Primary perioperative haemodynamic effects of ß-receptor blockade in patients with catecholamine-secreting tumours.

Introduction: Guidelines for the treatment of catecholamine-producing tumours strictly recommend starting ß-receptor blocking medication only after α-receptor blockade has been established. This recommendation is supported only by non-surgical case reports. However, in clinical practice ß-receptor blockade is often started before the diagnosis of a phaeochromocytoma is made. As we routinely treat patients with catecholamine-producing tumours without α-receptor blockade, our aim was to evaluate haemodynamic changes in such patients with and without ß-receptor blockade. Methods: Perioperative blood pressure was assessed prospectively for all patients. The primary outcome was the highest pre-, intra-, and postoperative systolic blood pressure in patients with or without a ß-receptor blockade. Secondary outcomes were the incidence of intraoperative systolic blood pressure peaks >250 mm Hg and hypotensive episodes. Subsequently, a propensity score matching (PSM) analysis was performed. Results: Out of 584 phaeochromocytoma and paraganglioma resections, 383 operations were performed without α-receptor blockade (including 84 with ß-receptor blockade). Before operation and intraoperatively, patients with ß-receptor blockade presented with higher systolic blood pressure (155 [25] and 207 [62] mm Hg) than patients without ß-receptor blockade (147 [24] and 183 [52] mm Hg; P=0.006 and P=0.001, respectively). Intraoperatively, patients with ß-receptor blockade demonstrated a higher incidence of hypotensive episodes (25% without vs 41% with ß-blockade; P<0.001). After propensity score matching no difference between the groups could be confirmed. Conclusion: Overall, patients with isolated ß-receptor blockade developed higher blood pressure before operation and intraoperatively. After propensity score matching a difference could no longer be detected. Overall, ß-receptor blockade seems to be more a sign for severe disease than a risk factor for haemodynamic instability.

Low anterior resection syndrome and its impact on quality of life of ovarian carcinoma patients: A prospective longitudinal study.

OBJECTIVES: Bowel dysfunction is frequently reported in patients with ovarian carcinoma (OC). Our aim was to evaluate the incidence of low anterior resection syndrome (LARS) like symptoms in patients with primary OC and its impact on quality of life (QoL). METHODS: A prospective longitudinal observational cohort study was performed, including patients with newly diagnosed OC treated by primary or interval surgery with residual tumor <1 cm, from 2018 until 2021. Patients with a stoma or recurrence of disease were excluded. Intestinal dysfunction was assessed using the validated LARS score questionnaire pre- and postoperatively. There are 3 subgroups based on the results: no, minor, or major LARS. The impact on QoL was evaluated by an additional question to demonstrate the severity of patient's life impairment. RESULTS: The questionnaire was answered by 78 patients pre- and post-operatively. LARS like symptoms were reported preoperatively in 34.6% (24.4% minor/10.2% major) and significantly increased postoperatively to 47.4% (28.2% minor/19.2% major; p = 0.011). Moderate to severe impairment of QoL correlated with LARS scores pre- (80%) and post-operatively (90%). Patients with two bowel anastomoses (mean score 18.6 pre- and 24.9 post-operatively, p = 0.041) showed a significant increase of the questionnaire score. CONCLUSIONS: Major LARS like symptoms appear in 10% of OC patients preoperatively and significantly increase to almost two-fold postoperatively. Multiple bowel anastomoses had a significant risk for higher postoperative LARS score. QoL impairment correlates linearly with LARS positive scoring, independent on the timing of the complaints.

[Minimally invasive techniques in adrenal gland surgery]. / Minimal-invasive Techniken der Nebennierenchirurgie.

Today, adrenalectomy can be performed by a variety of laparoscopic and retroperitoneoscopic approaches. Of particular importance are the lateral transperitoneal and the posterior retroperitoneoscopic access routes. Comparative studies of transperitoneal and retroperitoneal procedures still demonstrate heterogeneous results. Nevertheless, retroperitoneal access techniques seem to enable less postoperative pain and a faster recovery. Robotic procedures are gaining in popularity but the final importance cannot yet be determined. All minimally invasive techniques are considered to be so safe and reliable that open approaches are only justified in exceptional cases.

Tailored Approach in Adrenal Surgery: Retroperitoneoscopic Partial Adrenalectomy.

The interest on partial adrenalectomy has steadily increased over the past twenty years. Adrenal pathologies are mostly benign, making an organ-preserving procedure attractive for many patients. The introduction of minimally invasive techniques played probably an important role in this process because they transformed a complex surgical procedure, related to the difficult access to the retroperitoneal space, into a simple operation improving the accessibility to this organ. In this review we summarize the role of partial retroperitoneoscopic adrenalectomy over the years and the current indications and technique.

Surgical Outcomes After Neoadjuvant Chemoradiation Followed by Curative Surgery in Patients With Esophageal Cancer: An Intergroup Phase III Trial of the Swiss Group for Clinical Cancer Research (SAKK 75/08).

OBJECTIVE: To assess the impact of surgical technique in regard to morbidity and mortality after neoadjuvant treatment for esophageal cancer. BACKGROUND: The SAKK trial 75/08 was a multicenter phase III trial (NCT01107639) comparing induction chemotherapy followed by chemoradiation and surgery in patients with locally advanced esophageal cancer. METHODS: Patients in the control arm received induction chemotherapy with cisplatin and docetaxel, followed by concomitant chemoradiation therapy with cisplatin, docetaxel, and 45Gy. In the experimental arm, the same regimen was used with addition of cetuximab. After completion of neoadjuvant treatment, patients underwent esophagectomy. The experimental arm received adjuvant cetuximab. Surgical outcomes and complications were prospectively recorded and analyzed. RESULTS: Total of 259 patients underwent esophagectomy. Overall complication rate was 56% and reoperation rate was 15% with no difference in complication rates for transthoracic versus transhiatal resections (56% vs 54%, P = 0.77), nor for video assisted thoracic surgeries (VATS) versus open transthoracic resections (67% vs 55%, P = 0.32). There was a trend to higher overall complication rates in squamous cell carcinoma versus adenocarcinoma (65% vs 51%, P = 0.035), and a significant difference in ARDS in squamous cell carcinoma with 14% versus 2% in adenocarcinoma (P = 0.0002). For patients with involved lymph nodes, a lymph node ratio of ≥0.1 was an independent predictor of PFS (HR 2.5, P = 0.01) and OS (HR 2.2, P = 0.03). CONCLUSIONS: This trial showed no difference in surgical complication rates between transthoracic and transhiatal resections. For patients with involved lymph nodes, lymph node ratio was an independent predictor of progression free survival and overall survival.

Differentiating Benign from Malignant Adrenocortical Tumors by a Single Morphological Parameter-a Clinicopathological Study on 837 Adrenocortical Neoplasias.

The morphological differentiation between benign and malignant adrenocortical tumors is an ongoing problem in diagnostic pathology. In recent decades the complex scoring systems have been widely used to calculate the probability of malignancy in adrenocortical tumors on the basis of a variety of histomorphological parameters. We herewith present a substantially simplified method to diagnose adrenocortical carcinoma by a single histomorphological parameter on a consecutive series of more than 800 adrenocortical tumors. Between January 2000 and May 2019, altogether 2305 adrenalectomies for of all types of diseases were removed, approximately 98% by minimally invasive approaches. After exclusion of pheochromocytomas, adrenal ganglioneuromas, adrenal metastases, Cushing's disease related specimens, and Conn's adenomas, the present series finally consisted of 837 adrenocortical tumors. All tumors were analyzed by experienced pathologists of a single institution using standard histopathological methods (Hematoxylin-Eosin and Ki67 stained sections). Clinical and histopathologic data were prospectively collected and retrospectively analyzed. Clinically, 385 patients had 420 functioning tumors (FT), and 417 had non-functioning adrenal tumors (NFT). The mean size of FT was 3.8 ± 1.4 cm (range 0.5-16 cm) and for NFT 4.5 ± 1.6 cm (range 1.5-18 cm). Histomorphologically, 32 adrenal tumors were classified as adrenocortical carcinoma (ACC; 3.8%). In all 32 cases (tumor size 9.1 ± 4.0 cm, range 3-18 cm), confluenting tumor necrosis could be demonstrated. The remaining 805 tumors (control group) completely lacked this highly reproducible single morphological feature. Ki67 levels above 10% were found in 31 of 32 ACCs and never in adrenocortical adenomas (ACA). With a mean follow-up of 8.2 years, 24 out of 32 patients primarily diagnosed as ACC developed distant metastases (75.0%), whereas all patients in the control group remained free of local or distant recurrence. We conclude that a single morphological parameter (confluenting tumor necrosis) is sufficient to predict a poor clinical course in adrenocortical tumors. The histomorphological diagnosis of this parameter is straightforward and highly reproducible.

Adrenal Tumors: Are Gender Aspects Relevant?

The distribution of malignant tumors is strongly related to gender due to sex-related organ and tissue differentiation. Neoplasias of the adrenal glands are relatively common and typically benign. Mainly based on our recently published contributions, we analyzed the influence of gender on type of tumors, complexity of surgery, and long-term outcome. Cortisol-secreting adrenal tumors are more often diagnosed in female patients, while the incidence of Conn's syndrome and pheochromocytoma is similar between male and female patients. Adrenalectomy is more difficult in male patients because of longer operating time and higher blood loss. The probability of cure in male patients with Conn's syndrome is significantly lower. Gender does not influence long-term results in adrenal hypercortisolism and pheochromocytomas.

Fluorescence-enabled assessment of adrenal gland localization and perfusion in posterior retroperitoneoscopic adrenal surgery in a preclinical model.

BACKGROUND: The posterior retroperitoneoscopic adrenal access represents a challenge in orientation and working space creation. The aim of this experimental acute study was to evaluate the impact of computer-assisted quantitative fluorescence imaging on adrenal gland identification and assessment of intraoperative remnant perfusion for adrenal resection in the posterior retroperitoneoscopic approach. METHODS: Six pigs underwent simultaneous (n = 5) or sequential (n = 1) bilateral posterior retroperitoneoscopic adrenalectomy (n = 12). Fluorescence imaging was obtained via intravenous administration of 3 mL of Indocyanine Green (ICG) and by switching the camera systems to near-infrared mode (D-LIGHT P, KARL STORZ; Germany). Fluorescence-based visualization of adrenal glands before vascular division (n = 4), after the main vascular pedicle ligation (negative control, n = 1) or after adrenal resection (n = 7), was followed by completion adrenalectomy. The fluorescence signal intensity dynamics were recorded and analyzed using proprietary software. For each pixel, the slope of fluorescence signal intensity evolution over time was translated into a color-coded perfusion cartography, which was superimposed onto real-time images obtained with the corresponding left and right camera systems. Quantitative fluorescence signal analysis in the regions of interest (ROIs) served to assess adrenal remnant perfusion in divided adrenal glands. RESULTS: In the retroperitoneum, the vascular anatomy was illuminated in fluorescence imaging first. The adrenal glands were promptly highlighted after primary intravenous ICG administration (n = 9) or showed a fluorescence signal intensity increase upon reinjection (n = 3). Quantitative fluorescence analysis showed a statistically significant difference between perfused and ischemic segments in divided glands (p = 0.0156). CONCLUSIONS: Fluorescence imaging provides real-time guidance during minimally invasive adrenal surgery. Prior to dissection, it allows to easily discriminate the adrenal gland from surrounding retroperitoneal structures. After adrenal gland division, ICG injection associated with a computer-assisted quantitative analysis helps to distinguish between well-perfused and ischemic segments. Further studies are underway to establish the correlation between remnant perfusion and viability.

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.

Low anterior resection syndrome (LARS) in patients with epithelial ovarian cancer after primary debulking surgery.

OBJECTIVE: To evaluate the prevalence of low anterior resection syndrome (LARS) in patients with debulking surgery for primary advanced epithelial ovarian cancer and to identify potential risk factors for development of LARS. METHODS: We reviewed data on 552 consecutive patients with primary epithelial ovarian cancer (EOC), who underwent upfront or interval cytoreductive surgery including low anterior resection at two different academic institutions (Kliniken-Essen-Mitte, Germany, and Medical University of Vienna, Austria). Intestinal dysfunction was assessed by the validated LARS-questionnaire via telephone call. We performed descriptive statistics and a binary logistic regression model to evaluate risk factors for LARS. RESULTS: In total, 341 patients were eligible and 206 (60.4%) were successfully contacted and provided complete information. Major LARS was observed in 78 (37.9%) patients, minor LARS in 44 (21.4%) patients, and no LARS in 84 (40.8%) patients. The prevalence rate of major LARS was not influenced by time interval between surgery and LARS assessment, type of cytoreductive surgery, and recurrent disease at the time of assessment. In multivariate analyses, number of anastomosis was independently associated with an increased risk for presence of major LARS (OR 3.76 [1.95-7.24]). In the present cohort, 25.2% patients had more than one bowel anastomosis. CONCLUSIONS: LARS in general and major LARS in particular seem to be a frequent long-term complication after debulking surgery including low anterior resection in primary advanced EOC patients. Particularly EOC patients with more than one bowel anastomosis during surgery seem to be at an increased risk for major LARS.

Minimally Invasive Parathyroidectomy without Intraoperative PTH Performed after Positive Ultrasonography as the only Diagnostic Method in Patients with Primary Hyperparathyroidism.

BACKGROUND: A positive and concordant result of at least two diagnostic modalities is generally recommended prior to focused parathyroidectomy. The aim of this study was to analyze the results of surgery and the accurateness of preoperative ultrasonography (US) as single localization modality in patients who underwent parathyroidectomy without the adjunct of intraoperative Parathormone (PTH) measurement. METHODS: The cases with a preoperative US as the only localization technique, who underwent parathyroidectomy between 10/1999 and 12/2017, were selected from a prospectively maintained database. Therefore, a total number of 242 patients with a mean age of 58.6 ± 13.7 years were included in the present study. US was performed by referral endocrinologist or by the surgeon during office visits. RESULTS: The overall "cure rate" was 99.2% (240 out of 242 patients). In 228/242 patients (94.2%), a drop of perioperative PTH levels consistent with the definition of cure was observed on the day of surgery. In four of the remaining 14 patients, healing was confirmed by PTH level dropping into the normal range on the first postoperative day. Eight patients were cured after a reoperation was performed at our department. Postoperative complications included one case of permanent recurrent laryngeal nerve palsy (0.4%). CONCLUSIONS: If performed by an experienced endocrinologist and/or endocrine surgeon, a positive US could be the only preoperative localization study in patients with pHPT. Moreover, the add-value of intraoperative PTH is limited. Major advantages of US are a very high accuracy, the ease of performance (accessibility) and its cost-effectiveness compared with Sesta-MIBI scintigraphy.

A New Minimally Invasive Approach to the Posterior Right Segments of the Liver: Report of the First Two Cases.

Background: Minimally invasive liver surgery has gained increasing popularity over the past decade. Nevertheless, laparoscopic treatment of lesions located in the posterior-superior locations remains challenging because of the difficulty to reach a safe exposition of those regions of the liver. We present a new retroperitoneoscopic approach for the minimally invasive treatment of posterior tumors. Materials and Methods: Between May and July 2018, 2 patients with solitary liver metastasis of colorectal origin underwent retroperitoneoscopic liver resection in the prone position. The operation was conducted with three to four trocars, the CO2 insufflation pressure was set at 20 mmHg. Liver transection was carried out by alternating bipolar coagulation and clips, without clamping of the hepatic inflow. Results: There were no intra- or postoperative complications. The procedure was completed in both cases without conversion after 120 to 180 minutes, respectively. Complete resection was achieved in both cases. Hospital stay was 3 and 5 days. Conclusions: Retroperitoneoscopic liver resection is feasible and safe. This approach could be suggested as an additional therapeutic option, especially in cases of redo resection at the posterior segments.

Transcutaneous laryngeal ultrasonography (TLUS) as an alternative to direct flexible laryngoscopy (DFL) in the perioperative evaluation of the vocal cord mobility in thyroid surgery.

PURPOSE: Direct flexible laryngoscopy (DFL) is the golden standard to evaluate the vocal cord (VC) function in thyroid and parathyroid surgery pre- and postoperatively. Transcutaneous laryngeal ultrasonography (TLUS) could represent an alternative to the DFL and has been evaluated in the present study comparing the results of both methods performed at two referral centers for endocrine pathologies. METHODS: In the setting of a retrospective study, 668 patients (560 female, 118 male; mean age 50.3 ± 14.2) were included from two tertiary referral centers of endocrine surgery. In all patients, TLUS was performed pre- and postoperatively prior to transnasal DFL, which served as a golden standard. TLUS was performed by B-scan (probe 5-13 MHz, aperture 40 mm). RESULTS: Preoperative visualization of the vocal cords by TLUS was possible in 526 patients (78.7%). Due to the frequent thyroid cartilage calcification (TCC) in male patients, a significant difference in the visualization rate was found between female and male (88.7% vs. 26.8%) [p < 0.0001]. Additionally, the visualization rate was inversely related to the patient's age [p < 0.001]. The sensitivity of preoperative TLUS was found to be 66.7%, the specificity 100%. DFL confirmed a postoperative palsy in 34 out of 40 patients with supposed abnormal vocal cord mobility at TLUS and demonstrated a palsy in four more cases with supposed regular mobility at TLUS. Therefore, the sensitivity of postoperative TLUS was 86%, the specificity of 99.1%, positive predictive value 89.4%, negative predictive value 98.7%. CONCLUSIONS: TLUS could represent an alternative for the evaluation of vocal cords mobility. This method has the potential to replace the DFL in the majority of cases, especially in female patients. Nevertheless, DFL is still necessary in about 20% of the patients with failed visualization at TLUS.

Minimally Invasive Surgery (MIS) in Children and Adolescents with Pheochromocytomas and Retroperitoneal Paragangliomas: Experiences in 42 Patients.

BACKGROUND: Pheochromocytomas (PH) and paragangliomas (PGL) are rare tumours in children accounting for about 1% of the paediatric hypertension. While minimally invasive surgical techniques are well established in adult patients with PH, the experience in children is extremely limited. To the best of our knowledge, we herewith present the largest series of young patients operated on chromaffin tumours by minimally invasive access. MATERIALS: In the setting of a prospective study (1/2001-12/2016), 42 consecutive children and adolescents (33 m, 9 f) were operated on. Thirty-seven patients (88%) suffered from inherited diseases. Twenty-six patients had PH, 11 presented retroperitoneal PGL, and five patients suffered from both. Altogether, 70 tumours (mean size 2.7 cm) were removed (45 PH, 25 PGL). All operations were performed by a minimally invasive access (retroperitoneoscopic, laparoscopic, extraperitoneal). Partial adrenalectomy was the preferred procedure for PH (31 out of 39 patients). Twenty patients received α-receptor blockade preoperatively. RESULTS: One patient died after induction of anaesthesia due to cardiac arrest. All other complications were minor. Conversion to open surgery was necessary in two cases with PGL. Median operating time for unilateral PH was 55 min, in bilateral cases 125, 143 min in PGs, and 180 min in combined cases. Median blood loss was 20 ml (range 0-1000). Blood transfusion was necessary in two cases. Intraoperative, systolic peak pressure was 170 ± 39 mmHg with α-receptor blockade and 191 ± 33 mmHg without α-receptor blockade (p = 0.41). The median post-operative hospital stay was 3 days. After a mean follow-up of 8.5 years, two patients presented ipsilateral recurrence (after partial adrenalectomy). All patients with bilateral PH (n = 13) are steroid independent post-operatively. CONCLUSIONS: PH and PGL in children and adolescents should preferably be removed by minimally invasive surgery. Partial adrenalectomy provides long-term steroid independence in bilateral PH and a low rate of (ipsilateral) recurrence. α-Receptor blockade may not be necessary in these patients.

Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial.

BACKGROUND: Results of the PreOperative therapy in Esophagogastric adenocarcinoma Trial (POET) showed some benefits when including radiotherapy into the preoperative treatment. This article is reporting long-term results of this phase III study. PATIENTS AND METHODS: Patients with locally advanced adenocarcinomas of the oesophagogastric junction (Siewert types I-III) were eligible. Randomisation was done to chemotherapy (group A) or induction chemotherapy and chemoradiotherapy (CRT; group B) followed by surgery. RESULTS: The primary end-point of the study was overall survival at 3 years. The study was closed early after 119 patients having been randomised and were eligible. Local progression-free survival after tumour resection was significantly improved by CRT (hazard ratio [HR] 0.37; 0.16-0.85, p = value 0.01) and 20 versus 12 patients were free of local tumour progression at 5 years (p = 0.03). Although the rate of postoperative in-hospital mortality was somewhat higher with CRT (10.2% versus 3.8%, p = 0.26), more patients were alive at 3 and 5 years after CRT (46.7% and 39.5%) compared with chemotherapy (26.1% and 24.4%). Thus, overall survival showed a trend in favour of preoperative CRT (HR 0.65, 95% confidence interval [CI] 0.42-1.01, p = 0.055). CONCLUSION: Although the primary end-point overall survival of the study was not met, our long-term follow-up data suggest a benefit in local progression-free survival when radiotherapy was added to preoperative chemotherapy in patients with locally advanced adenocarcinoma of the oesophagogastric junction.

Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.

IMPORTANCE: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

Posterior retroperitoneoscopic adrenal surgery for clinical and subclinical Cushing's syndrome in patients with bilateral adrenal disease.

BACKGROUND: The treatment of hypercortisolism for patients with bilateral adrenal disease (BAD) is controversial. Bilateral total adrenalectomy results in permanent hypocortisolaemia requiring lifelong steroid replacement. A more conservative surgical approach, with less than bilateral total adrenalectomy (leaving functional adrenal tissue either unilaterally or bilaterally), represents an alternative option; however, long-term outcome or recurrence data are limited. We report our experience with the surgical management of hypercortisolism caused by BAD. METHODS: Between 2004 and 2016, 42 patients (12 male, 30 female; mean age 58 ± 10 years) with clinical or subclinical Cushing's syndrome (CS/sCS) caused by BAD underwent adrenal surgery via the posterior retroperitoneoscopic approach. Adrenal surgery was defined as "adrenalectomy" when total gland excision was performed or "resection" when a partial or subtotal adrenal resection was performed. Clinical, radiological and biochemical parameters were evaluated preoperatively and postoperatively. RESULTS: Seventy adrenal operations performed in total included unilateral resection (n = 3), unilateral adrenalectomy (n = 15), bilateral resection (n = 9), adrenalectomy and contralateral resection (n = 14) and bilateral total adrenalectomy (n = 3). Median operating time was 47.5 min (30-150) with no difference between unilateral and bilateral (synchronous included) procedures (p = 0.15). Mortality was zero. Clavien-Dindo grade of postoperative complications was I (n = 5) and IV (n = 3). All but one patient with CS and 17/31 patients with sCS received postoperative steroid supplementation for a median duration of 20 (1.5-129) months. After median follow-up of 40 months (3-129), the remission rate was 92%; 11 patients required ongoing steroid supplementation. There were three biochemical recurrences (two underwent contralateral resection); two patients with new/progressive radiological nodularity are biochemically eucortisolaemic. A significant reduction in BMI (p = 0.01) and antihypertensive requirements (p = 0.04) was observed postoperatively. CONCLUSION: A surgical approach which facilitates the conservation of functional adrenal tissue represents a suitable strategy for hypercortisolism caused by BAD. This approach avoids the necessity for lifelong steroid replacement in the majority of cases with low rates of adrenal insufficiency and recurrence.