Fukang Sun

Predictive Factors for Malignant Pheochromocytoma: Analysis of 136 Patients

PURPOSE We evaluated the clinical characteristic, tumor feature and immunohistochemistry factors predicting malignant pheochromocytoma. MATERIALS AND METHODS Between 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. RESULTS Of 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). CONCLUSIONS Several 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.

The PI3K/AKT/mTOR Signaling Pathway Is Overactivated in Primary Aldosteronism

Background To date, the available non-invasive remedies for primary aldosteronism are not satisfactory in clinical practice. The phosphoinositide 3-kinase (PI3Ks)/protein kinase B (PKB or AKT)/mammalian target of rapamycin (mTOR) signaling pathway is essential for tumorigenesis and metastasis in many types of human tumors, including renal cancer, adrenal carcinoma and pheochromocytoma. The possibility that this pathway is also necessary for the pathogenesis of primary aldosteronism has not yet been explored. To answer this question, we investigated the activity of the PI3K/AKT/mTOR signaling pathway in normal adrenal glands (NAGs), primary aldosteronism (PA) patients and NCI-H295R cells. Methodology/Principal Findings Between January 2005 and December 2011, we retrospectively reviewed the records of 45 patients with PA. We compared clinical characteristics (age, gender and biochemical data) and the expression of phospho-AKT (p-AKT), phospho-mTOR (p-mTOR), phospho-S6 (p-S6) and vascular endothelial growth factor (VEGF) by immunohistochemical staining and western blotting, analyzing 30 aldosterone-producing adenomas (APAs), 15 idiopathic hyperaldosteronism (IHA) tissues and 12 NAGs following nephrectomy for renal tumors (control group). Compared with the control group, most of the PA patients presented with polydipsia, polyuria, resistant hypertension, profound hypokalemia, hyperaldosteronemia and decreased plasma renin activity. Compared with normal zona glomerulosa, the levels of p-AKT, p-mTOR, p-S6 and VEGF were significantly upregulated in APA and IHA. No significant differences were found between APA and IHA in the expression of these proteins. Additionally, positive correlations existed between the plasma aldosterone levels and the expression of p-AKT and p-mTOR. In vitro studies showed that mTOR inhibitor rapamycin could inhibit cell proliferation in NCI-H295R cells in a dose- and time-dependent manner. Furthermore, this inhibitor also decreased aldosterone secretion. Conclusions Our data suggest that the PI3K/AKT/mTOR signaling pathway, which was overactivated in APA and IHA compared with normal zona glomerulosa, may mediate aldosterone hypersecretion and participate in the development of PA.

Prognostic factors for overall survival with targeted therapy in Chinese patients with metastatic renal cell carcinoma.

INTRODUCTON We wanted to identify the prognostic factors for overall survival (OS) in Chinese patients with metastatic renal cell carcinoma (mRCC) treated with first-line targeted therapy (sorafenib or sunitinib). METHODS We retrospectively reviewed clinical data from 119 mRCC patients administered sorafenib or sunitinib at the Ruijin Hospital since 2007. OS rates were calculated by the Kaplan-Meier method. Each variable was investigated univariately and then multivariately using a stepwise algorithm. A multivariate Cox regression model analyzed baseline variables for prognostic significance. RESULTS The mean patient age was 57 ± 12 years; 37 patients (31%) received sorafenib and 82 (69%) received sunitinib. The mean OS was 22.7 ± 15.6 months (range: 2.8- 68.7). OS rates at year 1, 3 and 5 were 74%, 57%, and 36%, respectively. Univariate analysis identified significant negative prognostic factors (p < 0.05) as Eastern Cooperative Oncology Group (ECOG) performance status ≥2, symptoms, no prior nephrectomy, microscopic necrosis, ≥2 metastatic sites, presence of liver, bone, or pancreas metastasis, hemoglobin less than the lower limit of normal(female <115 g/L, male <130 g/L), and serum alkaline phosphatase greater than the upper limit of normal (126 IU/L) at baseline, as well as a relative dose intensity of targeting agents in the first month (1M-RDI) of <50%. Multivariate analysis of OS identified 4 independent predictors: no symptoms, no bone or pancreas metastasis, and 1M-RDI of targeting agents (≥50%). CONCLUSIONS With targeted therapy, there is some change in the prognostic factors for mRCC and target drug therapies (1M-RDI ≥50%) play an important role in the prognosis of mRCC. Continued progress in the identification of patient-specific prognostic factors for mRCC will require further advances in the understanding of tumour biology.

The diagnosis and treatment of primary adrenal lipomatous tumors in Chinese patients: a 31-year follow-up study

INTRODUCTION Adrenal lipomatous tumours (ALTs) are rarely encountered in clinical practice and consequently little is known about their clinical features. METHODS We analyze the clinical features, diagnosis and treatment of ALTs based on cases presenting at a single centre over a 31-year period. We reviewed clinical data from patients with primary adrenal tumours treated at the Ruijin Hospital, Shanghai between January 1980 and December 2010. RESULTS A total of 73 cases of primary ALTs in 22 men and 51 women (mean age 51.1±14.2 years) were reviewed. The ALTs included 65 myelolipomas (89.0%), 3 lipomas (4.1%), 2 angiomyolipomas (2.7%), 2 teratomas (2.7%), and 1 liposarcoma (1.4%). Of the total 73 patients, 24 of them had tumours in the left adrenal gland, 47 in the right gland and 2 had bilateral tumours. In total, 51 patients underwent open surgery and 22 laparoscopic surgery. CONCLUSION Myelolipoma is predominant among the various types of lipomatous adrenal gland tumours; it accounts for about 90% of all cases. Surgery is recommended for tumours ≥3.5 cm in diameter, for all cases of symptomatic tumour, and for cases of teratoma or liposarcoma identified by preoperative imaging.

Pathologic analysis, diagnosis and treatment of adrenal myelolipoma

With the widespread use of non-invasive imaging modalities, the incidental detection of myelolipoma has become more common. We analyze the clinical data of 4 typical cases of unilateral adrenal myelolipomas, including 1 hormonally inactive patient and 3 hormonally active cases with hyperaldosteronemia, hypercortisolism and hyperandrogenemia. Obvious differences were found in the pathological sections. To our knowledge, this is the first article discussing the etiology of adrenal myelolipoma from pathologic analyses.

Analysis of the inheritance pattern of a Chinese family with phaeochromocytomas through whole exome sequencing.

Phaeochromocytomas (PCCs) and paragangliomas (PGLs) are rare, catecholamine-producing tumors. Most familial PCC/PGLs have been detected to be autosomal dominantly inherited. However, this study was undertaken in a family with PCCs to determine candidate genes in a dominant or recessive inheritance pattern. After excluding mutations in ten PCC/PGL susceptibility genes by Sanger sequencing, we used whole exome sequencing for screening on the four family members to discover novel candidate genes associated with PCCs. Based on the inexistence of non-synonymous mutations or indels in the ten known genes and the structure of this pedigree, 3 damaging loci with dominant inheritance pattern, and 5 damaging loci with recessive homozygous inheritance pattern and 6 damaging genes with compound heterozygous inheritance pattern were narrowed down to indicate the association with PCCs. According to the Gene Ontology (GO) category analysis on the combined results, cell adhesion showed the most significant enrichment.

Classification, diagnosis and treatment of ACTH-independent macronodular adrenal hyperplasia

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a distinctive subtype of Cushings syndrome (CS), with different clinical manifestations according to the level of serum cortisol. Based on clinical manifestations and serum cortisol, we divide AIMAH into three types, subclinical AIMAH, clinical AIMAH and high-risk AIMAH, with varied treatment methods being adapted to different subtypes. At the same time, we describe 3 patients who represent these subtypes of this disease, and review some cases of AIMAH which have been previously reported in the English literature. To our knowledge, this is the first article discussing classification, diagnosis and treatment of this disease and should be useful for future therapy of AIMAH.

Thulium laser vaporesection versus transurethral electrovaporization of the prostate in high-risk patients with benign prostatic hyperplasia.

OBJECTIVE The purpose of this study was to compare the safety and efficacy of the thulium laser vaporesection and transurethral electrovaporization of the prostate for the treatment of high-risk patients with benign prostatic hyperplasia. BACKGROUND DATA From September 2009 to March 2011, 98 consecutive patients with symptomatic bladder outlet obstruction caused by benign prostatic hyperplasia received either thulium laser vaporesection of the prostate (n=42) or transurethral electrovaporization of the prostate (n=56) at our institution. MATERIALS AND METHODS Functional follow-up included measurement of International Prostate Symptom Score, quality of life score, maximal urinary flow rate, and post-voiding residual urine volume. All complications were recorded. RESULTS Thulium laser vaporesection of the prostate was slightly superior to transurethral electrovaporization of the prostate in catheterization time (2.1±0.9 vs. 4.5±1.3 days, p<0.0001) and postoperative hospital stay (4.4±1.8 vs. 6.6±2.0 days, p<0.0001). Within the observation period, both groups had a significant improvement from baseline in subjective or objective success rates; however, no significant difference was found between the two groups. Peri- and postoperative complications were fewer in the thulium laser group. CONCLUSIONS Thulium laser vaporesection of the prostate is as effective as transurethral electrovaporization of the prostate in managing high-risk patients, with sufficient tissue ablation and acceptable hemostasis, and has the advantage of less morbidity and shorter catheter time and postoperative hospital stay.

LOH on chromosome 11q, but not SDHD and men1 mutations was frequently detectable in chinese patients with pheochromocytoma and paraganglioma

Recently, the succinate dehydrogenase subunit D (SDHD) gene has been reported as one of the major susceptibility genes for pheochromocytoma (PCC) and paraganglioma (PGL). In addition, loss of heterozygosity (LOH) on chromosome 11, mainly in 11 q23 and 11 q13, is observed frequently in PGL. Based on the fact that mutation frequency of the SDHD gene is less than that of allelic loss at chromosome 11 q, where the SDHD gene is located, this region may contain other candidate tumor-suppressor genes involved in pathogenesis of PCC/PGL. The tumor-suppressor gene Men1 located in 11 q13 is responsible for multiple endocrine neoplasia type 1 (Men1). However, the involvement of the Men1 gene in tumorigenesis of sporadic PCC/PGL is yet to be determined. To understand the roles of the two tumor-suppressor genes and LOH on chromosome 11q in Chinese patients with sporadic PCC or PGL, we performed mutation detection of the SDHD and Men1 genes in tumors from 35 Chinese patients with PCC/PGL; we also did LOH analysis at chromosome 11q for 25 patients out of the 35. No mutation was found in all of 35 patients. However, LOH was detected at one or more loci in 11 of the 25 (44%) tumor samples. The highest frequency of LOH occurred at D11S2006 (41%). Our results suggested that mutation in SDHD or Men1 gene was not found in Chinese patients with sporadic PCC/PGL. However the loss of chromosome 11q might be critical in development of PCC or PGL.

Study on the mechanism behind lncRNA MEG3 affecting clear cell renal cell carcinoma by regulating miR-7/RASL11B signaling: HE et al.

The goal of this research was to study the relationships between maternally expressed gene 3 (MEG3), microRNA‐7 (miR‐7), and RASL11B, and explore their influence on the progression of clear cell renal cell carcinoma (CCRCC). Microarray analysis was conducted using the data provided by The Cancer Genome Atlas. The expression levels of MEG3 and miR‐7 in CCRCC and adjacent tissue samples were ascertained by quantitative real‐time polymerase chain reaction (qRT‐PCR). The cell proliferation activity was unmasked by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, and cell apoptosis and cell cycle were investigated by flow cytometry. A dual luciferase reporter assay was used to verify target relationships. Wound healing assay and transwell assay were used to detect cell migration and invasion ability. Decreased MEG3 expression was observed in CCRCC tissues and cells. Overexpression of MEG3 accelerated apoptosis; inhibited cell proliferation, migration and invasion; and induced G0/G1 phase cell cycle arrest in CCRCC. MiR‐7, directly binding to MEG3, was overexpressed in the CCRCC tissues and could inhibit the apoptosis and promote the migration and invasion of CCRCC cells. RASL11B, lowly expressed in CCRCC, was a target of miR‐7. After the overexpression of RASL11B, G0/G1 phase cell cycle arrest was induced; cell apoptosis was promoted; and the proliferation, invasion, and migration of CCRCC cells were inhibited. MEG3 could up‐regulate RASL11B to inhibit the cell proliferation, invasion, and migration; induce G0/G1 cell cycle arrest; and promote cell apoptosis by suppressing miR‐7 in CCRCC.