Molecular Frontiers in Melanoma: Pathogenesis, Diagnosis, and Therapeutic Advances.

Melanoma, a highly aggressive skin cancer, is characterized by rapid progression and high mortality. Recent advances in molecular pathogenesis have shed light on genetic and epigenetic changes that drive melanoma development. This review provides an overview of these developments, focusing on molecular mechanisms in melanoma genesis. It highlights how mutations, particularly in the BRAF, NRAS, c-KIT, and GNAQ/GNA11 genes, affect critical signaling pathways. The evolution of diagnostic techniques, such as genomics, transcriptomics, liquid biopsies, and molecular biomarkers for early detection and prognosis, is also discussed. The therapeutic landscape has transformed with targeted therapies and immunotherapies, improving patient outcomes. This paper examines the efficacy, challenges, and prospects of these treatments, including recent clinical trials and emerging strategies. The potential of novel treatment strategies, including neoantigen vaccines, adoptive cell transfer, microbiome interactions, and nanoparticle-based combination therapy, is explored. These advances emphasize the challenges of therapy resistance and the importance of personalized medicine. This review underlines the necessity for evidence-based therapy selection in managing the increasing global incidence of melanoma.

Neuromuscular blocking agent re-exposure in a retrospective cohort with neuromuscular blocking agent-associated anaphylaxis.

BACKGROUND: Neuromuscular blocking agents (NMBAs) are one of the most common causes of perioperative anaphylaxis. Although skin test positivity may help identify reactive NMBAs, it is unclear whether skin test negativity can guarantee the safety of systemically administered NMBAs. OBJECTIVE: This study aimed to evaluate the real-world safety of alternative NMBAs screened using skin tests in patients with suspected NMBA-induced anaphylaxis. METHODS: A retrospective cohort of suspected NMBA-induced anaphylaxis were recruited among patients at Seoul National University Hospital from June 2009 to May 2021, and their characteristics and outcomes were assessed. RESULTS: A total of 47 cases (0.017%) of suspected anaphylaxis occurred in 282,707 patients who received NMBAs. Cardiovascular manifestations were observed in 95.7%, whereas cutaneous findings were observed in 59.6%. Whereas 83% had a history of undergoing general anesthesia, 17% had no history of NMBA use. In skin tests, the overall positivity to any NMBA was 94.6% (81.1% to culprit NMBAs) and the cross-reactivity was 75.7%, which is related to the chemical structural similarity among NMBAs; the cross-reactivity and chemical structure similarity of rocuronium were 85.3% and 0.814, respectively, with vecuronium; this is in contrast to 50% and 0.015 with cisatracurium and 12.5% and 0.208 with succinylcholine. There were 15 patients who underwent subsequent surgery with a skin test-negative NMBA; whereas 80.0% (12/15) safely completed surgery, 20.0% (3/15) experienced hypotension. CONCLUSION: Similarities in chemical structure may contribute to the cross-reactivity of NMBAs in skin tests. Despite the high negative predictability of skin tests for suspected NMBA-induced anaphylaxis, the potential risk of recurrent anaphylaxis has not been eliminated.

Factors Associated with Visual Acuity in Advanced Glaucoma.

This study aimed to comprehensively analyze various parameters in advanced glaucoma patients to identify the factors that can affect best-corrected visual acuity (BCVA) in advanced glaucoma. This cross-sectional retrospective study included 113 patients (mean age, 61.66 ± 13.26 years; males, 67) who had advanced glaucomatous damage (113 eyes; mean BCVA, 0.18 ± 0.38 logMAR; mean deviation of 30-2 visual field [VF], -19.08 ± 6.23 dB). Peripapillary retinal nerve fiber layer (RNFL) and total and segmented macular thickness (RNFL, ganglion cell layer (GCL), and inner plexiform layer (GCL)) were measured using Spectralis optical coherence tomography (OCT). Correlations between BCVA and OCT parameters or 30-2 VF parameters were assessed using Pearson correlation analysis. Multivariate regression analysis was performed to determine the factors associated with BCVA in advanced glaucoma patients. Peripapillary RNFL thickness, subfoveal choroidal thickness, and global macular RNFL, GCL, IPL, and total thickness were found to be significantly correlated with BCVA and central visual function. Multivariate analysis showed a significant correlation between subfoveal choroidal thickness and BCVA. In addition, central VF mean sensitivity, especially inferior hemifield, showed a significant relationship with BCVA. In conclusion, subfoveal choroidal thickness and central VF sensitivity, especially the inferior hemifield area, are factors that affect BCVA in advanced glaucoma.

Predictors of long-term visual field outcome after an episode of acute primary angle closure.

BACKGROUND: To investigate the long-term visual field (VF) outcome and baseline factors associated with functional sequelae in patients who experienced an episode of acute primary angle closure (APAC) and underwent subsequent lens extraction. METHODS: Fifty patients (50 eyes) who experienced an APAC episode and underwent subsequent lens extraction at Chonnam National University Hospital were enrolled in this retrospective study. Patients underwent VF examinations after 1 year of an acute episode. They were classified into two groups based on whether they had significant VF defects or not. Demographic data were recorded, and baseline anterior-segment OCT (AS-OCT) images were analysed. Multivariate logistic regression analysis was performed to assess baseline risk factors for presence of VF defects. RESULTS: Twenty-five (50%) eyes were found to have varied degree of VF defects after 1 year of an acute episode. Longer duration between the symptom onset and IOP lowering (p = 0.005), a higher presenting IOP (p = 0.014), and flat iris curvature (p = 0.037) at baseline AS-OCT measurement were significant predictors of VF loss. The area under the receiver operating characteristic curve (AUC) revealed that combination of these three potential baseline factors could predict the long-term VF outcome (AUC = 0.921). CONCLUSIONS: Patients exhibiting a long duration between symptom onset and IOP lowering, a high presenting IOP, and flat iris curvature were at a higher risk of visual impairment after an episode of APAC. The eyes with such features may require more careful follow-up after an episode of APAC.

Clinical and Economic Impact of Pharmacists' Intervention on Care of Pediatric Hematology and Oncology Patients.

INTRODUCTION: Children with cancer may be one of the most vulnerable groups to drug-related adverse events because they possess characteristics of patients with cancer as well as pediatric patients. To evaluate the clinical and economic impact of pharmacists' intervention on the care of pediatric hematology and oncology patients in the inpatient and outpatient settings of a children's hospital. METHODS: The pharmacist-intervention records from 2017 were retrospectively reviewed. Intervention rate, type of drug-related problems, acceptance rate, and frequently involved drugs in pharmacist interventions were analyzed. One physician and one pharmacist evaluated the clinical significance of each intervention. A cost-benefit analysis was conducted from hospital and patient perspective. The benefit from cost savings by reducing the number of prescribed drugs that are disposed was estimated as the benefit from hospital perspective. The benefit from cost avoidance based on the potential to avoid an adverse drug event (ADE) was estimated as the benefit from patient perspective. The cost of reviewing prescriptions was estimated based on the pharmacists' salary and the time involved. RESULTS: In 2017, 2361 interventions were performed in 381 pediatric patients with cancer. The acceptance rate was 97.2%. More than half of the interventions were regarded as clinically "significant" (58.8%) and "very significant" (14.6%). The cost-benefit of US$28,705 was determined from hospital perspective, with a cost-benefit ratio of 1.45:1. The cost-benefit of US$35,611 was calculated from patient perspective, with a cost-benefit ratio of 1.55:1. CONCLUSIONS: Pharmacists' intervention in the care of hematology and oncology pediatric patients was effective in preventing clinically significant ADEs and had a positive economic impact on the health-care budget from both hospital and patient perspective.

Influence of scan direction on subfoveal choroidal vascularity index using optical coherence tomography.

We investigated the influence of scan direction on subfoveal choroidal vascularity index (CVI) measurements using spectral-domain optical coherence tomography (SD-OCT) in young healthy subjects. Seventy-eight eyes of 41 healthy volunteers were included. Choroidal structures were obtained using SD-OCT with enhanced depth imaging (EDI) through radial scans at the center of the macula. The subfoveal choroidal images in the horizontal (0°), 45°, vertical (90°) and - 45° directions were recorded and CVIs were analyzed according to their respective directions using image binarization. Additionally, subfoveal choroidal thickness (SFCT), and axial eye length were measured. The SFCT and subfoveal CVI showed a negative correlation but were only significant for the 45° scan (Pearson's r = - 0.262, P = 0.021). The axial eye length and subfoveal CVI had no significant correlation in any direction (all P > 0.05). In the Bland-Altman plot, the subfoveal CVI measurement showed high agreement among the four scan directions. When the SFCT was ≥ 300 µm, there was no difference in the measured values of the subfoveal CVI among the four scan directions; however, when the SFCT was < 300 µm, there was a significant difference in subfoveal CVI among the scan directions (one-way analysis of variance, F = 4.685, P = 0.004). In subfoveal CVI measurement, it is considered that the horizontal (0°) scan can represent the vertical (90°) or oblique (45°, - 45°) scans. However, when the SFCT is thinner, the subfoveal CVI in each direction of radial scan may vary significantly. Hence, caution is required in the interpretation.

Autophagy: Guardian of Skin Barrier.

Autophagy is a major degradation pathway that removes harmful intracellular substances to maintain homeostasis. Various stressors, such as starvation and oxidative stress, upregulate autophagy, and the dysregulation of autophagy is associated with various human diseases, including cancer and skin diseases. The skin is the first defense barrier against external environmental hazards such as invading pathogens, ultraviolet rays, chemical toxins, and heat. Although the skin is exposed to various stressors that can activate autophagy, the roles of autophagy in the skin have not yet been fully elucidated. Accumulating evidence suggests that autophagy is closely associated with pathogenesis and the treatment of immune-related skin diseases. In this study, we review how autophagy interacts with skin cells, including keratinocytes and immune cells, enabling them to successfully perform their protective functions by eliminating pathogens and maintaining skin homeostasis. Furthermore, we discuss the implications of autophagy in immune-related skin diseases, such as alopecia areata, psoriasis, and atopic dermatitis, and suggest that a combination of autophagy modulators with conventional therapies may be a better strategy for the treatment of these diseases.

Risk for Behçet's disease gauged via high-density lipoprotein cholesterol: a nationwide population-based study in Korea.

Behçet's disease (BD) is a chronic inflammatory disease. Low levels of plasma high-density lipoprotein cholesterol (HDL-C) are associated with Crohn's disease, another chronic inflammatory disease. However, the effects of low HDL-C levels on BD are unclear. We investigated the effects of HDL-C levels, and variability therein, on the risk for BD. We used the Korean National Health Insurance System database to identify 5,587,754 adults without a history of BD who underwent ≥ 3 medical examinations between 2010 and 2013. Mean HDL-C levels at each visit were used to calculate variability independent of the mean (VIM) and the coefficient of variation (CV). There were 676 new cases of BD (0.012%). The risk for BD was increased in participants with highly variable and low mean HDL-C levels. In a multivariate-adjusted model, the hazard ratios (95% confidence intervals) for BD incidence were 1.335 (1.058-1.684) in a high mean/high VIM group, 1.527 (1.211-1.925) in a low mean/low VIM group, and 2.096 (1.67-2.63) in a low mean/high VIM group compared to a high mean/low VIM group. Low mean HDL-C levels, and high variability therein, are independent risk factors for BD.

Allergic-like Hypersensitivity Reactions to Gadolinium-based Contrast Agents: An 8-year Cohort Study of 154 539 Patients.

Background With the widespread use of gadolinium-based contrast agents (GBCAs), the incidence of allergic-like hypersensitivity reactions (HSRs) to GBCAs is increasing. Research on the incidence and risk factors for HSRs to GBCAs is needed for their safe use. Purpose To determine the incidence of acute and delayed reactions to GBCAs and to discuss the risk factors and strategies for the prevention of HSRs to GBCAs. Materials and Methods All cases of HSRs to contrast media that occurred at the Seoul National University Hospital from July 1, 2012, to June 30, 2020, were assessed. Information including age, sex, GBCA type, onset, and severity of HSRs was retrospectively analyzed. Results Among the 331070 cases of GBCA exposure in 154539 patients, 1304 cases of HSRs (0.4%) were reported. Acute HSRs accounted for 1178 cases (0.4%), while 126 cases (0.04%) were delayed HSRs. While both premedication (odds ratio [OR] = 0.7, P = .041) and changing the type of GBCA (OR = 0.2, P < .001) showed preventative effects in patients with a history of acute HSRs, only premedication (OR = 0.2, P = .016) significantly reduced the incidence of HSRs in patients with a history of delayed reactions. The risk of an HSR to GBCA was higher in those with a history of an HSR to iodinated contrast media (OR = 4.6, P < .001). Conclusion The rate of hypersensitivity reactions (HSRs) to gadolinium-based contrast agents (GBCAs) was 0.4%. The absence of premedication, repeated exposures to the culprit GBCA, and a history of HSRs to iodinated contrast media and GBCAs were risk factors for HSRs to GBCAs. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Kallmes and McDonald in this issue.

Association of Actinic Keratosis with Rheumatoid Arthritis and Psoriasis: A Nationwide Population-Based Study in Korea.

There have been no epidemiological studies identifying associations between systemic inflammatory diseases and actinic keratosis. This study used a large nationwide database to investigate the associations between actinic keratosis and systemic inflammatory diseases. Records of patients over 20 years of age newly diagnosed with actinic keratosis (n = 64,659) from 2012 to 2017 were analysed. A control population of individuals without actinic keratosis, matched for age, sex, and year of claim, who visited an outpatient clinic, was sampled at a ratio of 1:1 (n = 64,659). Both cohorts were analysed for the presence of systemic inflammatory diseases within at least 5 years prior to diagnosis of actinic keratosis. Patients with actinic keratosis exhibited higher odds ratios for rheumatoid arthritis (1.336; 95% confidence interval (95% CI) 1.161-1.537)) and psoriasis (1.513; 95% CI 1.435-1.595) compared with the control group on multivariate analysis. However, the proportions of Behçet's disease, Crohn's disease, ulcerative colitis, and multiple sclerosis in the actinic keratosis group were not statistically significant.

Nasal Turbinate Mesenchymal Stromal Cells Preserve Characteristics of Their Neural Crest Origin and Exert Distinct Paracrine Activity.

The sources of mesenchymal stromal cells (MSCs) for cell therapy trials are expanding, increasing the need for their characterization. Here, we characterized multi-donor, turbinate-derived MSCs (TB-MSCs) that develop from the neural crest, and compared them to bone marrow-derived MSCs (BM-MSCs). TB-MSCs had higher proliferation potential and higher self-renewal of colony forming cells, but lower potential for multi-lineage differentiation than BM-MSCs. TB-MSCs expressed higher levels of neural crest markers and lower levels of pericyte-specific markers. These neural crest-like properties of TB-MSCs were reflected by their propensity to differentiate into neuronal cells and proliferative response to nerve growth factors. Proteomics (LC-MS/MS) analysis revealed a distinct secretome profile of TB-MSCs compared to BM and adipose tissue-derived MSCs, exhibiting enrichments of factors for cell-extracellular matrix interaction and neurogenic signaling. However, TB-MSCs and BM-MSCs exhibited comparable suppressive effects on the allo-immune response and comparable stimulatory effects on hematopoietic stem cell self-renewal. In contrast, TB-MSCs stimulated growth and metastasis of breast cancer cells more than BM-MSCs. Altogether, our multi-donor characterization of TB-MSCs reveals distinct cell autonomous and paracrine properties, reflecting their unique developmental origin. These findings support using TB-MSCs as an alternative source of MSCs with distinct biological characteristics for optimal applications in cell therapy.

Investigation of Genetic Mutations in High-risk and Low-risk Basal Cell Carcinoma in a Non-Caucasian Population by Whole Exome Sequencing.

This study analysed genomic mutations in basal cell carcinoma using whole exome sequencing of DNA specimens obtained from 20 Korean patients. Histological evaluation determined that 15 (75%) were low-risk basal cell carcinomas, and 5 (25%) were high-risk basal cell carcinomas. Seventy-five percent of the basal cell carcinomas harboured somatic mutations in hedge-hog pathway genes (PTCH1, 40% and SMO, 50%) and 45% harboured mutations in TP53. LRP1B was the most frequently mutated gene in high-risk basal cell carcinomas, SMO was the most frequently mutated gene in low-risk basal cell carcinomas. Specifically, LRP1B, ROS1, PTCH1, KMT2C, NSD1 and ARID1A mutations were more frequent in high-risk basal cell carcinomas than in low-risk basal cell carcinomas. However, copy number gains of the ROS1 gene were observed only in low-risk basal cell carcinomas. Other basal cell carcinoma related genes found in this study include: KDR, KMT2D, FAT1, FAT4, GRIN2A, ERBB4, NOTCH2, PDE4DIP, TET1, ZFHX3 and PREX2. These results provide insight into basal cell carcinoma in non-Caucasians.

Practical Considerations in Providing End-of-Life Care for Dying Patients and Their Family in the Era of COVID-19.

In the era of coronavirus disease 2019 (COVID-19), social distancing and strict visitation policies at hospitals have made it difficult for medical staff to provide high-quality end-of-life (EOL) care to dying patients and their families. There are various issues related to EOL care, including psychological problems of patients and their families, difficulties in EOL decision-making, the complicated grief of the bereaved family, moral distress, and exhaustion of medical staff. In relation to these issues, we aimed to discuss practical considerations in providing high-quality EOL care in the COVID-19 pandemic. First, medical staff should discuss advance care planning as early as possible and use the parallel planning strategy. Second, medical staff should play a role in facilitating patient-family communication. Third, medical staff should actively and proactively evaluate and alleviate dying patients' symptoms using non-verbal communication. Lastly, medical staff should provide care for family members of the dying patient, who may be particularly vulnerable to post-bereavement problems in the COVID-19 era. Establishing a system of screening high-risk individuals for complicated grief and connecting them to bereavement support services might be considered. Despite the challenging and limited environment, providing EOL care is essential for patients to die with dignity in peace and for the remaining family to return to life after the loved one's death. Efforts considering the practical issues faced by all medical staff and healthcare institutions caring for dying patients should be made.

Anti-Diabetic Obesity Effects of Wasabia Japonica Matsum Leaf Extract on 45% Kcal High-Fat Diet-Fed Mice.

The present study examined the effects of Wasabi leaf (WL) on 45% Kcal high-fat diet (HFD)-fed mild diabetic obese mice. In particular, the hepatoprotective (i.e., liver weight, histopathology of liver, serum aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase) effects of 12 weeks of continuous oral administration of 250 mg/kg metformin, and 200, 100, or 50 mg/kg WL were investigated. In addition, the hypolipidemic (i.e., serum triglyceride, total cholesterol, high-density lipoprotein-cholesterol, and low-density lipoprotein levels), hypoglycemic (i.e., glycated hemoglobin, blood glucose and insulin levels, pancreatic weight, and immunohistochemical-histopathological analysis of the pancreas), and anti-obesity effects (i.e., body weight, mean food consumption, total and abdominal body fat mass, periovarian fat weight, and histopathology of the periovarian and abdominal wall adipocytes) were monitored. The liver and general antioxidant defense systems were also assessed by lipid metabolism-related gene expression. All diabetes manifestations and related complications, including obesity and non-alcoholic fatty liver disease (NAFLD), were dose-dependently reduced after 84 days of oral treatment with metformin or each of the three dosages of WL. In particular, 50 mg/kg WL showed effective suppression effects against HFD-induced diabetes and related complications of obesity, NAFLD, and hyperlipidemia, comparable to the effects of metformin.