José Luis Chambô

ARMC5 Mutations Are a Frequent Cause of Primary Macronodular Adrenal Hyperplasia

CONTEXT Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushings syndrome, usually characterized by functioning adrenal macronodules and increased cortisol production. Familial clustering of PMAH has been described, suggesting an inherited genetic cause for this condition. OBJECTIVE The aim of the present study was to identify the gene responsible for familial PMAH. PATIENTS AND METHODS Forty-seven individuals of a Brazilian family with PMAH were evaluated. A single-nucleotide polymorphism-based genome-wide linkage analysis followed by whole-exome sequencing were then performed in selected family members. Additionally, 29 other patients with PMAH and 125 randomly selected healthy individuals were studied to validate the genetic findings. Moreover, PMAH tissue was also analyzed through whole-exome sequencing, conventional sequencing, and microsatellite analysis. RESULTS A heterozygous germline variant in the ARMC5 gene (p.Leu365Pro) was identified by whole-exome sequencing in a candidate genomic region (16p11.2). Subsequently, the same variant was confirmed by conventional sequencing in all 16 affected family members. The variant was predicted to be damaging by in silico methods and was not found in available online databases or in the 125 selected healthy individuals. Seven additional ARMC5 variants were subsequently identified in 5 of 21 patients with apparently sporadic PMAH and in 2 of 3 families with the disease. Further molecular analysis identified a somatic mutational event in 4 patients whose adrenal tissue was available. CONCLUSIONS Inherited autosomal dominant mutations in the ARMC5 gene are a frequent cause of PMAH. Biallelic inactivation of ARMC5 is consistent with its role as a potential tumor suppressor gene.

Adrenal autografts following bilateral adrenalectomy.

Bilateral adrenalectomy followed by immediate transplantation of adrenal slices into muscular tissue was performed in 7 patients with Cushings disease and 1 with bilateral pheochromocytoma. Patients were followed for 1 to 7 years and only 1 had evidence of a functional graft (serum cortisol level at the lower limit of normality). Low levels of dehydroepiandrosterone sulfate, aldosterone and cortisol were found in the remaining patients. Acute stimulation with adrenocorticotropichormone did not increase either cortisol or aldosterone levels in any patient. We conclude that prospective studies are needed to elucidate factors that could improve the success of adrenal implantation, since the literature shows examples of functional grafts, while the majority of the cases are unsuccessful.

The Use of Three-dimensional Printers for Partial Adrenalectomy: Estimating the Resection Limits

OBJECTIVE To avoid hormonal replacement after partial adrenalectomy (PA), establishing the precise limit of an adrenal gland resection is essential. Herein, we evaluated the use of three-dimensional (3D) adrenal gland printing and volumetry measurement before PA to improve the determination of the remnant gland volume. METHODS Concomitant total adrenalectomy and a contralateral PA were performed in a patient with primary macronodular adrenal hyperplasia that exhibited mild hypercortisolism, arterial hypertension, and diabetes. Before surgery, a 3D replica of the adrenal gland to be partially resected was printed and given to the surgeon. The volumetry of the gland was measured by computed tomography 3D image reconstruction. RESULTS No postoperative complications were noted. Immediately after the surgery, the patient initiated corticosteroid replacement, which was interrupted 52 days later. At the 6-month follow-up, the patient stopped using medications for diabetes and reduced the number of antihypertensive medications from 5 to 1. The pre- and postoperative serum cortisol levels were, respectively, 28 and 8.7 mcg/dl (n 5-25 mcg/dl). The pre- and postoperative adrenocorticotropic hormone levels were, respectively, <5 and 88 pg/ml (n 7.2-63 pg/ml). The postoperative adrenal volume was 12% of the total preoperative adrenal volume. CONCLUSION The use of 3D printing associated with adrenal volumetry might be a useful tool for the surgeon when performing PA, enabling an estimation of the remnant gland volume.

Juxtaglomerular cell tumor as a rare cause of hypertension in adults

The juxtaglomerular cell tumor is a cause of secondary hypertension in adults. A 35-year-old female patient suffering from hypertension and low serum potassium had a 3 x 3 cm solid mass at the lower pole of left kidney diagnosed by abdominal sonography. Partial nephrectomy was performed and the postoperatory was uneventful. Normalization of blood pressure was observed within the first month.

The role of ARMC5 in human cell cultures from nodules of primary macronodular adrenocortical hyperplasia (PMAH)

The participation of aberrant receptors and intra-adrenal ACTH in hyperplastic tissue are considered mechanisms that regulate hypercortisolism in PMAH. Additionally, germline ARMC5 mutations have been described as the most frequent genetic abnormality found in patients diagnosed with PMAH. Previous functional studies analyzed ARMC5 role using H295R cells. Therefore, we investigated the role of ARMC5 in cell cultures obtained from PMAH nodules containing steroidogenic cells, aberrant receptors and intra-adrenal ACTH. ARMC5 silencing in non-mutated PMAH cell cultures decreased steroidogenesis-related genes and increased CCNE1 mRNA expression and proliferative capacity without affecting cell viability. Additionally, ARMC5 overexpression induced cell death in PMAH mutated cell cultures, thereby decreasing cell viability. We confirmed the role of ARMC5 as an important pro-apoptotic protein involved in PMAH-related steroidogenesis. We also report for the first time the involvement of ARMC5 in controlling proliferation and regulating cell cycle in PMAH cell cultures; these effects need to be explored further.

Lessons from 90 consecutive laparoscopic dismembered pyeloplasties in a residency program

Abstract Objective. The aim of this study was to report on the safety and efficacy of 90 consecutive laparoscopic pyeloplasties carried out in a university hospital. Material and methods. The outcomes of 90 transperitoneal dismembered pyeloplasties that were performed by residents at the hospital from March 2004 to March 2010 were analyzed. All of the surgeries were performed because of symptomatic ureteropelvic junction obstruction. The laparoscopic Anderson–Hynes dismembered technique was used in all cases, and a double-J stent was routinely placed and left in place for 4 weeks. The patients were followed up clinically and with imaging studies. Clinical data, outcomes and complication rates for the patients were retrospectively reviewed using a prospectively maintained database. Results.The mean patient age was 38.9 (10–80) years, and 46 patients (51.1%) were males. The mean operative time was 222.5 (125–400) min. The surgery was completed laparoscopically in 96.6% of cases (87 patients). Conversion was required owing to technical difficulties in three cases. Overall, four (4.4%) patients had major complications. Seventy-six of the 87 patients (87.3%) presented improvements in symptomatology at a median follow-up of 39.7 (6–75) months. Conclusion. Laparoscopic pyeloplasty is feasible and associated with high success and low complication rates, even in a residency program.

Presentation and surgery outcomes in elderly with pheocromocytoma: a comparative analysis with young patients

ABSTRACT Purpose: To evaluate the presentation and early surgical outcomes of elderly patients undergoing adrenalectomy for phaeochromocytoma. Patients and Methods: A retrospective search was performed of our adrenal disorders database for patients who underwent surgery for phaeochromocytoma or paraganglioma between 2009 and 2014. Patients >60 years old were classified as elderly. The clinical manifestations, intraoperative course, and early postoperative outcomes of elderly patients were compared to those of younger individuals (<60 years old). Results: The mean (±standard deviation) age in the older (n=10) and younger (n=36) groups was 69.6±5.3 years and 34.0±12.9 years. Germ-line mutations were more common in younger patients (50.0% versus 0%; p=0.004), whereas incidental lesions were more common in the elderly (40.0% versus 5.3%; p=0.003). In both groups, surgery was most commonly performed by videolaparoscopy (90% in the elderly and 82% in the younger group), with similar intraoperative anesthetic and surgical outcomes. Postoperatively, the older group more commonly received vasoactive drugs (60.0% versus 10.5%; p<0.001) and had a longer intensive care unit stay (3.1±2.8 versus 1.4±1.0 days; p=0.014), more clinical complications (60% versus 18.9%; p=0.01), and longer hospital stay (10.2±8.4 versus 5.7±4.9 days; p=0.028). Conclusions: Although all patients received the same preoperative preparation, the elderly group exhibited a slower and more complicated recovery after adrenalectomy. Meticulous perioperative care should be used in the elderly when treating phaeochromocytoma; nevertheless, adrenalectomy is a relatively safe procedure in this patient population.

Comparison between laparoscopic and subcostal mini-incision for live donor nephrectomy

OBJECTIVES The aim of this study was to compare the results of laparoscopic donor nephrectomy with open donor nephrectomy. METHODS A non-randomized prospective analysis was conducted of living donor kidney transplantations (118 open donor nephrectomies; 57 laparoscopic donor nephrectomies) between January 2005 and December 2007 in the Kidney Transplantation Unit of Hospital das Clínicas of Faculdade de Medicina of the Universidade de São Paulo. RESULTS Mean donor operative time, mean donor hospital stay, mean postoperative creatinine values, and rates of complications and graft survival were similar for both groups. A significant statistical difference in warm ischemia time was observed between the open donor nephrectomy and laparoscopic donor nephrectomy groups (p < 0.001). There was only one conversion in the laparoscopic donor nephrectomy group. CONCLUSIONS Laparoscopic donor nephrectomy is a safe procedure for a donor nephrectomy, comparable to an open procedure with similar results despite a longer warm ischemia time.

MP37-08 A NEW INSIGHT FOR THE TREATMENT OF PRIMARY MACRONODULAR ADRENAL HYPERPLASIA: ADRENAL SPARING SURGERY EARLY OUTCOMES

INTRODUCTION AND OBJECTIVES: Treatment planning for adrenal tumors depends on a variety of qualitative and quantitative data, including tumor nature and anatomy, as well as the experience of the operating surgeon. Here, we have developed and propose a scoring system for adrenal masses designated as the A.D.R.E.N.A.L Score, to quantify the nature and anatomical characteristics of adrenal masses based on endocrinological assessment, computerized tomography and patient habitus. METHODS: The A.D.R.E.N.A.L score consists of 7 components including (A)ldosterone/cortisol/catecholamine secretion or suspicion of malignancy based on endocrinological and radiological study, (D)imension (tumor size as the maximal diameter), (R)elationship to adjacent organs, (E)nhancement on computerized tomography, (N)earness of the tumor to major vessels, (A)dipose (patient habitus as body mass index), and a combination of two (L)ocation descriptors [anterior (a) or posterior (p), left (L) or right (R)]. The A.D.R.E.N.A.L score was applied to 345 cases, including 212 laparoscopic retroperitoneal adrenalectomy cases and 105 robotic retroperitoneal adrenalectomy cases and 28 robotic transperitoneal adrenalectomy cases. RESULTS: For all three series, the A.D.R.E.N.A.L score accurately classified the complexity of cases in the above three series as evidenced by the positive correlation between the A.D.R.E.N.A.L score and surgical outcomes including the operative time and estimated blood loss, while BMI or tumor size did not as independent risk factor. CONCLUSIONS: Standardized evaluation of an adrenal tumor is essential for individualized patient preparation, surgical planning and postoperative care which translate to patient safety and cost-effectiveness. The A.D.R.E.N.A.L score is a reproducible classification system based on endocrinological, oncological and anatomical characteristics of adrenal masses. This novel scoring system of adrenal masses may provide a common reference for the decision making of both endocrinologist and urologist, assessment of the surgical risks, patient safetyguided designing of adrenalectomy training programs, and stratified analysis and comparisons of adrenal surgeries within a single or among multiple institutions.

Laparoscopic anti-reflux plasty: experience of the university of São Paulo

OBJECTIVES Vesicoureteric reflux (VUR) is a common cause of urinary tract infections in children, being less commonly diagnosed in adults. Several anti-reflux plasties have been used successfully for the treatment of such condition, such as Politano-Leadbetter, Cohen and Gregoir-Lich techniques, the latter being our preferred approach in open procedures. Here we describe our experience with laparoscopic Gregoir-Lich anti-reflux plasty (LGLP) in children and adults. METHODS The LGLP was used for the treatment of VUR in 15 patients (7 adults and 8 children). Four adults and 5 children had bilateral disease and both sides were treated at the same procedure. Data was collected prospectively and we analysed age at treatment, laterality, degree of VUR, previous anti-reflux procedures, operative time, number of detrusor stitches used in each side, intra-operative and post-operative complications, success rate and follow-up. RESULTS A total of 23 ureteral units were treated. VUR was graded as I in one unit, II in 4 units, III in 10 units, IV in 7 units and 1 unit was not classified, as it was diagnosed by radioisotopic cystography. Two children had failed previous endoscopic procedures. There were no open conversions. Two muccosal perforations occurred during the procedure and were successfully treated laparoscopically. Nineteen out of 21 ureteral units (90%) presented no VUR at the cystographic control, and no bladder dysfunction was identified on follow-up. CONCLUSIONS The LGLP is a feasible, minimally invasive alternative for VUR that reproduces the open procedure. It has an excelent success rate and is not associated to bladder disfunction, even in bilateral procedures.