MRI-based Deep Learning Models for Preoperative Breast Volume and Density Assessment Assisting Breast Reconstruction.

BACKGROUND: The volume of the implant is the most critical element of breast reconstruction, so it is necessary to accurately assess the preoperative volume of the healthy and affected breasts and select the appropriate implant for placement. Accurate and automated methods for quantitative assessment of breast volume can optimize breast reconstruction surgery and assist physicians in clinical decision making. The aim of this study was to develop an artificial intelligence model for automated segmentation of the breast and measurement of volume. MATERIAL AND METHODS: A total of 249 subjects undergoing breast reconstruction surgery were enrolled in this study. Subjects underwent preoperative breast MRI, and the breast region manually outlined by the imaging physician served as the gold standard for volume measurement by the automated segmentation model. In this study, we developed three automated algorithms for automatic segmentation of breast regions, including a simple alignment model, an alignment dynamic encoding model, and a deep learning model. The volumetric agreement between the three automated segmentation algorithms and the breast regions manually segmented by imaging physicians was evaluated by calculating the mean square error (MSE) and intragroup correlation coefficient (ICC), and the reproducibility of the automated segmentation of the breast regions was assessed by the test-retest step. RESULTS: The three breast automated segmentation models developed in this study (simple registration model, dynamic programming model, and deep learning model) showed strong ICC with manual segmentation of the breast region, with MSEs of 1.124, 0.693, and 0.781, and ICCs of 0.975 (95% CI, 0.869-0.991), 0.986 (95% CI, 0.967-0.996), and 0.983 (95% CI, 0.961-0.992), respectively. Regarding the test-retest results of breast volume, the dynamic programming model performed the best with an MSE of 0.370 and an ICC of 0.993 (95% CI, 0.982-0.997), followed by the deep learning algorithm with an MSE of 0.741 and an ICC of 0.983 (95% CI, 0.956-0.993), and the simple registration algorithm with an MSE of 0.763 and an ICC of 0.982 (95% CI, 0.949-0.993). The reproducibility of the breast region segmented by the three automated algorithms was higher than that of manual segmentation by different radiologists. CONCLUSION: The three automated breast segmentation algorithms developed in this study generate accurate and reliable breast regions, enable highly reproducible breast region segmentation and automated volume measurements, and provide a valuable tool for surgical selection of appropriate prostheses. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. 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 .

Combining Liposuction and Thread-Lifting for Middle-Lower Facial Rejuvenation.

BACKGROUND: Thread-lifting (TL) is a minimally-invasive technique for facial rejuvenation, whereas liposuction is commonly used for facial contouring. This retrospective cohort study aims to introduce and evaluate a novel technique that combines liposuction and thread-lifting for mid-lower facial rejuvenation. METHODS: Consecutive patients who underwent TL for mid-lower facial rejuvenation from May 2016 to May 2021 were divided into thread-lifting group (TL group) or thread-lifting plus liposuction group (TLL group) according to whether liposuction was performed adjunctively. The co-primary outcomes were the changes between the preoperative and 6-month postoperative Wrinkle Severity Rating Scale (WSRS) and Facial Aging Evaluation Scale (FAES). RESULTS: A total of 185 patients (184 females) with an average age of 34.5±5.5 years were included. There were no significant differences in patients' age, number of threads, and preoperative WSRS and FAES between the two groups. The TLL group (n = 128) had significantly lower postoperative WSRS (1.5±0.6 vs. 1.8±0.8, p<0.001) and FAES (2.5±1.4 vs. 3.8±2.1, p<0.001) than the TL group (n = 57). The decrease in WSRS (0.8±0.6 vs. 0.2±0.7, p<0.001) and FAES (2.7±1.3 vs. 1.6±1.6, p<0.001) were greater in the TLL group. Only 3.8% patients experienced slight side effects and totally recovered. CONCLUSIONS: The combination of TL and liposuction is an effective and safe technique for simultaneous contour improvement and facial rejuvenation in middle-aged East Asian females. LEVEL OF EVIDENCE II: 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 https://www.springer.com/00266 .

Complications Following Facial Injection of Growth Factor Solution.

OBJECTIVE: Topical injection of growth factor (GF) for facial rejuvenation is unauthorized, but it is commonly performed in China, leading to emerging and challenging complications. The purpose of this study is to investigate the clinical, imaging, and histopathologic characteristics of complications caused by facial GF injection, as well as their treatments and outcomes. METHODS: We performed a retrospective single-centered case series study on consecutive patients who were treated for complications following facial injection of GF. The primary outcome was the recurrence over follow-up period. The secondary outcomes were the subjective evaluations of the facial aesthetic, symptomatic, and psychological improvements using the Global Aesthetic Improvement Scale (GAIS) and a patient-reported outcome measurement (PROM). Kaplan-Meier analysis and log-rank test were performed to investigate the recurrence. RESULTS: A total of 32 females with an average age of 42.6 ± 9.4 years were included. Most patients received GF injections in non-medical institutes such as beauty spas and presented with uncontrollable soft tissue hyperplasia, diffuse subcutaneous swelling, and skin redness. Ultrasonography showed heterogeneous hypoechoic or echogenic areas in a thickened and disorganized subcutaneous tissue hierarchy. MRI showed flaky isointensive or hypointensive signals on T1WI and hyperintensive signals on T2WI. 37.5% patient underwent triamcinolone acetonide injection, whereas 62.5% patients underwent surgical interventions. Lipoma-like hyperplastic tissue was found during surgery. HE staining confirmed intramuscular lipoma and fibrolipomatous tissue hyperplasia. Recurrence was found in 37.5% patients over a median follow-up of 6 months. KM curves and log-rank test demonstrated no significant difference in the recurrence between patients who underwent nonsurgical or surgical interventions (p = 0.77). GAIS and PROM scores indicated substantial aesthetic, symptomatic, and psychological improvements in 70%, 91.7%, and 75% patients, respectively. CONCLUSIONS: Both surgical and nonsurgical interventions are feasible and effective treatment options for GF-induced complications. Although recurrence rate was relatively high, aesthetic, symptomatic, and psychological improvements were achieved in most patients. We developed a workflow that might help diagnose and treat complications following unknown dermal filler injections. LEVEL OF EVIDENCE IV: 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 .

Tension-reduced closure of large abdominal wall defect caused by shotgun wound: A case report.

BACKGROUND: Large abdominal wall defect (LAWD) caused by shotgun wound is rarely reported. CASE SUMMARY: Herein, we describe a case of LAWD caused by a gunshot wound in which the abdominal wall was reconstructed in stages, including debridement, tension-reduced closure (TRC), and reconstruction with mesh and a free musculocutaneous flap. During a 3-year follow-up, the patient recovered well without hernia or other problems. CONCLUSION: TRC is a practical approach for the temporary closure of LAWD, particularly in cases when one-stage abdominal wall restoration is unfeasible due to significant comorbidities.

Lipid nanoparticle-encapsulated VEGFa siRNA facilitates cartilage formation by suppressing angiogenesis.

Cartilage is an important tissue that is widely found in joints, ears, nose and other organs. The limited capacity to regenerate makes cartilage reconstruction an urgent clinical demand. Due to the avascular nature of cartilage, we hypothesized that inhibition of vascularization contributes to cartilage formation. Here, we used VEGFa siRNA to inhibit the infiltration of the local vascular system. Optimized lipid nanoparticles were prepared by microfluidics for the delivery of siRNA. Then, we constructed a tissue engineering scaffold. Both seed cells and VEGFa siRNA-LNPs were loaded in a GELMA hydrogel. Subcutaneous implantation experiments in nude mice indicate that this is a promising strategy for cartilage reconstruction. The regenerated cartilage was superior, with significant upregulation of SOX9, COL-II and ACAN. This is attributed to an environment deficient in oxygen and nutrients, which facilitates cartilage formation by upregulating HIF-1α and FOXO transcription factors. In conclusion, a GelMA/Cells+VEGFa siRNA-LNPs scaffold was constructed to achieve superior cartilage regeneration.

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.

Construction of immunotherapy-related prognostic gene signature and small molecule drug prediction for cutaneous melanoma.

Background: Cutaneous melanoma (CM), a kind of skin cancer with a high rate of advanced mortality, exhibits a wide variety of driver and transmitter gene alterations in the immunological tumor microenvironment (TME) associated with tumor cell survival and proliferation. Methods: We analyzed the immunological infiltration of TME cells in normal and malignant tissues using 469 CM and 556 normal skin samples. We used a single sample gene set enrichment assay (ssGSEA) to quantify the relative abundance of 28 cells, then used the LASSO COX regression model to develop a riskScore prognostic model, followed by a small molecule drug screening and molecular docking validation, which was then validated using qRT-PCR and IHC. Results: We developed a prognosis model around seven essential protective genes for the first time, dramatically elevated in tumor tissues, as did immune cell infiltration. Multivariate Cox regression results indicated that riskScore is an independent and robust prognostic indicator, and its predictive value in immunotherapy was verified. Additionally, we identified Gabapentin as a possible small molecule therapeutic for CM. Conclusions: A riskScore model was developed in this work to analyze patient prognosis, TME cell infiltration features, and treatment responsiveness. The development of this model not only aids in predicting patient response to immunotherapy but also has significant implications for the development of novel immunotherapeutic agents and the promotion of tailored treatment regimens.

A novel inflammatory response-related signature predicts the prognosis of cutaneous melanoma and the effect of antitumor drugs.

Cutaneous melanoma (CM) is a skin cancer that is highly metastatic and aggressive, with a dismal prognosis. This is the first study to use inflammatory response-related genes to build a model and evaluate their predictive significance in CM. This study used public databases to download CM patients' mRNA expression profiles and clinical data to create multigene prognostic markers in the UCSC cohort. We compared overall survival (OS) between high- and low-risk groups using the Kaplan-Meier curve and determined independent predictors using Cox analysis. We also used enrichment analysis to assess immune cell infiltration fraction and immune pathway-related activity using KEGG enrichment analysis. Furthermore, we detected prognostic genes' mRNA and protein expression in CM and normal skin tissues using qRT-PCR and immunohistochemistry. Finally, we developed a 5-gene predictive model that showed that patients in the high-risk group had a considerably shorter OS than those in the low-risk group. The analysis of the receiver operating characteristic (ROC) curve proved the model's predictive ability. We also conducted a drug sensitivity analysis and discovered that the expression levels of prognostic genes were substantially linked with cancer cell sensitivity to antitumor medicines. The findings show that the model we developed, which consists of five inflammatory response-related genes, can be used to forecast the prognosis and immunological state of CM, giving personalized and precision medicine a new goal and direction.

The Multi-Omics Landscape and Clinical Relevance of the Immunological Signature of Phagocytosis Regulators: Implications for Risk Classification and Frontline Therapies in Skin Cutaneous Melanoma.

Tumor-associated macrophages (TAMs) have gained considerable attention as therapeutic targets. Monoclonal antibody treatments directed against tumor antigens contribute significantly to cancer cell clearance by activating macrophages to phagocytose tumor cells. Due to its complicated genetic and molecular pathways, skin cutaneous melanoma (SKCM) has not yet attained the expected clinical efficacy and prognosis when compared to other skin cancers. Therefore, we chose TAMs as an entrance point. This study aimed to thoroughly assess the dysregulation and regulatory role of phagocytosis regulators in SKCM, as well as to understand their regulatory patterns in SKCM. This study subtyped prognosis-related phagocytosis regulators to investigate prognostic differences between subtypes. Then, we screened prognostic factors and constructed phagocytosis-related scoring models for survival prediction using differentially expressed genes (DEGs) between subtypes. Additionally, we investigated alternative treatment options using chemotherapeutic drug response data and clinical cohort treatment data. We first characterized and generalized phagocytosis regulators in SKCM and extensively examined the tumor immune cell infiltration. We created two phagocytosis regulator-related system (PRRS) phenotypes and derived PRRS scores using a principal component analysis (PCA) technique. We discovered that subtypes with low PRRS scores had a poor prognosis and decreased immune checkpoint-associated gene expression levels. We observed significant therapeutic and clinical improvements in patients with higher PRRS scores. Our findings imply that the PRRS scoring system can be employed as an independent and robust prognostic biomarker, serving as a critical reference point for developing novel immunotherapeutic methods.

Multiple datasets to explore the tumor microenvironment of cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most frequent types of cutaneous cancer. The composition and heterogeneity of the tumor microenvironment significantly impact patient prognosis and the ability to practice precision therapy. However, no research has been conducted to examine the design of the tumor microenvironment and its interactions with cSCC. MATERIAL AND METHODS: We retrieved the datasets GSE42677 and GSE45164 from the GEO public database, integrated them, and analyzed them using the SVA method. We then screened the core genes using the WGCNA network and LASSO regression and checked the model's stability using the ROC curve. Finally, we performed enrichment and correlation analyses on the core genes. RESULTS: We identified four genes as core cSCC genes: DTYMK, CDCA8, PTTG1 and MAD2L1, and discovered that RORA, RORB and RORC were the primary regulators in the gene set. The GO semantic similarity analysis results indicated that CDCA8 and PTTG1 were the two most essential genes among the four core genes. The results of correlation analysis demonstrated that PTTG1 and HLA-DMA, CDCA8 and HLA-DQB2 were significantly correlated. CONCLUSIONS: Examining the expression levels of four primary genes in cSCC aids in our understanding of the disease's pathophysiology. Additionally, the core genes were found to be highly related with immune regulatory genes, suggesting novel avenues for cSCC prevention and treatment.

Complications following thread rhinoplasty.

BACKGROUND: The debate on thread rhinoplasty (TR) has never stopped owing to its complications. However, few studies have reported the clinical characteristics of TR complications, as well as their treatment. AIMS: We aim to summarize the clinical, ultrasonographic, and histopathologic characteristics of TR complications. PATIENTS/METHODS: This retrospective case series study included consecutive patients presenting with TR complications. Patients' demographics, medical history, complications, ultrasonography, treatment, histopathology, and follow-up outcome were collected through the electronic medical record. RESULTS: A total of 30 patients (28 females) with an average age of 28.7±6.8 years were included. The most common complication leading to consultation was infection (46.7%), followed by thread extrusion (30%), chronic inflammation (16.7%), and dimpling (6.7%). Most patients who developed complications received TRs at illegal nonmedical places (70%). Ultrasonography of infection showed multiple dotted heterogeneous hyperecho signals surrounded by a hypoecho area. Twenty patients (66.7%) received debridement, thread removal, or release of dimpling. Threads could be completely removed within one month of TR. Histopathological examination showed multifocal crystal-like material surrounded by excessive inflammatory cells in hyperplastic granulation tissues. All patients were satisfied with the clinical outcomes over a follow-up of 25.6 ± 14 months. CONCLUSIONS: Infection is the most common complication that always warrants thread removal. Ultrasonography is helpful in detecting the remaining threads and delineating the infection area. We do not recommend threading as a regular method for rhinoplasty owing to its complications for an expedience with short-lasting effect.

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.

A Bayesian Network Meta-Analysis of Complications Related to Breast Reconstruction Using Different Skin Flaps After Breast Cancer Surgery.

BACKGROUND AND OBJECTIVES: As the incidence of breast cancer rises, the number of mastectomy surgeries surges, so does the importance of postoperative breast reconstruction. The implementation of autologous flap restoration methods is becoming prevalent, although which is the best flap remains controversial. As a result, we performed a Bayesian network meta-analysis to compare the eight most common flap in the reconstruction processor of breast cancer surgery. Our findings may help surgeons decide which skin flaps to use for breast reconstruction. METHODS: We searched PubMed, Medline, Embase, and the Cochrane library for relevant literature. For our Bayesian network meta-analysis, we scrutinized 37 papers and evaluated the postoperative complications of eight commonly used breast reconstruction procedures. We also registered this study on PROSPERO, with the number CRD42021251989. RESULTS: A total of 21,184 patients were included in this Bayesian network meta-analysis from 37 different studies. The results demonstrate that TRAM flaps are more prone to complications such as hernias in the abdominal wall and blood flow problems. Hematoma and seroma are more likely to follow LDP flaps. Combining LDP flaps with a prosthetic or autologous adipose tissue does not enhance the risk of postoperative problems appreciably. Fat liquefaction are relatively common in DIEP. CONCLUSIONS: After breast reconstruction, several skin flaps can be employed as clinical choices. TRAM flaps are not recommended for patients with a weak abdominal wall structure, although LDP flaps or SIEA flaps can be considered instead. We do not advocate LDP flaps for patients who have had breast surgery because of the higher risk of hematoma or seroma, but DIEP flaps or LAP flaps can be utilized instead. We do not propose DIEP flaps for individuals who are at a higher risk of postoperative fat liquefaction, but LDP flaps or SIEA flaps can be used instead. However, this Bayesian network meta-analysis has limitations, and further randomized controlled trials are needed to confirm its findings. 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 .

Development and Validation of a Nomogram to Predict the Risk of Blood Transfusion in Orthognathic Patients.

OBJECTIVE: This study aims to establish a nomogram to predict the probability of blood transfusion in patients with preoperative autologous blood donation before orthognathic surgery. METHODS: The authors conducted a retrospective case-control study on consecutive orthognathic patients with preoperative autologous blood donation from January 2014 to December 2020. The outcome variable was the actual transfusion of autologous blood (ATAB). Predictors included patients' demographics, preoperative blood cell test, vital signs, American Society of Anesthesiologists classification, surgical procedure, operation duration, and blood loss. Univariable and multivariable logistic regressions were performed to identify independent risk factors associated with ATAB. A nomogram was constructed to predict the risk for ATAB. The performance of the nomogram was evaluated using the area under the receiver operating characteristic curve, calibration curve and the consistency index. RESULTS: A total of 142 patients (75 males and 67 females) with an average age of 22.72 ± 5.34 years donated autologous blood before their orthognathic surgery. Patients in the transfusion group (n = 56) had significantly lower preoperative red blood cell counts (4.74 ± 0.55 × 10 9 /L versus 4.98 ± 0.45 × 10 9 /L, P = 0.0063), hemoglobin (141.48 ± 15.18g/dL versus 150.33 ± 14.73g/dL, P = 0.0008), and hematocrit (41.05% ± 4.03% versus 43.32% ± 3.42%, P = 0.0006), more bimaxillary osteotomies (92.86% versus 56.98%, P < 0.001), longer operation duration (348.4 ± 111.10 minutesversus261.6 ± 115.44 minutes, P < 0.001), and more intraoperative blood loss (629.23±273.06 ml versus 359.53 ± 222.84 ml, P < 0.001) than their counterparts (n = 86) in the non- transfusion group. Univariable and multivariable logistic regression demonstrated that only hemoglobin (adjusted odds ratio [OR] 0.864, 95% confidence interval [CI]:0.76-0.98, P = 0.026), operation procedures (adjusted OR 8.14, 95% CI:1.69-39.16, P = 0.009), and blood loss (adjusted OR 1.006, 95% CI:1.002-1.009, P < 0.001) were independent risk factors for ATAB. The area under the receiver operating characteristic curve of the nomogram was 0.823. The consistency index of the nomogram was 0.823. The calibration curve illustrated that the nomogram was highly consistent with the actual observation. CONCLUSIONS: The nomogram is a simple and useful tool with good accuracy and performance in predicting the risk for blood transfusion.

KLF9 (Kruppel Like Factor 9) induced PFKFB3 (6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3) downregulation inhibits the proliferation, metastasis and aerobic glycolysis of cutaneous squamous cell carcinoma cells.

Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer in humans with increasing incidence. In this paper, we focused on the effects of krueppel-like factor 9 (KLF9) on the progression of CSCC cells by binding to PFKFB3. mRNA and protein expressions of KLF9 and PFKFB3 in human HaCaT and CSCC cells were, respectively, examined by RT-qPCR analysis and Western blot. The viability, proliferation, invasion and migration of A431 cells after transfection were analyzed with MTT, clone formation, transwell and wound healing assays. The levels of glucose, lactic acid and ATP in transfected A431 cells were detected by their commercial kits. Ki-67 expression in transfected A431 cells was determined using immunofluorescence analysis and in tumor tissues was analyzed by immunohistochemistry. The levels of migration, EMT and aerobic glycolysis-related proteins were tested with Western blot. The combination of KLF9 and PFKFB3 was confirmed by dual-luciferase reporter assay and ChIP. As a result, PFKFB3 expression was elevated in CSCC cells compared with HaCaT. Knockdown of PFKFB3 restrained the proliferation, metastasis, and aerobic glycolysis of CSCC cells. In addition, KLF9 could bind to PFKFB3. Downregulation of KLF9 crippled the inhibitory effect of knockdown of PFKFB3 on the proliferation, metastasis, and aerobic glycolysis of CSCC cells. In conclusion, PFKFB3 was transcriptionally regulated by KLF9, and PFKFB3 silencing inhibits the proliferation, metastasis, and aerobic glycolysis of cutaneous squamous cell carcinoma cells.

Contralateral risk-reducing local therapy in breast cancer patients with BRCA1/2 mutations: systemic review and meta-analysis.

BACKGROUND: Unilateral breast cancer (UBC) patients with germline pathogenic BRCA1/2 variants have a higher risk of developing contralateral breast cancer (CBC) and need contralateral risk-reducing local treatments, including contralateral risk-reducing mastectomy (CRRM) and prophylactic irradiation (CPI). The aim of our study was to systematically explore the efficacy of CRRM and CPI in reducing CBC risk and increasing survival. METHODS: A search was done, and eligible randomized trials and cohort studies should include and compare UBC patients with germline pathogenic BRCA1/2 variants who have and have not received contralateral risk-reducing local treatment. Random-effects meta-analysis was used in this study. Primary outcomes of the studies included overall survival (OS) and the incidence of contralateral breast cancer (CBC), and secondary outcomes included breast cancer-specific survival (BCSS). RESULTS: A total of five studies with 1769 UBC patients with germline pathogenic BRCA1/2 variants were enrolled in our meta-analysis. CRRM was correlated with a lower risk of CBC in UBC patients with germline pathogenic BRCA1/2 variants (summary RR = 0.07; 95%CI 0.03-0.13, I2 = 3%), a significantly increased OS (summary RR, 1.15; 95%CI 1.04-1.26, I2 = 26%) and a significantly increased BCSS (summary RR, 1.18; 95%CI 1.07-1.31, I2 = 64%) compared with surveillance. CPI also decreased the risk of CBC (RR 0.02; 95%CI 0.05-0.88) but did not significantly improve OS (RR 0.97; 95%CI 0.90-1.05) and BCSS (RR 0.97; 95%CI 0.90-1.05) compared with surveillance. CONCLUSIONS: CRRM reduces CBC risk and increases OS and BCSS in UBC patients with germline pathogenic BRCA1/2 variants, and could be offered as a risk-reducing local treatment. For those who oppose CRRM, CPI could be offered for CBC-risk reduction, while its survival benefit is still uncertain.

Biomimetic nerve guidance conduit containing engineered exosomes of adipose-derived stem cells promotes peripheral nerve regeneration.

BACKGROUND: Efficient and stable delivery of neurotrophic factors (NTFs) is crucial to provide suitable microenvironment for peripheral nerve regeneration. Neurotrophin-3 (NT-3) is an important NTF during peripheral nerve regeneration which is scarce in the first few weeks of nerve defect. Exosomes are nanovesicles and have been served as promising candidate for biocarrier. In this work, NT-3 mRNA was encapsulated in adipose-derived stem cell (ADSC)-derived exosomes (ExoNT-3). These engineered exosomes were applied as NT-3 mRNA carrier and then were loaded in nerve guidance conduit (ExoNT-3-NGC) to bridge rat sciatic nerve defect. METHOD: NT-3 mRNA was encapsulated in exosomes by forcedly expression of NT-3 mRNA in the donor ADSCs. ExoNT-3 were co-cultured with SCs in vitro; after 24 h of culture, the efficiency of NT-3 mRNA delivery was evaluated by qPCR, western blotting and ELISA. Then, ExoNT-3 were loaded in alginate hydrogel to construct the nerve guidance conduits (ExoNT-3-NGC). ExoNT-3-NGC were implanted in vivo to reconstruct 10 mm rat sciatic nerve defect. The expression of NT-3 was measured 2 weeks after the implantation operation. The sciatic nerve functional index (SFI) was examined at 2 and 8 weeks after the operation. Moreover, the therapeutic effect of ExoNT-3-NGC was also evaluated by morphology assay, immunofluorescence staining of regenerated nerves, function evaluation of gastrocnemius muscles after 8 weeks of implantation. RESULTS: The engineered exosomes could deliver NT-3 mRNA to the recipient cells efficiently and translated into functional protein. The constructed NGC could realize stable release of exosomes at least for 2 weeks. After NGC implantation in vivo, ExoNT-3-NGC group significantly promote nerve regeneration and improve the function recovery of gastrocnemius muscles compared with control exosomes (Exoempty-NGC) group. CONCLUSION: In this work, NGC was constructed to allow exosome-mediated NT-3 mRNA delivery. After ExoNT-3-NGC implantation in vivo, the level of NT-3 could restore which enhance the nerve regeneration. Our study provide a potential approach to improve nerve regeneration.

HER2 transmembrane domain mutation: comprehensive characteristics and real-world evidence of treatment response in Chinese lung adenocarcinoma.

BACKGROUND: HER2 transmembrane domain (TMD) mutation has been reported as a rare driver mutation associated with advanced stage disease and a poor prognosis in patients with lung adenocarcinoma (LUAD). We aimed to comprehensively profile the genetic landscape and treatment response information of HER2 TMD-mutant LUAD. METHODS: An in-house database of 7,812 LUAD patients was screened for mutation prevalence. A multi-center cohort of 16 HER2 V659E-mutant patients and an external cohort of 38 HER2-mutant patients from cBioPortal with overall survival (OS) data were analyzed. Eight patients from the in-house cohort were included in the real-world study of treatment response. Molecular docking simulation and binding affinity prediction were performed. RESULTS: In Chinese LUAD, the prevalence of HER2 TMD mutation was 0.18% (14/7,812), and 0.14% (11/7,812) for the HER2 V659E mutation. The most recurrent co-alteration was TP53 mutation (n=4, 25%) and HER2 amplification (n=2, 12.5%). TMD-mutant patients were diagnosed at more advance stages (P<0.001) and had poorer OS (median OS 10.0 vs. 61.6 months, HR =7.9, 95% CI: 1.0-61.0, P<0.001) than non-TMD mutations. The overall response rate of targeted therapy, chemo-based therapy, and immunotherapy was 57.1%, 22.2%, and 0%, respectively. We postulated to challenge the resistance of tyrosine kinase inhibitor (TKI) with another with stronger binding energy to HER2 and supported the conclusion with a successful case. Additionally, we demonstrated a three-month response to the off-label use of pyrotinib in fifth-line therapy. CONCLUSIONS: Comapred with non-TMD mtuations, HER2 TMD mutation is a rare driver mutation with poorer prognosis in LUAD. Targeted therapy is the dominant choice for patients harboring this targetable mutation and longer OS could possibly be achieved through rechallenge with TKI of stronger binding affinity. Response to fifth-line pyrotinib was observed.

Quantification of intracranial arterial stenotic degree evaluated by high-resolution vessel wall imaging and time-of-flight MR angiography: reproducibility, and diagnostic agreement with DSA.

OBJECTIVES: The purpose of this study was to compare the reproducibility and diagnostic agreement of high-resolution vessel wall imaging (HR-VWI) and time-of-flight magnetic resonance angiography (TOF-MRA) with digital subtraction angiography (DSA) to evaluate intracranial arterial stenosis. METHODS: We retrospectively enrolled patients who underwent HR-VWI and TOF-MRA with suspected intracranial artery disease and had DSA results from our institutional imaging database. Two neuroradiologists separately and independently evaluated anonymous image data for the stenotic lesions. DSA was analyzed by two neurointerventionalists and it served as a standard criterion. The reproducibility of these two MR techniques was determined by the intraclass correlation coefficients (ICCs). The diagnostic agreement to DSA was assessed by the concordance correlation coefficients (CCCs). RESULTS: A total of 246 lesions from 106 individuals were analyzed for stenotic degrees. The total intra-observer and inter-observer reproducibility of HR-VWI was excellent for identifying stenosis and better than of TOF-MRA. The overall concordance of HR-VWI with DSA was excellent with CCC = 0.932, whereas TOF-MRA was 0.694. In addition, HR-VWI could provide additional vessel wall information. CONCLUSIONS: HR-VWI has more advantages over TOF-MRA, such as better reproducibilities and diagnostic agreements with DSA to analyze intracranial arterial stenosis. It provides additional information that helps in clinical diagnosis and management. KEY POINTS: • High-resolution vessel wall imaging can assess intracranial arterial stenosis with a better reproducibility than TOF-MRA and has a higher diagnostic agreement with DSA. • High-resolution vessel wall imaging had a higher diagnostic agreement with DSA compared with TOF-MRA. • Apart from evaluating vascular stenosis, HR-VWI provided additional vessel wall information to help in clinical diagnosis.