Skin-directed radiotherapy for primary cutaneous T-cell lymphomas.

PURPOSE: To evaluate the efficacy and toxicities of skin-directed radiotherapy (RT) in primary cutaneous T-cell lymphoma (CTCL). MATERIALS AND METHODS: We retrospectively analyzed 57 CTCL lesions treated with skin-directed RT between January 2000 and December 2022. Lesions were categorized into three distinct groups: early-stage disease treated with local RT, advanced-stage disease treated with local RT, and advanced-stage disease treated with total skin electron beam therapy (TSEBT). Treatment outcomes, including response rates, recurrence patterns, and local progression probability, were assessed for each group. RESULTS: Mycosis fungoides (MF) constituted 90.9% of the advanced-stage pathologies, while CD4+ primary cutaneous small/medium T-cell lymphoproliferative disorder was common in the early stage lesions (55%). Median RT doses were 30.6 Gy, 27 Gy, and 32 Gy for the local RT with early stage, the local RT with advanced stage, and TSEBT with advanced stage, respectively. The complete response rates were high across the groups: 95.5%, 70.8%, and 90.9%, respectively. Seven local recurrences (29.2%) occurred in the local RT group with advanced stage, while seven patients (63.6%) in the TSEBT group experienced local failure. All recurrences were observed in lesions and patients with MF. Acute toxicities were mainly grade 1 or 2, with no grade 3 or higher events. No significant association between RT dose and local progression rates in MF lesions was found. CONCLUSION: Skin-directed RT in CTCL is effective for local control and well-tolerated with less toxicity.

Association between grit and insomnia: A population-based study.

BACKGROUND: This study aimed to investigate the association of the grit scale, a personality trait characterized by perseverance and passion, with both the presence and the severity of insomnia in the Korean adult population. METHODS: A nationwide population-based cross-sectional survey was conducted through face-to-face interviews using structured questionnaires between September and December 2018 in Korea. Grit was assessed by using the 8-item Short Grit Scale. Participants were categorized into insomnia and non-insomnia groups based on a threshold of 10 on the Insomnia Severity Index (ISI). The association between girt and insomnia was analyzed using multiple linear regression and multivariable logistic regression, controlling for sociodemographic factors, lifestyles, and comorbidities. RESULTS: A total of 2453 participants (49.9 % male; aged 19-92 years) were enrolled in the study. Individual grit scores ranged from 1.75 to 5.00 points (mean [SD], 3.27 [0.42]), and insomnia was present in 16.5 % of the population. The insomnia group exhibited lower grit score compared to the non-insomnia group (3.11 [0.40] vs. 3.30 [0.42], p < 0.001, Cohen's d = 0.46). Grit was negatively associated with ISI scores (ß = -0.15, 95 % CI = -0.19, -0.11, p < 0.001) and with having insomnia (OR 0.40, 95 % CI = 0.30, 0.55, p < 0.001), after controlling for covariates. CONCLUSIONS: Individuals with higher grit were less likely to have insomnia. Clinicians should consider personality traits, such as grit, in the evaluation and the management of insomnia.

A Narrative Review of the Evolution of Diagnostic Techniques and Treatment Strategies for Acral Lentiginous Melanoma.

Acral melanoma (AM) is a subtype of cutaneous melanoma located on the palms, soles, and nails. The pathogenesis of AM involves mechanical stimulation and characteristic tumor-promoting mutations, such as those in the KIT proto-oncogene. Dermoscopy is useful for diagnosing AM, which is characterized by parallel ridge patterns and irregular diffuse pigmentation. Although histopathological confirmation is the gold standard for diagnosing AM, lesions showing minimal histopathological changes should be considered early-stage AM if they clinically resemble it. Recently, immunohistochemical staining of preferentially expressed antigen in melanoma has been recognized as a useful method to distinguish benign from malignant melanocytic tumors. Research reveals that AM is associated with an immunosuppressive microenvironment characterized by increased numbers of M2 macrophages and regulatory T cells, alongside a decreased number of tumor-infiltrating lymphocytes. Mohs micrographic surgery or digit-sparing wide local excision has been explored to improve quality of life and replace wide local excision or proximal amputation. AM has a worse prognosis than other subtypes, even in the early stages, indicating its inherent aggressiveness.

Miltefosine induces reproductive toxicity during sperm capacitation by altering PI3K/AKT signaling pathway.

Miltefosine is the first and only drug approved for the treatment of leishmaniasis. It is also known as a PI3K/AKT signaling pathway inhibitor utilized in anti-cancer or anti-viral therapies. However, the impact of miltefosine on male fertility has not been fully understood. Therefore, this study was performed to investigate the effects of miltefosine on sperm function during capacitation. Duroc spermatozoa were exposed to 0, 2.5, 5, 10, 20, 40, and 80 µM miltefosine and induced for capacitation. Our results showed that miltefosine dramatically increased the expression of PI3K/AKT signaling pathway-associated proteins. Sperm motility, motion kinetics, capacitation, and tyrosine phosphorylation were significantly suppressed by miltefosine. However, intracellular ATP levels and cell viability were not significantly affected. Our findings suggest that miltefosine may disrupt sperm function by abnormally increasing the levels of PI3K/AKT signaling pathway-associated proteins. Therefore, the harmful effects of miltefosine on male reproduction should be considered when using this drug.

Prevalence, clinical features, and survival outcome trends of 627 patients with primary cutaneous lymphoma over 29 years: a retrospective review from single tertiary center in Korea.

The relative frequency of primary cutaneous lymphoma (PCL) subtypes shows wide variation across different geographical regions. This retrospective study was conducted in a tertiary referral center located in Korea to describe the relative frequency, demographics, survival outcomes, and temporal trend in PCL. A total of 627 PCL cases diagnosed between January 1994 and December 2022 were included. The majority of PCL cases (87.2%) were of T-/NK-cell lineage (CTCL), while the remaining cases (12.8%) were B-cell lineage lymphomas (CBCL). The prevalence of mycosis fungoides (MF) in CTCL increased significantly over time, while other CTCL subtypes, including primary cutaneous extranodal NK/T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma (SPTCL), decreased in frequency. Notably, the prevalence of CD4-positive small/medium T-cell lymphoproliferative disorder showed a substantial increase over time. Primary cutaneous marginal zone lymphoma was consistently the commonest CBCL subtype. Survival analysis demonstrated that CTCL had a more favorable 5-year overall survival (OS) than CBCL. OS rate of MF, SPTCL, and primary cutaneous peripheral T-cell lymphoma, NOS improved significantly over time. This study provides comprehensive insights into the dynamic change in the relative frequency and overall survival of PCL subtypes over time.

Assessing the Risks of Pesticide Exposure: Implications for Endocrine Disruption and Male Fertility.

Pesticides serve as essential tools in agriculture and public health, aiding in pest control and disease management. However, their widespread use has prompted concerns regarding their adverse effects on humans and animals. This review offers a comprehensive examination of the toxicity profile of pesticides, focusing on their detrimental impacts on the nervous, hepatic, cardiac, and pulmonary systems, and their impact on reproductive functions. Additionally, it discusses how pesticides mimic hormones, thereby inducing dysfunction in the endocrine system. Pesticides disrupt the endocrine system, leading to neurological impairments, hepatocellular abnormalities, cardiac dysfunction, and respiratory issues. Furthermore, they also exert adverse effects on reproductive organs, disrupting hormone levels and causing reproductive dysfunction. Mechanistically, pesticides interfere with neurotransmitter function, enzyme activity, and hormone regulation. This review highlights the effects of pesticides on male reproduction, particularly sperm capacitation, the process wherein ejaculated sperm undergo physiological changes within the female reproductive tract, acquiring the ability to fertilize an oocyte. Pesticides have been reported to inhibit the morphological changes crucial for sperm capacitation, resulting in poor sperm capacitation and eventual male infertility. Understanding the toxic effects of pesticides is crucial for mitigating their impact on human and animal health, and in guiding future research endeavors.

Nilotinib treatment outcomes in autosomal dominant spinocerebellar ataxia over one year.

We evaluated the efficacy and safety of 1-year treatment with nilotinib (Tasigna®) in patients with autosomal dominant spinocerebellar ataxia (ADSCA) and the factors associated with responsiveness. From an institutional cohort, patients with ADSCA who completed a 1-year treatment with nilotinib (150-300 mg/day) were included. Ataxia severity was assessed using the Scale for the Rating and Assessment of Ataxia (SARA), scores at baseline and 1, 3, 6, and 12 months. A subject was categorized 'responsive' when the SARA score reduction at 12 M was > 0. Pretreatment serum proteomic analysis included subjects with the highest (n = 5) and lowest (n = 5) SARA score change at 12 months and five non-ataxia controls. Thirty-two subjects (18 [56.2%] females, median age 42 [30-49.5] years) were included. Although SARA score at 12 M did not significantly improve in overall population, 20 (62.5%) subjects were categorized as responsive. Serum proteomic analysis identified 4 differentially expressed proteins, leucine-rich alpha-2-glycoprotein (LRG1), vitamin-D binding protein (DBP), and C4b-binding protein (C4BP) beta and alpha chain, which are involved in the autophagy process. This preliminary data suggests that nilotinib might improve ataxia severity in some patients with ADSCA. Serum protein markers might be a clue to predict the response to nilotinib.Trial Registration Information: Effect of Nilotinib in Cerebellar Ataxia Patients (NCT03932669, date of submission 01/05/2019).

Effects of oridonin on sperm function and the PI3K/PDK1/AKT signaling pathway: Implications for reproductive toxicity.

Oridonin, a natural terpenoid isolated from the leaves of Isodon rubescens (Hemsley) H.Hara, is widely used in oriental medicine for its anticancer properties across various cancer types. Despite its prevalent use, the toxic effects of oridonin on male reproduction, particularly its impact on sperm functions and the mechanisms involved, are not well understood. This study aimed to explore the effects and underlying mechanisms of oridonin on sperm functions. We initially treated Duroc boar spermatozoa with varying concentrations of oridonin (0, 5, 50, 75, 100, and 150 µM) and incubated them to induce capacitation. We then assessed cell viability and several sperm functions, including sperm motility and motion kinematics, capacitation status, and ATP levels. We also analyzed the expression levels of proteins associated with the phosphatidylinositol 3-kinase (PI3K)/phosphoinositide-dependent kinase-1 (PDK1)/protein kinase B (AKT) signaling pathway and phosphotyrosine proteins. Our results indicate that oridonin adversely affects most sperm functions in a dose-dependent manner. We observed significant decreases in AKT, p-AKT (Thr308), phosphatase and tensin homolog (PTEN), p-PDK1, and p-PI3K levels following oridonin treatment, alongside an abnormal increase in phosphotyrosine proteins. These findings suggest that oridonin may disrupt normal levels of tyrosine-phosphorylated proteins by inhibiting the PI3K/PDK1/AKT signaling pathway, which is crucial for cell proliferation, metabolism, and apoptosis, thus potentially harming sperm functions. Consequently, we recommend considering the reproductive toxicity of oridonin when using it as a therapeutic agent.

Ethylene oxide suppresses boar sperm function during capacitation.

Ethylene oxide (E.O) is an epoxide compound, and it has been utilized as a sterilizer or production of ether compounds in several industries. Although the toxic effects of E.O on bacteria and mammals have been reported, its effects on male reproductive toxicity during sperm capacitation are not fully understood. Therefore, this study was designed to evaluate the effects of E.O exposure during sperm capacitation. Boar spermatozoa were treated with various E.O concentrations (0, 0.1, 1, 10, and 100 µÐœ). After exposure, sperm motility, motion kinematics, capacitation status, intracellular ATP levels, cell viability, expression levels of protein kinase A (PKA) activation, and tyrosine phosphorylation were evaluated. Results revealed that E.O exposure significantly decreased sperm motility, motion kinematics, and intracellular ATP levels but significantly increased the capacitated spermatozoa. In addition, the PKA activation and tyrosine phosphorylation were abnormally changed. According to our results, E.O may cause toxic effects on sperm function during capacitation, which induces male reproductive toxicity. Consequently, we suggest that male reproductive toxicity should be considered when using E.O.

Spatial transcriptomic analysis of amelanotic acral melanoma versus pigmented acral melanoma reveals distinct molecular determinants.

BACKGROUND: Amelanotic acral melanoma (AAM) is a rare type of acral melanoma that has a poor prognosis. OBJECTIVES: To investigate the transcriptomic differences between AAM and pigmented acral melanoma (PAM). METHODS: Differences in the spatially resolved transcriptomic profiles of 9 patients with AAM with 29 regions of interest (ROIs) and 11 patients with PAM with 46 ROIs were investigated using S100b and CD3 morphology markers. RESULTS: In S100b+ tumour cell areas, we detected 11 upregulated differentially expressed genes (DEGs; including chaperone/ubiquitin--associated DEGs) and 82 downregulated DEGs (including human leucocyte antigen) in AAMs vs. PAMs. Protein-protein interaction network and pathway analyses revealed significant enrichment of dysregulated translational and nonsense-mediated decay pathways but significant decreases in antigen processing and presentation, interferon signalling and melanin biosynthesis pathways in S100b+ ROIs of AAMs compared with PAMs. In tumour-associated immune cell areas, the numbers of CD8 T cells (P = 0.04) and M1 macrophages (P = 0.01) were significantly decreased, whereas those of monocytes (P = 0.04) and endothelial cells (P = 0.04) were increased in AAMs compared with PAMs. CONCLUSIONS: These findings could widen our understanding of the biological differences between AAMs and PAMs, which might result in a different clinical course.

Melanoma is one of the most serious types of skin cancer. As melanoma starts in cells that produce melanin (the substance that produces hair, eye and skin colouration), melanoma tumours are usually brown or black. 'Amelanotic melanoma' is a subtype of melanoma that has little or no melanin pigmentation. Less than 2% of melanomas are amelanotic melanomas. 'Acral melanoma' is a type of melanoma that occurs on the hands and feet. In acral melanoma, the lack of pigmentation has been associated with worse outcomes for patients. Why amelanotic acral melanoma (or 'AAM') has a worse prognosis than pigmented acral melanoma (or 'PAM') is unclear. Using a type of technology called 'spatial transcriptomic analysis', we analysed a type of nucleic acid called RNA in 9 people with AAM and 11 with PAM. Seventy-five 'regions of interest' were selected. These regions of interest are known to be associated with tumour cells or immune cells around tumours. We found that pathways involved in making proteins (translation) and in a process that removes faulty proteins called 'messenger RNA' were more active in AAM. However, pathways involved in processing and presenting antigens (substances that can trigger an immune response), the signalling of other proteins called 'interferons' and melanin production were less active in AAM. The number of specific types of white blood cells that recognize and attack tumours were decreased, whereas other cell types such as cells that line blood vessels were increased in AAM. Our findings could increase our understanding of the differences between AAMs and PAMs. This may lead to an improvement in prognosis.

Nirmatrelvir has detrimental effects on sperm function by altering the PI3K/PDK1/AKT signaling pathway.

Nirmatrelvir (NMV) is a recently developed selective inhibitor of the main protease of Sars-Cov-2 that reduces the severity of infection. Despite its widespread use and various side effects, NMV's effect on male fertility is still unclear. This study was thus established to investigate how NMV affects male fertility. For experiments, Duroc spermatozoa were incubated with various concentrations of NMV (0, 0.1, 1, 10, 50, and 100 µM). Then, sperm motility, motion kinematics, capacitation status, intracellular ATP level, and cell viability were evaluated. In addition, the expression levels of phospho-PKA substrates, tyrosine-phosphorylated proteins, and PI3K/PDK1/AKT signaling pathway-related proteins were measured by western blotting. Our results showed that sperm motility, motion kinematics, proportion of capacitated spermatozoa, and intracellular ATP level were significantly decreased by NMV in a dose-dependent manner. Moreover, PKA activation was significantly suppressed by NMV, and expression levels of PI3K, phospho-PDK1, AKT, and phospho-AKT (Thr308 and Ser473) were significantly increased in a dose-dependent manner. Combining these findings, it is suggested that NMV has detrimental effects on sperm function by inducing abnormal changes in the PI3K/PDK1/AKT signaling pathway, resulting in PKA deactivation. Therefore, there is a need to pay particular attention to its male reproductive toxicity when NMV is administered.

Effect of dynamic binaural beats on sleep quality: a proof-of-concept study with questionnaire and biosignals.

Binaural beat (BB) has been investigated as a potential modality to enhance sleep quality. In this study, we introduce a new form of BB, referred to as dynamic BB (DBB), which incorporates dynamically changing carrier frequency differences between the left and right ears. Specifically, the carrier frequency of the right ear varied between 100 and 103 Hz over a period, while the left ear remained fixed at 100 Hz, yielding a frequency difference range of 0 to 3 Hz. The objective of this study was to examine the effect of DBB on sleep quality. Ten healthy participants were included in a cross-over design, where they experienced both DBB and a SHAM (absence of sound) condition across two consecutive nights, with polysomnography evaluation. DBB was administrated during pre-sleep initiation, sleep onset, and transition from rapid eye movement (REM) to non-REM stage. DBB significantly reduced sleep latency compared to the SHAM condition. Electrocardiogram analysis revealed that exposure to DBB led to diminished heart rate variability during the pre-sleep initiation and sleep onset periods, accompanied by a decrease in low-frequency power of heart rate during the sleep onset period. DBB might be effective in improving sleep quality, suggesting its possible application in insomnia treatments.

Facial Dermatoses Associated With Mask-Wearing in the COVID-19 Era: A Nationwide, Cross-Sectional, Multicenter, Questionnaire-based Study.

BACKGROUND: Daily usage of facial masks during coronavirus disease 2019 pandemic influenced on facial dermatoses. OBJECTIVE: This study investigated the impact of mask-wearing habits on facial dermatoses. METHODS: A nationwide, observational, questionnaire-based survey was conducted from July through August 2021, involving 20 hospitals in Korea. RESULTS: Among 1,958 facial dermatoses, 75.9% of patients experienced aggravation or development of new-onset facial dermatoses after wearing masks. In aggravated or newly developed acne patients (543 out of 743), associated factors were healthcare provider, female gender, and a long duration of mask-wearing. Irritating symptoms, xerosis, and hyperpigmentation were more frequently observed in this group. Aggravated or newly developed rosacea patients (515 out of 660) were likely to be female, young, and have a long duration of mask-wearing per day. Seborrheic dermatitis patients who experienced aggravation or de novo development (132 out of 184) were younger, and they more frequently involved the chin and jaw in addition to the nasolabial folds and both cheeks. Contact dermatitis patients (132 out of 147) with aggravation or de novo development tended to be female, involve both cheeks, and complain of pruritus. Aggravated or newly developed atopic dermatitis patients (165 out of 224) were more likely to be female, and had a higher baseline investigator global assessment score before mask-wearing. CONCLUSION: Clinical features and factors related to aggravation were different according to the types of facial dermatoses.

Dynamic Contrast-enhanced MRI Quantification of Altered Vascular Permeability in Autoimmune Encephalitis.

Background Blood-brain barrier (BBB) permeability change is a possible pathologic mechanism of autoimmune encephalitis. Purpose To evaluate the change in BBB permeability in patients with autoimmune encephalitis as compared with healthy controls by using dynamic contrast-enhanced (DCE) MRI and to explore its predictive value for treatment response in patients. Materials and Methods This single-center retrospective study included consecutive patients with probable or possible autoimmune encephalitis and healthy controls who underwent DCE MRI between April 2020 and May 2021. Automatic volumetric segmentation was performed on three-dimensional T1-weighted images, and volume transfer constant (Ktrans) values were calculated at encephalitis-associated brain regions. Ktrans values were compared between the patients and controls, with adjustment for age and sex with use of a nonparametric approach. The Wilcoxon rank sum test was performed to compare Ktrans values of the good (improvement in modified Rankin Scale [mRS] score of at least two points or achievement of an mRS score of ≤2) and poor (improvement in mRS score of less than two points and achievement of an mRS score >2) treatment response groups among the patients. Results Thirty-eight patients with autoimmune encephalitis (median age, 38 years [IQR, 29-59 years]; 20 [53%] female) and 17 controls (median age, 71 years [IQR, 63-77 years]; 12 [71%] female) were included. All brain regions showed higher Ktrans values in patients as compared with controls (P < .001). The median difference in Ktrans between the patients and controls was largest in the right parahippocampal gyrus (25.1 × 10-4 min-1 [95% CI: 17.6, 43.4]). Among patients, the poor treatment response group had higher baseline Ktrans values in both cerebellar cortices (P = .03), the left cerebellar cortex (P = .02), right cerebellar cortex (P = .045), left cerebral cortex (P = .045), and left postcentral gyrus (P = .03) than the good treatment response group. Conclusion DCE MRI demonstrated that BBB permeability was increased in all brain regions in patients with autoimmune encephalitis as compared with controls, and baseline Ktrans values were higher in patients with poor treatment response in the cerebellar cortex, left cerebral cortex, and left postcentral gyrus as compared with the good response group. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Filippi and Rocca in this issue.

Consensus Report on Truncal Acne: The Korean Acne and Rosacea Society Experts Panel.

BACKGROUND: More than half of acne patients have truncal acne on their chest, back, and shoulders. However, since most studies on acne have focused on the face, data on clinical characteristics and proper management for truncal acne are insufficient. OBJECTIVE: To establish a Korean Acne Rosacea Society (KARS) consensus for experts' perception and treatment patterns of truncal acne. METHODS: We conducted two rounds of the Dephi technique to gather expert opinion and reach a consensus on truncal acne. The first round comprised 48 questionnaires focusing on various aspects such as epidemiology, clinical features, diagnosis, treatment, prognosis and more, while second rounds consisted of 26 questionnaires. RESULTS: A total of 36 dermatologists (36/38 KARS members, 94.7%) completed this survey. In the first-round survey, consensus was reached on 20 out of the 48 questions (41.7%). In the second-round questionnaire, consensus was achieved on 9 of the 26 questions (34.6%). The most unresponsive lesion to truncal acne treatment was scars (atrophic/hypertrophic). The most commonly used treatments for each non-inflammatory and inflammatory truncal acne lesions were selected to use topical retinoids (78.1% of the responders) and oral antibiotics (93.8% of the responders). CONCLUSION: Our study has yielded valuable insights into the epidemiology, clinical manifestations, diagnosis, treatment, and quality of life of patients with truncal acne. We anticipate that this study will inspire further comprehensive research for individuals with truncal acne.

Application of plasma circulating KRAS mutations as a predictive biomarker for targeted treatment of pancreatic cancer.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in circulating tumor deoxyribonucleic acid (ctDNA) have been reported as representative noninvasive prognostic markers for pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to evaluate single KRAS mutations as prognostic and predictive biomarkers, with an emphasis on potential therapeutic approaches to PDAC. A total of 128 patients were analyzed for multiple or single KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, and G13D) in their tumors and plasma using droplet digital polymerase chain reaction (ddPCR). Overall, KRAS mutations were detected by multiplex ddPCR in 119 (93%) of tumor DNA and 68 (53.1%) of ctDNA, with a concordance rate of 80% between plasma ctDNA and tumor DNA in the metastatic stage, which was higher than the 44% in the resectable stage. Moreover, the prognostic prediction of both overall survival (OS) and progression-free survival (PFS) was more relevant using plasma ctDNA than tumor DNA. Further, we evaluated the selective tumor-suppressive efficacy of the KRAS G12C inhibitor sotorasib in a patient-derived organoid (PDO) from a KRAS G12C-mutated patient using a patient-derived xenograft (PDX) model. Sotorasib showed selective inhibition in vitro and in vivo with altered tumor microenvironment, including fibroblasts and macrophages. Collectively, screening for KRAS single mutations in plasma ctDNA and the use of preclinical models of PDO and PDX with genetic mutations would impact precision medicine in the context of PDAC.