Citations

Abstract Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observed comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identified distinct NSCLC-like (KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling revealed stable mutational but shifting transcriptomic landscapes over time. NSCLC-like LCNECs showed elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression, while SCLC-like subtypes expressed higher levels of DLL3. Immunofluorescence confirmed FGL-1 in NSCLC-like LCNECs, and H&E slide analyses indicated fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become the first-line treatment of unresectable hepatocellular carcinoma (HCC). The prognostic value of immune-related adverse events (irAEs) in these patients remains controversial. We aimed to investigate the association between irAEs and clinical outcomes in patients with HCC treated with ICIs. METHODS: We searched the PubMed, Scopus, Web of Science, and Central Register of Controlled Trials databases for articles published from inception to June 2024, using keywords including ICI, HCC, and irAEs. Statistical analysis was performed with a random effects model. RESULTS: Of 3,028 studies, 24 (4,127 patients) met the criteria for inclusion. Atezolizumab plus bevacizumab was the most common treatment regimen (n = 10 studies). IrAEs were associated with an increased objective response rate (pooled relative ratio: 1.73; 95% confidence interval [CI]: 1.36–2.21, I 2 = 41%), a higher disease control rate (pooled relative ratio: 1.45; 95% CI: 1.21–1.74, I 2 = 74%), and longer progression-free survival (pooled hazard ratio [HR]: 0.66; 95% CI: 0.52–0.84, I 2 = 71%). There was a trend toward longer overall survival for patients with irAEs compared with those without (pooled HR: 0.84; 95% CI: 0.63–1.12, I 2 = 73%). Subgroup analysis indicated a survival benefit for patients with grade 1–2 irAEs (pooled HR: 0.50; 95% CI: 0.36–0.67, I 2 = 0%) and for those with endocrine irAEs (pooled HR: 0.63; 95% CI: 0.48–0.83, I 2 = 12%). DISCUSSION: The development of irAEs is associated with favorable clinical outcomes in HCC, including improved progression-free survival and higher objective response rate. Overall survival benefit was noted in patients with mild irAEs but not those with severe irAEs.

INTRODUCTION: Little is known about the impact of gender-affirming hormone therapy (GAHT) on transgender and gender diverse adults with inflammatory bowel disease (IBD). The primary aim was to evaluate the incidence of IBD flare in the year before and after GAHT initiation. METHODS: A retrospective study across 5 IBD centers. Flare was defined as need for steroids, IBD-associated emergency department visit, or need for IBD medication change. Factors associated with IBD flare were assessed with univariate analysis and multivariable logistic regression controlling for age and IBD type. RESULTS: A total of 85 transgender and gender diverse adults with IBD who initiated GAHT were included in this study. Forty-six (54.1%) received estrogen and 39 (45.9%) received testosterone. In the year before GAHT, 42 (49%) flared compared with 32 (38%) in the year after, P = 0.06. There was no statistically significant difference in incidence of flare by age, IBD type, or IBD therapy type. Individuals with active IBD at GAHT initiation were more likely to flare in univariate (58% vs 24%, P = 0.003) and multivariable analyses (adjusted odds ratio 5.1, 95% confidence interval 1.7–15.2). In both univariate and multivariable analyses, individuals who received testosterone were more likely to flare in the year after starting GAHT, testosterone: 51% vs estrogen: 26%, P = 0.02 with an adjusted odds ratio 3.1 (95% confidence interval 1.2–8.1). DISCUSSION: Although there was no overall increased risk of flare in the year after GAHT start, those with active IBD before hormone start and those who received testosterone were more likely to experience an IBD flare.

Background: Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory condition and is associated with significant psychosocial impacts on patient quality of life. Objective: This study aimed to characterize the utilization of patient-reported outcomes (PROs) in HS clinical trials and their concordance with trial primary endpoints. Methods: A systematic review of clinical trials was performed using the publicly available U.S. National Library of Medicine (ClinicalTrials.gov) in June 2023 utilizing the search terms hidradenitis, hidradenitis suppurativa, and suppurativa hidradenitis. Study title, start year, trial status, intervention, design, location, and primary and secondary outcomes were collected. To assess for concordance of patient and provider-reported outcomes, we identified published placebo-controlled trials that included Dermatology Life Quality Index (DLQI) and/or a numeric rating scale (NRS) for pain, the 2 most utilized PROs. Results: One hundred sixty-four HS clinical trials were identified, of which 115 were interventional studies. A total of 65.2% ( n = 107) of HS trials included at least one PRO. Pain NRS (42.7%, n = 70) and DLQI (42.1%, n = 69) were the most frequently used PRO instruments. The use of PROs in clinical trials increased over time, with 50% of trials between 2020 and 2023 utilizing PROs. Of 11 published HS trials, 82% ( n = 9) trials showed concordance of provider-assessed and PROs in at least one treatment arm. Limitations: Significance and standard deviations of PROs were rarely reported, preventing the calculation of significance and is a limitation of this review. Conclusion: While lesion counts provide single snapshots of disease, PROs can capture perceptions of lesions not actively present. PROs are frequently concordant with both achievement and nonachievement of primary endpoints in clinical trials.

Background: Solid organ transplant (SOT) recipients are living longer and, consequently, more of them require elective total hip arthroplasty (THA) to restore mobility and improve quality of life. Because these patients are chronically immunosuppressed and often burdened by multiple comorbidities, their peri-operative risk profile may differ substantially from that of the general THA population. This study aimed to evaluate risk factors associated with acute medical and surgical complications, implant survivorship, and overall mortality in patients with a history of SOT who underwent THA. Methods: A total of 173 THA procedures were reviewed in patients with previous SOT. Among them, 64 had undergone liver transplantation (LT), 83 had received renal transplants (RT), and 26 had experienced more than one type of organ transplant (MT). Kaplan–Meier survival analysis was employed to estimate median survival. Complications were examined using univariate analysis through mixed-effects logistic regression, while Cox regression was utilized to assess mortality risk. The median follow-up period extended to 99 months. Results: The proportion of patients experiencing at least one acute medical event was 27% in the LT group, 33% in the RT group, and 38% in the MT group, with no statistically significant difference between groups (p = 0.5). American Society of Anesthesiologists Class (ASA) 4 (Odds Ratio (OR) = 28; p = 0.006) and treatment with bisphosphonates (OR = 2.25; p = 0.03) were associated with higher risk of acute medical complications. Increased age at the time of SOT was linked to a reduced likelihood of surgical complications (OR = 0.94, p = 0.008), as was older age at the time of undergoing THA (OR = 0.92, p = 0.001). The observed rates of reoperation and implant revision were 3% and 1%, respectively. The estimated patient survivorship rates at 1, 5, and 10 years were 98.6, 82, and 58.4%, respectively. Older age at SOT (Hazard Ratio (HR) = 1.06, p < 0.001), at THA (HR = 1.08, p < 0.001), ASA 4 at THA (HR = 7.57, p = 0.02), and atrial fibrillation (AFib) (HR = 3.13, p = 0.02) were associated with higher mortality. Conclusions: ASA 4 and bisphosphonates were associated with a higher risk of acute medical complications, whereas older age was associated with lower surgical complications. Additionally, older age, ASA 4, and AFib were associated with higher mortality.

Background/Objectives: Facial analysis is critical for preoperative planning in facial plastic surgery, but traditional methods can be time consuming and subjective. This study investigated the potential of Artificial Intelligence (AI) for objective and efficient facial analysis in plastic surgery, with a specific focus on Multimodal Large Language Models (MLLMs). We evaluated their ability to analyze facial skin quality, volume, symmetry, and adherence to aesthetic standards such as neoclassical facial canons and the golden ratio. Methods: We evaluated four MLLMs—ChatGPT-4o, ChatGPT-4, Gemini 1.5 Pro, and Claude 3.5 Sonnet—using two evaluation forms and 15 diverse facial images generated by a Generative Adversarial Network (GAN). The general analysis form evaluated qualitative skin features (texture, type, thickness, wrinkling, photoaging, and overall symmetry). The facial ratios form assessed quantitative structural proportions, including division into equal fifths, adherence to the rule of thirds, and compatibility with the golden ratio. MLLM assessments were compared with evaluations from a plastic surgeon and manual measurements of facial ratios. Results: The MLLMs showed promise in analyzing qualitative features, but they struggled with precise quantitative measurements of facial ratios. Mean accuracy for general analysis were ChatGPT-4o (0.61 ± 0.49), Gemini 1.5 Pro (0.60 ± 0.49), ChatGPT-4 (0.57 ± 0.50), and Claude 3.5 Sonnet (0.52 ± 0.50). In facial ratio assessments, scores were lower, with Gemini 1.5 Pro achieving the highest mean accuracy (0.39 ± 0.49). Inter-rater reliability, based on Cohen’s Kappa values, ranged from poor to high for qualitative assessments (κ > 0.7 for some questions) but was generally poor (near or below zero) for quantitative assessments. Conclusions: Current general purpose MLLMs are not yet ready to replace manual clinical assessments but may assist in general facial feature analysis. These findings are based on testing models not specifically trained for facial analysis and serve to raise awareness among clinicians regarding the current capabilities and inherent limitations of readily available MLLMs in this specialized domain. This limitation may stem from challenges with spatial reasoning and fine-grained detail extraction, which are inherent limitations of current MLLMs. Future research should focus on enhancing the numerical accuracy and reliability of MLLMs for broader application in plastic surgery, potentially through improved training methods and integration with other AI technologies such as specialized computer vision algorithms for precise landmark detection and measurement.

Abstract Aims Significant advancements have been made in the management of obstructive hypertrophic cardiomyopathy (oHCM), yet the extent of left ventricular outflow tract (LVOT) gradient reduction achieved with commonly used pharmacological therapies [beta-blockers (BBs), calcium channel blockers (CCBs), disopyramide, and cardiac myosin inhibitors (CMIs)] relative to each other is still unclear. Methods and results PubMed and Scopus were searched up to September 2024. Clinical trials or observational studies that assessed the changes associated with BBs, CCBs, disopyramide, or CMIs in LVOT gradient at rest or with provocation in patients with oHCM were included. Mean changes in LVOT gradients were pooled as mean differences (MD) with 95% confidence intervals (CIs) in a random-effects model. Thirty-seven studies, with 44 arms and 1898 patients, were included in the analysis. At the therapeutic class level, pooled analysis showed that disopyramide was associated with the highest reduction in LVOT gradient at rest [MD: −43.5 (95% CI, −51.6 to −35.3)], followed by CMIs [MD: −34.8 (95% CI, −40.6 to −29.0)], BBs [MD: −20.7 (95% CI, −29.4 to −12.0)], and then CCBs [MD: −14.7 (95% CI, −23.3 to −6.1)], inter-action P &lt; 0.01. Within CMIs, mavacamten had a higher effect than aficamten on gradient reduction; among the included BBs, metoprolol showed the highest gradient reduction, while among CCBs, verapamil was the most effective (inter-action P &lt; 0.01). Similar results were observed for provocable LVOT gradients. Conclusion Pharmacological therapies effectively reduced LVOT gradients in oHCM patients to varying degrees, with disopyramide and CMIs showing the highest effect, followed by BBs and CCBs.

Background/Objectives: Staphylococci are the most common causes of periprosthetic joint infection (PJI); new antimicrobials are needed to manage these difficult infections. Nisin A is a lantibiotic peptide derived from Lactococcus lactis that has antimicrobial activity against Gram-positive bacteria, including staphylococci, and is an FDA-approved preservative used in the food and dairy industry. Here, the in vitro nisin A susceptibility of PJI-associated staphylococci was assessed. Methods: The minimum inhibitory concentrations (MICs), minimum biofilm inhibitory concentrations (MBICs), and minimum biofilm bactericidal concentrations (MBBCs) of nisin A were measured by broth microdilution against 106 staphylococcus isolates isolated from PJI. MICs were assessed using 5 × 105 CFU/mL plus nisin A. For MBICs, biofilms were grown on pegged lids for 6 h, followed by 20 h of treatment. For MBBCs, pegged lids were transferred to plates containing media only for 20 h. The results were determined as the lowest concentrations with no visual growth. Two-dimensional MICs with nisin A and vancomycin were assessed for 20 isolates. Fractional inhibitory concentrations (FICs) were calculated to determine synergistic, additive, antagonistic, or indifferent interactions. Results: The MIC that inhibited 90% of S. aureus and S. epidermidis was 4 µg/mL, apart from for the MRSA subset (8 µg/mL). The MBIC that inhibited 90% of isolates was 4 µg/mL. The MBBCs ranged from 4 to 256 µg/mL. When tested together, nisin A and vancomycin yielded an FIC between 1.25 and 1.5, indicative of indifference, except for one isolate each of MRSA and MSSA, for which an additive effect (FIC of 1) was observed. Conclusions: Nisin A showed inhibitory activity against staphylococci that cause PJI.

Background: Young women with breast cancer (YWBC) typically undergo intensive treatment that negatively impacts their quality of life (QoL). However, limited information is available on how their QoL changes, as most research has focused on older patients. Objectives: To assess changes in QoL among YWBC, identify the most affected QoL domains, and identify the factors associated with these changes. Design: Joven & Fuerte is a multicenter cohort of women aged ⩽40 in Mexico with newly diagnosed BC from 2014 to 2020. Methods: Participants completed the European Organization for Research and Treatment of Cancer Breast Cancer module QLQ-BR23 questionnaire at five different time points from enrollment until year 5 postdiagnosis. Clinical and treatment data were also collected. Group-based multivariate trajectory modeling was used to analyze longitudinal changes across QoL domains and classify patients into appropriate groups. Logistic models were then employed to identify associations between variables and group classification. Results: A total of 477 women (median age: 36 years; interquartile range 32–38) were included. Most had public health insurance (87%) and were diagnosed with stage II (49%) or III (39%) BC. Two trajectory groups, namely, “good” and “poor,” were identified based on QLQ-BR23 scores. Most patients ( n = 294, 62%) were in the poor group. In the good group, sexual enjoyment scores remained stable from baseline to year 5 (51.4), whereas those in the poor group decreased (51.0–37.3). Distress related to hair loss over time declined, with scores decreasing from 36.3 to 27.0 in the good trajectory group and from 43.4 to 31.2 in the poor trajectory group. For future perspective, the good group improved from 56.4 to 79.0, while the poor group increased from 39.3 to 57.2. Patients with human epidermal growth factor receptor 2-positive BC (adjusted odds ratio (aOR) = 0.57, 95% confidence interval (CI) 0.35–0.94, p = 0.028) and those with public health insurance (aOR = 0.41, 95% CI 0.16–0.90, p = 0.035) were less likely to belong to the poor trajectory group. Conclusion: A high proportion of YWBC experience a poor QoL trajectory over time, particularly in areas related to sexual health, future perspective, and hair loss.