The association between statin medication and progression after surgery for localized renal cell carcinoma.

PURPOSE: Evidence suggests that statins may influence pathways of renal cell carcinoma proliferation, although to our knowledge no study has examined the influence of statin medications on the progression of renal cell carcinoma in humans. MATERIALS AND METHODS: We identified 2,608 patients with localized renal cell carcinoma who were treated surgically between 1995 and 2010 at our tertiary referral center. Competing risks Cox proportional hazards models were used to evaluate the relationship between statin use and time to local recurrence or progression (metastases or death from renal cell carcinoma) and overall survival. Statin use was modeled as a time dependent covariate as a sensitivity analysis. Models were adjusted for clinical and demographic features. RESULTS: Of 2,608 patients 699 (27%) were statin users at surgery. Statin users had similar pathological characteristics compared to nonusers. At a median followup of 36 months there were 247 progression events. Statin use was associated with a 33% reduction in the risk of progression after surgery (HR 0.67, 95% CI 0.47-0.96, p = 0.028) and an 11% reduction in overall mortality that was not significant (HR 0.89, 95% CI 0.71-1.13, p = 0.3). Modeling statin use as a time dependent covariate attenuated the risk reduction in progression to 23% (HR 0.77, p = 0.12) and augmented the risk reduction in overall survival (HR 0.71, p = 0.002). CONCLUSIONS: In our cohort statin use was associated with a reduced risk of progression and overall mortality, although this effect was sensitive to the method of analysis. If validated in other cohorts, this finding warrants consideration of prospective research on statins in the adjuvant setting.

Postcoital Hemorrhage of a Recurrent Seminal Vesicle Cyst Requiring Embolization.

Herein is a case of a 23-year-old man with recurrence of a seminal vesicle cyst after percutaneous drainage and laparoscopic excision complicated by hemorrhage requiring embolization. He presented to the emergency department for pain after ejaculation. Computed tomographic scan of his pelvis revealed extravasation of contrast near his cyst and pelvic fluid collection suspicious for a hematoma. The patient had steadily decreasing hemoglobin and hematocrit levels. An interventional radiologist performed an embolization of the left seminal vesicle cystic arteries. Hemoglobin and hematocrit values improved and he was discharged. Hemorrhage resolved with embolization procedure and pain dissipated over the course of follow up care.

Recovery of a catalase-negative Staphylococcus epidermidis strain in blood and urine cultures from a patient with pyelonephritis.

This report describes a 60-year-old patient with bilateral nephrolithiasis. A catalase-negative Staphylococcus epidermidis strain was recovered from both urine and blood cultures. Although rare, isolates of catalase-negative Staphylococcus spp., including Staphylococcus aureus, have been reported. Here, we describe the first report of a catalase-negative S. epidermidis strain.

Paclitaxel-resistant cells have a mutation in the paclitaxel-binding region of beta-tubulin (Asp26Glu) and less stable microtubules.

Resistance to paclitaxel-based therapy is frequently encountered in the clinic. The mechanisms of intrinsic or acquired paclitaxel resistance are not well understood. We sought to characterize the resistance mechanisms that develop upon chronic exposure of a cancer cell line to paclitaxel in the presence of the P-glycoprotein reversal agent, CL-347099. The epidermoid tumor line KB-3-1 was exposed to increasing concentrations of paclitaxel and 5 micromol/L CL-347099 for up to 1 year. Cells grown in 15 nmol/L paclitaxel plus CL-347099 (KB-15-PTX/099) developed 18-fold resistance to paclitaxel and were dependent upon paclitaxel for maximal growth. They grew well and retained resistance to paclitaxel when grown in athymic mice. Cross-resistance (3- to 5-fold) was observed in tissue culture to docetaxel, the novel taxane MAC-321, and epothilone B. Collateral sensitivity (approximately 3-fold) was observed to the depolymerizing agents vinblastine, dolastatin-10, and HTI-286. KB-15-PTX/099-resistant cells did not overexpress P-glycoprotein nor did they have an alteration of [14C]paclitaxel accumulation compared with parental cells. However, a novel point mutation (T to A) resulting in Asp26 to glutamate substitution in class I (M40) beta-tubulin was found. Based on an electron crystallography structure of Zn-stabilized tubulin sheets, the phenyl ring of C-3' NHCO-C6H5 of paclitaxel makes contact with Asp26 of beta-tubulin, suggesting a ligand-induced mutation. Optimized model complexes of paclitaxel, docetaxel, and MAC-321 in beta-tubulin show a novel hydrogen bonding pattern for the glutamate mutant and rationalize the observed resistance profiles. However, a mutation in the paclitaxel binding pocket does not explain the phenotype completely. KB-15-PTX/099 cells have impaired microtubule stability as determined by a reduced percentage of tubulin in microtubules and reflected by less acetylated tubulin. These results suggest that a mutation in tubulin might affect microtubule stability as well as drug binding and contribute to the observed resistance profile.

Cells resistant to HTI-286 do not overexpress P-glycoprotein but have reduced drug accumulation and a point mutation in alpha-tubulin.

HTI-286, a synthetic analogue of hemiasterlin, depolymerizes microtubules and is proposed to bind at the Vinca peptide site in tubulin. It has excellent in vivo antitumor activity in human xenograft models, including tumors that express P-glycoprotein, and is in phase II clinical evaluation. To identify potential mechanisms of resistance induced by HTI-286, KB-3-1 epidermoid carcinoma cells were exposed to increasing drug concentrations. When maintained in 4.0 nmol/L HTI-286, cells had 12-fold resistance to HTI-286. Cross-resistance was observed to other Vinca peptide-binding agents, including hemiasterlin A, dolastatin-10, and vinblastine (7- to 28-fold), and DNA-damaging drugs, including Adriamycin and mitoxantrone (16- to 57-fold), but minimal resistance was seen to taxanes, epothilones, or colchicine (1- to 4-fold). Resistance to HTI-286 was retained when KB-HTI-resistant cells were grown in athymic mice. Accumulation of [(3)H]HTI-286 was lower in cells selected in intermediate (2.5 nmol/L) and high (4.0 nmol/L) concentrations of HTI-286 compared with parental cells, whereas accumulation of [(14)C]paclitaxel was unchanged. Sodium azide treatment partially reversed low HTI-286 accumulation, suggesting involvement of an ATP-dependent drug pump. KB-HTI-resistant cells did not overexpress P-glycoprotein, breast cancer resistance protein (BCRP/ABCG2/MXR), MRP1, or MRP3. No mutations were found in the major beta-tubulin isoform. However, 4.0 nmol/L HTI-286-selected cells had a point mutation in alpha-tubulin that substitutes Ser for Ala(12) near the nonexchangeable GTP-binding site of alpha-tubulin. KB-HTI-resistant cells removed from drug became less resistant to HTI-286, no longer had low HTI-286 accumulation, and retained the Ala(12) mutation. These data suggest that HTI-286 resistance may be partially mediated by mutation of alpha-tubulin and by an ATP-binding cassette drug pump distinct from P-glycoprotein, ABCG2, MRP1, or MRP3.