Long-term mortality and cardiovascular events in patients with unilateral primary aldosteronism after targeted treatments.

OBJECTIVE: Long-term outcomes (especially mortality and/or major cardiovascular events (MACE)) of the unilateral primary aldosteronism (uPA) patients who underwent medical or surgery-targeted treatment, relative to those with essential hypertension (EH), have been scarcely reported. DESIGN AND SETTINGS: Using the prospectively designed observational Taiwan Primary Aldosteronism Investigation cohort, we identified 858 uPA cases among 1220 primary aldosteronism patients and another 1210 EH controls. EXPOSURES: Operated uPA patients were grouped via their 1-year post-therapy statuses. RESULTS: Primary Aldosteronism Surgical Outcome clinical complete success (hypertension remission) was achieved in 272 (49.9%) of 545 surgically treated uPA patients. After follow-up for 6.3 ± 4.0 years, both hypertension-remissive (hazard ratio (HR): 0.54; P < 0.001) and not-cured (HR: 0.61; P < 0.001) uPA patients showed a lower risk of all-cause mortality than that of EH controls; whereas the not-cured group had a higher risk of incident MACE (sub-hazard ratio (sHR), 1.41; P = 0.037) but similar atrial fibrillation (Af) and congestive heart failure (CHF). Mineralocorticoid receptor antagonist (MRA)-treated uPA patients had higher risks of MACE (sHR: 1.38; P = 0.033), Af (sHR:1.62, P = 0.049), and CHF (sHR: 1.44; P = 0.048) than those of EH controls, with mortality as a competing risk. Using inverse probability of treatment-weighted matching and counting adrenalectomy as a time-varying factor, treatment with adrenalectomy was associated with lower risks of all-cause mortality (HR: 0.57; P = 0.035), MACE (HR: 0.67; P = 0.037), and CHF (HR: 0.49; P = 0.005) compared to those of MRA therapy. CONCLUSIONS: Adrenalectomy, independent of post-surgical hypertension remission, was associated with lower all-cause mortality of uPA patients, compared to that of EH patients. We further documented a more beneficial effect of adrenalectomy over MRA treatment on long-term mortality, MACE, and CHF in uPA patients.

Adrenal biopsy, as a diagnostic method, is associated with decreased overall survival in patients with T1/T2 adrenocortical carcinoma: A propensity score-matched analysis.

INTRODUCTION: The standard diagnosis for adrenocortical carcinoma (ACC) is clinical diagnosis (CD) based on radiographic and biochemical studies. Biopsy diagnosis (BD) is seldom required for the suspicion of secondary malignancy. We aim to study the impact of BD in the context of underlying T1/T2 ACC on overall survival (OS) compared with CD. METHODS: National Cancer Database (NCDB) for endocrine malignancies was utilized. Only patients with non-metastatic ACC, whose method of diagnosis and local disease extension were reported, and received a surgical adrenalectomy with curative intent were included. Patients were divided by disease stage into T1/T2, T3, and T4 groups. A propensity score match was applied to those with T1/T2 disease who received CD versus BD and the Kaplan-Meier method was used to compare OS. RESULTS: In total, 4000 patients with ACC were reported in the database, 1410 met selection criteria. Eight hundred and thirty patients had T1/T2, 365 had T3, and 162 had T4 ACC. Of patients with T1/T2 ACC, 742 (89.4%) received CD versus 88 (11.6%) with BD. A propensity score was calculated per a multivariable regression model with 79 patients matched from each group. Exact matching was applied for margin status and adjuvant therapies. Kaplan-Meier analysis showed a significant difference in median OS between CD versus BD patients in the matched data set (103.89 ± 15.65 vs. 54.93 ± 8.22 months; p = 0.001). In all comers, patients with T1/T2 ACC and BD had comparable median OS to that of patients with T3 ACC (52.21 ± 9.69 vs. 36.01 ± 3.33 months; p = 0.446). CONCLUSION: BD in T1/T2 ACC could be associated with disease upstaging and worse OS outcomes.

Contemporary Experience of Posterior Retroperitoneoscopic Adrenalectomy in the US.

BACKGROUND: As the incidence of adrenalectomy increases steadily, so does the use of minimally invasive approaches like posterior retroperitoneoscopic adrenalectomy (PRA). To date, the largest studies of PRA have been from abroad, and we sought to provide a contemporary US update on the outcomes after PRA. METHODS: A retrospective chart review was conducted on all PRAs performed at a single tertiary care institution between 2013 and 2020. Patient demographic characteristics, indication for operation, operative details, and postoperative course were abstracted. Outcomes of interest included 30-day mortality, conversion to open or transabdominal approach, postoperative complication, and 30-day readmission. RESULTS: A total of 249 PRAs were performed between 2013 and 2020. The population was 54.2% women and mean (SD) age was 54.1 (14.1) years. Most lesions (60.6%) were left-sided, and the most common diagnosis was nonfunctioning adenoma (39.4%), followed by pheochromocytoma (21.3%) and aldosteronoma (16.6%). Mean (SD) tumor size was 3.2 cm (range 0.5 to 9.4 cm). Median operative length was 110 minutes (range 30 to 319 minutes). Overall, the complication rate was 6.4%. Nine patients (3.6%) had a minor postoperative complication (Clavien-Dindo I to III) and 5 patients (2.0%) had a major postoperative complication (Clavien-Dindo IV to V), including 1 mortality (0.4%). There were 2 conversions of approach (0.8%). The majority of patients (58.2%) were discharged on postoperative day 1, and 92.0% were discharged by postoperative day 3. The 30-day readmission rate was 1.6%. CONCLUSIONS: Current practice demonstrates that PRA is an extremely safe approach, with a complication rate < 7% and mortality rate < 1%. In addition, the vast majority of patients are able to return home in an expedient manner.

Reassessing the impact of tumor size on operative approach in adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is often a contraindication to minimally invasive adrenalectomy (MIA). We used an administrative data set to analyze postoperative outcomes. We hypothesized that small tumors would have better short- and long-term outcomes, independent of the operative approach. METHODS: The National Cancer Database (2010-2016) identified patients with ACC who underwent adrenalectomy. Tumors were grouped: <5 cm (n = 125), 5-10 cm (n = 431), and >10 cm (n = 443). The primary and secondary outcomes were margin positivity and overall survival, respectively. RESULTS: Nine hundred and ninety-nine patients were analyzed: 37% MIA and 63% open adrenalectomy (OA). As the size increased, the rate of attempted MIA decreased. Larger tumors were associated with conversion to open. Although tumors with local invasion and those which required conversion to open were associated with an increased likelihood of a positive margin, tumor size was not. Although "complete" MIA (vs. OA) and tumor size were not associated with differences in survival, conversion (HR = 1.83, p = .02), positive margins (HR = 1.54, p = .01), and local invasion (HR = 1.84, p < .001) were associated with poor survival. CONCLUSION: Positive margins are associated with poor survival in ACC. Tumors ≥ 5 cm were associated with an increased conversion rate and subsequent increase in margin positivity. MIA may be considered for select patients with small tumors but adequate oncologic resection is critical.

Treatment outcomes of percutaneous radiofrequency ablation versus adrenalectomy for adrenal metastases: a retrospective comparative study.

PURPOSE: To retrospectively evaluate the clinical outcomes of percutaneous ultrasound (US)-guided radiofrequency ablation (RFA) in treatment of adrenal metastasis (AM), and to compare with adrenalectomy (Adx). METHODS: From June 2008 to August 2018, a total of 60 patients with AM treated at our hospital were retrospectively reviewed, of whom 29 treated by RFA (RFA group) and 31 by Adx (Adx group). The technical success, local tumor progression (LTP) and overall survival (OS) after the treatment were evaluated and compared. RESULTS: In RFA group, the first technical success was 72.4% and the second technical success was 86.2%. In Adx group, all the AMs were successfully resected. After 24.5 ± 19.1 months follow-up period, a total of 8 patients (6 in RFA group and 2 in Adx group) were detected LTP. The 1-, 2- and 3- LTP rates after treatment were 17.1%, 30.9% and 44.7% in RFA group, and 6.5%, 6.5% and 6.5% in Adx group, respectively (P = 0.028). However, for AM ≤ 5 cm, the LTP between the two groups were comparable (P = 0.068). The 1-, 2- and 3- OS rates after treatment for AM were 85.0%, 42.4% and 27.8% in RFA group, and 93.0%, 66.1% and 52.3% in Adx group, respectively (P = 0.057). RFA offered shorter treatment time (23.6 ± 16.9 vs. 155.6 ± 58.8 min, P < 0.001), shorter hospital stay (7.8 ± 3.9 vs. 15.0 ± 4.9 days, P < 0.001), and lower hospital cost ($3405.7 ± 1067.8 vs. $5248.0 ± 2261.3, P = 0.003) than Adx. CONCLUSION: In comparison with Adx, percutaneous US-guided RFA, as an alternative treatment, is feasible and effective in controlling AM, especially in AM ≤ 5 cm in diameter.

Influence of Different Treatment Strategies on New-Onset Atrial Fibrillation Among Patients With Primary Aldosteronism: A Nationwide Longitudinal Cohort-Based Study.

Background Primary aldosteronism (PA) is associated with higher atrial fibrillation prevalence and other cardiovascular complications. However, the effect of target treatment to prevent new-onset atrial fibrillation (NOAF) remains unclear. This study investigated incidence of NOAF under different treatment strategies in patients with PA. Methods and Results We analyzed longitudinal data for patients with PA without atrial fibrillation history from 1997 to 2009 within the National Health Insurance Research Database in Taiwan. Patients with essential hypertension matched by propensity score were enrolled as controls. The primary outcome measurement was NOAF, and secondary outcome measurements were mortality, major cardiac and cardiac/cerebrovascular events, and a combined end point of NOAF and mortality. We identified 2202 patients with PA (534 adrenalectomy, 1668 mineralocorticoid receptor antagonist [MRA] therapy) and 8808 essential hypertension controls with mean follow-up of 4.4 years. In primary outcome measurement, patients with PA who underwent adrenalectomy had a lower incidence of NOAF (adjusted hazard ratio; 0.28, P=0.011) than controls. In contrast, the patients with PA who received MRA therapy had comparable risk of NOAF (adjusted hazard ratio, 1.20; P=0.224). In secondary outcome measurement, patients with PA who underwent adrenalectomy had a lower rate of mortality and combined end point of NOAF and mortality than controls. Patients with PA who received MRA therapy had a higher risk of mortality, major cardiac and cardiac/cerebrovascular events, and combined NOAF with mortality than the essential hypertension controls. Conclusions Compared with patients with essential hypertension, patients with PA who underwent adrenalectomy had a lower incidence of NOAF. However, this finding was not observed in patients with PA who received MRA therapy with a lower dose. Differences between the 2 strategies may reduce with a higher dose of MRA therapy.

Extension of Survival in Bilaterally Adrenalectomized Mice by Implantation of SF-1/Ad4BP-Induced Steroidogenic Cells.

Mesenchymal stroma/stem cells (MSCs) exist in adult tissues, such as adipose tissue and bone marrow, and differentiate into cells of multiple lineages. In previous studies, we found that MSCs differentiate into steroidogenic cells by forced expression of steroidogenic factor 1 (SF-1)/adrenal 4 binding protein (Ad4BP), the master regulator of steroidogenesis and differentiation of pituitary gonadotrophs, adrenal glands, and gonads. In this study, SF-1/Ad4BP-induced steroidogenic cells derived from mouse adipose tissue-derived MSCs (ADSCs) were implanted under the kidney capsule of bilateral adrenalectomized (bAdx) mice. bAdx mice did not survive after 7 days. However, 4 of 9 bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells, 1 of 10 bAdx mice transplanted with control ADSCs, and bAdx mice transplanted with an adrenal gland survived for 30 days. Plasma corticosterone levels in bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells and control ADSCs were 5.41 ±â€…2.26 ng/mL (mean ±â€…SEM) and undetectable at 7 days after implantation, respectively. After removal of the kidney bearing the graft from the surviving mice at 30 days after implantation, plasma corticosterone was not detected in any of the samples. Immunohistochemical staining revealed SF-1/Ad4BP-positive cells under the capsule of the kidney. Although we performed an adrenocorticotropin (ACTH) loading test on bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells, ACTH responsiveness was not observed. Implantation of steroidogenic cells derived from ADSCs into bAdx mice increased the basal plasma corticosterone level and extended the survival of bAdx mice, suggesting the capability of restoring steroidogenic cells by cell transplantation therapy for adrenal insufficiency.

Meta-analysis of α-blockade versus no blockade before adrenalectomy for phaeochromocytoma.

BACKGROUND: Preoperative α-blockade in phaeochromocytoma surgery is recommended by all guidelines to prevent intraoperative cardiocirculatory events. The aim of this meta-analysis was to assess the benefit of such preoperative treatment compared with no treatment before adrenalectomy for phaeochromocytoma. METHODS: A systematic literature search was undertaken in MEDLINE, Web of Science and CENTRAL without language restrictions. Randomized and non-randomized comparative studies investigating preoperative α-blockade in phaeochromocytoma surgery were included. Data on perioperative safety, effectiveness and outcomes were extracted. Pooled results were calculated as an odds ratio or mean difference with 95 per cent confidence interval. RESULTS: A total of four retrospective comparative studies were included investigating 603 patients undergoing phaeochromocytoma surgery. Mortality, cardiovascular complications, mean maximal intraoperative systolic and diastolic BP, and mean maximal intraoperative heart rate did not differ between patients with or without α-blockade. The certainty of the evidence was very low owing to the inferior quality of studies. CONCLUSION: This meta-analysis has shown a lack of evidence for preoperative α-blockade in surgery for phaeochromocytoma. RCTs are needed to evaluate whether preoperative α-blockade can be abandoned.

ANTECEDENTES: Todas las guías recomiendan el bloqueo alfa preoperatorio en la cirugía del feocromocitoma para prevenir eventos cardiocirculatorios intraoperatorios. El objetivo de este metaanálisis fue evaluar el beneficio de dicho tratamiento preoperatorio antes de la adrenalectomía por feocromocitoma en comparación con ningún tratamiento. MÉTODOS: Se realizó una búsqueda sistemática de la literatura en MEDLINE, Web of Science y CENTRAL sin restricciones de idioma. Se incluyeron estudios comparativos aleatorizados y no aleatorizados que investigaron el bloqueo alfa preoperatorio en la cirugía del feocromocitoma. Se extrajeron los datos en relación a la seguridad perioperatoria, la efectividad y los resultados. Los resultados agrupados se mostraron como razón de oportunidades (odds ratio, OR) o diferencia de medias (MD) con el correspondiente i.c. del 95%. RESULTADOS: Se incluyeron un total de cuatro estudios comparativos retrospectivos que analizaron a 603 pacientes sometidos a cirugía del feocromocitoma. La mortalidad, las complicaciones cardiovasculares, la media del valor máximo de la presión arterial sistólica y diastólica intraoperatoria y la media del valor máximo de la frecuencia cardíaca intraoperatoria no difirieron entre pacientes con o sin bloqueo. La certeza de la evidencia fue muy baja debido a la baja calidad de los estudios. CONCLUSIÓN: Este metaanálisis demuestra la falta de evidencia del bloqueo alfa preoperatorio en la cirugía del feocromocitoma. Se necesitan ensayos controlados aleatorizados para evaluar si se puede abandonar el bloqueo alfa preoperatorio.

International multicentre review of perioperative management and outcome for catecholamine-producing tumours.

BACKGROUND: Surgery for catecholamine-producing tumours can be complicated by intraoperative and postoperative haemodynamic instability. Several perioperative management strategies have emerged but none has been evaluated in randomized trials. To assess this issue, contemporary perioperative management and outcome data from 21 centres were collected. METHODS: Twenty-one centres contributed outcome data from patients who had surgery for phaeochromocytoma and paraganglioma between 2000 and 2017. The data included the number of patients with and without α-receptor blockade, surgical and anaesthetic techniques, complications and perioperative mortality. RESULTS: Across all centres, data were reported on 1860 patients with phaeochromocytoma or paraganglioma, of whom 343 underwent surgery without α-receptor blockade. The majority of operations (78·9 per cent) were performed using minimally invasive techniques, including 16·1 per cent adrenal cortex-sparing procedures. The cardiovascular complication rate was 5·0 per cent overall: 5·9 per cent (90 of 1517) in patients with preoperative α-receptor blockade and 0·9 per cent (3 of 343) among patients without α-receptor blockade. The mortality rate was 0·5 per cent overall (9 of 1860): 0·5 per cent (8 of 517) in pretreated and 0·3 per cent (1 of 343) in non-pretreated patients. CONCLUSION: There is substantial variability in the perioperative management of catecholamine-producing tumours, yet the overall complication rate is low. Further studies are needed to better define the optimal management approach, and reappraisal of international perioperative guidelines appears desirable.

ANTECEDENTES: La cirugía de los tumores productores de catecolaminas puede complicarse por la inestabilidad hemodinámica intraoperatoria y postoperatoria. Se han propuesto distintas estrategias de manejo perioperatorio, pero ninguna ha sido evaluada en ensayos aleatorizados. Para evaluar este tema, se han recogido los datos de los resultados y del manejo perioperatorio contemporáneo de 21 centros. MÉTODOS: Veintiún centros aportaron datos de los resultados de los pacientes operados por feocromocitoma y paraganglioma entre 2000-2017. Los datos incluyeron el número de pacientes con y sin bloqueo del receptor α, las técnicas quirúrgicas y anestésicas, las complicaciones y la mortalidad perioperatoria. RESULTADOS: Los centros en su conjunto aportaron datos de 1.860 pacientes con feocromocitoma y paraganglioma, de los cuales 343 pacientes fueron intervenidos sin bloqueo del receptor α. La gran mayoría (79%) de las cirugías se realizaron utilizando técnicas mínimamente invasivas, incluido un 17% de procedimientos con preservación de la corteza suprarrenal. La tasa de complicaciones cardiovasculares fue de 5,0% en total; 5,9% (90/1517) en pacientes con bloqueo preoperatorio de los receptores α y 0,9% (3/343) en pacientes no pretratados. La mortalidad global fue del 0,5% (9/1860); 0,5% (8/1517) en pacientes pretratados y 0,3% (1/343) en pacientes no tratados previamente. CONCLUSIÓN: Existe una variabilidad sustancial en el manejo perioperatorio de los tumores productores de catecolaminas, aunque la tasa global de complicaciones es baja. Este estudio brinda la oportunidad para efectuar comparaciones sistemáticas entre estrategias de prácticas terapéuticas variables. Se necesitan más estudios para definir mejor el enfoque de manejo óptimo y parece conveniente volver a evaluar las guías internacionales perioperatorias.

Adrenalectomy: should urologists not be doing more?

PURPOSE: Adrenalectomy is an operation performed by both urologists and general surgeons; however, the majority are performed by general surgeons. We investigated whether there was a difference in outcomes based on surgical specialty performing the procedure. If no differences exist, an argument can be made that urologists should be doing more adrenalectomies. METHODS: The National Surgical Quality Improvement Project (NSQIP) Participant Use File (PUF) was queried to extract all cases of adrenalectomies performed from 2011 to 2015. Current Procedural Technology (CPT) codes 60540 and 60650 were used. The data were stratified by surgical specialty performing the adrenalectomy (urology or general surgery). Our outcomes of interest included post-surgical complications, reoperations, 30-day readmission, mortality, and hospital length of stay. RESULTS: A total of 3358 patients who underwent adrenalectomy between 2011 and 2015 were included. General surgeons performed 90% of these (n = 3012) and urologists performed 10% (n = 334). Differences in number of post-surgical complications, length of stay, rate of reoperation, 30-day readmission, and mortality were not statistically significant between general surgeons and urologists (p = 0.76, p = 0.29, p = 0.37, p = 0.98, and p = 0.59, respectively). Small complication rates disallowed multivariable analyses, but unadjusted rates for reoperation, presence of any post-operative complication, readmission within 30 days, and mortality were similar between specialties. CONCLUSIONS: Surgical specialty did not make a difference in outcomes for patients undergoing adrenalectomy, despite a large disparity in the number of procedures performed by general surgeons versus urologists. Urologists should continue performing adrenalectomies and, given their familiarity with the retroperitoneum, perhaps perform more than is the current trend.

Adrenalectomy Risk Score: An Original Preoperative Surgical Scoring System to Reduce Mortality and Morbidity After Adrenalectomy.

OBJECTIVE: To explore the determinants of postoperative outcomes of adrenal surgery in order to build a proposition for healthcare improvement. SUMMARY OF BACKGROUND DATA: Adrenalectomy is the recommended treatment for many benign and malignant adrenal diseases. Postoperative outcomes vary widely in the literature and their determinants remain ill-defined. METHODS: We based this retrospective cohort study on the "Programme de médicalisation des systèmes d'information" (PMSI), a national database that compiles discharge abstracts for every admission to French acute health care facilities. Diagnoses identified during the admission were coded according to the French adaptation of the 10th edition of the International Classification of Diseases (ICD-10). PMSI abstracts for all patients discharged between January 2012 and December 2017 were extracted. We built an Adrenalectomy-risk score (ARS) from logistic regression and calculated operative volume and ARS thresholds defining high-volume centers and high-risk patients with the CHAID method. RESULTS: During the 6-year period of the study, 9820 patients (age: 55 ±â€Š14; F/M = 1.1) were operated upon for adrenal disease. The global 90-day mortality rate was 1.5% (n = 147). In multivariate analysis, postoperative mortality was independently associated with age ≥75 years [odds ratio (OR): 5.3; P < 0.001], malignancy (OR: 2.5; P < 0.001), Charlson score ≥2 (OR: 3.6; P < 0.001), open procedure (OR: 3.2; P < 0.001), reoperation (OR: 4.5; P < 0.001), and low hospital caseload (OR: 1.8; P = 0.010). We determined that a caseload of 32 patients/year was the best threshold to define high-volume centers and 20 ARS points the best threshold to define high-risk patients. CONCLUSION: High-risk patients should be referred to high-volume centers for adrenal surgery.

Comparison of Pheochromocytoma-Specific Morbidity and Mortality Among Adults With Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy.

Importance: Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. Objective: To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. Design, Setting, and Participants: This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. Exposures: Total or cortical-sparing adrenalectomy. Main Outcomes and Measures: Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. Results: Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. Conclusions and Relevance: Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.

National Treatment Practice for Adrenocortical Carcinoma: Have They Changed and Have We Made Any Progress?

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. Two landmark trials published in 2007 and 2012 showed efficacy for adjuvant mitotane in resectable ACC and etoposide/doxorubicin/cisplatin plus mitotane for unresectable ACC, respectively. In this study, we used the National Cancer Database to examine whether treatment patterns and outcomes changed after these trials. METHODS: The National Cancer Database was used to examine treatment patterns and survival in patients diagnosed with ACC from 2006 to 2015. Treatment modalities were compared within that group and with a historical cohort (1985 to 2005). χ2 tests were performed, and Cox proportional hazards models were created. RESULTS: From 2006 to 2015, 2752 patients were included; 38% of patients (1042) underwent surgery alone, and 31% (859) underwent surgery with adjuvant therapy. Overall 5-year survival rates for all stages after resection were 43% (median, 41 months) in the contemporary cohort and 39% (median, 32 months) in the historical cohort. After 2007, patients who underwent surgery were more likely to receive adjuvant chemotherapy (P = 0.005), and 5-year survival with adjuvant chemotherapy improved (41% vs 25%; P = 0.02). However, survival did not improve in patients with unresectable tumors after 2011 compared with 2006 to 2011 (P = 0.79). Older age, tumor size ≥10 cm, distant metastases, and positive margins were associated with lower survival after resection (hazard ratio range: 1.39 to 3.09; P < 0.03). CONCLUSIONS: Since 2007, adjuvant therapy has been used more frequently in patients with resected ACC, and survival for these patients has improved but remains low. More effective systemic therapies for patients with ACC, especially those in advanced stages, are desperately needed.

Body mass index and outcomes of patients with laparoscopic adrenalectomy: a systematic review and meta-analysis protocol.

INTRODUCTION: Recent advances in the field of medical imaging and minimal invasive surgery have improved the diagnosis and treatment of adrenal incidentalomas. Recent studies suggest increased morbidity and mortality among patients with obesity following laparoscopic adrenalectomy compared with patients without obesity. However, this claim remains to be ascertained. This review seeks to assess the outcome of patients with and without obesity after adrenalectomy. METHODS AND DESIGN: We will include cohort studies, case-control studies, cross-sectional studies and case series with more than 30 participants. EMBASE, Medline and Web of Science (Web of Science Core Collection, Current Contents Connect, KCI-Korean Journal Database, SciELO Citation Index, Russian Science Citation Index) will be searched for relevant abstracts of studies published between 1 January 2000 and 31 May 2019, without language restriction. The review will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. After screening of abstracts, study selection, data extraction and methodological quality assessment, we shall assess the studies individually for clinical and statistical heterogeneity. Random-effect meta-analysis will be used to pool studies judged to be clinically homogenous. The Harbord's test and visual inspection of funnel plots will be used to assess publication bias. Results will be presented by country and region. ETHICS AND DISSEMINATION: Since primary data are not collected in this study, ethical approval is not required. This review is expected to provide relevant data on the impact of body mass index on the outcome of laparoscopic adrenalectomy. The final report will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42018117070. REVIEW STATUS: Preliminary searches.

Transperitoneal versus retroperitoneal laparoscopic adrenalectomy for adrenal tumours in adults.

BACKGROUND: Laparoscopic adrenalectomy is an accepted treatment worldwide for adrenal gland disease in adults. The transperitoneal approach is more common. The retroperitoneal approach may be preferred, to avoid entering the peritoneum, but no clear advantage has been demonstrated so far. OBJECTIVES: To assess the effects of laparoscopic transperitoneal adrenalectomy (LTPA) versus laparoscopic retroperitoneal adrenalectomy (LRPA) for adrenal tumours in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal, and ClinicalTrials.gov to 3 April 2018. We applied no language restrictions. SELECTION CRITERIA: Two review authors independently scanned the abstract, title, or both sections of every record retrieved to identify randomised controlled trials (RCTs) on laparoscopic adrenalectomy for preoperatively assessed adrenal tumours. Participants were affected by corticoid and medullary, benign and malignant, functional and silent tumours or masses of the adrenal gland, which were assessed by both laboratory and imaging studies. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed trials for risk of bias, and evaluated overall study quality using GRADE criteria. We calculated the risk ratio (RR) for dichotomous outcomes, or the mean difference (MD) for continuous variables, and corresponding 95% confidence interval (CI). We primarily used a random-effects model for pooling data. MAIN RESULTS: We examined 1069 publications, scrutinized 42 full-text publications or records, and included five RCTs. Altogether, 244 participants entered the five trials; 127 participants were randomised to retroperitoneal adrenalectomy and 117 participants to transperitoneal adrenalectomy. Two trials had a follow-up of nine months, and three trials a follow-up of 31 to 70 months. Most participants were women, and the average age was around 40 years. Three trials reported all-cause mortality; in two trials, there were no deaths, and in one trial with six years of follow-up, four participants died in the LRPA group and one participant in the LTPA group (164 participants; low-certainty evidence). The trials did not report all-cause morbidity. Therefore, we analysed early and late morbidity, and included specific adverse events under these outcome measures. The results were inconclusive between LRPA and LTPA for early morbidity (usually reported within 30 to 60 days after surgery; RR 0.56, 95% CI 0.27 to 1.16; P = 0.12; 5 trials, 244 participants; very low-certainty evidence). Nine out of 127 participants (7.1%) in the LRPA group, compared with 16 out of 117 participants (13.7%) in the LTPA group experienced an adverse event. Participants in the LRPA group may have a lower risk of developing late morbidity (reported as latest available follow-up; RR 0.12, 95% CI 0.01 to 0.92; P = 0.04; 3 trials, 146 participants; very low-quality evidence). None of the 78 participants in the LRPA group, compared with 7 of the 68 participants (10.3%) in the LTPA group experienced an adverse event.None of the trials reported health-related quality of life. The results were inconclusive for socioeconomic effects, assessed as time to return to normal activities and length of hospital stay, between the intervention and comparator groups (very low-certainty evidence). Participants who had LRPA may have had an earlier start on oral fluid or food intake (MD -8.6 hr, 95% CI -13.5 to -3.7; P = 0.0006; 2 trials, 89 participants), and ambulation (MD -5.4 hr, 95% CI -6.8 to -4.0 hr; P < 0.0001; 2 trials, 89 participants) than those in the LTPA groups. Postoperative and operative parameters (duration of surgery, operative blood loss, conversion to open surgery) showed inconclusive results between the intervention and comparator groups. AUTHORS' CONCLUSIONS: The body of evidence on laparoscopic retroperitoneal adrenalectomy compared with laparoscopic transperitoneal adrenalectomy is limited. Late morbidity might be reduced following laparoscopic retroperitoneal adrenalectomy, but we are uncertain about this effect because of very low-quality evidence. The effects on other key outcomes, such as all-cause mortality, early morbidity, socioeconomic effects, and operative and postoperative parameters are uncertain. LRPA might show a shorter time to oral fluid or food intake and time to ambulation, but we are uncertain whether this finding can be replicated. New long-term RCTs investigating additional data, such as health-related quality of life, surgeons' level of experience, treatment volume of surgical centres, and details on techniques used are needed.

Role of Additional Organ Resection in Adrenocortical Carcinoma: Analysis of 167 Patients from the U.S. Adrenocortical Carcinoma Database.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive cancer. This report describes factors and outcomes associated with resection of extra-adrenal organs en bloc during index adrenalectomy. METHODS: Patients who underwent ACC resection for non-metastatic disease from 1993 to 2014 at 13 participating institutions of the US-ACC Group were included in the study. Factors associated with en bloc resection were assessed by uni- and multivariate analysis. The primary end point was overall survival. RESULTS: In this study, 167 patients were included and categorized as adrenalectomy with en bloc resection (AdEBR) if they had extra-adrenal organs removed or adrenalectomy (Ad) if they did not. The demographics were similar between the AdEBR (n = 68, 40.7%) and Ad groups, including age, gender, race, American Society of Anesthesiology (ASA) class, and body mass index (BMI). The AdEBR group had larger tumors (13 vs. 10 cm), more open operations (97.1 vs. 63.6%), and more lymph node dissections (LNDs) (36.8 vs. 12.1%). The most common organs removed were kidney (55.9%), liver (27.9%), and spleen (23.5%). Multiple organs were removed in 38.2% (n = 26) of the patients. Margin-negative resections were similar between the two groups. In the multivariate Cox regression adjusted for T and N stages, LND, margin, size, and hormone hypersecretion, en bloc resection was not associated with improved survival (hazard ratio [HR], 1.42; p = 0.323). CONCLUSION: The study findings validated current practice by showing that en bloc resection should occur at index adrenalectomy for ACC when a T4 lesion is suspected pre- or intraoperatively, or when it is necessary to avoid tumor rupture. However, in this study, when a negative margin resection was otherwise achieved, removal of extra-adrenal organs en bloc was not associated with additional survival benefit.

Bilateral Adrenalectomy in Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis.

CONTEXT: Management of congenital adrenal hyperplasia (CAH) involves suppression of the hypothalamic-pituitary-adrenal axis using supraphysiological doses of exogenous glucocorticoids. This can pose a challenge, with Cushing syndrome a frequent complication of adequate suppression. Bilateral adrenalectomy, with subsequent replacement of glucocorticoids and mineralocorticoids at physiological doses, has been proposed as an alternative therapeutic strategy. OBJECTIVE: To review the outcomes after bilateral adrenalectomy for CAH. DATA SOURCES: A systematic search of PubMed/MEDLINE and Web of Science, identifying relevant reports published up to 10 January 2018. STUDY SELECTION: Case reports or case series were included if they reported individual patient data from patients with CAH who had undergone bilateral adrenalectomy. DATA EXTRACTION: Information regarding the following was extracted: first author, country, sex, age at adrenalectomy, year of adrenalectomy, diagnosis, molecular abnormality, pre- and postoperative biochemistry, pre- and postoperative medications, pre- and postoperative body mass index, indication for adrenalectomy, surgical technique, gross and microscopic adrenal characteristics, follow-up duration, and short- and long-term postoperative outcomes. DATA SYNTHESIS: We identified 48 cases of bilateral adrenalectomy for CAH, with patients aged from 4 months to 56 years at surgery. The most common indication for surgery was the inability to control hyperandrogenism/virilization and/or Cushing syndrome (n = 30; 62%). Most patients (n = 34; 71%) reported symptomatic improvement postoperatively, with some cases of short-term (n = 5; 10%) and long-term (n = 13; 27%) adverse outcomes. CONCLUSIONS: Bilateral adrenalectomy for CAH appears to be a reasonable therapeutic option for carefully selected patients who have had unsatisfactory outcomes with conventional medical management.

Factors related to improved clinical outcomes associated with adrenalectomy for metachronous adrenal metastases from solid primary carcinomas.

BACKGROUND: Surgery for metachronous adrenal metastases from solid primary carcinoma has increased with the development of technical skills. Here we analyzed the postoperative clinical outcomes of patients who underwent adrenalectomy for metachronous adrenal metastases from solid primary carcinomas. METHODS: Patients who underwent adrenalectomy for metachronous adrenal metastases after initial treatment of primary carcinoma at Asan Medical Center from 2000 to 2010 were included. Clinicopathological parameters were analyzed to evaluate prognostic outcomes. RESULTS: A total of 30 patients with 19 hepatocellular carcinomas and 11 lung carcinomas were included. The mean age was 54.3 years. The mean time until adrenalectomy was 23 months. The size of the metastatic adrenal tumor and the disease status of the primary carcinoma at the time of adrenalectomy were associated with second recurrence after adrenalectomy (P < 0.05). There was no significant difference in disease-specific recurrence-free survival between patients who underwent open adrenalectomy and laparoscopic adrenalectomy (P = 0.646). CONCLUSIONS: Surgical treatment should be recommended for metachronous adrenal metastases in patients with no evidence of primary carcinoma and/or in those having metastatic adrenal tumors ≤4.4 cm. This approach may increase the recurrence-free interval related to second recurrence. Further, laparoscopic adrenalectomy appears sufficient for the treatment of such patients.

Metabolic syndrome is associated with increased postoperative complications and use of hospital resources in patients undergoing laparoscopic adrenalectomy.

BACKGROUND: Rates of obesity and metabolic syndrome continue to rise worldwide; however, the impact of metabolic syndrome on outcomes following adrenalectomy has not been described. In this study, we sought to investigate the effects of metabolic syndrome on postoperative 30-day morbidity, mortality, and utilization of hospital resources in a large cohort of patients undergoing elective laparoscopic adrenalectomy. METHODS: Patients who underwent laparoscopic adrenalectomy from 2005 to 2014 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Patients with body mass index ≥30 kg/m2 who also had diabetes and hypertension requiring medications were defined as having metabolic syndrome. Univariate and multivariable analyses were performed for the outcomes of 30-day mortality/morbidity, major complications, and utilization of hospital resources (prolonged duration of stay ≥3 days and requirement for perioperative blood transfusion). RESULTS: Of the 3,502 patients included in the study, 395 had metabolic syndrome (11.3%). Patients with metabolic syndrome were older (P < .001) and had a greater percentage of preoperative comorbidities (P < .05) than patients without metabolic syndrome. On unadjusted analysis, metabolic syndrome was associated with an increased risk for mortality/morbidity, major complications, duration of stay, operative time, and risk for blood transfusion (all P < .001). On multivariable analysis, metabolic syndrome was an independent predictor of overall mortality/morbidity (odds ratio, 1.86; P < .001), major complications (odds ratio, 1.99; P < .001), pulmonary complications (odds ratio, 1.83; P = .049), the need for blood transfusion (odds ratio, 1.94; P = .04), and prolonged length of stay (odds ratio odds ratio, 1.34; P = .02). CONCLUSION: The presence of metabolic syndrome increased the risk for postoperative complications after laparoscopic adrenalectomy and was associated with 2-fold risk for blood transfusion and 34% increased odds of a prolonged hospital stay.

A Novel T-Stage Classification System for Adrenocortical Carcinoma: Proposal from the US Adrenocortical Carcinoma Study Group.

BACKGROUND: The 7th AJCC T-stage system for adrenocortical carcinoma (ACC), based on size and extra-adrenal invasion, does not adequately stratify patients by survival. Lymphovascular invasion (LVI) is a known poor prognostic factor. We propose a novel T-stage system that incorporates LVI to better risk-stratify patients undergoing resection for ACC. METHOD: Patients undergoing curative-intent resections for ACC from 1993 to 2014 at 13 institutions comprising the US ACC Group were included. Primary outcome was disease-specific survival (DSS). RESULTS: Of the 265 patients with ACC, 149 were included for analysis. The current T-stage system failed to differentiate patients with T2 versus T3 disease (p = 0.10). Presence of LVI was associated with worse DSS versus no LVI (36 mo vs. 168 mo; p = 0.001). After accounting for the individual components of the current T-stage system (size, extra-adrenal invasion), LVI remained a poor prognostic factor on multivariable analysis (hazard ratio 2.14, 95% confidence interval 1.05-4.38, p = 0.04). LVI positivity further stratified patients with T2 and T3 disease (T2: 37 mo vs. median not reached; T3: 36 mo vs. 96 mo; p = 0.03) but did not influence survival in patients with T1 or T4 disease. By incorporating LVI, a new T-stage classification system was created: [T1: ≤ 5 cm, (-)local invasion, (+/-)LVI; T2: > 5 cm, (-)local invasion, (-)LVI OR any size, (+)local invasion, (-)LVI; T3: > 5 cm, (-)local invasion, (+)LVI OR any size, (+)local invasion, (+)LVI; T4: any size, (+)adjacent organ invasion, (+/-)LVI]. Each progressive new T-stage group was associated with worse median DSS (T1: 167 mo; T2: 96 mo; T3: 37 mo; T4: 15 mo; p < 0.001). CONCLUSIONS: Compared with the current T-stage system, the proposed T-stage system, which incorporates LVI, better differentiates T2 and T3 disease and accurately stratifies patients by disease-specific survival. If externally validated, this T-stage classification should be considered for future AJCC staging systems.