Christopher P. Bambach

miR-195 and miR-483-5p Identified as Predictors of Poor Prognosis in Adrenocortical Cancer

Purpose: Adrenocortical adenomas are common, whereas adrenocortical carcinomas are rare. Discriminating between benign and malignant adrenocortical tumors using conventional histology can be difficult. In addition, adrenocortical carcinomas generally have poor prognosis and limited treatment options. MicroRNAs are short noncoding RNAs that are involved in regulation of gene transcription. Experimental Design: To identify microRNAs involved in the pathogenesis of adrenocortical tumors, expression profiling of microRNAs was done on a cohort of 22 adrenocortical carcinomas, 27 adrenocortical adenomas, and 6 normal adrenal cortices. Results: Twenty-three microRNAs were found to be significantly differentially expressed between adrenocortical carcinomas and adrenocortical adenomas. miR-335 and miR-195 were significantly downregulated in adrenocortical carcinomas compared with adrenocortical adenomas. This result was further validated in an external cohort of six adrenocortical carcinomas and four adrenocortical adenomas. Using Kaplan-Meier analysis, downregulation of miR-195 and upregulation of miR-483-5p in adrenocortical carcinomas were significantly associated with poorer disease-specific survival. Conclusions: These findings indicate that deregulation of microRNAs is a recurring event in human adrenocortical carcinomas and that aberrant expression of miR-195 and miR-483-5p identifies a subset of poorer prognosis adrenocortical carcinomas. (Clin Cancer Res 2009;15(24):7684–92)

Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas

Phaeochromocytomas arising in adrenal or extra-adrenal sites and paragangliomas of the head and neck, in particular of the carotid bodies, occur sporadically and also in a familial setting. In addition to mutations in RET and VHL in familial disease, germline mutations in SDHD and SDHB genes that encode subunits of mitochondrial complex II have also been associated with the development of familial phaeochromocytomas. To further investigate the role of SDHD and SDHB in the development of these tumours we determined the occurrence of germline SDHD and SDHB mutations in four patients with a family history of phaeochromocytoma with associated head and neck paraganglioma, one patient with a family history of phaeochromocytoma only and two patients with apparently sporadic extra-adrenal phaeochromocytoma, one of whom had early onset disease. Secondly, we investigated whether somatic SDHB mutations correlated with loss of heterozygosity at 1p36 in a subgroup of 11 sporadic and three MEN 2-associated RET-mutation-positive phaeochromocytomas. Novel SDHB mutations were identified in the probands from four families and two apparently sporadic cases (six of seven probands studied), including two missense mutations, a single nonsense and frameshift mutation, as well as two splice site mutations, one of which was shown to have partial penetrance resulting in ‘leaky’ splicing. Further, five intronic polymorphisms in SDHB were found. No SDHD mutations were identified. In addition, no somatic SDHB mutations were found in the remaining allele of the 11 sporadic adrenal phaeochromocytomas with allelic loss at 1p36 or the three MEN 2-associated RET-mutation-positive phaeochromocytomas. Therefore, we conclude that SDHB has a major role in the pathogenesis of familial phaeochromocytomas, but the possible role of SDHB in sporadic tumours showing allelic loss at 1p36 has yet to be ascertained.

Comparison of Outcomes following Transhiatal or Ivor Lewis Esophagectomy for Esophageal Carcinoma

p= 0.05); if two surgeons operated concurrently, THO could be performed 40 minutes quicker than THO or ILO performed by a single surgeon (p= 0.018). The mean initial intensive care unit stay was 2.9 days for ILO versus 1.7 days for THO (p= 0.014). The 30-day mortality was 5.1%; total in-hospital mortality was 7.1% with no difference for operation type. There were similar morbidity rates for the procedures. Kaplan-Meier survival analysis indicated no significant effect of surgical technique; there were no apparent advantages for either operation when patients were compared by tumor type or matched for stage. Hence THO is a valid alternative to ILO, particularly for stage II and III cancer.

Clinical and molecular aspects of adrenocortical tumourigenesis

Adrenal masses are a common problem affecting 3−7% of the population. The majority turn out to be benign adrenocortical adenomas, which may be functional or non‐functional. Much more rarely, these masses represent a primary adrenal carcinoma. It is becoming increasingly recognized that of the benign functioning adenomas or hyperplasias, the majority will hypersecrete aldosterone and this will be more frequently detected when hypertensive populations are screened for this disease. In contrast, the incidence of primary adrenocortical carcinoma has remained steady and for this disease, surgery represents the mainstay of treatment. The advent of laparoscopic adrenal surgery has lowered the threshold size for recommending surgery for asymptomatic adrenal masses and as such, an increased proportion of adrenocortical cancers are being resected and detected at an earlier stage. Recent progress has been made in our understanding of the key genetic changes which underpin the biology of this disease. Progression from adrenal adenoma to carcinoma involves a monoclonal proliferation of cells which, among other defects, have undergone chromosomal duplication at the 11p15.5 locus leading to overexpression of the IGF2 gene and abrogation of expression of the CDKN1C and H19 genes. TP53 is involved in progression to carcinoma in a subset of patients and the frequency of ACTH receptor deletion needs to be more fully explored. Other key oncogenes and tumour suppressor genes remain to be identified although the chromosomal loci in which they lie can be identified at 17p, 1p, 2p16 and 11q13 for tumour suppressor genes and chromosomes 4, 5 and 12 for oncogenes.

Laparoscopic adrenalectomy: A 6‐year experience of 59 cases

Background:  The aims of this paper were to review our experience with laparoscopic transperitoneal adrenalectomy, report on outcomes in comparison with the published literature, and demonstrate any learning curve with the technique.

Changing pattern of adrenalectomy at a tertiary referral centre 1970−2000

Background:  In 1987, a report from this unit described the changing indications for open adrenalectomy over a 15‐year period. The indications for adrenalectomy had switched from it being the principal therapeutic procedure used in advanced breast cancer in the early 1970s, to being predominately performed for Cushings disease or incidental, asymptomatic, adrenal masses by the early 1980s. The aim of the present study was to evaluate the changes in the presentation and management of adrenal disease in the last 15 years and to compare these findings with our previously published results.

Fibrolamellar Carcinoma as a Cause of Bile Duct Obstruction

&NA; Obstructive jaundice due to growth within bile ducts of hepatocellular carcinoma is uncommon and usually a manifestation of advanced, lethal tumour. We report a case of fibrolamellar carcinoma of the liver presenting with obstructive jaundice, caused by tumorous permeation of the left hepatic duct with migration of tumour fragments into the common bile duct. Immunocytochemical and ultrastructural features are described. Two and a half years after complete surgical resection the patient is free of tumour. The importance of accurate diagnosis of such tumours is emphasized.

THE UNIVERSITY OF SYDNEY ENDOCRINE SURGERY DATABASE: 50 YEARS OF DATA ACCRUAL

Surgical databases are now a fundamental part of clinical practice and research but have only been commonplace in the past decade or so. The University of Sydney Endocrine Surgery Database has now been in existence for more than 50 years since it was started by Tom Reeve in 1957. It includes comprehensive documentation of every aspect of every thyroid, parathyroid and adrenal procedure carried out by its surgeons while they were active members of the unit. During those 50 years, 17 466 such procedures have been documented. In the first year of data collection, only 20 thyroid procedures carried out by one surgeon in one hospital were entered, whereas in the most recent year, 1092 major endocrine procedures carried out by three surgeons in 10 separate hospitals required entry. As well as providing for surgical audit, the database has been integral to the writing of 130 published articles and articles in press on the topic of thyroid, parathyroid and adrenal surgery. The database has been instrumental to significant changes in the practice of endocrine surgery, including introduction of total thyroidectomy for benign bilateral multinodular goitre by this unit two decades ago, leading to changed practice in most countries around the globe. Data acquisition has also allowed documentation of the safety and efficacy of new minimally invasive endocrine procedures such as minimally invasive parathyroidectomy and minimally invasive thyroid surgery. Audit‐based research with accumulation of data based on surgical outcomes, that is, evidence‐based surgery, remains the fundamental basis of sound surgical practice with the potential to lead important changes in clinical practice.

MicroRNA Microarray Analysis of Human Adrenocortical Tumors Identifies miR-195 and miR-483-5p as Predictors of Poor Prognosis in Adrenocortical Cancer – Response

We thank Dr. Tombol and colleagues for their interest in our article and their comments. As with our study, Dr. Tombol and colleagues also performed microRNA (miRNA) profiling of adrenocortical tumors. There were however only two miRNAs in common between the two studies. This is, of course,

ES19P LAPAROSCOPIC ADRENALECTOMY FOR PHAEOCHROMOCYTOMA IS SAFE AND EFFECTIVE

Purpose  The management of phaeochromocytomas (PC) can present a significant medical and technical operative challenge, however, few studies have assessed whether the outcome of LA of PC differs from other adrenal tumour types. The aim of this study was to determine whether there is any demonstrable difference in outcome for patients undergoing laparoscopic adrenalectomy (LA) for PC compared to other functioning or non‐functioning adrenal tumours.