Georgios Zografos

High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas

Objectives  Previous studies based on standard endocrine testing have shown a variable incidence of autonomous cortisol secretion (ACS) or autonomous aldosterone secretion (AAS) in patients with single adrenal adenomas (SAA). We tested whether the use of appropriate controls and modification of standard testing, aiming at eliminating interference from endogenous ACTH, reveals previously undetected subtle ACS and AAS by SAA.

Tumor Heterogeneity Revealed by KRAS, BRAF, and PIK3CA Pyrosequencing: KRAS and PIK3CA Intratumor Mutation Profile Differences and Their Therapeutic Implications

Current clinical problems in colorectal cancer (CRC) diagnostics and therapeutics include the disease complexity, tumor heterogeneity, and resistance to targeted therapeutics. In the present study, we examined 171 CRC adenocarcinomas from Greek patients undergoing surgery for CRC to determine the frequency of KRAS, BRAF, and PIK3CA point mutations from different areas of tumors in heterogeneous specimens. Ninety two out of 171 (53.8%) patients were found to bear a KRAS mutation in codons 12/13. Of the 126 mutations found, 57.9% (73/126) were c.38G>A mutations (p.G13D) and 22.2% (28/126) were c.35G>T (p.G12V). Remarkably, RAS mutations in both codons 12 and 13 were recorded in the same tumor by pyrosequencing. Moreover, differences in KRAS mutations between tumor center and periphery revealed tumor heterogeneity in 50.7% of the specimens. BRAF c.1799T>A (V600E) mutations were moderately detected in 4/171 (2.3%) specimens, whereas most PIK3CA mutations were revealed by pyrosequencing 6/171 (3.5%). Remarkable tumor heterogeneity is revealed, where double mutations of KRAS in the same tumor and different KRAS mutation status between tumor core and margin are detected with high frequency. It is expected that these findings will have a major impact in cancer diagnosis and personalized therapies.

High prevalence of autonomous aldosterone secretion among patients with essential hypertension

Eur J Clin Invest 2011; 41 (11): 1227–1236

Newly established tumourigenic primary human colon cancer cell lines are sensitive to TRAIL-induced apoptosis in vitro and in vivo

Most data on the therapeutic potential of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as resistance to FAS ligand (FASL) in colorectal cancer have come from in vitro studies using cell lines. To gain a clearer understanding about the susceptibility of patient tumours to TRAIL and FASL, we derived primary human cancer epithelial cells from colon cancer patients. Characterisation of primary cultures PAP60 and MIH55 determined their highly proliferating advantage, transforming capability and tumorigenicity in vitro and in vivo. Although FASL treatment appeared to cause little apoptosis only in the PAP60 primary culture, increased apoptosis independent of p53 was observed in both primary PAP60 and MIH55 and control cell lines Caco-2, HT29 and DLD-1 after treatment with SuperKiller TRAIL. Expression analysis of death receptors (DR) in the original parental tumours, the primary cultures before and after engraftment as well as the mouse xenografts, revealed a significant upregulation of both DR4 and DR5, which correlated to differences in sensitivity of the cells to TRAIL-induced apoptosis. Treating patient tumour xenograft/SCID mouse models with Killer TRAIL in vivo suppressed tumour growth. This is the first demonstration of TRAIL-induced apoptosis in characterised tumorigenic primary human cultures (in vitro) and antitumour activity in xenograft models (in vivo).

Metastatic pheochromocytoma and paraganglioma

Metastatic pheochromocytomas (PCs) and paragangliomas (PGLs) are rare neuroendocrine tumours with a strong genetic background.

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

Tumourigenesis is a relatively common event in endocrine tissues. Currently, specific guidelines have been developed for common malignant endocrine tumours, which also incorporate advances in molecular targeted therapies (MTT), as in thyroid cancer and in gastrointestinal neuroendocrine malignancies. However, there is little information regarding the role and efficacy of MTT in the relatively rare malignant endocrine tumours mainly involving the adrenal medulla, adrenal cortex, pituitary, and parathyroid glands. Due to the rarity of these tumours and the lack of prospective studies, current guidelines are mostly based on retrospective data derived from surgical, locoregional and ablative therapies, and studies with systemic chemotherapy. In addition, in many of these malignancies the prognosis remains poor with individual patients responding differently to currently available treatments, necessitating the development of new personalised therapeutic strategies. Recently, major advances in the molecular understanding of endocrine tumours based on genomic, epigenomic, and transcriptome analysis have emerged, resulting in new insights into their pathogenesis and molecular pathology. This in turn has led to the use of novel MTTs in increasing numbers of patients. In this review, we aim to present currently existing and evolving data using MTT in the treatment of adrenal, pituitary and malignant parathyroid tumours, and explore the current utility and effectiveness of such therapies and their future evolution.

Death receptor 5 ( DR5 ) and a 5-gene apoptotic biomarker panel with significant differential diagnostic potential in colorectal cancer

High expression of Inhibitor of apoptosis proteins (IAPs) has been related to colorectal cancer (CRC) progression, resistance to treatment and poor prognosis. TRAIL (TNF-related apoptosis-inducing ligand) through its receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2) can selectively induce cancer cell apoptosis. The mRNA expression of DR4, DR5, c-IAP1, c-IAP2, XIAP and BIRC5/Survivin genes was examined in 100 paired (cancerous-normal) colorectal tissue specimens by real-time PCR, 50 of which were KRAS wild-type and 50 KRAS-mutant. DR5, XIAP and BIRC5/Survivin genes are significantly up-regulated (p < 0.0001, p = 0.012 and p = 0.0003, respectively), whereas c-IAP1 and c-IAP2 genes are significantly down-regulated at mRNA and protein levels in CRC (p < 0.0001 for both). ROC analyses showed that DR5, cIAP1 and cIAP2 expression has discriminatory value between CRC and normal tissue (AUC = 0.700, p < 0.0001 for DR5; AUC = 0.628, p = 0.011 for cIAP1; AUC = 0.673, p < 0.0001 for cIAP2). Combinatorial ROC analysis revealed the marginally fair discriminatory value of 5 genes as a panel (AUC = 0.685, p < 0.0001). Kaplan-Meier survival curves revealed significant association of cIAP2 down-regulation in CRC with lower overall survival probability of CRC patients (p = 0.0098). DR5, BIRC5/Survivin, XIAP, c-IAP1 and c-IAP2 mRNA expression are significantly deregulated in CRC and could provide a panel of markers with significant discriminatory value between CRC and normal colorectal tissue.

Surgical Considerations in Subclinical Cushing’s Syndrome. When is it Time to Operate?

Subclinical Cushing’s syndrome (SCS) is a disorder characterized by autonomous cortisol secretion and the presence of an adrenal incidentaloma, in the absence of clinical features of Cushing’s syndrome. SCS is of special interest because it has been associated with several disorders, such as atherosclerosis and arterial hypertension. Despite decades of research, SCS continues to generate controversy regarding its diagnosis and subsequent management. Several issues remain to be resolved. A universal agreement on the hormonal diagnosis of the syndrome remains elusive. Autonomous cortisol secretion has been ill defined and several definitions have been offered. The heterogeneity in diagnostic criteria creates heterogeneity in studies evaluating optimal management. Minimally invasive adrenalectomy has been documented to ameliorate SCS associated disorders in certain patients. Identifying these patients should be the focus of future research on the subject. In this review we summarize current concepts regarding SCS and indications for its surgical management.

A Rare Case of Synchronous Cervical Lymph Node Metastasis from Renal and Thyroid Cancer

Papillary thyroid cancer (PTC) has a propensity to metastasize to the cervical lymph nodes (LNs). Renal cancer (RC) can also spread to the cervical LNs and is the most common cause of metastatic infiltration of the thyroid gland. We describe here the case of a 71-year-old patient with a previous history of surgically treated RC who underwent evaluation of a large left cervical mass. Initial cytological investigation on fine needle aspiration (FNA) indicated metastatic PTC. Computed tomography (CT) scanning revealed no other suspicious foci. The patient underwent total thyroidectomy and central and left lateral cervical LN dissection, during which a large neck mass along the left jugular vein was also removed. Histology demonstrated metastatic spread of RC to the thyroid gland and lateral cervical LNs and concurrent LN metastases from PTC. One LN showed evidence of synchronous RC and PTC metastasis. Only a small papillary thyroid microcarcinoma with no aggressive histological features was detected in the thyroid, raising the possibility that the primary focus of metastatic PTC was the large left lateral neck mass. The patient was discharged after successful treatment for transient hypoparathyroidism. The synchronous presence of RC and PTC in the thyroid and cervical LNs and the concurrent metastases in one of the LNs renders this case unique. Evaluation of a cervical mass in a patient with a prior history of malignancy can prove vexing, and surgery may be the only option for the establishment of a definitive diagnosis.

Anesthesia Management and Recovery after Laparoscopic Colorectal Surgery

Open abdominal procedures are associated with high levels of postoperative surgical stress that can impede recovery of physiological functions. Trauma resulting from aggressive manipulation of organs, and especially the intestine, can increase postoperative complications and result in delay in normal recovery. In an attempt to minimize complications and overall duration of hospital stay, fast track strategies, called “early recovery after surgery” (ERAS) protocols, have been adopted. Laparoscopic surgery has recently been identified as a major component of rapid recovery. One of the key differences between the open and the laparoscopic approach is the use of pneumoperitoneum for organ exposure during laparoscopy. Prolonged increase in abdominal pressure in addition to patient positioning can have a profound effect on hemodynamic parameters such as central venous pressure (CVP), cardiac output and intracranial pressure. Modifications in fluid administration, the choice of anesthetic agent and the depth of neuromuscular blockade are indicated to accommodate to the conditions imposed by pneumoperitoneum. Postoperatively, laparoscopic surgery is usually associated with less aggressive analgesia management. Based on ERAS protocols, patients are encouraged to initiate early oral feeding and to resume physical activity as soon as possible after abdominal surgery. While laparoscopic abdominal surgery is associated with reduced needs for pain medication, there appear to be no significant differences in early enteral feeding and mobilization between laparoscopic procedures and open surgery. When all factors are taken into consideration, however, laparoscopic colorectal surgery is associated with significant reduction in the duration of the total hospital stay, and is therefore recommended whenever feasible.