Citations

Background/Objectives: Although endoscopic dacryocystorhinostomy (DCR) has been widely accepted as the procedure of choice for nasolacrimal duct obstruction (NLDO) management due to most etiologies, concerns regarding the reactivation of disease and involvement of surrounding structures add to hesitation in its utilization for granulomatosis with polyangiitis (GPA) patients. No study has directly compared outcomes of external vs. endoscopic DCR in GPA patients. This information can be helpful for patient counselling and choosing a personalized surgical approach for the best results. Methods: A scoping review of the literature was performed in January 2024. The following databases were searched using a combination of MeSH (Medical Subject Headings) and keywords: Ovid MEDLINE, Ovid EMBASE, Scopus, and Web of Science. This scoping review is not registered. Medical records of two GPA patients who underwent endoscopic DCR at our center were reviewed. Results: The search yielded 96 articles; 15 articles met the inclusion criteria for a full review. Six studies with 22 procedures reported 100% success with endoscopic DCR. Nine studies with 122 procedures reported success in 88.5% of cases with external DCRs. Additional perioperative immunosuppression was recommended in patients with severe mucosal inflammation. The case series presents the disease course, details of surgery, and perioperative management in two GPA patients with NLDO who underwent endoscopic DCR successfully. Conclusions: Endoscopic DCR was associated with equivalent or better success rates and lower complications compared to external DCR in GPA patients. Ensuring disease remission state and appropriate immunomodulatory therapy can help prevent the proposed risk of endonasal disease reactivation with endoscopic DCR.

Lymphoscintigraphy, which is commonly used for sentinel lymph node mapping, can help diagnose lymphedema, lymphatic leakage, and lymphatic malformations and provides valuable information for surgical planning and treatment.

ABSTRACT Background This medical center migrated from alcohol to sotradecol foam sclerotherapy (SFS) because of perceived improved efficacy in managing symptomatic kidney and liver cysts. We report technical aspects, change in short- and long-term cyst volumes, patient-reported outcomes, safety and applications of the technique. Methods In this retrospective observational study, cases from January 2017 to December 2021 had TKCV/TLCV (per Targeted Kidney or Liver or Cyst analysis) segmented using a deep-learning algorithm and cyst segmentation software (pre-, post-procedure and longitudinally). TKCV/TLCV % change were evaluated using the one-sample Wilcoxon signed rank test. For analyses involving changes in cyst volumes, the median % change in cyst volume per patient was assessed. Longitudinal changes in cyst volumes were assessed using linear mixed models. Changes in quality of life (QOL) [Linear Analog Self-Assessment (LASA), Polycystic Liver Disease Quality of life Questionnaire (PLD-Q) and 12-item short-form (SF12)] were also assessed. Results There were 102 SFS sessions (38 kidney, 58 liver, 6 combined liver/kidney cysts) performed on 77 unique individuals included for analysis. Median [interquartile range (IQR)] % reductions in TKCV were –92.0% (IQR –98.2%, –82.7%, P < .001) and for TLCV were –83.1% (IQR –93.5%, –52.9%, P < .001). Among patients with multiple kidney procedures (n = 7), median % reduction in TKCV was –94.3% (IQR –96.6%, –92.4%, P = .023). For patients with multiple liver procedures (n = 11), median % reduction in TLCV was –63.3% (IQR –85.2%, –28.3%, P = .004). Results were similar among the four patients undergoing multi-stage procedures (n = 1 kidney, n = 3 liver). When measured longitudinally, both liver and kidney cyst volumes declined to levels near 0 mL by 1 year follow-up and remained stable several years later. LASA physical domain and PLD-Q QOL scores improved post-SFS procedure. Conclusion SFS led to substantial long-term reductions in TKCV/TLCV and improved QOL. SFS can augment cyst volume reduction in addition to tolvaptan (kidney cysts) and octreotide (liver cysts). In some individuals with large symptomatic cysts, multiple SFS procedures were safe and effective in reducing TLCV/TKCV and improving symptoms.

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Organoids are three-dimensional (3D) structures that mimic the architecture and functionality of human organs, providing a novel approach to study diseases such as colorectal cancer (CRC). This review aims to explore the impact of organoids on understanding CRC and their potential use in exploring therapeutic outcomes. Colorectal cancer, characterized by the transformation of colonic epithelial cells into adenomas and carcinomas, remains one of the top causes of cancer-related morbidity and mortality worldwide. Traditional two-dimensional (2D) cell cultures fail to replicate the tumor microenvironment in an effective manner, which highlights the need for advanced 3D models. Organoids preserve the genetic and phenotypic properties of the original tumors, allowing for improved disease modeling, drug screening, and personalized medicine applications. When using patient-derived organoids (PDOs), researchers can gain insights into CRC initiation, progression, and treatment outcome. Ultimately, organoids represent an encouraging platform for improving therapeutic strategies for CRC, potentially leading to better patient outcomes through tailored treatment approaches.

Abstract INTRODUCTION Neurofilament light chain (NfL) quantification aids in diagnosing and predicting neurological disorders, but clinical and laboratory practices vary across centers. Differences in result interpretation and reporting further challenge test commutability. This study aimed to review the global analytical and post‐analytical methods used for NfL measurement in routine clinical practice across different contexts. METHODS We established an international working group (WG) and distributed a survey to its members to gather information on context of use (COU), (pre) analytical methods, cutoff usage, as well as the interpretation and reporting of NfL measurements. RESULTS Among the centers, 63% measured NfL in cerebrospinal fluid (CSF), 87% in blood, and 53% in both. COU was widespread, with 50% defining pathological cutoffs based on publications and 42% considering age. Reporting was primarily done through numeric results (95%). DISCUSSION Harmonizing cutoffs, reporting, and interpretation across various clinical contexts will facilitate the incorporation of this biomarker into routine clinical practice. Highlights Unique international overview of current analytical and post‐analytical methods for neurofilament light chain (NfL) measurement in routine clinical practice. Tailored sheets for each neurological application. Strategies to harmonize cutoffs, reporting, and interpretation of NfL's measurement.

OBJECTIVE In many individuals, type 2 diabetes (T2D) remains poorly controlled despite taking multiple glucose-lowering therapies. Several studies have demonstrated that endogenous hypercortisolism is prevalent among these individuals. We tested whether cortisol-directed therapy improves their glycemic control. RESEARCH DESIGN AND METHODS In this prospective, multicenter, double-blind study, 136 individuals with T2D (hemoglobin A1c [HbA1c] 7.5%–11.5% [58–102 mmol/mol] on multiple medications) and hypercortisolism (by dexamethasone suppression test) were randomized 2:1 to the glucocorticoid receptor antagonist mifepristone (300–900 mg once daily; n = 91) or placebo (n = 45) for 24 weeks, with stratification by presence/absence of an adrenal imaging abnormality. The primary end point was the change in HbA1c. Secondary end points included changes in glucose-lowering medications, weight, and waist circumference and safety. RESULTS Mean baseline HbA1c in the study cohort was 8.55% (69.9 mmol/mol). At 24 weeks, the least squares mean (LSM) difference from placebo in HbA1c was −1.32% (95% CI −1.81 to −0.83; P < 0.001). Participants receiving mifepristone experienced reductions in body weight and waist circumference (placebo-adjusted LSM differences of −5.12 kg [95% CI −8.20 to −2.03] and −5.1 cm [−8.23 to −1.99], respectively). Of participants on mifepristone, 46% discontinued therapy, compared with 18% on placebo. Adverse events with mifepristone (>10% of participants) included hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea, and dizziness, consistent with mifepristone’s known tolerability profile. Increases in blood pressure also occurred. CONCLUSIONS In individuals with inadequately controlled T2D and hypercortisolism, cortisol-directed medical therapy with mifepristone reduced HbA1c, with a manageable tolerability profile.

ABSTRACT Background Membranous nephropathy (MN) associated with phospholipase A2 receptor (PLA2R) antibodies is the most common cause of nephrotic syndrome in non-diabetic adult patients. This study investigated the relationship between clinical phenotypes and renal outcomes in this population, emphasizing the potential for phenotype-based treatment stratification. Methods We conducted a retrospective, multi-center cohort study of PLA2R-positive MN. Unsupervised cluster analysis grouped patients based on clinicopathological characteristics. Primary outcomes included complete or partial remission within 2 years of biopsy and end-stage kidney disease (ESKD) or death during follow-up. Results Among 178 patients, three distinct clusters emerged (n = 89, 70, and 19). Within 2 years of biopsy, 102 patients (57%) achieved complete or partial remission. Cluster 1, characterized by the mildest disease markers, including the lowest body mass index, serum anti-PLA2R titer, serum creatinine, proteinuria, and triglycerides, had the highest remission rate of 72%, compared with 50% in cluster 2 and 54% in cluster 3. Cluster 2 had significantly lower remission compared to cluster 1 (HR 0.64, 95% CI 0.42–0.96, P = .03); results were similar in cluster 3, albeit not statistically significant (HR 0.50, 95% CI 0.23–1.09, P = .08). Elevated anti-PLA2R levels (>100 U/ml) and proteinuria (>8 g/24-hour) predicted reduced remission (HR 0.56, 95% CI 0.36–0.88, P = .01; HR 0.43, 95% CI 0.26–0.73, P = .002, respectively), while high high-density lipoprotein levels were protective (HR 1.01, 95% CI 1.00–1.02, P = .048). Overall, 21 patients (12%) developed ESKD or died. ESKD-free survival differed significantly across clusters (log-rank test P = .04). Conclusions Unsupervised clustering identified distinct clinical phenotypes in PLA2R-positive MN, each associated with different renal prognoses. Phenotype-based risk stratification could enhance treatment precision, improve patient outcomes, and potentially reduce treatment-related adverse effects.

ABSTRACTBackgroundAdvances in fibril typing by mass spectrometry have improved the accuracy of amyloidosis diagnosis. Dual amyloidogenic proteins have been reported in deposits in sole and multiple different organs.MethodsFive patients with dual amyloidoses were diagnosed between 1995 and 2022 by Congo red staining and fibril typing using the best available methods at the time of evaluation. Sequencing of TTR and GSN genes was performed. Literature search identified 46 additional cases.ResultsThree patients exhibited Waldenström macroglobulinemia‐associated AL (n = 3) amyloidoses in conjunction with ATTRwt or AGel amyloidosis; two patients featured AL/ATTRwt and AA/ATTRwt amyloidoses. One patient demonstrated dual amyloidoses within one anatomical site; three patients featured two amyloidosis types at different anatomical sites; and one patient had dual amyloid deposits in a single anatomical site along with different sites. The time interval between diagnoses was 0–288 months, with the heart and kidneys being the most affected organs.ConclusionsOur findings underscore the complexity of clinical presentation in amyloidosis, as multiple amyloid types can co‐exist in a single individual and affect various anatomical sites. Accurate assessment of the clinical phenotype and thorough amyloid fibril typing from the target organs are essential for precise diagnosis and tailored treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT00898235