Development and validation of a liquid chromatography coupled to a diode array detector (LC-DAD) method for measuring mitotane (DDD) in plasma samples.

INTRODUCTION: Mitotane (o,p'-DDD) is the drug of choice for Adrenocortical Carcinomas (ACC) and its measurement in plasma is essential to control drug administration. OBJECTIVE: To develop and validate a simple, reliable and straightforward method for mitotane determination in plasma samples. METHOD: Drug-free plasma samples were collected in potassium-ethylenediamine tetraacetate (K-EDTA) tubes and spiked with 1.0, 2.5, 10.0, 25.0 and 50.0 µg/mL of mitotane (DDD). The p,p'-DDD was used as an Internal Standard (IS) and was added at 25.0 µg/mL concentration to all samples, standards and controls. Samples were submitted to protein precipitation with acetonitrile and then centrifuged. 50 uL of the supernatant was injected into an HPLC system coupled to a Diode Array Detector (DAD). DDD and IS were detected at 230 nm in a 12 min isocratic mode with a solvent mixture of 60 % acetonitrile and 40 % formic acid in water with 0.1 % pump mixed, at 0.6 mL/min flow rate, in a reversed-phase (C18) chromatographic column kept at 28°C. The sensitivity, selectivity, precision, presence of carry-over, recovery and matrix-effect, linearity, and method accuracy were evaluated. RESULTS: The present study's method resulted in a symmetrical peak shape and good baseline resolution for DDD (mitotane) and 4,4'-DDD (internal standard) with retention times of 6.0 min, 6.4 mim, respectively, with resolutions higher than 1.0. Endogenous plasma compounds did not interfere with the evaluated peaks when blank plasma and spiked plasma with standards were compared. Linearity was assessed over the range of 1.00-50.00 µg/mL for mitotane (R2 > 0.9987 and a 97.80 %‒105.50 % of extraction efficiency). Analytical sensitivity was 0.98 µg/mL. Functional sensitivity (LOQ) was 1.00 µg/L, intra-assay and inter-assay coefficient of variations were less than 9.98 %, and carry-over was not observed for this method. Recovery ranged from 98.00 % to 117.00 %, linearity ranged from 95.00 % to 119.00 %, and high accuracy of 89.40 % to 105.90 % with no matrix effects or interference was observed for mitotane measurements. Patients' sample results were compared with previous measurements by the GC-MS method with a high correlation (r = 0.88 and bias = -10.20 %). CONCLUSION: DDD determination in plasma samples by the developed and validated method is simple, robust, efficient, and sensitive for therapeutic drug monitoring and dose management to achieve a therapeutic index of mitotane in patients with adrenocortical cancer.

Surgical Management of Metastatic Adrenocortical Carcinoma.

Introduction: Adrenocortical carcinoma (ACC) is a notoriously aggressive cancer with a dismal prognosis, especially for patients with metastatic disease. Metastatic ACC is classically a contraindication to operative management. Here, we evaluate the impact of primary tumor resection and metastasectomy on survival in metastatic ACC. Methods: We performed a retrospective cohort study of patients with metastatic ACC (2010-2019) utilizing the National Cancer Database. The primary outcome was overall survival (OS). Cox proportional hazards models were developed to evaluate the associations between surgical management and survival. Propensity score matching (PSM) was utilized to account for selection bias in receipt of surgery. Results: Of 976 subjects with metastatic ACC, 38% underwent surgical management. Median OS across all patients was 7.6 months. On multivariable Cox proportional hazards regression, primary tumor resection alone (HR: 0.523; p<0.001) and primary resection with metastasectomy (HR: 0.372; p<0.001) were significantly associated with improved OS. Metastasectomy alone had no association with OS (HR: 0.909; p=0.740). Primary resection with metastasectomy was associated with improved OS over resection of the primary tumor alone (HR: 0.636; p=0.018). After PSM, resection of the primary tumor alone remained associated with improved OS (HR 0.593; p<0.001), and metastasectomy alone had no survival benefit (HR 0.709; p=0.196) compared with non-operative management; combined resection was associated with improved OS over primary tumor resection alone (HR 0.575, p=0.008). Conclusion: In metastatic ACC, patients may benefit from primary tumor resection alone or in combination with metastasectomy, however further research is required to facilitate appropriate patient selection.

Clinical and Pathological Predictors of Death for Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare and lethal disease with a poor prognosis. This study aims to share our 41-year experience as a referral center, focusing on identifying risk factors associated with ACC mortality. Our retrospective analysis included a cohort of 150 adult patients with ACC in all stage categories, treated between 1981 and 2022. Tumor hormonal hypersecretion was observed in 78.6% of the patients, and the median age of diagnosis was 40 years. The majority presented as European Network for the Study of Adrenal Tumors (ENSAT) III or IV (22.9% and 31.2%, respectively), and the overall mortality rate was 54.6%. Independent predictors of death were elevated secretion of cortisol (HR = 2.0), androstenedione (HR = 2.2), estradiol (HR = 2.8), 17-OH progesterone (HR = 2.0), and 11-deoxycortisol (HR = 5.1), higher Weiss (HR = 4.3), modified Weiss (HR = 4.4), and Helsinki scores (HR = 12.0), advanced ENSAT stage (HR = 27.1), larger tumor size (HR = 2.7), higher Ki-67 percentage (HR = 2.3), and incomplete surgical resection (HR = 2.5). Mitosis greater than 5/50 high-power field (HR = 5.6), atypical mitosis (HR = 2.3), confluent necrosis (HR = 15.4), venous invasion (HR = 2.8), and capsular invasion (HR = 2.4) were also identified as independent predictors of death. Knowing the risk factors for ACC's mortality may help determine the best treatment option.

Comprehensive Characterization of the Regulatory Landscape of Adrenocortical Carcinoma: Novel Transcription Factors and Targets Associated with Prognosis.

We reconstructed a transcriptional regulatory network for adrenocortical carcinoma (ACC) using transcriptomic and clinical data from The Cancer Genome Atlas (TCGA)-ACC cohort. We investigated the association of transcriptional regulatory units (regulons) with overall survival, molecular phenotypes, and immune signatures. We annotated the ACC regulons with cancer hallmarks and assessed single sample regulon activities in the European Network for the Study of Adrenal Tumors (ENSAT) cohort. We found 369 regulons associated with overall survival and subdivided them into four clusters: RC1 and RC2, associated with good prognosis, and RC3 and RC4, associated with worse outcomes. The RC1 and RC3 regulons were highly correlated with the 'Steroid Phenotype,' while the RC2 and RC4 regulons were highly correlated with a molecular proliferation signature. We selected two regulons, NR5A1 (steroidogenic factor 1, SF-1) and CENPA (Centromeric Protein A), that were consistently associated with overall survival for further downstream analyses. The CENPA regulon was the primary regulator of MKI-67 (a marker of proliferation KI-67), while the NR5A1 regulon is a well-described transcription factor (TF) in ACC tumorigenesis. We also found that the ZBTB4 (Zinc finger and BTB domain-containing protein 4) regulon, which is negatively associated with CENPA in our transcriptional regulatory network, is also a druggable anti-tumorigenic TF. We anticipate that the ACC regulons may be used as a reference for further investigations concerning the complex molecular interactions in ACC tumors.

Carcinoma corticosuprarrenal virilizante en un niño / Virilizing adrenocortical carcinoma in a child

Introducción: Los tumores suprarrenales en niños son poco frecuentes y el carcinoma suprarrenal representa menos de un 10 %. En el prepúber, la manifestación más típica es el desarrollo de pubertad precoz. Objetivo: Describir las características clínicas, los procederes diagnósticos y terapéuticos de un paciente con carcinoma adrenal en edad pediátrica. Presentación de caso: Paciente de 8 años, masculino y de piel blanca con antecedentes de salud. Acude a la consulta por crecimiento de vello pubiano y aumento del pene en longitud y grosor de aproximadamente 2 años de evolución. En el examen físico se constatan aumento de la velocidad de crecimiento y signos sugestivos de virilización (voz gruesa, vello axilar, vello sexual púbico y genitales externos estadio III de Tanner). Se realizaron estudios hormonales que corroboraron el hiperandrogenismo por secreción endógena autónoma, con niveles de gonadotropinas suprimidas, niveles de testosterona y dehidroepiandrosterona elevados. También se realizaron estudios imagenológicos que evidenciaron edad ósea acelerada y la existencia de un tumor. Se realizó una adrenalectomía izquierda y se confirmó por anatomía patológica el carcinoma corticosuprarrenal virilizante izquierdo en estadío 2. Inició un tratamiento con quimioterapia por dicho diagnóstico y actualmente se mantiene en seguimiento. Conclusiones: Los carcinomas corticosuprarrenales en niños son mayoritariamente funcionantes y constituyen una de las causas de pubertad precoz periférica. Estos son infrecuentes y agresivos, por lo que la realización de estudios genéticos en familias con síndromes hereditarios contribuiría a su diagnóstico precoz para un adecuado tratamiento y mejor pronóstico(AU)

Introduction: Adrenal tumors in children are rare and adrenal carcinoma represents less than the 10 percent. In the prepubescent, the most typical manifestation is the development of early puberty. Objective: Describe the clinical characteristics and diagnostic and therapeutic procedures of a patient with adrenal carcinoma in a pediatric age. Case presentation: 8-year-old male, white-skinned patient with a history of health conditions. He attentds to the consultation due to pubic hair growth and penis enlargement in length and thickness of approximately 2 years of evolution. Physical examination shows increased growth rate and signs suggestive to virilization (deep voice, axillary hair, pubic sexual hair and external genitalia in Tanner's stage III). Hormonal studies were carried out that corroborated hyperandrogenism by autonomic endogenous secretion, with suppressed gonadotropin levels, elevated testosterone and dehydroepiandrosterone levels. Imaging studies were also performed that showed accelerated bone age and the existence of a tumor. A left adrenalectomy was performed and stage 2 left virilizing adrenocrotical carcinoma was confirmed by pathological anatomy studies. He began chemotherapy treatment for this diagnosis and is currently being followed up. Conclusions: Adrenocortical carcinomas in children are mostly functioning and are one of the causes of peripheral early puberty. These are uncommon and aggressive, so genetic studies in families with hereditary syndromes would contribute to their early diagnosis for adequate treatment and better prognosis(AU)

Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients' Survival.

CONTEXT: The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood. OBJECTIVE: To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC. DESIGN AND SETTING: We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance collaborative research group. PATIENTS: Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019. INTERVENTION: Performance (or not) of cytoreductive surgery of the primary tumor. MAIN OUTCOME AND MEASURES: A propensity score match was done using age and the number of organs with metastasis (≤2 or >2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients. RESULTS: Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (hazard ratio [HR] = 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65). CONCLUSION: Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.

Carcinoma de corteza suprarrenal. Presentación de un caso y revisión de la literatura

RESUMEN El carcinoma suprarrenal es un tumor raro pero devastador, esto se debe fundamentalmente a que en la mayoría de los casos se encuentra en estadios avanzados en el momento del diagnóstico. Tiene una incidencia de 0,5-2 casos por un millón habitantes al año. Entre el 40 y el 70 % de los pacientes tienen metástasis cuando se inicia el estudio. Se presenta de manera general en adultos, aunque también afecta a los niños. La mediana de edad en el momento del diagnóstico es 46 años, siendo más frecuente en el sexo masculino. Se presenta el caso de una paciente con antecedentes de hipertensión arterial de un año de evolución, ante los síntomas presentados se le realizan estudios por imágenes y de laboratorio diagnosticándose un tumor suprarrenal izquierdo. Se le realizó supraadrenalectomía izquierda obteniéndose como resultado histopatológico un carcinoma adenocortical suprarrenal. Se presenta este caso porque el carcinoma suprarrenal representa una entidad poco frecuente y es relevante exponer esta experiencia para el manejo de este tipo de neoplasia.

ABSTRACT Adrenal carcinoma is a rare devastating tumor, mainly because in most cases it is in advanced stages at the time of diagnosis. It has an incidence of 0.5-2 cases per one million inhabitants per year, in which 40 to 70 % of patients have metastases when the study begins. It occurs mainly in adults, although it also affects children. The median age at the time of diagnosis is 46 years, being more frequent in males. The case of a patient with a history of arterial hypertension of one year of evolution is presented. In view of the symptoms presented, imaging and laboratory studies are performed, diagnosing a left adrenal tumor. A left supraadrenelectomy was performed, obtaining an adenocortical adrenal carcinoma as a histopathological result.

Adrenocortical carcinoma, case report.

The adrenocortical carcinoma is rare and aggressive. It has a bimodal presentation, predominantly female, > 20% of cases will be diagnosed incidentally. 43-year-old male, with colic pain in the left flank, weight loss and intermittent fever. Computed tomography with a tumor on the left adrenal with liver metastases, block resection surgery was performed, pathological report of adrenocortical carcinoma with a 7 points of Weiss score and Ki67 40%. Adrenocortical carcinoma is a rare and aggressive neoplasm; the clinical presentation is variable. Systemic therapy is important even in patients with localized disease and independent of surgical approach.

El carcinoma corticoadrenal es una neoplasia rara, altamente agresiva, de distribución bimodal, con predominio en el sexo femenino, de la cual el 20% de los casos se diagnostican de manera incidental. Se presenta el caso de un varón de 43 años con dolor de tipo cólico en el flanco izquierdo, pérdida de peso y fiebre intermitente. La tomografía computarizada mostró un tumor en la glándula suprarrenal izquierda y metástasis hepática. Se realizó adrenalectomía radical en bloque, con reporte anatomopatológico de carcinoma corticoadrenal, Weiss de 7 puntos y Ki67 40%. El carcinoma corticoadrenal es una neoplasia agresiva y de presentación clínica variable. La terapia sistémica es importante incluso en pacientes con enfermedad localizada e independientemente de la cirugía.

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.

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.

Giant virilising adrenal cortical carcinoma.

Androgen secreting adrenocortical carcinoma (ACC) is a very rare disease with a poor prognosis. Approximately 80% of tumors are functional, most commonly secreting glucocorticoids. We herewith report a case of a huge functional ACC of the right adrenal gland in a 33-year-old female who presented with complaints of hirsutism, amenorrhea and an abdominal lump. On abdominal examination a large lump was palpable in the right hypochondrium reaching up to the umbilicus. Contrast-enhance computed tomography (CECT) revealed a mass in the right suprarenal region. The tumor measured 29 cm × 20 cm × 12 cm and weighed 7.8 kg, the largest reported case of ACC in the world to the best of our knowledge.

In vitro cytotoxic effect of a chitin-like polysaccharide produced by Mortierella alpina on adrenocortical carcinoma cells H295R, and its use as mitotane adjuvant.

This study presents an in vitro evaluation of the antitumor potential of a chitin-like exopolysaccharide (EPS, produced by Mortierella alpina) on Adrenocortical carcinoma cells (ACC) compared to mitotane, a commercial drug commonly used in ACC treatment, and known for its side effects. Techniques of cellular viability determination such as MTT and fluorescence were used to measure the cytotoxic effects of the EPS and mitotane in tumoral cells (H295R) and non-tumoral cells (VERO), observing high cytotoxicity of mitotane and a 10% superior pro-apoptotic effect of the EPS compared to mitotane (p < 0.05). The cytotoxic effect of the EPS was similar to the effect of 50 µM mitotane on tumoral cells (p < 0.05). A decrement of the lysosomal volume was also noted in tumoral cells treated with the EPS. To enhance the antitumor effect, a combination of mitotane at a lower dosage and the EPS (as adjuvant) was also tested, showing a slight improvement of the cytotoxicity effect on tumoral cells. Therefore, the results indicate a cytotoxic effect of the EPS produced by Mortierella alpina on adrenocortical carcinoma, and a possible application in biomedical formulations or additional treatments.

Clinical Impact of Pathological Features Including the Ki-67 Labeling Index on Diagnosis and Prognosis of Adult and Pediatric Adrenocortical Tumors.

Adrenocortical tumors (ACT) in the adult and pediatric population are generally considered distinct entities due to differences in molecular events related to tumorigenesis, clinical presentation, and outcome. Furthermore, pathological criteria used for diagnosis and prognostication of ACT in adults are usually inadequate for predicting the biological behavior of ACT in children. Here, we analyzed 146 adult and 44 pediatric (< 15y/o) ACT with long-term clinical follow-up and furthered current evidence on the clinical and pathological differences between pediatric and adult tumors. Predilection for female over male gender was observed in both cohorts, but more so in adults (84% vs. 61%, p = 0.003). Cushing syndrome was more frequent in adults (p < 0.001), whereas virilization, either isolated (p < 0.001) or combined to Cushing (p = 0.047), was more common in children. The Ki67 labelling index (LI) of pediatric adenomas and carcinomas was much higher than their corresponding tumors in adults (p < 0.001). Despite these differences, pathological analyses including the evaluation of Ki67 greatly improved patient prognostication in both age cohorts. Indeed, increased Weiss scores and Ki67 indexes correlated with poor overall- and disease-free survival in adult patients with carcinoma. Among the proliferative indexes tested, Ki67 LI ≥ 10% showed the highest hazard ratio (HR) for recurrence and the Ki67 LI ≥ 3% showed the highest HR for survival. In pediatric tumors, the Wieneke score (p < 0.001) and the Ki67 LI (p < 0.001) showed high accuracy for predicting biological behavior, and increased scores/indexes correlated with worse overall and disease-free survival. In this age cohort, Ki67 LI < 10% was able to rule out malignant behavior, whereas Ki67 LI ≥ 15% may be used to predict the patients with higher risks of recurrence and/or poor outcome.

Low Protein Expression of both ATRX and ZNRF3 as Novel Negative Prognostic Markers of Adult Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy that is associated with a dismal prognosis. Pan-genomic studies have demonstrated the involvement of ATRX and ZNRF3 genes in adrenocortical tumorigenesis. Our aims were to evaluate the protein expression of ATRX and ZNRF3 in a cohort of 82 adults with ACC and to establish their prognostic value. Two pathologists analyzed immuno-stained slides of a tissue microarray. The low protein expression of ATRX and ZNRF3 was associated with a decrease in overall survival (OS) (p = 0.045, p = 0.012, respectively). The Cox regression for ATRX protein expression of >1.5 showed a hazard ratio (HR) for OS of 0.521 (95% CI 0.273-0.997; p = 0.049) when compared with ≤1.5; for ZNRF3 expression >2, the HR for OS was 0.441 (95% CI, 0.229-0.852; p = 0.015) when compared with ≤2. High ATRX and ZNRF3 protein expressions were associated with optimistic recurrence-free survival (RFS) (p = 0.027 and p = 0.005, respectively). The Cox regression of RFS showed an HR of 0.332 (95%CI, 0.111-0.932) for ATRX expression >2.7 (p = 0.037), and an HR of 0.333 (95%CI, 0.140-0.790) for ZNRF3 expression >2 (p = 0.013). In conclusion, low protein expression of ATRX and ZNRF3 are negative prognostic markers of ACC; however, different cohorts should be evaluated to validate these findings.

Management of Pediatric Tumors With Vascular Extension.

Background: Pediatric tumors can present with vascular extension to the inferior vena cava and right atrium, which impacts the surgical strategy and can be challenging during surgical treatment. Wilms tumor (WT) is the most common retroperitoneal tumor that can present with vascular extension, but also adrenal tumors, clear cell tumors from the kidney, and hepatoblastomas can present with this situation. Surgical aims include obtaining complete tumor resection without risk for patients, to avoid severe bleeding, cardiac arrest, and embolization, and to avoid cardiac bypass if possible. Objective: To describe and discuss the surgical strategies to deal with pediatric tumors with vascular extension and propose a protocol. Method: Retrospectivly review the experience of treating patients with vascular extension in a single institution, describing different scenarios and a decision making fluxogram based on the preoperative evaluation regarding the surgical techniques and the need for cardiac bypass that are adequate for each situation. Image studies are important to guide the surgical strategy. Depending on the quality of image available, computerized tomography (CT) or magnetic resonance imaging (MRI) can be enough to give the information needed for surgical decisions. Ultrasonography (US) with Doppler is helpful to confirm diagnosis and describes factors to guide the adequate surgical strategy, like the upper level extension and presence or absence of blood flow around the thrombus. Neoadjuvant chemotherapy is indicated in most cases, in order to reduce the upper level of extension (and avoid the need for cardiac bypass) and to lower the risk of embolization. The approach is based on the upper level of the thrombus and can include cavotomy or cavectomy, sometimes with cardiac bypass and cardiac arrest with hypothermia, when the thrombus reaches the diaphragmatic level or above. Pathology analysis of the thrombus can guide staging and the need for radiotherapy postoperatively. Results: A decision making fluxogram protocol is presented focusing on the surgical treatment of such condition. Conclusion: Surgery strategy is highly impacted by the presence of vascular extension in pediatric tumors. Surgeons should be aware of potential complications and how to prevent them. Such cases should be treated in reference centers.

Upregulation of TCF21 inhibits migration of adrenocortical carcinoma cells.

BACKGROUND: Adrenocortical carcinomas (ACC) are rare and aggressive cancer. Our previous study has revealed that the transcription factor 21, TCF21, is downregulated in ACC and regulates steroidogenic factor 1 (SF-1) binding to the SF-1 E-box promoter. In addition, it could be found that TCF21 is a predictor of overall survival (OS) in adult carcinomas. METHODS: In this study, it was investigated the correlation between TCF21 expression and the promoter methylation status in adrenocortical tumor cells, carcinomas and adenoma. The biological function and potential molecular mechanism of TCF21 restoration in migration and invasion of ACC cells was examined. RESULTS: We could be demonstrated a negative correlation between the level of TCF21 expression and methylation of its promoter in adenoma and carcinoma cells indicating the epigenetic control of TCF21 expression. It was also demonstrated that the expression of TCF21 inhibits migration and invasion in the ACC cell line, H295R cells, using plasmid transfection to express TCF21. Furthermore, it could be investigated the TCF21 function as tumor suppressor probably through Kisspeptin 1 (KISS-1) expression and epithelial-mesenchymal transition (EMT) reversion, as well as the modulation of several metalloproteinases in ACC cells. CONCLUSIONS: Our results suggest that enhancement of TCF21 expression levels may be a potential strategy to revert invasive abilities in adrenocortical carcinomas.

Pharmacological profile and effects of mitotane in adrenocortical carcinoma.

Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour tissues; it induces cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids, which are involved in the pathogenesis of ACC. However, high doses of mitotane are usually necessary to reach the therapeutic plasma concentration, which may result in several adverse effects. This suggests that important pharmacological processes, such as first pass metabolism, tissue accumulation and extensive time for drug elimination, are associated with mitotane administration. Few studies have reported the pharmacological aspects and therapeutic effects of mitotane. Therefore, the aim of this review was to summarize the chemistry, pharmacokinetics and pharmacodynamics, and therapeutic and toxic effects of mitotane. This review also discusses new perspectives of mitotane formulation that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects.

Giant virilising adrenal cortical carcinoma

Androgen secreting adrenocortical carcinoma (ACC) is a very rare disease with a poor prognosis. Approximately 80% of tumors are functional, most commonly secreting glucocorticoids. We herewith report a case of a huge functional ACC of the right adrenal gland in a 33-year-old female who presented with complaints of hirsutism, amenorrhea and an abdominal lump. On abdominal examination a large lump was palpable in the right hypochondrium reaching up to the umbilicus. Contrast-enhance computed tomography (CECT) revealed a mass in the right suprarenal region. The tumor measured 29 cm × 20 cm × 12 cm and weighed 7.8 kg, the largest reported case of ACC in the world to the best of our knowledge.