Organoids derived from metastatic cancers: Present and future.

Organoids are three-dimensional structures derived from primary tissue or tumors that closely mimic the architecture, histology, and function of the parental tissue. In recent years, patient-derived organoids (PDOs) have emerged as powerful tools for modeling tumor heterogeneity, drug screening, and personalized medicine. Although most cancer organoids are derived from primary tumors, the ability of organoids from metastatic cancer to serve as a model for studying tumor biology and predicting the therapeutic response is an area of active investigation. Recent studies have shown that organoids derived from metastatic sites can provide valuable insights into tumor biology and may be used to validate predictive models of the drug response. In this comprehensive review, we discuss the feasibility of culturing organoids from multiple metastatic cancers and evaluate their potential for advancing basic cancer research, drug development, and personalized therapy. We also explore the limitations and challenges associated with using metastasis organoids for cancer research. Overall, this review provides a comprehensive overview of the current state and future prospects of metastatic cancer-derived organoids.

Hidden blood loss and its influencing factors after cement augmentation for vertebral metastasis.

Introduction: Few studies have focused on the risk factors for hidden blood loss (HBL) during cement augmentation surgery for pathologic vertebral compression fraction (PVCFs). Method: From January 2014 to December 2020, the clinical data of 169 PVCF patients (283 levels) who underwent cement augmentation were retrospectively analysed. HBL was calculated according to the linear Gross formula using the patient's average Hct during the perioperative course and PBV. Multivariate linear regression analysis was performed to evaluate the independent factors associated with HBL. Results: The mean HBL was 448.2 ± 267.2 ml, corresponding to 10.8% ± 6.2% of the patient blood volume (PBV). There were significant differences between pre- and postoperative haematocrit (Hct) (P < 0.001) and Hb (P < 0.001), and 132 patients developed anaemia postoperatively, while 79 patients had anaemia preoperatively (P < 0.001). Multivariate linear regression revealed that bone lesion quality (p = 0.028), number of PVCFs (p = 0.002), amount of bone cement (p = 0.027), bone cement leakage (p = 0.001), and percentage of vertebral height loss (VHL) (p = 0.011) were independent risk factors for HBL. Conclusion: In conclusion, patients with lytic vertebral destruction, larger amounts of bone cement, greater amounts of bone cement leakage, more PVCF(s), and greater percentages of VHL may be more prone to HBL.

CFLAR: A novel diagnostic and prognostic biomarker in soft tissue sarcoma, which positively modulates the immune response in the tumor microenvironment.

Anoikis is highly associated with tumor cell apoptosis and tumor prognosis; however, the specific role of anoikis-related genes (ARGs) in soft tissue sarcoma (STS) remains to be fully elucidated. The present study aimed to use a variety of bioinformatics methods to determine differentially expressed anoikis-related genes in STS and healthy tissues. Subsequently, three machine learning algorithms, Least Absolute Shrinkage and Selection Operator, Support Vector Machine and Random Forest, were used to screen genes with the highest importance score. The results of the bioinformatics analyses demonstrated that CASP8 and FADD-like apoptosis regulator (CFLAR) exhibited the highest importance score. Subsequently, the diagnostic and prognostic value of CFLAR in STS development was determined using multiple public and in-house cohorts. The results of the present study demonstrated that CFLAR may be considered a diagnostic and prognostic marker of STS, which acts as an independent prognostic factor of STS development. The present study also aimed to explore the potential role of CFLAR in the STS tumor microenvironment, and the results demonstrated that CFLAR significantly enhanced the immune response of STS, and exerted a positive effect on the infiltration of CD8+ T cells and M1 macrophages in the STS immune microenvironment. Notably, the aforementioned results were verified using multiplex immunofluorescence analysis. Collectively, the results of the present study demonstrated that CFLAR may act as a novel diagnostic and prognostic marker for STS, and may positively regulate the immune response of STS. Thus, the present study provided a novel theoretical basis for the use of CFLAR in STS diagnosis, in predicting clinical outcomes and in tailoring individualized treatment options.

The efficacy of re-excision after unplanned excision for synovial sarcoma.

Background: This investigation studied the clinical features and outcomes of synovial sarcoma (SS) patients from a single institution. Methods: A retrospective clinicopathologic study was conducted on 129 postoperative SS patients during 2003-2018. Kaplan-Meier curves and Cox proportional hazards regression (Cox) models were performed to determine the parameters associated with recurrence-free survival (RFS), metastasis-free survival (MFS), and cancer-specific survival (CSS) via univariate and multivariate analysis. The impact of unplanned excision (UE) and residual tumor in re-excision specimens was evaluated. Results: The 3-year RFS, MFS and 5-year CSS were 72 %, 70 %, and 76 %, respectively. Independent factors associated with significantly inferior survival included older age, UE without re-excision, UE with residual tumors, high grade, and deep tumor for RFS, trunk-related tumor, UE without re-excision, UE with residual tumors, and deep tumor for MFS, UE with residual tumors, high grade, and deep tumor for CSS. Re-excision after UE was significantly associated with better RFS (P < 0.001). Residual tumors were remarkably correlated with inferior RFS (P = 0.0012), MFS (P = 0.0016), and CSS (P = 0.048), especially in patients at stage II (MFS: P < 0.001, CSS: P = 0.0014). Conclusion: UE and residual tumors have a marked impact on the long-term survival of SS patients. Primary wide excision and re-excision is especially essential for patients at stage II.

Global, Regional, and National Incidence Trend Analysis of Malignant Skin Melanoma Between 1990 and 2019, and Projections Until 2034.

BACKGROUND: The goal of this study was to evaluate the global burden of malignant skin melanoma (MSM) from 1990 to 2019 using MSM-related data from the Global Burden of Disease study. METHODS: The incidences' relationships with the social-demographic index (SDI) and human developmental index (HDI) were investigated. To determine significant changes in incidence trends, the joinpoint regression model was used. To demonstrate trends in MSM mortality rates, an Age-Period-Cohort framework was conducted. For the projection of new cases and the age-standardized incidence rate (ASR) of MSM incidence to 2034, the Nordpred method was used. RESULTS: In 2019, the ASR incidence per 100, 000 people for MSM was 3.6 (95% UI, 2.6-4.2). MSM prevalence increased in most countries between 1990 and 2019 (average annual percentage change >0). HDI and annual percentage change (APC) (ρ = .63, P < .001), as well as SDI and ASR, had a positive correlation. The total MSM mortality rate declined globally, with an APC of -.61%. Likewise, the mortality rate for the age group of people with ages <77.5 years declined. Predictive analysis demonstrated a declining trend in ASR incidence and a growing number of MSM. CONCLUSION: There are significant differences in ASR incidence among regions and countries. Despite decreases in ASR incidence and fatality, MSM remains one of the leading sources of cancer mortality and morbidity globally. MSM necessitates more primary prevention measures and screening in high-risk areas.

Comprehensive Analysis Reveals Prognostic and Therapeutic Immunity-Related Biomarkers for Pediatric Metastatic Osteosarcoma.

Background and Objectives: Osteosarcoma, the most prevalent malignant bone tumor in children and adolescents, presents a complex pathogenesis characterized by various genetic and epigenetic alterations. This study aims to identify key differentially expressed genes (DEGs) in pediatric osteosarcoma, with a focus on those influencing metastasis and patient survival. Materials and Methods: We utilized the GSE33382 dataset from the GEO database for a comprehensive bioinformatic analysis. This included a protein-protein interaction (PPI) network analysis, Cox regression, and Kaplan-Meier survival analysis to identify central DEGs associated with osteosarcoma metastasis and patient survival. Results: Our analysis identified 88 DEGs related to osteosarcoma metastasis. Among them, three survival-related central DEGs-C1QA, CD74, and HLA-DMA-were significantly linked to patient outcomes. Further correlation analysis established a strong relationship between these genes, tumor mutation burden (TMB), immune checkpoint gene expression, and overall survival. Notably, C1QA and CD74 exhibited higher expression in non-metastatic osteosarcoma cases, suggesting a potential role in disease progression. Conclusions: The identified DEGs, particularly C1QA, CD74, and HLA-DMA, may serve as critical biomarkers for pediatric osteosarcoma prognosis and potential targets for immunotherapy. These findings provide a deeper understanding of the molecular landscape of osteosarcoma and open new avenues for therapeutic intervention.

Acral Lentiginous Melanoma: A Clinicoprognostic Study of 149 Cases at a Single Institution.

OBJECTIVE: The objective of this study is to investigate the epidemiological features, clinical characteristics, and pathological characteristics of acral lentiginous melanoma (ALM) and identify prognostic factors. METHODS: A total of 149 patients diagnosed with ALM between August 2008 and December 2019 at the National Cancer Center (NCC) of China were retrospectively analyzed. Follow-up data on patient survival status were collected. Survival curves were generated using the Kaplan-Meier method, and statistical significance was assessed using the log-rank test. Additionally, a Cox proportional hazards model was constructed to identify prognostic factors. RESULTS: All patients included in this study were of Chinese ethnicity, with an average age of 52.4 ± 14.8 years (range, 15-80 years) at the time of diagnosis. No gender predilection or genetic susceptibility was observed. The plantar region was the most frequently affected site among primary lesions. Notably, only 17 (11.4%) patients reported a history of trauma. Statistical analysis revealed that a lesion duration of ≤2.5 years, Breslow thickness >4.0 mm, high mitotic rate (>6 mm-2), presence of vascular invasion, and regional lymph node metastasis were identified as independent prognostic factors. CONCLUSION: Our findings indicate that a lesion duration of ≤2.5 years, Breslow thickness >4.0 mm, high mitotic rate (>6 mm-2), presence of vascular invasion, and regional lymph node metastasis are significantly associated with a poorer prognosis for patients with ALM.

A Modification of the American Joint Committee on Cancer Nomogram for Undifferentiated Sarcoma With External Validation and Risk Stratification.

BACKGROUND: The aim of this study is to establish a model to predict the overall survival (OS) and stratify the risk of postoperative patients with undifferentiated sarcoma. METHODS: A total of 452 postoperative patients with undifferentiated sarcoma in the trunk and extremity from the Surveillance, Epidemiology, and End Results database were enrolled as the training cohort. We collected a group of 163 undifferentiated sarcoma patients from our center as the external validation cohort. Cox proportional hazards regression model was used to screen survival-associated factors for the construction of the nomogram. Concordance-indexes (C-indexes), calibration curves, and receiver operating characteristics (ROCs) curves were applied for the discrimination and calibration of the nomogram. The cutoff value of nomogram-based total points was applied to stratify the risk of patients. RESULTS: A nomogram was developed incorporating four independent factors: age, tumor site, eighth AJCC stage, and radiotherapy. The nomogram showed good prognostic accuracy and excellent agreement in the training and validation cohort, with C-indexes of .701 (95% confidence interval [CI]: .683-.719) and .700 (95% CI: 0.659-.741), respectively. Furthermore, we identified the best cutoff value of nomogram total points (103.2) as the predicted risk and divided the patients into a high-risk group and a low-risk group. Significant differences in OS between the two groups were indicated in the training cohort and external validation cohort, showing the appreciable clinical validity and clinical utility of the nomogram (P < .001). CONCLUSION: This nomogram provides an insightful and applicable tool for individual evaluations and the distinguishment of risk for patients with undifferentiated sarcoma.

Quality of life issues in patients with bone metastases: A systematic review.

INTRODUCTION: Bones are frequent sites of metastatic disease, observed in 30-75% of advanced cancer patients. Quality of life (QoL) is an important endpoint in studies evaluating the treatments of bone metastases (BM), and many patient-reported outcome tools are available. The primary objective of this systematic review was to compile a list of QoL issues relevant to BM and its interventions. The secondary objective was to identify common tools used to assess QoL in patients with BM, and the QoL issues they fail to address. METHODS: A search was conducted on Ovid MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases between 1946 and 27 January 2023 with the keywords "bone metastases", "quality of life", and "patient reported outcomes". Specific QoL issues in original research studies and the QoL tools used were extracted. RESULTS: The review identified the QoL issues most prevalent to BM in the literature. Physical and functional issues observed in patients included pain, interference with ambulation and daily activities, and fatigue. Psychological symptoms, such as helplessness, depression, and anxiety were also common. These issues interfered with patients' relationships and social activities. Items not mentioned in existing QoL tools were related to newer treatments of BM, such as pain flare, flu-like symptoms, and jaw pain due to osteonecrosis. CONCLUSIONS: This systematic review highlights that QoL issues for patients with BM have expanded over time due to advances in BM-directed treatments. If they are relevant, additional treatment-related QoL issues identified need to be validated prospectively by patients and added to current assessment tools.

Risk factors for pulmonary cement embolism after percutaneous vertebroplasty and radiofrequency ablation for spinal metastases.

Objective: Pulmonary cement embolism is a rare but underestimated complication of vertebroplasty due to the relative lack of study and examination. This study aims to investigate the incidence of pulmonary cement embolism in patients with spinal metastasis who undergo PVP with RFA and to analyze the relative risk factors. Methods: A total of 47 patients were retrospectively included and classified into pulmonary cement embolism (PCE) group and non-pulmonary cement embolism (NPCE) group by comparing pre- and postoperative pulmonary CT scan images. The demographic and clinical information of the patients was obtained. Demographic data in the two groups were compared using the chi-square test for qualitative data and the unpaired t test for quantitative data. Multiple logistic regression analysis was used to identify risk factors related to pulmonary cement embolism. Results: Pulmonary cement embolism was detected in 11 patients (23.4%), and all patients were asymptomatic and followed up regularly. Risk analysis showed that multiple segments (≥3, p=0.022), thoracic vertebrae (p=0.0008), and unipedicular puncture approach (p=0.0059) were risk factors for pulmonary cement embolism. There was a high incidence of pulmonary cement embolism if bone cement leaked into the para vertebral venous plexus in the thoracic vertebra (p<0.0001). Vein leakage of cement was related to the integrity of the vertebral cortex. Conclusion: The number of involved vertebrae, lesion location, and puncture approach are independent risk factors for pulmonary cement embolism. There was a high incidence of pulmonary cement embolism if bone cement leaked into the para vertebral venous plexus in the thoracic vertebra. Surgeons should consider these factors when formulating therapeutic strategies.

Transcription-associated cyclin-dependent kinase 12 (CDK12) as a potential target for cancer therapy.

Cyclin-dependent kinase 12 (CDK12), a transcription-related cyclin dependent kinase (CDK), plays a momentous part in multitudinous biological functions, such as replication, transcription initiation to elongation and termination, precursor mRNA (pre-mRNA) splicing, intron polyadenylation (IPA), and translation. CDK12 can act as a tumour suppressor or oncogene in disparate cellular environments, and its dysregulation likely provokes tumorigenesis. A comprehensive understanding of CDK12 will tremendously facilitate the exploitation of novel tactics for the treatment and precaution of cancer. Currently, CDK12 inhibitors are nonspecific and nonselective, which profoundly hinders the pharmacological target validation and drug exploitation process. Herein, we summarize the newly comprehension of the biological functions of CDK12 with a focus on recently emerged advancements of CDK12-associated therapeutic approaches in cancers.

Can the Unipedicular Approach Replace Bipedicular Percutaneous Balloon Kyphoplasty for the Management of Metastatic Vertebral Lesions?

RATIONALE AND OBJECTIVES: To compare the clinical and radiographic results of bipedicular and unipedicular approaches(UPK and BPK) in the management of metastatic vertebral lesions MATERIALS AND METHODS: Eighty-two patients with 159 metastatic vertebral lesions who underwent UPK(25 cases, 69 lesions) or BPK(57 cases, 90 lesions) were retrospectively evaluated. Clinical results were assessed mainly depending on the Visual Analogue Scale(VAS) score, Oswestry Disability Index(ODI) and Quality of Life(QoL). Radiographic outcomes were evaluated primarily on the basis of bone cement distribution and changes in vertebral body height(VBH). Major and minor complications were systematically evaluated and compared to assess the safety of the 2 procedures. RESULTS: No statistically significant differences were observed in age, sex, types of lesions, location of lesions, posterior vertebral body and/or pedicle involvement, percentage of vertebra invasion between the groups(p=0.17-0.83). The radiographic parameter VBH was similarly improved in both groups(p=0.26-0.93). There was a significant improvement in the clinical parameters VAS score, ODI, and QoL at each follow-up examination compared with the preoperative results(p<0.001). Significant improvement was observed in the VBH at each follow-up point(p<0.05) compared to pre-procedure. UPK was superior to BPK in terms of the operative duration(p<0.001), cement volume(p=0.004), and surgical complications(p=0.04). CONCLUSION: Both UPK and BPK resulted in similar clinical and radiographic outcomes in patients with metastatic vertebral lesions. The UPK had advantages including a shorter operation and lower cement volume than the BPK, which may have played an important role in reducing the incidence of complications. UPK can replace BPK in the treatment of metastatic vertebral lesions.

Clinical analysis of percutaneous kyphoplasty for spinal metastases in older adults with comorbidities.

INTRODUCTION: We aimed to investigate the clinical outcomes of percutaneous kyphoplasty (PKP) for spinal metastases in older adult patients with comorbidities. MATERIALS AND METHODS: Ninety-two older adults (age ≥ 60 years) with spinal metastases who underwent 148 PKP procedures were retrospectively analyzed. Tokuhashi scores, Tomita scores, age-adjusted Charlson Comorbidity Index (aCCI) scores, and American Society of Anesthesiologists (ASA) scores were evaluated before the procedure. The visual analog scale (VAS), Oswestry Disability Index (ODI), vertebral body height (VBH), and quality of life (QoL) were used to assess the efficacy of the procedure. Clinical safety was evaluated based on periprocedural complications. RESULTS: Tokuhashi scores and Tomita scores were 7.3 ± 4.0 and 5.8 ± 2.1, respectively. Excluding cancer-related factors, twelve patients (13.0%) had aCCI scores ≥4. Forty-three patients (46.7%) had ASA status ≥ III. Compared to preoperative status, average VAS scores, ODI scores, VBH variation, and QoL scores significantly improved at each follow-up examination point after PKP (p < 0.001). No major complications occurred, nor was there decompensation of comorbidities in the perioperative period. Seventeen segments (11.5%) of twelve patients (13.0%) suffered bone cement leakage. Among them, one patient suffered intercostal neuralgia cured by steroid injection, and the other patient suffered hyperesthesia, which disappeared after taking gabapentin (0.3 g, bid) for five weeks. Another minor complication of local hematoma occurred in one patient, which spontaneously resolved without surgical intervention. DISCUSSION: PKP serves as a safe approach to provide significant pain relief, vertebral body height restoration, and QoL improvements for spinal metastases in older adults, independent of underlying disease.

The influence of diverse bone cement distribution patterns for metastatic vertebral lesions after bilateral percutaneous kyphoplasty.

OBJECTIVE: To investigate the influence of diverse bone cement distribution patterns in patients with metastatic vertebral lesions after bilateral percutaneous kyphoplasty (PKP). METHODS: Fifty-nine patients with single-level metastatic vertebral lesions who received bilateral PKP were retrospectively reviewed. According to the different bone cement distribution patterns, patients were divided into confluent (n = 35, CF) and separated (n = 24, SP) groups. Indicators including visual analogue scale (VAS), Oswestry Disability Index (ODI), vertebral body height (VBH) variation, quality of life (QoL), and related complications were reviewed and compared between the two groups. RESULTS: No statistically significant differences were observed between the two groups in age, sex, types of lesions, locations of lesions, posterior vertebral body and/or pedicle involvement, percentage of vertebral invasion, procedure duration or cement volume (p > 0.05). There was significant improvement in VAS, ODI, VBH and QoL at any follow-up examination (p < 0.05) compared with those preoperatively. The CF group exhibited better pain relief in VAS scores than did the SP group just at 3 days and 1 month after PKP (p < 0.05). There were no significant differences between the two groups in VAS scores at 3 months or 1 year after PKP (p > 0.05). No statistically significant differences were observed between the two groups in terms of ODI, VBH or QoL (p > 0.05). There was no statistically significant difference in the incidence of complications between the two groups (p > 0.05). CONCLUSIONS: More rapid pain relief was achieved with confluent rather than separated bone cement distribution patterns in PKP for patients with metastatic vertebral lesions.

Undifferentiated pleomorphic sarcoma of the extremity and trunk: a retrospective cohort study of 166 cases in a large institution.

Background: An imperative need for better management strategies to improve the survival in patients with undifferentiated pleomorphic sarcoma (UPS). Methods: The retrospective analysis of clinicopathological data of 166 UPS patients, who have undergone surgical treatment in our hospital, was carried out from January 2005 to January 2018. Cox regression model and Kaplan-Meier method were employed to identify the relevant factors affecting the rate of local recurrence (LR), distant metastasis (DM), and overall survival (OS) via univariate and multivariate analysis. The P<0.05 were found to be statistically considerable. Results: At the end of follow-up, the rate of LR, DM and OS in 166 UPS patients was 22.9% (38/166), 32.5% (54/166) and 75.3% (125/166) with a median follow-up time of 55 months. The existing study reveals that the UPS in trunk, tumor size ≥5 cm and R1/R2 resection margin are the prognostic markers of poor survival rate. Women are more susceptible to LR, and R1/R2 resection margin is significantly correlated with a high rate of LR. Old Patients (>60 years), the UPS in trunk and R1/R2 resection margin are susceptible to DM. Conclusions: R0 resection margin was an only independent favorable prognostic factor, which was correlated with LRFS, DMFS, and OS.

Lower Expression of GBP2 Associated With Less Immune Cell Infiltration and Poor Prognosis in Skin Cutaneous Melanoma (SKCM).

Guanylate binding protein 2 (GBP2) could bind to guanine nucleotides (GMP, GDP, and GTP) and exhibits antiviral activity against influenza virus through the innate immune response. Some researchers have demonstrated that the value of GBP2 in predicting the prognosis of multiple cancers and the complex correlation with immune response. However, the correlation of GBP2 to prognosis and immune cell infiltration level were unknown in skin cutaneous melanoma (SKCM). The GBP2 expression in multiple cancers were evaluated through Tumor Immune Estimation Resource (TIMER) and Oncomine. We also evaluated the influence of GBP2 on overall survival in multiple caners through GEPIA, TIMER, and tissue microarray. The correlation between GBP2 expression level and immune cell or gene markers of immune infiltration level was explored on TIMER and GEPIA. Gene set enrichment analysis was performed using the TCGA dataset. The GBP2 expression level represented a significant reduction and the GBP2 expression was lower compared with the SKCM-Metastasis with P<0.01. Lower GBP2 expression was significantly correlated with the poor overall survival of SKCM patients. Simultaneously, higher GBP2 expression predicted the better SKCM-free survival with P=0.019. GBP2 expression was positively correlated with the infiltration cells of B-cell, CD8+ T-cell, CD4+ T-cell, macrophage, neutrophil, and dendritic cell in SKCM. And there was a significant negative correlation between the expression of GBP2 and DNA methylation in the cBioPortal database (P=3.39e-42). Gene set enrichment analysis revealed that GBP2 was closely correlated with multiple pathways of immune response in cancer. In conclusion, Lower expression of GBP2 associated with less immune cell infiltration and poor prognosis in SKCM and the high promoter methylation of GBP2 represented a promising biomarker for poor prognostication in SKCM.

Patient-derived Tumour Organoids: A Bridge between Cancer Biology and Personalised Therapy.

Patient-derived tumour organoids (PDOs) have revolutionised our understanding of cancer biology and the applications of personalised therapies. These advancements are principally ascribed to the ability of PDOs to consistently recapitulate and maintain the genomic, proteomic and morphological characteristics of parental tumours. Given these characteristics, PDOs (and their extended biobanks) are a representative preclinical model eminently suited to translate relevant scientific findings into personalized therapies rapidly. Here, we summarise recent advancements in PDOs from the perspective of cancer biology and clinical applications, focusing on the current challenges and opportunities of reconstructing and standardising more sophisticated PDO models. STATEMENT OF SIGNIFICANCE: Patient-derived tumour organoids (PDOs), three-dimensional (3D) self-assembled organotypic structures, have revolutionised our understanding of cancer biology and the applications of personalised therapies. These advancements are principally ascribed to the ability of PDOs to consistently recapitulate and maintain the genomic, proteomic and morphological characteristics of parental tumours. Given these characteristics, PDOs (and their extended biobanks) are a representative preclinical model eminently suited to translate relevant scientific findings into personalized therapies rapidly.

Melanoma Molecular Subtypes and Development of Prognostic and Immunotherapy-Related Genetic Characteristics by Ferroptosis Gene Analysis.

The dissimilarity is a major problem in clinical therapy of skin cutaneous melanoma (SKCM). Objective and reproducible classification systems may help decode SKCM heterogeneity. ConsensusClusterPlus was used to establish a stable immune molecular classification based on ferroptosis-related genes that had been acquired from FerrDb. Moreover, the prognosis, somatic mutations, immune microenvironment characteristics, functional enrichment, and clinical responsiveness to the immune checkpoint blockade of different subtypes in two independent melanin datasets were compared. Kaplan-Meier curves, univariate, multivariate, least absolute contraction, and selection operator (LASSO) Cox regression analysis were used to develop a molecular model for predicting survival, which was verified by a nomogram on the basis of independent prognostic indicators. Two molecular subtypes (C1 and C2) for SKCM were first identified according to ferroptosis-related genes; C1 showed a poor prognosis, with lower infiltration degree of immune cells and TIED score and higher homologous recombination defects, fraction altered, the number of segments, and copy number amplification and deletion. These characteristics of C2 were the opposite of C1. A ferroptosis-related prognosis risk score (FPRS) model was constructed using 6 of 463 genes with differential expression between C1 and C2. This model splits patients into low- and high-risk cohorts. There were significant differences in the infiltration and proportion of immune cells, immune checkpoint gene expression, responsiveness to immune checkpoint therapy, and sensitivity to chemotherapeutic medications between low- and high-risk cohorts. This model was an independent prognostic marker for SKCM and has a high AUC. In summary, we have identified two subtypes of SKCM with different molecular and immune characteristics on the basis of ferroptosis-related genes and further developed and verified an FPRS model, which might independently serve as a prognostic marker for SKCM.

Inhibition of CDK7-dependent transcriptional addiction is a potential therapeutic target in synovial sarcoma.

Synovial sarcoma is typical aggressive malignant without satisfactory treatment outcome in adult series. Cyclin-dependent kinases (CDKs) in transcription have been considered promising molecular targets in cancer. Among these, CDK7 has been shown to play important roles in the pathogenesis of malignancies. However, the modulation mechanism of CDK7-regulated transcription in synovial sarcoma is unknown. In the present study, we aim to determine the expression and function of CDK7 in the transcription cycle of RNA polymerase II (RNAP II), and evaluate its prognostic and therapeutic significance in synovial sarcoma. Results showed that overexpression of CDK7 correlates with higher clinical stage and grade, and worse outcomes in clinic. High CDK7 expression was confirmed in all tested human synovial sarcoma cell lines and CDK7 was largely localized to the cell nucleus. Downregulation through siRNA or inhibition with the CDK7-targeting agent BS-181 exhibited dose-dependent cytotoxicity and prevented cell colony formation. Western blots demonstrated that inhibition of CDK7 paused transcription by a reduction of RNAP II phosphorylation. Blocking CDK7-dependent transcriptional addiction was accompanied by promotion of apoptosis. Furthermore, the CDK7-specific inhibitor reduced 3D spheroid formation and migration of synovial sarcoma. Collectively, our findings highlight the role of CDK7-dependent transcriptional addiction in human synovial sarcoma. CDK7-specific cytotoxic agents are therefore promising novel treatment options for synovial sarcoma.