Citations

Background/Objectives: The Visual Function and Corneal Health Status (V-FUCHS) questionnaire assesses vision-related quality of life in patients affected by Fuchs endothelial corneal dystrophy (FECD) through 15 items, which are divided into the “visual acuity (VA) Factor” and “glare Factor” domains. The purpose of this study was to translate and validate the Italian version of the V-FUCHS instrument. Methods: The original V-FUCHS questionnaire was translated into Italian using certified forward and backward translation methods and administered to patients with FECD undergoing a unilateral or bilateral Descemet membrane endothelial keratoplasty (DMEK) for FECD and healthy controls. Its test–retest reliability was assessed by administering the questionnaire twice, four weeks apart. Modified Krachmer grade, best-corrected visual acuity (BCVA) and central corneal thickness (CCT) were also measured. Results: A total of 74 participants, aged 45 to 83 years, were prospectively enrolled and divided into five subgroups: mild-to-moderate FECD (n = 18), advanced FECD (n = 15), unilateral DMEK (n = 9), bilateral DMEK (n = 12), and healthy controls (n = 20). Retest reliability confirmed the consistency and agreement of their responses (intraclass correlation coefficient > 0.90 for both factors). The Italian V-FUCHS effectively discriminated between different stages of FECD severity, with significant differences in VA and glare factor scores across all subgroups (p < 0.001). While both BCVA and CCT showed correlations with V-FUCHS scores, only the association between the VA factor and BCVA was statistically significant (p < 0.05), indicating that the VA factor meaningfully reflects patients’ measured VA. Conclusions: The proposed Italian version of the V-FUCHS questionnaire is a valid and reliable tool for assessing visual disability in patients with FECD before and after DMEK. This instrument may aid in optimizing endothelial keratoplasty timings and evaluating postoperative symptomatic improvements in FECD patients.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

Aims To determine the associations between measures of oestrogen exposure and Fuchs endothelial corneal dystrophy (FECD) severity. Methods Clinic-based cross-sectional study of 32 postmenopausal women and 11 men with mild or severe FECD, age>55 years. Participants completed questionnaires for data on demographics, anthropometric factors, medical history and potential risk factors for FECD. Women completed an additional reproductive history questionnaire used to calculate the months of lifetime oestrogen exposure. Slit-lamp biomicroscopy, specular microscopy, corneal Scheimpflug tomography and laboratory testing ( TCF4 repeat expansion quantification, total estradiol, free estradiol, sex hormone binding globulin (SHBG), calcaneal bone density) were performed. Logistic regression models were developed to predict FECD severity based on three-way interactions of each oestrogen exposure measure, sex and TCF4 genotype. Results 43 patients were enrolled in the study (mild FECD: 17 women, 3 men; severe FECD: 15 women, 8 men). Serum-free estradiol was higher in the severe compared with mild FECD group (0.21±0.2 vs 0.09±0.1 pg/mL; p=0.046). When stratified by sex, men showed no significant associations between oestrogen measures and FECD severity. However, in women, the odds of severe FECD were increased with more months of lifetime oestrogen exposure (all women; log OR (95% credible interval): 1.3 (0.14 to 4.3)), higher concentrations of free estradiol (all women; 2.1 (0.0049 to 10)), greater % free estradiol (only women without TCF4 repeat expansion; 1.3 (0.16 to 3.8)) and higher concentrations of SHBG (only women with TCF4 repeat expansion; 2.2 (0.45 to 9.1)). Conclusions While the application of these data is constrained by the limited number of participants, a clinic-based sample, small number of men compared with women and single-point measures of serum hormone measures, these data suggest that FECD severity is associated with higher oestrogen exposures in women but not men and may be dependent on TCF4 repeat expansion status.

Observational studies have demonstrated that aspirin and/or PTSG2 inhibitor (e.g., celecoxib) use, before or after colon cancer (CC) diagnosis, is associated with a lower risk of recurrence. However, a randomized trial of adjuvant celecoxib therapy in stage III CC did not show improved survival compared to placebo treatment. We therefore hypothesized that immune microenvironment features may identify patient subgroups with stronger survival benefits from anti-inflammatory celecoxib treatment. Drawing from an NCI-Intergroup trial (Cancer and Leukemia Group B [now Alliance for Clinical Trials in Oncology]/SWOG 80702) for patients with stage III resected CC that compared 3 versus 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin ± 3 years of celecoxib, we conducted tissue-based tumor microenvironment profiling on 1,098 resected tumors using a custom 9-plex, T-cell multiplex immunofluorescence assay coupled with digital image analysis and supervised machine learning. The Kaplan-Meier method was used to describe disease-free survival, based on T cell density, and log-rank testing was performed. Cox proportional hazards models were used to examine unadjusted and adjusted associations between T cell density and disease-free survival (DFS). Two-sided P values ≤0.05 were considered statistically significant. We found that higher CD3+ T cell density was associated with longer DFS with an adjusted hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.52-0.91) for patients with densities in the highest tertile as compared the lowest tertile (P=0.01). T cell subset analysis showed that stromal regulatory T helper cells (HR 0.42 comparing highest to lowest tertile, CI 0.31-0.58, P&lt;0.001) and stromal memory cytotoxic T cells (HR 0.55 comparing highest to lowest tertile, CI 0.42-0.74, P&lt;0.001) were most strongly associated with longer DFS. Compared to the placebo group, adjuvant celecoxib use associated with improved DFS for patients with low but not high stromal CD3+ T cell density (adjusted HRs of 0.45 [CI 0.31-0.65] for lowest tertile and 1.13 [CI 0.73-1.74] for highest tertile; Pinteraction=0.01). This association was also seen when the analysis was restricted to microsatellite stable tumors (HR 0.50 [CI 0.32-0.80] for lowest density tertile and 1.50 [CI 0.87-2.59] for highest density tertile; Pinteraction=0.01). T cell subset analysis showed that DFS benefit for celecoxib use most strongly associated with stromal memory helper T cell density (HR 0.38 [CI 0.26-0.56] for lowest density tertile and 1.26 [CI 0.80-1.97] for highest density tertile; Pinteraction&lt;0.001). Together, these results show that while higher T cell infiltration is associated with improved DFS, lower T cell infiltration is associated with improved DFS for patients treated with celecoxib. This unexpected finding may inform immunomodulatory treatment strategies for CC. Citation Format: Yasutoshi Takashima, Chao Ma, Qian Shi, Andressa Dias Costa, Tyler Twombly, Juha P. Väyrynen, Melissa Zhao, Ardaman Shergill, Pankaj Kumar, Felix Couture, Philip Kuebler, Smitha Krishnamurthi, Benjamin Tan, Eileen M. O'Reilly, Anthony F. Shields, Shuji Ogino, Charles S. Fuchs, Jeffrey A. Meyerhardt, Jonathan A. Nowak. Prognostic and predictive role of T cell infiltration in stage III colon cancer (CC) treated with celecoxib: CALGB/SWOG 80702 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5858.

Abstract Background The Global Leadership Initiative on Malnutrition (GLIM) introduced an approach for malnutrition diagnosis in 2019 that comprised screening followed by assessment of three phenotypic criteria (weight loss, low body mass index [BMI], and low muscle mass) and two etiologic criteria (reduced food intake/assimilation and inflammation/disease burden). This planned update reconsiders the GLIM framework based on published knowledge and experience over the past 5 years. Methods A working group ( n = 43 members) conducted a literature search spanning 2019–2024 using the keywords “Global Leadership Initiative on Malnutrition or GLIM.” Prior GLIM guidance activities for using the criteria on muscle mass and inflammation were reviewed. Successive rounds of revision and review were used to achieve consensus. Results More than 400 scientific reports were published in peer‐reviewed journals, forming the basis of 10 systematic reviews, some including meta‐analyses of GLIM validity that indicate strong construct and predictive validity. Limitations and future priorities are discussed. Working group findings suggest that assessment of low muscle mass should be guided by experience and available technological resources. Clinical judgment may suffice to evaluate the inflammation/disease burden etiologic criterion. No revisions of the weight loss, low BMI, or reduced food intake/assimilation criteria are suggested. After two rounds of review and revision, the working group secured 100% agreement with the conclusions reported in the 5‐year update. Conclusion Ongoing initiatives target priorities that include malnutrition risk screening procedures, GLIM adaptation to the intensive care setting, assessment in support of the reduced food intake/assimilation criterion, and determination of malnutrition in obesity.

AbstractBackgroundScanning laser ophthalmoscopy (SLO) visualizes two important markers of cognitive dysfunction in the retina: vascular changes and amyloid plaque (AP) deposition. The relationship between retinal arteriolar versus venular changes and perivascular amyloid deposition across the continuum of neurodegeneration is imperfectly understood. We investigate the retinal perivascular AP distribution in relationship to cognitive and neuroimaging measures in a cohort of cognitively normal and impaired individuals.Method34 subjects with normal or impaired cognition underwent retinal SLO, brain magnetic resonance imaging and standard neuropsychometric testing. Retinal peri‐arteriolar and peri‐venular curcumin positive AP were quantified in the supero‐temporal retinal quadrant, in the first, second and third‐order retinal vascular branches. The peri‐venular and peri‐arteriolar AP count were compared between patients with normal and impaired cognition, and their correlation with brain volumes, white matter hyperintensities and cognitive Z‐scores was determined.ResultWe analyzed retinal para‐venous and para‐arteriolar amyloid count in 28 subjects, mean (SD) age 65 (7.3), 50% female, 19 (52.6%) with impaired cognition. Para‐arteriolar plaque count was higher than peri‐venular plaque in the entire cohort (p<0.0001). Secondary branch peri‐venular amyloid plaque count was higher in patients with MOCA ≤26. Tertiary branch perivascular AP count significantly and negatively correlated with hippocampal volume and positively correlated white matter hyperintensity lesion count.ConclusionRetinal AP deposit peri‐arteriolarly overall and peri‐venularly in the secondary branches in cognitively impaired. Perivascular amyloid burden in small retinal branches correlates with hippocampal volume and white matter hyperintensities.

Background: For patients undergoing abdominal surgery, postoperative pulmonary complications (PPCs) are a major source of morbidity and mortality. The use of point-of-care ultrasonography (POCUS), and specifically POCUS of the lungs, has seen many advancements in recent years. Objectives: We hypothesize that perioperative lung ultrasonography can be used as a predictor for PPCs. Methods: In a Single, 1000 beds, trauma level I medical center, patients presenting for elective intra-abdominal surgery with no severe pulmonary or cardiac diseases were evaluated preoperatively with a standardized 12-point lung ultrasound exam. A second identical exam was performed after surgery in the post-anesthesia care unit. PPCs were also documented. All lung ultrasound exams were presented to a blinded researcher and a lung ultrasound score (LUS) was calculated. Statistical analysis comparing pre- and postoperative LUS and PPC scores were performed. Results: A total of 61 patients were evaluated. The pre-surgery median LUS was 0 (in the range of 0–6) and the post-surgery median LUS was 3 (in the range of 0–14). The pre- to postsurgical LUS delta was 3.4 (standard deviation of 3.3). A postoperative LUS of 6 or more was defined as “high.” A High LUS did not correlate with prolonged post-anesthesia care unit or hospital stay, prolonged oxygen support, or number of desaturation events. Conclusion: For elective abdominal surgery in relatively healthy patients, preoperative LUS usually begins at a normal level and becomes worse after general anesthesia. However, this difference in LUS is not significantly associated with clinically relevant postoperative pulmonary complications such as prolonged oxygen therapy, pneumonia, and noninvasive or invasive mechanical ventilation. Trial registration: Clinicaltrials.gov identifier: NCT05502926. Summary: This paper explores the use of point-of-care ultrasonography as a predictor for postoperative pulmonary complications. The findings suggest that while the lung ultrasound score worsens with general anesthesia, the differences are not significantly associated with postoperative pulmonary complications.

Abstract Disclosure: M. Fleseriu: Consulting Fee; Self; Novo Nordisk, Amryt Pharma Holdings Ltd, Ascend Therapeutics (A Besins Healthcare company). Speaker; Self; Xeris Pharmaceuticals, Inc., RECORDATI_RARE_DISEASES_INC., Ipsen Pharma SAS. S.L. Samson: Advisory Board Member; Self; Amryt. Research Investigator; Self; Amryt. N. Biermasz: Advisory Board Member; Self; Recordati, Pfizer Global R&D. Grant Recipient; Self; Macro Registry Grant, Amryt. C.J. Strasburger: Advisory Board Member; Self; Sandoz, Ipsen, Recordati. Consulting Fee; Self; Ascendis, Amryt, Novo Nordisk, Merck, Sandoz, Recordati. Speaker; Self; Ipsen, Novo Nordisk, HRA-Pharma. S. Fuchs Orenbach: Employee; Self; Chiesi Global Rare Diseases. J.A. Crompton: Employee; Self; Chiesi Global Rare Diseases. S. Melmed: Advisory Board Member; Self; Ionis, Crinetics. Consulting Fee; Self; Ipsen. Grant Recipient; Self; Pfizer. Background: Treatment with oral octreotide capsules (OOC) was evaluated in three phase 3 trials (CH-ACM-01, OPTIMAL, MPOWERED) in patients with acromegaly who previously tolerated and responded to the injectable somatostatin receptor ligands (iSRLs) octreotide and lanreotide. Results demonstrated efficacy and safety despite differences in trial design. Pooling data from all three trials can provide further insight into the biochemical response, symptom improvement, and safety profile of OOC. Objective: Analyze the biochemical changes, symptom control, and safety of OOC through a pooled analysis of phase 3 clinical trial datasets. Methods: Patients included were aged ≥18 years with acromegaly and responded biochemically to iSRL therapy before the initiation of OOC (defined as IGF-I &lt;1.3 × ULN and mean integrated GH &lt;2.5 ng/mL for CH-ACM-01 and MPOWERED, and IGF-I ≤1.0 × ULN for OPTIMAL). Data analyzed were from the following periods: baseline until the end of the double-blind placebo-controlled phase of OPTIMAL (36 weeks); the run-in phase of MPOWERED (26 weeks); end of dose escalation (2-5 months; efficacy data) and end of fixed dose phase (up to 7 months, safety data) for CH-ACM-01. Effect of prior iSRL dose was analyzed using a random effects meta-analysis. Symptom severity was scored using the Acromegaly Index of Severity (AIS) tool. Results: Efficacy, symptom, and safety data were available for 318, 194, and 329 patients, respectively. The overall response rate was 65% with no effect of prior iSRL dose (p&gt;0.05). Mean (SD) IGF-I change from baseline was +0.17 (0.32; n=214), +0.19 (0.39; n=81), and +0.22 (0.57; n=23) for patients with baseline IGF-I levels ≤1 × ULN, 1 to &lt;1.3 × ULN, and ≥1.3 × ULN. Twenty percent (16/81) and 35% (8/23) of patients with baseline IGF-I of 1 to &lt;1.3 x ULN and ≥1.3 x ULN shifted to an improved category of response. There was a median decrease of one symptom per patient (p&lt;0.05) and a mean decrease of 0.8 in AIS (p&lt;0.05). The proportion of OOC responders reporting ≤1, 2, or 3 moderate/severe acromegaly symptoms at baseline and month 6 decreased from 56% to 39%, 32% to 20%, and 20% to 12%. At month 6, improvement was seen for all individual symptoms (joint pain, swelling, sweating, fatigue, headache) of moderate/severe grade and was significant for joint pain (36% to 22%) and swelling (15% to 10%) (p&lt;0.02). Most adverse events (AEs) were gastrointestinal (GI) in nature (54%, n=179/329) with a median onset and duration of 15 and 12 days for first reported GI events. Conclusion: Pooled analysis confirms overall maintenance of biochemical control in patients previously responding to iSRL therapy, with decreased symptom burden in OOC responders. OOC was generally well tolerated with no new safety signals. GI-related AEs were largely transient. These results support OOC as a therapeutic option for treating acromegaly. Presentation: 6/3/2024

Purpose: The purpose of this study was to evaluate and compare the anatomic characteristics of eyes with Fuchs endothelial corneal dystrophy (FECD) with eyes without FECD. Methods: This study was a retrospective chart review performed at an academic medical center. Patients with FECD were identified through a search of the electronic medical records. Eligible patients underwent Scheimpflug imaging and optical biometry and were compared with age and sex-matched control subjects who underwent similar testing in preparation for cataract surgery. Several measurements of the cornea, anterior chamber, and eyes were evaluated using multivariable linear regression models and multivariable logistic regression models. Results: A total of 404 eyes (202 eyes with FECD and 202 control eyes) were included in this study. Compared with controls, eyes with FECD had shallower AC depths, lower AC volumes, and narrower angles. Conversely, the spherical equivalent before cataract surgery, corneal pachymetry, and corneal volume were higher in eyes with FECD. On Scheimpflug imaging analysis, these anatomical differences were present in FECD eyes with and without corneal edema. After adjusting for sex, these differences remained statistically significant. Shorter axial length was found to be statistically significant in male eyes but not in female eyes with FECD. Conclusions: This study reports new ocular characteristics in FECD eyes with and without edema. Optical biometry and Scheimpflug imaging established that the anatomic findings in eyes with FECD were not simply due to the larger volume of an edematous cornea but rather unique to eyes with FECD. These findings will provide reliable, normative data for future studies examining surgical, medical, and anatomical factors in FECD.