Xiaozhi Zhao

Radio Frequency Ablation versus Partial Nephrectomy for Clinical T1b Renal Cell Carcinoma: Long-Term Clinical and Oncologic Outcomes

PURPOSE We compared outcomes in patients treated with radio frequency ablation or partial nephrectomy for clinical cT1b renal cell carcinoma. MATERIALS AND METHODS We retrospectively reviewed the records of all patients who underwent radio frequency ablation or nephrectomy between February 2006 and December 2010. Radiographic followup with contrast imaging was performed 7 days, 3 and 6 months, and every 6 months thereafter after radio frequency ablation sequentially. The followup protocol for partial nephrectomy was every 6 months in the initial 3 years and annually thereafter. The Kaplan-Meier method was used to generate survival curves, which were compared with the log rank test. Multivariable regression analysis was done to determine predictors of survival. RESULTS A total of 56 patients who met selection criteria were included in study. Patients in the radio frequency ablation group had relatively higher mean age and a higher mean ASA® score than those in the partial nephrectomy group. Mean tumor diameter was significantly larger in the partial nephrectomy cohort. For radio frequency ablation vs partial nephrectomy 5-year overall, cancer specific and disease-free survival was 85.5% (95% CI 72.2-98.8) vs 96.6% (95% CI 95.9-97.3), 92.6% (95% CI 82.4-98.1) vs 96.6% (95% CI 95.9-97.3) and 81.0% (95% CI 66.2-95.8) vs 89.7% (95% CI 78.5-97.9), respectively. The percent decrease in the glomerular filtration rate was significantly lower in the radio frequency ablation group at early and last followup. CONCLUSIONS In appropriately selected patients with stage cT1b renal cell carcinoma radio frequency ablation is an effective treatment option that provides 5-year overall, cancer specific and disease-free survival comparable to that of partial nephrectomy as well as better renal function preservation than partial nephrectomy.

Gender disparity of living donor renal transplantation in East China

Gender disparity among living kidney donors is common world wide, which demonstrates different social and economic problems in different countries. However, few data are available for China. Therefore, we retrospectively analyzed all 139 living donor renal transplants performed in our center between 2003 and 2010. The annual number of living donor renal transplants increased from six to 26 cases per year during the observation period. Among them, 69.2% of all kidney donors were females, whereas 79.5% of the recipients were male. The average age of recipients was 34.1 ± 7.6 yr and 94% (110/117) were younger than 44 yr. In contrast, 53% (62/117) of all donors were “middle‐aged” (45–59 yr) with an average donor age of 47.8 ± 9.2 yr. The first‐degree relatives accounted for the majority of the donor pool, as the most common donor‐recipient combination consisted of mother to son. In conclusion, there was a male and young preponderance among recipients, and a female and middle‐aged one among donors of living kidney transplants in our transplant center, which might be related to socio‐cultural as well as economic factors.

In Situ Floating Hydrogel for Intravesical Delivery of Adriamycin Without Blocking Urinary Tract

Drug solution is commonly used in conventional intravesical instillation. However, most of them would be easily eliminated by voiding, which significantly limit their efficacy. Recent advances in intravesical drug delivery are to use hydrogels as drug reservoir to extend the drug residence time in bladder. However, because of the high viscosity of hydrogel, urinary obstruction is usually existed during the intravesical instillation. To overcome these, we developed a floating hydrogel for the delivery of Adriamycin (ADR). The floating hydrogel was made of ADR, thermosensitive polymer (Poloxamer 407) and NaHCO₃, which was liquid at low temperature, whereas formed gel at high temperature. In the presence of H⁺, NaHCO₃ decomposed and produced CO₂ that attached on the surface of hydrogel and helped the hydrogel float on the urine. Hence, the urinary tract will not be blocked. Meanwhile, the encapsulated ADR released in a controlled manner. These results suggest that the floating gel may have promising applications in intravesical therapy for bladder cancer.

Steroid Receptor Coactivator-3 Regulates Glucose Metabolism in Bladder Cancer Cells through Coactivation of Hypoxia Inducible Factor 1α

Background: Steroid receptor coactivator-3 (SRC-3) is frequently overexpressed in human urinary bladder cancer. Results: SRC-3 promotes urinary bladder cancer (UBC) cells proliferation through coactivating HIF1α and up-regulating the expression of genes involved in the glycolytic pathway. Conclusion: SRC-3 plays an important role in UBC development through enhancing glycolysis. Significance: Targeting SRC-3 or enzymes in glycolytic pathway could be an attractive approach in UBC therapy. Cancer cell proliferation is a metabolically demanding process, requiring high glycolysis, which is known as “Warburg effect,” to support anabolic growth. Steroid receptor coactivator-3 (SRC-3), a steroid receptor coactivator, is overexpressed and/or amplified in multiple cancer types, including non-steroid targeted cancers, such as urinary bladder cancer (UBC). However, whether SRC-3 regulates the metabolic reprogramming for cancer cell growth is unknown. Here, we reported that overexpression of SRC-3 accelerated UBC cell growth, accompanied by the increased expression of genes involved in glycolysis. Knockdown of SRC-3 reduced the UBC cell glycolytic rate under hypoxia, decreased tumor growth in nude mice, with reduction of proliferating cell nuclear antigen and lactate dehydrogenase expression levels. We further revealed that SRC-3 could interact with hypoxia inducible factor 1α (HIF1α), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1α-target genes, such as glut1 and pgk1. The positive correlation of expression levels between SRC-3 and Glut1 proteins was demonstrated in human UBC patient samples. Inhibition of glycolysis through targeting HK2 or LDHA decelerated SRC-3 overexpression-induced cell growth. In summary, overexpression of SRC-3 promoted glycolysis in bladder cancer cells through HIF1α to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy.

TGFβƒ1 Promotes Gemcitabine Resistance Through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

High tumor recurrence is frequently observed in patients with urinary bladder cancers (UBCs), with the need for biomarkers of prognosis and drug response. Chemoresistance and subsequent recurrence of cancers are driven by a subpopulation of tumor initiating cells, namely cancer stem-like cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment remains largely unclear. In this study, we found that during gemcitabine treatment lncRNA-Low Expression in Tumor (lncRNA-LET) was downregulated in chemoresistant UBC, accompanied with the enrichment of CSC population. Knockdown of lncRNA-LET increased UBC cell stemness, whereas forced expression of lncRNA-LET delayed gemcitabine-induced tumor recurrence. Furthermore, lncRNA-LET was directly repressed by gemcitabine treatment-induced overactivation of TGFβ/SMAD signaling through SMAD binding element (SBE) in the lncRNA-LET promoter. Consequently, reduced lncRNA-LET increased the NF90 protein stability, which in turn repressed biogenesis of miR-145 and subsequently resulted in accumulation of CSCs evidenced by the elevated levels of stemness markers HMGA2 and KLF4. Treatment of gemcitabine resistant xenografts with LY2157299, a clinically relevant specific inhibitor of TGFβRI, sensitized them to gemcitabine and significantly reduced tumorigenecity in vivo. Notably, overexpression of TGFβ1, combined with decreased levels of lncRNA-LET and miR-145 predicted poor prognosis in UBC patients. Collectively, we proved that the dysregulated lncRNA-LET/NF90/miR-145 axis by gemcitabine-induced TGFβ1 promotes UBC chemoresistance through enhancing cancer cell stemness. The combined changes in TGFβ1/lncRNA-LET/miR-145 provide novel molecular prognostic markers in UBC outcome. Therefore, targeting this axis could be a promising therapeutic approach in treating UBC patients.

The Comparison of R.E.N.A.L., PADUA and Centrality Index Score in Predicting Perioperative Outcomes and Complications after Laparoscopic Radio Frequency Ablation of Renal Tumors

PURPOSE We assessed the association between the R.E.N.A.L., PADUA and centrality index scores and perioperative outcomes, and determined the efficacy of each scoring system over the simple parameter of tumor size. MATERIALS AND METHODS We conducted a retrospective review of the records of patients who underwent laparoscopic radio frequency ablation of renal tumors from February 2006 to April 2014 at our institution. Tumors were categorized using the R.E.N.A.L., PADUA and centrality index score, which were determined by analyzing preoperative imaging. The relationships between each variable and change in glomerular filtration rate, estimated blood loss, operative time and postoperative complications were examined. RESULTS Laparoscopic radio frequency ablation was performed in 215 selected patients with preoperative imaging available. The interclass correlations coefficient of the 3 observers was 0.87, 0.84 and 0.82 for the C-Index, the R.E.N.A.L. and the PADUA scoring system, respectively. R.E.N.A.L. score, PADUA score and PADUA complexity were significantly associated with postoperative complications (p=0.040, 0.015 and 0.006, respectively). However, major complications were only associated with high PADUA complexity (chi-square 23.851, p <0.05). Each scoring system had a significant association with operative time and estimated blood loss (p <0.05), except that the C-index score had no relationship with estimated blood loss (p=0.083). The accuracy of each scoring system in predicting perioperative outcomes and postoperative complications was superior to that of tumor size. CONCLUSIONS Each scoring system has an advantage over tumor size in describing tumor complexity and may help with surgical decision making. Further studies are required to validate their efficacy in evaluating the intraoperative and postoperative results after renal laparoscopic radio frequency ablation.

A Floating Hydrogel System Capable of Generating CO2 Bubbles to Diminish Urinary Obstruction After Intravesical Instillation

ABSTRACTAimIntravesical instillation is commonly used to decrease the tumor recurrence after transurethral resection. However, most drug solutions would be eliminated from bladder after the first voiding of urine, so its clinical efficacy is limited. To overcome this obstacle, we developed a floating hydrogel system for controlled delivery of antitumor drugs.MethodsThe floating hydrogel was made of Adriamycin, thermo-sensitive polymer (Poloxamer 407) and NH4HCO3, which was liquid at low temperature while forming hydrogel at high temperature. Meanwhile, at high temperature, NH4HCO3 decomposed to produce CO2 bubbles, which helped hydrogel float in bladder without urinary obstruction.ResultsThe mixture containing 45% P407 and 6% NH4HCO3 was selected as the optimal formulation. At 37°C, the mixture formed hydrogel and produced many bubbles which could be observed by B ultrasound. The vitro study showed that the antitumor drug Doxorubicin was released in a controlled manner. After the mixture was instilled into rabbit bladder, it formed hydrogel and floated in the bladder. The bladder stimuli was reduced and antitumor drugs could be released continuously in the bladder.ConclusionOur results suggested that the floating hydrogel was a feasible intravesical drug delivery system and may have application prospects in intravesical therapy for bladder cancer.

Zero Ischemia Laparoscopic Radio Frequency Ablation Assisted Enucleation of Renal Cell Carcinoma: Experience with 42 Patients

PURPOSE We evaluated the safety and efficacy of zero ischemia, radio frequency ablation assisted tumor enucleation for renal cell carcinoma. We report the incidence of complications, positive surgical margins, local recurrence, and progression-free and disease specific survival rates. MATERIALS AND METHODS We retrospectively reviewed data on 42 patients with renal cell carcinoma treated with zero ischemia laparoscopic radio frequency ablation assisted tumor enucleation between March 2006 and November 2009. Median age was 60 years (range 37 to 82) and 31 patients (73.8%) were male. The median greatest tumor dimension was 3.4 cm (range 1.8 to 6.1). The Mann-Whitney U, chi-square and Fisher exact tests were used to compare bleeding and complications. The paired t and Mann-Whitney U tests were used to compare glomerular filtration rates. The Kaplan-Meier method was used to calculate survival. RESULTS We found 32 tumors with a greatest dimension of 4 cm or less and 10 with a greatest dimension of 4 to 7 cm. Median blood loss was 82.5 ml (range 15 to 210). Overall 7 complications (16.6%) occurred, including postoperative fever in 4 cases (Clavien grade II) and prolonged urinary leakage in 3 (Clavien grade III). The PADUA (preoperative aspects and dimensions used for an anatomical) score was associated with prolonged urinary leakage (p = 0.03) but not with overall complications. No patient had positive surgical margins. The glomerular filtration rate did not differ before vs 12 months after surgery. Three-year cancer specific, cumulative and progression-free survival was 100%, 97.3% and 96.4%, respectively. CONCLUSIONS Zero ischemia, laparoscopic radio frequency ablation assisted tumor enucleation of renal cell carcinoma is a safe, effective nephron sparing treatment that provides excellent oncological and functional outcomes.

Visualized intravesical floating hydrogel encapsulating vaporized perfluoropentane for controlled drug release

Abstract Intravesical drug delivery is the main strategy for the treatment of bladder disorders. To reduce the relief arising from frequent intravesical instillation, mucoadhesive hydrogel was used for the controlled release of the drug. However, the viscosity of mucoadhesive gel might cause severe urinary obstruction and bladder irritation. To solve all these problems, a floating hydrogel delivery system was developed using perfluoropentane (PFP) as the floating agent. After intravesical instillation of the floating hydrogel, the increased temperature in bladder vaporized PFP, resulting in the generation of microbubbles in the hydrogel. Then, it can float in urine to avoid the urinary obstruction and bladder irritation. In this study, systematic experiments were conducted to investigate the influences of PFP vaporization on the morphology and floating ability of hydrogels. The floating process is much milder and safer than other floating methods published before. In addition, PFP had been used as contrast agent, which affiliated the monitoring of gels during the operation. Therefore, this new drug delivery system addresses the problems of conventional intravesical instillation and is promising for clinic use.

Mitochondrial modulation is involved in the hepatoprotection of Limonium sinense extract against liver damage in mice.

AIM OF THE STUDY Limonium sinense (Girard) Ktze is a Chinese folk medicine used to treat fever, hemorrhage, hepatitis, and other disorders. The present research focused on the protective effects of L. sinense extracts (LSE) against liver damage. MATERIALS AND METHODS In this study the extract from the root of Limonium sinense was used. Aminotransferase activity detection, electron microscopy, mitochondrial function evaluation, RT-PCR and western blot were used to evaluate the hepatoprotection of LSE in LPS/d-GalN-intoxicated mice. RESULTS Pretreatment with 100, 200 or 400mg/kg LSE significantly blocked the increase in both serum aspartate aminotransferase (sAST) and serum alanine aminotransferase (sALT) levels induced by treatment with LPS plus d-GalN (LPS/d-GalN). Ultrastructural observation by electron microscopy showed reduced hepatocyte nuclear condensation and less lipid deposition. The decrease in both the mitochondrial membrane potential (14.6%) and sensitivity to mitochondrial swelling induced by Ca(2+) (45.9%) observed in the liver of LPS/d-GalN-treated mice were prevented by pretreatment with LSE. In addition, different doses of LSE increased both the transcription and the translation of voltage-dependent anion channels (VDAC), which was down-regulated by LPS/d-GalN treatment. CONCLUSIONS In summary, LSE protects livers against LPS/d-GalN-induced damage, possibly by mitochondrial mechanisms related to increased expression of VDAC.