Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial.

BACKGROUND: Adrenocortical carcinoma is a rare malignancy with poor response to systemic chemotherapy. Mitotane is the only approved therapy for adrenocortical carcinoma. Cabozantinib is a multikinase inhibitor approved in multiple malignancies. This is the first prospective trial to explore the anti-tumour activity, safety, and pharmacokinetic profile of cabozantinib in patients with advanced adrenocortical carcinoma. METHODS: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with advanced adrenocortical carcinoma was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients had histologically confirmed adrenocortical carcinoma, were not candidates for surgery with curative intent, had measurable disease, had an estimated life expectancy of at least 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 with adequate organ function. Patients who had used mitotane within 6 months of study participation were required to have a serum mitotane level of less than 2 mg/L. Patients were given oral cabozantinib 60 mg daily with the option of dose reduction to manage adverse events. The primary endpoint was progression-free survival at 4 months, assessed in all patients who received at least one dose of study drug per protocol. This study is registered with ClinicalTrials.gov, NCT03370718, and is now complete. FINDINGS: Between March 1, 2018, and May 31, 2021, we enrolled 18 patients (ten males and eight females), all of whom received at least one dose of study treatment. Of the 18 patients, eight (44%) had an ECOG performance status of 0, nine (50%) patients had a performance status of 1, and one (6%) patient had a performance status of 2. Median follow-up was 36·8 months (IQR 30·2-50·3). At 4 months, 13 (72·2%; 95% CI 46·5-90·3) of 18 patients had progression-free survival and median progression-free survival was 6 months (95% CI 4·3 to not reached). One patient remains on treatment. Treatment-related adverse events of grade 3 or worse occurred in 11 (61%) of 18 patients. The most common grade 3 adverse events were lipase elevation (three [17%] of 18 patients), elevated γ-glutamyl transferase concentrations (two [11%] patients), elevated alanine aminotransferase concentrations (two [11%] patients), hypophosphatemia (two [11%] patients), and hypertension (two [11%] patients). One (6%) of 18 patients had grade 4 hypertension. No treatment related deaths occurred on study. INTERPRETATION: Cabozantinib in advanced adrenocortical carcinoma showed promising efficacy with a manageable and anticipated safety profile. Further prospective studies with cabozantinib alone and in combination with immune checkpoint therapy are ongoing. FUNDING: Exelixis.

Clinicopathological characteristics of adrenocortical carcinoma in the Kyushu-Okinawa area of Japan.

OBJECTIVE: Adrenocortical carcinoma is a rare condition, with limited comprehensive reports from Japan. This study aimed to review Japan's data on adrenocortical carcinoma by assessing information from 46 patients-with adrenocortical carcinoma across 10 Japanese university hospitals. METHODS: We conducted a retrospective multi-institutional analysis of the clinical characteristics of adrenocortical carcinoma in Japan. We evaluated data from 46 patients across 10 university hospitals over 10 years and analyzed the relationship between clinicopathological characteristics and overall survival. RESULTS: Five- and 10-year overall survival rates were 59% and 53%, respectively. Overall survival was significantly different among the tumor-node-metastasis system for adrenocortical carcinoma of the American Joint Committee on Cancer/International Union Against Cancer, with the worst prognosis in stage IV (p = 0.0044). In our cohort, neither the Weiss score nor the Ki-67 proliferation index correlated with overall survival. Adjuvant treatment did not yield improved overall survival, whereas resection of the primary tumor in stage IV disease was significantly associated with improved overall survival (p = 0.0262). Out of the cases evaluated for plasma hormones, plasma cortisol, aldosterone, testosterone, and DHEA-S levels were measured at 23%, 42%, 29%, and 62%, respectively, demonstrating higher levels than the upper normal limits. CONCLUSION: Patients with stage IV adrenocortical carcinoma had a poor prognosis; however, resection of the primary tumor in stage IV disease was associated with prolonged survival. The results of this study are expected to contribute to future treatment of adrenocortical carcinoma in Japan.

Identification of novel lipid metabolic biomarkers associated with poor adrenocortical carcinoma prognosis using integrated bioinformatics.

BACKGROUND: Adrenocortical carcinoma while rare, often presents with advanced metastatic disease carrying a 5-year survival of <15%. Despite adrenocortical carcinoma tumors having high avidity for cholesterol, the role of lipids in adrenocortical carcinoma has not been well described. Therefore, we performed an integrated bioinformatic analysis to identify novel lipid biomarkers correlating with poor survival that may help identify adrenocortical carcinoma tumor progression or therapy resistance. METHODS: A meta-analysis of collated adrenocortical carcinoma studies from the correlation engine identified lipid metabolism genes differentially expressed between adrenocortical carcinoma and the normal adrenal, which were then selected for enrichment analysis by the Database for Annotation, Visualization and Integrated Discovery database. A protein-protein interaction network of genes was constructed using Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape. Top hub genes identified were validated using the Xena database. Survival analysis of hub genes was performed in the R2 genomic analysis platform using The Cancer Genome Atlas program data set. RESULTS: Examination of pathways by correlation engine identified a unique subset of lipid metabolism-related genes that are differentially regulated in adrenocortical carcinoma tumors versus normal tissues (P < .01). Enrichment pathway analysis in Database for Annotation, Visualization and Integrated Discovery indicated that genes involved in sphingolipid, steroid, and peroxisome proliferator-activated receptor-α metabolism is upregulated in adrenocortical carcinoma, whereas glycerol phospholipid, fatty acid, and phosphatidylinositol metabolism are downregulated. Survival analysis of differentially regulated genes indicated that upregulation of SGPL1, FDFT1, SQLE and downregulation of PIK3C2B, PIK3CD, SYNJ2, DGAT1, PLA2G16, PLD1, GPD1 are all significantly associated with poor overall survival (P < .05) in adrenocortical carcinoma patients. CONCLUSION: Upregulation of sphingolipid and steroid synthesis genes and downregulation of phosphatidylinositol and glycerol phospholipid metabolism are associated with worse survival in patients with adrenocortical carcinoma.

Multiplatform computational analysis of mast cells in adrenocortical carcinoma tumor microenvironment.

BACKGROUND: Immunotherapeutic response failure of adrenocortical carcinomas highlights a need for novel strategies targeting immune cell populations in the tumor microenvironment to overcome tumor resistance and enhance therapeutic response. A recent study explored a new link between tumor mast cell infiltration and improved outcomes in patients with adrenocortical carcinomas. We further dissect the role of mast cells in the tumor microenvironment of adrenocortical carcinomas by examining the tumor mast cell expression signatures and mast cell activity within the tumor microenvironment to provide additional insight into potential novel immunotherapeutic targets. METHODS: Using the CIBERSORTx computational immunogenomic deconvolution algorithm to analyze adrenocortical carcinoma tumor gene messenger RNA expression data (The Cancer Genome Atlas, N = 79), we estimated the abundance of tumor immune infiltrating mast cells and assessed prognostic potential of mast cell signaling genes as pro or antitumor signatures, as well as examined the impact on overall and disease-free survival. RESULTS: We stratified mast cell signaling genes with survival prognostic values (overall survival, disease-free survival, P < .05) into antitumor (ALOX5, CCL2, CCL5, CXCL10, HDC, IL16, TNF, TPSAB1, VEGFD) and protumor (CXCL1, CXCL3, CXCL8, IL4, IL13, PTGS3, TNSF4, VEGFD) groups. Antitumor mast cell signature, as the predominant phenotype, was associated with improved overall and disease-free survival. CONCLUSION: The deconvolution analysis of The Cancer Genome Atlas data identified mast cell infiltration in the adrenocortical carcinoma microenvironment as predominantly associated with antitumor activity. Future studies stemming from our findings may help define the role of mast cells in the tumor microenvironment and the impact on patient survival in patients with adrenocortical carcinomas. Modulation of tumor mast cell infiltration may serve as a potential target for novel synergistic immunotherapies for the treatment and improved survival of patients with adrenocortical carcinomas.

Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 - 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 - 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials.

Identification of prognostic metabolic genes in adrenocortical carcinoma and establishment of a prognostic nomogram: A bioinformatic study.

ABSTRACT: Adrenocortical carcinoma is an invasive malignancy with poor prognosis, high recurrence rate and limited therapeutic options. Therefore, it is necessary to establish an effective method to diagnose and evaluate the prognosis of patients, so as to realize individualized treatment and improve their survival rate.This study investigated metabolic genes that may be potential therapeutic targets for Adrenocortical carcinoma (ACC). Level 3 gene expression data from the ACC cohort and the relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database. To verify, other ACC datasets (GSE76021, GSE19750) were downloaded from the Gene Expression Omnibus (GEO) database. The ACC datasets from TCGA and GEO were used to screen metabolic genes through the Molecular Signatures Database using gene set enrichment analysis. Then, the overlapping metabolic genes of the 2 datasets were identified.A signature of five metabolic genes (CYP11B1, GSTM2, IRF9, RPL31, and UBE2C) was identified in patients with ACC. The signature could be used to divide the patients with ACC into high- and low-risk groups based on their median risk score. Multivariate Cox regression analysis was performed to determine the independent prognostic factors of ACC. Time-dependent receiver operating characteristic (ROC) curve analysis was conducted to assess the prediction accuracy of the prognostic signature. Last, a nomogram was established to assess the individualized prognosis prediction model.The results indicated that the signature of 5 metabolic genes had excellent predictive value for ACC. These findings might help improve personalized treatment and medical decisions.

S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study.

OBJECTIVE: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC. DESIGN: This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy. METHODS: The S-GRAS score was calculated as a sum of the following points: tumour stage (1-2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0-9% = 0; 10-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell's Concordance index (C-index) and Royston-Sauerbrei's R2D statistic. RESULTS: We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5. CONCLUSION: The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).

MSI2 expression in adrenocortical carcinoma: Association with unfavorable prognosis and correlation with steroid and immune-related pathways.

Adrenocortical carcinoma (ACC) is a rare, but highly aggressive cancer of the adrenal cortex with a generally poor prognosis. Despite being rare, completely resected ACCs present a high risk of recurrence. Musashi-2 (MSI2) has recently been recognized as a potential prognostic biomarker and therapeutic target in many cancers. However, no studies have evaluated the clinical significance of MSI2 expression in ACC. Here, we addressed MSI2 expression and its association with ACC prognosis and clinicopathological parameters. MSI2 expression was analyzed in TCGA, GSE12368, GSE33371, and GSE49278 ACC datasets; and its correlation with other genes and immune cell infiltration were investigated by using the R2: Genomics Analysis and Visualization Platform and TIMER databases, respectively. Enrichment analysis was performed with the DAVID Functional Annotation Tool. Kaplan-Meier curves, log-rank tests, and Cox regression analyses were used to explore the prognostic role of MSI2 in ACC. Our findings demonstrated the potential value of MSI2 overexpression as an independent predictor of poor prognosis in patients with completely resected ACC (hazard ratio 6.715, 95% confidence interval 1.266 - 35.620, p =.025). In addition, MSI2 overexpression was associated with characteristics of unfavorable prognosis, such as cortisol excess (p = .002), recurrence (p =.003), and death (p =.015); positively correlated with genes related to steroid biosynthesis (p < .05); and negatively correlated with immune-related pathways (p < .05). Our findings demonstrate that MSI2 has value as a prognostic marker for completely resected ACC and reinforce the investigation of its role as a possible therapeutic target for patients with ACC.

Adrenal biopsy, as a diagnostic method, is associated with decreased overall survival in patients with T1/T2 adrenocortical carcinoma: A propensity score-matched analysis.

INTRODUCTION: The standard diagnosis for adrenocortical carcinoma (ACC) is clinical diagnosis (CD) based on radiographic and biochemical studies. Biopsy diagnosis (BD) is seldom required for the suspicion of secondary malignancy. We aim to study the impact of BD in the context of underlying T1/T2 ACC on overall survival (OS) compared with CD. METHODS: National Cancer Database (NCDB) for endocrine malignancies was utilized. Only patients with non-metastatic ACC, whose method of diagnosis and local disease extension were reported, and received a surgical adrenalectomy with curative intent were included. Patients were divided by disease stage into T1/T2, T3, and T4 groups. A propensity score match was applied to those with T1/T2 disease who received CD versus BD and the Kaplan-Meier method was used to compare OS. RESULTS: In total, 4000 patients with ACC were reported in the database, 1410 met selection criteria. Eight hundred and thirty patients had T1/T2, 365 had T3, and 162 had T4 ACC. Of patients with T1/T2 ACC, 742 (89.4%) received CD versus 88 (11.6%) with BD. A propensity score was calculated per a multivariable regression model with 79 patients matched from each group. Exact matching was applied for margin status and adjuvant therapies. Kaplan-Meier analysis showed a significant difference in median OS between CD versus BD patients in the matched data set (103.89 ± 15.65 vs. 54.93 ± 8.22 months; p = 0.001). In all comers, patients with T1/T2 ACC and BD had comparable median OS to that of patients with T3 ACC (52.21 ± 9.69 vs. 36.01 ± 3.33 months; p = 0.446). CONCLUSION: BD in T1/T2 ACC could be associated with disease upstaging and worse OS outcomes.

Adrenocortical Carcinoma Steroid Profiles: In Silico Pan-Cancer Analysis of TCGA Data Uncovers Immunotherapy Targets for Potential Improved Outcomes.

Despite progress in understanding the biology of adrenocortical carcinoma (ACC), treatment options have not dramatically changed in the last three decades, nor have we learned how to avoid some of its long-term side effects. Our goal was to improve the understanding of immune pathways that may include druggable targets to enhance immune responses of patients with ACC, focusing on immune evasion and the activation of immune cells against ACC. Our strategy was aimed at improving insight regarding gene expression without steroid interference. Using approaches based on high and low steroid phenotypes (HSP and LSP, respectively), we characterized immune pathways using The Cancer Genome Atlas (TCGA) ACC cohort data. Although previous studies have suggested that patients with ACC receive minimal benefit from immunotherapy, high expression of immune modulators was noted in patients with LSP, suggesting the activation of these biomarkers may be an important adjuvant therapy target after clearance of excess glucocorticoids. In addition, patients with LSP ACC had higher immune cell infiltration than patients with HSP ACC and other cancer subtypes. Our findings can be summarized as follows (1): we confirmed and improved the definition of two immune response pathways to ACC (HSP and LSP) based on in silico transcriptome analysis (2), we demonstrated the steroid profile should be considered, otherwise analyses of ACC immune characteristics can generate confounding results (3), among the overexpressed immunotherapy targets, we demonstrated that LSP was rich in PDCD1LG2 (PD-L2) and both HSP and LSP overexpressed CD276 (B7-H3), which was associated with resistance to anti-PD1 therapy and may have accounted for the modest results of previous clinical trials, and (4) identification of patients with LSP or HSP ACC can be used to help determine whether immunotherapy should be used. In conclusion, we highlighted the differences between LSP and HSP, drawing attention to potential therapeutic targets (CD276, PDCD1, and PDCD1LG2). Treatments to reduce immune evasion, as well as the use of other natural and pharmacological immune activators, should include prior pharmacological inhibition of steroidogenesis. Attempts to combine these with tumor cell proliferation inhibitors, if they do not affect cells of the immune system, may produce interesting results.

The underlying molecular mechanism and drugs for treatment in adrenal cortical carcinoma.

Purpose: The study aimed to predict and explore the possible clinical value and mechanism of genetic markers in adrenal cortical carcinoma using a bioinformatics analysis method. Methods: The RNA-seqs and miRNAs data were downloaded from TCGA database to identify the differentially expressed genes and differentially expressed miRNAs. The hub-genes were screened by building protein-protein interaction sub-networks with 12 topological analysis methods. We conducted the receiver operating characteristic curve to elevate the diagnostic value of hub-genes in distinguishing the death and alive groups. The survival analysis of hub-genes and key miRNAs were conducted using Kaplan-Meier curves. Furthermore, most significant small molecules were identified as therapeutic candidates for adrenal cortical carcinoma by the CMap analysis. Results: Compared to survival group, we found 475 up-regulated genes and 354 genes and the key pathways leading to the death of different ACC individual patients. Then we used 12 topological analysis methods to found the most possible 22 hub-genes. Among these hub-genes, nine hub-genes (C3, CXCL5, CX3CR1, GRM8, HCAR2, HTR1B, SUCNR1, PTGER3 and SSTR1) could be used to distinguish the death and survival groups for patients. We also revealed that mRNA expressions of 12 genes (C3, CXCL8, CX3CR1, GNAT3, GNGT1, GRM8, HCAR2, HTR1B, HTR1D, PTGER3, SSTR1 and SUCNR1) and four key miRNAs (hsa-mir-330, hsa-mir-489, hsa-mir-508 and hsa-mir-513b) were related to survival. Three most small molecules were identified (H-9, AZ-628 and phensuximide) as potential therapeutic drugs for adrenal cortical carcinoma. Conclusion: The hub-genes expression was significant useful in adrenal cortical carcinoma, provide new diagnostic, prognosis and therapeutic approaches for adrenal cortical carcinoma. Furthermore, we also explore the possible miRNAs involved in regulation of hub-genes.

Identification of oncological characteristics associated with improved overall survival in patients with adrenocortical carcinoma treated with adjuvant radiation therapy: Insights from the National Cancer Database.

OBJECTIVES: To test for an association between oncological risk factors and overall survival in patients with non-metastatic adrenocortical carcinoma treated with adjuvant radiation therapy at high-risk for recurrence per NCCN guidelines. MATERIALS AND METHODS: We analyzed data from patients undergoing surgical resection with or without aRT in the NCDB from 2004 to 2017. A multivariable Cox proportional hazards model was fit to assess for an association of aRT and OS. To determine whether aRT was associated with improved OS in patients with specific NCCN risk factors, we fit three multivariable Cox proportional hazard models with an interaction term between NCCN risk factors and the use of aRT. RESULTS: We identified 1,433 patients treated surgically for adrenocortical carcinoma with at least one risk factor. 259 patients received adjuvant radiation therapy (18%) while 1,174 (82%) patients did not. After adjustment, we noted a significant association between adjuvant radiation therapy and overall survival in the entire cohort in the multivariable Cox proportional hazards model (HR 0.68, 95% CI 0.55-0.85, P = 0.001). Adjuvant radiation therapy was associated with increased overall survival in patients with positive surgical margins (HR 0.47, 95% CI 0.35-0.65, P < 0.001), large tumor size ≥6 cm (HR 0.69, 95% CI 0.55-0.87, P = 0.002), and high-grade disease (HR 0.61, 95% CI 0.37-0.99, P = 0.046). CONCLUSIONS: Patients with ACC at high-risk for recurrence were associated with improved overall survival when treated with adjuvant radiation therapy. These data may help identify which patients should consider aRT after resection of clinically localized ACC.

Bioinformatic analyses and experimental validation of the role of m6A RNA methylation regulators in progression and prognosis of adrenocortical carcinoma.

M6A-related genes have been proven to play an important role in many cancers. However, the role of that in adrenocortical carcinoma (ACC) has not been fully elucidated. In the present study, 77 ACC samples from TCGA database were divided into localized (n = 46) and metastatic (n = 31) groups. Three differential expression genes (DEGs) and five prognostic m6A genes were screened out. M6A-related risk signature (RBM15 and HNRNPC) was constructed by the Lasso regression analysis. In TCGA cohort (training cohort), the risk signature was identified as an ACC-independent prognostic factor and can distinguish the prognostic difference of ACC patients with clinical stage I-II, T3-4 and N0 stages. A nomogram combining T stage and m6A risk score was constructed to predict the overall survival rate (OSR) of individual at 1,2,3 year. Meanwhile, its prognostic value was also confirmed in the validation cohort (GSE33371 dataset). The potential associations between m6A risk level and immune checkpoint inhibitors (ICIs) therapy were also investigated via the TISIDB online tool. High m6A risk not only can suppress immunotherapy-related biological processes, but also repress the expressions of immune-checkpoint markers. Moreover, five pairs of clinical specimens were collected to confirm the overexpression of HNRNPC and non-ectopic expression of RBM15 in tumor tissues. HNRNPC was proven to promote the proliferation, migration and invasion of H295R and SW13 cells through MTT and Transwell assays. In conclusion, the m6A-related risk signature was beneficial for prognostic analysis and can affect immune microenvironment in ACC. HNRNPC played a pro-cancer role in ACC progression.

Disparate Practice Patterns and Survival Outcomes: The Impact of Centralization of Cancer Care for Adrenocortical Carcinoma in the United States.

PURPOSE: Adrenocortical carcinoma is a rare but aggressive malignancy. While centralization of care to referral centers improves outcomes across common urological malignancies, there exists a paucity of data for low-incidence cancers. We sought to evaluate differences in practice patterns and overall survival in patients with adrenocortical carcinoma across types of treating facilities. MATERIALS AND METHODS: We identified all patients diagnosed with adrenocortical carcinoma from 2004-2016 in the National Cancer Database. The Kaplan-Meier method was used to evaluate overall survival and multivariable Cox regression analysis was used to investigate independent predictors of overall survival. The chi-square test was used to analyze differences in practice patterns. RESULTS: We identified 2,886 patients with adrenocortical carcinoma. Median overall survival was 21.8 months (95% CI 19.8-23.8). Academic centers had improved overall survival versus community centers on unadjusted Kaplan-Meier analysis (p <0.05) and had higher rates of adrenalectomy or radical en bloc resection (p <0.001), performed more open surgery (p <0.001), administered more systemic therapy (p <0.001) and had lower rates of positive surgical margins (p=0.03). On multivariable analysis, controlling for treatment modality, academic centers were associated with significantly decreased risk of death (HR 0.779, 95% CI 0.631-0.963, p=0.021). CONCLUSIONS: Treatment of adrenocortical carcinoma at an academic center is associated with improved overall survival compared to community programs. There are significant differences in practice patterns, including more aggressive surgical treatment at academic facilities, but the survival benefit persists on multivariable analysis controlling for treatment modality. Further studies are needed to identify the most important predictors of survival in this at-risk population.

Prognostic Alternative mRNA Splicing in Adrenocortical Carcinoma.

Background: This paper aims to identify alternative RNA splicing landscape and its prognostic value in adrenocortical carcinoma. Methods: The alternative splicing events data with corresponding clinical information data of 79 ACC patients were obtained from the Cancer Genome Atlas and SpliceSeq package. Prognosis-associated AS events by using univariate Cox regression analysis were selected. Gene functional enrichment analysis demonstrated the potential pathways enriched by survival-associated AS. Prognosis-related splicing events were submitted to develop moderate predictors using Lasso regression model. Results: One thousand five survival-associated alternative splicing events were identified. The prognostic genes included ATXN2L, MEIS1, IKBKB, COX4I1. Functional enrichment analysis suggested that prognostic splicing events are associated with Wnt signaling pathway. A prediction model including 12 alternative splicing events was constructed by Lasso regression using train set. ROC analysis showed good performance of the prediction model in test set. Then, a nomogram integrating the clinical-pathological factors and riskscore was constructed for predicting 1- and 3-year survival rate. Conclusion: Our data provide a comprehensive bioinformatics analysis of AS events in ACC, providing biomarkers for disease progression and a potentially rich source of novel therapeutic targets.

Identification of NDRG Family Member 4 (NDRG4) and CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) as Key Prognostic Genes in Adrenocortical Carcinoma by Transcriptomic Analysis.

BACKGROUND Adrenocortical carcinoma (ACC) is an aggressive cancer with heterogeneous outcomes. In this study, we aimed to investigate genomic and prognostic features of ACC. MATERIAL AND METHODS Clinical, pathologic, and transcriptomic data from 2 independent datasets derived from ACC samples (TCGA-ACC dataset, GEO-GSE76021 dataset) were collected. Weighted gene co-expression network analysis (WGCNA) and survival analyses were performed to identify prognostic genes. Pathway analysis was performed for mechanistic analysis. xCell deconvolution was performed for tumor microenvironment analysis. RESULTS In the TCGA-ACC cohort, WGCNA identified a prognostic module of 5408 genes. Differential expression analysis identified 1969 genes that differed in expression level between long-term and short-term survivors. Univariate Cox regression model analysis identified 8393 genes with prognostic value. The intersection of these gene sets included 820 prognostic genes. Similar protocols were performed for the GSE76021 dataset, and 5 candidate genes were identified. Further intersection of these genes finally identified NDRG4 and CKS2 as key prognostic genes. Multivariate Cox regression model analysis validated the prognostic value of NDRG4 (HR=0.61, 95% CI 0.46-0.80) and CKS2 (HR=2.52, 95% CI 1.38-4.60). Moreover, NDRG4 and CKS2 expression predicted survival in patients treated with mitotane (P<0.001). Further mechanism exploration found an association between CKS2 and DNA mismatch repair pathways. Moreover, NDRG4 positively correlated with CD8⁺ T cell infiltration, while CKS2 negatively correlated with it. CONCLUSIONS We identified NDRG4 and CKS2 expression as key prognostic genes in ACC, which may help in risk stratification of ACC. Moreover, a close relationship was found between CKS2 and mismatch repair pathways. Moreover, immune cell infiltration differed according to NDRG4 and CKS2 expression.

Expression patterns and prognostic value of m6A RNA methylation regulators in adrenocortical carcinoma.

ABSTRACT: Adrenocortical carcinoma (ACC) is considered a rare cancer with poor prognosis. We used public datasets from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases to assess the relationships between N6-methyladenosine (m6A)-related genes and ACC.We used the Wilcoxon signed-rank test to compare m6A-related gene expression in ACC tissues with that in normal tissues. Then, ACC patients were grouped based on a cluster analysis of m6A-related gene expression. m6A-related genes that were significantly associated with survival were incorporated into a risk signature, and 2 groups were divided according to median risk score. Fisher exact tests were utilized to analyze differences in clinical variables between groups. We compared the overall survival (OS) rates of the groups by means of Kaplan-Meier curves and Cox regression analyses.We found that RBM15, ZC3H3, YTDHF1, YTDHF2, and ALBH5 were overexpressed in ACC and that KIAA1429, YTHDC1, HNRNPC, WTAP, METTL3, and FTO were down regulated in ACC. In addition, membership in cluster 2 or the high-risk group was associated with advanced clinical factors and poor prognosis. The univariable and multivariable Cox regression analyses showed that risk score can be considered an independent prognostic factor for ACC.We found that the expression of m6A-related genes could be used as an independent prognostic factor in ACC. However, the current study has some limitations, and further studies of m6A-related genes in ACC are needed.

Comparative performances of nomograms and conditional survival after resection of adrenocortical cancer.

BACKGROUND: Adrenocortical carcinomas (ACCs) carry a poor prognosis. This study assessed the comparative performance of existing nomograms in estimating the likelihood of survival, along with the value of conditional survival estimation for patients who had already survived for a given length of time after surgery. METHODS: This was an observational study based on a prospectively developed departmental database that recorded details of patients operated for ACC in a UK tertiary referral centre. RESULTS: Of 74 patients with ACC managed between 2001 and 2020, data were analysed for 62 patients (32 women and 30 men, mean(s.d.) age 51(17) years) who had primary surgical treatment in this unit. Laparoscopic (9) or open adrenalectomies (53) were performed alone or in association with a multivisceral resection (27). Most of the tumours were left-sided (40) and 18 were cortisol-secreting.Overall median survival was 33 months, with 1-, 3- and 5-year survival rates of 79, 49, and 41 per cent respectively. Age over 55 years, higher European Network for Study of Adrenal Tumours stage, and cortisol secretion were associated with poorer survival in univariable analyses. Four published nomograms suggested widely variable outcomes that did not correlate with observed overall survival at 1, 3 or 5 years after operation. The 3-year conditional survival at 2 years (probability of surviving to postoperative year 5) was 65 per cent, compared with a 5-year actuarial survival rate of 41 per cent calculated from the time of surgery. CONCLUSION: Survival of patients with ACC correlates with clinical parameters but not with published nomograms. Conditional survival might provide a more accurate estimate of survival for patients who have already survived for a certain amount of time after resection.

IL-13Rα2 gene expression is a biomarker of adverse outcome in patients with adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare but aggressive endocrine malignancy that usually results in a fatal outcome. To allow the better clinical management and reduce mortality, we searched for clinical and molecular markers that are reliable predictor of disease severity and clinical outcome in ACC patients. We determined a correlation between the overexpression of IL-13Rα2 and the clinical outcome in ACC patients using comprehensive data available in The Cancer Genome Atlas (TCGA) database. The dataset of 79 ACC subjects were divided into groups of low, medium, or high expression of IL-13Rα2 as determined by RNA-seq. These patients were also stratified by length of survival, overall survival, incidence of a new tumor event, incidence of metastasis, and production of excess hormones. We report a correlation between IL-13Rα2 expression and survival of subjects with ACC. High expression of IL-13Rα2 in ACC tumors was significantly associated with a lower patient survival rate and period of survival compared to low expression (p = 0.0084). In addition, high IL-13Rα2 expression was significantly associated with a higher incidence of new tumor events and excess hormone production compared to low or medium IL-13Rα2 expression. Within the cohort of patients that produced excess hormone, elevated IL-13Rα2 expression was significantly associated with a lower survival rate. Additionally, IL-13Rα1 had a potential relationship between transcript level and ACC survival. Our results and promising antitumor activity in preclinical models and trials indicate that IL-13Rα2 expression is an important prognostic biomarker of ACC disease outcome and a promising target for therapeutic treatment of ACC.