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Background After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy. Methods In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort ( n  = 268). For both approaches, we accounted for immortal time bias. Results Of the 31 patients in the platinum cohort (R0 n  = 25, RX n  = 4, R1 n  = 2; ENSAT Stage II n  = 11, III n  = 16, IV n  = 4, median Ki67 30%, mitotane n  = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95% CI 0.09–0.42; P  < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29–0.89, P  = 0.021) and for OS 0.25 (0.09–0.69; P  = 0.007). Conclusions Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.

In 2007, a retrospective case-control study provided evidence that adjuvant mitotane prolongs recurrence-free survival (RFS) in patients with radically resected adrenocortical carcinoma (ACC). We aimed to confirm the prognostic role of adjuvant mitotane in the same series after 9 additional years of follow-up. One hundred sixty-two ACC patients who did not recur or die after a landmark period of 3 months were considered. Forty-seven patients were enrolled in four Italian centers where adjuvant mitotane was routinely recommended (mitotane group), 45 patients in four Italian centers where no adjuvant strategy was undertaken (control group 1), and 70 German patients left untreated after surgery (control group 2). The primary aim was RFS, the secondary was overall survival. An increased risk of recurrence was found in both control cohorts [group 1: hazard ratio (HR) = 2.98; 95% confidence interval (CI), 1.75 to 5.09; P < 0.0001; group 2: HR = 2.61; 95% CI, 1.56 to 4.36; P < 0.0001] compared with the mitotane group. The risk of death was higher in control group 1 (HR = 2.03; 95% CI, 1.17 to 3.51; P = 0.011) but not in control group 2 (HR = 1.60; 95% CI, 0.94 to 2.74; P = 0.083), which had better prognostic factors and more aggressive treatment of recurrences than control group 1. The benefit of adjuvant mitotane on RFS was observed regardless of the hormone secretory status. Adjuvant mitotane is associated with prolonged RFS, without any apparent influence by the tumor secretory status. The retrospective nature of the study is a major limitation.

Abstract Background Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia type 1 (MEN1). However, adrenocortical carcinomas (ACC) and primary aldosteronism (PA) are rare in MEN1. Case A 48-year-old woman known to have primary hyperparathyroidism and hypertension with hypokalemia was referred for a right complex 8-cm adrenal mass with a 38.1 SUVmax uptake on 18F-FDG PET/CT. PA was confirmed by saline suppression test (aldosterone 1948 pmol/L-1675 pmol/L; normal range [N]: <165 post saline infusion) and suppressed renin levels (<5 ng/L; N: 5-20). Catecholamines, androgens, 24-hour urinary cortisol, and pituitary panel were normal. A right open adrenalectomy revealed a concomitant 4-cm oncocytic ACC and a 2.3-cm adrenocortical adenoma. Immunohistochemistry showed high expression of aldosterone synthase protein in the adenoma but not in the ACC, supporting excess aldosterone production by the adenoma. Genetic analysis After genetic counseling, the patient underwent genetic analysis of leucocyte and tumoral DNA. Sequencing of MEN1 revealed a heterozygous germline pathogenic variant in MEN1 (c.1556delC, p.Pro519Leufs*40). The wild-type MEN1 allele was lost in the tumoral DNA of both the resected adenoma and carcinoma. Sequencing analysis of driver genes in PA revealed a somatic pathogenic variant in exon 2 of the KCNJ5 gene (c.451G>A, p.Gly151Arg) only in the aldosteronoma. Conclusion To our knowledge, we describe the first case of adrenal collision tumors in a patient carrying a germline pathogenic variant of the MEN1 gene associated with MEN1 loss of heterozygosity in both oncocytic ACC and adenoma and a somatic KCNJ5 pathogenic variant leading to aldosterone-producing adenoma. This case gives new insights on adrenal tumorigenesis in MEN1 patients.

The benefit of adjuvant radiation therapy (RT) in adrenocortical carcinoma (ACC) is not well characterized for those who undergo initial R0 surgical resection. Patients in the NCDB who underwent R0 resection were placed into two cohorts – those who underwent adjuvant RT and those who did not. 388 patients were identified with 51 receiving RT. No difference was observed between Kaplan-Meier survival estimates of the two cohorts (p ​= ​0.54). After adjusting for age, sex, co-morbidity index, race, receipt of chemotherapy, tumor size, grade, stage, and nodal stage, RT was not associated with improved OS. However, tumor size ≥6 ​cm (HR 1.54, [1.03–2.32], p ​= ​0.04), high tumor-grade (HR 3.46, [1.83–6.55], p ​< ​0.001), and N1-stage (HR 2.30, [1.06–4.94], p ​= ​0.03) were associated with worse OS, without benefit of RT on subgroup analysis of these factors. Treatment with adjuvant RT in patients with ACC who underwent R0 resection was not associated with an OS benefit. •A cohort of R0 resected ACCs from the NCDB were analyzed.•Adjuvant radiation is not associated with improved survival after R0 resection.•Large, high grade, or node positive tumors did not benefit on subanalysis.

Abstract Context Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). Objective, Design, Setting This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. Patients and Methods 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography–mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. Results Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine “steroid fingerprint” at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). Conclusion Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

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.

BackgroundSurgical resection with negative margins is the treatment of choice for adrenocortical carcinoma (ACC). This study was undertaken to determine factors associated with negative resection margins.MethodsNational Cancer Database was queried from 2010 to 2016 to identify patients with AJCC/ENSAT Stage I–III ACC who underwent adrenalectomy. Patient, tumor, facility, and operative characteristics were compared by margin status (positive—PM or negative—NM) and operative approach (open—OA, laparoscopic—LA, or robotic—RA). Multivariable logistic regression was used to identify factors associated with PM.ResultsEight hundred and eighty-one patients were identified, of which 18.4% had PM and 81.6% had NM. Patients with advanced pathologic T stage and pathologic N1 stage were more likely to have PM (vs. NM) (T3, 49.7% vs. 24.8%, p < 0.01; T4, 26.2% vs. 10.0%, p < 0.01; N1, 6.7% vs. 3.5%, p < 0.01). Patients undergoing OA (vs. LA and RA) were more likely to have advanced clinical T stage (T4, 16.6% vs. 5.7% vs. 7.8%, p < 0.01) and larger tumors (> 6 cm, 84.6% vs. 64.1% vs. 62.3%, p < 0.01). High-volume centers (≥ 5 cases) were more likely to utilize OA. Patients undergoing LA (vs. RA) were more likely to require conversion to open (20.3% vs. 7.8%, p = 0.011). On multivariable analysis, factors associated with higher odds of PM included T3 disease (OR 7.02, 95% CI 2.66–18.55), T4 disease (OR 10.22, 95% CI 3.66–28.53), and LA (OR 1.99, 95% CI 1.28–3.09). High-volume centers were associated with lower odds of PM (OR 0.67, 95% CI 0.45–0.98). There was no significant difference in margin status between OA and RA (OR 1.44, 95% CI 0.71–2.90).ConclusionCenters with higher ACC case volumes have lower odds of PM and utilize OA more often. LA is associated with higher odds of PM, whereas RA is not. These factors should be considered when planning the operative approach for ACC.

This study examines the combined impact of margin status and adjuvant therapy utilization on overall survival (OS) for adrenocortical carcinoma (ACC) patients undergoing surgery with curative intent. The 2004–2020 National Cancer Database (NCDB) was queried for ACC patients ≥18yrs undergoing curative surgery (no debulking), subdivided into R0 and R1/R2-groups, and analyzed using inverse-probability-weighted Cox Proportional Hazard-model. Of 5023 ACC patients, 3193 underwent curative surgery, 2213 (69 ​%) had R0 margins. Compared to the R0, the R1/R2 group had a decreased OS by 15.6 months (HR ​= ​1.89, p ​= ​0.002). While there has been no significant improvement in margin status over the years studied (2008–2017), there has been an overall increase in the proportion of patients receiving adjuvant therapy regardless of margin status, and the adverse impact of a positive margin on survival has decreased [HR 2.20 vs 1.76] R1/R2 margins are associated with decreased OS. The adverse impact of R1/R2 margins on OS decreased over time while adjuvant therapy utilization increased for all patients. •One-third of adrenal cancer patients have positive margins after adrenal surgery.•Adrenal cancer patients with positive margins have decreased survival by 15.6 months after surgery.•Adjuvant therapy utilization has increased regardless of margin status after adrenal surgery.•Adverse impact of positive margins on survival after adrenalectomy for cancer has decreased over time.

Background Adrenocortical carcinoma (ACC), a rare and aggressive malignancy, accounts for up to14% of adrenal incidentalomas. The only chance of cure for ACC is diagnosis at an early stage; therefore, a main indication for adrenalectomy in patients with adrenal incidentaloma has been the potential risk of ACC. Recent studies suggest that this has led to earlier stage of ACC at diagnosis, more curative operations, and better survival. Methods We analyzed data on ACC from The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Four equal time quartiles (1973–1979, 1980–1986, 1987–1993, and 1994–2000) were compared for changes in demographics, pathology, treatment, and cause‐specific mortality. Results The average age was 51.2 years (range: 1–97), and 45.9% of patients were men. The average tumor size was 12 cm (range: 2–36 cm), and only 4.2% were ≤ 6 cm. Most (88%) patients had surgical resection of their tumor, and external beam radiotherapy was used in only 12% of patients. Between the time quartiles compared (as well as annually), there was no significant difference at presentation in age at diagnosis, sex, race/ethnicity, tumor size, tumor grade, the frequency of distant metastasis, and overall TNM stage. Low tumor grade, lower stage of ACC, later time quartile, and surgical resection were associated with a lower cause‐specific mortality by univariate analysis (P ≤ 0.002) and by multivariate analysis (P ≤ 0.031). Conclusions Although adrenal incidentalomas have become a common indication for adrenalectomy, this has not resulted in patients with ACC being diagnosed earlier or treated at a lower stage of disease at the national level. The most important predictors of survival in these patients are tumor grade, tumor stage, and surgical resection.

This retrospective analysis assessed the efficacy of adjuvant mitotane treatment in prolonging recurrence-free survival in adrenocortical cancer, which carries a high risk of recurrence. Survival was significantly prolonged in patients receiving mitotane, as compared with those who did not. Adjuvant mitotane may prolong recurrence-free survival in patients with radically resected adrenocortical carcinoma. This retrospective analysis assessed the efficacy of adjuvant mitotane treatment in prolonging recurrence-free survival in adrenocortical cancer. Survival was significantly prolonged in patients receiving mitotane, as compared with those who did not. Adrenocortical carcinoma is a rare neoplasm characterized by a dismal prognosis, with only 16 to 38% of patients surviving for more than 5 years after diagnosis. 1 – 3 Although a majority of patients have resectable disease at presentation, 4 – 6 as many as 75 to 85% have a relapse after radical resection. 7 , 8 This high recurrence rate has prompted investigators to consider the use of adjuvant therapy, 1 – 3 , 9 and mitotane (a synthetic derivative of the insecticide dichlorodiphenyltrichloroethane [DDT]) has been widely used for this purpose. 10 – 21 However, available studies do not provide data as to whether adjuvant mitotane is efficacious, mainly . . .