Yu Zhu

Predictive Factors for Malignant Pheochromocytoma: Analysis of 136 Patients

PURPOSEnWe evaluated the clinical characteristic, tumor feature and immunohistochemistry factors predicting malignant pheochromocytoma.nnnMATERIALS AND METHODSnBetween January 1999 and December 2008 we retrospectively reviewed the records of 136 patients with pheochromocytoma at Ruijin Hospital. We compared clinical characteristics (age, gender, symptoms and biochemical analysis), tumor features (site, weight and diameter) and the expression of 3 angiogenesis/metastasis related genes (VEGF, Cox-2 and MVD) by immunohistochemical analysis of benign vs malignant pheochromocytomas.nnnRESULTSnOf the 136 patients 105 (77%) had benign and 31 (23%) had malignant pheochromocytoma. Malignant tumors were larger and heavier than benign tumors, and accompanied by higher plasma metanephrine secretion (each p <0.001). Mean tumor catecholamine and preoperative 24-hour urinary metanephrine or normetanephrine were obviously higher in malignant than in benign tumors (p <0.001). Also, 25 malignant tumors (81%) were immunopositive for VEGF while only 24 benign tumors (23%) showed this characteristic (p <0.001). Microvessel density and the rate of positive staining for Cox-2 protein in malignant samples were higher than in benign samples (p <0.001).nnnCONCLUSIONSnSeveral promising predictive parameters are currently available to distinguish benign from malignant pheochromocytoma. Large (5 cm or greater) or heavy (250 gm or greater) tumors, multifocal and extra-adrenal tumors, early onset postoperative hypertension and higher plasma or urine metadrenaline are high risk factors predictive of malignant pheochromocytoma. Also, expression of the 3 angiogenesis or metastasis related genes VEGF, Cox-2 and MVD helps determine the diagnosis of malignancy and suggests strict followup.

Significance of heparanase-1 and vascular endothelial growth factor in adrenocortical carcinoma angiogenesis: potential for therapy

The purpose of this study was to determine the correlation between human adrenocortical carcinoma (ACC) and the proteins involved in tumor angiogenesis, and to evaluate the angiogenic status of ACC. The expression of heparanase-1 (HPA-1), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor-2 (VEGFR-2) as well as microvessel density (MVD) were measured in a series of tissue samples from 44 human sporadic adrenocortical tumors by immunohistochemistry. These specimens were classified as adenomas (nxa0=xa020) and carcinomas (nxa0=xa024) according to the histological criteria defined by Weiss. A total of 22 of 24 (91.67%) malignant cases showed positive staining for HPA-1 and 3 of 20 (15%) benign cases showed positive, the difference of HPA-1 expression between ACA and ACC was statistically significant (Pxa0<xa00.001). Similarly, VEGF staining was seen in 70.83% (17/24) of the malignant cases versus 25% (5/20) of the benign, the difference of VEGF expression among two groups was statistically significant (Pxa0=xa00.002). VEGFR-2 expressed highly in the ACC group (79.17%, 19/24) and lowly in the benign group (25%, 5/20), the two groups had extremely significant difference (Pxa0<xa00.001). Malignant cases showed higher MVD compared to benign tumors (84.70xa0±xa012.44 vs. 21.05xa0±xa08.07, Pxa0<xa00.001). HPA-1 and VEGF expression were positively correlated with MVD in all specimens (r_sxa0=xa00.812, Pxa0=xa00.001; r_sxa0=xa00.834, Pxa0<xa00.001). In conclusion, these results suggest that angiogenesis of human ACC maybe mediated by these proteins and they could represent selective targets for the molecularly targeted treatments of ACC.

Selective α1-adrenoceptor antagonist (controlled release tablets) in preoperative management of pheochromocytoma.

The objective of this article is to evaluate the efficacy of Doxazosin Mesylate Controlled Release Tablets for preoperative treatment of patients with pheochromocytoma. Between 2003 and 2008, 67 patients with confirmed diagnoses of pheochromocytoma were enrolled in this study. According to the drug used in preoperative management, patients were divided into two groups: Doxazosin Mesylate pretreatment group (nxa0=xa036) and Phenoxybenzamine pretreatment group (nxa0=xa031). Surgery was performed only in patients who met the optimal preoperative condition. The hematocrit decreased significantly (Pxa0<xa00.001) after antiadrenergic therapy in patients pretreated with phenoxybenzamine or doxazosin. There was no significant difference between the fluid intakes during operation in both groups. The systolic arterial pressures both before and after induction of anesthesia were all significantly higher in the doxazosin patients than in the phenoxybenzamine group (Pxa0<xa00.05). After tumor removed, the lowest systolic arterial pressure was significantly higher in doxazosin group than in phenoxybenzamine group (Pxa0<xa00.05). The fluctuation of systolic arterial pressure during operation was more stable in doxazosin group than in phenoxybenzamine group (Pxa0<xa00.05). Doxazosin mesylate controlled release tablet was as effective as phenoxybenzamine in preoperative volume expansion. Although phenoxybenzamine provided better arterial pressure control, patients pretreated with DOX experienced more stable perioperative hemodynamic changes, shorter preoperative management periods and more simple medication.

The Role of Unilateral Adrenalectomy in Corticotropin-Independent Bilateral Adrenocortical Hyperplasias

BackgroundThe objective of the present study was twofold: to demonstrate our experience with unilateral adrenalectomy in the treatment of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS) caused by bilateral adrenocortical hyperplasias, and to evaluate the long-term results as evidenced by the main laboratory and clinical findings.MethodsFrom February 2000 to August 2009, unilateral adrenalectomy was performed on 27 patients with ACTH-independent CS and bilateral adrenocortical hyperplasias, including 14 patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH) and 13 patients with primary pigmented nodular adrenocortical disease (PPNAD). Signs and symptoms of CS, endocrine examinations, and radiographic imaging were evaluated preoperatively and postoperatively.ResultsAt a median follow-up of 69xa0months (range: 23–120xa0months) for AIMAH and 47xa0months (range: 16–113xa0months) for PPNAD, 25 patients were cured by unilateral adrenalectomy. Serum cortisol level, daily urinary free cortisol (UFC), and plasma ACTH regained the normal range in both AIMAH and PPNAD patients at monthly follow-up visits; the circadian serum cortisol rhythm returned to normal, and a normal responsiveness to overnight low-dose dexamethasone administration (LDDST) became obvious. Both systolic and diastolic blood pressure (BP) levels were significantly reduced: 85xa0% of patients recovered normal BP levels, and the remaining patients need antihypertensive drugs, but at a reduced dose. No surgery-related morbidity occurred, and there was no sign of further enlargement of the residual adrenal gland after successful unilateral adrenalectomy. One patient with PPNAD and another patient with AIMAH with similar weights and sizes of the bilateral adrenals needed contralateral adrenalectomy.ConclusionsUnilateral adrenalectomy may be the suitable treatment for selected patients with AIMAH and PPNAD. It can achieve long-term remission of CS and improve glycemic control and BP values.

Retroperitoneoscopic partial adrenalectomy for small adrenal tumours (≤1 cm): the Ruijin clinical experience in 88 patients

Study Type – Therapy (case series)u2028Level of Evidenceu20034

Retroperitoneal Adrenal-Sparing Surgery for the Treatment of Cushing’s Syndrome Caused by Adrenocortical Adenoma: 8-Year Experience With 87 Patients

BackgroundThe objective of this study was to present our 8-year experience with partial adrenalectomy via the retroperitoneal approach for the treatment of Cushing’s adenoma.MethodsA total of 93 patients who underwent adrenal surgery for Cushing’s adenoma from March 2003 to December 2010 were enrolled in this study. Preoperative, intraoperative, and postoperative variables were reviewed from the database. Student’s t test was used to analyze the continuous data, and the χ2 test was used to analyze the categoric data. A value of pxa0<xa00.05 was considered statistically significant.ResultsAdrenal-sparing surgery was performed in 87 cases (31 by open surgery, 56 by retroperitoneal laparoscopy). Six patients underwent open/laparoscopic total adrenalectomy because of recurrent disease or a large size. The cure rate in our series was 97.8%. Hypertension resolved in 34 of 64 patients (53.1%), diabetes in 7 of 27 patients (25.9%) and obesity in 28 of 48 patients (58.3%). One patient died during the postoperative period. The intraoperative complication rate for the open surgery group was significantly higher than that for the retroperitoneal laparoscopy group (9.1 vs. 1.7%).ConclusionsThe retroperitoneal approach is reliable and safe for treating Cushing’s syndrome. The laparoscopic technique can decrease the prevalence of intraoperative complications. Retroperitoneal laparoscopic partial adrenalectomy can be performed with extremely low morbidity and achieves an excellent outcome, although death may occur during the postoperative period in high-risk patients. Postoperative management plays an important role in the surgical treatment of Cushing’s syndrome.

Heparanase-1 and Cyclooxygenase-2: prognostic indicators of malignancy in pheochromocytomas

The objective of this article is to evaluate Heparanase-1 and Cyclooxygenase-2 as tissue-based markers of pheochromocytoma prognosis. Ninety-two sporadic pheochromocytoma patients with a minimum of 8-year follow-up post-diagnosis were enrolled. Slides of normal adrenal glands in nephrectomy specimens from 20 patients with benign renal tumors were as control. Heparanase-1 and Cyclooxygenase-2 expression as well as microvessel density were examined using immunohistochemistry in tissues from these patients. Positive staining for Heparanase-1 was observed in 23.68% of the benign and 77.78% of the malignant cases, whereas none of the normal adrenal controls showed positive staining. Similarly, Cyclooxygenase-2 staining was seen in 23.68% of the benign versus 83.33% of the malignant cases, and none of the normal controls appeared positive for Cyclooxygenase-2. Using both HPA-1 and Cox-2 combined, the positive predictive value of malignancy was significantly increased to 0.72, compared to about 0.45 by their own. Malignant cases showed higher microvessel density compared to benign tumors and normal controls (36.41, 21.43, and 13.36%, respectively). Heparanase-1 and Cyclooxygenase-2 may contribute to the invasive characteristics of malignant pheochromocytomas. Heparanase-1 and Cyclooxygenase-2 combined is better than their own to be used as a marker to distinguish malignant from benign pheochromocytoma.

Co-inhibition of EGFR and IGF1R synergistically impacts therapeutically on adrenocortical carcinoma

Purpose Adrenocortical carcinoma (ACC) is a rare tumor with very poor prognosis and no effective treatment. The aim of this study was to explore a novel therapy co-targeting EGFR and IGF1R in vitro and vivo. Methods The expression of EGFR and IGF1R were evaluated in a series of adrenocortical tumors by immunohistochemistry. Cell viability of ACC cell lines H295R and SW13 were determined by MTT assay after treatment with the combination of EGFR inhibitor Erlotinib and IGF1R inhibitor NVP-AEW541. Apoptosis was assessed by flow cytometry. The mechanism within intracellular signaling pathways was analyzed by Western blot. Mice bearing human ACC xenografts were treated with Erlotinib and NVP-AEW541, and the effects on tumour growth were assessed. Results Our results show a significant over-expression of EGFR (66.67%) and IGF1R (80.0%) in ACC. Besides, the co-overexpression of EGFR and IGF1R was seen in 8/15 ACCs, as compared with ACAs (P<0.05). Erlotinib and NVP-AEW541 significantly inhibited cell viability and induced apoptosis by blocking phosphorylation of MEK/ERK and AKT, respectively. Meanwhile, we found that single inhibition of IGF1R induced compensatory activation of MEK/ERK, leading to sustained activation of mTOR, which represent as aggregation of EGFR and IGF1R downstream components. More importantly, the combination of Erlotinib and NVP-AEW541 enhances anti-tumour efficacy compared to treatment with either agent alone or to untreated control in vitro and vivo. Conclusions In conclusion, coinhibition therapy targeting EGFR and IGF1R may be considerable for treatment of ACC in the future.

Molecular markers and targeted therapies for adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a lethal disease with poor prognosis and lack of effective therapeutic options. Systemic treatment is often employed to treat patients with advanced ACC, but outcomes are disappointing. During the last decade, some of the causative genetic mutations in sporadic ACCs have been identified. Molecular analysis has had a significant impact on the understanding of the pathogenetic mechanism of ACC development and the evaluation of prognostic and predictive markers. Preclinical investigations and clinical trials of tyrosine kinase inhibitors and anti‐angiogenic compounds have been initiated to seek target therapy of ACCs. This review summarizes the current view of molecular alterations involved in the pathophysiology of adrenocortical carcinogenesis. The rationale for testing targeted therapies of ACC is also presented.

Sphingosine kinase 1 is overexpressed and promotes adrenocortical carcinoma progression

Adrenocortical carcinoma (ACC) is a rare endocrine tumor with a very poor prognosis. Sphingosine kinase 1 (SphK1), an oncogenic kinase, has previously been found to be upregulated in various cancers. However, the role of the SphK1 in ACC has not been investigated. In this study, SphK1 mRNA and protein expression levels as well as clinicopathological significance were evaluated in ACC samples. In vitro siRNA knockdown of SphK1 in two ACC cell lines (H295R and SW13) was used to determine its effect on cellular proliferation and invasion. In addition, we further evaluated the effect of SphK1 antagonist fingolimod (FTY720) in ACC in vitro and in vivo, as a single agent or in combination with mitotane, and attempted to explore its anticarcinogenic mechanisms. Our results show a significant over-expression of SphK1 mRNA and protein expression in the carcinomas compared with adenomas (P < 0.01 for all comparisons). Functionally, konckdown of SphK1 gene expression in ACC cell lines significantly decreased cell proliferation and invasion. FTY720 could result in a decreased cell proliferation and induction of apoptosis, and the combination of mitotane and FTY720 resulted in a greater anti-proliferative effect over single agent treatment in SW13 cells. Furthermore, FTY720 could markedly inhibit tumor growth in ACC xenografts. SphK1 expression is functionally associated to cellular proliferation, apoptosis, invasion and mitotane sensitivity of ACC. Our data suggest that SphK1 might be a potential therapeutic target for the treatment of ACC.