Evaluating Mixtures of Urinary Phthalate Metabolites and Serum Per-/Polyfluoroalkyl Substances in Relation to Adolescent Hair Cortisol: The HOME Study.

Results of toxicological studies indicate that phthalates and per-/polyfluoroalkyl substances (PFAS), 2 classes of endocrine-disrupting chemicals, may alter the functioning of the hypothalamic-pituitary-adrenocortical (HPA) axis. We evaluated the associations of urinary phthalate metabolites and serum PFAS during gestation and childhood with adolescent hair cortisol concentrations (pg/mg hair) at age 12 years, an integrative marker of HPA axis activity (n = 205 mother-child pairs; Cincinnati, Ohio; enrolled 2003-2006). We used quantile-based g-computation to estimate associations between mixtures of urinary phthalate metabolites or serum PFAS and hair cortisol. We also examined whether associations of individual phthalate metabolites or PFAS with cortisol varied by the timing of exposure. We found that a 1-quartile increase in all childhood phthalate metabolites was associated with 35% higher adolescent hair cortisol (phthalate mixture ψ = 0.13; 95% confidence interval: 0.03, 0.22); these associations were driven by monoethyl phthalate, monoisobutyl phthalate, and monobenzyl phthalate. We did not find evidence that phthalate metabolites during gestation or serum PFAS mixtures were related to adolescent hair cortisol concentrations. We found suggestive evidence that higher childhood concentrations of individual PFAS were related to higher and lower adolescent hair cortisol concentrations. Our results suggest that phthalate exposure during childhood may contribute to higher levels of chronic HPA axis activity.

A review of mitotane in the management of adrenocortical cancer.

IMPORTANCE: Mitotane (Lysodren, o,p'-DDD [1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane)] is currently the only United States Food and Drug Administration and European Medicines Agency-approved product for the treatment of adrenocortical carcinoma. OBSERVATIONS: Mitotane is challenging to administer; however, its toxicities (specifically adrenal insufficiency) are well known, and the management of adverse consequences has established approaches. While often viewed through the prism of a cytotoxic agent, it can also interfere with hormone production making it a valuable asset in managing functional ACC. A recently completed prospective trial has shed some light on its use in the adjuvant setting, but further clarity is needed. Many think mitotane has a role in the advanced or metastatic setting, although prospective data are lacking and retrospective analyses are often difficult to interpret. CONCLUSIONS AND RELEVANCE: When used carefully and thoughtfully, especially in patients with hormonal excess, mitotane is an important component of the treatment armamentarium for ACC.

Clinical outcomes of image-guided therapies in patients with adrenocortical carcinoma: a tertiary referral center retrospective study.

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.

Adrenocortical Carcinomas: Molecular Pathogenesis, Treatment Options, and Emerging Immunotherapy and Targeted Therapy Approaches.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy in the advanced setting with poor prognosis. This narrative review provides an overview of the epidemiology of ACC and its molecular pathogenesis with a summary of the main involved signaling pathways. We then provide an update on the clinical presentation, diagnosis, and current management strategies of both localized and metastatic disease from a multidisciplinary perspective. We highlight the debate around the use of mitotane in the adjuvant setting and review the use of combination chemotherapy with etoposide, doxorubicin, and cisplatin. The review also focuses on emerging data providing hope for the use of immune checkpoint inhibitors and targeted therapies in ACC with a summary of ongoing trials.

Venous thromboembolism in adrenocortical carcinoma: a retrospective analysis.

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of death in patients with cancer. Limited data exist about VTE in patients with adrenocortical carcinoma (ACC). The primary objective of this study was to identify the prevalence of VTE in a cohort of patients with ACC. Secondary objectives were to determine the impact of VTE events on overall survival (OS) and to describe the characteristics of VTE in patients with ACC. PATIENTS AND METHODS: We retrospectively reviewed data from 289 patients with ACC cared for at a major referral center from February 2010 to June 2022. RESULTS: VTE prevalence was 18.7% (54 events). Thirty patients (55.6%) had pulmonary embolism (PE); 12 patients (22.2%) had deep vein thrombosis (DVT); and 12 patients (22.2%) had both PE and DVT. VTE occurred after ACC diagnosis in 50 patients (92.6%) including 44 patients (88%) with stage 3 or 4 ACC. VTEs were CTCAE grade ≤2 in 32 cases (59.3%), grade 3 in 17 (31.5%), and grade 4 in 2 (3.7%). Thirteen patients (24%) died within 6 months after VTE diagnosis, although there was no statistically significant association between VTE and overall survival. CONCLUSION: Despite the potential to underestimate the prevalence of VTEs, we found a high frequency of VTE events in patients with ACC. A majority of VTEs occurred in the context of advanced ACC and we observed high short-term mortality. Further studies are needed to validate our findings and investigate mechanisms associated with VTE in ACC.

Ante Situm Liver Resection for Tumors Invading the Inferior Vena Cava Hepatic Vein Confluence.

BACKGROUND: Liver malignancy invading the retrohepatic inferior vena cava beyond the cavo-hepatic vein venous confluence can be resected by an ante situm technique first described by Hannoun et al.1 In this approach, a major hepatectomy is performed and the hepatic veins are sectioned to allow the inferior vena cava reconstruction while the liver is cold perfused and the liver remains within the abdominal cavity. The hepatic vein is then reimplanted on the reconstructed inferior vena cava in "a liver autotransplantation fashion." PATIENT AND METHODS: The patient was a 66-year-old with a recurrent adrenocortical carcinoma cancer invading the right liver and the retrohepatic inferior vena cava with intraluminal thrombus extending beyond to the hepatic vein confluence. A right hepatectomy extended to segment 1 and the retrohepatic inferior vena cava was planned because of the intracaval tumoral thrombus and the infiltration of the right liver. The future liver remnant (FLR) (646 cc) to total liver volume (1526 cc) ratios was 42% while the FLR to patient weight ratio was 0.9%. RESULTS: The parenchymal liver transection was performed under a total vascular exclusion, venovenous bypass, and hypothermic perfusion of the left liver.2 The common trunk of the left and middle hepatic veins was sectioned, allowing the liver to be rotated toward the left. Vena cava reconstruction was achieved by a ringed Gore-Tex prosthesis, with reimplantation of the left and middle hepatic veins directly over the prosthesis. Surgery lasted 580 min, total duration of venovenous bypass and liver vascular exclusion was 143 min and 140 min, respectively. Blood loss was 2 liters and 8 red blood cell (RBC) units were transfused. The patient spent 5 days in the ICU, liver function tests normalized by postoperative day 8 and patient was discharged home on postoperative day 20; 1 year later, the patient is alive and disease free under mitotane treatment. CONCLUSIONS: The ante situm technique represents a safe surgical option for complex liver resection for malignancy involving the cavo-hepatic venous confluence. Compared with the ex situ liver resection, this technique allows liver remnant outflow reconstruction to be performed while the liver is cold perfused within the abdominal cavity with an intact hepatic pedicle.

Radiomics in the characterization of lipid-poor adrenal adenomas at unenhanced CT: time to look beyond usual density metrics.

OBJECTIVES: In this study, we developed a radiomic signature for the classification of benign lipid-poor adenomas, which may potentially help clinicians limit the number of unnecessary investigations in clinical practice. Indeterminate adrenal lesions of benign and malignant nature may exhibit different values of key radiomics features. METHODS: Patients who had available histopathology reports and a non-contrast-enhanced CT scan were included in the study. Radiomics feature extraction was done after the adrenal lesions were contoured. The primary feature selection and prediction performance scores were calculated using the least absolute shrinkage and selection operator (LASSO). To eliminate redundancy, the best-performing features were further examined using the Pearson correlation coefficient, and new predictive models were created. RESULTS: This investigation covered 50 lesions in 48 patients. After LASSO-based radiomics feature selection, the test dataset's 30 iterations of logistic regression models produced an average performance of 0.72. The model with the best performance, made up of 13 radiomics features, had an AUC of 0.99 in the training phase and 1.00 in the test phase. The number of features was lowered to 5 after performing Pearson's correlation to prevent overfitting. The final radiomic signature trained a number of machine learning classifiers, with an average AUC of 0.93. CONCLUSIONS: Including more radiomics features in the identification of adenomas may improve the accuracy of NECT and reduce the need for additional imaging procedures and clinical workup, according to this and other recent radiomics studies that have clear points of contact with current clinical practice. CLINICAL RELEVANCE STATEMENT: The study developed a radiomic signature using unenhanced CT scans for classifying lipid-poor adenomas, potentially reducing unnecessary investigations that scored a final accuracy of 93%. KEY POINTS: • Radiomics has potential for differentiating lipid-poor adenomas and avoiding unnecessary further investigations. • Quadratic mean, strength, maximum 3D diameter, volume density, and area density are promising predictors for adenomas. • Radiomics models reach high performance with average AUC of 0.95 in the training phase and 0.72 in the test phase.

Non-contrast spectral CT vs chemical-shift MRI in discriminating lipid-poor adrenal lesions.

OBJECTIVES: To compare the diagnostic performance of conventional non-contrast CT, dual-energy spectral CT, and chemical-shift MRI (CS-MRI) in discriminating lipid-poor adenomas (> 10-HU on non-contrast CT) from non-adenomas. METHODS: A total of 110 patients (69 men; 41 women; mean age 66.5 ± 13.4 years) with 80 lipid-poor adenomas and 30 non-adenomas who underwent non-contrast dual-layer spectral CT and CS-MRI were retrospectively identified. For each lesion, non-contrast attenuation on conventional 120-kVp images, ΔHU-index ([attenuation difference between virtual monoenergetic 140-keV and 40-keV images]/conventional attenuation × 100), and signal intensity index (SI-index) were quantified. Each parameter was compared between adenomas and non-adenomas using the Mann-Whitney U-test. The area under the receiver operating characteristic curve (AUC) and sensitivity to achieve > 95% specificity for adenoma diagnosis were determined. RESULTS: Conventional non-contrast attenuation was lower in adenomas than in non-adenomas (22.4 ± 8.6 HU vs 32.8 ± 48.5 HU), whereas ΔHU-index (148.0 ± 103.2 vs 19.4 ± 25.8) and SI-index (41.6 ± 19.6 vs 4.2 ± 10.2) were higher in adenomas (all, p < 0.001). ΔHU-index showed superior performance to conventional non-contrast attenuation (AUC: 0.919 [95% CI: 0.852-0.963] vs 0.791 [95% CI: 0.703-0.863]; sensitivity: 75.0% [60/80] vs 27.5% [22/80], both p < 0.001), and near equivalent to SI-index (AUC: 0.952 [95% CI: 0.894-0.984], sensitivity 85.0% [68/80], both p > 0.05). Both the ΔHU-index and SI-index provided a sensitivity of 96.0% (48/50) for hypoattenuating adenomas (≤ 25 HU). For hyperattenuating (> 25 HU) adenomas, SI-index showed higher sensitivity than ΔHU-index (66.7% [20/30] vs 40.0% [12/30], p = 0.022). CONCLUSIONS: Non-contrast spectral CT and CS-MRI outperformed conventional non-contrast CT in distinguishing lipid-poor adenomas from non-adenomas. While CS-MRI demonstrated superior sensitivity for adenomas measuring > 25 HU, non-contrast spectral CT provided high discriminative values for adenomas measuring ≤ 25 HU. CLINICAL RELEVANCE STATEMENT: Spectral attenuation analysis improves the diagnostic performance of non-contrast CT in discriminating lipid-poor adrenal adenomas, potentially serving as an alternative to CS-MRI and obviating the necessity for additional diagnostic workup in indeterminate adrenal incidentalomas, particularly for lesions measuring ≤ 25 HU. KEY POINTS: Incidental adrenal lesion detection has increased as abdominal CT use has become more frequent. Non-contrast spectral CT and CS-MRI differentiated lipid-poor adenomas from non-adenomas better than conventional non-contrast CT. For lesions measuring ≤ 25 HU, spectral CT may obviate the need for additional evaluation.

Current Management Strategies and Outcomes in Children With Adrenocortical Carcinoma

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.

Laparoscopic surgery for adrenocortical carcinoma: Estimating the risk of margin-positive resection.

BACKGROUND: Over recent years, there has been increasing adoption of minimally invasive surgery (MIS) in the treatment of adrenocortical carcinoma (ACC). However, MIS has been associated with noncurative resection and locoregional recurrence. We aimed to identify risk factors for margin-positivity among patients who undergo MIS resection for ACC. We hypothesized that a simple nomogram can accurately identify patients most suitable for curative MIS resection. METHODS: Curative-intent resections for ACC were identified through the National Cancer Database spanning 2010-2018. Trends in MIS utilization were reported using Pearson correlation coefficients. Factors associated with margin-positive resection were identified among preoperatively available variables using multivariable logistic regression, then incorporated into a predictive model. Model quality was cross validated using an 80% training data set and 20% test data set. RESULTS: Among 1260 ACC cases, 38.6% (486) underwent MIS resection. MIS utilization increased over time at nonacademic centers (R = 0.818, p = 0.007), but not at academic centers (R = 0.009, p = 0.982). Factors associated with margin-positive MIS resection were increasing age, nonacademic center (odds ratio [OR]: 1.8, p = 0.006), cT3 (OR: 4.7, p < 0.001) or cT4 tumors (OR: 14.6, p < 0.001), and right-sided tumors (OR: 2.0, p = 0.006). A predictive model incorporating these four factors produced favorable c-statistics of 0.75 in the training data set and 0.72 in the test data set. A pragmatic nomogram was created to enable bedside risk stratification. CONCLUSIONS: An increasing proportion of ACC are resected via minimally invasive operations, particularly at nonacademic centers. Patient selection based on a few key factors can minimize the risk of noncurative surgery.

Adrenal Mass Biopsy in Patients Without Extraadrenal Primary Malignancy: A Multicenter Study.

BACKGROUND. Adrenal washout CT is not useful for evaluating incidental adrenal masses in patients without known or suspected primary extraadrenal malignancy. OBJECTIVE. The purpose of our study was to evaluate the diagnostic utility of adrenal mass biopsy in patients without known or suspected extraadrenal primary malignancy. METHODS. This retrospective six-center study included 69 patients (mean age, 56 years; 32 men, 37 women) without known or suspected extraadrenal primary malignancy who underwent image-guided core needle biopsy between January 2004 and June 2021 of a mass suspected to be arising from the adrenal gland. Biopsy results were classified as diagnostic or nondiagnostic. For masses resected after biopsy, histopathologic concordance was assessed between diagnoses from biopsy and resection. Masses were classified as benign or malignant by resection or imaging follow-up, and all nondi-agnostic biopsies were classified as false results. RESULTS. The median mass size was 7.4 cm (range, 1.9-19.2 cm). Adrenal mass biopsy had a diagnostic yield of 64% (44/69; 95% CI, 51-75%). After biopsy, 25 masses were resected, and 44 had imaging follow-up. Of the masses that were resected after diagnostic biopsy, diagnosis was concordant between biopsy and resection in 100% (12/12). Of the 13 masses that were resected after nondiagnostic biopsy, the diagnosis from re-section was benign in eight masses and malignant in five masses. The 44 masses with imaging follow-up included one mass with diagnostic biopsy yielding benign adenoma and two masses with nondiagnostic biopsy results that were classified as malignant by imaging follow-up. Biopsy had overall sensitivity and specificity for malignancy of 73% (22/30) and 54% (21/39), respectively; diagnostic biopsies had sensitivity and specificity for malignancy of 96% (22/23) and 100% (21/21), respectively. Among nine nondi-agnostic biopsies reported as adrenocortical neoplasm, six were classified as malignant by the reference standard (resection showing adrenocortical carcinoma in four, resection showing adrenocortical neoplasm of uncertain malignant potential in one, imaging follow-up consistent with malignancy in one). CONCLUSION. Adrenal mass biopsy had low diagnostic yield, with low sensitivity and low specificity for malignancy. A biopsy result of adrenocortical neoplasm did not reliably differentiate benign and malignant adrenal masses. CLINICAL IMPACT. Biopsy appears to have limited utility for the evaluation of incidental adrenal masses in patients without primary extraadrenal malignancy.

Current Status and Future Direction in the Treatment of Advanced Adrenocortical Carcinoma.

PURPOSE OF REVIEW: To provide a comprehensive overview of the current understanding and developments in the treatment options for adrenocortical carcinoma (ACC), focusing on the strategies utilized for advanced disease. RECENT FINDINGS: Research has delved into the genomic landscape of ACC, revealing potential targets for therapy. Despite the failure of inhibitors aimed at the insulin like growth factor 1(IGF-1) receptor, other approaches, including vascular endothelial growth factor receptor (VEFGR) tyrosine kinase inhibitors and immune checkpoint inhibitors, are being investigated. There are also ongoing trials of combination treatments such as lenvatinib with pembrolizumab and cabozantinib with atezolizumab. ACC remains a challenging malignancy with limited effective treatment options. Although EDP-M stands as the frontline treatment, the search for effective second-line therapies is ongoing. Targeted therapies and immunotherapies, especially in combination regimens, are demonstrating potential and are the subject of continued research. The evolving genomic landscape emphasizes the significance of targeted therapies and the need for further in-depth studies to solidify effective treatment regimens for ACC.

Systemic Management of Advanced Adrenocortical Carcinoma.

OPINION STATEMENT: Adrenocortical cancer (ACC) is a rare and aggressive disease. Surgery has traditionally been the primary treatment for locally advanced disease with ongoing controversy around the optimal neoadjuvant and adjuvant treatment options. Unfortunately, local recurrence and the eventual development of metastatic disease is common and five-year survival rates are poor. While many trials have evaluated novel systemic agents to treat advanced adrenocortical cancer, only a few drugs have demonstrated any response at all. To date, only one drug, mitotane, is approved in the US for ACC and no regimen has clearly shown an increase in overall survival. In advanced metastatic or unresectable disease, data supports the first line regimen of EDP chemotherapy + mitotane as the primary treatment modality. In the second line, while data is limited, we would recommend consideration of immunotherapy using a PD(L)1 agent combined with a TKI/VEGF inhibitor or combination immunotherapy with PD1/CTLA-4 drugs. In all cases, we always prefer a clinical trial as available. This article reviews data from multiple studies evaluating novel systemic agents against ACC and discusses current systemic therapy combinations and ongoing clinical trials.

Hypopituitarism with secondary adrenocortical insufficiency and arginine vasopressin deficiency due to hypophysitis after COVID-19 vaccination: a case report.

BACKGROUND: Although vaccination against coronavirus disease (COVID-19) has several side effects, hypopituitarism due to hypophysitis has rarely been reported. CASE PRESENTATION: An 83-year-old healthy woman, who had received her fourth COVID-19 vaccine dose 2 days before admission, presented to the emergency department with difficulty moving. On examination, impaired consciousness (Glasgow Coma Scale: 14) and fever were observed. Computed tomography and magnetic resonance imaging of the head revealed swelling from the sella turcica to the suprasellar region. Her morning serum cortisol level was low (4.4 µg/dL) and adrenocorticotropic hormone level was normal (21.6 pg/mL). Central hypothyroidism was also suspected (thyroid stimulating hormone, 0.46 µIU/mL; free triiodothyronine, 1.86 pg/mL; free thyroxine, 0.48 ng/dL). Secondary adrenocortical insufficiency, growth hormone deficiency, delayed gonadotropin response, and elevated prolactin levels were also observed. After administration of prednisolone and levothyroxine, her consciousness recovered. On the 7th day of admission, the patient developed polyuria, and arginine vasopressin deficiency was diagnosed using a hypertonic saline test. On the 15th day, the posterior pituitary gland showed a loss of high signal intensity and the polyuria resolved spontaneously. On the 134th day, the corticotropin-releasing hormone loading test showed a normal response; however, the thyrotropin-releasing hormone stimulation test showed a low response. The patient's disease course was stable with continued thyroid and adrenal corticosteroid supplementation. CONCLUSIONS: Herein, we report a rare case of anterior hypopituitarism and arginine vasopressin deficiency secondary to hypophysitis following COVID-19 vaccination.

Adrenocortical suppression in children with nephrotic syndrome treated with corticosteroids.

BACKGROUND: Children with nephrotic syndrome are exposed to alternate day steroids for prolonged periods and this poses the need for evaluation of adrenocortical suppression using the adrenocorticotropic hormone (ACTH) stimulation test. METHODS: This cross-sectional study enrolled children (2-18 years) both with steroid sensitive nephrotic syndrome (SSNS) (n = 27) and steroid resistant (SRNS) (n = 25); those on daily prednisolone or having serious bacterial infections or hospitalized were excluded. The primary objective was to determine prevalence of adrenocortical suppression in those on low dose alternate day steroids for more than 8 weeks or having received > 2 mg/kg/d for > 2 weeks in the past 1 year and currently in remission. A baseline morning fasting sample of serum cortisol was taken and 25 IU of ACTH (Acton Prolongatum*) injected intramuscularly and repeat serum cortisol sample taken after 1 h. All patients with 1 h post ACTH cortisol < 18.0 µgm/dl were diagnosed with adrenal insufficiency. Receiver operating characteristic curve was drawn to predict the prednisolone dose for adrenal insufficiency. RESULTS: Fifty-two (33 males) children were enrolled (mean age 9.4 years); proportion of adrenal insufficiency was 50% and 64% using baseline and post stimulation cutoffs. The total cumulative annual dose of prednisolone 0.22 mg/kg/day predicted adrenocortical suppression with AUC 0.76 (95% CI 0.63-0.89), with sensitivity of 63.9% and specificity of 81.3%. CONCLUSIONS: A significant proportion of children with nephrotic syndrome were detected with adrenal insufficiency on ACTH stimulation test. A cumulative steroid intake of > 0.22 mg/kg/day on an alternate day basis emerged as a risk factor for predicting adrenocortical suppression.

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.

Incidence and Geographical Distribution of Adrenocortical Carcinoma: Retrospective Analysis of a State Cancer Registry.

OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare malignancy without established association with environmental risk factors. ACC incidence is stable based on large surgical databases while referral centers data reported increasing number of cases seen. We studied ACC incidence and distribution at a county level to find potential ACC "hot spots" that could be linked to environmental exposures. METHODS: A retrospective analysis of Texas Cancer Registry that included ACC patients diagnosed between 2000 and 2018. County-level heatmaps were created and compared with breast, prostate, and lung cancer. RESULTS: We identified 448 ACC cases during the study period. Cases were registered in 110 of the 254 counties (43.3%) in Texas, representing 92.74% of the total population. The median incidence was 23 new cases/y (range 14-33). The mean population-adjusted ACC incidence rate was 0.104 per 100 000 per year (standard deviation 0.005; 95% CI, 0.092-0.116). Seven counties (6.3%) accounted for 215 (48.0%) cases, with more than 10 cases each and median standardized incidence ratio (SIR) of 0.1 (range, 0.0-0.9). One hundred three counties (93.7%) accounted for the remaining 233 cases (52%), with fewer than 10 cases per county. The highest standardized incidence ratios were found in counties with a median population of fewer than 14 000 residents and with only one reported case. CONCLUSION: Our analysis is the first report to create ACC heatmap and could not detect any geographic clustering of ACC in Texas. The incidence of ACC remained stable and consistent with data from other large databases.

Outcome of brain metastases from adrenocortical carcinoma: a pooled analysis.

PURPOSE: Brain metastases rarely complicate the natural history of patients with adrenocortical carcinoma (ACC). No information is available regarding the life expectancy and efficacy of treatments in ACC patients with brain involvement. METHODS: A pooled analysis was performed by searching on PubMed and using the keywords: "brain metastases in adrenocortical carcinoma", and "leptomeningeal metastases in adrenocortical carcinoma". Four patients diagnosed at Spedali Civili Hospital in Brescia were added to the analysis. Data concerning demographic, disease characteristics, adopted treatments and patient prognosis were collected. RESULTS: A total of 27 patients (18 adults and 9 children) were included in this study, 22 of them had an adequate follow-up. Brain metastases occurred late in the natural history of adult patients but not in that of children. Surgery plus/minus radiation therapy was the treatment of choice. Adult patients with brain metastases had a poor prognosis with a median progression-free survival (PFS) and overall survival (OS) of 2 and 7 months, respectively. Median PFS and OS were not attained in children. CONCLUSION: Brain metastases in ACC patients are rare and are associated with poor prognosis, particularly in adults. Surgery plus/minus radiotherapy is the only therapeutic approach that can offer patients a chance to obtain durable local disease control.

Inflammation-based scores in a large cohort of adrenocortical carcinoma and adrenocortical adenoma: role of the hormonal secretion pattern.

BACKGROUND: Serum inflammation-based scores can predict clinical outcome in several cancer types, including adrenocortical carcinoma (ACC). It is unclear whether the extent of inflammation-based scores alterations in ACC reflects malignancy, steroid excess, or both. METHODS: We investigated a large retrospective cohort of adrenocortical adenomas (ACA, n = 429) and ACC (n = 61) with available baseline full blood count and hormonal evaluation. We examined the relationship between different inflammation-based scores [neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and prognostic nutrition index (PNI)] and both malignancy and steroid secretion patterns. RESULTS: All inflammation-based scores differed between ACC and ACA: patients with ACC had higher NLR, PLR, SII and lower LMR and PNI levels compared to ACA (all p values < 0.001). NLR showed a positive correlation with cortisol levels after overnight 1 mg-dexamethasone suppression test (1 mg-DST), both in ACC and ACA (p < 0.01). The ROC curve analysis determined NLR > 2.6 as the best cut-off to discriminate ACC from ACA [AUC = 0.846, p < 0.01]. At multivariable analysis, NLR > 2.6 was independently associated with ACC, 1 mg-DST cortisol levels and age, but not with tumour size. Considering the ACC, NLR and SII were higher and PNI was lower in patients with cortisol excess compared to those without cortisol excess (p = 0.002, p = 0.007, and p = 0.044 respectively). Finally, LMR and NLR differed between inactive-ACC (n = 10) and inactive-ACA (n = 215) (p = 0.040 and p = 0.031, respectively). CONCLUSION: Inflammation-based scores are related to steroid secretion both in ACC and ACA. ACCs present a higher grade of inflammation regardless of their hormonal secretion, likely as a feature of malignancy itself.

Predicting postoperative hypocortisolism in patients with non-aldosterone-producing adrenocortical adenoma: a retrospective single-centre study.

BACKGROUND: Limited information exists on postoperative hypocortisolism and hypothalamus-pituitary-adrenal axis recovery in patients with adrenal incidentaloma following unilateral adrenalectomy. We evaluated frequency of postoperative hypocortisolism and predictors for recovery in non-aldosterone-producing adrenocortical adenoma patients after unilateral adrenalectomy. METHODS: A retrospective analysis of 32 adrenal incidentaloma patients originally included in the ITACA trial (NCT04127552) with confirmed non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy from September 2019 to April 2023 was conducted. Preoperative assessments included adrenal MRI, anthropometrics, evaluation of comorbidities, adrenal function assessed via ACTH, urinary free cortisol, and 1 mg dexamethasone suppression test. ACTH and serum cortisol or Short Synacthen test were performed within 6 days, 6 weeks, 6 months, and a year after surgery. RESULTS: Six days postoperative, 18.8% of patients had normal adrenal function. Among those with postoperative hypocortisolism, 53.8% recovered by 6 weeks. Patients with earlier adrenal recovery (6 weeks) had lower preoperative 1 mg dexamethasone suppression test (median 1 mg dexamethasone suppression test 76.2 [61.8-111.0] nmol/L vs 260.0 [113.0-288.5] nmol/L, p < 0.001). Univariate analysis showed preoperative 1 mg dexamethasone suppression test negatively related with baseline ACTH levels (r = - 0.376; p = 0.041) and negatively associated with the 6-week baseline (r = - 0.395, p = 0.034) and 30-min cortisol levels during Short Synacthen test (r = - 0.534, p = 0.023). Logistic regression analysis demonstrated preoperative 1 mg dexamethasone suppression test as the only biochemical predictor for 6-week adrenal recovery: ROC curve identified a 1 mg dexamethasone suppression test threshold of 131 nmol/L predicting 6-week recovery with 89.5% sensitivity and 72.7% specificity (AUC 0.87; 95% CI 66.9-98.7, p < 0.001). Other preoperative assessments (tumor size, ACTH levels and anthropometrics) were not associated with postoperative hypothalamus-pituitary-adrenal axis function, but the presence of diabetes was associated with a lower probability of recovery (OR = 24.55, p = 0.036). ACTH levels increased postoperatively in all patients but did not predict hypothalamus-pituitary-adrenal axis recovery. CONCLUSIONS: The preoperative 1 mg dexamethasone suppression test cortisol value and presence of diabetes are the only relevant predictor of hypothalamus-pituitary-adrenal axis recovery in patients with non-aldosterone- producing adrenocortical adenoma undergoing surgery, regardless other clinical and biochemical variables. Notably, pre- and postoperative ACTH levels did not predict hypothalamus-pituitary-adrenal axis recovery. These findings point towards the potential for saving resources by optimizing their allocation during follow-up assessments for patients with non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy.