bluuebunny/crossref_metadata_2025 huggingface dataset:
The question of screening organ donors for hepatitis e virus: a case report of transmission by kidney transplantation in France and a review of the literature
Authors: Solignac Justine , Boschi Celine , Pernin Vincent , Fouilloux Virginie , Motte Anne , Aherfi Sarah , Fabre-Aubrespy Maxime , Legris Tristan , Brunet Philippe , Colson Philippe , Moal Valérie
Published: June 2024

Background

Hepatitis E is a potentially serious infection in organ recipients, with an estimated two-thirds of cases becoming chronic, and with a subsequent risk of cirrhosis and death. In Europe, transmission occurs most often through the consumption of raw or undercooked pork, more rarely through blood transfusion, but also after solid organ transplantation. Here we describe a case of Hepatitis E virus (HEV) infection transmitted following kidney transplantation and review the literature describing cases of HEV infection transmitted by solid organ transplantation.

Case presentation

Three weeks after kidney transplantation, the patient presented with an isolated minimal increase in GGT and hepatic cytolysis 6 months later, leading to the diagnosis of genotype 3c hepatitis E, with a plasma viral load of 6.5 log10IU/mL. In retrospect, HEV RNA was detected in the patient's serum from the onset of hepatitis, and in the donor's serum on the day of donation, with 100% identity between the viral sequences, confirming donor-derived HEV infection. Hepatitis E had a chronic course, was treated by ribavirin, and relapsed 10 months after the end of treatment.

Discussion

Seven cases of transmission of HEV by solid organ transplantation have been described since 2012 without systematic screening for donors, all diagnosed at the chronic infection stage; two patients died. HEV organ donor transmission may be underestimated and there is insufficient focus on immunocompromised patients in whom mild liver function test impairment is potentially related to hepatitis E. However, since HEV infection is potentially severe in these patients, and as evidence accumulates, we believe that systematic screening of organ donors should be implemented for deceased and living donors regardless of liver function abnormalities, as is already the case in the UK and Spain. In January 2024, the French regulatory agency of transplantation has implemented mandatory screening of organ donors for HEV RNA.
Functional characterization of two DYRK1B variants causative of AOMS3
Authors: Detro-Dassen Silvia , Sternberg Anna , Lehmann Sonja Maria , Schwandt Katharina , Düsterhöft Stefan , Becker Walter
Published: June 2024

Background

Two new missense variants (K68Q and R252H) of the protein kinase DYRK1B were recently reported to cause a monogenetic form of metabolic syndrome with autosomal dominant inheritance (AOMS3).

Results

Our in vitro functional analysis reveals that neither of these substitutions eliminates or enhances the catalytic activity of DYRK1B. DYRK1B-K68Q displays reduced nuclear translocation.

Conclusion

The pathogenicity of DYRK1B variants does not necessarily correlate with the gain or loss of catalytic activity, but can be due to altered non-enzymatic characteristics such as subcellular localization.
Study protocol for a single-blind, parallel-group, randomized, controlled superiority trial of intensive versus weekly delivered prolonged exposure for adults with post-traumatic stress disorder
Authors: Bragesjö Maria , Fina Brooke , Ivanova Ekaterina , Ivanov Volen Z , Rück Christian
Published: June 2024

Background

Prolonged exposure (PE) therapy is widely recognized as an effective treatment for post-traumatic stress disorder (PTSD) and is often considered one of the primary options for addressing this condition. Nevertheless, a significant proportion of patients (30–51%) fail to demonstrate clinically significant symptom changes. One of the reasons is that a high proportion of patients drop out from treatment, which often lasts for a minimum of 3–4 months. Hence, there is an urgent need for PTSD treatments that can be delivered to decrease dropout rates. A more intensive PE treatment approach has been suggested to decrease dropout rates and in addition achieve faster recovery rates and has shown promising effects on reducing PTSD symptoms but needs to be tested against firsthand treatment.

Methods

This single-blind, randomized controlled trial (N = 140) will compare an intensive delivery format of prolonged exposure (iPE) against standard weekly delivered sessions of PE. The primary outcome is change on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Secondary outcomes include self-rated measures of symptoms of PTSD and complex PTSD, depression and quality of life, speed of recovery, cost effectiveness, dropout rates, and adverse events.

Discussion

This study will be the first to compare iPE with first-line treatment in a psychiatric outpatient setting. One of the key strengths of this study lies in its implementation within a clinical setting and the broad eligibility criteria. Additionally, the utilization of gold-standard assessment measures ensures the accuracy and reliability of the outcomes. However, several potential challenges may arise during the study’s execution. These challenges may include difficulties in participant recruitment, ensuring adequate participant retention, adherence to the treatment protocol, and maintaining therapist retention mostly due to recruitment taking place at one single clinic.

Trial registration number

Clinicaltrials.gov NCT05934175. Registered on June 6, 2023. Open Science Framework (OSF) https://osf.io/7qsb3. Registered on September 2, 2023.
Host specificity and virulence of Flavobacterium psychrophilum: a comparative study in ayu (Plecoglossus altivelis) and rainbow trout (Oncorhynchus mykiss) hosts
Authors: Fujiwara-Nagata Erina , Rochat Tatiana , Lee Bo-Hyung , Lallias Delphine , Rigaudeau Dimitri , Duchaud Eric
Published: June 2024

Flavobacterium psychrophilum, the causative agent of bacterial cold-water disease, is a devastating, worldwide distributed, fish pathogen causing significant economic loss in inland fish farms. Previous epidemiological studies showed that prevalent clonal complexes (CC) differ in fish species affected with disease such as rainbow trout, coho salmon and ayu, indicating significant associations between particular F. psychrophilum genotypes and host species. Yet, whether the population structure is driven by the trade of fish and eggs or by host-specific pathogenicity is uncertain. Notably, all F. psychrophilum isolates retrieved from ayu belong to Type-3 O antigen (O-Ag) whereas only very few strains retrieved from other fish species possess this O-Ag, suggesting a role in outbreaks affecting ayu. Thus, we investigated the links between genotype and pathogenicity by conducting comparative bath infection challenges in two fish hosts, ayu and rainbow trout, for a collection of isolates representing different MLST genotypes and O-Ag. Highly virulent strains in one host species exhibited low to no virulence in the other. F. psychrophilum strains associated with ayu and possessing Type-3 O-Ag demonstrated significant variability in pathogenicity in ayu, ranging from avirulent to highly virulent. Strikingly, F. psychrophilum strains retrieved from rainbow trout and possessing the Type-3 O-Ag were virulent for rainbow trout but not for ayu, indicating that Type-3 O-Ag alone is not sufficient for pathogenicity in ayu, nor does it prevent pathogenicity in rainbow trout. This study revealed that the association between a particular CC and host species partly depends on the pathogen’s adaptation to specific host species.
Multiple time servers timed-release encryption based on Shamir secret sharing for EHR cloud system
Authors: Yuan Ke , Cheng Ziwei , Chen Keyan , Wang Bozhen , Sun Junyang , Zhou Sufang , Jia Chunfu
Published: June 2024

Electronic health record (EHR) cloud system, as a primary tool driving the informatization of medical data, have positively impacted both doctors and patients by providing accurate and complete patient information. However, ensuring the security of EHR cloud system remains a critical issue. Some patients require regular remote medical services, and controlling access to medical data involving patient privacy during specific times is essential. Timed-release encryption (TRE) technology enables the sender to preset a future time T at which the data can be decrypted and accessed. It is a cryptographic primitive with time-dependent properties. Currently, mainstream TRE schemes are based on non-interactive single time server methods. However, if the single time server is attacked or corrupted, it is easy to directly threaten the security applications of TRE. Although some research schemes “distribute” the single time server into multiple ones, they still cannot resist the single point of failure problem. To address this issue, we propose a multiple time servers TRE scheme based on Shamir secret sharing and another variant derived from it. In our proposed schemes, the data receiver does not need to interact with the time servers; instead, they only need to obtain the time trapdoors that exceed or equal the preset threshold value for decryption, which ensures the identity privacy of the data sender and tolerates partial downtime or other failures of some time servers, significantly improving TRE reliability. Security analysis indicates that our proposed schemes demonstrate data confidentiality, verifiability, anti-advance decryption, and robust decryption with multiple time trapdoors, making them more practical. Efficiency analysis indicates that although our schemes have slightly higher computational costs than most efficient existing TRE schemes, such differences are insignificant from a practical application perspective.
Association between estimated glucose disposal rate and atrial fibrillation recurrence in patients undergoing radiofrequency catheter ablation: a retrospective study
Authors: Li Xiaozhong , Zhou Zheng , Xia Zhen , Dong Youzheng , Chen Si , Zhan Fenfang , Wang Zhichao , Chen Yang , Yu Jianhua , Xia Zirong , Li Juxiang
Published: June 2024

Objective

Previous studies have shown a clear link between insulin resistance (IR) and an elevated risk of atrial fibrillation (AF). However, the relationship between the estimated glucose disposal rate (eGDR), which serves as a marker for IR, and the risk of AF recurrence after radiofrequency catheter ablation (RFCA) remains uncertain. Therefore, this study aimed to examine the potential association between the eGDR and the risk of AF recurrence following RFCA.

Methods

This retrospective study was conducted at Nanchang University Affiliated Second Hospital. The study enrolled 899 patients with AF who underwent RFCA between January 2015 and January 2022. The formula used to calculate the eGDR was as follows: 19.02 − (0.22 * body mass index) − (3.26 * hypertension) − (0.61 * HbA1c). Cox proportional hazard regression models and exposure–effect curves were used to explore the correlation between the baseline eGDR and AF recurrence. The ability of the eGDR to predict AF recurrence was evaluated using the area under the receiver operating characteristic curve (AUROC).

Results

The study observed a median follow-up period of 11.63 months, during which 296 patients experienced AF recurrence. K‒M analyses revealed that the cumulative incidence AF recurrence rate was significantly greater in the group with the lowest eGDR (log-rank p < 0.01). Participants with an eGDR ≥ 8 mg/kg/min had a lower risk of AF recurrence than those with an eGDR < 4 mg/kg/min, with a hazard ratio (HR) of 0.28 [95% confidence interval (CI) 0.18, 0.42]. Additionally, restricted cubic spline analyses demonstrated a linear association between the eGDR and AF recurrence (p nonlinear = 0.70). The area under the curve (AUC) for predicting AF recurrence using the eGDR was 0.75.

Conclusions

The study revealed that a decrease in the eGDR is associated with a greater AF recurrence risk after RFCA. Hence, the eGDR could be used as a novel biomarker for assessing AF recurrence risk.
Dropout intention: a valid predictor of actual dropout?
Authors: Findeisen Stefanie , Brodsky Alexander , Michaelis Christian , Schimmelpenningh Beatrice , Seifried Jürgen
Published: June 2024

Evidence on the extent to which dropout intention can serve as a valid predictor of dropout decisions remains scarce. This study first presents the results of a systematic literature review of 14 studies examining the relationship between dropout intention and actual dropout in post-secondary education (vocational education and training [VET] or higher education). Second, we examine a longitudinal dataset of prospective chefs surveyed at the beginning (t1), the second half of the first year (t2), and the second year of the dual VET programme (t3). We examine the relationship between self-reported dropout intention and trainees’ actual dropout behaviour. Additionally, we analyse development profiles of trainees’ dropout intention using latent profile analysis. The review results provide strong support for a significant positive relationship between dropout intention and actual dropout (effect sizes vary between studies and contexts/types of dropout). In line, aspiring chefs’ dropout intention is significantly positively correlated with actual dropout (r = 0.201). Three development profiles were identified during VET: (1) stable, low dropout intention, (2) stable, medium dropout intention, and (3) increasing dropout intention. We conclude that dropout intention is positively related to actual dropout. As the extent to which dropout intention actually leads to dropout behaviour in VET also depends on external factors (e.g., labour market situation, alternative options), the predictive power of dropout intention may be limited. This is suggested by the weak correlation between dropout intention and actual dropout and the profile of trainees with increasing dropout intention who nevertheless persisted until year 2 of VET.
Effects of different tooth grinding procedures on the occurrence of tooth injuries, skin lesions, performance and behaviour of suckling piglets
Authors: kleine Kruthaup Franziska Anna , Fels Michaela , Timphaus Carolin Bernarda , Freise Fritjof , Herbrandt Swetlana , große Beilage Elisabeth
Published: June 2024

Background

Immediately after birth, newborn piglets fight to establish a teat order. During this process, lesions appear on the piglets’ faces and on the sows’ teats, which is why tooth resection is carried out on many farms in Germany even though it is known that this procedure is frequently resulting in pulp openings. The opening of a pulp cave is suspected to cause painful tooth alterations and may be an entrance for infectious agents. The purpose of this study was to analyse the effect of tooth resection on skin lesions, development of bodyweight and behaviour in suckling piglets. Four days prepartum, 110 sows in farrow-to-finish production were assigned to one of three treatments. Litters had their teeth left intact (control group, CG), ground with a tea-cup roller head (Tea-cup head grinder group, TCG, Wilofa Diamant, D-56,133 Fachbach, Germany) or ground with a diamond rolling head (rolling head grinder group, RG, IBS/E Company Proxxon GmbH, 54,343 Föhren, Germany). The number of pulp openings in the RG and TCG was examined using a random sample. Piglet body weight and skin lesion scores were recorded within the first 24 h after birth and during each week of the suckling period. Each sow’s udder was examined before farrowing, in the second week of lactation and at weaning. The behaviour of the litters from nine sows was video-recorded throughout the suckling period. The aim of this study was to investigate the effects of tooth grinding by a tea-cup head (compared to grinding by a diamond roller head and no grinding [control group]) on the behaviour and average daily gain of piglets as well as on skin lesions on sow udder.

Results

The number of dental injuries was significantly greater in the RG than in the TCG (p < 0.01). Head lesions on piglets were significantly more common in the CG than in the RG (p = 0. 02). Compared to CG piglets, TCG piglets had a significantly greater weight at the end of the suckling period (p = 0.02). No significant difference between treatments was found in the sows’ udder (parenchyma, skin, or teat) or in the behaviour of the litters.

Conclusion

As tooth grinding is frequently inducing pulp openings, the necessity of the procedure should be carefully and critically scrutinised. In case tooth resection seems inevitable until the underlying management problems have been solved, the Tea-cup grinding head should be used due to significantly fewer pulp openings.
Determining the vitamin D supplementation duration to reach an adequate or optimal vitamin D status and its effect on blood lipid profiles: a longitudinal study
Authors: Saeidlou Sakineh Nouri , Vahabzadeh Davoud , Karimi Fozieh , Babaei Fariba
Published: June 2024

Background

Recently, Serum vitamin D (Vit. D) levels evaluation and the use of Vit. D supplements have increased substantially. There is no specific guideline for the duration of Vit. D supplementation, so yet Vit. D supplementation duration has remained a critical and controversial issue. This study aimed to determine the vit. D supplementation duration to reach an adequate or optimal Vit. D status and its effect on lipid profile.

Methods

In this longitudinal study, 345 women with different status of Vit. D levels were enrolled and followed up for one year. Eligible participants received 50,000 IU Vit. D3 (cholecalciferol) once a month for 12 consecutive months. The serum Vit. D levels and lipid profiles were measured at baseline, 3rd, 6th, and 12th months after the intervention. Participants were categorized based on Vit. D level at baseline into deficiency (< 20 ng/mL), inadequate (20–30 ng/mL), and adequate (> 30 ng/mL) groups, and the data were compared at different times between the three groups.

Results

Three deficiency (n = 73), inadequate (n = 138) and adequate (n = 134) groups of participants were followed. In all participants the average amount of Vit. D level changes were 8 ng/mL after one year of supplementation. The mean changes of serum Vit. D level in 6th and 12th months vs. 3th month was as below: In deficiency group: 4.08 ± 0.85 and 10.01 ± 1.02 ng/mL; (p < 0.001), in inadequate group: 3.07 ± 0.59 and 7.26 ± 0.78 ng/mL; (p = 0.001) and in adequate group: 2.02 ± 0.88 and 6.44 ± 1.005 ng/ml; (p = 0.001). Lipid profiles were improved in three groups. So, the mean changes of lipid profiles at the end of the study comparing with the baseline were: -5.86 ± 2.09, -7.22 ± 1.43 and − 6.17 ± 1.72 (mg/dl) for LDL (p < 0.05); -12.24 ± 3.08, -13.64 ± 3.21 and − 17.81 ± 2.94 (mg/dl) for cholesterol (p < 0.05) in deficiency, inadequate and adequate groups, respectively. For triglyceride, the mean changes were − 13.24 ± 5.78 and − 15.85 ± 7.49 (mg/dl) in deficiency and adequate groups, respectively (p < 0.05). Although the triglyceride decreased in the inadequate group at the end of the study but this difference was not significant (p = 0.67).

Conclusion

Taking of 50,000 IU Vit. D 3 monthly for 12 months resulted in reaching its level to adequate level in both deficiency and insufficient groups; however, in the adequate group its level did not reach above than 50 ng/mL. Therefore, 50,000 IU Vit. D3 supplementation monthly for one year can have beneficial effects on lipid profiles and there is no risk of toxicity in healthy women.
Global research trends on the relationship between IBD and CRC: a bibliometric analysis from 2000 to 2023
Authors: Zhang Hao , Xin Huiru , Zhao Mengqi , Bi Chenyang , Xiao Yafei , Li Yifan , Qin Changjiang
Published: June 2024

Objective

This study aimed to conduct a bibliometric analysis of research articles on the relationship between inflammatory bowel disease (IBD) and colorectal cancer (CRC) using CiteSpace to summarize the current research status, hotspots, and trends in this field and present the results visually.

Method

Research articles on the relationship between IBD and CRC published from 2000 to 2023 and in English were selected from the Web of Science Core Collection (Woscc) database. The articles were downloaded as “full record and references”. CiteSpace was used to conduct cooperative, cluster, co-citation, and burst analyses.

Results

The literature search revealed 4244 articles; of which, 5 duplicates were removed, resulting in the inclusion of 4239 articles in this study. The United States of America had the highest number of publications, with Mayo Clinic and Harvard University being the most active institutions, and Bas Oldenburg being the most active author. Collaboration among core authors was inadequate. JA Eaden was the most cited author, and CRC was the most common keyword. Burst analysis indicated that Sun Yat-sen University might be one of the institutions with a large contribution to this research field in the future. Cluster analysis showed that earlier research focused more on microsatellite instability, whereas “gut microbiota” and “oxidative stress” are considered current research hotspots and trends.

Conclusion

At present, the primary focus areas of research are “gut microbiota” and “oxidative stress”. With the improvement of healthcare policies and standards, regular endoscopic monitoring of patients with IBD has become an indispensable diagnostic and therapeutic practice. More drugs will be developed to reduce the risk of progression from IBD to CRC. The findings of this study provide valuable insights into the relationship between IBD and CRC for researchers in the same field.
The effect of forward head posture on dynamic lung volumes in young adults: a systematic review
Authors: Deniz Yasemin , Ertekın Damla , Cokar Dılek
Published: June 2024

Purpose

The study aimed to investigate whether there is a difference in pulmonary function between individuals with forward head posture and those with neutral head posture.

Methods

A systematic search was conducted using the ResearchGate, PubMed, and Scholar databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. The eligibility criteria for the studies were that they investigated the relationship between Forward Head Posture (FHP) and Forced Vital Capacity (FVC) and/or Forced Expiratory Volume in one second (FEV1).

Results

A total of four comparison studies and two correlation studies met the inclusion criteria for this study. Across these four studies, encompassing a total of 115 participants, the observed reduction range for FVC was between -0.25 L and -0.81 L, while the reduction values for FEV1 ranged from -0.16 to -0.93 L. According to the results of the correlation studies, a positive correlation was observed between craniovertebral angle (CVA) and dynamic pulmonary volumes.

Conclusion

The existing evidence indicates that FHP can potentially cause abnormalities in pulmonary function. In this context, it is suggested that individuals with FHP should be monitored for changes in pulmonary function.
Nanoplastics as emerging cardiovascular hazards: a narrative review of current evidence
Authors: Olatunji Gbolahan , Kokori Emmanuel , Ogieuhi Ikponmwosa Jude , Chidinma Udojike I. , Omoworare Oluwatobi , Olatunji Doyin , Oluwatomiwa Ajekiigbe Victor , Oyewale Oyebiyi Babajide , Dorcas Omotade Omolade , Zuhair Varisha , Shu Bonu Innocent , Stanley Anthony Chidera , Aderinto Nicholas
Published: June 2024

Background

Nanoplastics (NPs) have emerged as significant environmental pollutants, raising concerns due to their ubiquitous presence and potential adverse effects on human health. The migration and fate of NPs in the environment are subjects of intense study, with human exposure pathways expanding through ingestion, inhalation, and dermal contact.

Body

Studies indicate that NPs can infiltrate the cardiovascular system, potentially causing adverse effects. Mechanistic insights from in vitro and animal studies suggest that oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction contribute to nanoplastic-induced cardiovascular toxicity. Animal models demonstrate altered heart rate, myocardial fibrosis, and dysfunction following NPs exposure, with specific adverse effects observed in cardiac valves and mitochondrial structure. Clinical studies provide further evidence of NPs accumulation in cardiovascular tissues, with implications for cardiovascular pathologies such as atherosclerosis and myocardial infarction. Notably, patients with higher levels of nanoplastics in carotid plaque exhibit an increased risk of adverse cardiovascular outcomes.

Conclusion

However, challenges in studying nanoplastics persist, including methodological limitations, ethical considerations, and the need for standardized detection methods. Addressing these challenges requires interdisciplinary collaboration, innovative research approaches, and robust regulatory measures to mitigate NPs pollution and protect cardiovascular health.
Variant of uncertain significance (VUS) genetic testing results and mastectomy choice in lumpectomy-eligible patients.
Authors: Nunez Jr. Osvaldo , Govind Vasanth , Wolde Tizeta M. , Heath Rainya , Donenberg Talia R. , Silva-Smith Rachel , Jeanjean Marie B. , Moore Jessica Firdman , Crystal Jessica S. , Kesmodel Susan , Rojas Kristin E.
Published: June 2024

10601

Background: Germline variants of uncertain significance (VUS) should not change surgical decision-making in breast cancer (BC) patients based on current guidelines. We sought to evaluate whether VUS may drive surgical choice in lumpectomy-eligible BC patients. Methods: A single-institution retrospective analysis included breast surgery patients (2020-2021). ‘Lumpectomy-eligible’ was defined as unilateral cT0-2 BC, excluding those with pathogenic mutations. Descriptive analyses compared those undergoing lumpectomy or bilateral mastectomy (BLMast), accounting for testing results. Multivariate analysis to predict the likelihood mastectomy receipt was limited to tested patients without pathogenic mutations using binomial logistic regression. Results: Of 741 patients, 549 (74%) were lumpectomy-eligible and 326 received genetic testing (235 negative, 91 VUS). Median age was 55.0 (26 - 84). Of those tested, 206 underwent lumpectomy, and 58 underwent BLMast. Insurance type, race, ethnicity, language, tobacco use, marital status, and axillary management did not differ between groups. Compared to lumpectomy patients, a higher proportion with a VUS (40% vs 25%, p=0.026), AJCC Stage 2 disease (41% vs 31%, p=0.023), or with ≥ 2 MRI-recommended biopsies (31.3% vs 13.8%, p=0.021) underwent BLMast. Multivariate analysis found that VUS patients were twice as likely to undergo BLMast compared to those with negative testing (OR 2.213 95% CI 1.113-4.400, p=0.023) (Table). Young patients and those with more advanced disease were also more likely to undergo BLMast. Conclusions: VUS genetic testing results may significantly influence lumpectomy-eligible patient decision-making. In an era of expanded genetic testing access, the present analysis informs the implementation of robust but accessible genetic counseling education initiatives in breast surgical oncology to decrease unnecessary mastectomies in patients with VUS. [Table: see text]
Reasons for unmet care needs in older adults with cancer: Analyses from the 2015–2019 National Health and Aging Trends Study.
Authors: Wang Ying , Williams AnnaLynn , Jensen-Battaglia Marielle , Loh Kah Poh , Norton Sally , Seplaki Christopher
Published: June 2024

11112

Background: Despite extensive research on unmet care needs in older adults (ages ≥65) with cancer, few studies explore the reasons for unmet care needs, knowledge of which can inform future interventions. We aimed to identity reasons for unmet care needs in older adults with cancer and associated factors. Methods: Our analyses included community-dwelling older adults with cancer from the 2015–2019 National Health and Aging Trends Study (NHATS). NHATS captures unmet care needs in 12 activities from three domains: activities of daily living (ADL), instrumental ADL (IADL), and mobility. We separately evaluated two categories of reasons for unmet care needs: “difficulty performing activities independently” (for participants without a caregiver), and “caregivers’ inability to help” (for those receiving caregiver assistance). Personal characteristics included demographic (gender, age, marital status, race, ethnicity, educational level), clinical (cancer type, years since cancer diagnosis), and health variables (physical function, nutritional status, cognition, psychological status). We built logistic models to assess characteristics associated with unmet care needs, adjusting for NHATS year and cancer type. In exploratory analyses, we further evaluated associations of years since cancer diagnosis with unmet care needs. All models were built separately for participants with and without a caregiver. Results: Our analysis included 1829 participants. In 2015, participants had a mean age of 81 years; more than half were female (55%), White (79%), non-Hispanic (96%), had impaired physical function (92%), and received caregiver assistance (51%). From 2015 to 2019, 29% to 32% participants without a caregiver reported any unmet care needs due to difficulty with performing the activity independently, with toileting (45-53%) and managing medications (27-31%) being the most prevalent. Between 18% and 20% participants with a caregiver reported any unmet care needs due to caregivers’ inability to help, with toileting (26-44%) and going around inside home (20-29%) being the most prevalent. Hispanic ethnicity, being separated/divorced, living alone or with non-spouses, and worse health status were independently associated with unmet care needs due to either reason. Compared to pre-diagnosis, being 1-2, [odds ratio (OR) 1.7], 3-4 (OR 1.8) and 5+ (OR 2.2) years from cancer diagnosis was significantly associated with higher odds of unmet care needs among those without a caregiver, but not those with a caregiver. Conclusions: Unmet care needs due to difficulty performing activities independently are common among older adults with cancer. Caregivers generally meet care recipients’ needs in IADLs, but may face challenges in toileting and mobility needs. Tailored interventions addressing specific reasons for unmet needs are needed, particularly for those at greater risk.
Sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC (CodeBreaK 202).
Authors: Barlesi Fabrice , Felip Enriqueta , Popat Sanjay , Solomon Benjamin J. , Wolf Juergen , Li Bob T. , Wu Yi-Long , Kerr Keith , Akamatsu Hiroaki , Camidge David Ross , Gupta Ravi G. , Meloni Alison , Dai Tian , Borghaei Hossein
Published: June 2024

TPS8653

Background: The 5-year progression free survival (PFS) rate of patients with metastatic, PD-L1 negative, non-small cell lung cancer (NSCLC) remains poor, ranging from approximately 2% to 10% with standard immunotherapy-based treatment regimens. Based on promising anti-tumor activity in the phase 1 CodeBreaK 101 study, with partial responses observed in 62% (8/13) of PD-L1 negative patients in the first-line setting, we hypothesize that sotorasib plus platinum doublet chemotherapy will demonstrate durable clinical response and improved outcomes in this population. CodeBreaK 202 (NCT05920356) is a global phase 3 randomized study evaluating the efficacy of sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC. Methods: Patients will be randomized 1:1 to either sotorasib 960 mg once daily or pembrolizumab administered in combination with carboplatin and pemetrexed for 4 cycles, followed by maintenance treatment with sotorasib or pembrolizumab administered in combination with pemetrexed. Key eligibility criteria include treatment-naïve metastatic or locally advanced stage IIIB/C disease that is not amenable to definitive chemoradiation, PD-L1 <1% expression, presence of KRAS G12C mutation, non-squamous tumor histology, and absence of actionable genomic alterations such as EGFR mutations and ALK rearrangements. Patients with both treated and untreated brain metastases are eligible if clinically asymptomatic. The primary endpoint is PFS per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints include overall survival and objective response rate. Exploratory endpoints include intra-cranial PFS per RANO-BM criteria. Approximately 750 patients are planned to be enrolled and recruitment began on November 18, 2023. Contact Amgen Medical Information for more information: medinfo@amgen.com . Clinical trial information: NCT05920356 .
SWOG S2302, PRAGMATICA-LUNG: A prospective randomized study of ramucirumab plus pembrolizumab (PR) versus standard of care (SOC) for participants previously treated with immunotherapy for stage IV or recurrent non-small cell lung cancer.
Authors: Reckamp Karen L. , Redman Mary Weber , Dragnev Konstantin H. , Iams Wade Thomas , Henick Brian S. , Miao Jieling , LeBlanc Michael Leo , Carrizosa Daniel R. , Herbst Roy S. , Blanke Charles D. , Gray Jhanelle E.
Published: June 2024

TPS8657

Background: Most patients (pts) with advanced non-small cell lung cancer (NSCLC) will receive treatment with immunotherapy and develop tumor resistance. Several trials investigating combination therapy have not shown benefit over chemotherapy. Additional therapeutic options are needed. Complex clinical trials increase barriers to enrollment. Pragmatic trial designs may overcome challenges with accrual and representativeness in the appropriate setting. S1800A was a randomized phase II trial within Lung-MAP that showed a statistically significant improvement in overall survival (OS) with PR versus SOC for pts with advanced NSCLC who had tumor progression on prior chemotherapy and immunotherapy (JCO 2023). As a follow-on, we designed a pragmatic, randomized, registration intent trial to validate OS results and enhance representative accrual reflecting real-world practice. Methods: S2302 is a registration-intent randomized trial for pts who previously received PD-(L)1 inhibitor therapy for at least 84 days and platinum-based therapy, stratified by immediate prior line of therapy including PD-(L)1 inhibition (yes/no) and PS (0/1 v. 2). Pts are randomized to PR or investigator’s choice SOC (recommended to be based on NCCN guidelines). The primary objective is to compare OS between the arms. The only secondary objective is to summarize serious and unexpected high-grade (Grade 3-4) treatment-related adverse events and all Grade 5 adverse events. The accrual goal is 700 pts based on a design with 85% power to detect a hazard ratio of 0.77, using a 1-sided 2.5% level log-rank test. Estimated accrual duration is 24 months. As of January 2024, 286 pts were randomized, and enrollment is ongoing. S2302 Pragmatica-Lung presents a novel and potentially practice-changing paradigm to conduct a study with a combination of FDA approved drugs with well-known safety profiles and limited toxicity overlap. There are no onerous radiology or specimen requirements, and SOC treatment is provided as per FDA-approved package inserts and institutional policies. The goal is to empower practicing clinicians to enroll pts they see every day by reducing the study barriers and burden of clinical trial participation. The resulting pts enrolled will be more representative than other registration-intent trials. This approach allows the trial to reach more patients and holds the potential to better inform the field across a more representative set of pts with broader impact. Clinical trial information: NCT05633602 .
Early detection of side effects in patients with metastatic melanoma receiving immune checkpoint inhibitors by investigation of CD8+ immune infiltrate with [89Zr] crefmirlimab berdoxam PET.
Authors: Amaral Teresa , Kneilling Manfred , Forschner Andrea , Leiter Ulrike M. , Schwenck Johannes , Kienzle Gabriele , Gückel Brigitte , Sonanini Dominik , Reischl Gerald , Wilson Ian , Pichler Bernd J. , la Fougère Christian , Flatz Lukas
Published: June 2024

TPS9601

Background: Immune checkpoint inhibitors (ICI) improved outcomes of patients (pts) with advanced melanoma. Nevertheless, a significant number have immune-mediated adverse event (iAE). Due to the impact on quality of life and other therapeutic options, early identification of pts with increased risk of iAE is needed. CD8 immuno-PET with [89Zr] crefmirlimab berdoxam (Zr-Df-IAB22M2C) has shown to be a specific tool to visualize CD8+ T cells mediating both anti-tumor immune response and inflammatory adverse effects rendering this an innovative evaluation method in the field of immuno-oncology. Methods: Trial design: Open-label, single-arm, single center study to determine if CD8+ T-cell infiltration evaluated by immune-PET provides diagnostic gain in early detection of severe iAE. Pts with irresectable stage III/IV melanoma receiving nivolumab + ipilimumab (NIVO+IPI) may be included. Primary objective: Feasibility of early detection of iAE by semiquantitative assessment of CD8+ T-cell infiltration using immune-PET. Secondary objectives: 1) Prediction of iAE using immuno-PET for semiquantitative assessment of CD8+ T-cell infiltration; 2) Correlation between CD8+ T-cell infiltration in metastasis and lymphoid organs and response. Baseline Imaging. To assess glucose metabolism in metastases, primary and secondary lymphatic organs [18F] FDG PET/CT (60 min p.i. 1.5 MBq/KG/BW) is performed on a high sensitivity PET/CT with large field of view (Siemens Vision Quadra). Immediately after PET/CT data acquisition, pts are injected with [89Zr] crefmirlimab berdoxam (37 MBq ±20%) and undergo immuno-PET/CT 24 hours p.i. to detect CD8+ T-cells in metastases and lymphoid organs. NIVO+IPI is administered immediately after completion of [89Zr] crefmirlimab berdoxam-PET/CT. Blood samples are taken for immune cell composition analysis, activation state, proteomic investigation (cytokine/chemokines) as well as metabolic profile. Therapy Phase Imaging: Three weeks after first ICI cycle and before second cycle, follow-up PET/CT are performed with both radiotracers [18F]FDG and [89Zr] crefmirlimab berdoxam following the identical protocol described above. Clinical trial information: EudraCT number - 2021-004328-13 .
A pilot trial of autologous tumor infiltrating lymphocytes (lifileucel, LN-144) for patients with asymptomatic melanoma brain metastases.
Authors: Betof Warner Allison , Smithy James William , Postow Michael A. , Panageas Katherine , Schoenfeld Adam Jacob , Wolchok Jedd D. , Shoushtari Alexander Noor
Published: June 2024

TPS9603

Background: Melanoma brain metastases (MBM) are a leading cause of morbidity and mortality for patients with advanced melanoma. Modern systemic therapies are insufficient at controlling MBM, resulting in median overall survival (OS) of <1 year. Adoptive T cell therapy, using tumor infiltrating lymphocytes (TIL), has demonstrated efficacy in treating advanced melanoma. Lifileucel (LN-144), an autologous TIL product, was recently shown to be safe and effective for patients with PD-1 refractory melanoma. However, no trials have yet explored lifileucel in patients with active MBM. Methods: This single-center pilot trial (NCT05640193) aims to enroll 10 pts with asymptomatic MBM from non-uveal melanoma to receive lifileucel. Patients must have ≥1 intracranial lesion measuring 5-30mm visible on MRI to be used as a target lesion for modified (m)RECIST measurement, progression on prior anti-PD-1 therapy (with or without anti-CTLA-4), progression on targeted therapy (if BRAF V600E/K-mutated), ECOG PS ≤1, ≥1 resectable lesion(s) (≥1.5 cm), recovered from prior surgery/anticancer treatment-related AEs (grade ≤1). Patients are ineligible if they have symptomatic MBM and/or require corticosteroids of ≥10 mg/day of prednisone or equivalent. Lifileucel is generated from resected tumor in a centralized GMP process. The regimen includes nonmyeloablative lymphodepletion with cyclophosphamide 750 mg/m2 on days 1-3 and fludarabine 30 mg/kg on days 1-4 (reduced dose compared with standard lifileucel protocol), lifileucel infusion, and up to 6 doses of high-dose IL-2. The primary endpoint is feasibility, defined as ≥7/10 patients who undergo tumor resection successfully receiving lifileucel infusion. Secondary endpoints are safety, feasibility of manufacturing lifileucel in patients with MBM, and brain metastasis response rate (BMRR) per mRECIST 1.1. Exploratory endpoints include overall objective response rate by mRECIST 1.1, best extracranial response rate, intracranial progression-free survival (PFS), overall PFS, OS. Extensive correlative analyses of peripheral blood mononuclear cells, plasma, tumors, and cerebrospinal fluid are planned to better understand MBM growth, treatment resistance, and response of the central nervous system to lifileucel. Clinical trial information: NCT05640193 .
Randomized phase II trial of pembrolizumab/lenvatinib (P+L) +/- responder fecal microbiota transplant (R-FMT) in PD-1 relapsed/refractory (R/R) cutaneous melanoma (MEL).
Authors: Davar Diwakar , Wang Hong , Hurd Drew , Nguyen Madison , Schwartz Marc B. , Dubner Howard M. , Najjar Yana G. , Luke Jason J. , Kirkwood John M. , Trinchieri Giorgio , Zarour Hassane M.
Published: June 2024

TPS9607

Background: A significant portion of patients (pts) with advanced MEL develop resistance to immune checkpoint inhibitors (ICI). The gut microbiome is a major tumor-extrinsic regulator of ICI response. In mice, gut microbiota modulate therapeutic activity of ICI, and administration of certain gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy in melanoma-bearing mice. In the LEAP-004 trial, P+L produced 21% ORR in PD-1 R/R MEL with Gr3+ TRAE 45.6%. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key species including Actinobacteria and Firmicutes are associated with favorable response. We and others have previously demonstrated that microbiome modulation using R-FMT reversed PD-1 non-response in PD-1 R/R MEL. In PD-1 naïve MEL, healthy donor FMT (hdFMT) augments benefit of PD-1 monotherapy. We hypothesized that intestinal dysbiosis mediates PD-1 resistance in PD-1 R/R MEL, microbiome modulation may reverse TKI toxicity, and that R-FMT may resensitize MEL to PD-1 blockade. Methods: This is an investigator-initiated, randomized, phase II trial of P+L vs. P+L+R-FMT in PD-1 R/R MEL. Pts must have measurable disease per RECIST v1.1, no active CNS metastases (or if present, previously treated and stable on repeat imaging), and no contraindications to FMT administration. R-FMT is derived from non-obese, advanced MEL with durable response (mPFS ≥24 months) following prior PD-1 ICI, with no recent (≤1 month) antibiotic exposure. Donors are screened broadly for infectious agents including SARS-CoV-2 using bookend screening. R-FMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts are randomized 1:1 to either P+L [P 200mg every 3 weeks (Q3W) along with L 20mg orally once daily] or P+L+R-FMT. R-FMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo biopsies at baseline and W8, with optional biopsy at progression. Primary endpoint: ORR assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 20% will be tested versus a one-sided alternative hypothesis of ≥50%. This design has a type I error rate 0.10 and power 0.8 when the true response rate is 0.25. Enrollment has commenced. Clinical trial information: NCT06030037 .
Reduced dose fludarabine/cyclophosphamide lymphodepletion for tumor-infiltrating lymphocytes therapy (LN-144, lifileucel) in metastatic melanoma.
Authors: Mushtaq Muhammad Umair , Abdelhakim Haitham , Selby Luke , Abhyankar Sunil H. , McGuirk Joseph , Doolittle Gary C.
Published: June 2024

TPS9608

Background: Metastatic melanoma (MM) patients who have progressed following immune checkpoint inhibitors (ICI; anti–PD-1/CTLA-4 therapy) and targeted agents (BRAF/MEK inhibitors) have limited treatment options and dismal prognosis. An autologous tumor-infiltrating lymphocytes (TIL) therapy (LN-144, lifileucel) has demonstrated efficacy and durable responses in heavily pretreated advanced melanoma. In a phase II study of TIL therapy (lifileucel) with traditional lymphodepletion (LD), using fludarabine 25 mg/m2 for 5 days and cyclophosphamide (Cy) 60 mg/kg for 2 days, in 153 MM patients previously treated with ICI and BRAF/MEK inhibitors, an overall response rate (ORR) of 31% was noted, and the median duration of response (DOR) was not reached after 27.6 month follow up. We hypothesize that a reduced dose of Flu/Cy LD for TIL therapy will have similar TIL expansion and persistence post-infusion, resulting in similar efficacy with a reduced toxicity profile. Methods: Study NCT06151847 is a single-center, open-label phase II pilot trial evaluating the efficacy, in vivo persistence, and safety of TIL therapy after reduced dose Flu/Cy LD. Key inclusion criteria include unresectable or metastatic melanoma (stage IIIC-IV) with disease progression after one or more lines of therapy. Four of the 12 planned patients have been enrolled as of February 2, 2024. Central TIL manufacturing from at least a 1.5 cm tumor specimen involves ex vivo expansion through cell culture in the presence of the interleukin (IL)-2 and an anti-CD3 monoclonal antibody (1-150 x109 viable cells). Patients will receive an outpatient reduced-dose Flu/Cy LD regimen of Flu (30 mg/m2 on days -4, -3, -2, -1) and Cy (750 mg/m2 on days -4, -3, -2). Infusion of TIL will be performed on day 0 followed by high-dose IL-2 (600,000 IU/kg up to 6 doses). The primary objective will be to ascertain TIL persistence using T-cell receptor (TCR) sequencing at day 42 which will be compared to historical data already generated utilizing traditional Flu/Cy LD. The secondary objectives will be to evaluate the efficacy parameters including ORR, DOR, progression-free survival (PFS), and overall survival (OS), and the safety profile of TIL in combination with a reduced dose Flu/Cy LD regimen. Exploratory objectives will involvecorrelative analyses to characterize the immunome and microenvironment. If TIL persistence is roughly equivocal between the reduced and high-dose Flu/Cy LD regimens, the design of a larger-scale trial using reduced-dose Flu/Cy LD for TIL therapy may be considered. Study follow-up will continue for one year. Clinical trial information: NCT06151847 .