1 months (14.5-24.3). Medicaid and Medicare-insured had significantly worse outcomes vs. private-insured patients – mOS of 14.62 months (12.75-16.49) and 8.84 months (8.41-9.36) vs. 21.72 months (20.37-23.29). In multivariate analyses, compared to White, Asians had an HR of 0.61 (0.53-0.70). Hispanic had a HR of 0.77 (0.67-0.88) compared to non-Hispanic patients (P<0.05). Compared to academic centers, patients treated at CCC (HR 1.42 (1.29-1.57)) and CCCC (HR 1.25 (1.19, 1.32)) had worse outcomes. Patients with higher annual income (>$74063) had better outcomes compared to those with low income (<$46277) (HR 0.83 (0.78-0.89), P<0.002). Conclusions: Asian and Hispanic patients with NSCLC BM had better 3-year survival compared to White and non-Hispanic patients, respectively. Patients at community centers had worse outcomes than those at academic centers. Medicare-insured and Medicaid-insured patients had unfavorable outcomes. Targeted efforts are warranted to improve disparities in outcomes across racial and ethnic groups. [Table: see text]
A randomized phase II trial of 8 months of afatinib switching to osimertinib (A) versus osimertinib alone (B) as first-line treatment in advanced NSCLC patients with common EGFR mutation: YAMATO study (TORG1939/WJOG12919L).
Authors: Nakamura Atsushi , Yoshioka Hiroshige , Misumi Toshihiro , Yokoyama Toshihide , Itani Hidetoshi , Tachihara Motoko , Tanaka Kaoru , Akamatsu Hiroaki , Ono Akira , Ikeda Satoshi , Tokito Takaaki , Sato Yuki , Mori Masahide , Uemura Takehiro , Hata Akito , Hosokawa Shinobu , Ishikawa Hideki , Yamamoto Nobuyuki , Okamoto Hiroaki , Kurata Takayasu
Published: June 2024

8574

Background: NSCLC with common EGFR mutation (L858R or exon 19 deletion (Del19)) is known to originally comprise small portion of uncommon and compound EGFR variant cells including T790M-mutant ones albeit treatment-naïve. To overcome concomitant heterogeneous EGFR mutations, we planned a randomized phase II trial to assess the strategy of switching to osimertinib following 8 months of afatinib compared with osimertinib alone. Methods: YAMATO study is an open-label, multi-center, randomized phase II study. Patients with newly diagnosed stage III/IV/recurrent NSCLC harboring EGFR activating mutations (L858R or Del19) were randomized in a 1:1 ratio to receive up-front 8 months of afatinib (30 mg or 40 mg QD) followed by osimertinib (80 mg QD) (arm A) or osimertinib (80mg QD) alone (arm B) until disease progression or intolerable toxicity. The primary endpoint is 2-year progression free survival (PFS) rate with threshold rate of 22% and expected rate of 40% (one-tailed alpha of 0.1, beta of 0.2). Secondary endpoints are objective response rate (ORR), PFS, time to treatment failure, overall survival and adverse events. Results: Between May 2020 and Apr 2021, 113 patients were enrolled from 27 institutions (A/B 56/57). Patient characteristics were as follows: median ages, 73.5/71 years (range 41-85/41-92 years); proportion of males, 42.9/35.1%; EGFR mutation types, L858R/Del19 59/41% in A, 58/42% in B. The difference of two-year PFS rate was not observed statistically significant between groups (37.3% [80% CI, 29.0 to 45.5] in arm A vs 47.4% [80% CI, 38.5 to 55.7] in arm B; p=0.44; HR:1.28 [80% CI, 0.95-1.73]). The ORR was 82% in arm A and 87% in arm B. With the median follow-up of 27.5 months, median PFS was 16.8 months in arm A, and 22.2 months in arm B (HR: 1.280, p = 0.29). Severe pneumonitis occurred in 7% in arm A, most of which developed after switching to osimertinib, and 1.8% in arm B. Conclusions: YAMATO study failed to demonstrate the superiority of EGFR-TKI switching therapy of 8 months afatinib to osimertinib over osimertinib alone in terms of 2-year PFS rate in untreated advanced NSCLC patients with common EGFR mutations. Clinical trial information: 031200021 .
A real-world study on biomarker retesting among patients with non-small cell lung cancer and disparity in outcomes.
Authors: Crawford Samuel , Aggarwal Charu , Ng Sophia , Xu Qingqing , Simmons Archana , Gulati Ashish , Beasley Mary Beth
Published: June 2024

8590

Background: Prior studies revealed sociodemographic disparities in biomarker testing among patients (pts) with advanced/metastatic non-small cell lung cancer (a/mNSCLC). However, the association of testing disparities with clinical outcomes among real-world pts requires further characterization. Methods: This retrospective study used ConcertAI Patient360™ US dataset to assess biomarker testing disparities and their association with median overall survival (mOS) among adults with a/mNSCLC (2017–2022) who received ≥1 line of therapy with ≥90-day follow-up. Analyses were conducted in pts who initiated first-line (1L) treatment and stratified by setting (community vs academic) and race. Biomarker testing is a curated data element in this database, leveraging structured and unstructured electronic medical record data and includes the following biomarkers ALK, BRAF, EGFR, KRAS, MET amp, MET exon 14, NTRK, PD-L1, RET, and ROS1. Biomarker testing to inform 1L decision was defined as testing before 1L start. Testing to inform second-line (2L) decision was defined as testing after 1L start and before 2L start. Variables were compared using chi-square or ANOVA tests. Unadjusted and adjusted OS using multivariate Cox proportional hazards are reported. Results: Of 3678 pts included in the 1L cohort, 3127 (85%) received 1L testing. In community settings, 22% of Black pts vs 15% of White pts did not receive 1L testing (P=0.002), whereas 1L testing rates between races were similar in academic settings (Table). In 2L community setting among pts who received 1L but not 2L testing, mOS was 5.9 vs 9.9 months in Black (n=54) vs White (n=529) pts, respectively (P=0.35). In 2L community setting among pts who were and were not tested prior to 1L and not tested at 2L, mOS was 5.9 vs 10.1 months in Black (n=62) vs White (n=613) pts, respectively (P=0.27). Accounting for recorded sociodemographic and clinical characteristics at baseline, differences in OS by testing setting and status start to normalize to the reference group. Disparities within groups appear to potentially exist despite no statistical significance (except for ECOG score of 2+). Conclusions: Despite small 2L sample sizes and lack of significance, disparities in testing rates and outcomes were observed, which may be overcome by normalizing testing across race and treatment setting to potentially improve pt outcomes. Further analysis can be performed across census regions. Further research is needed to confirm the impact of lack of biomarker testing on pt outcomes on a broader scale, particularly around characteristics that may impact outcomes but were undetected in this dataset. [Table: see text]