Low Burden Research Articles

Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer.

Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second-leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. Here, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared to their castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer (CSPC) populations, the obligate sGC heterodimer was repressed via methylation of its beta subunit. Genetically abrogating sGC complex formation in CSPC cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and co-treatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44+ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell-intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy.

Primary adenocarcinoma of the spermatic cord: a case report and review of the literature

BackgroundPrimary malignant neoplasms of the spermatic cord are extremely rare, with most reported cases being sarcomas or metastatic carcinomas. However, primary adenocarcinoma of the spermatic cord has not been previously reported.Case presentationA 34-year-old male with a solid mass in the right spermatic cord, was eventually diagnosed with primary adenocarcinoma. Histological examination revealed a moderately-to-poorly differentiated adenocarcinoma exhibiting glandular, cribriform, or nested growth patterns, characterized by medium to large-sized cells and focal extracellular mucus. Immunohistochemical analysis demonstrated positive staining for CK (AE1/AE3), CK8/18, CK19, MOC31 (EP-CAM), and Ber-EP4, while negative staining was observed for CK7, D2-40, WT-1, MC, PAX-8, NKX3.1, PSA, CEA, TTF-1, and NapsinA. Furthermore, a complete loss of INI-1 expression and consistent BRG1 expression were noted in all tumor cells. Next-generation sequencing revealed SMARCB1 deletion, low tumor mutation burden (TMB-L), and microsatellite stability (MSS).ConclusionWe reported the first case of primary adenocarcinoma of the spermatic cord with SMARCB1 (INI-1) deficiency. This case contributes to the expanding understanding of rare neoplasms and underscores the importance of further research into therapeutic strategies targeting SMARCB1-deficient tumors.

Monocyte subsets in breast cancer patients under treatment with aromatase inhibitor and mucin-1 cancer vaccine

BackgroundMonocytes comprise subsets of classical, intermediate and non-classical monocytes with distinct anti- or pro-tumor effects in breast cancer (BC). They are modulated by estrogen, and can contribute to BC control by endocrine therapy in preclinical models.MethodsTo elucidate whether changes in monocyte subsets are associated with treatment and response, we investigated peripheral blood samples of 73 postmenopausal women with estrogen receptor (ER) positive BC, who received aromatase inhibitor therapy with or without the mucin-1 vaccine tecemotide in the ABCSG34 trial. Blood was retrieved at baseline, midterm and end of therapy, and was analyzed for the distribution and ER expression of monocyte subsets by flow cytometry.ResultsWhen 40 healthy, age-matched women were compared with BC patients before treatment start, ER levels of monocytes did not differ, yet patients presented with a higher frequency of classical and fewer non-classical monocytes. Endocrine therapy triggered a significant increase in ER levels in all monocyte subsets, without affecting subset distribution. Vaccination had no overall impact on subset frequency and ER expression. Yet, a shift from intermediate to classical monocytes during therapy correlated with changes in plasma cytokines and chemokines and was significantly associated with low residual cancer burden in vaccinated patients. Without tecemotide, baseline ER levels in classical monocytes were significantly higher in women with good response to endocrine therapy.ConclusionsThis study identified classical monocytes to be associated with ER positive BC and with patient response to neoadjuvant endocrine treatment and cancer vaccination.

Pioneering precision in markerless strain development for Synechococcus sp. PCC 7002

Marine cyanobacteria such as Picosynechococcus sp. (formerly called Synechococcus sp.) PCC 7002 are promising chassis for photosynthetic production of commodity chemicals with low environmental burdens. Genetic engineering of cyanobacteria conventionally employs antibiotic resistance markers. However, limited availability of antibiotic-resistant markers is a problem for highly multigenic strain engineering. Although several markerless genetic manipulation methods have been developed for PCC 7002, they often lack versatility due to the requirement of gene disruption in the host strain. To achieve markerless transformation in Synechococcus sp. with no requirements for the host strain, this study developed a method in which temporarily introduces a mutated phenylalanyl-tRNA synthetase gene (pheS) into the genome for counter selection. Amino acid substitutions in the PheS that cause high susceptibility of PCC 7002 to the phenylalanine analog p-chlorophenylalanine were examined, and the combination of T261A and A303G was determined as the most suitable mutation. The mutated PheS-based selection was utilized for the markerless knockout of the nblA gene in PCC 7002. In addition, the genetic construct containing the lldD and lldP genes from Escherichia coli was introduced into the ldhA gene site using the counter selection strategy, resulting in a markerless recombinant strain. The repeatability of this method was demonstrated by the double markerless knockin recombinant strain, suggesting it will be a powerful tool for multigenic strain engineering of cyanobacteria.

Combined Method Comprising Low Burden Physiological Measurements with Dry Electrodes and Machine Learning for Classification of Visually Induced Motion Sickness in Remote-Controlled Excavator

The construction industry is actively developing remote-controlled excavators to address labor shortages and improve work safety. However, visually induced motion sickness (VIMS) remains a concern in the remote operation of construction machinery. To predict the occurrence and severity of VIMS, we developed a prototype system that acquires multiple physiological signals with different mechanisms under a low burden and detects VIMS from the collected data. Signals during VIMS were recorded from nine healthy adult males operating excavator simulators equipped with multiple displays and a head-mounted display. Light gradient-boosting machine-based VIMS detection binary classification models were constructed using approximately 30,000 s of time-series data, comprising 23 features derived from the physiological signals. These models were validated using leave-one-out cross-validation on seven participants who experienced severe VIMS and evaluated through area under the curve (AUC) scores. The mean receiver operating characteristic curve AUC score was 0.84, and the mean precision–recall curve AUC score was 0.71. All features were incorporated into the models, with saccade frequency and skin conductance response identified as particularly important. These trends aligned with subjective assessments of VIMS severity. This study contributes to advancing the use of remote-controlled machinery by addressing a critical challenge to operator performance and safety.

Determination of MYD88 and CXCR4 mutation for clinical detection and their significance in Waldenström macroglobulinemia.

This study aims to explore the incidence and clinical features of MYD88 and CXCR4 mutations in patients with Waldenström macroglobulinemia (WM) and determine the optimal method for routine clinical practice. Additionally, we seek to evaluate the prognostic significance of these features across various therapeutic backgrounds [cytotoxic group, the Rituximab/Bortezomib-based group, and the Bruton's tyrosine kinase inhibitor (BTKi) group]. 385 symptomatic WM patients were analyzed for MYD88 and CXCR4 mutations using Sanger sequencing, next-generation sequencing (NGS), allele-specific quantitative polymerase chain reaction (AS-PCR), and/or droplet digital PCR (ddPCR). The overall MYD88 mutation rate was 87.8%, relatively lower than that in Western cohort. Both AS-PCR and ddPCR demonstrated high sensitivity in unsorted samples, detecting 98.5% and 97.7% of mutations, respectively, including those with low tumor burdens. The total CXCR4 mutation rate was 30.9%, with NGS exhibiting the highest sensitivity of 78.0%. CXCR4 mutation was significantly linked to shorter OS only within the BTKi treatment group. The multivariate analysis indicated that MYD88 and CXCR4 mutations were not independent prognostic factors in the non-BTKi group when considering IPSSWM clinical staging. However, in the BTKi treatment group, these mutations emerged as independent adverse prognostic factors, overshadowing the prognostic significance of IPSSWM classification (MYD88: HR=0.229, P=0.030; CXCR4: HR=3.349, P=0.012). Testing for MYD88 mutations using AS-PCR or ddPCR in unsorted samples is viable for routine clinical practice. Under BTKi treatment, MYD88 and CXCR4 mutations hold greater prognostic importance than IPSSWM staging in WM.

Understanding the Experiences of Nurses' Work: Development and Psychometric Evaluation of an End of Shift Survey.

To explore and validate an end of shift survey with a low response burden, practical application and generated evidence of related associations between workload, quality of work and patient care, missed care and job satisfaction. A retrospective cross-sectional survey of the experiences of nursing staff. Data were collected from 265 nurses who responded to a questionnaire at the end of their shift in 2022. Exploratory factor analysis was undertaken using IBM SPSS v.27 and confirmatory factor analysis was undertaken using IBM AMOS v27. Hypotheses testing was undertaken using IBM SPSS v.27 using multiple regression analyses. All of the hypotheses were supported. There was a negative association between workload and quality of work and job satisfaction. Quality of work was negatively associated with workload and missed care and positively associated with job satisfaction. The association between missed care and job satisfaction was negative. The EOSS is a valid and reliable tool with a low response burden. The tool supports previous research which demonstrated there is a negative relationship between level of workload and shift type with satisfaction, quality of work and potentially nurse retention. In the context of a global nursing shortage nursing leaders must ensure that care we provide is of the highest quality. We must take every action to address high workload to reduce the risk that fundamental care is not sacrificed, job satisfaction is improved and nurses remain in the profession. The EOSS gives nurse leaders a reliable, practical, consistent, applied tool that will better enable associations to be observed between resource configuration, workload and critical impacts on nursing and patient care. We have adhered to the relevant EQUATOR guidelines using the STROBE reporting method. No Patient or Public Contribution.

6550 National Statin Prescription Trends in Patients With Breast Cancer and Diabetes for Primary Cardiovascular Disease Prevention

Abstract Disclosure: A.B. Yang: None. G. Mhango: None. C. Kong: None. J.J. Lin: None. J.P. Wisnivesky: Consulting Fee; Self; Sanofi, Banook, PPD. Grant Recipient; Self; Sanofi, Regeneron Pharmaceuticals, Axella, Arnold Consultants. A. Leiter: None. Background: Cardiovascular disease (CVD) is the leading cause of death in older early-stage breast cancer (BC) survivors. Due to cardiotoxic BC treatments such as chemotherapy and radiation, patients with BC and diabetes (DM) are at increased risk of CVD. In patients with BC and DM, statins decrease CVD mortality. Since 2013, many clinical guidelines broadened statin indications for primary CVD prevention in patients with DM, making >85% of patients eligible. Little is known about statin prescription (Rx) patterns in older BC survivors with DM, a group at high risk of CVD. Hypothesis: We hypothesized that statin Rxs increased over time, but were less likely in BC survivors with more advanced locoregional BC and lower comorbidity burden. Methods: A population-based, retrospective cohort study was conducted using Surveillance, Epidemiology and End Results (SEER) cancer registry data linked to Medicare claims. We identified women with preexisting DM who were diagnosed with stage 0-III primary BC between 2008-17. We excluded patients with prior CVD who died <1 year after BC diagnosis. Statin Rx (atorvastatin, pravastatin, rosuvastatin, simvastatin, fluvastatin, lovastatin) was defined as ≥1 statin pharmacy claim <1 year after BC diagnosis. Comorbidity burden was assessed with a modified Charlson Comorbidity Index (CCI). We compared patient demographic and clinical characteristics by statin Rx status using the chi-square test. Using a multivariate logistic regression adjusting for age, race, CCI, BC stage, and diagnosis year, independent predictors of statin Rx were identified. Results: Of 8,423 BC patients with pre-existing DM, 5,698 (68%) had a statin Rx. Statin Rx increased over time (BC diagnosis year 2008-10: 66%, 2011-13: 66%, 2014-15: 69%, 2016-17: 70%; p=0.01) and differed by age (66-69: 66%, 70-74: 70%, 75-79: 69%, ≥80: 65%; p<0.01) and race (White: 68%, Black: 62%, Latinx: 66%, Other: 72%; p<0.01). Statin Rx did not differ by comorbidity burden (CCI 0: 68%, 1-2: 67%, ≥3: 67%; p=0.87) and declined with higher BC stage (0: 73%, I: 70%, II: 65%, III: 63%; p<0.01). In adjusted analyses, more recent BC diagnosis (2016-17 vs. 2008-10: odds ratio [OR]: 1.19, 95% confidence interval [CI]: 1.04-1.38), age group (70-74 vs. 66-69: OR: 1.24, 95% CI: 1.09-1.41), race (Black vs. White: OR 0.77, 95% CI: 0.66-0.89) and higher BC stages (II vs. 0: OR: 0.76, 95% CI: 0.58-1.00; III vs. 0: OR: 0.72, 95% CI: 0.54-0.97) remained predictors of statin Rx. Conclusions: In a nationally representative cohort analysis of older early-stage BC patients, statin Rx increased between 2008-17 and varied by age, race, and BC stage. Elucidating gaps in statin Rx can potentially improve guideline-concordant Rx in a group at high risk for CVD and reduce disparities. Presentation: 6/2/2024

9359 Patients’ Perspectives On Telemedicine In Endocrinology

Abstract Disclosure: P. Rotman Pikielny: None. L. Barzilay Yoseph: None. M. Kasher Meron: None. K. Rodrig: None. S. Shapira: None. Background: Telemedicine has emerged as an important and sometimes crucial tool in patient care, particularly during the COVID-19 pandemic. It offers numerous benefits, including time efficiency and improved access to specialized services. However, its adoption by endocrinology is constrained by the traditional emphasis on the physician-patient relationship and physical examinations. Objectives: This study evaluated patients’ perspectives on telemedicine, regarding specific aspects of satisfaction, including communication, wait times, and financial and time burdens. Methods: Surveys were delivered via text messages sent after telephone vs. frontal visits in an outpatient endocrinology clinic in a tertiary referral center. The surveys, sent from Nov 2022 to Dec 2023, investigated various aspects of satisfaction with the appointment and were based on the Telemedicine Satisfaction Questionnaire, a 5-point Likert scale questionnaire. Variations in preference levels across diverse patient groups were also examined. Answers were received via the REDCap application. Patients were told that responses were optional and answering the survey granted informed consent. Results: A total 135 patients completed the questionnaire, 93 who attended telephone and 42 after frontal visits. The groups were similar clinically: 77% were women, with an average age of 63 years. Visits were held mainly due to diabetes (22%), osteoporosis (31%), or obesity 10%), with no statistical differences between groups. 60% were followed more than a year. More patients who had telephone visits (69.9%) had previous experience with telephone visits vs. patients who had frontal visits (40.5%; p<0.004). Patients who had telephone visits reported higher satisfaction with wait time (p=0.002), physicians' explanations (p=0.03) and lower financial and time burdens (p<0.001). However, they were less able to share personal situations with the physician (p<0.001). More patients who experienced telephone visits thought they were preferrable to frontal visits (p<0.001). Notably, individuals with long-term follow-up and non-diabetic endocrine conditions had more interest in telemedicine. Conclusions: Patients report high satisfaction with telemedicine, but constrained in-person interactions remain a notable limitation. Telemedicine may not suit all patient groups or all time-points of patient care, requiring adaptation for broader use. Further research with higher response rate and specifications of different patient populations are essential to generalize these findings. Presentation: 6/2/2024

Advanced frequency control schemes and technical analysis for large-scale PEM and Alkaline electrolyzer plants in renewable-based power systems

Integrating electrolyzers into power systems can significantly contribute to sustainable energy via the generation of green hydrogen while also enhancing frequency stability through effective regulation of the electrolyzers’ operating power. This study gives a comprehensive analysis of large-scale electrolyzer plants when providing frequency support to power systems. First, the authors present a model predictive control (MPC)-based secondary frequency controller, combined with a droop controller as the primary frequency controller and a virtual inertia controller. Additionally, the study introduces a universal system frequency response (U-SFR) modeling approach that enables high accuracy, low computation burden, and reduced initial parameters as a testbed. Finally, an in-depth analysis is conducted, focusing on different technical aspects of large-scale electrolyzer plants when providing frequency support services. Case studies integrating PEM and Alkaline electrolyzers into the modified IEEE 39-bus system with over 50% wind power penetration are conducted. It is found that the proposed U-SFR model achieves high accuracy with lower computational time compared to detailed physical models. Additionally, model predictive controllers improve frequency quality more effectively than PID and PID-FLC methods. PEM electrolyzers are found to be more efficient in providing grid frequency support than alkaline electrolyzers due to their technical characteristics. Finally, smaller hydrogen tanks may frequently breach storage constraints, negatively impacting the system’s frequency response capability.

Robust adaptive event-triggered control for unmanned surface vessel–unmanned aerial vehicle: Application to sea–air synchronized lawn mowing search operation

This paper investigates a robust adaptive event-triggered control algorithm with a consideration of the synchronized lawn mowing search guidance for a heterogeneous system comprising both an unmanned surface vessel (USV) and an unmanned aerial vehicle (UAV). For ensuring a cooperative global search navigation of the USV–UAV, a synchronized lawn mowing search guidance is developed with two key elements: the L1-based virtual ship (L1VS) and L1-based virtual aerial (L1VA), where the former can generate the smooth reference path for a USV according to the search task scope, while the latter can program the reference path for a UAV on the basis of its search requirements (search speed, detected capacity and communication distance). In the control loop, a robust adaptive path following control law is designed by utilizing an event-triggered mechanism and a minimal learning parameter (MLP) technique. In particular, the event-triggered mechanism has a potential role for a reduction of the unnecessary transmission resource usage for the channel of the controller to the actuator. Besides, only one learning parameters on each channel by introducing the MLP technique, implying a lower computational burden. Through the Lyapunov theorem, the semi-global uniform ultimate bounded (SGUUB) stability properties of the proposed control system. Finally, two numerical simulations are carried out to evaluate the effectiveness of the proposed strategy and the advantages compared with existing techniques.

Effects of Medicare Eligibility at Age 65 Among Individuals With and Without Functional Disability.

Medicare coverage at age 65 improves access to and use of care and alleviates financial hardship for the general population. However, less is known whether the effects differ between individuals without and with functional disability. To examine the effects of Medicare eligibility at age 65 on health insurance coverage, financial burden of care, and access to care among individuals without and with functional disability. We used a regression discontinuity design, which exploits the discontinuity in eligibility for Medicare at age 65 and compares individuals just before and after age 65. Our analysis included 19,876 individuals (aged 59-71) without functional disability and 8376 individuals with functional disability from the 2014-2021 Medical Expenditure Panel Survey. We assessed health insurance coverage, financial burden of care, and access to care. Medicare eligibility led to increases in any and Medicare coverage for both groups, but those with functional disability had a decrease in Medicaid coverage by - 2.6 percentage points. Medicare eligibility resulted in lower financial burden of care for both groups, but the effects were greater among those with functional disability (- $578 vs. - $344 for out-of-pocket spending, - 3.7 vs. - 4.9 percentage points for cost-sharing, and - 2.5 vs. - 0.8 percentage points for paying medical bills over time). Although Medicare eligibility led to a decrease in delayed medical care among those without functional disability (- 2.1 percentage points), no change was observed among those with functional disability. Notably, access to care remained limited among those with functional disability after obtaining Medicare eligibility (8.6% and 3.9% for being unable to get medical care and experiencing delay in getting medical care). Medicare coverage can reduce financial hardship, especially for individuals with functional disability. However, there is a need to develop policies that ensure equitable access to care for those with functional disability.

Unraveling the Role of JMJD1B in Genome Stability and the Malignancy of Melanomas.

Genome instability relies on preserving the chromatin structure, with any histone imbalances threating DNA integrity. Histone synthesis occurs in the cytoplasm, followed by a maturation process before their nuclear translocation. This maturation involves protein folding and the establishment of post-translational modifications. Disruptions in this pathway hinder chromatin assembly and contribute to genome instability. JMJD1B, a histone demethylase, not only regulates gene expression but also ensures a proper supply of histones H3 and H4 for the chromatin assembly. Reduced JMJD1B levels lead to the cytoplasmic accumulation of histones, causing defects in the chromatin assembly and resulting in DNA damage. To investigate the role of JMJD1B in regulating genome stability and the malignancy of melanoma tumors, we used a JMJD1B/KDM3B knockout in B16F10 mouse melanoma cells to perform tumorigenic and genome instability assays. Additionally, we analyzed the transcriptomic data of human cutaneous melanoma tumors. Our results show the enhanced tumorigenic properties of JMJD1B knockout melanoma cells both in vitro and in vivo. The γH2AX staining, Micrococcal Nuclease sensitivity, and comet assays demonstrated increased DNA damage and genome instability. The JMJD1B expression in human melanoma tumors correlates with a lower mutational burden and fewer oncogenic driver mutations. Our findings highlight JMJD1B's role in maintaining genome integrity by ensuring a proper histone supply to the nucleus, expanding its function beyond gene expression regulation. JMJD1B emerges as a crucial player in preserving genome stability and the development of melanoma, with a potential role as a safeguard against oncogenic mutations.

Clinical importance of cerebrospinal fluid protein levels in HIV-associated cryptococcal meningitis: Insights from a prospective cohort study in Uganda.

Cerebrospinal fluid (CSF) protein levels exhibit high variability in HIV-associated cryptococcal meningitis; however, its clinical implications remain unclear. We analyzed data from 890 adults with HIV-associated cryptococcal meningitis randomized into two clinical trials in Uganda between 2015 and 2021. CSF protein was grouped into < 100mg/dl (72%, n =641) and ≥ 100mg/dl (28%, n =249). We described baseline clinical variables and 18-week mortality by CSF protein groups. Those with CSF protein ≥ 100mg/dl were more likely to present with Glasgow coma scale score<15 (P < .01), self-reported seizures at baseline (P = .02), higher CD4 T-cell count (P < .001), and higher CSF white blood cells (P < .001). Moreover, those with a baseline CSF protein ≥ 100mg/dl also had a lower baseline CSF fungal burden (P < .001) and a higher percentage of sterile CSF cultures at day 14 (P = .02). Individuals with CSF protein ≥ 100mg/dl demonstrated a more pronounced immune response consisting of upregulation of immune effector molecules, pro-inflammatory cytokines, T-helper cell type 1 and 17 cytokines, and immune-exhaustion marker (P < .05). 18-week mortality risk in individuals with a CSF protein < 100mg/dl was 34% higher (unadjusted Hazard Ratio 1.34; 95% Confidence Interval, 1.05-1.70; P = .02) than those with CSF protein ≥ 100mg/dl. In HIV-associated cryptococcal meningitis, individuals with baseline CSF protein ≥ 100mg/dl more frequently presented with neurological symptoms, higher CSF inflammatory cytokines, reduced fungal burden, and lower mortality risk. The findings underscore the prognostic significance of baseline CSF protein levels in predicting disease severity and mortality risk in cryptococcal meningitis.

Environmental footprints in divergent cuisines: a case study of eight Chinese culinary traditions

The sustainable dietary transitions must account for the varied culinary traditions and regional food cultures to ensure a balanced and culturally sensitive approach. This study aims to explore the impact of regional preferences on culinary culture and examine ways to achieve environmentally friendly dietary transitions in China by considering the differences in the environmental burdens of various cuisines. We investigate the eight Chinese culinary traditions and depict their respective popularity in China at the city level via POI characterization based on ArcGIS. Water, carbon, and ecological footprints are selected to investigate the environmental performance of each type of cuisine. Results show that the eight cuisines vary significantly in spreads of influence and environmental performances. Chuan cuisine is the most widely disseminated cuisine with a relatively low environmental burden. The remaining seven cuisines have limited spreads of influence and are mainly distributed in small cultural regions and the surrounding areas. Hui Cuisine, Zhe Cuisine, and Min Cuisine have the worst environmental performances. This study reveals the significant impact of regional cuisines on the environmental footprint of diets and highlights the necessity of considering this impact when promoting dietary transition, especially in culturally diverse countries.

Quality of life in women with early-stage and metastatic hormone receptor-positive, HER2-negative breast cancer receiving endocrine therapy.

Early discontinuation of endocrine therapy (ET) is higher among patients with early breast cancer (EBC) compared to patients with metastatic hormone receptor-positive (HR+) breast cancer (MBC). In our clinical experience the reasons for this may include a significant burden of ET side effects impacting quality of life (QOL) in patients with EBC. We hypothesized that QOL is lower in patients with HR + EBC compared to patients with HR + MBC on ET. We conducted a cross-sectional observational study to assess QOL utilizing FACT-ES & EORTC QLQ C30 tools among patients with EBC and MBC receiving ET across 5 Irish hospitals. A total of 417 patients were enrolled-EBC (79% n = 331) and MBC 21% (n = 86). Using the FACT-ES, we found no difference in overall QOL by stage (139.2 vs 141, P = .33). Patients with HR + MBC had a lower symptom burden from ET compared to HR + EBC (61.4 vs 54, P < .01). In adjusted multivariate linear regression models, there was no difference in QOL for patients with EBC and MBC receiving ET. There was no significant difference in overall QOL for patients with EBC and MBC. However, patients with EBC experienced more endocrine symptoms. In adjusted multivariate linear regression models, the stage did not predict QOL. Our results suggest that endocrine symptoms are significant contributors to impaired QOL for patients with EBC but the role of other determinants of QOL (eg, stage) is less clear. Future work could include the development of stage-specific QOL tools and utilization of electronic patient-reported outcomes (ePROs) to identify and manage emergent toxicities.

Experience with luspatercept therapy in patients with transfusion-dependent low-risk myelodysplastic syndromes in real-world clinical practice: exploring the positive effect of combination with erythropoietin alfa.

Luspatercept, an inhibitor of the transforming growth factor beta (TGF-β) pathway, is a novel treatment for anemic patients with lower-risk myelodysplastic syndromes (MDS) with transfusion dependence (TD) who do not respond to erythropoiesis-stimulating agents (ESA) therapy or are not suitable candidates for this treatment. We present real-world experience with luspatercept therapy from two hematology centers in the Czech Republic. By January 2024, 54 MDS patients (33 men, 21 women) with a median age of 74 years (range, 55-95) were treated with luspatercept ± ESA at two Charles University hematology centers in Prague and Hradec Králové. According to the WHO 2016 classification, the cohort included 32 MDS-RS-MLD, seven MDS-MLD, two patients with 5q- + ring sideroblasts (RS), 12 RARS-T, and 1 patient with CMML-0 + RS. SF3B1 mutation data were available for 45 patients. All patients were in the IPSS-R and IPSS-M lower-risk groups (except four IPSS-M high). The median follow-up was 17 months (range, 1-54). All patients were transfusion-dependent. Thirty-five (64.8%) patients had a high transfusion burden (HTB) with ≥ 4 transfusion units (TU)/8 weeks, and 19 (35.2%) had a low transfusion burden (LTB) (< 4 TU/8 weeks). The median time between diagnosis and initiation of luspatercept was 27 months (range, 4-156). ESA were used prior to luspatercept in 45 patients, and luspatercept was used as first-line treatment in nine patients. Thirty-one (61%) patients were treated simultaneously with ESA. Only patients who received luspatercept for ≥ 8 weeks (51 patients) were assessed. We evaluated the achievement of transfusion independence (TI) lasting 8, 12, 16, and 24 weeks. Thirty-two (62.7%) patients achieved TI for ≥ 8 weeks, 31 (60.7%) for ≥ 12 weeks, 29 (56.8%) for ≥ 16 weeks, and 25 (49%) for ≥ 24 weeks. Hematologic improvement (HI) without TI was achieved in six patients (11.7%). Overall, HI + TI was achieved in 38 patients (74.5%). Epoetin alfa was used simultaneously in 31 patients (60.7%). In 21 (55.2%) of all responding patients, concomitant therapy with epoetin alfa led to an improved response, with 16 reaching TI. Thirteen (25.5%) patients were nonresponders. Eight (21%) patients experienced therapy failure and became transfusion-dependent again. Optimal response required a gradual increase in the luspatercept dose to 1.75 mg/kg in up to 35 patients, with 23 responders (TI + HI). Response rates varied by transfusion burden: 79% in LTB and 50% in HTB reached TI. Of RS+ patients, 70% reached TI, while only one out of five RS- patients achieved TI. Among 39 SF3B1-positive patients, 61.6% achieved TI. In the low and very low IPSS-M groups, 86% of patients responded (TI + HI), compared to 62% in the moderate-low group. Luspatercept was well-tolerated, with no adverse events higher than grade II toxicity. We have demonstrated in real-world clinical practice that luspatercept is a very effective agent, even in an unselected, pretreated, significantly TD MDS population. The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.

Machine learning explains response variability of deep brain stimulation on Parkinson’s disease quality of life

Improving health-related quality of life (QoL) is crucial for managing Parkinson’s disease. However, QoL outcomes after deep brain stimulation (DBS) of the subthalamic nucleus (STN) vary considerably. Current approaches lack integration of demographic, patient-reported, neuroimaging, and neurophysiological data to understand this variability. This study used explainable machine learning to analyze multimodal factors affecting QoL changes, measured by the Parkinson’s Disease Questionnaire (PDQ-39) in 63 patients, and quantified each variable’s contribution. Results showed that preoperative PDQ-39 scores and upper beta band activity (>20 Hz) in the left STN were key predictors of QoL changes. Lower initial QoL burden predicted worsening, while improvement was associated with higher beta activity. Additionally, electrode positions along the superior-inferior axis, especially relative to the z = −7 coordinate in standard space, influenced outcomes, with improved and worsened QoL above and below this marker. This study emphasizes a tailored, data-informed approach to optimize DBS treatment and improve patient QoL.

MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution.

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution.

Varying effect of atrial fibrillation ablation in patients with heart failure with preserved ejection fraction according to CHA2DS2-VASc score

BackgroundThe impact of comorbidity burden on outcomes of radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) in patients with heart failure and preserved ejection fraction (HFpEF) remains unclear. ObjectiveThe purpose of this study was to evaluate how comorbidity burden influences the association between RFCA and cardiovascular outcomes in AF patients with HFpEF. MethodsAF patients with HFpEF from the prospective China-AF cohort, recruited between August 2011 and December 2020, were categorized into 2 groups based CHA2DS2-VASc score: low comorbidity burden (score ≤4) and high comorbidity burden (score >4). The associations between RFCA and cardiovascular outcomes and interaction effects of comorbidity burden on these associations were assessed. ResultsAmong 1700 patients with median follow-up of 65.9 months, those in the low comorbidity burden group who received RFCA had a lower risk of composite events (cardiovascular death and ischemic stroke/transient ischemic attack [TIA]) (adjusted hazard ratio [HR] 0.35, 95% confidence interval [CI] 0.21–0.59] and all-cause death (adjusted HR 0.31, 95% CI 0.17–0.54) compared to those without RFCA. However, significant associations were not observed in the high comorbidity burden group. The differences between low and high comorbidity burden groups were significant, with interaction effects noted between comorbidity burden and RFCA for cardiovascular death (Pinteraction = 0.045) and ischemic stroke/TIA (Pinteraction = 0.010). RFCA was associated with a reduced risk of AF recurrence in both comorbidity burden groups. ConclusionRFCA for AF is associated with reduced AF recurrence and improved cardiovascular outcomes in patients with HFpEF. However, these benefits may be limited for patients with a CHA2DS2-VASc score >4 (high comorbidity burden).