Adrenocortical Carcinoma Patients Research Articles

Expression and clinical significance of VISTA and PD-L1 in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis and challenging management. The present study aimed to investigate the expression of programmed death ligand-1 (PD-L1) and V-domain Ig-containing suppressor of T cell activation (VISTA) in ACC and their associations with clinicopathological features and survival outcomes. Immunohistochemistry was performed on formalin-fixed paraffin-embedded specimens from 54 ACC patients. Chi-square/Fisher's exact tests or independent samples t/Mann-Whitney U tests were performed to assess correlations between immunoscores and clinicopathological parameters. The Kaplan-Meier method and Cox regression were conducted for survival analysis and to identify independent predictors of overall (OS) and disease-free (DFS) survival. Results showed that VISTA was expressed in tumor cells (TCs) and tumor-infiltrating immune cells (TICs) in 81.5% (44/54) and 40.7% (22/54) of the patients, respectively. PD-L1 positivity was found in either TCs or TICs in 11.1% (6/54) of the patients. Patients with positive VISTA expression in TCs had a higher tumor stage (56.9% vs 20%, P = 0.036) and Ki-67 index (30.50 ± 23.51% vs 14.76 ± 11.75%, P = 0.006). However, PD-L1 positivity in either TCs or TICs had no association with patient clinicopathological features. A higher VISTA expression intensity, a larger area and a higher immunoscore were associated with increased risks of disease progression and overall mortality, but PD-L1 expression in TCs or TICs was not associated with OS or DFS. In conclusion, positive TC VISTA expression was correlated with pathological parameters related to malignancy in ACC patients. This finding provides novel evidence of the value of VISTA, in addition to PD-L1, as an immunotherapeutic target in ACC.

The Effects of Cumulative Dose and Polymorphisms in CYP2B6 on the Mitotane Plasma Trough Concentrations in Chinese Patients With Advanced Adrenocortical Carcinoma.

Mitotane is the only drug approved to treat adrenocortical carcinoma (ACC), and a relationship of pharmacokinetic/pharmacodynamic has been characterized. However, limited evidence concerning affecting factors in large interindividual variability of the pharmacokinetics of mitotane is available. To address this question, a retrospective analysis was performed on ACC Chinese patients treated with mitotane for more than 3 months. Mitotane plasma trough concentrations were detected at the steady state, and CYP2B6, CYP3A4, and pregnane X receptor (PXR) polymorphisms were genotyped. After examining homogeneous pharmacologic data, we restricted the analyses to 36 patients that received mitotane for a median (interquartile range, IQR) of 9 months (5.00–22.50) with a median dose of 2 g/day (2.00–2.50). As a result, drug exposure was significantly influenced by the cumulative dose of mitotane, and CYP2B6 516GG and CYP2B6 26570CC were at high risk to be below the therapeutic range of mitotane. No association was found between mitotane concentrations with CYP3A4 or PXR polymorphism. Our data firstly indicated that the cumulative dose of mitotane and polymorphisms of CYP2B6 516 and CYP2B6 26570 might significantly affect mitotane plasma trough concentrations in Chinese ACC patients.

Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options.

Simple SummaryAdrenocortical carcinoma is a rare disease for which in silico analysis may help to identify therapy options. Here, we look at the potential of already FDA-approved drugs and therapies in clinical trials based on genes mutated in ACC and genomic alterations known to be targeted by these drugs. Overall, 67% of the ACCs presented in silico drugability, especially for new emerging options such as TP53-modulating drugs or Wnt signaling pathway inhibitors. These results might help plan future clinical trials.In rare diseases such as adrenocortical carcinoma (ACC), in silico analysis can help select promising therapy options. We screened all drugs approved by the FDA and those in current clinical studies to identify drugs that target genomic alterations, also known to be present in patients with ACC. We identified FDA-approved drugs in the My Cancer Genome and National Cancer Institute databases and identified genetic alterations that could predict drug response. In total, 155 FDA-approved drugs and 905 drugs in clinical trials were identified and linked to 375 genes of 89 TCGA patients. The most frequent potentially targetable genetic alterations included TP53 (20%), BRD9 (13%), TERT (13%), CTNNB1 (13%), CDK4 (7%), FLT4 (7%), and MDM2 (7%). We identified TP53-modulating drugs to be possibly effective in 20–26% of patients, followed by the Wnt signaling pathway inhibitors (15%), Telomelysin and INO5401 (13%), FHD-609 (13%), etc. According to our data, 67% of ACC patients exhibited genomic alterations that might be targeted by FDA-approved drugs or drugs being tested in current clinical trials. Although there are not many current therapy options directly targeting reported ACC alterations, this study identifies emerging options that could be tested in clinical trials.

Identification of Four Novel Prognostic Biomarkers and Construction of Two Nomograms in Adrenocortical Carcinoma: A Multi-Omics Data Study via Bioinformatics and Machine Learning Methods.

Background: Adrenocortical carcinoma (ACC) is an orphan tumor which has poor prognoses. Therefore, it is of urgent need for us to find candidate prognostic biomarkers and provide clinicians with an accurate method for survival prediction of ACC via bioinformatics and machine learning methods. Methods: Eight different methods including differentially expressed gene (DEG) analysis, weighted correlation network analysis (WGCNA), protein-protein interaction (PPI) network construction, survival analysis, expression level comparison, receiver operating characteristic (ROC) analysis, and decision curve analysis (DCA) were used to identify potential prognostic biomarkers for ACC via seven independent datasets. Linear discriminant analysis (LDA), K-nearest neighbor (KNN), support vector machine (SVM), and time-dependent ROC were performed to further identify meaningful prognostic biomarkers (MPBs). Cox regression analyses were performed to screen factors for nomogram construction. Results: We identified nine hub genes correlated to prognosis of patients with ACC. Furthermore, four MPBs (ASPM, BIRC5, CCNB2, and CDK1) with high accuracy of survival prediction were screened out, which were enriched in the cell cycle. We also found that mutations and copy number variants of these MPBs were associated with overall survival (OS) of ACC patients. Moreover, MPB expressions were associated with immune infiltration level. Two nomograms [OS-nomogram and disease-free survival (DFS)-nomogram] were established, which could provide clinicians with an accurate, quick, and visualized method for survival prediction. Conclusion: Four novel MPBs were identified and two nomograms were constructed, which might constitute a breakthrough in treatment and prognosis prediction of patients with ACC.

Prognosis and Therapeutic Efficacy Prediction of Adrenocortical Carcinoma Based on a Necroptosis-Associated Gene Signature.

Background Adrenocortical carcinoma (ACC) is a rare and poor prognosis malignancy. Necroptosis is a special type of cell apoptosis, which is regulated in caspase-independent pathways and mainly induced through the activation of receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed lineage kinase domain-like pseudokinase. A precise predictive tool based on necroptosis is needed to improve the level of diagnosis and treatment. Method Four ACC cohorts were enrolled in this study. The Cancer Genome Atlas ACC (TCGA-ACC) cohort was used as the training cohort; three datasets (GSE19750, GSE33371, and GSE49278) from Gene Expression Omnibus (GEO) platform were combined as the GEO testing cohort after removing of batch effect. Forty-nine necroptosis-associated genes were obtained from a prior study and further filtered by least absolute shrinkage and selection operator Cox regression analysis; corresponding coefficients were used to calculate the necroptosis-associated gene score (NAGs). Patients in the TCGA-ACC cohort were equally divided into two groups with the mean value of NAGs. We investigated the associations between NAGs groups and clinicopathological feature distribution and overall survival (OS) in ACC, the molecular mechanisms, and the value of NAGs in therapy prediction. A nomogram risk model was established to quantify risk stratification for ACC patients. Finally, the results were confirmed in the GEO-combined cohort. Result Patients in the TCGA-ACC cohort were divided into high and low NAGs groups. The high NAGs group had more fatal cases and advanced stage patients than the low NAGs group (P < 0.001, hazard ratio (HR) = 13.97, 95% confidence interval (95% CI): 4.168–46.844; survival rate: low NAGs, 7.69% vs. high NAGs, 61.53%). NAGs were validated to be negatively correlated with OS (R = −0.48, P < 0.001) and act as an independent factor in ACC with high discriminative efficacy (P < 0.001, HR = 11.76, 95% CI: 2.86–48.42). In addition, a high predictive efficacy nomogram risk model was established combining NAGs with tumor stage. Higher mutation rates were observed in the high NAGs group, and the mutation of TP53 may lead to a high T cell infiltration level among the NAGs groups. Patients belonged to the high NAGs are more sensitive to the chemotherapy of cisplatin, gemcitabine, paclitaxel, and etoposide (all P < 0.05). Ultimately, the same statistical algorithms were conducted in the GEO-combined cohort, and the crucial role of NAGs prediction value was further validated. Conclusion We constructed a necroptosis-associated gene signature, revealed the prognostic value between ACC and it, systematically explored the molecular alterations among patients with different NAGs, and manifested the value of drug sensitivity prediction in ACC.

S-GRAS score performs better than a model from SEER for patients with adrenocortical carcinoma.

Purpose To externally validate the performance of the S-GRAS score and a model from the Surveillance, Epidemiology, and End Results (SEER) database in a Chinese cohort of patients with adrenocortical carcinoma (ACC).Methods We first developed a model using data from the SEER database, after which we retrospectively reviewed 51 ACC patients hospitalized between 2013 and 2018, and we finally validated the model and S-GRAS score in this Chinese cohort.Results Patient age at diagnosis, tumor size, TNM stage, and radiotherapy were used to construct the model, and the Harrell’s C-index of the model in the training set was 0.725 (95% CI: 0.682–0.768). However, the 5-year area under the curve (AUC) of the model in the validation cohort was 0.598 (95% CI: 0.487–0.708). The 5-year AUC of the ENSAT stage was 0.640 (95% CI: 0.543–0.737), but the Kaplan–Meier curves of stages I and II overlapped in the validation cohort. The resection status (P = 0.066), age (P=0.68), Ki67 (P = 0.69), and symptoms (P = 0.66) did not have a significant impact on cancer-specific survival in the validation cohort. In contrast, the S-GRAS score group showed better discrimination (5-year AUC: 0.683, 95% CI: 0.602–0.764) than the SEER model or the ENSAT stage.Conclusion The SEER model showed favorable discrimination and calibration ability in the training set, but it failed to distinguish patients with various prognoses in our institution. In contrast, the S-GRAS score could effectively stratify patients with different outcomes.

Persistent Properties of a Subpopulation of Cancer Cells Overexpressing the Hedgehog Receptor Patched.

Despite the development of new therapeutic strategies, cancer remains one of the leading causes of mortality worldwide. One of the current major challenges is the resistance of cancers to chemotherapy treatments inducing metastases and relapse of the tumor. The Hedgehog receptor Patched (Ptch1) is overexpressed in many types of cancers. We showed that Ptch1 contributes to the efflux of doxorubicin and plays an important role in the resistance to chemotherapy in adrenocortical carcinoma (ACC), a rare cancer which presents strong resistance to the standard of care chemotherapy treatment. In the present study, we isolated and characterized a subpopulation of the ACC cell line H295R in which Ptch1 is overexpressed and more present at the cell surface. This cell subpopulation is more resistant to doxorubicin, grows as spheroids, and has a greater capability of clonogenicity, migration, and invasion than the parental cells. Xenograft experiments performed in mice and in ovo showed that this cell subpopulation is more tumorigenic and metastatic than the parental cells. These results suggest that this cell subpopulation has cancer stem-like or persistent cell properties which were strengthened by RNA-seq. If present in tumors from ACC patients, these cells could be responsible for therapy resistance, relapse, and metastases.

Pathological stage-associated non-coding RNA long intergenic non-protein coding RNA 1234 (LINC01234) participation in cell cycle regulation in adrenocortical carcinoma through bromodomain-containing protein 4 (BRD4) expression mediation via sponging microRNA (miR)-140-3p

ABSTRACT Many researches indicated that long non-coding RNAs (lncRNAs) were involved in the malignant progression of tumors, including Adrenocortical Carcinoma (ACC). However, as for most lncRNAs, their biological behaviors and molecular mechanism remain unclear in ACC. In the present research, weighted gene co-expression network analysis (WGCNA) was used to identify pathologically relevant gene, including lncRNAs. By comparing their expressions in GSE61359 tumors and normal controls, long intergenic non-protein coding RNA 1234 (LINC01234) was selected to investigate the clinical significance, biological function, and mechanism in ACC. Data mining revealed that LINC01234 expression was significantly up-regulated in ACC patients, and a shorter survival time presents in patients with higher LINC01234 expression compared to that in patients with lower LINC01234 expression. Further, LINC01234 silencing resulted in cells growth arrest in vitro and in vivo. Mechanism studies suggested that LINC01234 silencing induced cell cycle arrest, and bromodomain-containing protein 4 (BRD4) overexpression could restore this phenomenon. Further research showed that LINC01234 could mediate BRD4 expression through competitively sequestering microRNA (miR)-140-3p, as evidenced by the positive correlation of LINC01234 with BRD4 and inverse correlation with miR-140-3p expression. Luciferase activity assay also verified the targeting relationship between LINC01234, BRD4 and miR-140-3p. And up-regulated LINC01234 in ACC cells significantly reversed the degradation of BRD4 by miR-140-3p. Collectively, we deduce that LINC01234 functions as a ceRNA to regulate BRD4 expression by sponging miR-140-3p in ACC progress. Our findings have the potential to provide a new target for the diagnosis and treatment of ACC.

Ferroptosis‐based molecular prognostic model for adrenocortical carcinoma based on least absolute shrinkage and selection operator regression

BackgroundThis study aimed to find ferroptosis‐related genes linked to clinical outcomes of adrenocortical carcinoma (ACC) and assess the prognostic value of the model.MethodsWe downloaded the mRNA sequencing data and patient clinical data of 78 ACC patients from the TCGA data portal. Candidate ferroptosis‐related genes were screened by univariate regression analysis, machine‐learning least absolute shrinkage, and selection operator (LASSO). A ferroptosis‐related gene‐based prognostic model was constructed. The effectiveness of the prediction model was accessed by KM and ROC analysis. External validation was done using the GSE19750 cohort. A nomogram was generated. The prognostic accuracy was measured and compared with conventional staging systems (TNM stage). Functional analysis was conducted to identify biological characterization of survival‐associated ferroptosis‐related genes.ResultsSeventy genes were identified as survival‐associated ferroptosis‐related genes. The prognostic model was constructed with 17 ferroptosis‐related genes including STMN1, RRM2, HELLS, FANCD2, AURKA, GABARAPL2, SLC7A11, KRAS, ACSL4, MAPK3, HMGB1, CXCL2, ATG7, DDIT4, NOX1, PLIN4, and STEAP3. A RiskScore was calculated for each patient. KM curve indicated good prognostic performance. The AUC of the ROC curve for predicting 1‐, 3‐, and 5‐ year(s) survival time was 0.975, 0.913, and 0.915 respectively. The nomogram prognostic evaluation model showed better predictive ability than conventional staging systems.ConclusionWe constructed a prognosis model of ACC based on ferroptosis‐related genes with better predictive value than the conventional staging system. These efforts provided candidate targets for revealing the molecular basis of ACC, as well as novel targets for drug development.

Pan-cancer analysis of necroptosis-related gene signature for the identification of prognosis and immune significance

BackgroundNecroptosis is a novel programmed cell death mode independent on caspase. A number of studies have revealed that the induction of necroptosis could act as an alternative therapeutic strategy for drug-resistant tumors as well as affect tumor immune microenvironment.MethodsGene expression profiles and clinical data were downloaded from XENA-UCSC (including The Cancer Genome Atlas and Genotype-Tissue Expression), Gene Expression Omnibus, International Cancer Genome Consortium and Chinese Glioma Genome Atlas. We used non-negative matrix factorization method to conduct tumor classification. The least absolute shrinkage and selection operator regression was applied to establish risk models, whose prognostic effectiveness was examined in both training and testing sets with Kaplan–Meier analysis, time-dependent receiver operating characteristic curves as well as uni- and multi-variate survival analysis. Principal Component Analysis, t-distributed Stochastic Neighbor Embedding and Uniform Manifold Approximation and Projection were conducted to check the risk group distribution. Gene Set Enrichment Analyses, immune infiltration analysis based on CIBERSORT, EPIC, MCPcounter, ssGSEA and ESTIMATE, gene mutation and drug sensitivity between the risk groups were also taken into consideration.ResultsThere were eight types of cancer with at least ten differentially expressed necroptosis-related genes which could influence patients’ prognosis, namely, adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), pancreatic adenocarcinoma (PAAD), liver hepatocellular carcinoma (LIHC), skin cutaneous melanoma (SKCM) and thymoma (THYM). Patients could be divided into different clusters with distinct overall survival in all cancers above except for LIHC. The risk models could efficiently predict prognosis of ACC, LAML, LGG, LIHC, SKCM and THYM patients. LGG patients from high-risk group had a higher infiltration level of M2 macrophages and cancer-associated fibroblasts. There were more CD8+ T cells, Th1 cells and M1 macrophages in low-risk SKCM patients’ tumor microenvironment. Gene mutation status and drug sensitivity are also different between low- and high-risk groups in the six cancers.ConclusionsNecroptosis-related genes can predict clinical outcomes of ACC, LAML, LGG, LIHC, SKCM and THYM patients and help to distinguish immune infiltration status for LGG and SKCM.

Surgical resection for adrenocortical carcinoma: Current trends affecting survival.

Adrenocortical carcinoma (ACC) is associated with a poor prognosis. We reviewed the National Cancer Database (NCDB) to analyze the prognostic factors in surgically resected ACC patients and the association of surgical approaches with overall survival (OS). A retrospective NCDB (2004-2014) review of patients undergoing curative-intent surgical resection for ACC was performed. Effects of patient demographics, tumor characteristics, histopathology, and perioperative course on OS were analyzed. Log-rank statistics were used to associate clinical variables with OS. The multivariable Cox proportional hazard model included only statistically significant variables. A total of 1599 patients with ACC were included. A majority of patients were female (60.73%) and presented with a Charlson-Deyo score of zero (75.42%). A majority of the ACC cases were Grade 3 (45.69%), and almost a third (30.64%) underwent margin-positive resections. Univariate analysis demonstrated a decrease in OS associated with increasing age and comorbidities. A negative resection margin and lack of lymphovascular invasion predicted better OS. Multivariable analysis showed that age, grade, surgical resection margins, and hospital length of stay were associated with OS. Advanced age, grade, presence of lymphovascular invasion, and positive surgical margins predicted a worse overall survival for adrenocortical cancer in our analysis. Resection with negative margins improves outcomes.

Synergistic effects of telomerase reverse transcriptase and regulator of telomere elongation helicase 1 on aggressiveness and outcomes in adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is one of the deadliest endocrine malignancies and telomere maintenance by activated telomerase is critically required for ACC development and progression. Because telomerase reverse transcriptase (TERT) and regulator of telomere elongation helicase 1 (RTEL1) play key roles in telomere homeostasis, we determined their effect on ACC pathogenesis and outcomes. Analyses of TCGA and GEO datasets showed significantly higher expression of RTEL1 but not TERT in ACC tumors, compared to their benign or normal counterparts. Furthermore, gains/amplifications of both TERT and RTEL1 genes were widespread in ACC tumors and their expression correlated with their gene copy numbers. Higher expression of either TERT or RTEL1 was associated with shorter overall and progression-free survival (OS and PFS) in the TCGA ACC patient cohort, and higher levels of both TERT and RTEL1 mRNA predicted the shortest patient OS and PFS. However, multivariate analyses showed that only RTEL1 independently predicted patient OS and PFS. Gene set enrichment analysis further showed enrichments of wnt/β-catenin, MYC, glycolysis, MTOR, and DNA repair signaling pathways in ACC tumors expressing high TERT and RTEL1 mRNA levels. Taken together, TERT and RTEL1 promote ACC aggressiveness synergistically and may serve as prognostic factors and therapeutic targets for ACC.

Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide dichlorodiphenyltrichloroethane, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking.This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 ± 2.2 years). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose ratios as well as time-in-range (TR) in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane TR was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options.

Clinical Spectrum of Adrenal Cushing's Syndrome and the Caution for Interpretation of Adrenocorticotrophic Hormone: A Single-Center Experience.

Retrospective, single-center, observational study. Fifty-eight adrenal CS patients [Adrenocortical carcinoma (ACC), n=30; Adenoma (ACA), n=15; Primary pigmented nodular adrenocortical disease (PPNAD), n=10; ACTH independent macronodular adrenal hyperplasia (AIMAH), n=3) evaluated at a tertiary care center in western India between January 2006 to March 2020 were included. Data on demography, clinical evaluation, biochemistry, imaging, management, histopathology, and outcome were recorded in a standard format and analyzed. Cortisol secreting ACC presented at 38(1-50) years with abdominal mass in 26/30 (86.7%) and 16/30 (53.3%) had metastases at presentation. ACA with autonomous cortisol excess presented at 25(4.9-40) years with discriminating features of CS in 14/15 (93.3%), sex steroid production in 2/15, unenhanced HU <10 in only one, and relative washout >40% in 8/11 (72.7%). One ACA and eight ACC patients had plasma ACTH (by Siemens Immulite assay) > 20 pg/ml, despite hypercortisolemic state. Cortisol-secreting ACC and ACA most often present with mass effects and florid CS, respectively. Baseline HU has low sensitivity to differentiate cortisol-secreting ACA from ACC. Plasma ACTH measured by Seimens Immulite is often unsuppressed, especially in ACC patients, which can be addressed by measuring ACTH by more accurate assays.

Identification and Verification of Immune-Related Genes Prognostic Signature Based on ssGSEA for Adrenocortical Carcinoma (ACC).

PurposeAdrenocortical carcinoma (ACC) is an endocrine malignant tumor with poor prognosis. The study aimed to construct ACC immune-related gene prognostic signature and verify the efficacy of prognostic signature.MethodsACC RNA-seq data and clinical information are downloaded from TCGA databases and GEO databases. We used single sample gene set enrichment analysis (ssGSEA) to assess immune cell infiltration in ACC patients and ACC patients were divided into high- and low-immune cell infiltration clusters. The validity of ssGSEA grouping was verified using the ESTIMATE algorithm. A total of 275 differentially expressed immune-related genes (IRGs) were obtained from the intersection of IRGs and differentially expressed genes (DEGs) in high and low immune cell infiltration clusters. LASSO analysis was used to identify 13 IRGs that regulate the prognosis of ACC patients through immune infiltration. Kaplan–Meier analysis, ROC curve, univariate and multivariate Cox regression further confirmed that these 13 immune-related gene signatures were innovative and significant prognostic factors, which were independent of clinical features. Finally, ACC prognostic nomogram was constructed, ROC curve and calibration curve were drawn to evaluate the accuracy of the prognostic nomogram.ResultsLASSO regression analysis was used to screen out ACC survival-related genes. Univariate and multivariate Cox proportional risk regression models were used to analyze and construct the ACC prognosis nomogram. The AUC for predicting 1-, 3- and 5-year overall survival rate of ACC patients was 0.799, 0.966 and 0.969, suggesting good prediction accuracy. The calibration curve shows that the predicted results of the prognostic nomogram are in good agreement with the actual situation.ConclusionssGSEA technique plays an important role in the construction of ACC prognostic model. Based on IRGs associated with survival independently predicted ACC prognosis, we identified thirteen immune-related genes as prognostic signature for ACC.

Temporal Trends in Outcomes in Patients With Adrenocortical Carcinoma: A Multidisciplinary Referral-center Experience.

Reporting temporal trends in adrenocortical carcinoma (ACC) helps guide management strategies. This work aimed to report the trends in disease burden and clinical outcomes over time that cannot be adequately captured from individual clinical trials. A retrospective study was held of ACC patients seen at a referral cancer center between February 1998 and August 2019. Clinical outcomes were compared between an early cohort (February 1998-June 2007) and a late cohort (July 2007-August 2019). A total of 621 patients included with a median age at diagnosis of 49.3 years (range, 0.5-86.6 years). There were 285 (45.9%) patients with hormonal overproduction. More patients in the late cohort had stage IV disease compared to the early cohort (36.8% vs 23.1%; P < .0001). Resection of the primary tumor was performed in 502 patients (80.8%). Complete resection (R0) was more common in the late cohort (165 [60.2%]) than in the early cohort (100 [44.6%]; P = .0005). Of 475 patients with metastatic disease (stage IV or recurrent metastatic disease), 352 (74.1%) received mitotane, 320 (67.4%) received chemotherapy, and 53 (11.2%) received immunotherapy. In the early cohort, 70 (33%) received 2 or more lines of therapy, whereas in the late cohort, 127 (48%) received 2 or more lines of therapy. The 5-year overall survival (OS) rates were 65%, 58%, 45%, and 10% for stage I, II, III, and IV disease, respectively, whereas the 2-year OS rates in patients with stage IV disease was 24% in the early cohort and 46% in the late cohort (P = .01). ACC clinical outcomes improved over the past 2 decades as more patients had complete resection or received more lines of systemic therapy.

The Effect of Surgeon Expertise on the Outcome of Patients with Adrenocortical Carcinoma.

Complete surgical removal of adrenocortical carcinoma (ACC) represents the only chance of long-term cure. In this study, we compared the long-term outcomes of ACC patients depending on whether they had adrenal surgery performed in a high-volume (HVC) or in a low-volume (LVC) center. This retrospective study included 49 patients from the Croatian ACC Registry with the European Network for the Study of Adrenal Tumors (ENSAT) stage I–III ACC, of which 35 underwent surgery in a HVC whereas 14 of them were operated in one of the LVCs. Patients operated in the LVCs had a significantly higher rate of ACC recurrence (57.1% vs. 22.9%; p = 0.02). Accordingly, RFS was significantly longer in patients operated on in HVC (p = 0.04). The difference in RFS remained significant after controlling for age, gender, tumor size, Ki-67 index, Weiss score, and type of surgery (HR 4.55; 95% CI 1.16–17.88; p = 0.03). In addition, there is a tendency towards longer DSS in patients in the HVC group compared to those in the LVC group (p = 0.05). These results point to the centralization of adrenal surgery as a key prerequisite for improving the outcomes of ACC patients.

N-type calcium channel v2.2 is a target of TCF21 in adrenocortical carcinomas.

Transcription factor 21 (TCF21) directly binds and regulates SF1 mRNA expression in tumor and normal adrenocortical cells, and both are involved in the development and steroidogenesis of the adrenal cortex. TCF21 is a tumor suppressor gene and its expression is reduced in malignant tumors. In adrenocortical tumors, it is less expressed in adrenocortical carcinomas (ACC) than in adrenocortical adenomas (ACA) and normal tissues. However, a comprehensive analysis to identify TCF21 targets has not yet been conducted in any type of cancer. In this study, we performed Chromatin Immunoprecipitation and Sequencing (ChIP-Seq) in an adrenocortical carcinoma cell line (NCI-H295R) overexpressing TCF21, with the aim of identifying TCF21 new targets. The five most frequently identified sequences corresponded to the PRDM7, CNTNAP2, CACNA1B, PTPRN2, and KCNE1B genes. Validation experiments showed that, in NCI-H295R cells, TCF21 negatively regulates the expression of the CACNA1B gene. Recently, it was observed that the N-type calcium channel v2.2 (Cav2.2) encoded by the CACNA1B gene is important in Angiotensin II signal transduction for corticosteroid biosynthesis in NCI-H295R adrenocortical carcinoma cells. Indeed, TCF21 inhibits CACNA1B and Cav2.2 expression in NCI-H295R. In addition, in a cohort of 55 adult patients with adrenocortical tumors, CACNA1B expression was higher in ACC than ACA and was related to poor disease-free survival in ACC patients. These results suggest a mechanism of steroidogenesis control by TCF21 in adrenocortical tumor cells, in addition to the control observed through SF1 inhibition. Importantly, steroid production could impair tumor immunogenicity, contributing to the immune resistance described in adrenal cancer.

Identification and validation of a tumor mutation burden-related signature combined with immune microenvironment infiltration in adrenocortical carcinoma.

Tumor mutation burden (TMB), an emerging molecular determinant, is accompanied by microsatellite instability and immune infiltrates in various malignancies. However, whether TMB is related to the prognosis or immune responsiveness of adrenocortical carcinoma (ACC) remains to be elucidated. This paper aims to investigate the impact of TMB on the prognosis and immune microenvironment infiltration in ACC. The somatic mutation data, gene expression profile, and corresponding clinicopathological information were retrieved from TCGA. The mutation landscape was summarized and visualized with the waterfall diagram. The ACC patients were divided into low and high TMB groups based on the median TMB value and differentially expressed genes (DEGs) between the two groups were identified. Diverse functional analyses were conducted to determine the functionality of the DEGs. The immune cell infiltration signatures were evaluated based on multiple algorithms. Eventually, a TMB Prognostic Signature (TMBPS) was established and its predictive accuracy for ACC was evaluated. Single nucleotide polymorphism and C > T were found to be more common than other missense mutations. In addition, lower TMB levels indicated improved survival outcomes and were correlated with younger age and earlier clinical stage. Functional analysis suggested that DEGs were primarily related to the cell cycle, DNA replication, and cancer progression. Additionally, significant differences in infiltration levels of activated CD4+ T cells, naive B cells, and activated NK cells were observed in two TMB groups. We also found that patients with higher TMBPS showed worse survival outcomes, which was validated in the Gene Expression Omnibus database. Our study systematically analyzed the mutation and identified a TMBPS combined with immune microenvironment infiltration in ACC. It is expected that this paper can promote the development of ACC treatment strategies.

Progression of Vertebral Fractures in Patients with Adrenocortical Carcinoma Undergoing Mitotane Therapy.

Patients with adrenocortical carcinoma (ACC) are frequently on mitotane therapy for a long time period. The drug exerts adrenolytic activity requiring glucocorticoid supplementation, which can be potentially detrimental for bone. To explore whether mitotane with/without chemotherapy is associated with an increased proportion of morphometric vertebral fractures (VFs) in ACC patients. Secondary objectives were proportion of patients with VF progression, or worsening of the spinal deformity index (SDI) during mitotane therapy; and to explore predictive factors of VF progression and a prognostic role of VF progression. Multicenter, retrospective cohort study of patients with ACC who received mitotane alone or in association to chemotherapy, recruited from January 2010 to January 2020 in 2 reference centers in Italy and France. A significant increase in the frequency of VFs before and after mitotane therapy was seen both in Italian (28.3% vs 47.8%, P = .04) and French (17.8% vs 35.6%, P = .04) series. VF progression was observed in 39.1%, and 28.9% of patients, respectively. Baseline VFs and increased patient body mass index, but not the dose of cortisol supplementation, showed an independent association with VF progression at multivariate analysis. Among the 72 advanced ACC patients, progression of VFs was associated with a poorer survival. The administration of mitotane with/without chemotherapy in ACC patients impairs bone health independently from cortisol supplementation. Appropriate preventive measures to decrease the fracture risk should be implemented in these patients.