William C. Huang

Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study

BACKGROUND Chronic kidney disease is a graded and independent risk factor for substantial comorbidity and death. We aimed to examine new onset of chronic kidney disease in patients with small, renal cortical tumours undergoing radical or partial nephrectomy. METHODS We did a retrospective cohort study of 662 patients with a normal concentration of serum creatinine and two healthy kidneys undergoing elective partial or radical nephrectomy for a solitary, renal cortical tumour (</=4 cm) between 1989 and 2005 at a referral cancer centre. Glomerular filtration rate (GFR) was estimated with the abbreviated Modification in Diet and Renal Disease Study equation. Separate analysis was undertaken, with chronic kidney disease defined as GFR lower than 60 mL/min per 1.73 m(2) and GFR lower than 45 mL/min per 1.73 m(2). FINDINGS 171 (26%) patients had pre-existing chronic kidney disease before surgery. After surgery, the 3-year probability of freedom from new onset of GFR lower than 60 mL/min per 1.73 m(2) was 80% (95% CI 73-85) after partial nephrectomy and 35% (28-43; p<0.0001) after radical nephrectomy; corresponding values for GFRs lower than 45 mL/min per 1.73 m(2) were 95% (91-98) and 64% (56-70; p<0.0001), respectively. Multivariable analysis showed that radical nephrectomy remained an independent risk factor for patients developing new onset of GFR lower than 60 mL/min per 1.73 m(2) (hazard ratio 3.82 [95% CI 2.75-5.32]) and 45 mL/min per 1.73 m(2) (11.8 [6.24-22.4]; both p<0.0001). INTERPRETATION Because the baseline kidney function of patients with renal cortical tumours is lower than previously thought, accurate assessment of kidney function is essential before surgery. Radical nephrectomy is a significant risk factor for the development of chronic kidney disease and might no longer be regarded as the gold standard treatment for small, renal cortical tumours.

Partial nephrectomy versus radical nephrectomy in patients with small renal tumors--is there a difference in mortality and cardiovascular outcomes?

PURPOSE Compared with partial nephrectomy, radical nephrectomy increases the risk of chronic kidney disease, which is a significant risk factor for cardiovascular events and death. Given equivalent oncological efficacy in patients with small renal tumors, radical nephrectomy may result in overtreatment. We analyzed a population based cohort of patients to determine whether radical nephrectomy is associated with an increase in cardiovascular events and mortality compared with partial nephrectomy. MATERIALS AND METHODS Using Surveillance, Epidemiology and End Results cancer registry data linked with Medicare claims we identified 2,991 patients older than 66 years who were treated with radical or partial nephrectomy for renal tumors 4 cm or less between 1995 and 2002. The primary end points of cardiovascular events and overall survival were assessed using Kaplan-Meier survival estimation, Cox proportional hazards regression and negative binomial regression. RESULTS A total of 2,547 patients (81%) underwent radical nephrectomy and 556 (19%) underwent partial nephrectomy. During a median followup of 4 years 609 patients experienced a cardiovascular event and 892 died. When adjusting for preoperative demographic and comorbid variables, radical nephrectomy was associated with an increased risk of overall mortality (HR 1.38, p <0.01) and a 1.4 times greater number of cardiovascular events after surgery (p <0.05). However, radical nephrectomy was not significantly associated with time to first cardiovascular event (HR 1.21, p = 0.10) or with cardiovascular death (HR 0.95, p = 0.84). CONCLUSIONS Radical nephrectomy, which is currently the most common treatment for small renal tumors, may be associated with significant, adverse treatment effects compared with partial nephrectomy. Partial nephrectomy should be considered in most patients with small renal tumors.

An Interval Longer than 12 Weeks Between the Diagnosis of Muscle Invasion and Cystectomy is Associated with Worse Outcome in Bladder Carcinoma

PURPOSE The standard of care for muscle invasive transitional cell carcinoma of the bladder is radical cystectomy. Definitive therapy may often be delayed for various reasons. We assessed whether pathological stage and survival correlated with the length of time between diagnosis of muscle invasion and cystectomy. MATERIALS AND METHODS The records of 290 consecutive patients who underwent radical cystectomy between February 1987 and July 2000 were reviewed. Of 265 (91.4%) cystectomies performed for transitional cell carcinoma data were available for 247 (85.2%) and 189 (65.2%) patients were identified who underwent surgery for muscle invasive disease (T2 or greater). The interval between diagnosis of muscle invasion and cystectomy was calculated for each patient. Patients were divided into groups based on time to surgery as group 1-less than 4 weeks, 2-4 to 6 weeks, 3-7 to 9 weeks, 4-10 to 12 weeks, 5-13 to 16 weeks, and 6-greater than 16 weeks. Exploratory univariate and multivariate analyses were performed to test the association of time lag with clinical features and postoperative survival. RESULTS Mean patient age was 66 years (range 37 to 84) and overall 3-year Kaplan-Meier estimated survival was 59.1% +/- 4% (median followup 36 months). For all patients mean interval from diagnosis to cystectomy was 7.9 weeks (range 1 to 40). Extravesical disease (P3a or greater) or positive nodes were identified in 84% (16 of 19) of patients when the delay was longer than 12 weeks, compared with 48.2% (82 of 170) in those with a time lag of 12 weeks or less (p < 0.01). Similarly 3-year estimated survival was lower (34.9% +/- 13.5%) for patients with a surgery delay longer than 12 weeks compared to those with a shorter interval 62.1% +/- 4.5% (hazards ratio 2.51, 95% CI 1.30-4.83, p = 0.006). When adjusted for nodal status, and clinical and pathological stages the interval was still statistically significant (adjusted hazards ratio 1.93, 95% CI 0.99-3.76, p = 0.05). CONCLUSIONS In patients undergoing radical cystectomy a delay in surgery of greater than 12 weeks was associated with advanced pathological stage and decreased survival. Although this relationship persisted after adjusting for nodal status, and clinical and pathological stages, the presence of lymph node metastasis remained the strongest predictor of patient outcome.

A Prospective, Blinded Comparison of Magnetic Resonance (MR) Imaging–Ultrasound Fusion and Visual Estimation in the Performance of MR-targeted Prostate Biopsy: The PROFUS Trial

BACKGROUND Increasing evidence supports the use of magnetic resonance (MR)-targeted prostate biopsy. The optimal method for such biopsy remains undefined, however. OBJECTIVE To prospectively compare targeted biopsy outcomes between MR imaging (MRI)-ultrasound fusion and visual targeting. DESIGN, SETTING, AND PARTICIPANTS From June 2012 to March 2013, prospective targeted biopsy was performed in 125 consecutive men with suspicious regions identified on prebiopsy 3-T MRI consisting of T2-weighted, diffusion-weighted, and dynamic-contrast enhanced sequences. INTERVENTION Two MRI-ultrasound fusion targeted cores per target were performed by one operator using the ei-Nav|Artemis system. Targets were then blinded, and a second operator took two visually targeted cores and a 12-core biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Biopsy information yield was compared between targeting techniques and to 12-core biopsy. Results were analyzed using the McNemar test. Multivariate analysis was performed using binomial logistic regression. RESULTS AND LIMITATIONS Among 172 targets, fusion biopsy detected 55 (32.0%) cancers and 35 (20.3%) Gleason sum ≥7 cancers compared with 46 (26.7%) and 26 (15.1%), respectively, using visual targeting (p=0.1374, p=0.0523). Fusion biopsy provided informative nonbenign histology in 77 targets compared with 60 by visual (p=0.0104). Targeted biopsy detected 75.0% of all clinically significant cancers and 86.4% of Gleason sum ≥7 cancers detected on standard biopsy. On multivariate analysis, fusion performed best among smaller targets. The study is limited by lack of comparison with whole-gland specimens and sample size. Furthermore, cancer detection on visual targeting is likely higher than in community settings, where experience with this technique may be limited. CONCLUSIONS Fusion biopsy was more often histologically informative than visual targeting but did not increase cancer detection. A trend toward increased detection with fusion biopsy was observed across all study subsets, suggesting a need for a larger study size. Fusion targeting improved accuracy for smaller lesions. Its use may reduce the learning curve necessary for visual targeting and improve community adoption of MR-targeted biopsy.

Trends in Renal Tumor Surgery Delivery Within the United States

Most small renal tumors are amenable to partial nephrectomy (PN). Studies have documented the association of radical nephrectomy (RN) with an increased risk of comorbid conditions, such as chronic kidney disease. Despite evidence of equivalent oncologic outcomes, PN remains under used within the United States. In this study, the authors identified the most recent trends in kidney surgery for small renal tumors and determined which factors were associated with the use of PN versus RN within the United States.

Prognostic Impact of the 2009 UICC/AJCC TNM Staging System for Renal Cell Carcinoma with Venous Extension

BACKGROUND The prognostic significance of venous involvement and tumour thrombus level in renal cell carcinoma (RCC) remains highly controversial. In 2010, the American Joint Committee on Cancer (AJCC) and the Union International Centre le Cancer (UICC) revised the RCC staging system (7th edition) based on tumour thrombus level, differentiating the T stage of tumours limited to renal-vein-only involvement. OBJECTIVE We aimed to evaluate the impact of tumour thrombus extension in a multi-institutional cohort of patients. DESIGN, SETTING, AND PARTICIPANTS An international consortium of 11 institutions was established to retrospectively review a combined cohort of 1215 patients undergoing radical nephrectomy and tumour thrombectomy for RCC, including 585 patients with inferior vena cava (IVC) involvement or higher. MEASUREMENTS Predictive factors of survival, including histology, tumour thrombus level, nodal status, Fuhrman grade, and tumour size, were analysed. RESULTS AND LIMITATIONS A total of 1122 patients with complete data were reviewed. The median follow-up for all patients was 24.7 mo, with a median survival of 33.8 mo. The 5-yr survival was 43.2% (renal vein involvement), 37% (IVC below the diaphragm), and 22% with caval involvement above the diaphragm. On multivariate analysis, tumour size (hazard ratio [HR]: 1.64 [range: 1.03-2.59]; p=0.036), Fuhrman grade (HR: 2.26 [range: 1.65-3.1]; p=0.000), nodal metastasis (HR: 1.32 [range: 1.09-1.67]; p=0.005), and tumour thrombus level (HR: 2.10 [range: 1.53-3.0]; p=0.00) correlated independently with survival. CONCLUSIONS Based on analysis of the largest known cohort of patients with RCC along with IVC and atrial thrombus involvement, tumour thrombus level is an independent predictor of survival. Our findings support the changes to the latest AJCC/UICC staging system.

Changes in Renal Function Following Nephroureterectomy May Affect the Use of Perioperative Chemotherapy

BACKGROUND Nephroureterectomy alone fails to adequately treat many patients with advanced upper tract urothelial carcinoma (UTUC). Perioperative platinum-based chemotherapy has been proposed but requires adequate renal function. OBJECTIVE Our aim was to determine whether the ability to deliver platinum-based chemotherapy following nephroureterectomy is affected by postoperative changes in renal function. DESIGN, SETTINGS, AND PARTICIPANTS We retrospectively reviewed data on 388 patients undergoing nephroureterectomy for UTUC between 1991 and 2009. Four institutions were included. INTERVENTION All patients underwent nephroureterectomy. MEASUREMENTS All patients had serum creatinine measured before and after surgery. The value closest to 3 mo after surgery was taken as the postoperative value (range: 2-52 wk). Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease study equation. eGFR values before and after surgery were compared using the paired t test. We chose an eGFR of 45 and 60 ml/min per 1.73 m(2) as possible cut-offs for chemotherapy eligibility and compared eligibility before and after surgery using the chi-square test. RESULTS AND LIMITATIONS Our cohort of 388 patients included 233 men (60%) with a median age of 70 yr. Mean eGFR decreased by 24% after surgery. Using a cut-off of 60 ml/min per 1.73 m(2), 49% of patients were eligible for chemotherapy before surgery, but only 19% of patients remained eligible postoperatively. Using a cut-off of 45 ml/min per 1.73 m(2), 80% of patients were eligible preoperatively, but only 55% remained eligible after surgery. This distribution persisted when we limited the analysis to patients with advanced pathologic stage (T3 or higher). Patients older than the median age of 70 yr were more likely to be ineligible for chemotherapy both pre- and postoperatively by either definition, and they were significantly more likely to have an eGFR <45 ml/min per 1.73 m(2) postoperatively, regardless of their starting eGFR. This study is limited by its retrospective nature, and there was some variability in the timing of postoperative serum creatinine measurements. CONCLUSIONS eGFR is significantly diminished after nephroureterectomy, particularly in elderly patients. These changes in renal function likely affect eligibility for adjuvant cisplatin-based therapy. Accordingly, we suggest strong consideration of neoadjuvant regimens.

Relationship Between Prebiopsy Multiparametric Magnetic Resonance Imaging (MRI), Biopsy Indication, and MRI-ultrasound Fusion–targeted Prostate Biopsy Outcomes

BACKGROUND Increasing evidence supports the use of magnetic resonance imaging (MRI)-ultrasound fusion-targeted prostate biopsy (MRF-TB) to improve the detection of clinically significant prostate cancer (PCa) while limiting detection of indolent disease compared to systematic 12-core biopsy (SB). OBJECTIVE To compare MRF-TB and SB results and investigate the relationship between biopsy outcomes and prebiopsy MRI. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of a prospectively acquired cohort of men presenting for prostate biopsy over a 26-mo period. A total of 601 of 803 consecutively eligible men were included. INTERVENTIONS All men were offered prebiopsy MRI and assigned a maximum MRI suspicion score (mSS). Men with an MRI abnormality underwent combined MRF-TB and SB. OUTCOMES Detection rates for all PCa and high-grade PCa (Gleason score [GS] ≥7) were compared using the McNemar test. RESULTS AND LIMITATIONS MRF-TB detected fewer GS 6 PCas (75 vs 121; p<0.001) and more GS ≥7 PCas (158 vs 117; p<0.001) than SB. Higher mSS was associated with higher detection of GS ≥7 PCa (p<0.001) but was not correlated with detection of GS 6 PCa. Prediction of GS ≥7 disease by mSS varied according to biopsy history. Compared to SB, MRF-TB identified more GS ≥7 PCas in men with no prior biopsy (88 vs 72; p=0.012), in men with a prior negative biopsy (28 vs 16; p=0.010), and in men with a prior cancer diagnosis (42 vs 29; p=0.043). MRF-TB detected fewer GS 6 PCas in men with no prior biopsy (32 vs 60; p<0.001) and men with prior cancer (30 vs 46; p=0.034). Limitations include the retrospective design and the potential for selection bias given a referral population. CONCLUSIONS MRF-TB detects more high-grade PCas than SB while limiting detection of GS 6 PCa in men presenting for prostate biopsy. These findings suggest that prebiopsy multiparametric MRI and MRF-TB should be considered for all men undergoing prostate biopsy. In addition, mSS in conjunction with biopsy indications may ultimately help in identifying men at low risk of high-grade cancer for whom prostate biopsy may not be warranted. PATIENT SUMMARY We examined how magnetic resonance imaging (MRI)-targeted prostate biopsy compares to traditional systematic biopsy in detecting prostate cancer among men with suspicion of prostate cancer. We found that MRI-targeted biopsy detected more high-grade cancers than systematic biopsy, and that MRI performed before biopsy can predict the risk of high-grade cancer.

H-Ras forms dimers on membrane surfaces via a protein–protein interface

Significance Ras is a key signaling molecule in living cells, and mutations in Ras are involved in 30% of human cancers. It is becoming progressively more clear that the spatial arrangement of proteins within a cell, not just their chemical structure, is an important aspect of their function. In this work, we use a series of quantitative physical techniques to map out the tendency of two Ras molecules to bind together to form a dimer on membrane surfaces. Insights from this work, as well as the technical assays developed, may help to discover new therapeutic drugs capable of modulating the errant behavior of Ras in cancer. The lipid-anchored small GTPase Ras is an important signaling node in mammalian cells. A number of observations suggest that Ras is laterally organized within the cell membrane, and this may play a regulatory role in its activation. Lipid anchors composed of palmitoyl and farnesyl moieties in H-, N-, and K-Ras are widely suspected to be responsible for guiding protein organization in membranes. Here, we report that H-Ras forms a dimer on membrane surfaces through a protein–protein binding interface. A Y64A point mutation in the switch II region, known to prevent Son of sevenless and PI3K effector interactions, abolishes dimer formation. This suggests that the switch II region, near the nucleotide binding cleft, is either part of, or allosterically coupled to, the dimer interface. By tethering H-Ras to bilayers via a membrane-miscible lipid tail, we show that dimer formation is mediated by protein interactions and does not require lipid anchor clustering. We quantitatively characterize H-Ras dimerization in supported membranes using a combination of fluorescence correlation spectroscopy, photon counting histogram analysis, time-resolved fluorescence anisotropy, single-molecule tracking, and step photobleaching analysis. The 2D dimerization Kd is measured to be ∼1 × 103 molecules/µm2, and no higher-order oligomers were observed. Dimerization only occurs on the membrane surface; H-Ras is strictly monomeric at comparable densities in solution. Analysis of a number of H-Ras constructs, including key changes to the lipidation pattern of the hypervariable region, suggest that dimerization is a general property of native H-Ras on membrane surfaces.

Diffusion-weighted intravoxel incoherent motion imaging of renal tumors with histopathologic correlation

PurposeThe aim of this study was to use intravoxel incoherent motion diffusion-weighted imaging to discriminate subtypes of renal neoplasms and to assess agreement between intravoxel incoherent motion (perfusion fraction, fp) and dynamic contrast-enhanced magnetic resonance imaging (MRI) metrics of tumor vascularity. Subjects and MethodsIn this Health Insurance Portability and Accountability Act–compliant, institutional review board–approved prospective study, 26 patients were imaged at 1.5-T MRI using dynamic contrast-enhanced MRI with high temporal resolution and diffusion-weighted imaging using 8 b values (range, 0-800 s/mm2). Perfusion fraction (fp), tissue diffusivity (Dt), and pseudodiffusivity (Dp) were calculated using biexponential fitting of the diffusion data. Apparent diffusion coefficient (ADC) was calculated with monoexponential fit using 3 b values of 0, 400, and 800 s/mm2. Dynamic contrast-enhanced data were processed with a semiquantitative method to generate model-free parameter cumulative initial area under the curve of gadolinium concentration at 60 seconds (CIAUC60). Perfusion fraction, Dt, Dp, ADC, and CIAUC60 were compared between different subtypes of renal lesions. Perfusion fraction was correlated with CIAUC60. ResultsWe examined 14 clear cell, 4 papillary, 5 chromophobe, and 3 cystic renal cell carcinomas (RCCs). Although fp had higher accuracy (area under the curve, 0.74) for a diagnosis of clear cell RCC compared with Dt or ADC, the combination of fp and Dt had the highest accuracy (area under the curve, 0.78). The combination of fp and Dt diagnosed papillary RCC and cystic RCC with 100% accuracy, and clear cell RCC and chromophobe RCC, with 86.5% accuracy. There was significant strong correlation between fp and CIAUC60 (r = 0.82; P < 0.001). ConclusionIntravoxel incoherent motion parameters fp and Dt can discriminate renal tumor subtypes. Perfusion fraction demonstrates good correlation with CIAUC60 and can assess degree of tumor vascularity without the use of exogenous contrast agent.