Juping Zhao

Sorafenib or sunitinib as postoperative adjuvant therapy for Chinese patients with locally advanced clear cell renal cell carcinoma at high risk for disease recurrence.

OBJECTIVE To evaluate the efficacy and safety of targeted agents (sorafenib and sunitinib) as postoperative adjuvant therapy in Chinese patients with clear cell renal cell carcinoma (CC-RCC) who are at high risk for disease recurrence. MATERIALS AND METHODS Forty-three patients treated at our center between December 2007 and December 2010 with locally advanced CC-RCC who were at a high risk for disease recurrence were enrolled into the study. The criteria for high risk of CC-RCC recurrence postoperatively were defined according to the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score for CC-RCC. After radical nephrectomy, patients received either sorafenib (group A, n = 20) or sunitinib (group B, n = 23) and were followed up for at least 1 year to determine the efficacy and safety of the test products. The duration of maintenance targeted medication treatment was approximately 1 year. Group C consisted of 388 CC-RCC patients treated at our center between 1992 and 2007, who were at high risk for disease recurrence and who received no adjuvant therapy. RESULTS The demography characteristics were similar among the 3 groups. The overall rate of recurrence in groups A and B was not different (15.0% and 17.4% (P > 0.05), respectively), which was lower than that of group C (38.7%, P < 0.05 compared with groups A and B). Disease-free survival (DFS) was longer in groups A and B (18.9 ± 5.9 months and 16.9 ± 6.1 months [P > 0.05], respectively), compared with group C (13.3 ± 7.2 months, P < 0.05 compared with groups A and B). The common adverse effects of targeted therapy included hand-foot syndrome, fatigue, diarrhea, taste disturbance, rash, hypertension, alopecia, stomatitis, neutropenia, nausea, pruritus, hypothyroidism in groups A and B. The adverse effects were mild in both groups and the incidence was not significantly different between groups A and B. CONCLUSIONS Targeted adjuvant therapy postoperatively with sorafenib or sunitinib in patients with CC-RCC who are at a high risk for disease recurrence was well tolerated and effective in reducing the rate of CC-RCC recurrence in these patients. This study is an attempt to assess the utility of adjuvant tyrosine kinase inhibitors (TKIs) after surgery for renal carcinoma. The apparently improved outcomes, compared with a historical control population, are of sufficient interest to support the continuation of an ongoing randomized clinical trial to validate the hypothesis.

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.

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.

Expression and diagnostic relevance of heat shock protein 90 and signal transducer and activator of transcription 3 in malignant pheochromocytoma.

Background Malignant pheochromocytoma (PCC) is a rare catecholamine producing tumour with a poor prognosis. For many years predicting PCC behaviour has remained a highly difficult task. The aim of this study was to evaluate heat shock protein 90 (HSP90) and signal transducer and activator of transcription 3 (STAT3) as tissue-based markers to predict malignant PCC. Methods Ninety-two sporadic PCC patients were enrolled. We compared the expression of HSP90 and STAT3 by immunohistochemistry of benign versus malignant PCCs. In addition, in 17 snap frozen PCC and in 7 healthy adrenal tissues, we investigated the expression of HSP90 and STAT3 by means of western immunoblot. Results Positive staining for HSP90 was observed in 22.37% (95% CI 13.00% to 31.74%) of the benign and 66.67% (95% CI 44.89% to 88.45%) of the malignant cases. Similarly, STAT3 staining was seen in 26.32% (95% CI 16.42% to 36.22%) of the benign versus 83.33% (95% CI 66.11% to 100.55%) of the malignant cases. Using HSP90 and STAT3 combined, the positive predictive value of malignancy was significantly increased to 0.70 (95% CI 0.45 to 0.86). Besides, logistic regression analysis showed that HSP90 (OR=3.667, p=0.039) and STAT3 (OR=9.474, p=0.002) were independently associated with malignant PCC. Conclusions This study has confirmed that malignant PCC overexpress HSP90 and STAT3, and the combination of HSP90 and STAT3 can be used as helpful diagnostic markers to distinguish malignant from benign PCCs.

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.

Tip60 is associated with resistance to X‐ray irradiation in prostate cancer

Tip60, an oncogene, accelerates cell growth by regulating androgen receptor translocation into the nucleus in prostate cancer. However, the mechanism of Tip60 in the response of prostate cancer to radiotherapy, and radioresistance, has not been studied. Using human prostate cancer samples and two human prostate cancer cell lines (LNCaP and DU145), Tip60 protein expression and the acetylation of ataxia telangiectasia mutant (ATM) were analysed by western blotting and immunoprecipitation. Tip60 was downregulated with small interfering RNA. Cells were irradiated using X‐rays at 0.25 Gy·min−1. Cell viability was assessed by the MTT assay. The expression of Tip60 protein was increased in radioresistant prostate cancer tissues in comparison with radiosensitive tissues, which was also confirmed in both irradiated DU145 and LNCaP cells. Furthermore, the acetylation of ATM was also upregulated in a time‐dependent manner after irradiation of both DU145 and LNCaP cells. Additionally, depletion of Tip60 decreased the survival of LNCaP and DU145 cells by inducing apoptosis, reduced the acetylation of ATM and decreased the expression of phosphorylated ATM, Chk2 and cdc25A in both DU145 and LNCaP cells after X‐ray irradiation. The results of this study demonstrated that the expression of Tip60 may be related to the radioresistance of prostate cancer and could serve as a promising predictive factor for prostate cancer patients receiving radiotherapy.

Predictors of hypertension urgency in primary aldosteronism patients during the first 24 hours after surgery

Study about blood pressure variation in the first 24 hours post-operation is limited in patients with adrenal aldosterone-producing adenoma. We aim to evaluate the potential predictors for postoperative hypertension urgency during the first 24 hours after laparoscopic adrenalectomy in patients with aldosterone-producing adenoma. Clinical data of 177 patients with aldosterone-producing adenoma were retrospectively collected from January 2009 to December 2015 and the potential factors that may influence postoperative blood pressure during the first 24 hours after surgery were analyzed. The factors included gender, age, body mass index, preoperative maximum systolic blood pressure, number of antihypertensive medicines, preoperative spironolactone treatment, duration of hypertension, surgical method and approach, adenoma diameter, preoperative proteinuria, estimated glomerular filtration rate, serum potassium and serum aldosterone. Univariate and multivariate regression analyses were used to evaluate the relationship between the above variables and postoperative hypertension urgency. We found that the proportion of patients with a higher systolic blood pressure ≥ 160 mmHg and ≥ 180 mmHg were significantly increased post-operation (both p < 0.001). In multivariate analysis, the maximum systolic blood pressure was an independent predictor of postoperative hypertension urgency, and the cut-off point was 157 mmHg with the sensitivity of 66% and specificity of 82%. Multivariable analysis also showed that preoperative maximum systolic blood pressure and number of antihypertensive medicines were independent risk factors for higher postoperative systolic blood pressure. This study was derived from a high volume adrenal tumor center, and these data may provide a potential tool to guide preoperative counseling.