-
Endocrine Journal Jun 2024The aim of this study was to determine the tissue expressions of vascular endothelial growth factor (VEGF) and endocan in adrenal cortical tumors and the factors...
The aim of this study was to determine the tissue expressions of vascular endothelial growth factor (VEGF) and endocan in adrenal cortical tumors and the factors associated with them. The study included 6 subjects with adrenocortical adenoma (ACA), 7 subjects with adrenocortical carcinoma (ACC), and 13 control subjects with a normal adrenal cortex. The status of VEGF and endocan expression was determined by the proportions of cells staining on a scale ranging from negative (not staining at all) to strongly positive. VEGF expression was detected in 1 (16.7%) of 6 subjects in the ACA group and in 6 (85.7%) of 7 subjects in the ACC group. VEGF expression was not detected in any of the subjects in the control group. Endocan expression was detected in 6 (100%) of 6 subjects in the ACA group and in 7 (100%) of 7 subjects in the ACC group, while it was detected in only 4 (30.7%) of 13 subjects in the control group. VEGF was expressed with a high frequency in subjects with ACC and with a low frequency in subjects with ACA, but it was not expressed in subjects with normal adrenal cortex tissue. Although endocan was expressed with a higher frequency in subjects with ACC and ACA, it was also expressed in subjects with normal adrenal cortex tissue. The percentage of cells expressed endocan in subjects with ACC was also significantly higher than in subjects with both ACA and normal adrenal cortex.
PubMed: 38945931
DOI: 10.1507/endocrj.EJ24-0032 -
ESMO Open Jun 2024Adrenocortical carcinoma (ACC) is one of the most lethal endocrine malignancies and there is a lack of clinically useful markers for prognosis and patient...
BACKGROUND
Adrenocortical carcinoma (ACC) is one of the most lethal endocrine malignancies and there is a lack of clinically useful markers for prognosis and patient stratification. Therefore our aim was to identify clinical and genetic markers that predict outcome in patients with ACC.
METHODS
Clinical and genetic data from a total of 162 patients with ACC were analyzed by combining an independent cohort consisting of tumors from Yale School of Medicine, Karolinska Institutet, and Düsseldorf University (YKD) with two public databases [The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO)]. We used a novel bioinformatical pipeline combining differential expression and messenger RNA (mRNA)- and DNA-dependent survival. Data included reanalysis of previously conducted whole-exome sequencing (WES) for the YKD cohort, WES and RNA data for the TCGA cohort, and RNA data for the GEO cohort.
RESULTS
We identified 3903 significant differentially expressed genes when comparing ACC and adrenocortical adenoma, and the mRNA expression levels of 461/3903 genes significantly impacted survival. Subsequent analysis revealed 45 of these genes to be mutated in patients with significantly worse survival. The relationship was significant even after adjusting for stage and age. Protein-protein interaction showed previously unexplored interactions among many of the 45 proteins, including the cancer-related proteins DNA polymerase delta 1 (POLD1), aurora kinase A (AURKA), and kinesin family member 23 (KIF23). Furthermore 14 of the proteins had significant interactions with TP53 which is the most frequently mutated gene in the germline of patients with ACC.
CONCLUSIONS
Using a multiparameter approach, we identified 45 genes that significantly influenced survival. Notably, many of these genes have protein interactions not previously implicated in ACC. These findings may lay the foundation for improved prognostication and future targeted therapies.
PubMed: 38935991
DOI: 10.1016/j.esmoop.2024.103617 -
The Journal of Surgical Research Jun 2024Adrenocortical carcinoma (ACC) is a rare but aggressive pediatric endocrine tumor. However, there is no recent US national report on the management or outcomes of...
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare but aggressive pediatric endocrine tumor. However, there is no recent US national report on the management or outcomes of pediatric ACC. We aimed to examine the clinical characteristics, current management strategies, and outcomes of pediatric ACC.
METHODS
In this retrospective National Cancer Database study between 2004 and 2019, children (<18 y) with ACC were included. Overall survival was examined by means of Kaplan-Meier method, log-rank tests, and Cox regression modeling.
RESULTS
Seventy-eight children with ACC were included. The median age was 10 y, the median tumor size was 10.2 cm, and 35.9% had metastasis at diagnosis. Most patients underwent surgical treatment (84.6%), 56.4% received chemotherapy, and 7.7% received radiation. The 1-, 3-, and 5-y overall survival rates were 87.0%, 62.0%, and 60.1%, respectively. In unadjusted analysis, surgical treatment was associated with improved overall survival (log-rank test, P < 0.001). In multivariable Cox regression, metastasis at diagnosis was associated with inferior overall survival (hazard ratio: 2.72, 95% confidence interval: 1.15-6.40, P = 0.02), when adjusting for age, tumor size, receipt of surgical treatment, and chemotherapy. In patients with nonmetastatic ACC, increasing age was associated with inferior overall survival (hazard ratio: 1.12, 95% confidence interval: 1.00-1.24, P = 0.04), when adjusting for tumor size, receipt of surgical treatment, and chemotherapy.
CONCLUSIONS
Most children with ACC in the USA undergo surgical treatment with about half of these also receiving chemotherapy. Metastasis at diagnosis was independently associated with inferior overall survival; in patients with nonmetastatic ACC, increasing age was independently associated with inferior overall survival.
PubMed: 38925097
DOI: 10.1016/j.jss.2024.04.086 -
European Journal of Endocrinology Jun 2024Pediatric adrenocortical carcinoma (pACC) is rare, and prognostic stratification remains challenging. We aimed to confirm the prognostic value of the previously...
Assessment of prognostic factors in pediatric adrenocortical tumors: The modified pediatric S-GRAS score in an international multicenter cohort: A work from the ENSAT-PACT working group.
OBJECTIVE
Pediatric adrenocortical carcinoma (pACC) is rare, and prognostic stratification remains challenging. We aimed to confirm the prognostic value of the previously published pediatric scoring system (pS-GRAS) in an international multicenter cohort.
DESIGN
Analysis of pS-GRAS items of pACC from six countries in collaboration of ENSAT-PACT, GPOH-MET and IC-PACT.
METHODS
We received patient data of the pS-GRAS items including survival information from nine centers. PS-GRAS score was calculated as a sum of tumor stage (1 = 0; 2-3 = 1; 4 = 2 points), grade (Ki67 index: 0-9%=0; 10-19%=1; ≥ 20%=2 points), resection status (R0 = 0; RX/R1/R2 = 1 point), age (<4 years = 0; ≥ 4 years = 1 point), and hormone production (androgen production = 0; glucocorticoid-/mixed/-no hormone production = 1 point) generating eight scores and four groups (1: 0-2, 2: 3-4, 3: 5, 4: 6-7). Primary endpoint was overall survival (OS).
RESULTS
We included 268 patients with median age of 4 years. The analysis of the pS-GRAS score showed a significantly favorable prognosis in patients with a lower scoring compared to higher scoring groups (5-year OS: group 1 98%; group 2 87%(HR of death 3.6, 95% CI of HR 1.6-8.2); group 3 43%(HR of death 2.8, 95% CI 1.9-4.4); group 4: OS 18%(HR of death 2.1, 95% CI 1.7-2.7)). In the multivariable analysis age (HR of death 3.5, 95% CI 1.8-7.0), resection status (HR of death 5.5, 95% CI 2.7-11.1), tumor stage (HR of death 1.9, 95%-CI of HR 1.2-3.0) and Ki67-index (HR of death 1.7, 95% CI 1.2-2.4) remained strong independent outcome predictors. Especially infants < 4 years showed more often low risk constellations with a better OS for all tumor stages.
CONCLUSION
In an international multicenter study, we confirmed that the pS-GRAS score is strongly associated with overall survival among patients with pACC. Age, resection status, stage and Ki67-index are important parameters for risk stratification.
PubMed: 38924056
DOI: 10.1093/ejendo/lvae079 -
European Journal of Endocrinology Jun 2024Adrenal cortical carcinoma (ACC) is a rare malignancy with a generally poor but heterogeneous prognosis, especially depending on the tumour stage at diagnosis....
OBJECTIVE
Adrenal cortical carcinoma (ACC) is a rare malignancy with a generally poor but heterogeneous prognosis, especially depending on the tumour stage at diagnosis. Identification of somatic gene alterations combined with clinical/histopathological evaluation of the tumour can help improve prognostication. We applied a simplified targeted-NGS panel to characterise the mutational profiles of ACCs, providing potentially relevant information for better patient management.
DESIGN AND METHODS
Thirty frozen tumour specimens from a local ACC series were retrospectively analysed by a custom-NGS panel (CDKN2A, CTNNB1, DAXX, MED12, NF1, PRKAR1A, RB1, TERT, TP53, ZNRF3) to detect somatic prioritized single-nucleotide variants. This cohort was integrated with 86 patients from the ACC-TCGA series bearing point-mutations in the same genes and their combinations identified by our panel. Primary endpoints of the analysis on the total cohort (113 patients) were overall (OS) and progression-free (PFS) survival, and hazard-ratio (HR) for the different alterations grouped by the signalling pathways/combinations affected.
RESULTS
Different PFS, OS and HR were associated to the different pathways/combinations, being NF1 + TP53 and Wnt/β-catenin + Rb/p53 combined mutations the most deleterious, with a statistical significance for progression HR which is retained only in low-(I/II) stages - NF1+TP53 combination: HR = 2.96[1.01-8.69] and HR = 13.23[3.15-55.61], all and low stages, respectively; Wnt/β-catenin + Rb/p53 combined pathways: HR = 6.47[2.54-16.49] and HR = 16.24[3.87-68.00], all and low-stages, respectively.
CONCLUSIONS
A simplified targeted-NGS approach seems the best routinely applicable first step towards somatic genetic characterisation of ACC for prognostic assessment. This approach proved to be particularly promising in low-stage cases, suggesting the need for more stringent surveillance and personalised treatment.
PubMed: 38917236
DOI: 10.1093/ejendo/lvae077 -
European Journal of Nuclear Medicine... Jun 2024In patients affected with adrenocortical carcinoma (ACC), C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in sites of disease in an ex-vivo setting. We...
BACKGROUND
In patients affected with adrenocortical carcinoma (ACC), C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in sites of disease in an ex-vivo setting. We aimed to determine the predictive value of CXCR4-targeting [Ga]Ga-PentixaFor PET/CT for outcome when compared to clinical parameters.
METHODS
We identified 41 metastasized ACC patients imaged with [Ga]Ga-PentixaFor PET/CT. Scans were assessed visually and on a quantitative level by manually segmenting the tumor burden (providing tumor volume [TV], peak/mean/maximum standardized uptake values [SUV] and tumor chemokine receptor binding on the cell surface [TRB], defined as SUV multiplied by tumor volume). Clinical parameters included sex, previous therapies, age, Weiss-Score, and Ki67 index. Following imaging, overall survival (OS) was recorded.
RESULTS
After [Ga]Ga-PentixaFor PET/CT, median OS was 9 months (range, 1-96 months). On univariable analysis, only higher TRB (per 10 ml, HR 1.004, 95%CI: 1.0001-1.007, P = 0.005) and presence of CXCR4-positive peritoneal metastases (PM) were associated with shorter OS (HR 2.03, 95%CI: 1.03-4.02, P = 0.04). Presence of CXCR4-positive liver metastases (LM) trended towards significance (HR 1.85, 0.9-4.1, P = 0.11), while all other parameters failed to predict survival. On multivariable analysis, only TRB was an independent predictor for OS (HR 1.0, 95%CI: 1.00-1.001, P = 0.02). On Kaplan-Meier analysis, TRB above median (13.3 months vs. below median, 6.4 months) and presence of CXCR4-positive PM (6.4 months, vs. no PM, 11.4 months) were associated with shorter survival (P < 0.05, respectively). Presence of LM, however, was also linked to less favorable outcome (8.5 months vs. no LM, 18.1 months), without reaching significance (P = 0.07).
CONCLUSIONS
In advanced ACC, elevated tumor chemokine receptor binding on the tumor cell surface detected through [Ga]Ga-PentixaFor PET/CT is an independent predictor for OS, while other imaging and clinical parameters failed to provide relevant prognostic information.
PubMed: 38896128
DOI: 10.1007/s00259-024-06800-z -
Translational Cancer Research May 2024Elevated expression of SLC7A11, in conjunction with glucose deprivation, has revealed disulfidptosis as an emerging cell death modality. However, the prevalence of...
BACKGROUND
Elevated expression of SLC7A11, in conjunction with glucose deprivation, has revealed disulfidptosis as an emerging cell death modality. However, the prevalence of disulfidptosis across tumor cell lines, irrespective of SLC7A11 levels, remains uncertain. Additionally, deletion of the ribophorin I () gene imparts resistance to disulfidptosis, yet the precise mechanism linking to disulfidptosis remains elusive. The aim of this study is to determine the mechanism of -induced disulfidptosis and to determine the possibility of RPN1 as a pan-cancer marker.
METHODS
We hypothesized the widespread occurrence of disulfidptosis in various tumor cells, and proposed that -mediated disulfidptosis may be executed through cell skeleton breakdown. Experimental validation was conducted via flow cytometry, immunofluorescence, and western blot techniques. Furthermore, given 's status as an emerging cell death marker, we utilized bioinformatics to analyze its expression in tumor tissues, clinical relevance, mechanisms within the tumor microenvironment, and potential for immunotherapy.
RESULTS
Conducting experiments on breast cancer (MDA-MB-231) and lung cancer (A549) cell lines under glucose-starved conditions, we found that primarily induces cell skeleton breakdown to facilitate disulfidptosis. demonstrated robust messenger RNA (mRNA) expression across 16 solid tumors, validated by data from 12 tumor types in the Gene Expression Omnibus (GEO). Across 12 cancer types, exhibited significant diagnostic potential, particularly excelling in accuracy for glioblastoma (GBM). Elevated expression in tumor tissues was found to correlate with improved overall survival (OS) in certain cancers [diffuse large B-cell lymphoma (DLBC) and thymoma (THYM)] but poorer prognosis in others [adrenocortical carcinoma (ACC), kidney chromophobe (KICH), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), and pancreatic adenocarcinoma (PAAD)]. is enriched in immune-related pathways and correlates with immune scores in tumor tissues. In urothelial carcinoma (UCC), demonstrates potential in predicting the efficacy of anti-programmed cell death ligand 1 (PD-L1) immune therapy.
CONCLUSIONS
This study underscores 's role in facilitating disulfidptosis, its broad relevance as a pan-cancer biomarker, and its association with the efficacy of anti-PD-L1 immune therapy.
PubMed: 38881923
DOI: 10.21037/tcr-24-581 -
Arkhiv Patologii 2024To develop the mathematical model with high sensitivity and specificity to assess the malignant potential of adrenal cortical tumors, which can be used to diagnose...
OBJECTIVE
To develop the mathematical model with high sensitivity and specificity to assess the malignant potential of adrenal cortical tumors, which can be used to diagnose adrenocortical carcinoma (ACC) in adults.
MATERIAL AND METHODS
Pathomorphological examination of surgical and consultative material of adrenocortical neoplasms was carried out. All cases were verified according to the WHO Classification of adrenal gland tumors (5 ed., 2022), the tumor's histogenesis was confirmed by immunohistochemical examination. Statistical analysis of the histological and immunohistochemical factors in terms of their value in relation to the diagnosis of ACC was carried out on Python 3.1 in the Google Colab environment. ROC analysis was used to identify critical values of predictors. The cut-off point was selected according to the Youden`s index. Logistic regression analysis using l1-regularisation was performed. To validate the model, the initial sample was divided into training and test groups in the ratio of 9:1, respectively.
RESULTS
The study included 143 patients divided into training (128 patients) and test (15 patients) samples. A prognostic algorithm was developed, which represent a diagnostically significant set of indicators of the currently used Weiss scale. The diagnosis is carried out in 3 stages. This mathematical model showed 100% accuracy (95% CI: 96-100%) on the training and test samples.
CONCLUSION
The developed algorithm could solve the problem of subjectivity and complexity in the interpretation of some of the criteria of current diagnostic algorithms. The new model is unique in that, unlike others, it allows verification of all morphological variants of ACC.
Topics: Humans; Adrenal Cortex Neoplasms; Algorithms; Male; Female; Adult; Middle Aged; Adrenocortical Carcinoma; Models, Theoretical; ROC Curve; Prognosis; Aged
PubMed: 38881002
DOI: 10.17116/patol20248603121 -
The Oncologist Jun 2024Image-guided therapies (IGTs) are commonly used in oncology, but their role in adrenocortical carcinoma (ACC) is not well defined.
BACKGROUND
Image-guided therapies (IGTs) are commonly used in oncology, but their role in adrenocortical carcinoma (ACC) is not well defined.
MATERIALS AND METHODS
A retrospective review of patients with ACC treated with IGTs. We assessed response to therapy using RECIST v1.1, time to next line of systemic therapy, disease control rate (DCR), local tumor progression-free survival (LTPFS), and complications of IGTs (based on the Common Terminology Criteria for Adverse Events [CTCAE] version 5.0).
RESULTS
Our cohort included 26 patients (median age 56 years [range 38-76]; n = 18 female) who had 51 IGT sessions to treat 86 lesions. IGTs modalities included cryoablation (n = 49), microwave ablation (n = 21), combined microwave and bland trans-arterial embolization (n = 8), bland trans-arterial embolization alone (n = 3), radio-embolization (n = 3), and radiofrequency ablation (n = 2). DCR was 81.4% (70 out of 86), of which 66.3% of tumors showed complete response, 18.6% showed progressive disease, 8.1% showed partial response, and 7.0% showed stable disease. LTPFS rates were 73% and 63% at 1 and 2 years, respectively. Fourteen lesions underwent re-ablation for incomplete response on initial treatment. Sixteen patients (61.5%) received new systemic therapy following IGTs, with a median time to systemic therapy of 12.5 months (95% CI: 8.6 months upper limit not reached). There was 1 reported CTCAE grade 3 adverse event (biloma) following IGT.
CONCLUSIONS
IGT use in properly selected patients with ACC is safe and associated with prolonged disease control and delay in the need for systemic therapy.
PubMed: 38869364
DOI: 10.1093/oncolo/oyae130 -
Innere Medizin (Heidelberg, Germany) Jul 2024Adrenal tumors are among the most common tumors in humans. They are most frequently discovered incidentally during abdominal imaging for other reasons or due to clinical...
Adrenal tumors are among the most common tumors in humans. They are most frequently discovered incidentally during abdominal imaging for other reasons or due to clinical symptoms (e.g. Conn's or Cushing's syndrome, pheochromocytoma or androgen excess). Although over 80% of adrenal tumors are benign, in cases of hormone excess, they are associated with significantly increased morbidity. In highly malignant adrenocortical carcinoma (ACC), early diagnosis is of particular prognostic relevance. Therefore, this review presents the diagnostic procedure for what are referred to as adrenal incidentalomas and provide recommendations for the management of ACC and pheochromocytomas/paragangliomas (PPGL). In primary diagnosis, sufficient hormone diagnostics is required for all adrenal tumors, as this is the only way to identify all patients with relevant hormone excess. Imaging has increasingly improved in recent years and allows a reliable assessment of the tumor's malignancy in most cases. Imaging of first choice is unenhanced computed tomography (CT), while magnetic resonance imaging (MRI) and fluorodeoxyglucose-18 positron emission tomography (FDG-PET/CT) are reserved for special situations, as published evidence on these procedures is more limited. The treatment of ACC and PPGL is complex and is carried out on an interdisciplinary basis at specialized centers. In the case of localized disease, surgery is the only curative treatment option. There are now clear recommendations for individualized adjuvant therapy for ACC. In metastatic disease, mitotane with or without platinum-containing chemotherapy is the standard. Other lines of therapy should be discussed with a reference center. Over 35% of PPGL have a germline mutation; therefore, genetic testing should be offered. In metastatic PPGL, an individual decision is required between active surveillance, radionuclide therapy, sunitinib or chemotherapy.
Topics: Humans; Adrenal Gland Neoplasms; Pheochromocytoma
PubMed: 38864873
DOI: 10.1007/s00108-024-01727-x