Sheng-Tang Wu

Ketamine-associated bladder dysfunction

Objective:  To assess the impact of ketamine abuse on genitourinary tract dysfunction.

Dual Degradation of Aurora A and B Kinases by the Histone Deacetylase Inhibitor LBH589 Induces G2-M Arrest and Apoptosis of Renal Cancer Cells

Purpose: This study is aimed at investigating antineoplastic efficacy of histone deacetylase inhibitor (HDACI) LBH589 on renal cell carcinoma (RCC) and elucidating the novel molecular mechanisms involved in growth arrest and apoptosis by targeting the important nonhistone molecules. Experimental Design: We analyzed the growth-inhibitory effect of LBH589 on RCC by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in vitro and antitumor efficacy by xenograft experiments in vivo. To verify the associated molecular mechanisms involved in LBH589-mediated cell death and cell cycle progression by Western blotting and fluorescence-activated cell sorting analysis. Results: HDACI LBH589 induced degradation of both Aurora A and B kinases through a proteasome-mediated pathway by targeting HDAC3 and HDAC6. The dual degradation of Aurora A and B kinases mediated by LBH589 resulted in inducing G2-M arrest and apoptosis of renal cancer cell lines and our results also showed that LBH589 potently inhibited renal cancer cell growth in vitro and suppressed tumor formation in vivo. The Aurora A and B kinases and HDAC3 are overexpressed in the human RCC tumor tissues examined, which make them perfect targets for HDACI LBH589 treatment. Conclusions: Our in vitro and in vivo data showed that LBH589 has potent anticancer effect of renal cancer cells. LBH589 and other HDACI treatment resulted in inducing G2-M arrest and apoptosis of renal cancer cells through degradation of Aurora A and B kinases by inhibition of HDAC3 and HDAC6. The clinical efficacy of LBH589 in the treatment of patients with metastatic RCC, especially those with high Aurora kinase and HDAC expression, is worthy of further investigation.

The HDAC Inhibitor LBH589 Induces ERK-Dependent Prometaphase Arrest in Prostate Cancer via HDAC6 Inactivation and Down-Regulation

Histone deacetylase inhibitors (HDACIs) have potent anti-cancer activity in a variety of cancer models. Understanding the molecular mechanisms involved in the therapeutic responsiveness of HDACI is needed before its clinical application. This study aimed to determine if a potent HDACI, LBH589 (Panobinostat), had differential therapeutic responsiveness towards LNCaP and PC-3 prostate cancer (PCa) cells. The former showed prometaphase arrest with subsequent apoptosis upon LBH589 treatment, while the latter was less sensitive and had late G2 arrest. The LBH589 treatment down-regulated HDAC6 and sustained ERK activation, and contributed to prometaphase arrest. Mechanistically, LBH589 inhibited HDAC6 activity, caused its dissociation from protein phosphatase PP1α, and increased 14-3-3ζ acetylation. Acetylated 14-3-3ζ released its mask effect on serine 259 of c-Raf and serine 216 of Cdc25C subsequent to de-phosphorylation by PP1α, which contributed to ERK activation. Enhanced ERK activity by LBH589 further down-regulated HDAC6 protein levels and sustained ERK activation by free-forward regulation. The sustained Cdc25C and ERK activation resulted in early M-phase (prometaphase) arrest and subsequent apoptosis in the most sensitive LNCaP cells but not in PC-3 cells. This study provides pre-clinical evidence that HDAC6 may serve as a sensitive therapeutic target in the treatment of prostate cancer with HDACI LBH589 for clinical translation. This study also posits a novel mechanism of HDAC6 participation in regulating the c-Raf-PP1-ERK signaling pathway and contributing to M phase cell-cycle transition.

Emodin modulates epigenetic modifications and suppresses bladder carcinoma cell growth.

The deregulation of epigenetics was involved in early and subsequent carcinogenic events. Reversing cancer epigenetics to restore a normal epigenetic condition could be a rational approach for cancer treatment and specialized prevention. In the present study, we found that the expression levels of two epigenetic markers, histone H3K27 trimethylation (H3K27me3), was low but histone H3S10 phosphorylation (pH3Ser10) was high in human bladder cancer tissues, which showed opposite expression patterns in their normal counterparts. Thus, we investigated whether a natural product, emodin, has the ability to reverse these two epigenetic modifications and inhibit bladder cancer cell growth. Emodin significantly inhibited the cell growth of four bladder cancer cell lines in a dose‐ and time‐dependent manner. Emodin treatment did not induce specific cell cycle arrest, but it altered epigenetic modifications. Emodin treatment resulted in the suppression of pH3Ser10 and increased H3K27me3, contributing to gene silencing in bladder cancer cells. Microarray analysis demonstrated that oncogenic genes including fatty acid binding protein 4 (FABP4) and fibroblast growth factor binding protein 1 (HBP17), RGS4, tissue inhibitor of metalloproteinase 3 (TIMP3), WNT5b, URB, and collagen, type VIII, alpha 1 (COL8A1) responsible for proliferation, survival, inflammation, and carcinogenesis were significantly repressed by emodin. The ChIP assays also showed that emodin increased H3K27me3 but decreased pH3Ser10 modifications on the promoters of repressed genes, which indicate that emodin reverses the cancer epigenetics towards normal epigenetic situations. In conclusion, our work demonstrates the significant anti‐neoplastic activity of emodin on bladder cancer cells and elucidates the novel mechanisms of emodin‐mediated epigenetic modulation of target genes. Our study warrants further investigation of emodin as an effective therapeutic or preventive agent for bladder cancer.

Renal Angiosarcoma- A Case Report And Literature Review

PURPOSE In adults renal cell carcinoma (RCC) accounts for over 85% of all diagnosed renal cancers. A much more rare and aggressive malignant tumor of the kidney is angiosarcoma (AS) with less than 25 cases described internationally. Both RCC and AS have similar radiological appearances and thus require histological evaluation for definitive diagnosis. We present a case of renal AS in a 63-year old male who was initially radiologically diagnosed as RCC, and review the current renal AS literature. METHODS The current English literature from 1981 and onwards on renal AS was reviewed and compared to our current case. RESULTS The median age and sex of patients with renal AS at presentation was 63 years old (mean 61 years) and common in males with a left kidney predominance. Symptoms included flank pain, palpable mass, and hematuria with imaging suggestive of RCC. Hematogenous metastatic spread often occurred with median survival time of 3.5 months from time of diagnosis (mean 5.8 months). Histologically, the tumors have classical features of angiosarcoma with numerous blood-filled vascular spaces lined by plump pleomorphic endothelial cells with CD31 and CD34 staining positivity. Overall treatment was radical nephrectomy with radiation therapy for local control and metastases. The use of chemotherapy was not consistent. CONCLUSION Although RCC accounts for the majority of malignant renal tumors, the poor prognosis of AS and its similar radiological appearance to RCC imparts the importance of histological evaluation and the potential radiological mimicry of AS.

Testicular Microlithiasis in Taiwanese Men

Testicular microlithiasis (TM) is an unusual ultrasonographic manifestation in testicular parenchyma. Limited information is available about TM in Taiwanese men. We performed a retrospective analysis to investigate the characteristics of TM and its association with testicular cancer and infertility in Taiwan. Male patients who had received scrotal ultrasonography because of scrotal symptoms or infertility between January 2000 and December 2003 were recruited. The incidence of TM was 7.6%. Both testicular microlithiasis and testicular cancer occurred chiefly in the third decade. Patients with TM exhibit a higher chance of testicular cancer (6% vs. 0.9%). No local field effect between TM and testicular cancer was observed. Testicular microlithiasis severity is not positively correlated with sperm quality and sterility. Forty-eight patients (32%) were available at follow-up. No patient developed a testicular tumor or elevated tumor markers (AFP, ß-hCG) during follow-up. We suggest monthly self-examination, annual scrotal ultrasonography and tumor markers screening between the age of 20 and 30 years of patients with TM.

Correlation of CD44v5 Expression with Invasiveness and Prognosis in Renal Cell Carcinoma

BACKGROUND AND PURPOSE The expression of specific CD44 isoforms is associated with metastasis and poor prognosis in human malignant tumors. We retrospectively investigated the expression of the CD44 variant isoform v5 (CD44v5) in human renal cell carcinoma (RCC) specimens by immunohistochemistry. METHODS We studied the expression of CD44v5 immunohistochemistry in archival tissue specimens from 72 RCC patients (47 men and 25 women) with a mean age of 60.1 years (range, 30 to 83 years) who underwent resection in our hospital from 1986 to 1996. The patients were divided into non-invasive (pT1, pT2, and pT3a; n = 49) and invasive groups (pT3b, pT3c, and any T with N+; n = 23). Among the 72 patients, 67 were followed for at least 60 months (up to 190 months) after radical nephrectomy. Twenty nine renal specimens, including 15 of normal renal parenchyma and 14 of inflammatory or immune renal diseases, were used as controls. RESULTS All control group tissues expressed CD44v5. CD44v5 expression was detected in 66 of 72 RCC specimens (91.7%). In general, the expression of CD44v5 was higher in the non-invasive group [47/49 (95.9%) vs 19/23 (82.6%), p < 0.05]. Five cases were lost to follow-up. Thirty three of 67 patients (49.3%) died of RCC-related causes during the follow-up period. The CD44v5 non-expression group had a higher mortality rate than the expression group [4/5 (80%) vs 29/62 (46.8%), p < 0.001]. The 5-year and 10-year survival rates were significantly higher in patients with CD44v5 expression than in those without (p < 0.001). CONCLUSIONS This study found that CD44v5 expression was greater in early stage than in advanced stage RCC and was associated with tumor progression and long-term survival. Although the survival analysis showed both tumor stage and CD44v5 expression were significant prognostic factors in RCC, only tumor stage remained an independent factor.

Renal infarction secondary to ketamine abuse

Renal infarction is an uncommon condition that resulted from inadequate perfusion of the kidney and is easily missed diagnosed due to its nonspecific clinical presentations. Major risk factors for renal infarction are atrial fibrillation, previous embolism, and ischemic and valvular heart disease. Progressive decrease in renal function or even death can occur if renal infarction is not diagnosed accurately and promptly. Ketamine abuse may cause variable urinary tract injury. However, renal infarction caused by ketamine abuse has never been reported. To our knowledge, this is the first documented case of renal infarction following nasal insufflation of ketamine.

URETERODUODENAL FISTULA: A RARE COMPLICATION OF DUODENAL ULCER

A 20-year-old man was admitted to the hospital for anemia. History was significant for duodenal ulcer 8 years before presentation with no regular treatment, 2 episodes of upper gastrointestinal tract bleeding and frequent attacks of right flank soreness for 2 years. Physical examination was unremarkable. Laboratory studies revealed only microcystic anemia. Right hydronephrosis was found incidentally on ultrasound. Excretory urography confirmed severe hydronephrosis and delayed excretion of the right kidney. Retrograde pyelography showed the duodenal mucosa coated with contrast medium (see figure). On exploration inflammation with severe adhesion was noted in the right kidney. The right upper ureter had fibrosis 2 inches long which appeared as a band below the ureteropelvic junction. There was an adhesion between the ureter and secondary portion of the duodenum. At dissection an obvious penetration defect of the secondary portion of the duodenum was found. The bowel defect was repaired and segmental ureterectomy with primary ureteroureterostomy over a 7Fr ureteral stent was performed. Convalescence was uneventful. The ureteral stent was removed 6 weeks postoperatively. Followup excretory urography demonstrated a normal caliber ureter and improvement in excretion of the right kidney.

Ipsilateral Synchronous Neoplasms of Kidney Presenting as Acute Pyelonephritis and Bladder Metastasis

Ipsilateral multiple synchronous primary renal neoplasms is an uncommon presentation, and only a few cases have been reported in published studies. We report the case of a 57-year-old woman with acute pyelonephritis as the initial presentation, in whom conservative treatment had no effect. Surgical intervention revealed the presence of concomitant renal cell carcinoma, collecting duct carcinoma, and urothelial carcinoma (transitional cell carcinoma) of the kidney. Metastatic renal cell carcinoma to the bladder, liver, and lung subsequently developed. Deceptive inflammatory presentations can occur in aggressive synchronous renal malignancies. Recognition of this rare disease entity could prevent delays in diagnosis and treatment.