Ferroptosis-related lncRNA signature predicts prognosis and immunotherapy efficacy in cutaneous melanoma.

Purpose: Ferroptosis-related lncRNAs are promising biomarkers for predicting the prognosis of many cancers. However, a ferroptosis-related signature to predict the prognosis of cutaneous melanoma (CM) has not been identified. The purpose of this study was to construct a ferroptosis-related lncRNA signature to predict prognosis and immunotherapy efficacy in CM. Methods: Ferroptosis-related differentially expressed genes (FDEGs) and lncRNAs (FDELs) were identified using TCGA, GTEx, and FerrDb datasets. We performed Cox and LASSO regressions to identify key FDELs, and constructed a risk score to stratify patients into high- and low-risk groups. The lncRNA signature was evaluated using the areas under the receiver operating characteristic curves (AUCs) and Kaplan-Meier analyses in the training, testing, and entire cohorts. Multivariate Cox regression analyses including the lncRNA signature and common clinicopathological characteristics were performed to identify independent predictors of overall survival (OS). A nomogram was developed for clinical use. We performed gene set enrichment analyses (GSEA) to identify significantly enriched pathways. Differences in the tumor microenvironment (TME) between the 2 groups were assessed using 7 algorithms. To predict the efficacy of immune checkpoint inhibitors (ICI), we analyzed the association between PD1 and CTLA4 expression and the risk score. Finally, differences in Tumor Mutational Burden (TMB) and molecular drugs Sensitivity between the 2 groups were performed. Results: We identified 5 lncRNAs (AATBC, AC145423.2, LINC01871, AC125807.2, and AC245041.1) to construct the risk score. The AUC of the lncRNA signature was 0.743 in the training cohort and was validated in the testing and entire cohorts. Kaplan-Meier analyses revealed that the high-risk group had poorer prognosis. Multivariate Cox regression showed that the lncRNA signature was an independent predictor of OS with higher accuracy than traditional clinicopathological features. The 1-, 3-, and 5-year survival probabilities for CM patients were 92.7%, 57.2%, and 40.2% with an AUC of 0.804, indicating a good accuracy and reliability of the nomogram. GSEA showed that the high-risk group had lower ferroptosis and immune response. TME analyses confirmed that the high-risk group had lower immune cell infiltration (e.g., CD8+ T cells, CD4+ memory-activated T cells, and M1 macrophages) and lower immune functions (e.g., immune checkpoint activation). Low-risk patients whose disease expressed PD1 or CTLA4 were likely to respond better to ICIs. The analysis demonstrated that the TMB had significantly difference between low- and high- risk groups. Chemotherapy drugs, such as sorafenib, Imatinib, ABT.888 (Veliparib), Docetaxel, and Paclitaxel showed Significant differences in the estimated IC50 between the two risk groups. Conclusion: Our novel ferroptosis-related lncRNA signature was able to accurately predict the prognosis and ICI outcomes of CM patients. These ferroptosis-related lncRNAs might be potential biomarkers and therapeutic targets for CM.

A Novel Pyroptotic and Inflammatory Gene Signature Predicts the Prognosis of Cutaneous Melanoma and the Effect of Anticancer Therapies.

Purpose: The purpose of this study was to construct a gene signature comprising genes related to both inflammation and pyroptosis (GRIPs) to predict the prognosis of patients with cutaneous melanoma patients and the efficacy of immunotherapy, chemotherapy, and targeted therapy in these patients. Methods: Gene expression profiles were collected from The Cancer Genome Atlas. Weighted gene co-expression network analysis was performed to identify GRIPs. Univariable Cox regression and Lasso regression further selected key prognostic genes. Multivariable Cox regression was used to construct a risk score, which stratified patients into high- and low-risk groups. Areas under the ROC curves (AUCs) were calculated, and Kaplan-Meier analyses were performed for the two groups, following validation in an external cohort from Gene Expression Omnibus (GEO). A nomogram including the GRIP signature and clinicopathological characteristics was developed for clinical use. Gene set enrichment analysis illustrated differentially enriched pathways. Differences in the tumor microenvironment (TME) between the two groups were assessed. The efficacies of immune checkpoint inhibitors (ICIs), chemotherapeutic agents, and targeted agents were predicted for both groups. Immunohistochemical analyses of the GRIPs between the normal and CM tissues were performed using the Human Protein Atlas data. The qRT-PCR experiments validated the expression of genes in CM cell lines, Hacat, and PIG1 cell lines. Results: A total of 185 GRIPs were identified. A novel gene signature comprising eight GRIPs (TLR1, CCL8, EMP3, IFNGR2, CCL25, IL15, RTP4, and NLRP6) was constructed. The signature had AUCs of 0.714 and 0.659 for predicting 3-year overall survival (OS) in the TCGA entire and GEO validation cohorts, respectively. Kaplan-Meier analyses revealed that the high-risk group had a poorer prognosis. Multivariable Cox regression showed that the GRIP signature was an independent predictor of OS with higher accuracy than traditional clinicopathological features. The nomogram showed good accuracy and reliability in predicting 3-year OS (AUC = 0.810). GSEA and TME analyses showed that the high-risk group had lower levels of pyroptosis, inflammation, and immune response, such as lower levels of CD8+ T-cell infiltration, CD4+ memory-activated T-cell infiltration, and ICI. In addition, low-risk patients whose disease expressed PD-1 or CTLA-4 were likely to respond better to ICIs, and several chemotherapeutic and targeted agents. Immunohistochemical analysis confirmed the distinct expression of five out of the eight GRIPs between normal and CM tissues. Conclusion: Our novel 8-GRIP signature can accurately predict the prognosis of patients with CM and the efficacies of multiple anticancer therapies. These GRIPs might be potential prognostic biomarkers and therapeutic targets for CM.

Development and Validation of a Novel Survival Model for Cutaneous Melanoma Based on Necroptosis-Related Genes.

Background: Necroptosis is crucial for organismal development and pathogenesis. To date, the role of necroptosis in skin cutaneous melanoma (SKCM) is yet unveiled. In addition, the part of melanin pigmentation was largely neglected in the bioinformatic analysis. In this study, we aimed to construct a novel prognostic model based on necroptosis-related genes and analysis the pigmentation phenotype of patients to provide clinically actionable information for SKCM patients. Methods: We downloaded the SKCM data from the TCGA and GEO databases in this study and identified the differently expressed and prognostic necroptosis-related genes. Patients' pigmentation phenotype was evaluated by the GSVA method. Then, using Lasso and Cox regression analysis, a novel prognostic model was constructed based on the intersected genes. The risk score was calculated and the patients were divided into two groups. The survival differences between the two groups were compared using Kaplan-Meier analysis. The ROC analysis was performed and the area under curves was calculated to evaluate the prediction performances of the model. Then, the GO, KEGG and GSEA analyses were performed to elucidate the underlying mechanisms. Differences in the tumor microenvironment, patients' response to immune checkpoint inhibitors (ICIs) and pigmentation phenotype were analyzed. In order to validate the mRNA expression levels of the selected genes, quantitative real-time PCR (qRT-PCR) was performed. Results: Altogether, a novel prognostic model based on four genes (BOK, CD14, CYLD and FASLG) was constructed, and patients were classified into high and low-risk groups based on the median risk score. Low-risk group patients showed better survival status. The model showed high accuracy in the training and the validation cohort. Pathway and functional enrichment analysis indicated that immune-related pathways were differently activated in the two groups. In addition, immune cells infiltration patterns and sensitivity of ICIs showed a significant difference between patients from two risk groups. The pigmentation score was positively related to the risk score in pigmentation phenotype analysis. Conclusion: In conclusion, this study established a novel prognostic model based on necroptosis-related genes and revealed the possible connections between necroptosis and melanin pigmentation. It is expected to provide a reference for clinical treatment.

Nonsurgical Treatment for Congenital Auricular Deformities: A Systematic Review and Meta-analysis.

BACKGROUND: The effectiveness and safety of non-surgical correction for congenital auricular deformities (CADs) remain unclear owing to a lack of high-level evidence. This systematic review and meta-analysis aimed to estimate the overall success and complication rates of the non-surgical correction for CAD. METHODS: We searched PubMed, Medline, and Cochrane Library for eligible studies. The pooled success and complication rates of non-surgical correction were estimated using a random effects model. Subgroup analyses were performed to compare the success rates between patients treated with splints and molding systems, between those younger and older than 6-weeks, and among those with different types of CADs. RESULTS: The review yielded 14 studies. The pooled success rate of non-surgical treatment was 93% (95% CI: 88%-97%). The success rates with splints and commercialized molding systems were 94% and 92%, respectively. The success rate was higher if non-surgical correction was initiated before age 6 weeks (96% vs. 82%). Prominent ears showed a lower success rate (85%) than other types of CADs (all > 90%). The pooled complication rate was 18% (95% CI: 10%-29%). Complications, including skin wound, irritation, and rash, were mild and easily treatable. CONCLUSION: The non-surgical correction of CADs is highly effective and safe. Splints and molding systems offer similar effectiveness. Non-surgical correction is more beneficial if applied within 6 weeks of birth. Prominent ears have a lower, but still acceptable, success rate compared to other types of CAD. We recommend the early use of non-surgical correction to achieve favorable outcomes. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Construction and validation of a novel pyroptosis-related signature to predict prognosis in patients with cutaneous melanoma.

Skin cutaneous melanoma (SKCM) is one of the most malignant skin cancers and remains a health concern worldwide. Pyroptosis is a newly recognized form of programmed cell death and plays a vital role in cancer progression. We aim to construct a prognostic model for SKCM patients based on pyroptosis-related genes (PRGs). SKCM patients from The Cancer Genome Atlas (TCGA) were divided into training and validation cohorts. We used GSE65904 downloaded from GEO database as an external validation cohort. We performed Cox regression and the least absolute shrinkage and selection operator (LASSO) regression to identify prognostic genes and built a risk score. Patients were divided into high- and low-risk groups based on the risk score. Differently expressed genes (DEGs), immune cell infiltration and immune-related pathways activation were compared between the two groups. We established a model containing 4 PRGs, i.e., GSDMA, GSDMC, AIM2 and NOD2. The overall survival (OS) time was significantly different between the 2 groups. The risk score was an independent predictor for prognosis in both the uni- and multi-variable Cox regressions. Gene ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) analyses showed that DEGs were enriched in immune-related pathways. Most types of immune cells were highly expressed in the low risk group. All immune pathways were significantly up-regulated in the low-risk group. In addition, low-risk patients had a better response to immune checkpoint inhibitors. Our novel pyroptosis-related gene signature could predict the prognosis of SKCM patients and their response to immune checkpoint inhibitors.

Silencing FYVE, RhoGEF, and PH domain containing 1 (FGD1) suppresses melanoma progression by inhibiting PI3K/AKT signaling pathway.

Cutaneous melanoma is the leading cause of death among skin cancers despite the availability of diverse treatments. FGD1 plays an important role in multiple cancers, but how it works in cutaneous melanoma has not been illustrated. Thus, this study was intended to investigate the roles of FGD1 and its underlying mechanisms in cutaneous melanoma. Bioinformatics tools and quantitative real-time polymerase chain reaction (qRT-PCR) were used to analyze the expression of FGD1 in cutaneous melanoma. After the knockdown of FGD1 in melanoma cells, the proliferation, migration, and invasion of cells were analyzed by cell counting kit-8 (CCK8) assay, colony formation assays and transwell assays. Western blot was used to check the expression of key factors in PI3K/AKT pathway. In addition, nude mice models were used to study the role of FGD1 in melanoma development and metastasis in vivo. The data demonstrated that FGD1 was up-regulated and predicted a poor clinical outcome for cutaneous melanoma patients. Knockdown of FGD1 inhibited melanoma cell proliferation, migration, and invasion. The expressions of p-PI3K and p-AKT were significantly decreased, while the expressions of PI3K and AKT showed no marked difference in the knockdown group. Meanwhile, knockdown of FGD1 suppressed the development of melanoma in vivo. This study suggested that knockdown of FGD1 could block melanoma formation and proliferation by inhibiting PI3K/AKT signaling pathway. FGD1 might be a promising therapeutic target for melanoma.

Treatment of Severe Postburn Contracture of the Elbow via Distraction With External Circular Frame in Pediatric Patient.

BACKGROUND: Although external circular frame (ECF) has been widely used for the correction of knee and ankle deformities, few studies reported the use of ECF for the treatment of severe postburn elbow contracture and stiffness (SPECS). The purpose of this retrospective study was to investigate the effectiveness and safety of the distraction using ECF in treating SPECS. METHODS: After institutional review board approval, we implemented a retrospective single-center case series study composed of consecutive patients treated for SPECS at Chinese PLA General Hospital between January 2010 and January 2018. After scar release and skin grafting, distraction with ECF was performed for 4 to 6 weeks, and the frame was retained for 2 more weeks before removal. Four weeks of splinting and at least 1 year of rehabilitation were recommended. Patient demographics, active and passive range of motion (ROM) of the elbow at different time points (preoperative, postdistraction, and final follow-up), and complications were collected from the electronic medical record. The primary outcome was the long-term improvement of the ROM. Other outcomes included complications and recurrence. RESULTS: The ECF was used to treat SPECS in 6 patients (3 males and 3 females, average age of 11.7 ± 2.6 years). Scar release and distraction with ECF significantly increased both active (from 3° preoperative to 38.7° postdistraction) and passive (from 3.5° preoperative to 48.3° postdistraction) ROM over an average distraction duration of 5.2 weeks. The long-term improvement of active and passive ROM was 38° ± 13.4° and 46° ± 14.7°, respectively, over a median follow-up of 4.1 years. Pin-tract infection occurred in 2 patients and were treated with local wound care and oral antibiotics. A tendon readhesion developed in 1 of the 6 patients because of noncompliance with splinting and physiotherapy, and was treated with revision surgery. CONCLUSIONS: The 3C strategy (i.e., contracture release, coverage of the defect with skin grafting, and correction of articular angle with gradual distraction using the ECF) is able to increase the ROM with minor complications. We recommend distraction with ECF as part of the treatment arsenal, particularly for severe contractures in which 1-stage correction is unfeasible because of considerable soft tissue shortening.

Three-dimensional measurement and analysis of botulinum toxin A injection for improving the aesthetic appearance of upper lip.

This study evaluated the efficacy of botulinum toxin A (BTX A) in improving the aesthetic appearance of lips. Twenty-four outpatients with clinical evidence indicating decreased fullness of lips or gummy smile were selected and received BTX A injection on the orbicularis oris. We observed a significant decrease in wrinkles and improvement in gummy smile in all patients 4 weeks after the injection. Aesthetic lines also changed significantly. Local injection of BTX A on the orbicularis oris could simultaneously achieve mild lip enhancement, improvement in fine wrinkles around lips, and mild gummy smile.

A Meta-Analysis and Systematic Review of the Incidences of Complications Following Facial Thread-Lifting.

BACKGROUND: Facial thread-lifting (FTL) has gained more popularity, but the incidences of complications following FTL remain controversial. We aimed to perform a meta-analysis and systematic review to estimate the incidences of complications and to compare the short- and long-term satisfaction rates following FTL. METHODS: We searched PubMed, Web of Science, Embase and Cochrane library for eligible studies. The primary outcome was the incidences of complications following FTL. The secondary outcome was the satisfaction rate immediately and 6-month after FTL. The pooled incidences of complications and 95% confidence intervals were estimated using random-effects models. RESULTS: A total of 26 studies were included in this meta-analysis. Swelling was the most commonly reported complication with a pooled incidence of 35%, followed by skin dimpling (10%), paresthesia (6%), thread visibility/palpability (4%), infection (2%), and thread extrusion (2%). Absorbable threads were associated with a significantly lower risk of paresthesia (3.1% vs. 11.7%) and thread extrusion (1.6% vs. 7.6%) than non-absorbable threads. Patients older than 50 years had a significantly higher risk of dimpling (16% vs. 5.6%) and infection (5.9% vs. 0.7%) than their younger counterparts. In addition, the pooled long-term satisfaction rate was significantly decreased compared to it immediately after FTL (88% vs. 98%). CONCLUSION: Non-absorbable threads and older age of patients are associated with higher risks of complications. Therefore, we recommend a judicious use of non-absorbable threads and FLT in older patients. Furthermore, it should be discussed with patients preoperatively that the rejuvenation effect of FTL may not maintain in the long-term. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Is Decreased Local Bone Quality an Independent Risk Factor for Complications Following Fracture Fixation of Facial Bones.

PURPOSE: Although osteoporosis is associated with increased risks of complications of fracture fixation in the orthopedic literature, the association between local bone quality (LBQ) and complications of facial fracture fixation is unknown. The authors aim to identify that if decreased LBQ is an independent risk factor for complications following facial fracture fixation? METHODS: The authors conducted a prospective cohort study on patients over age of 50 years who underwent open reduction and rigid internal fixation for facial fractures. The primary predictor was LBQ (low or normal), decided by a combination of 3 panoramic indices. Other predictors included age, gender, body mass index (BMI), comorbidities, trauma-related characteristics, etc. The outcome variable was the presence of hardware-related, fracture-healing, wound, or neurosensory complications during 2-year follow-up. Univariate and multivariate regressions were performed to identify any significant association between predictor and outcome variables. RESULTS: The sample was composed of 69 patients (27 females) with an average age of 58.6 ±â€Š8.6 years and BMI of 25 ±â€Š3.8. Low-LBQ patients were significantly older, more females, had lower BMI, mainly injured from falls, had more complications compared to their normal-LBQ counterparts. However, multivariable logistic regressions demonstrated that only age (adjusted OR: 1.12, P = 0.031, 95% CI: 1.01, 1.23) and diabetes (adjusted OR: 12.63, P = 0.029, 95% CI: 1.3, 122.53) were significantly associated with overall complications after confounding adjustment. CONCLUSIONS: The results of the present study indicate that reduced LBQ is not an independent risk factor for complications following facial fracture fixation. The increased risk of complications in low-LBQ patients is more likely to be attributed to other age-related comorbidities such as diabetes. Therefore, the authors recommend detailed workup and good control of comorbidities in elderly trauma patient.

Comparison of Donor Site Morbidity Between Anterolateral Thigh and Radial Forearm Free Flaps for Head and Neck Reconstruction: A Systematic Review and Meta-Analysis.

ABSTRACT: This meta-analysis aimed to provide an up-to-date comparison of donor site morbidity (DSM) between patients who underwent head and neck reconstruction with Anterolateral thigh (ALT) and radial forearm free (RFF) flaps. We searched the PubMed, Web of Science, EMBASE, and Cochrane Library databases to identify studies that compared DSM between ALT and RFF patients. Study quality was assessed using the Newcastle-Ottawa Scale. The pooled odds ratio (OR) of each DSM between ALT and RFF patients was estimated using a random- or fixed-effect model depending on the degree of interstudy heterogeneity. Sensitivity and subgroup analyses were performed if substantial heterogeneity was detected. Eighteen cohort studies with 1,018 patients (535 ALT and 483 RFF patients) were included. Compared with RFF, ALT were associated with lower risks of wound dehiscence (OR = 0.2, 95%CI: 0.10-0.42, P < 0.01), strength impairment (OR = 0.18, 95%CI: 0.07-0.47, P < 0.01), and movement impairment (OR = 0.19, 95%CI:0.07-0.49, P < 0.01). A subgroup analysis showed that ALT were associated with a lower risk of donor site numbness among patients undergoing tongue reconstruction (OR = 0.05, 95%CI: 0.01-0.25, P < 0.01), but not among all patients undergoing head and neck reconstruction. The pooled ORs of other DSMs demonstrated no significant difference between ALT and RFF patients. ALT are superior to RFF for head and neck reconstruction in terms of donor site wound dehiscence, strength impairment, movement impairment, and for tongue reconstruction specifically in terms of donor site numbness. No significant differences in the incidence of donor site hematoma/seroma, infection, or dissatisfaction with donor site appearance were identified between ALT and RFF patients.

Ultrasound-Activated Bioresorbable Osteosynthesis in the Treatment of Craniosynostosis.

ABSTRACT: The purpose of this study is to estimate the incidence of fixation-related complications following ultrasound-activated biodegradable osteosynthesis (UBO) in the treatment of craniosynostosis. The authors searched MEDLINE, PubMed, Embase, Google Scholar, and Cochrane Library from January 2005 to January 2020 for clinical studies reporting the use of UBO for fixation in the treatment of craniosynostosis. The primary outcome was the incidence of fixation-related complications, including unstable fixation; swelling, plate visibility, or palpability; infection; inflammation, sinus formation, and discharge; implant exposure; reoperation or implant removal. The pooled incidence rates were estimated using random-effects models. Of 155 studies identified, 10 were included, representing 371 patients. Forty-six (12.4%) patients presented fixation-related complications. The incidence rates of swelling/visibility/palpability, infection, and reoperation/implant removal were pooled based on the available data. The pooled incidence rate of chronic swelling/visibility/palpability was 0.21 (95% confidence interval [CI], 0.05-0.43). Sensitivity analysis by omitting the outlier study demonstrates that the incidence of swelling/visibility/palpability was 0.07 (95% CI, 0.04-0.11). The pooled incidence rate of infection and reoperation/implant removal was 0.07 (95% CI, 0.01-0.16) and 0.04 (95% CI, 0.01-0.09), respectively. Results show that although UBO can provide stable fixation, chronic swelling/visibility/palpability, infection, and reoperation for removal are not uncommon. Based on the literature, the authors recommend judicious use of UBO in patients with large frontorbital advancement and in the area of the coronal suture or other sites with thin overlying skin/subcutaneous tissue. The high possibility of chronic swelling/palpability/visibility during degradation, needs to be discussed preoperatively.