Chronic Ocular GVHD Treatment at Two Locations of a Tertiary Referral Center.

Purpose: To compare baseline characteristics and treatment of chronic ocular graft-versus-host disease (oGVHD) patients in two treatment locations. Patients and Methods: Patients diagnosed with definite chronic oGVHD between September 1, 2014 and September 20, 2021 at two locations were identified. IRB-approved retrospective chart review was conducted for the following data: demographic information, ocular surface disease index (OSDI), corneal fluorescein staining (CFS), and treatment(s) used. Differences by site were assessed using Pearson's Chi-Square tests and two-sample t-tests; differences by time were assessed using paired t-tests. Results: At baseline, Clinic 1 (C1) patients had a worse mean OSDI score (47.8 vs 36.3, p = 0.011) and CFS in both OD (1.3 vs 0.8, p = 0.005) and OS (1.3 vs 0.6, p < 0.001) compared to Clinic 2 (C2). Comparing baseline to endpoint, C1 patients experienced an improvement in OSDI (-17.26, p < 0.001), CFS OD (-0.50, p < 0.001), and CFS OS (-0.51, p < 0.001) at C1. Change in OSDI, CFS OD, or CFS OS was not statistically significant at C2. Despite similar follow-up length, C1 demonstrated more clinic visits (10.4 vs 3.4, p < 0.001) and more treatment trials (4.9 vs 2.4, p < 0.001) compared to C2. Punctal plugs (85.5% vs 61.2%, p = 0.002), punctal cautery (69.7% vs 28.6%, p < 0.001), topical steroids (72.4% vs 22.4%, p < 0.001), and autologous serum tears (AST) (52.6% vs 8.2%, p < 0.001) were used more frequently at C1 than at C2. Conclusion: oGVHD patients at C1 experienced significant improvement in OSDI and corneal fluorescein staining and compared to patients at C2, had more frequent follow-up and use of punctal plugs, punctal cautery, topical steroids, and AST.

Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome.

With aging, the body's ability to maintain regular functions declines, increasing susceptibility to age-related diseases. Therapeutic interventions targeting the underlying biological changes of aging hold promise for preventing or delaying multiple age-related diseases. Metformin, a drug commonly used for diabetes treatment, has emerged as a potential gerotherapeutic agent due to its established safety record and preclinical and clinical data on its anti-aging effects. Glycosylation, one of the most common and complex co- and post-translational protein modifications, plays a crucial role in regulating protein function and has been linked to aging and various diseases. Changes in immunoglobulin G (IgG) glycosylation patterns have been observed with age, and these alterations may serve as valuable biomarkers for disease predisposition, diagnosis, treatment monitoring, and overall health assessment. In this study, we analyzed the IgG glycosylation patterns of white men from Europe, aged 29-45 years, under treatment with metformin, testosterone, metformin plus testosterone, and placebo (trial registration number NCT02514629, 2013/07/04), and investigated the longitudinal changes in glycosylation over time. We observed statistically significant differences in the IgG glycome composition between participants on testosterone therapy and placebo, with decreased agalactosylation and increased galactosylation and sialylation. However, metformin therapy did not result in statistically significant changes in glycosylation patterns. These findings contribute to our understanding of the impact of therapeutic interventions on IgG glycosylation and confirm the value of IgG glycosylation as a significant biomarker, capable of assessing biological age using the GlycanAge index and providing insight into overall health compared to chronological age.

Structure Activity Optimization of Ryanodine Receptor Modulators for the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia disorder associated with potentially lethal arrhythmias. Most CPVT cases are caused by inherited variants in the ryanodine receptor type-2 (RYR2) gene. OBJECTIVE: To investigate the structure activity relationship of tetracaine derivatives and test a lead compound in a mouse model of CPVT. METHODS: We synthesized >200 tetracaine derivatives and characterized 11 of those. The effects of these compounds on Ca2+ handling in cardiomyocytes from R176Q/+ mice was tested using confocal microscopy. The effects of lead compound MSV1302 on arrhythmia inducibility and cardiac contractility were tested using programmed electrical stimulation and echocardiography, respectively. Plasma and microsomal stability and cytotoxicity assays were also performed. RESULTS: Ca2+ imaging revealed that 4 of 11 compounds suppressed sarcoplasmic reticulum Ca2+ leak through mutant RyR2. Two compounds selected for further testing exhibited an EC50 of 146 nM (MSV1302) and 49 nM (MSV1406), respectively. While neither compound altered baseline ECG intervals, only MSV1302 suppressed stress- and pacing-induced ventricular tachycardia in vivo in R176Q/+ mice. Echocardiography revealed that the lead compound MSV1302 did not negatively impact cardiac inotropy and chronotropy. Finally, compound MSV1302 did not block INa, ICa,L, or IKr, exhibited excellent stability in plasma and microsomes, and was not cytotoxic. CONCLUSION: Structure activity relationship studies of second generation tetracaine derivatives identified lead compound MSV1302 with a favorable pharmacokinetic profile. MSV1302 normalized aberrant RyR2 activity in vitro and in vivo, without altering cardiac inotropy, chronotropy or off-target effects on other ion channels. This compound may be a strong candidate for future clinical studies to determine its efficacy in CPVT patients.

Expert views on screening for tuberculosis infection in patients commencing treatment with a biologic agent.

OBJECTIVE: Many biologic agents cause some degree of immunosuppression, which can increase the risk of reactivation of tuberculosis infection (TBI). This risk is variable between individual biologics. We aimed to assess current (and recommended) clinical practice of TBI screening and treatment among patients initiating treatment with biologic agents. METHODS: An online questionnaire was distributed via email to members of the Global Tuberculosis Network and associated professional organisations to seek insights into the screening for and treatment of TBI in patients treated with biologics. RESULTS: A total of 163 respondents in 27 countries answered at least one question. For all biologics described in the questionnaire, respondents advised increasing screening relative to current practice. Observed and supported TBI screening rates in patients treated with TNF-a inhibitors were high, especially for older TNF-a inhibitors. Most participants supported TBI screening in patients treated with B- or T-cell inhibitors but not in those treated with interleukin inhibitors. Guideline awareness was higher for TNF-a inhibitors than for other biologic classes (79% vs. 34%). CONCLUSIONS: Although respondents stated that TBI screening rates are lower than what they consider ideal, there was a tendency to recommend TBI screening in patients treated with biologics not known to be associated with an increased risk of TBI. As a result, there is a potential risk of over-screening and over-treatment of TBI, potentially causing harm, in patients treated with biologics other than TNF-a inhibitors. There is a need to research the risk of TBI associated with biologics and for guidelines to address the spectrum of TBI risk across all types of biologics.

Differences in Mu rhythm when seeing grasping/motor actions in a real context versus on screens.

Mu rhythm (∼8-12 Hz) in the somatosensory cortex has traditionally been linked with doing and seeing motor activities. Here, we aimed to learn how the medium (physical or screened) in which motor actions are seen could impact on that specific brain rhythm. To do so, we presented to 40 participants the very same narrative content both in a one-shot movie with no cuts and in a real theatrical performance. We recorded subjects' brain activities with electroencephalographic (EEG) procedures, and analyzed Mu rhythm present in left (C3) and right (C4) somatosensory areas in relation to the 24 motor activities included in each visual stimulus (screen vs. reality) (24 motor and grasping actions x 40 participants x 2 conditions = 1920 trials). We found lower Mu spectral power in the somatosensory area after the onset of the motor actions in real performance than on-screened content, more pronounced in the left hemisphere. In our results, the sensorimotor Mu-ERD (event-related desynchronization) was stronger during the real-world observation compared to screen observation. This could be relevant in research areas where the somatosensory cortex is important, such as online learning, virtual reality, or brain-computer interfaces.

Pan-cancer γδ TCR analysis uncovers clonotype diversity and prognostic potential.

Gamma-delta T cells (γδ T cells) play a crucial role in both innate and adaptive immunity within tumors, yet their presence and prognostic value in cancer remain underexplored. This study presents a large-scale analysis of γδ T cell receptor (γδ TCR) reads from 11,000 tumor samples spanning 33 cancer types, utilizing the TRUST4 algorithm. Our findings reveal extensive diversity in γδ TCR clonality and gene expression, underscoring the potential of γδ T cells as prognostic biomarkers in various cancers. We further demonstrate the utility of TCR gamma (TRG) and delta (TRD) gene expression from standard RNA-sequencing (RNA-seq) data. This comprehensive dataset offers a valuable resource for advancing γδ T cell research, with implications for enhanced immunotherapy approaches or alternative therapeutic strategies. Additionally, our centralized database supports translational research into the therapeutic significance of γδ T cells.

Prospective observational study on scar sequelae after MPOX infection: an analysis of 40 patients.

BACKGROUND: Monkeypox (MPOX) caused a public health emergency of international concern (PHEIC) outbreak between 2022 and 2023, with a recent rise in cases that prompted the World Health Organization (WHO) to declare the disease a PHEIC once again. There is little information on its long-term scarring sequelae. OBJECTIVES: The objective of this study was to assess the risk and characteristics of scarring in patients with MPOX in a tertiary hospital. METHODS: This is a prospective cohort study including patients diagnosed using polymerase chain reaction (PCR) tests. Clinical data were collected and followed up at 12-15 months to assess scarring and its impact on quality of life. RESULTS: Of the 40 patients, 19 (47.5%) developed scars, which were more common in those with initial cutaneous manifestations. Scars significantly affected the quality of life, especially in the genital and mucosal areas. The limited sample and loss to follow-up may affect the validity of the results. CONCLUSION: Scarring is a frequent and disfiguring sequela of MPOX, particularly in patients with early skin symptoms. Prevention and close follow-up are crucial in mitigating these complications.

Anterior Cruciate Ligament Repair Results in Similar Patient Reported Outcome Measures as Anterior Cruciate Ligament Reconstruction: A Systematic Review of Prospective Comparative Studies.

PURPOSE: To investigate the patient-reported outcomes (PROs), knee stability, and complications in prospective comparative studies of patients undergoing augmented anterior cruciate ligament (ACL) repair compared to ACL reconstruction (ACLR). METHODS: A literature search was performed according to the 2020 PRISMA guidelines. Human clinical studies of level I-II evidence comparing PROs, knee stability and complications following ACL repair and reconstruction were included, and a qualitative analysis was performed. Excluded studies included those lacking reporting outcomes, studies that performed open ACLR or repair, studies published prior to the year 2000 and studies with evidence levels III-IV. Study quality was assessed using the Cochrane Collaboration's risk of bias tool. RESULTS: Seven level of evidence I-II studies were retained including 190 ACLR and 221 repairs (75 Bridge-Enhanced ACL Repair (BEAR), 49 Suture Augmentation (SA), and 97 Dynamic Intraligamentary Stabilization (DIS)). At final follow-up, re-rupture rates varied between 0-14% (BEAR) vs 0-6% (ACLR) and mean side-to-side differences measured using KT-1000 testing ranged from 1.6-1.9mm (BEAR) vs 1.7-3.14mm (ACLR). For DIS vs ACLR, mean anterior tibial translation values at final follow-up were 1.7mm (DIS) vs. 1.4mm (ACLR), and re-rupture rates ranged from 20.8%-29% (DIS) vs. 17%-27.2% (ACLR). For SA vs ACLR, the mean side to side difference ranged from 0.2-0.39mm (SA) vs 0.33-0.4mm (ALCR), while the re-rupture rates were 10% (SA) vs. 0% (ACLR). International Knee Documentation Committee (IKDC), Tegner, Lysholm and Knee Injury and Osteoarthritis Outcome (KOOS) scores across both cohorts exhibited statistically significant, and comparable improvement, from baseline to final follow-up ranging from 1 to 5 years. CONCLUSION: Augmented ACL repair results in similar patient reported outcomes measures in comparison to ACL reconstruction. However, augmented ACL repair may be associated with higher rates of failure given re-rupture rates of up to 14%, 29% and 10% for BEAR, DIS and SA, respectively. LEVEL OF EVIDENCE: II; Systematic review of level I-II studies.

Postoperative Feeding in Cleft Surgery: A Systematic Review.

INTRODUCTION: Postoperative feeding is crucial for the recovery of children after cleft surgery. The literature outlines diverse feeding methods with varying recommendations on the duration of non-nipple feeding postsurgery. This study aims to explore reported postoperative feeding modalities for infants undergoing primary cleft lip/palate repair, concentrating on their influence on feeding improvement and complication reduction. METHODS: PubMed, Cochrane, and Web of Science databases were queried for original English articles without any date restrictions. This review was conducted in accordance with the 2020 PRISMA. The MINORS criteria was used to assess quality of studies. RESULTS: Of 696 abstracts, 9 full-text articles were included, consisting of 459 children with cleft lip (n = 221) & cleft lip/palate (n = 238). Feeding modalities included bottle, breastfeeding, spoon, syringe, and nasogastric tube. Two studies found a significant increase in weight with breastfeeding compared to spoon or cup. Two studies found partial wound dehiscence using spoons, and two studies reported dehiscence using bottles. Post-palatoplasty, two studies showed a decrease in hospital stay in infants breastfed (2.1 & 5.8 days) vs spoon-fed (6 days). Analgesia was reduced in the breastfed group vs spoon/nasogastric tube. CONCLUSION: This review highlights the importance of postoperative feeding in the recovery of infants with cleft lip/palate. Evidence suggests that breastfeeding may offer advantages in terms of weight gain and reduced hospital stay, while potentially minimizing the need for postoperative analgesia. The limited number of studies and variability in their outcomes underscore the need for further research to establish evidence-based guidelines for postoperative feeding.

ACL Reconstruction in Patients Over Fifty Years of Age Results in Improvements in Functional Outcomes and Broad Complication Rates: A Systematic Review.

PURPOSE: To assess the patient-reported outcomes measures (PROMs), functional knee measures, and incidence of complications in patients aged 50 and older undergoing anterior cruciate ligament reconstruction (ACLR). METHODS: A literature search was conducted across PubMed, Embase, and Scopus databases, spanning from their inception to November 2023, in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Inclusion criteria consisted of clinical studies reporting PROMs, measures of knee stability, and complication rates, following ACLR in patients aged ≥ 50 with minimum 2 year follow-up. The Methodological Index for Non-Randomized Studies (MINORS) criteria was used to assess study quality. Primary outcome measures consisted of changes PROMs and complication rates following ACLR. RESULTS: A total of 17 studies, consisting of 1,163 patients undergoing ACLR were identified. Autografts were utilized in 90.3% of patients, compared to 9.7% of patients treated using allografts. At minimum 24-month follow-up, the mean International Knee Documentation Score (IKDC) ranged from 67.4 to 92.96, while mean Lysholm scores ranged from 84.4 to 94.8, and mean Tegner scores ranged from 0.3 to 5.4. The mean side to side difference at final follow-up ranged from 1.2 to 2.4mm while the rates of recurrent instability ranged from 0 to 18%. Complications and revisions ranged from 0% to 40.4% and 0% to 37.5% of cases, with the highest rates observed in studies noting a high incidence of intraoperative cartilage lesions. CONCLUSION: Anterior cruciate ligament reconstruction in patients above the age of 50 results in favorable IKDC, Lysholm and Tegner activity scores and improvements in functional knee measures. However, a wide range of reoperation and complications are reported, attributed to varying levels of chondral injury and osteoarthritis which warrant consideration when discussing expectations in patients 50 and above undergoing ACLR. LEVEL OF EVIDENCE: IV, Systematic Review of Level II-IV studies.

bio2Byte Tools deployment as a Python package and Galaxy tool to predict protein biophysical properties.

SUMMARY: We introduce a unified Python package for the prediction of protein biophysical properties, streamlining previous tools developed by the Bio2Byte research group. This suite facilitates comprehensive assessments of protein characteristics, incorporating predictors for backbone and sidechain dynamics, local secondary structure propensities, early folding, long disorder, beta-sheet aggregation, and fused in sarcoma (FUS)-like phase separation. Our package significantly eases the integration and execution of these tools, enhancing accessibility for both computational and experimental researchers. AVAILABILITY AND IMPLEMENTATION: The suite is available on the Python Package Index (PyPI): https://pypi.org/project/b2bTools/ and Bioconda: https://bioconda.github.io/recipes/b2btools/README.html for Linux and macOS systems, with Docker images hosted on Biocontainers: https://quay.io/repository/biocontainers/b2btools?tab=tags&tag=latest and Docker Hub: https://hub.docker.com/u/bio2byte. Online deployments are available on Galaxy Europe: https://usegalaxy.eu/root?tool_id=b2btools_single_sequence and our online server: https://bio2byte.be/b2btools/. The source code can be found at https://bitbucket.org/bio2byte/b2btools_releases.

The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis.

BACKGROUND: Leptomeningeal disease (LMD) is associated with poor survival and diminished quality of life. Trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). The DEBBRAH trial was designed to evaluate its efficacy and safety in patients with HER2-positive and HER2-low ABC with a history of brain metastases (BMs) and/or LMD. Here, we report results from cohort 5, which specifically included patients with pathologically confirmed LMD. METHODS: This single-arm, open-label, five-cohort, phase 2 trial enrolled seven patients in cohort 5 who received 5.4 mg/kg T-DXd intravenously every 21 days until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) and safety profile. FINDINGS: At data cutoff (April 4, 2023), the median duration of follow-up was 12.0 months (range, 2.5-18.6). The median OS was 13.3 months (95% confidence interval [CI], 5.7-NA, p < 0.001), meeting the primary endpoint. The median PFS was 8.9 months (95% CI, 2.1-NA). Two (28.6%) of seven patients remained on treatment after 18.6 and 11.9 months, respectively. Of the five patients who progressed and died, none had intracranial progression or clinical worsening of leptomeningeal symptoms. Notably, 71.4% (95% CI, 29.0-96.3) achieved prolonged stabilization (≥24 weeks) by response evaluation criteria in solid tumors (RECIST) v.1.1. No unexpected safety signals and no treatment-related deaths were observed. CONCLUSIONS: T-DXd showed promising antitumor activity in patients with HER2-positive and HER2-low ABC with previously untreated, pathologically confirmed LMD. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. FUNDING: This work was funded by Daiichi Sankyo/AstraZeneca. This trial is registered with ClinicalTrials.gov: NCT04420598.

Evaluation of the potential use of protoporphyrins as biomarkers of anemic disease in human urine from inflammatory bowel disease patients.

Protoporphyrins are organic compounds with cyclic structure that are synthesised by a wide variety of organisms. In humans, these compounds are detected in blood and urine, with significantly higher levels in blood. Their potential as biomarkers of anemia and other diseases is currently being investigated, as their levels change according to the biochemical processes associated with the disease. The most widely used biomarker of anemia is serum ferritin, but it is unreliable in patients with inflammatory bowel disease (IBD) because its levels can be altered by acute inflammation and/or infections. There is therefore a need to look for new markers to help diagnose anemia in IBD patients. This work develops and validates a method for the determination of three protoporphyrins in human urine: protoporphyrin IX (PPIX), protoporphyrin IX complex with Zn (ZnPPIX) and protoporphyrin IX complex with Fe (II) (FePPIX), the latter also known as heme. The aim is to evaluate their potential as biomarkers of anemic disease in patients diagnosed with IBD. The proposed analytical method is based on high performance liquid chromatography (HPLC) with dual detection based on photodiode array (PDA) and fluorescence (FD). Quantification of the analytes at very low concentrations is possible due to the efficient preconcentration provided by dispersive liquid-liquid microextraction (DLLME) and the sensitivity of the detection systems. The method was validated by evaluating linearity (25-1000 ng mL-1), matrix effect, sensitivity (limits of quantification were between 5 and 11 ng mL-1), selectivity, accuracy, carry-over, dilution integrity, stability and precision (< 12.1 %). Finally, statistical analyses applied to the sample quantification results showed these three markers, together with five clinical markers, were significantly different between anemic and non-anemic IBD patients.

The Prevalence of HIV Seroconversion in Healthcare Workers Following Sharp Injuries and Exposure to Biofluids.

Background and objective Workplace accidents (WPAs) are a common problem worldwide. They are often considered a public health concern due to the potential transmission of infections such as HIV, hepatitis B, and hepatitis C through sharp devices or direct exposure to biofluids. Post-exposure prophylaxis (PEP) has demonstrated effectiveness in such instances, especially immediately after exposure. The present study aimed to report the prevalence rate of HIV seroconversion following such exposure among healthcare workers (HCWs). Methods We conducted a cross-sectional study involving a database analysis of cases from 2015 to 2024. Central tendency measures were used to describe population characteristics, and rates were calculated using standard methods. Results A total of 514 HCWs were included in the study. The prevalence of WPAs was 13 per 100 HCWs. Regarding WPAs related to HIV exposure, the prevalence was 0.9 per 100 HCWs, with 0% seroconversion thanks to timely PEP. Conclusions WPAs related to HIV exposure are a serious issue for public health systems worldwide. Although protocols are available and no seroconversion cases were reported in the present study, PEP is not always accessible in several settings, increasing the risk of seroconversion. International public policy measures should be uniformly implemented to provide faster access to prophylaxis, educate the personnel, raise awareness about bloodborne diseases, and reduce excessive red tape.

Accuracy assessment of ChatGPT responses to frequently asked questions regarding anterior cruciate ligament surgery.

BACKGROUND: The emergence of artificial intelligence (AI) has allowed users to have access to large sources of information in a chat-like manner. Thereby, we sought to evaluate ChatGPT-4 response's accuracy to the 10 patient most frequently asked questions (FAQs) regarding anterior cruciate ligament (ACL) surgery. METHODS: A list of the top 10 FAQs pertaining to ACL surgery was created after conducting a search through all Sports Medicine Fellowship Institutions listed on the Arthroscopy Association of North America (AANA) and American Orthopaedic Society of Sports Medicine (AOSSM) websites. A Likert scale was used to grade response accuracy by two sports medicine fellowship-trained surgeons. Cohen's kappa was used to assess inter-rater agreement. Reproducibility of the responses over time was also assessed. RESULTS: Five of the 10 responses received a 'completely accurate' grade by two-fellowship trained surgeons with three additional replies receiving a 'completely accurate' status by at least one. Moreover, inter-rater reliability accuracy assessment revealed a moderate agreement between fellowship-trained attending physicians (weighted kappa = 0.57, 95% confidence interval 0.15-0.99). Additionally, 80% of the responses were reproducible over time. CONCLUSION: ChatGPT can be considered an accurate additional tool to answer general patient questions regarding ACL surgery. None the less, patient-surgeon interaction should not be deferred and must continue to be the driving force for information retrieval. Thus, the general recommendation is to address any questions in the presence of a qualified specialist.

Is it really over when it is over? physical, mental and emotional health status of long-term breast cancer survivors compared to healthy matched controls.

PURPOSE: This study aimed to assess pain, fitness condition, physical activity (PA) level, comorbidities, cancer-related fatigue (CRF), mood state and health-related quality of life (HRQoL) in long-term breast cancer survivors (LTBCS) compared to women without cancer history, matched by age, weight, height, and educational level. METHODS: A cross-sectional study conducted in Granada between April 2018 and July 2023 involved 80 LTBCS and 80 matched controls. Pain, fitness condition, PA level, comorbidities, CRF, mood state, and HRQoL were evaluated ≥ 5 years post-diagnosis using validated instruments. RESULTS: LTBCS, compared to the controls, reported significantly higher levels of "pain intensity and interference", CRF (in all domains and > 40% exhibited moderate-to-severe fatigue levels), "sadness-depression", "anxiety", "anger/hostility", and "symptom scales" (All: P = .000 to .027). Moreover, 66.25% of LTBCS not only did not reach recommended PA levels (P = .035), but also presented significantly lower levels of "general physical fitness", "muscular strength", "happiness", "functioning scales" (except "emotional functioning"), and "global health status" (All: P = .000 to .048). CONCLUSION: LTBCS still suffer from physical (pain, fitness condition, and CRF), both mental and emotional (sadness-depression, anxiety and anger/hostility) long-term side effects as well as multiple HRQoL issues (including lower levels of physical functioning and higher levels of symptoms). These findings highlight the chronic nature of this disease and the importance of continuing long- term follow-up care for survivors many years after the diagnosis of breast cancer.

The LEAP2 response to cancer-related anorexia-cachexia syndrome in male mice and patients.

The hormone ghrelin serves a protective role in cancer-related anorexia-cachexia syndrome (CACS) - a condition in which plasma levels of ghrelin rise, its administration lessens CACS severity, and experimentally-reduced signaling by its receptor (GHSR) worsens fat loss and anorexia and accelerates death. Yet, actions for the related hormone liver-expressed antimicrobial peptide-2 (LEAP2), which is an endogenous GHSR antagonist, are unexplored in CACS. Here, we found that plasma LEAP2 and LEAP2/ghrelin ratio were lower in Lewis Lung Carcinoma (LLC) and RM-9 prostate cancer CACS mouse models. Ghrelin deletion exaggerated losses of tumor-free body weight and fat mass, reduced food intake, reduced soleus muscle weight, and/or lowered grip strength in LLC or RM-9 tumor-bearing mice. LEAP2 deletion lessened reductions in tumor-free body weight and fat mass and increased food intake in LLC or RM-9 tumor-bearing mice. In a 55-subject cohort of patients with CACS or weight-stable cancer, the plasma LEAP2/total ghrelin ratio was negatively correlated with 6-month weight change preceding blood collection. These data demonstrate that ghrelin deletion exacerbates CACS in the LLC and RM-9 tumor-bearing mouse models while contrastingly, LEAP2 deletion reduces measures of CACS in these tumor-bearing mouse models. Further, they suggest that lower plasma LEAP2/ghrelin ratio protects against worsened CACS.