Discovery and Validation of Survival-Specific Genes in Papillary Renal Cell Carcinoma Using a Customized Next-Generation Sequencing Gene Panel.

PURPOSE: Papillary renal cell carcinoma (PRCC), the second most common kidney cancer, is morphologically, genetically, and molecularly heterogeneous with diverse clinical manifestations. Genetic variations of PRCC and their association with survival are not yet well-understood. This study aimed to identify and validate survival-specific genes in PRCC and explore their clinical utility. MATERIALS AND METHODS: Using machine learning, 293 patients from the Cancer Genome Atlas-Kidney Renal Papillary Cell Carcinoma (TCGA-KIRP) database were analyzed to derive genes associated with survival. To validate these genes, DNAs were extracted from the tissues of 60 Korean PRCC patients. Next generation sequencing was conducted using a customized PRCC gene panel of 202 genes, including 171 survival-specific genes. Kaplan-Meier and Log-rank tests were used for survival analysis. Fisher's exact test was performed to assess the clinical utility of variant genes. RESULTS: A total of 40 survival-specific genes were identified in the TCGA-KIRP database through machine learning and statistical analysis. Of them, 10 (BAP1, BRAF, CFDP1, EGFR, ITM2B, JAK1, NODAL, PCSK2, SPATA13, and SYT5) were validated in the Korean-KIRP database. Among these survival gene signatures, three genes (BAP1, PCSK2, and SPATA13) showed survival specificity in both overall survival (OS) (p = 0.00004, p = 1.38 × 10-7, and p = 0.026, respectively) and disease-free survival (DFS) (p = 0.00002, p = 1.21 × 10-7, and p = 0.036, respectively). Notably, the PCSK2 mutation demonstrated survival specificity uniquely in both the TCGA-KIRP (OS: p = 0.010 and DFS: p = 0.301) and Korean-KIRP (OS: p = 1.38 × 10-7 and DFS: p = 1.21 × 10-7) databases. CONCLUSIONS: We discovered and verified genes specific for the survival of PRCC patients in the TCGA-KIRP and Korean-KIRP databases. The survival gene signature, including PCSK2 commonly obtained from the 40 gene signature of TCGA and the 10 gene signature of the Korean database, is expected to provide insight into predicting the survival of PRCC patients and developing new treatment.

Identification of Predictors of Metastatic Potential in Paragangliomas to Develop a Prognostic Score (PSPGL).

Context: Paragangliomas (PGLs) are rare tumors in adrenal and extra-adrenal locations. Metastasis are found in approximately 5% to 35% of PGLs, and there are no reliable predictors of metastatic disease. Objective: This work aimed to develop a prognostic score of metastatic potential in PGLs. Methods: A retrospective analysis was conducted of clinical data from a cohort with PGLs and tumor histological assessment. Patients were divided into metastatic PGL (presence of metastasis) and nonmetastatic PGL (absence of metastasis ≥96 months of follow-up) groups. Univariate and multivariable analysis were performed to identify predictors of metastatic potential. A prognostic score was developed based on coefficients of multivariable analysis. Kaplan-Meier curves were generated to estimate disease-specific survival (DSS). Results: Out of 263 patients, 35 patients had metastatic PGL and 110 patients had nonmetastatic PGL. In multivariable analysis, 4 features were independently related to metastatic disease and composed the Prognostic Score of Paragangliomas (PSPGL): presence of central or confluent necrosis (33 points), more than 3 mitosis/10 high-power field (HPF) (28 points), extension into adipose tissue (20 points), and extra-adrenal location (19 points). A PSPGL of 24 or greater showed similar sensitivity with higher specificity than the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP). PSPGL less than or equal to 20 was associated with a risk of metastasis of approximately 10%, whereas a PSPGL of 40 or greater was associated with approximately 80%. The presence of metastasis and Ki-67 of 3% or greater were related to lower DSS. Conclusion: The PSPGL, composed of 4 easy-to-assess parameters, demonstrated good performance in predicting metastatic potential and good ability in estimating metastasis risk.

Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety.

PARP inhibitors have been approved by the FDA for use in the treatment of patients with ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors show diverse suppressive effects on PARP family members and PARP-DNA trapping potency. These properties are associated with distinct safety/efficacy profiles. Here, we report the nonclinical characteristics of venadaparib (also known as IDX-1197 or NOV140101), a novel potent PARP inhibitor. The physiochemical properties of venadaparib were analyzed. Furthermore, the efficacy of venadaparib against PARP enzymes, PAR formation, and PARP trapping activities, and growth inhibition of cell lines with BRCA mutations were evaluated. Ex vivo and in vivo models were also established to study pharmacokinetics/pharmacodynamics, efficacy, and toxicity. Venadaparib specifically inhibits PARP-1 and -2 enzymes. Oral administration of venadaparib HCl at doses above 12.5 mg/kg significantly reduced tumor growth in the OV_065 patient-derived xenograft model. Intratumoral PARP inhibition remained at over 90% until 24 hours after dosing. Venadaparib had wider safety margins than olaparib. Notably, venadaparib showed favorable physicochemical properties and superior anticancer effects in homologous recombination-deficient in vitro and in vivo models with improved safety profiles. Our results suggest the possibility of venadaparib as a next-generation PARP inhibitor. On the basis of these findings, phase Ib/IIa studies on the efficacy and safety of venadaparib have been initiated.

Clinical and Histological Effects of Topical Epidermal Growth Factor on Acne and Acne Scars.

BACKGROUND: The inflammatory lesions of acne leave scars which greatly affect patients' quality of life. Treatment options targeting both acne and acne scars are still lacking. OBJECTIVES: To evaluate the clinical efficacy of epidermal growth factor ointment (EGFO) on acne and acne scars. METHODS: The study design was 12-week, prospective, split-face, single-blinded. The 36 patients with mild to moderate acne vulgaris applied EGFO on one side of the face and the vehicle ointment on the other side twice daily. The patients were assessed every 4 weeks by acne lesion and scar counts, investigator's global assessment for acne (IGA) and scar (SGA), and the ECCA scar grading scale. Biopsies were performed before and after treatment. RESULTS: Acne and acne scars were significantly improved on EGFO-treated sides, while control sides were not. Acne lesion and scar counts were significantly reduced after 4 weeks, while IGA, SGA, and ECCA grade significantly decreased after 8 weeks. Immunohistochemistry showed decreased expression of keratin 16, NF-κB p65, IL-1α, and IL-8, and increased expression of TGF-ß1, elastin, and collagen type 1, 3 after treatment. CONCLUSIONS: EGFO can be a treatment option targeting acne and acne scars.

Clinical efficacy of herbal extracts in treatment of mild to moderate acne vulgaris: an 8-week, double-blinded, randomized, controlled trial.

BACKGROUND: Herbal extracts with fewer adverse effects can be an alternative to these drugs because they can target various molecular pathways of acne pathogenesis. OBJECTIVES: To evaluate the clinical efficacy of herbal extracts (mangosteen, Lithospermum officinale, Tribulus terrestris L., Houttuynia cordata Thunb) for the treatment of mild to moderate acne vulgaris. METHODS: Sixty patients were randomized in a 1:1 ratio to receive blinded treatment with herbal extracts or vehicle for 8 weeks. Inflammatory and non-inflammatory acne lesion counts, Investigator's Global Assessment, patient's satisfaction and safety profiles were assessed. We also performed skin biopsy at baseline and week 8 to confirm immunological changes with immunohistochemistry staining. RESULTS: By the end of the study period, both inflammatory and non-inflammatory acne lesion counts were significantly decreased in herbal extracts group (p< .05). In immunohistochemistry staining, expressions of IL-1α, IL-8, and keratin 16 were significantly decreased in herbal extracts group compared to vehicle group from baseline to week 8. There was no serious adverse events in both groups. CONCLUSIONS: This herbal extracts can be a new therapeutic option for patients with mild to moderate acne vulgaris who are reluctant to use drugs.

Granulomatous Rosacea in Korean Patients: Diagnosis Based on Combining Clinical and Histological Findings.

BACKGROUND: Granulomatous rosacea (GR) is a rare inflammatory skin disease, which is considered a variant of rosacea, apart from other types of rosacea. OBJECTIVE: This study aimed to summarize the characteristics of Korean patients diagnosed with GR by combining clinical and histological findings. METHODS: Fifteen cases, both clinically and histologically consistent with GR, were selected and were subsequently analyzed to describe clinical and histological characteristics. RESULTS: A total of 20 patients showed granulomatous infiltration in skin biopsies, but only 15 of them were clinically consistent with GR. Five patients who showed granulomatous inflammation were clinically consistent with erythematotelangiectatic or papulopustular rosacea. Among 15 patients, 13 (86.7%) were female and 2 (13.3%) were male. The most frequently involved area was the cheek, and none of the patients showed extrafacial lesions. There seems to be a possibility that treatment duration may be associated with the treatment response. CONCLUSIONS: This study confirms clinical characteristics of GR based on the diagnosis combining both clinical and histological findings.

Analysis of trends and status of physician-based evaluation methods in acne vulgaris from 2000 to 2019.

Various evaluation methods for acne severity have been used without standardization, and the diversity of acne outcome measures is an obstacle to the integrated analysis of various acne studies. In this study, we sought to investigate physician-based evaluation methods used in clinical studies of acne vulgaris and to determine differences according to time, region and study design. PubMed was searched for articles on acne published from January 2000 to June 2019 in five dermatology journals: Journal of the American Academy of Dermatology, JAMA Dermatology, British Journal of Dermatology, Journal of the European Academy of Dermatology and Venereology and Acta Dermato-Venereologica. A total of 186 articles with acne evaluation methods were selected. Among the selected studies, region, study design, type of intervention and the number of subjects were identified and analyzed. Articles from 2010 to 2019 used Investigator Global Assessment (IGA; odds ratio [OR], 5.808; 95% CI, 1.894-17.811) more often and the Leeds technique (OR, 0.282; 95% CI, 0.098-0.812) less often compared with articles from 2000 to 2009. Controlled experimental studies preferred lesion counting (OR, 238.637; 95% CI, 46.795-1216.954), IGA (OR, 9.177; 95% CI, 3.053-27.586) and Leeds Revised Acne Grading System (LRAGS; OR, 10.844; 95% CI, 3.050-38.559) compared with observational studies. North American studies applied lesion counting (OR, 4.573; 95% CI, 1.173-17.836) and IGA (OR, 11.330; 95% CI, 3.487-36.818) more often and LRAGS (OR, 0.171; 95% CI, 0.039-0.758) less often compared with European studies. This study demonstrated the diversity and heterogeneity of acne outcome measures even in highly influential dermatology journals. This is due to the limitations of current methods and suggests the importance of developing a core outcome measure.

Efficacy of liposome-encapsulated 4-n-butylresorcinol and resveratrol cream in the treatment of melasma.

BACKGROUNDS: We previously reported the efficacy of 0.1% 4-n-butylresorcinol (4nBR) cream in the treatment melasma and synergistic effect of 4nBR and resveratrol (RSV) to inhibit melanogenesis in vitro. AIMS: To evaluate efficacy and safety of a cream which contains liposome-encapsulated 4nBR and RSV in the treatment of melasma. PATIENTS/METHODS: A total of 21 female patients with melasma were treated with the cream for 4 weeks. At baseline, week 2, and week 4, melanin index (MI) of the lesional and preauricular nonlesional skin was measured and two blinded, independent dermatologists assessed the overall severity by 5-point scale. RESULTS: The lesional MI was significantly decreased at weeks 2 and 4 compared with the baseline while no significant change in the nonlesional MI was observed throughout the study. The mean investigator's global assessment score was also significantly improved at weeks 2 and 4. In patient's self-assessment, 8 (38.1%) and 11 (52.3%) patients answered moderate to significant improvement in their melasma at weeks 2 and 4, respectively. No serious adverse events were reported. CONCLUSION: The cream containing liposome-encapsulated 4nBR and RSV was shown to be effective and safe for the treatment of melasma with its effect appearing as early as 2 weeks.

Analysis of acne-related judicial precedents from 1997 to 2018 in South Korea.

Medicolegal disputes are increasing in practical medicine. Medications or procedures related to acne could lead to medical malpractice. This study analyzed medical litigation associated with acne in South Korea. Acne-related judgments were searched using the Supreme Court of Korea's Written Judgment Management System based on the keyword "acne". Eleven cases were selected; eight cases were related to acne scar and three cases were related to acne. Treatment modalities such as peeling, laser treatment, photodynamic therapy and antibiotics resulted in lawsuits. Claimed sequelae of the treatments were hyperpigmentation, scar worsening, erythema, skin bumps and liver transplant. Eight cases were awarded to the plaintiff, and the others were dismissed. This study shows that various treatments for acne can cause medical disputes.

Hair Follicle Nevus Located on the Neck: Comparison with Accessory Tragus, Cervical Chondrocutaneous Branchial Remnants and Trichofolliculoma.

Hair follicle nevus (HFN) is a rare, benign, follicular hamartoma that most frequently presents as a congenital nodule on the face. We experienced a rare case of HFN on the neck of a 14-year-old boy and performed a pilot immunohistochemical study with cytokeratin 19 (CK19) to compare the staining pattern of hair follicles in HFN and its differential diagnoses, accessory tragus, cervical chondrocutaneous branchial remnants (CCBR) and trichofolliculoma. With hematoxylin and eosin stain, HFN showed numerous tiny hair follicles in the dermis with several sebaceous and eccrine glands, and perifollicular fibrous thickening. With CK19 stain, some hair follicles in HFN and CCBR showed positive expression, a few hair follicles in accessory tragus showed weak expression, and no hair follicles in trichofolliculoma showed expression. The present report supports the view that HFN, accessory tragus and CCBR are within the same spectrum of hamartomas.

Demographic and clinical features of hidradenitis suppurativa in Korea.

Hidradenitis suppurativa (HS) is a chronic, relapsing, inflammatory skin disorder. Although several epidemiological studies have been conducted in Western countries, such data regarding Asian populations are scarce. In this study, we sought to investigate the demographic and clinical features of HS in Korea. A total of 438 patients, diagnosed with HS from May 2007 to April 2017, were enrolled and the electronic medical record of each patient was reviewed. Male patients were predominant with a male : female ratio of 2.5:1. Mean age of disease onset was 23.9 years and most patients had no family history. The most frequently affected area was the buttocks, followed by axillae and groin. Acne and diabetes mellitus were the most prevalent associated diseases and no patients with inflammatory bowel diseases were observed. In the univariable analysis, male patients had severe diseases compared with females with an odds ratio (OR) of 1.790. Two or more affected body regions were associated with HS severity with an OR of 1.693. While involvement of the perineum (OR, 4.067) and buttocks (OR, 1.471) tended to be associated with increased severity of the disease, the inguinal area (OR, 0.620) showed a tendency to be inversely associated with the severity. In multivariable analysis, identified risk factors were the involvement of the perineum (OR, 3.819) and buttocks (OR, 2.288). Smoking status and high body mass index seemed to be associated with more severe diseases. Our results will provide clinical characteristics of HS patients in Asia and help to broaden understanding of HS.

Expression of inflammatory and fibrogenetic markers in acne hypertrophic scar formation: focusing on role of TGF-ß and IGF-1R.

Acne vulgaris is a universal skin disease and it may leave a scar when the original skin lesion disappears. These scars can cause cosmetic problems and psychological burden, leading to poor quality of life of patients. Acne scars are classified into atrophic scars and hypertrophic scars. As most of the acne scars are atrophic, many studies have been conducted focusing on the treatment of atrophic lesions. This study was conducted to investigate the underlying pathogenesis of acne hypertrophic scars by identifying roles of fibrogenetic and inflammatory markers. Skin biopsy samples were obtained from hypertrophic scars of face and back and from adjacent normal tissues as control group. Some samples from back were immature hypertrophic scars and the other samples were in mature stages. Immunohistochemistry staining and quantitative PCR were performed for fibrogenetic and inflammatory markers. Both in mature and immature hypertrophic scars, vimentin and α-SMA were increased. Production of TGF-ß3 protein as well as transcription of TGF-ß3 was also significantly elevated. In contrast, expression of TGF-ß1 showed no increase. Instead, expression levels of SMAD2 and SMAD4 were increased. Elevations of CD45RO, TNF-α and IL-4 and reduction of IL-10 were observed. In immature hypertrophic scars, IGF-1R and insulin-degrading enzyme expression were increased. Increased apoptosis was observed in immature stages of hypertrophic scars but not in mature stages. Elevations of TGF-ß3, SMAD2 and SMAD4 in hypertrophic scars and increase of IGF-1R in immature stages may give some clues for acne hypertrophic scar formation.

Super anticorrosion of aluminized steel by a controlled Mg supply.

The current anticorrosion strategy makes use of coatings to passively protect the steel, which faces increasing challenge due to the tightened environmental regulations and high cost. This paper reports a new method for achieving a super anticorrosion function in Al-Si alloys through Mg nano-metallurgy, which was characterized by real-time synchrotron measurements. The unique function is based on the formation of an amorphous and self-charge-compensated MgAl2O4-SiO2 phase between the grain boundaries to help prevent the penetration of oxygen species through the grain boundaries. Through this, the corrosion resistance of pristine aluminized steel could be improved almost 20 fold. An analysis of the phases, microstructures of the Mg-coated aluminized layer and corrosion products consistently supported the proposed mechanism. This charge-compensated corrosion resistance mechanism provides novel insight into corrosion resistance.

Epidemiological and clinical features of rosacea in Korea: A multicenter cross-sectional study.

Rosacea is a common chronic inflammatory skin condition. Although several epidemiological and etiologic studies with large sample sizes have been conducted on Caucasians, such data regarding Asian populations are lacking. A total of 580 patients diagnosed with rosacea were enrolled from October 2014 to February 2015 at 14 general hospitals. Questionnaires, including the standard classification and grading system, were used for evaluation. The average age of the patients was 47.9 years. While 83.8% of patients revealed a single subtype, 16.2% of patients revealed mixed subtypes showing two or more subtypes simultaneously. Erythematotelangiectatic rosacea (ETR) was the most prevalent subtype. ETR combined with papulopustular rosacea showed the highest proportion in the mixed subtype group. Mild severity was revealed in 71.9% of patients. The most common aggravating factor was emotional changes (51.7%), followed by stress (48.4%). Approximately half of the patients (47.4%) showed relatively low awareness of rosacea. By identifying the epidemiological and etiologic features in Korea, we can suggest valuable clinical avenues for research, education and awareness among rosacea patients.

Platycodin D May Improve Acne and Prevent Scarring by Downregulating SREBP-1 Expression Via Inhibition of IGF-1R/PI3K/Akt Pathway and Modulating Inflammation with an Increase in Collagen.

BACKGROUND: Although many therapeutic agents have been developed, only a few drugs are known to target multiple pathogenic factors in the treatment of acne. OBJECTIVE: The purpose of this study was to identify a new drug candidate, platycodin D, which is a substance extracted from the root of Platycodon grandiflorum. METHODS: Using western blotting and Cell Counting Kit-8 assay, we studied the effects of platycodin D on SEB-1 sebocytes, fibroblasts, and keratinocytes. We investigated its effects in view of lipogenesis, collagen production, anti-inflammatory activity, and dyskeratinization. RESULTS: In SEB-1 sebocytes, platycodin D showed a sebosuppressive effect by downregulating ERK and insulin- like growth factor-1R/PI3K/Akt/sterol-regulatory element binding protein-1 signaling pathways. In addition, adiponectin, one of the adipokines responsible for sebum production, was decreased in platycodin D-treated SEB-1 sebocytes. In fibroblasts, platycodin D increased collagen production and reduced inflammation by inhibiting nuclear factor kappa B and matrix metalloproteinases. Platycodin D also showed anti-inflammatory effects on keratinocytes. It also suppressed keratin 16 expression induced by lipopolysaccharide. Furthermore, platycodin D showed no cytotoxicity on both SEB-1 sebocytes and fibroblasts. CONCLUSION: Our data demonstrate the clinical feasibility of platycodin D for acne treatment and the prevention of acne scarring by sebosuppressive and anti-inflammatory effects, as well as through an increase in collagen levels.

Desmoplastic Fibroblastoma of the Scalp Accompanied by Severe Pain; Unusual Location and Symptom.

Desmoplastic fibroblastoma is a rare fibrous tumor that usually presents as a painless, slow-growing mass in the subcutaneous tissues and skeletal muscles. It has a wide anatomic distribution, with the most common involvement being the arm and shoulder. Here, we report a case of a tiny painful desmoplastic fibroblastoma arising on the scalp. According to a microscopic examination, this tumor was composed of spindle-shaped fibroblasts in the dense collagenous stroma. On immunohistochemical staining, tumor cells were positive for vimentin and negative for smooth muscle actin, CD34, and S100. Our case is unique in that desmoplastic fibroblastoma developed on the scalp and there was presence of pain despite its small size.

Seeking new acne treatment from natural products, devices and synthetic drug discovery.

Despite lots of research on the pathogenesis of acne, the development of new therapeutic agents is still stagnant. Conventional agents which target multiple pathological processes have some serious side effects and this makes seeking new treatment options important for treating acne. As new therapeutic options, researchers are focusing on natural products, synthetic drugs and devices. From natural products, epigallocatechin-3 gallate, lupeol, cannabidiol and Lactobacillus fermented Chamaecyperis obtusa were reported to be possible candidates for novel drugs, targeting multiple pathogenic factors. Synthetic anti-P.acnes agent, nitric oxide nanoparticles and α-mangostin nanoparticles are shown to be effective in acne treatment. Device or procedural methods such as fractional microneedling radiofrequency, cryolysis, photothermolysis and daylight photodynamic therapy have potential as new treatment options for acne. Further large clinical trials comparing these new treatments with existing agents will be necessary in the future.