bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding the processes underpinning IMPlementing IMProved Asthma self-management as RouTine (IMP2ART) in primary care: study protocol for a process evaluation within a cluster randomised controlled implementation trial
Authors: Sheringham J. , Steed L. , McClatchey K. , Delaney B. , Barat A. , Hammersley V. , Marsh V. , Fulop N. J. , Taylor S. J. C. , Pinnock H.
Published: June 2024

Background

Providing supported self-management for people with asthma can reduce the burden on patients, health services and wider society. Implementation, however, remains poor in routine clinical practice. IMPlementing IMProved Asthma self-management as RouTine (IMP2ART) is a UK-wide cluster randomised implementation trial that aims to test the impact of a whole-systems implementation strategy, embedding supported asthma self-management in primary care compared with usual care. To maximise opportunities for sustainable implementation beyond the trial, it is necessary to understand how and why the IMP2ART trial achieved its clinical and implementation outcomes.

Methods

A mixed-methods process evaluation nested within the IMP2ART trial will be undertaken to understand how supported self-management was implemented (or not) by primary care practices, to aid interpretation of trial findings and to inform scaling up and sustainability. Data and analysis strategies have been informed by mid-range and programme-level theory. Quantitative data will be collected across all practices to describe practice context, IMP2ART delivery (including fidelity and adaption) and practice response. Case studies undertaken in three to six sites, supplemented by additional interviews with practice staff and stakeholders, will be undertaken to gain an in-depth understanding of the interaction of practice context, delivery, and response. Synthesis, informed by theory, will combine analyses of both qualitative and quantitative data. Finally, implications for the scale up of asthma self-management implementation strategies to other practices in the UK will be explored through workshops with stakeholders.

Discussion

This mixed-methods, theoretically informed, process evaluation seeks to provide insights into the delivery and response to a whole-systems approach to the implementation of supported self-management in asthma care in primary care. It is underway at a time of significant change in primary care in the UK. The methods have, therefore, been developed to be adaptable to this changing context and to capture the impact of these changes on the delivery and response to research and implementation processes.
Effects of robot-assisted upper limb training combined with functional electrical stimulation in stroke patients: study protocol for a randomized controlled trial
Authors: Yang Xu , Fengyi Wang , Yi Chen , Lin Qiu , Yang Lin , Xize Li , Shaxin Liu , Yonghong Yang
Published: June 2024

Introduction

About 17–80% stroke survivors experience the deficit of upper limb function, which strongly influences their independence and quality of life. Robot-assisted training and functional electrical stimulation are commonly used interventions in the rehabilitation of hemiplegia upper extremities, while the effect of their combination remains unclear. The aim of this trial is to explore the effect of robot-assisted upper limb training combined with functional electrical stimulation, in terms of neuromuscular rehabilitation, compared with robot-assisted upper limb training alone.

Methods

Individuals (n = 60) with the first onset of stroke (more than 1 week and less than 1 year after stroke onset) will be considered in the recruitment of this single-blinded, three-arm randomized controlled trial. Participants will be allocated into three groups (robot-assisted training combined with functional electrical stimulation group, robot-assisted training group, and conventional rehabilitation therapies group) with a ratio of 1:1:1. All interventions will be executed for 45 min per session, one session per day, 5 sessions per week for 6 weeks. The neuromuscular function of the upper limb (Fugl-Meyer Assessment of upper extremity), ability of daily life (modified Barthel Index), pain (visual analogue scale), and quality of life (EQ-5D-5L) will be assessed at the baseline, at the end of this trial and after 3 months follow-up. Two-way repeated measures analysis of variance will be used to compare the outcomes if the data are normally distributed. Simple effects tests will be used for the further exploration of interaction effects by time and group. Scheirer-Ray-Hare test will be used if the data are not satisfied with normal distribution.

Discussion

We expect this three-arm randomized controlled trial to explore the effectiveness of robot-assisted training combined with functional electrical stimulation in improving post-stroke upper limb function compared with robot-assisted training alone.

Trial registration

Effect of upper limb robot on improving upper limb function after stroke, identifier: ChiCTR2300073279. Registered on 5 July 2023.
Blood flow restriction Exercise in the perioperative setting to Prevent loss of muscle mass in patients with pancreatic, biliary tract, and liver cancer: study protocol for the PREV-Ex randomized controlled trial
Authors: Anandavadivelan Poorna , Cardinale Daniele , Blomhoff Rune , Sunde Berit , Lassen Kristoffer , Kleive Dyre , Sturesson Christian , Gilg Stefan , Raastad Truls , Mijwel Sara
Published: June 2024

Background

Patients diagnosed with pancreatic, biliary tract, and liver cancer often suffer from a progressive loss of muscle mass. Given the considerable functional impairments in these patients, high musculoskeletal weight loads may not be well tolerated by all individuals. The use of blood-flow restricted resistance training (BFR-T) which only requires low training loads may allow for a faster recovery of muscle due to avoidance of high levels of mechanical muscle stress associated with high-load resistance exercise. This study aims to investigate whether BFR-T can prevent or slow down the loss of skeletal muscle mass and enhance the functional capacity and mental health of patients with pancreatic, biliary tract, and liver cancer.

Methods

The PREV-Ex exercise trial is a multicenter two-armed randomized controlled trial. Patients will be randomized to an exercise program consisting of home-based low-load BFR-T during a combined pre- and postoperative period for a total of 6–10 weeks (prehabilitation and rehabilitation), or to a control group. Protein supplementation will be given to both groups to ensure adequate protein intake. The primary outcomes, skeletal muscle thickness and muscle cross-sectional area, will be assessed by ultrasound. Secondary outcomes include the following: (i) muscle catabolism-related and inflammatory bio-markers (molecular characteristics will be assessed from a vastus lateralis biopsy and blood samples will be obtained from a sub-sample of patients); (ii) patient-reported outcome measures (self-reported fatigue, health-related quality of life, and nutritional status will be assessed through validated questionnaires); (iii) physical fitness/performance/activity (validated tests will be used to evaluate physical function, cardiorespiratory fitness and maximal isometric muscle strength. Physical activity and sedentary behavior (assessed using an activity monitor); (iv) clinical outcomes: hospitalization rates and blood status will be recorded from the patients’ medical records; (v) explorative outcomes of patients’ experience of the exercise program which will be evaluated using focus group/individual interviews.

Discussion

It is worthwhile to investigate new strategies that have the potential to counteract the deterioration of skeletal muscle mass, muscle function, strength, and physical function, all of which have debilitating consequences for patients with pancreatic, biliary tract, and liver cancer. The expected findings could improve prognosis, help patients stay independent for longer, and possibly reduce treatment-related costs.

Trial registration

ClinicalTrials.gov NCT05044065. Registered on September 14, 2021.
A DRL-based resource allocation for IRS-enhanced semantic spectrum sharing networks
Authors: Zhang Yingzheng , Li Jufang , Mu Guangchen , Chen Xiaoyu
Published: June 2024

Semantic communication and spectrum sharing are pivotal technologies in addressing the perennial challenge of scarce spectrum resources for the sixth-generation (6G) communication networks. Notably, scant attention has been devoted to investigating semantic resource allocation within spectrum sharing semantic communication networks, thereby constraining the full exploitation of spectrum efficiency. To mitigate interference issues between primary users and secondary users while augmenting legitimate signal strength, the introduction of Intelligent Reflective Surfaces (IRS) emerges as a salient solution. In this study, we delve into the intricacies of resource allocation for IRS-enhanced semantic spectrum sharing networks. Our focal point is the maximization of semantic spectral efficiency (S-SE) for the secondary semantic network while upholding the minimum quality of service standards for the primary semantic network. This entails the joint optimization of parameters such as semantic symbol allocation, subchannel allocation, reflective coefficients of IRS elements, and beamforming adjustment of secondary base station. Recognizing computational intricacies and interdependence of variables in the non-convex optimization problem formulated, we present a judicious approach: a hybrid intelligent resource allocation approach leveraging dueling double-deep Q networks coupled with the twin-delayed deep deterministic policy. Simulation results unequivocally affirm the efficacy of our proposed resource allocation approach, showcasing its superior performance relative to baseline schemes. Our approach markedly enhances the S-SE of the secondary network, thereby establishing its prowess in advancing the frontiers of semantic spectrum sharing (S-SE).
Long non-coding RNA Small Nucleolar RNA Host Gene 4 ameliorates cigarette smoke-induced proliferation, apoptosis, inflammation, and airway remodeling in alveolar epithelial cells through the modulation of the mitogen-activated protein kinase signaling pathway via the microRNA-409-3p/Four and a Half LIM Domains 1 axis
Authors: Liu Meng , Meng JiGuang , Chen XuXin , Wang Fan , Han ZhiHai
Published: June 2024

The long non-coding RNA (lncRNA) Small Nucleolar RNA Host Gene 4 (SNHG4) has been demonstrated to be significantly downregulated in various inflammatory conditions, yet its role in chronic obstructive pulmonary disease (COPD) remains elusive. This study aims to elucidate the biological function of SNHG4 in COPD and to unveil its potential molecular targets. Our findings reveal that both SNHG4 and Four and a Half LIM Domains 1 (FHL1) were markedly downregulated in COPD, whereas microRNA-409-3p (miR-409-3p) was upregulated. Importantly, SNHG4 exhibited a negative correlation with inflammatory markers in patients with COPD, but a positive correlation with forced expiratory volume in 1s percentage (FEV1%). SNHG4 distinguished COPD patients from non-smokers with high sensitivity, specificity, and accuracy. Overexpression of SNHG4 ameliorated cigarette smoke extract (CSE)-mediated inflammation, apoptosis, oxidative stress, and airway remodeling in 16HBE bronchial epithelial cells. These beneficial effects of SNHG4 overexpression were reversed by the overexpression of miR-409-3p or the silencing of FHL1. Mechanistically, SNHG4 competitively bound to miR-409-3p, mediating the expression of FHL1, and consequently improving inflammation, apoptosis, oxidative stress, and airway remodeling in 16HBE cells. Additionally, SNHG4 regulated the miR-409-3p/FHL1 axis to inhibit the activation of the mitogen-activated protein kinase (MAPK) pathway induced by CSE. In a murine model of COPD, knockdown of SNHG4 exacerbated CSE-induced pulmonary inflammation, apoptosis, and oxidative stress. In summary, our data affirm that SNHG4 mitigates pulmonary inflammation, apoptosis, and oxidative damage mediated by COPD through the regulation of the miR-409-3p/FHL1 axis.

Graphical Abstract
Sperm epigenetics and male infertility: unraveling the molecular puzzle
Authors: Hosseini Maryam , Khalafiyan Anis , Zare Mohammadreza , Karimzadeh Haniye , Bahrami Basireh , Hammami Behnaz , Kazemi Mohammad
Published: June 2024

Background

The prevalence of infertility among couples is estimated to range from 8 to 12%. A paradigm shift has occurred in understanding of infertility, challenging the notion that it predominantly affects women. It is now acknowledged that a significant proportion, if not the majority, of infertility cases can be attributed to male-related factors. Various elements contribute to male reproductive impairments, including aberrant sperm production caused by pituitary malfunction, testicular malignancies, aplastic germ cells, varicocele, and environmental factors.

Main body

The epigenetic profile of mammalian sperm is distinctive and specialized. Various epigenetic factors regulate genes across different levels in sperm, thereby affecting its function. Changes in sperm epigenetics, potentially influenced by factors such as environmental exposures, could contribute to the development of male infertility.

Conclusion

In conclusion, this review investigates the latest studies pertaining to the mechanisms of epigenetic changes that occur in sperm cells and their association with male reproductive issues.
Symptom domains and psychosocial functioning in borderline personality disorder
Authors: Culina Ines , Ranjbar Setareh , Maillard Pauline , Martin-Soelch Chantal , Berney Sylvie , Kolly Stéphane , André Jérémie , Conus Philippe , Kramer Ueli
Published: June 2024

Background

Borderline personality disorder (BPD) is often characterized by severe functional impairment, even after a decrease in symptoms. A comprehensive understanding of psychosocial functioning in BPD is necessary to tailor treatment offer, which should address relevant aspects of daily life. The aims of the present study are to (1) conduct a cross-sectional comparison of functioning of a group with BPD and a non-BPD clinical comparison group at service entry, and to (2) assess the relationship between intensity of BPD symptom domains and psychosocial functioning.

Methods

The sample consists of N = 65 participants with BPD and N = 57 participants from the clinical comparison group without BPD (non-BPD group). The Revised Borderline Follow-up Interview (BFI-R) was used to evaluate psychosocial functioning and the Revised Diagnostic Interview for Borderlines (DIB-R) to assess BPD symptoms. Linear, logistic, and multinomial regression models were run separately for each aspect of functioning as a function of BPD status or BPD symptom domains.

Results

Only 23% of participants in the BPD group fulfilled criteria for good overall psychosocial functioning, compared to 53% in the non-BPD group. Furthermore, participants in the BPD group were less likely to have completed a high number of years of education, to work consistently, to be financially independent, to be in a cohabiting relationship and have a good relationship with parents. In addition, various links were identified between BPD symptom domains and functional impairments.

Conclusions

Consistent with prior research, the main impairments in functioning in the BPD group are found in the educational and vocational domains. Though some domains show impairment, others, like friendships, may act as potential resources. Further investigation on the relationships with symptom domains is required.
Epigenetic targets of Janus kinase inhibitors are linked to genetic risks of rheumatoid arthritis
Authors: Tsuchiya Haruka , Ota Mineto , Takahashi Haruka , Hatano Hiroaki , Ogawa Megumi , Nakajima Sotaro , Yoshihara Risa , Okamura Tomohisa , Sumitomo Shuji , Fujio Keishi
Published: June 2024

Background

Current strategies that target cytokines (e.g., tumor necrosis factor (TNF)-α), or signaling molecules (e.g., Janus kinase (JAK)) have advanced the management for allergies and autoimmune diseases. Nevertheless, the molecular mechanism that underpins its clinical efficacy have largely remained elusive, especially in the local tissue environment. Here, we aimed to identify the genetic, epigenetic, and immunological targets of JAK inhibitors (JAKis), focusing on their effects on synovial fibroblasts (SFs), the major local effectors associated with destructive joint inflammation in rheumatoid arthritis (RA).

Methods

SFs were activated by cytokines related to inflammation in RA, and were treated with three types of JAKis or a TNF-α inhibitor (TNFi). Dynamic changes in transcriptome and chromatin accessibility were profiled across samples to identify drug targets. Furthermore, the putative targets were validated using luciferase assays and clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing.

Results

We found that both JAKis and the TNFi targeted the inflammatory module including IL6. Conversely, specific gene signatures that were preferentially inhibited by either of the drug classes were identified. Strikingly, RA risk enhancers for CD40 and TRAF1 were distinctively regulated by JAKis and the TNFi. We performed luciferase assays and CRISPR-based genome editing, and successfully fine-mapped the single causal variants in these loci, rs6074022-CD40 and rs7021049-TRAF1.

Conclusions

JAKis and the TNFi had a direct impact on different RA risk enhancers, and we identified nucleotide-resolution targets for both drugs. Distinctive targets of clinically effective drugs could be useful for tailoring the application of these drugs and future design of more efficient treatment strategies.
Pomegranate extract-loaded surfactant-free zein nanoparticles as a promising green approach for hepatic cancer: optimization and in vitro cytotoxicity
Authors: Mohsen Salma , Bakr Mohamed Mofreh , ElDegwy Mohamed A. , Abouhussein Dalia M. N. , Fares Ahmed R. , ElMeshad Aliaa N.
Published: June 2024

Background

Hepatic cancer endures a major health scourge as the consequence of a high incidence of > 1 million cases by 2025. Plant-based products are typically effective in ameliorating health conditions. Pomegranate peel extract (PE) with its high polyphenolic content has anticancer effects against different types of cancer. Herein, we aimed to maximize the PE chemotherapeutic efficacy by loading it in a suitable delivery system to overcome the limitations of PE, to control its release and to achieve liver targeting.

Method

A nanoprecipitation procedure was adopted to incorporate PE into biodegradable and biocompatible natural polymeric zein (ZN)-based nanoparticles (NPs) (PE-ZN NPs). A full factorial design (22 × 31) was developed to study the effects of the formulation variables, namely pH of dispersion, PE-to-ZN ratio and surfactant concentration.

Results

The optimization revealed a surfactant-free stable PE-ZN NPs formula with a small particle size of 99.5 ± 6.43 nm, high PE encapsulation efficiency % of 99.31% ± 3.64 (w/w) and controlled release of PE over 24 h.

Conclusion

Moreover, the cytotoxicity of the optimum formula against hepatic cancer HepG2 cell lines was assessed and attained about a 2.5-fold reduction in the inhibitory concentration (IC50) values compared to the free PE affording a promising green platform to combat hepatic cancer.

Graphical abstract
The evolution and future of eye movement desensitisation and reprocessing therapy
Authors: Miller Paul W.
Published: June 2024

Eye movement desensitisation and reprocessing (EMDR), a therapy initially developed by Dr Francine Shapiro for treating post-traumatic stress disorder, has broadened its scope to include other forms of stress and trauma, even showing promise for physical health conditions. This commentary on a series of three articles on EMDR in this journal outlines the therapy's underlying theoretical model, adaptive information processing (AIP), which involves trauma-focused case conceptualisation. It also introduces the work of the EMDR Council of Scholars, which identified three categories of treatment: EMDR psychotherapy, EMDR treatment protocols and EMDR-derived techniques. Finally, it considers EMDR training and credentialing and the aim of current leaders in the EMDR community to solidify EMDR's standing as a scientifically validated, front-line trauma therapy, while honouring Shapiro's legacy of striving to end the cycle of violence, especially in low- and middle-income countries.
Influence of cognitive reserve on risk of depression and subsequent dementia: A large community-based longitudinal study
Authors: Yang Wenzhe , Wang Jiao , Dove Abigail , Yang Yonghua , Qi Xiuying , Guitart-Masip Marc , Papenberg Goran , Xu Weili
Published: June 2024

Background

Cognitive reserve (CR) has been linked to dementia, yet its influence on the risk of depression and related outcomes remains unknown. We aimed to examine the association of CR with depression and subsequent dementia or death, and to assess the extent to which CR is related to depression-free survival.

Methods

Within the UK Biobank, 436,232 participants free of depression and dementia were followed. A comprehensive CR indicator (low, moderate, and high) was created using latent class analysis based on information on education, occupation, mentally passive sedentary behavior, social connection, confiding with others, and leisure activities. Depression, dementia, and survival status were ascertained through self-reported medical history and/or linkages to medical records. Data were analyzed using multi-state Markov model and Laplace regression.

Results

Over a median follow-up of 12.96 years, 16,560 individuals developed depression (including 617 with subsequent dementia) and 28,655 died. In multivariable multi-state models, compared with low CR, high CR was associated with lower risk of depression (hazard ratio 0.53 [95% confidence interval 0.51–0.56]) and lower risk of post-depression dementia (0.55 [0.34–0.88]) or death (0.69 [0.55–0.88]) in middle-aged adults (aged <60 years). In Laplace regression, the depression-free survival time was prolonged by 2.77 (2.58–2.96) years in participants with high compared to low CR.

Conclusions

High CR is associated with lower risks of depression and subsequent transitions to dementia and death, particularly in middle age. High CR may prolong depression-free survival. Our findings highlight the importance of enhancing CR in the prevention and prognosis of depression.
Impact of prior anticancer treatments on palbociclib (PAL) clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer (ABC) in real-world settings.
Authors: Rocque Gabrielle Betty , Blum Joanne Lorraine , Ji Yan , Pluard Timothy J. , Migas John , Lakhanpal Shailendra , Jepsen Erin Stephany , Wang Yao , Montelongo Monica Z. , Zhang Zhe , Gauthier Eric Roland , Tripathy Debashish
Published: June 2024

1055

Background: Cyclin-dependent kinase 4/6 inhibitors (eg, PAL) combined with endocrine therapy (ET) is a standard of care for patients with HR+/HER2− ABC. The impact of prior anticancer treatments on clinical outcomes of patients with HR+/HER− ABC treated with palbociclib in routine care is not well known and was investigated in the POLARIS study. Methods: POLARIS is a prospective, observational, multicenter, real-world study in the US and Canada. Enrolled patients were adults (≥ 18 y) with HR+/HER2− ABC who received PAL + ET as standard of care. Real-world progression-free survival (rwPFS) and overall survival (OS) were described by prior treatment. Results: A total of 1250 patients were enrolled. Median age was 64 years (range, 22–97), 67.9% had recurrent disease, and 72.1% received PAL as first-line treatment (1LOT) vs 27.9% as ≥ 2LOT. Prior anticancer therapies (1LOT: adjuvant/neoadjuvant setting; ≥ 2LOT: metastatic setting) were received by 912 patients (73.0%), which included ET-alone (n=254), chemotherapy-alone (n=235), chemotherapy + ET (n=338) or other (n=85). The median follow-up duration was 35.7 months for rwPFS and 39.1 months for OS. In 1LOT, both rwPFS and OS were numerically shorter for patients who received prior chemotherapy (either alone or with ET) when compared with patients who received ET-alone or had no prior therapy (Table). In ≥ 2LOT, patients who received prior chemotherapy-alone or ET-alone had comparable rwPFS, which was numerically longer than for patients with prior chemotherapy + ET; OS was comparable regardless of prior treatment. Conclusions: Overall, patients with HR+/HER2− ABC with prior chemotherapy receipt tended to have shorter clinical benefit. Regardless of LOT, numerically longer rwPFS was achieved in patients who received prior ET-alone. In 1LOT, OS was longer in patients who received prior ET-alone while in ≥ 2LOT, OS was comparable across prior treatment subgroups. Small sample sizes of some ≥ 2LOT subgroups as well as observational nature of the study may limit interpretation. [Table: see text]
Interim analysis (IA) of the giredestrant (G) + everolimus (EVERO) arm in MORPHEUS Breast Cancer (BC): A phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative, locally advanced/metastatic BC (LA/mBC).
Authors: Wander Seth Andrew , Stemmer Salomon M. , Rugo Hope S. , Im Seock-Ah , Lau Peter Kar Han , Paluch-Shimon Shani , Cahuzac Clélia , Collier Annie , Shah Mona D. , Ngo Huy X. , Schwab Richard B. , Zhu Jing , Oliveira Mafalda
Published: June 2024

1059

Background: Endocrine therapy (ET) + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is a therapeutic mainstay for first-line tx of ER+ mBC. Finding effective ET combinations after progression remains a challenge; however, targeting the Akt/mTOR pathway is a promising approach. G is a highly potent, non-steroidal, oral (PO), selective ER antagonist and degrader that is well tolerated and achieves robust ER occupancy. EVERO is an approved mTOR inhibitor. Here, we present a 16-week IA of the G + EVERO arm in MORPHEUS BC (NCT04802759). Methods: Eligible pts with disease progression on 1–2 lines of ET (including a CDK4/6i) for LA/mBC were randomized 1:6 to receive G (30 mg PO daily [QD]) or G + EVERO (10 mg PO QD) until disease progression (PD)/unacceptable toxicity. The study was not designed to make explicit power and type I error considerations for a hypothesis test. Primary endpoints were safety and objective response rate (ORR); other endpoints included progression-free survival (PFS), overall survival, clinical benefit rate, disease control rate (DCR), duration of response, and pharmacokinetics. Steroid mouthwash was recommended for prophylaxis or treatment. Genetic alterations were defined using baseline circulating tumor DNA. Results: Results for the G arm have been presented previously and are not included here. As of July 24, 2023, 15 pts were enrolled in the G + EVERO arm: 66.7% and 33.3% received 1–2 prior lines of therapy for LA/mBC, respectively; 26.7% had prior fulvestrant, and 73.3% had liver metastasis at enrollment. One pt had prior capecitabine. Safety data are in the table. Confirmed ORR in the G + EVERO arm was 26.7% (n = 4). Partial responses were reported in 26.7% of pts (n = 4; all had ESR1 mutations, 1 also had an Akt pathway mutation), 46.7% of pts (n = 7) had stable disease, and the DCR was 53.3% (n = 8). Median PFS was not reached at data cutoff. No clinically relevant drug–drug interactions were observed. Conclusions: Safety of G + EVERO was aligned with the individual safety profile of each drug with no overlapping toxicities or new safety signals seen. An encouraging efficacy signal was observed with G + EVERO in pts with PD on 1–2 lines of ET (including a CDK4/6i). G + EVERO is being further investigated in the Phase III evERA BC trial (NCT05306340). Clinical trial information: NCT04802759 . [Table: see text]
SurvivorCHIP: Evaluation of clonal hematopoiesis in women treated for breast cancer.
Authors: Bahr Reem , Nosiri Chidera , Gui Gege , Mukherjee Devdeep , Hegde Pranay , Malloy Stacy K , Shastri Preeti , Peravali Monica , Chitalia Ami , Gallagher Christopher , DeStefano Christin , Dillon Laura W. , Shenoy Aarthi G. , Hourigan Christopher S.
Published: June 2024

1082

Background: Clonal hematopoiesis (CH) has been associated with reduced overall survival and is shown to be increased in patients with solid tumors after receiving chemotherapy and radiotherapy. However, the clinical implications of these observations have not been prospectively evaluated among different racial groups. This study was initiated in an urban cancer center to study CH rates before and after cancer therapy in a racially diverse population. Methods: Women aged ≥18 with newly diagnosed non-metastatic breast cancer provided written informed consent for this IRB approved study. Error-corrected DNA-sequencing was performed on 50ng gDNA isolated from blood prior to (pre-Tx), and following (post-Tx), chemotherapy(C), radiotherapy(R), and/or endocrine (E) therapy. Pathogenic or likely pathogenic variants were determined in regions recurrently mutated in CH. Results: 56 patients, median age 59.5y (29-82), provided both pre-Tx and post-Tx blood samples. Median BMI was 31.2 (range: 21.1-52.7) with 48 (85%) overweight (BMI≥25) and 33 (59%) obese (BMI≥30). 21 (38%) were active smokers. CH variants with an allele frequency (VAF) ≥2% were identified in 8 (14%) patients pre-Tx, most commonly DNMT3A (5 patients). For those with CH, median age was 64y (49-80) and 5 were active smokers. BMI was not statistically associated with pre-Tx CH in this cohort. 48 (86%) of the patients self-identified as African American and 7 (15%) had CH pre-Tx. Post-Tx, 10 patients had CH (18%), persistent from pre-Tx in 7. Of those with different CH classifications pre- and post-Tx, 1 had DNMT3A CH pre-Tx no longer detectable post-Tx (CRE), 2 had DNMT3A CH detectable at VAF ≥2% post-Tx (1 with CH undetected prior to RE Tx, 1 with the same DNMT3A variant at 1.2% VAF prior to CRE), and a 3rd had a ATRX variant increase from 1.5% to 2.1% VAF post-Tx (CRE). To investigate potential clinical implications of CH post-Tx, we utilized the clonal hematopoiesis risk score (CHRS) calculator which aims to predict risk of developing MDS and AML (Weeks et al, NEJM). Pre-Tx, 6 of the CH patients were classified as low risk, and 2 as intermediate risk. Patients developing CH post-Tx were all classified as low risk. Risk scores remained otherwise unchanged. At a median follow up of 2y, none of the patients in this study have been reported to develop MDS or AML. Conclusions: In this cohort of patients with newly diagnosed non-metastatic breast cancer, we did not find evidence to justify clinical screening/monitoring for CH before and after therapy.
Prognosis and tumor-infiltrating lymphocytes (TILs) in estrogen receptor (ER)-low metastatic breast cancer (MBC): Analysis from a large multi-institutional cohort and the TONIC phase II trial with nivolumab.
Authors: Miglietta Federica , Vernieri Claudio , de Graaf Manon , Secomandi Fabio , Cacciatore Matilde , Botticelli Andrea , Vingiani Andrea , Fotia Giuseppe , Griguolo Gaia , Giarratano Tommaso , Pellegrini Valerio , Iannaccone Daniela , Porra Francesca , Fassan Matteo , Pruneri Giancarlo , Dei Tos Angelo Paolo , Guarneri Valentina , Kok Marleen , Dieci Maria Vittoria
Published: June 2024

1100

Background: Although 1% as ER cutoff to discriminate ER+/HER2- from triple-negative (TN) BC serves the purpose of maximizing access to endocrine therapy, it may be suboptimally informative in terms of prognosis and immune checkpoint inhibitor (ICI) benefit. In the early setting, we reported that ER-low BC (ER 1-9%/HER2-) is immunologically and prognostically similar to TN (ER 0%) [Massa, 2023]. Here we focus on MBC and aim to assess prognosis of ER-low BC, including the conversion from ER+(≥10%)/HER2- to ER-low at relapse. We also compared ER-low and TN in terms of outcome after ICI, and TILs. Methods: We included two cohorts of MBC patients (pts): a multicentric retrospective cohort and pts with ER<10%/HER2- MBC enrolled in the TONIC trial testing nivolumab +/- induction therapy. All pts had ER and HER2 status assessed on metastatic tumor lesion; in the retrospective cohort ER and HER2 status on primary tumor was also available. Survival endpoints in the retrospective cohort: overall survival (OS, from BC diagnosis), post-relapse survival (PRS, from BC relapse). Exploratory endpoints from the TONIC trial: clinical benefit rate (CBR), OS and PFS (both from randomization). TILs were assessed on MBC samples (both cohorts) and on matched primary tumor (retrospective cohort). Results: We included 1112 pts in the retrospective cohort: the prevalence of ER-low BC was 3.6% in primary tumor and 5.9% in MBC lesions. In the TONIC trial, 15/110 pts had ER-low MBC. In the retrospective cohort, ER-low and TN MBC showed similar outcome, and significantly unfavorable vs ER+/HER2- MBC (Table). Among pts with ER+/HER2- primary BC, 6.7% converted to ER-low and 14.7% to TN at relapse. ER+/HER2- BC pts converting to ER-low had similar outcome than those converted to TN, and significantly poorer than pts with stable ER+/HER2- (Table). In the TONIC trial, ER-low MBC pts, compared to TN, showed similar response to ICI (CBR: 20.0% vs 22.1%, p=1), similar PFS and numerically worse OS (Table). TIL levels on MBC samples were similar between ER-low and TN both in the retrospective (median: 6% vs 5%, p=0.83) and the TONIC cohorts (median: 5.5% vs 5.0%, p=0.56) and were higher than ER+/HER2- (median: 3%). Conclusions: We confirmed that ER-low and TN MBC show similar poor outcome and the shift from ER+/HER2- to ER-low has a comparable unfavorable prognostic impact compared to conversion to TN. Our results support the hypothesis that ER-low and TN are immunologically akin and similarly prone to respond to ICI. [Table: see text]
Sequential combination of sacituzumab govitecan and talazoparib in metastatic triple negative breast cancer (mTNBC): Results from a phase II study.
Authors: Abelman Rachel Occhiogrosso , Spring Laura , Niemierko Andrzej , Abraham Elizabeth , McNeice Mary , Goff Jennifer , Valenti Amanda , Wander Seth Andrew , Isakoff Steven J. , Moy Beverly , Juric Dejan , Vidula Neelima , Waks Adrienne Gropper , Parsons Heather Anne , Ellisen Leif W. , Tolaney Sara M. , Bardia Aditya
Published: June 2024

1102

Background: The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) has demonstrated improvement in overall survival for patients with metastatic triple negative breast cancer (mTNBC). Despite great interest in enhancing efficacy of ADCs using combination therapy, there are no approved regimens. Preclinical data suggest that SG synergizes with Poly ADP-ribose polymerase inhibitors (PARPi) to induce DNA damage and cell death. Though the phase 1b study demonstrated intolerable myelosuppression with simultaneous dosing, tolerability was improved with sequential administration of SG and the PARPi talazoparib (Bardia AACR 2022). Here we report clinical outcomes from the phase II dose expansion cohort (NCT04039230). Methods: In a single-arm phase II study, adult patients with measurable mTNBC (per ASCO/CAP guidelines) were eligible. Starting dose was SG at 10mg/kg on days 1 and 8 with talazoparib 1mg on days 15-21. Growth factor (G-CSF) prophylaxis was required. The primary endpoint was the confirmed Objective Response Rate (ORR) calculated per RECIST v1.1 and secondary endpoints included progression-free survival (PFS) and overall survival (OS). The Clinical Benefit Rate (CBR) at 6 months was also measured. Results: From June 2021 to March 2023, 26 patients were enrolled. The median age was 54 (range, 35 to 81). Patients received a median of 2 prior therapy lines for metastatic disease (range, 0 to 7). 6/26 patients remain on treatment at time of data cutoff. Median PFS was 6.2 months (95% CI, 3.7 to 12.8), and median OS was 18.0 months (95% CI, 10.7 to not evaluable). The confirmed ORR was 30.1% (95% CI, 14 to 52) and the CBR at 6 months was 53.8% (95% CI, 33 to 73). Serious adverse events (AEs) were seen in 10 (38.5%) of patients; in 7 (26.9%) serious AEs were treatment related. The most common treatment related AEs were anemia (92.3%), neutropenia (88.5%), nausea (84.6%) fatigue (80.7%), and thrombocytopenia (65.3%). Grade ≥3 neutropenia and anemia were seen in 80.7% and 34.6% of cases, respectively. One or more dose reductions were required in 58.0% of patients. One patient with a germline BRCA mutation was treated for 625 days before disease progression. Updated biomarker and survival data will be presented at the meeting. Conclusions: In this single-arm phase II study, SG in combination with talazoparib was feasible and demonstrated preliminary evidence of efficacy. A randomized clinical trial is needed to determine if the SG-PARPi combination is superior to SG monotherapy. Clinical trial information: NCT04039230 .
Immune related adverse events in patients with breast cancer and autoimmune disease treated with immunotherapy.
Authors: Vidula Neelima , Hutchinson Jennifer , McLaren Abigail , Ryan Lianne , Niemierko Andrzej , Bardia Aditya
Published: June 2024

1103

Background: Pembrolizumab is approved for early and advanced triple negative breast cancer (TNBC), and atezolizumab was approved for advanced TNBC. Toxicity of immunotherapy (IO) and immune related adverse events (irAEs) in patients with breast cancer with an underlying autoimmune disease are not well understood as autoimmune disease is often an exclusion criterion in immunotherapy trials. Understanding real-world IO toxicity and irAEs in patients with breast cancer and autoimmune disease may inform clinical decision making. Methods: We studied IO toxicity and irAEs in patients with early and metastatic breast cancer, and underlying autoimmune disease vs. those without autoimmune disease (at IO start) who received IO at an academic institution. A retrospective review was conducted to identify IO toxicity and irAEs (CTCAE v 5.0). Cohorts were compared with Pearson’s chi-squared test (categorical variables) and Wilcoxon rank-sum test (continuous variables), with p<0.05 for statistical significance. Results: Cohorts had 23 patients with breast cancer and ≥1 autoimmune disease (AD) prior to receipt of IO (thyroid: 48%, rheumatologic: 26%, gastrointestinal: 13%, dermatologic: 9%), and 106 patients with breast cancer but without autoimmune disease (non-AD). Median age at IO start was 63 (interquartile range [IQR] 54-69) in AD vs. 50 in non-AD (IQR 39-59). Stage I-III/IV distribution was 39%/61% for AD and 67%/33% in non-AD. IO was mainly pembrolizumab (AD: 87%; non-AD: 85%) vs. atezolizumab. Table depicts characteristics of IO toxicity. A significantly higher overall rate of irAEs was seen in AD (96%) vs. non-AD (59%) [p<0.001]. Significantly greater immune related transaminitis was observed in AD (52%) vs. non-AD (24%) [p=0.006]. Immune related hypothyroidism (AD: 30% vs. non-AD: 15%, p=0.08), nephritis (AD: 9% vs. non-AD 2%, p=0.08), and hyperthyroidism (AD: 9% vs. non-AD: 3%, p=0.19) had numerically higher rates in AD, but these findings did not achieve statistical significance. Flare of the baseline AD with IO was observed in 6/23 (26%) patients, and 50% of flares occurred within 1 month of starting IO (range 1-5 months). Management of irAEs was similar in AD vs. non-AD, and rates of full resolution of irAEs were similar (AD: 55%; non-AD: 61%, p=0.65). Late onset irAEs (> 3 months after IO discontinuation) were rare (AD: 12%; non-AD: 4%, p=0.21). Conclusions: A higher overall rate of irAEs was observed in patients with underlying autoimmune disease, including greater immune related transaminitis and flare of the underlying autoimmune disease, suggesting the need for close monitoring of irAEs in this population. [Table: see text]
The influence of sarcopenia and myosteatosis on severe laboratory toxicity and overall mortality in older adults with cancer receiving chemotherapy.
Authors: Papadopoulos Efthymios , Wong Andy Kin On , Law Sharon Hiu Ching , Costa Sarah , Cheung Angela , Rozenberg Dmitry , Alibhai Shabbir M.H.
Published: June 2024

12131

Background: Older adults with cancer often present with suboptimal muscle quantity and quality prior to treatment due to disease-related catabolic effects combined with the aging process. Muscle catabolism is further exacerbated by cancer treatments leading to worse metabolic health, patient quality of life, and clinical outcomes. Our objective was to examine the impact of sarcopenia and myosteatosis on severe laboratory toxicity and overall mortality in older adults with cancer receiving chemotherapy. Methods: This was a retrospective cohort study of older adults who had undergone chemotherapy at the Princess Margaret Cancer Centre, Toronto, Canada from June 2015 to June 2022. A computed tomography scan after diagnosis but prior to treatment was used to assess skeletal muscle index (SMI) and skeletal muscle density (SMD) for each participant. Sarcopenia was defined as the presence of low muscle strength (grip strength <35.5kg for males and <20kg for females), low SMI, and low physical performance (walking speed <0.8m/s or a total Short Physical Performance Battery score of ≤8) prior to chemotherapy initiation. Myosteatosis was assessed through SMD in Hounsfield Units using previously published cut-offs. Severe laboratory toxicity was defined as occurrence of a grade ≥3 adverse event per the Common Terminology Criteria for Adverse Events (version 4.0). Severe laboratory toxicity and overall mortality were assessed from treatment initiation until treatment termination or loss to follow up. Multivariable logistic regression was used to determine the role of sarcopenia and myosteatosis in predicting occurrence of severe laboratory toxicity. Multivariable Cox regression was used to assess the risk of overall mortality. Results: A total of 115 older adults (mean age: 77.1 y) were included, of whom 63.5% had metastatic disease. Sarcopenia was identified in 27% of the cohort, whereas 80% had myosteatosis. A total of 132 severe laboratory toxicities occurred during the study period in 41 participants (35.7%). Sarcopenia was a significant predictor of severe laboratory toxicity (adjusted odds ratio (aOR)=3.19, 95%CI= 1.19 to 8.52, p= 0.012) after adjusting for sex, body mass index, and hemoglobin. Myosteatosis was significantly associated with overall mortality (adjusted hazard ratio (aHR)= 2.51, 95%CI= 1.12-5.61, p=0.025) after adjusting for albumin, alkaline phosphatase, and treatment intent. Conclusions: Sarcopenia may be used to inform the risk of severe laboratory toxicity in older adults prior to chemotherapy. Pre-treatment myosteatosis defined by low SMD predicts overall mortality in the same cohort. Optimization of skeletal muscle health through targeted exercise and nutritional interventions may improve patient quality of life and clinical outcomes in older adults with cancer receiving chemotherapy.
The influence of psychosocial factors on first-time chemotherapy-induced nausea and vomiting: A prospective multicenter cohort study.
Authors: Shi Xiaoxiao , Xu Liang , Liu Jie , Wang Ying , Yang Xiaoyun , Zhuo Hongyu , Zhang Jie , Chen Ye , Xiao Hongmei , Xie Ke , Zhong Wuning , Jiang Yu , Deng Yaotiao
Published: June 2024

12135

Background: Previous studies have suggested that if cancer patients experience no chemotherapy-induced nausea and vomiting (CINV) or mild symptoms during their first chemotherapy cycle, they are less likely to experience CINV in subsequent cycles, suggesting that the optimal intervention time may be before the first chemotherapy cycle. Consequently, attention should be paid to relevant risk factors. Currently, there is a lack of data on psychosocial risk factors related to chemotherapy among cancer patients in China. Methods: This study was a multicenter, prospective cohort study that included cancer patients from seven hospitals' oncology departments who were scheduled to undergo their first chemotherapy cycle. The chemotherapy regimens administered were either highly or moderately emetogenic protocols. Demographic and baseline clinical characteristics were recorded by clinical oncologists. Participants were asked to complete the Distress Thermometer (DT), the Mini-Mental Adjustment to Cancer (Mini-MAC), and a risk factor questionnaire the day before chemotherapy, and to keep a daily diary describing their CINV experiencing for 21 days after chemotherapy. Results: Between October 2022 and November 2023, a total of 1100 cancer patients were enrolled in this study and 972 cancer patients completed all the questionnaires. A total of 64.1% reported CINV during the first chemotherapy cycle. In logistic regression analysis, CINV was predicted by higher PS score (OR=1.411, p=0.049), highly emetogenic regimens (OR=1.846, p=0.004), failure to follow anti-emetics guidelines (OR=2.323, p<0.001), history of nausea/vomiting for other reasons(OR=1.817, p=0.001), lower number of hours slept before the night of chemotherapy (OR=8.987, p<0.001), expectancy of CINV(OR=1.505, p=0.032), maladaptive coping (OR = 1.03, p = 0.024) and distress (OR = 1.157, p =0.021). Conclusions: Psychosocial factors significantly correlate with chemotherapy-induced nausea and vomiting (CINV) among Chinese cancer patients. These findings underscore the importance of integrating psychosocial assessments into the management of CINV, potentially improving treatment outcomes and patient experiences.
The positive impact of Medicaid expansion on melanoma stage at presentation.
Authors: Win Shwe , Amini Arya , Modi Badri , Wang Edward Wenge , Villalona-Calero Miguel Angel , Salgia Ravi , Muddasani Ramya , Chan Aaron , Xing Yan
Published: June 2024

1533

Background: This study aims to evaluate the impact of the Affordable Care Act Medicaid expansion on melanoma stage at presentation. Methods: 12,667 non-elderly patients (age 40-64) who were newly diagnosed with melanoma and known Medicaid expansion status were identified from The National Cancer Database. We excluded patients with private insurance, Medicare, or other government or unknown insurance. The time period for the cohort spanned from 2010 to 2020 which includes pre-expansion (2010-2013) and post-expansion periods (2014-2020). Year-to-year trend analysis and difference-in-difference (DID) analysis was performed to analyze tumor staging between states with Medicaid expansion (MES) and without Medicaid expansion (non-MES) before and after the expansion. Results: Out of the 12,667 melanoma patients (56% male, 95% white), 41% of patients were uninsured and 59% had Medicaid during 2010 to 2020. The percentage of patients without insurance decreased significantly from 51% in 2010 to 16% in 2020. There were 21% of patients with stage III and 18% with stage IV melanoma. The trend of melanoma stage at presentation over the study period was shown (Table). Notably, the stage IV melanoma at presentation decreased from 21% to 17% from 2010 to 2020 in MES. In contrast, stage IV melanoma at presentation increased from 20% to 23% over the same period of time in non-MES. After adjusting for confounders, DID analysis revealed a statistically significant decrease in stage IV melanoma at presentation (DID -0.04, p < 0.001) as well as a statistically significant decrease in 3 year mortality (DID -0.05, p < 0.001) between MES and non-MES before and after Medicaid expansion. In addition, the use of immunotherapy in stage IV melanoma in MES was significantly higher than non-MES (47% vs 41%, p < 0.001). Conclusions: The findings reveal the positive impact of Medicaid expansion on melanoma stage at presentation and suggest that improved access to healthcare services can facilitate diagnosing early-stage melanoma and decreasing mortality rate. Despite these findings, there are still 16% of patients who still do not have insurance in 2020 which indicates that continued effort is needed to improve the outcomes of these uninsured patients.[Table: see text]