Cancer Liason Physician, Commission on Cancer - VA Palo Alto Health Care System (2010 - Present)
Director of Urologic Oncology, VA Palo Alto Health Care System (2010 - Present)
Honors & Awards
Faculty Mentor Award, Stanford Biodesign Program (2012)
Developmental Cancer Research Award, Stanford Cancer Institute (2011 - 2013)
Career Development Award (K23), The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (2010 - 2015)
MS, Stanford University School of Medicine, Epidemiology (2013)
Fellowship, UCLA, Minimally Invasive Surgery / Endourology (2008)
Residency, UCLA, Urology (2007)
Internship, UCLA, Surgery (2002)
MD, Northwestern University Medical School, Honors Program Medical Education (2001)
BA, Northwestern University, Biology (1996)
Current Research and Scholarly Interests
Our research aims to improve the global quality of care for patients with Urologic cancer with a particular focus on kidney cancer. We are evaluating the comparative effectiveness of various kidney cancer surgeries and their impact on chronic kidney disease and its downstream effects. We are investigating nano-proteomic and novel assays to diagnose kidney cancer and predict response to therapy. We are applying epidemiology, bioinformatics, and health services methods to urologic conditions.
Independent Studies (7)
- Directed Reading in Health Research and Policy
HRP 299 (Aut, Win, Spr, Sum)
- Directed Reading in Urology
UROL 299 (Aut, Win, Spr, Sum)
- Early Clinical Experience in Urology
UROL 280 (Aut, Win, Spr, Sum)
- Graduate Research
HRP 399 (Aut, Win, Spr, Sum)
- Graduate Research
UROL 399 (Aut, Win, Spr, Sum)
- Medical Scholars Research
UROL 370 (Aut, Win, Spr, Sum)
- Undergraduate Research
UROL 199 (Aut, Win, Spr, Sum)
- Directed Reading in Health Research and Policy
Contemporary Use of Partial Nephrectomy: Are Older Patients With Impaired Kidney Function Being Left Behind?
To assess whether patient factors, such as age and preoperative kidney function, were associated with receipt of partial nephrectomy in a national integrated healthcare system.We identified patients treated with a radical or partial nephrectomy from 2002 to 2014 in the Veterans Health Administration. We examined associations among patient age, sex, race or ethnicity, multimorbidity, baseline kidney function, tumor characteristics, and receipt of partial nephrectomy. We estimated the odds of receiving a partial nephrectomy and assessed interactions between covariates and the year of surgery to explore whether patient factors associated with partial nephrectomy changed over time.In our cohort of 14,186 patients, 4508 (31.2%) received a partial nephrectomy. Use of partial nephrectomy increased from 17% in 2002 to 32% in 2008 and to 38% in 2014. Patient race or ethnicity, age, tumor stage, and year of surgery were independently associated with receipt of partial nephrectomy. Black veterans had significantly increased odds of receipt of partial nephrectomy, whereas older patients had significantly reduced odds. Partial nephrectomy utilization increased for all groups over time, but older patients and patients with worse baseline kidney function showed the least increase in odds of partial nephrectomy.Although the utilization of partial nephrectomy increased for all groups, the greatest increase occurred in the youngest patients and those with the highest baseline kidney function. These trends warrant further investigation to ensure that patients at the highest risk of impaired kidney function are considered for partial nephrectomy whenever possible.
View details for DOI 10.1016/j.urology.2016.08.044
View details for PubMedID 27634733
Overall Survival in Patients with Localized Prostate Cancer in the US Veterans Health Administration: Is PIVOT Generalizable?
2016; 70 (2): 227-230
A better understanding of overall survival among patients with clinically localized prostate cancer (PCa) in the US Veterans Health Administration (VHA) is critical to inform PCa treatment decisions, especially in light of data from the Prostate Intervention Versus Observation Trial (PIVOT). We sought to describe patterns of survival for all patients with clinically localized PCa treated by the VHA. We created an analytic cohort of 35 954 patients with clinically localized PCa diagnosed from 1995 to 2001, approximating the PIVOT inclusion criteria (age of diagnosis ≤75 yr and clinical stage T2 or lower). Mean patient age was 65.9 yr, and median follow-up was 161 mo. Overall, 22.5% of patients were treated with surgery, 16.6% were treated with radiotherapy, and 23.1% were treated with androgen deprivation. Median survival of the entire cohort was 14 yr (25th, 75th percentiles, range: 7.9-20 yr). Among patients who received treatment with curative intent, median survival was 17.9 yr following surgery and 12.9 yr following radiotherapy. One-third of patients died within 10 yr of diagnosis compared with nearly half of the participants in PIVOT. This finding sounds a note of caution when generalizing the mortality data from PIVOT to VHA patients and those in the community.More than one-third of patients diagnosed with clinically localized prostate cancer treated through the US Veterans Health Administration from 1995 to 2001 died within 10 yr of their diagnosis. Caution should be used when generalizing the estimates of competing mortality data from PIVOT.
View details for DOI 10.1016/j.eururo.2016.02.037
View details for Web of Science ID 000378206600016
View details for PubMedID 26948397
- Accuracy of Prostate-Specific Antigen Values in Prostate Cancer Registries. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2016
- Perspective: Beyond the genome. Nature 2016; 537 (7620): S105-?
Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era.
International journal of cancer. Journal international du cancer
2014; 134 (9): 2245-2252
We sought to analyze utilization and survival outcomes of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (RCC) before and after introduction of targeted therapy. We identified patients with metastatic RCC between 1993 and 2010 in the SEER registry and examined temporal trends in utilization. We performed a joinpoint regression to determine when changes in utilization of cytoreductive nephrectomy occurred. We fitted multivariable proportional hazard models in full and propensity score-matched cohorts. We performed a difference-in-difference analysis to compare survival outcomes before and after introduction of targeted therapy. The proportion of patients undergoing cytoreductive nephrectomy increased from 1993 to 2004, from 29% to 39%. We identified a primary joinpoint of 2004, just prior to the introduction of targeted therapy. Beginning in 2005, there was a modest decrease in utilization of cytoreductive nephrectomy. Cytoreductive nephrectomy was associated with a lower adjusted relative hazard (0.41, 95% confidence interval 0.34 to 0.43). Median survival among patients receiving cytoreductive nephrectomy increased in the targeted therapy era (19 versus 13 months), while median survival among patients not receiving cytoreductive nephrectomy increased only slightly (4 versus 3 months). Difference-in-difference analysis showed a significant decrease in hazard of death among patients who received cytoreductive nephrectomy in the targeted therapy era. Despite decreased utilization in the targeted therapy era, cytoreductive nephrectomy remains associated with improved survival. Prospective randomized trials are needed to confirm the benefit of cytoreductive nephrectomy among patients with metastatic RCC treated with novel targeted therapies. © 2013 Wiley Periodicals, Inc.
View details for PubMedID 24135850
Utilization of renal mass biopsy in patients with renal cell carcinoma.
2014; 83 (4): 774-780
To examine the patient, tumor, and temporal factors associated with receipt of renal mass biopsy (RMB) in a contemporary nationally representative sample.We queried the Surveillance, Epidemiology, and End Results-Medicare data set for incident cases of renal cell carcinoma diagnosed between 1992 and 2007. We tested for associations among receipt of RMB and patient and tumor characteristics, type of therapy, and procedure type. Temporal trends in receipt of RMB were characterized over the study period.Approximately 1 in 5 (20.7%) patients diagnosed with renal cell carcinoma (n = 24,702) underwent RMB before instituting therapy. There was a steady and modest increase in RMB utilization, with the highest utilization (30%) occurring in the final study year. Of patients who underwent radical (n = 15,666) or partial (n = 2211) nephrectomy, 17% and 20%, respectively, underwent RMB in advance of surgery. Sixty-five percent of patients who underwent ablation (n = 314) underwent RMB before or in conjunction with the procedure. Roughly half of patients (50.4%) treated with systemic therapy alone underwent RMB. Factors independently associated with use of RMB included younger age, black race, Hispanic ethnicity, tumor size <7 cm, and metastatic disease at presentation.At present, most patients who eventually undergo radical or partial nephrectomy do not undergo RMB, whereas most patients who eventually undergo ablation or systemic therapy do. The optimal use of RMB in the evaluation of kidney tumors has yet to be determined.
View details for DOI 10.1016/j.urology.2013.10.073
View details for PubMedID 24529579
Diabetic Severity and Risk of Kidney Stone Disease
2014; 65 (1): 242-247
BACKGROUND: The prevalence of kidney stone disease is rising along with increasing rates of obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. OBJECTIVE: To investigate the associations among the presence and severity of T2DM, glycemic control, and insulin resistance with kidney stone disease. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional analysis of all adult participants in the 2007-2010 National Health and Nutrition Examination Survey (NHANES). A history of kidney stone disease was obtained by self-report. T2DM was defined by self-reported history, T2DM-related medication usage, and reported diabetic comorbidity. Insulin resistance was estimated using fasting plasma insulin (FPI) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) definition. We classified glycemic control using glycosylated hemoglobin A1c (HbA1c) and fasting plasma-glucose levels (FPG). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (OR) for having kidney stone disease were calculated for each individual measure of T2DM severity. Logistic regression models were fitted adjusting for age, sex, race/ethnicity, smoking history, and the Quételet index (body mass index), as well as laboratory values and components of metabolic syndrome. RESULTS AND LIMITATIONS: Correlates of kidney stone disease included a self-reported history of T2DM (OR: 2.44; 95% confidence interval [CI], 1.84-3.25) and history of insulin use (OR: 3.31; 95% CI, 2.02-5.45). Persons with FPG levels 100-126mg/dl and >126mg/dl had increased odds of having kidney stone disease (OR 1.28; 95% CI, 0.95-1.72; and OR 2.29; 95% CI, 1.68-3.12, respectively). Corresponding results for persons with HbA1c 5.7-6.4% and =6.5% were OR 1.68 (95% CI, 1.17-2.42) and OR 2.82 (95% CI, 1.98-4.02), respectively. When adjusting for patient factors, a history of T2DM, the use of insulin, FPI, and HbA1c remained significantly associated with kidney stone disease. The cross-sectional design limits causal inference. CONCLUSIONS: Among persons with T2DM, more-severe disease is associated with a heightened risk of kidney stones.
View details for DOI 10.1016/j.eururo.2013.03.026
View details for Web of Science ID 000327766500042
View details for PubMedID 23523538
Defining the Rate of Negative Ureteroscopy in the General Population Treated for Upper Tract Urinary Stone Disease.
Journal of endourology
2017; 31 (3): 266-271
Ureteroscopy is increasingly used to treat upper tract urinary stone disease. A negative ureteroscopy is a ureteroscopy performed with the intent of removing a kidney or ureteral stone, but in which ultimately no stone is removed. Negative ureteroscopy may occur when the stone is found to have already passed, or the presumed stone is found to be outside of the collecting system. We sought to determine the rate of negative ureteroscopy in a large population-based sample as well as factors associated with its use.We examined nonpublic data from the Office of Statewide Health Planning and Development (OSHPD) Database for all patients in California undergoing outpatient surgery from 2010 to 2012. We identified all patients with an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code for upper tract urinary stone disease, who underwent a ureteroscopic procedure. After excluding patients undergoing second look procedures or who had diagnosis codes for separate urologic pathology, the negative ureteroscopy rate was defined as the proportion of those ureteroscopy cases coded as a diagnostic ureteroscopy. We fit logistic regression models to evaluate patient factors associated with negative ureteroscopy.During the years 2010 to 2012, 20,236 eligible patients underwent ureteroscopic procedures for upper tract stone disease. Of these, 1287 patients underwent diagnostic ureteroscopy and 19,039 underwent ureteroscopy with stone removal accounting for a negative ureteroscopy rate of 6.3%. The odds of receipt of a negative ureteroscopy rate were higher in females compared to males (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.25, 1.58) and lower in self-pay patients compared with insured patients (OR = 0.55, 95% CI 0.33, 0.91).Negative ureteroscopy is common, occurring in nearly 1 in 16 procedures to treat urinary stone disease.
View details for DOI 10.1089/end.2016.0751
View details for PubMedID 28049343
- Intraoperative Optical Biopsy during Robotic Assisted Radical Prostatectomy Using Confocal Endomicroscopy JOURNAL OF UROLOGY 2016; 195 (4): 1110-1117
A Protective Role for Androgen Receptor in Clear Cell Renal Cell Carcinoma Based on Mining TCGA Data.
2016; 11 (1)
Androgen receptor (AR) is expressed in normal murine and human kidneys of both genders, but its physiologic role is uncertain. Several studies showed loss of AR in renal cell carcinoma (RCC) in conjunction with increasing clinical stage and pathological grade, but others found that higher AR expression correlated with worse outcomes. Limited functional studies with renal cell lines suggested tumor-promoting activity of AR. In this study, we queried transcriptomic, proteomic, epigenetic and survival data from The Cancer Genome Atlas (TCGA) to evaluate AR expression and its association with overall survival in three subtypes of RCC (clear cell [ccRCC], papillary [pRCC], and chromophobe [chRCC]). We found that although there was no significant difference in AR mRNA expression in ccRCC of males vs. females, AR protein expression in ccRCC was significantly higher in male compared to female patients. More importantly, higher expression of AR at both transcript and protein levels was associated with improved overall survival in both genders with ccRCC, but did not predict survival of either gender with pRCC or chRCC. Genes whose transcript levels were associated with AR mRNA levels significantly overlapped between ccRCC and pRCC, but not with chRCC, suggesting a similar transcriptional program mediated by AR in ccRCC and pRCC. Ingenuity pathway analysis also identified overlapping pathways and upstream regulators enriched in AR-associated genes in ccRCC and pRCC. Hypermethylation of CpG sites located in the promoter and first exon of AR was associated with loss of AR expression and poor overall survival. Our findings support a tumor suppressor role for AR in both genders that might be exploited to decrease the incidence or progression of ccRCC.
View details for DOI 10.1371/journal.pone.0146505
View details for PubMedID 26814892
A Pilot Study of In Vivo Confocal Laser Endomicroscopy of Upper Tract Urothelial Carcinoma
JOURNAL OF ENDOUROLOGY
2015; 29 (12): 1418-1423
Tissue diagnosis of upper tract urothelial carcinoma (UTUC) is limited by variance in tumor sampling by standard ureteroscopic biopsy. Optical imaging technologies can potentially improve UTUC diagnosis, surveillance, and endoscopic treatment. We previously demonstrated in vivo optical biopsy of urothelial carcinoma of the bladder using confocal laser endomicroscopy (CLE). In this study, we evaluated a new 0.85-mm imaging probe in the upper urinary tract and demonstrated feasibility and compatibility with standard ureteroscopes to achieve in vivo optical biopsy of UTUC.Fourteen patients scheduled for ureteroscopy of suspected upper tract lesions or surveillance of UTUC were recruited. After intravenous (IV) administration of fluorescein, CLE was performed using a 0.85-mm-diameter imaging probe inserted through the working channel of standard ureteroscopes. Acquired confocal video sequences were reviewed and analyzed. A mosaicing algorithm was used to compile a series of images into a single larger composite image. Processed CLE images were compared with standard histopathologic analysis.Optical biopsy of the UTUC using CLE was effectively achieved during standard ureteroscopy. There were no adverse events related to IV fluorescein administration or image acquisition. Confocal imaging of UTUC showed characteristic features similar to urothelial carcinoma of the bladder, including papillary structure, fibrovascular stalks, and pleomorphism. Lamina propria in normal areas of the renal pelvis and ureter was also identified.We report an initial feasibility of CLE of UTUC. Pending further clinical investigation, CLE may become a useful adjunct to ureteroscopic biopsy, endoscopic ablation, and surveillance of UTUC.
View details for DOI 10.1089/end.2015.0523
View details for Web of Science ID 000366602600015
View details for PubMedID 26413927
- Biochemical Measures of Diabetes are Not Independent Predictors of Urinary Incontinence in Women JOURNAL OF UROLOGY 2015; 194 (6): 1668-1674
- Editorial Comment. Urology 2015; 86 (5): 899-?
Biologic Differences Between Peripheral and Transition Zone Prostate Cancer
2015; 75 (2): 183-190
Prostate cancer arises in the transition zone (TZ) in approximately 20-25% of cases. Modern biopsy and surveillance protocols, and advances in prostate cancer imaging, have renewed interest in TZ prostate cancers. We compared TZ and PZ prostate cancer to determine if cancer location is independently associated with better outcomes.We evaluated an expanded cohort of 1354 men who underwent radical prostatectomy between 1983 and 2003 with updated long-term clinical follow-up. Regression models were used to compare the volume of high-grade (Gleason 4 or 5) cancer and total cancer volume by location. Uni- and multi-variable logistic regression models tested the associations between cancer location and adverse pathologic features. Multivariable proportional hazard models were fit to examine cancer recurrence.Patients with TZ cancer presented with higher pre-operative serum PSA values (11.07 vs. 7.86 ng/ml) and larger total cancer volume (7.1 vs. 3.8 cc). Patients with TZ cancer had decreased odds of seminal vesicle invasion (OR 0.08, 95% CI 0.03, 0.21), extra-capsular extension (OR 0.56, 95% CI 0.35, 0.92), and lymphovascular invasion (OR 0.48, 95% CI 0.27, 0.87) in multivariable models. TZ cancers were independently associated with decreased hazard of tumor recurrence (HR 0.62, 95% CI 0.43, 0.90).TZ cancer prostate is associated with favorable pathologic features and better recurrence-free survival despite being diagnosed with larger cancers and higher PSA values. Tumor location should be taken into account when stratifying patient risk before and after prostatectomy, particularly with the evolving role of imaging in prostate cancer management. Prostate 75:183-190, 2015. © 2014 Wiley Periodicals, Inc.
View details for DOI 10.1002/pros.22903
View details for Web of Science ID 000346482600007
View details for PubMedID 25327466
- Editorial comment. Urology 2014; 83 (6): 1291-1292
Trends and perioperative outcomes for laparoscopic and robotic nephrectomy using the National Surgical Quality Improvement Program (NSQIP) database
UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS
2014; 32 (4): 473-479
We sought to examine the trends in perioperative outcomes of kidney cancer surgery stratified by type (radical nephrectomy [RN] vs. partial nephrectomy [PN]) and approach (open vs. minimally invasive).We queried the National Surgical Quality Improvement Program database to identify kidney cancer operations performed from 2005 to 2011. We examined 30-day perioperative outcomes including operative time, transfusion rate, length of stay, major morbidity (cardiovascular, pulmonary, renal, and infectious), and mortality.A total of 2,902 PN and 5,459 RN cases were identified. The use of PN increased over time, accounting for 39% of all nephrectomies in 2011. Minimally invasive approaches also increased over time for both RN and PN. Open surgery was associated with increased length of stay, receipt of transfusion, major complications, and perioperative mortality. Resident involvement and open approach were independent predictors of major complications for both PN and RN. Additionally, the presence of a medical comorbidity was also a risk factor for complications after RN. The overall complication rates decreased for all approaches over the study period.Minimally invasive approaches to kidney cancer renal surgery have increased with favorable outcomes. The safety of open and minimally invasive PN improved significantly over the study period. Although pathologic features cannot be determined from this data set, these data show that complications from renal surgical procedures are decreasing in an era of increasing use.
View details for DOI 10.1016/j.urolonc.2013.09.012
View details for Web of Science ID 000335422300015
View details for PubMedID 24332644
- Reply. Urology 2014; 83 (4): 779-780
Systematic evaluation of environmental and behavioural factors associated with all-cause mortality in the United States National Health and Nutrition Examination Survey.
International journal of epidemiology
2013; 42 (6): 1795-1810
Environmental and behavioural factors are thought to contribute to all-cause mortality. Here, we develop a method to systematically screen and validate the potential independent contributions to all-cause mortality of 249 environmental and behavioural factors in the National Health and Nutrition Examination Survey (NHANES).We used Cox proportional hazards regression to associate 249 factors with all-cause mortality while adjusting for sociodemographic factors on data in the 1999-2000 and 2001-02 surveys (median 5.5 follow-up years). We controlled for multiple comparisons with the false discovery rate (FDR) and validated significant findings in the 2003-04 survey (median 2.8 follow-up years). We selected 249 factors from a set of all possible factors based on their presence in both the 1999-2002 and 2003-04 surveys and linkage with at least 20 deceased participants. We evaluated the correlation pattern of validated factors and built a multivariable model to identify their independent contribution to mortality.We identified seven environmental and behavioural factors associated with all-cause mortality, including serum and urinary cadmium, serum lycopene levels, smoking (3-level factor) and physical activity. In a multivariable model, only physical activity, past smoking, smoking in participant's home and lycopene were independently associated with mortality. These three factors explained 2.1% of the variance of all-cause mortality after adjusting for demographic and socio-economic factors.Our association study suggests that, of the set of 249 factors in NHANES, physical activity, smoking, serum lycopene and serum/urinary cadmium are associated with all-cause mortality as identified in previous studies and after controlling for multiple hypotheses and validation in an independent survey. Whereas other NHANES factors may be associated with mortality, they may require larger cohorts with longer time of follow-up to detect. It is possible to use a systematic association study to prioritize risk factors for further investigation.
View details for DOI 10.1093/ije/dyt208
View details for PubMedID 24345851
Estimating the risk of chronic kidney disease after nephrectomy
CANADIAN JOURNAL OF UROLOGY
2013; 20 (6): 7035-7041
To identify factors associated with the development of chronic kidney disease (CKD) after nephrectomy and to create a clinical model to predict CKD after nephrectomy for kidney cancer for clinical use.We identified 144 patients who had normal renal function (eGFR > 60) prior to undergoing nephrectomy for kidney cancer. Selected cases occurred between 2007 and 2010 and had at least 30 days follow up. Sixty-six percent (n = 95) underwent radical nephrectomy and 62.5% (n = 90) developed CKD (stage 3 or higher) postoperatively. We used univariable analysis to screen for predictors of CKD and multivariable logistic regression to identify independent predictors of CKD and their corresponding odds ratios. Interaction terms were introduced to test for effect modification. To protect against over-fitting, we used 10-fold cross-validation technique to evaluate model performance in multiple training and testing datasets. Validation against an independent external cohort was also performed.Of the variables associated with CKD in univariable analysis, the only independent predictors in multivariable logistic regression were patient age (OR = 1.27 per 5 years, 95% CI: 1.07-1.51), preoperative glomerular filtration rate (GFR), (OR = 0.70 per 10 mL/min, 95% CI: 0.56-0.89), and receipt of radical nephrectomy (OR = 4.78, 95% CI: 2.08-10.99). There were no significant interaction terms. The resulting model had an area under the curve (AUC) of 0.798. A 10-fold cross-validation slightly attenuated the AUC to 0.774 and external validation yielded an AUC of 0.930, confirming excellent model discrimination.Patient age, preoperative GFR, and receipt of a radical nephrectomy independently predicted the development of CKD in patients undergoing nephrectomy for kidney cancer in a validated predictive model.
View details for Web of Science ID 000328717300007
View details for PubMedID 24331345
Diabetes Severity, Metabolic Syndrome, and the Risk of Erectile Dysfunction
JOURNAL OF SEXUAL MEDICINE
2013; 10 (12): 3102-3109
Erectile dysfunction (ED) is more common in men with type 2 diabetes mellitus (T2DM), obesity, and/or the metabolic syndrome (MetS).The aim of this study is to investigate the associations among proxy measures of diabetic severity and the presence of MetS with ED in a nationally representative U.S. data sample.We performed a cross-sectional analysis of adult participants in the 2001-2004 National Health and Nutrition Examination Survey.ED was ascertained by self-report. T2DM severity was defined by calculated measures of glycemic control and insulin resistance (IR). IR was estimated using fasting plasma insulin (FPI) levels and the homeostasis model assessment of IR (HOMA-IR) definition. We classified glycemic control using hemoglobin-A1c (HbA1c) and fasting plasma glucose (FPG) levels. MetS was defined by the American Heart Association and National Heart, Lung, and Blood Institute criteria. Logistic regression models, adjusted for sociodemographics, risk factors, and comorbidities, were fitted for each measure of T2DM severity, MetS, and the presence of ED.Proxy measures of glycemic control and IR were associated with ED. Participants with FPG between 100-126 mg/dL (5.6-7 mmol/L) and ≥ 126 mg/dL (>7 mmol/L) had higher odds of ED, odds ratio (OR) 1.22 (confidence interval or CI, 0.83-1.80), and OR 2.68 (CI, 1.48-4.86), respectively. Participants with HbA1c 5.7-6.4% (38.8-46.4 mmol/mol) and ≥ 6.5% (47.5 mmol/mol) had higher odds of ED (OR 1.73 [CI, 1.08-2.76] and 3.70 [CI, 2.19-6.27], respectively). When FPI and HOMA-IR were evaluated by tertiles, there was a graded relation among participants in the top tertile. In multivariable models, a strong association remained between HbA1c and ED (OR 3.19 [CI,1.13-9.01]). MetS was associated with >2.5-fold increased odds of self reported ED (OR 2.55 [CI, 1.85-3.52]).Poor glycemic control, impaired insulin sensitivity, and the MetS are associated with a heightened risk of ED.
View details for DOI 10.1111/jsm.12318
View details for Web of Science ID 000327583600021
View details for PubMedID 24010555
View details for PubMedCentralID PMC3891923
Utilization of renal mass biopsy in patients with renal cell carcinoma
12th International Kidney Cancer Symposium
WILEY-BLACKWELL. 2013: 14–14
View details for Web of Science ID 000325992100024
Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era
12th International Kidney Cancer Symposium
WILEY-BLACKWELL. 2013: 14–16
View details for Web of Science ID 000325992100026
- Turning on the lights: new technologies in optical diagnostics and therapeutics. journal of urology 2013; 190 (2): 381-382
Interobserver agreement of confocal laser endomicroscopy for bladder cancer.
Journal of endourology
2013; 27 (5): 598-603
Emerging optical imaging technologies such as confocal laser endomicroscopy (CLE) hold promise in improving bladder cancer diagnosis. The purpose of this study was to determine the interobserver agreement of image interpretation using CLE for bladder cancer.Experienced CLE urologists (n=2), novice CLE urologists (n=6), pathologists (n=4), and nonclinical researchers (n=5) were recruited to participate in a 2-hour computer-based training consisting of a teaching and validation set of intraoperative white light cystoscopy (WLC) and CLE video sequences from patients undergoing transurethral resection of bladder tumor. Interobserver agreement was determined using the κ statistic.Of the 31 bladder regions analyzed, 19 were cancer and 12 were benign. For cancer diagnosis, experienced CLE urologists had substantial agreement for both CLE and WLC+CLE (90%, κ 0.80) compared with moderate agreement for WLC alone (74%, κ 0.46), while novice CLE urologists had moderate agreement for CLE (77%, κ 0.55), WLC (78%, κ 0.54), and WLC+CLE (80%, κ 0.59). Pathologists had substantial agreement for CLE (81%, κ 0.61), and nonclinical researchers had moderate agreement (77%, κ 0.49) in cancer diagnosis. For cancer grading, experienced CLE urologists had fair to moderate agreement for CLE (68%, κ 0.64), WLC (74%, κ 0.67), and WLC+CLE (53%, κ 0.33), as did novice CLE urologists for CLE (53%, κ 0.39), WLC (66%, κ 0.50), and WLC+CLE (61%, κ 0.49). Pathologists (65%, κ 0.55) and nonclinical researchers (61%, κ 0.56) both had moderate agreement for CLE in cancer grading.CLE is an adoptable technology for cancer diagnosis in novice CLE observers after a short training with moderate interobserver agreement and diagnostic accuracy similar to WLC alone. Experienced CLE observers may be capable of achieving substantial levels of agreement for cancer diagnosis that is higher than with WLC alone.
View details for DOI 10.1089/end.2012.0549
View details for PubMedID 23072435
View details for PubMedCentralID PMC3643225
TEMPORAL TRENDS IN UTILIZATION OF CYTOREDUCTIVE NEPHRECTOMY AND PATIENT SURVIVAL IN THE TARGETED THERAPY ERA
Annual Meeting of the American-Urological-Association (AUA)
ELSEVIER SCIENCE INC. 2013: E753–E753
View details for Web of Science ID 000320281602402
- Editorial Comment. Urology 2013
Clinical, Molecular, and Genetic Correlates of Lymphatic Spread in Clear Cell Renal Cell Carcinoma
2012; 61 (5): 888-895
While it is well known that clear cell renal cell carcinoma (ccRCC) that presents with lymphatic spread is associated with an extremely poor prognosis, its molecular and genetic biology is poorly understood.Define the clinicopathologic, molecular, and genetic biological characteristics of these tumors in comparison to nonmetastatic (N0M0) renal cell carcinomas.A retrospective study defined clinicopathologic features, expression of 28 molecular markers, and occurrence of chromosomal aberrations for their correlation with lymphatic spread in three cohorts of 502, 196, and 272 patients, respectively.Fisher exact test or the χ(2) test were used to compare categorical variables; continuous variables were compared with the Mann-Whitney U test or student t test. Cut-off values were calculated based on receiver operating characteristic curves and the Youden Index. Uni- and multivariate regression analyses were used to investigate the correlation with lymphatic spread.In clinical analyses, a predictive model consisting of smoking history (p=0.040), T stage (p<0.0001), Fuhrman grade (p<0.0001), Eastern Cooperative Oncology Group performance status (p<0.0001), and microvascular invasion (p<0.0001) was independently associated with lymphatic spread. After adjustment with these clinical variables, low carbonic anhydrase IX (CAIX) (p=0.043) and high epithelial vascular endothelial growth factor receptor 2 (p=0.033) protein expression were associated with a higher risk of lymphatic spread, and loss of chromosome 3p (p<0.0001) with a lower risk. The current study is limited by its retrospective design, small sample size, and single-center experience.The low rates of CAIX expression and loss of chromosome 3p suggest that lymphatic spread in ccRCC occurs independently of von Hippel-Lindau tumor suppressor inactivation.
View details for DOI 10.1016/j.eururo.2012.01.012
View details for Web of Science ID 000302267900016
View details for PubMedID 22269604
The use of mannitol in partial and live donor nephrectomy: an international survey.
World journal of urology
PURPOSE: Animal studies have shown the potential benefits of mannitol as renoprotective during warm ischemia; it may have antioxidant and anti-inflammatory properties and is sometimes used during partial nephrectomy (PN) and live donor nephrectomy (LDN). Despite this, a prospective study on mannitol has never been performed. The aim of this study is to document patterns of mannitol use during PN and LDN. MATERIALS AND METHODS: A survey on the use of mannitol during PN and LDN was sent to 92 high surgical volume urological centers. Questions included use of mannitol, indications for use, physician responsible for administration, dosage, timing and other renoprotective measures. RESULTS: Mannitol was used in 78 and 64 % of centers performing PN and LDN, respectively. The indication for use was as antioxidant (21 %), as diuretic (5 %) and as a combination of the two (74 %). For PN, the most common dosages were 12.5 g (30 %) and 25 g (49 %). For LDN, the most common doses were 12.5 g (36.3 %) and 25 g (63.7 %). Overall, 83 % of centers utilized mannitol, and two (percent or centers??) utilized furosemide for renoprotection. CONCLUSIONS: A large majority of high-volume centers performing PN and LDN use mannitol for renoprotection. Since there are no data proving its value nor standardized indication and usage, this survey may provide information for a randomized prospective study.
View details for DOI 10.1007/s00345-012-1003-1
View details for PubMedID 23242033
Standardized Linear Port Configuration to Improve Operative Ergonomics in Laparoscopic Renal and Adrenal Surgery: Experience with 1264 cases
JOURNAL OF ENDOUROLOGY
2011; 25 (11): 1769-1773
Traditional laparoscopic port placement for upper urinary tract surgery involves camera access via the umbilicus with working ports placed on either side of the camera at various locations. This diamond configuration requires the camera operator to cross hands with the surgeon, resulting in poor ergonomics. A standardized linear port configuration has been used for nearly all transperitoneal urologic surgery at our institution. The purpose of this article is to describe our experience with this simplified approach and its advantages.A retrospective review was conducted of all laparoscopic cases by a single surgeon from 2000 to June 2009. The linear port configuration includes three ports placed along the ipsilateral pararectal line with the most superior port one fingerbreadth below the costal margin and the inferior port at the level of the umbilicus. A 5-mm camera is used through the most superior port. A low transverse extraction site is typically used, if necessary.There were 1264 laparoscopic cases performed using the linear port configuration. Of these, there were 1038 donor/radical/simple and 60 partial nephrectomies, 35 nephroureterectomies, 49 adrenalectomies, 50 pyeloplasties, 20 renal cryoablations, and 12 miscellaneous renal procedures. Of these, 98.2% were performed successfully via this port configuration. Three cases needed an additional port. The intraoperative complication rate was 0.9%, and mean estimated blood loss was 60 mL. There were 20 (1.6%) open conversions: 16 were elective and 4 secondary to complications.Simplifying port placement via a linear configuration for both right and left renal and adrenal surgery is feasible, easy to learn, simplifies strategic planning preoperatively, and provides excellent exposure. Using camera access through the superior port allows for direct visualization and minimizes interaction between the camera holder and surgeon's working envelope.
View details for DOI 10.1089/end.2011.0127
View details for Web of Science ID 000296788100011
View details for PubMedID 21864025
Laparoendoscopic Single-Site Porcine Nephrectomy Using A Novel Valveless Trocar System
JOURNAL OF ENDOUROLOGY
2011; 25 (1): 119-122
The AirSeal™ access system is a novel laparoscopic trocar that uses airflow to create insufflation pressure without the need for a physical seal or valve. By eliminating all valve elements within the lumen of the canula, the port provides a platform that accommodates multiple instruments of any diameter, shape, or combination and is ideally suited for laparoendoscopic single-site surgery (LESS). We present our initial experience with valveless trocars in traditional urologic laparoscopic cases and a porcine LESS nephrectomy series.Nine transperitoneal LESS nephrectomies were performed in a live porcine model using the 27-mm oval valveless trocar. All working instruments were placed through the single port, and the specimen was extracted through the 4-cm port site.All cases were completed without technical or operative complications. The porcine single-port nephrectomy (n=9) was successfully performed in a mean operative time of 24 minutes through the single 27-mm oval trocar. This accommodated a 5-mm laparoscope, multiple 5-mm instruments, the Endo GIA stapler, and the 15-mm Endocatch bag without loss of insufflation pressure. Condensation and smudging of the laparoscope were minimized, improving visualization and efficiency. The system allowed for use of suction without significant loss of insufflation pressure.The initial experience with the AirSeal valveless trocar system in LESS is encouraging. This technology may offer significant benefits over traditional laparoscopic trocars and single -port platforms and appears particularly suited to facilitate LESS.
View details for DOI 10.1089/end.2010.0199
View details for Web of Science ID 000286377200023
View details for PubMedID 20977374
Experience With 750 Consecutive Laparoscopic Donor Nephrectomies-Is it Time to Use a Standardized Classification of Complications?
JOURNAL OF UROLOGY
2010; 183 (5): 1941-1946
Laparoscopic living donor nephrectomy offers patients the benefits of decreased morbidity and improved cosmesis, while maintaining equivalent graft outcomes and complication rates similar to those of open donor surgery. With expressed concern for donor safety, using a standardized complication scale would allow combining data in a donor registry so potential donors could be adequately followed and counseled. We present the largest series to our knowledge of laparoscopic living donor nephrectomy by a single surgeon.The institution's initial 750 laparoscopic living donor nephrectomies were included in the study, and a retrospective and prospective chart and database analysis was performed.Mean donor age was 40.5 years and average body mass index was 25.7 kg/m(2). There were 175 patients (23%) with 2 or more renal arteries while 161 (21.5%) had early arterial bifurcations. There were 3 open conversions (0.4%) and the overall complication rate was 5.46%. Median hospital stay was 1 day and the readmission rate was 1.2%. There were 5 reoperations (0.67%), none of which was for the control of bleeding. No patients required a blood transfusion and there were no mortalities. Using a modified Clavien classification of complications for living donor nephrectomy 65.8% were grade 1, 31.7% grade 2 (12.2% grade 2a, 14.6% grade 2b, 4.9% grade 2c) and 2.4% grade 3. There were no grade 4 complications.With appropriate patient selection and operative experience, laparoscopic living donor nephrectomy is a safe procedure associated with low morbidity. The use of a standardized complication system specific for this procedure is encouraged and could aid in counseling potential donors in the future.
View details for DOI 10.1016/j.juro.2010.01.021
View details for Web of Science ID 000276747600112
View details for PubMedID 20303114
Percutaneous Cystolithotomy for Calculi in Reconstructed Bladders: Initial UCLA Experience
JOURNAL OF UROLOGY
2010; 183 (5): 1989-1993
Following bladder augmentation, patients are at significant risk for bladder calculi. We present our experience with a minimally invasive treatment approach using endoscopically assisted percutaneous cystolithotomy.A retrospective chart review identified 74 patients who underwent percutaneous cystolithotomy following bladder augmentation between 2002 and 2009. Cystogram was performed to determine the ideal location for percutaneous bladder access and a guidewire was inserted in the bladder through a bile needle. A balloon dilator was used to place a 30Fr sheath. Rigid cystoscopy with a 26Fr nephroscope allowed stone treatment by basketing and ultrasonic lithotripsy. A suprapubic 22Fr catheter was then placed. Patients were seen on postoperative day 14 and abdominal ultrasound was performed. If no significant residual calculi were visualized, the suprapubic tube was removed.Mean +/- SD patient age at operation was 20 +/- 10.7 months (range 4 to 40). Mean +/- SD time between bladder augmentation and percutaneous cystolithotomy was 4.8 +/- 2.05 years. Of the patients 38 (51%) were male and 36 (49%) were female. Mean +/- SD number of stones per patient was 4.6 +/- 7.8 (range 1 to 60). Ultrasonic lithotripsy was performed in 49 cases (66%). In 25 cases (34%) only stone basketing was performed. A total of 70 patients (95%) were stone-free on abdominal plain film at 14 days. Of the procedures 24 (32%) were performed on an outpatient basis and 50 were performed on an inpatient basis with a mean +/- SD hospital stay of 1.3 +/- 2.7 days (range 1 to 21). There were 9 minor complications noted (12%).Endoscopic percutaneous cystolithotomy offers a safe and effective treatment option for bladder calculi in reconstructed bladders and is the preferred method at our institution.
View details for DOI 10.1016/j.juro.2010.01.033
View details for Web of Science ID 000276747600133
View details for PubMedID 20303534
Comparison of accuracy of 14-, 18-and 20-G needles in ex-vivo renal mass biopsy: a prospective, blinded study
2010; 105 (7): 940-945
To prospectively determine the accuracy of 14-, 18- and 20-G core needle biopsies to render the appropriate histological diagnosis of solid, enhancing renal masses, using a controlled, ex-vivo biopsy technique.From March 2007 to September 2007, 31 patients undergoing partial or radical nephrectomy were randomly selected for biopsy. After extirpative surgery, three ex-vivo biopsies were taken from each lesion with 14-, 18- and 20-G biopsy needles. One experienced genitourinary pathologist, unaware of patient identifiers and final pathology results, determined the biopsy histology and tumour grade, based on standard haematoxylin and eosin (H&E) techniques and immunohistochemistry.The final pathological evaluation classified 21 masses (68%) as clear cell renal cell carcinoma (RCC), three (10%) as papillary RCC, three (10%) as chromophobe RCC, three (10%) as oncocytoma and one (3%) as a benign lymphoid infiltrate. The biopsy histology correlated with the final pathology in 29/31 cases (94%) with the 14-G, 30/31 cases (97%) with the 18-G and 25/31 cases (81%) with the 20-G needles. In two cases chromophobe RCC was misdiagnosed with oncocytoma, and vice versa.In this study a minimum of an 18-G biopsy needle was the most accurate in determining the histological diagnosis. Clear cell and papillary RCCs were accurately diagnosed on biopsy using an 18-G, whereas oncocytoma and chromophobe RCC were difficult to differentiate using standard H&E techniques and immunohistochemistry.
View details for DOI 10.1111/j.1464-410X.2009.08989.x
View details for Web of Science ID 000275204900012
View details for PubMedID 19888984
Flexible Ureteroscopy and Laser Lithotripsy for Multiple Unilateral Intrarenal Stones
2009; 55 (5): 1190-1196
External shock wave lithotripsy (ESWL) and percutaneous nephrolithotomy (PNL) have been the standard of care for the treatment of intrarenal calculi.We sought to determine the safety and efficacy of flexible ureteroscopy and holmium laser lithotripsy for the treatment of multiple intrarenal calculi and further stratify the efficacy by stone burden less than and greater than 20mm.Patients with multiple unilateral renal calculi treated between 2000 and 2006 at a single tertiary academic center were retrospectively evaluated.All patients underwent retrograde flexible ureteroscopy and holmium laser lithotripsy.Stone-free status was determined by ureteroscopy 15 d after the last procedure and was defined as the absence of stones in the kidney or residual fragments <1mm. A renal ultrasound was performed 30 d after the last treatment to confirm the absence of stones and hydronephrosis.Fifty-one patients were identified for a total of 161 intrarenal calculi with a mean stone size per patient of 6.6+/-3mm (range: 2-15). The mean number of stones per patient was 3.1+/-1 (range: 2-6). The mean number of primary procedures was 1.4+/-0.6 (range: 1-3). The overall stone-free rates after one and two procedures were 64.7% and 92.2%, respectively. The stone-free rates for patients with a stone burden greater than and less than 20mm were 85.1% and 100%, respectively. The overall complication rate was 13.6%; 97.6% of cases were performed as outpatient procedures. There are some limitations to this study, however: This is a retrospective review from a single institution, and our results are based on a relatively small sample size.For select patients with multiple intrarenal calculi, flexible ureteroscopy with holmium laser lithotripsy may represent an alternative therapy to ESWL or PNL, with acceptable efficacy and low morbidity.
View details for DOI 10.1016/j.eururo.2008.06.019
View details for Web of Science ID 000265592300035
View details for PubMedID 18571315
Flexible ureteroscopy and laser lithotripsy for single intrarenal stones 2 cm or greater - Is this the new frontier?
JOURNAL OF UROLOGY
2008; 179 (3): 981-984
Percutaneous nephrolithotomy has been the standard of care for intrarenal calculi greater than 2 cm. Flexible ureteroscopy with holmium laser lithotripsy is a minimally invasive treatment modality that is able to treat large intrarenal calculi with the potential to decrease morbidity, while maintaining a high level of efficacy.A total of 15 patients with a single intrarenal calculus 2 cm or greater were treated with retrograde ureteroscopic nephrolithotripsy. Lithotripsy was performed with a 7.2Fr flexible ureteroscope and 200 micron laser fiber. The stone-free rate was defined as the absence of any stones in the kidney or residual stone fragments less than 1 mm, which is too small to be extracted with a basket or a grasper. All patients underwent followup ureteroscopy within 15 days after the last procedure and renal ultrasound 30 days after the last treatment.There were a total of 15 intrarenal calculi 20 to 25 mm (mean 22) in diameter. The mean number of procedures was 2.3 (range 2 to 4). The overall stone-free rate was 93.3%. One patient (6.6%) had a residual 5 mm stone fragment in the lower pole of the kidney, which was followed expectantly for 2 years with no change in size. There were no major complications. There were 3 minor complications (20%), including 1 emergency room visit for fever and pain, and 2 cases of gross hematuria. All cases were performed on an outpatient basis.In select patients with a single intrarenal calculus 2 cm or greater small diameter flexible ureteroscopy with holmium laser lithotripsy may represent an alternative therapy to standard percutaneous nephrolithotomy with acceptable efficacy and low morbidity.
View details for DOI 10.1016/j.juro.2007.10.083
View details for Web of Science ID 000253176000056
View details for PubMedID 18207179
The chemokine receptor CXCR3 is an independent prognostic factor in patients with localized clear cell renal cell carcinoma
JOURNAL OF UROLOGY
2008; 179 (1): 61-66
Through its binding with interferon inducible angiostatic chemokines the chemokine receptor CXCR3 has an important role in regulating tumor mediating immunity, angiogenesis and metastatic spread. To evaluate its role in the biology of clear cell renal cell carcinoma we performed a tissue microarray based study.The tissue microarray comprised 154 patients who underwent nephrectomy for localized (N0M0) clear cell renal cell carcinoma at UCLA from 1989 to 2000. Immunohistochemical staining was evaluated by 2 anatomical pathologists who were blinded to outcome. The end point of this study was disease-free survival. Median followup was 5.9 years.A total of 96% of the tumor specimens stained positive for CXCR3. The mean percent of cells staining positive was 68% (range 0 to 100%). CXCR3 expression was not associated with other common clinicopathological features, such as Eastern Cooperative Oncology Group performance status, T stage, Fuhrman grade, vascular invasion or sarcomatoid features. Patients with low CXCR3 expression (less than 30%) had a significantly worse prognosis than patients with high CXCR3 expression with a 5-year disease-free survival rate of 57% vs 82% (p = 0.009). Multivariate Cox regression analysis retained T stage, Eastern Cooperative Oncology Group performance status, sarcomatoid features and CXCR3 as independent prognostic factors.CXCR3 is a novel molecular marker in patients with clear cell renal cell carcinoma. Its higher expression is an independent predictor of improved disease-free survival following nephrectomy for localized disease. Since CXCR3 is not associated with other clinicopathological prognostic factors, it may represent an ideal complementary molecular marker for identifying patients who are at higher risk for recurrence after nephrectomy.
View details for DOI 10.1016/j.juro.2007.08.148
View details for Web of Science ID 000251650200015
View details for PubMedID 17997430
In vivo efficacy of laparoscopic assisted percutaneous renal cryotherapy: Evidence based guidelines for the practicing urologist
JOURNAL OF UROLOGY
2008; 179 (1): 333-337
The treatment of small renal tumors continues to evolve in parallel with advances in ablative technology. We compared the lesion geometry of 3, 17 gauge cryoneedles to determine the most effective distance and configuration of the cryoneedles in an in vivo porcine kidney model.Argon gas based renal cryoablation was performed in 6 pigs using a laparoscopically assisted percutaneous approach. Cryoablation using a single cryoneedle and a template of 3 cryoneedles with various ice ball shapes, including elliptical, bulb-shaped and standard 17 gauge cryoneedles (Galil Medical, Plymouth Meadow, Pennsylvania) was performed in 3 pigs. Three additional pigs underwent renal cryoablation using elliptical cryoneedles in 3 triangular template configurations with the cryoneedles spaced 1, 1.5 and 2 cm apart, respectively. The animals were sacrificed a minimum of 2 weeks following treatment.Elliptical cryoneedles achieved the largest area of necrosis when used in single and template configurations. When used in a template configuration of 3 needles 1, 1.5 and 2 cm apart from each other the calculated volume of necrosis was 4.3 x 4.5 x 2.5, 4.9 x 4.1 x 2.5 and 4.0 x 4.5 x 2.5 cm, respectively.Using a single 17 gauge cryoneedle is inadequate for treating most small renal tumors. Cryoneedles with an elliptical ice ball are most effective for achieving consistent and reliable tissue destruction. The 1.5 cm template configuration generated the largest area of necrosis. Our data suggest that with the current technology renal cryoablation should be limited to lesions not greater than 4 cm.
View details for DOI 10.1016/j.juro.2007.08.089
View details for Web of Science ID 000251650200084
View details for PubMedID 18006012
Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma
CLINICAL CANCER RESEARCH
2007; 13 (24): 7388-7393
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays an important role in tumoral adaptation to hypoxic conditions by serving as a transcription factor for several crucial proteins, including vascular endothelial growth factor and carbonic anhydrase IX (CAIX). Here, we evaluated the significance of HIF-1 alpha in renal cell carcinoma (RCC).Immunohistochemical analysis was done on a tissue microarray constructed from paraffin-embedded primary tumor specimens from 357 patients treated by nephrectomy for RCC. Nuclear expression was evaluated by a single pathologist who was blinded to outcome. The expression levels were associated with pathologic variables and survival.HIF-1 alpha expression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1 alpha was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family. HIF-1 alpha was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1 alpha expression predicted outcome in metastatic patients: patients with high HIF-1 alpha expression (>35%) had significantly worse survival than patients with low expression (< or =35%); median survival, 13.5 versus 24.4 months, respectively (P = 0.005). Multivariate analysis retained HIF-1 alpha and CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC.HIF-1 alpha is an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1 alpha and CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.
View details for DOI 10.1158/1078-0432.CCR-07-0411
View details for Web of Science ID 000251954200025
View details for PubMedID 18094421
Complications of laparoscopic renal surgery.
Minerva urologica e nefrologica = The Italian journal of urology and nephrology
2007; 59 (4): 417-423
Initial excitement for laparoscopy's potential to decrease patient morbidity and convalescence by avoiding a flank incision was initially tempered by concerns for increased operative time, technical complexity and the suitability of laparoscopy approaches to oncologic surgery. With experience, the benefits of laparoscopic approaches to renal surgery have become clear. As laparoscopic techniques are mastered and the indications expanded, it is important to remember that minimally invasive surgery remains associated with significant risks and potential complications. Several complications are theoretically more difficult to control laparoscopically than with open exposure. Control of bleeding, identification of injury to solid organs, and positive margins due to the lack of haptic feedback have been of special concern during the rapid advancement of laparoscopic surgical technique between 1991 and today. It is critical for the urologist to be familiar with these complications in order to maximize patients' clinical outcomes through appropriate patient selection and intraoperative planning. Know-ledge of the complications of laparoscopic renal surgery will also aid in providing patients with true informed consent and realistic surgical expectations. The purpose of this manuscript is to review the complications associated with laparoscopic renal surgery in general, with specific attention paid to laparoscopic radical, partial, pediatric, and donor nephrectomy.
View details for PubMedID 17947959
Prognostic relevance of the mTOR pathway in renal cell carcinoma - Implications for molecular patient selection for targeted therapy
2007; 109 (11): 2257-2267
The mammalian target of rapamycin (mTOR) pathway is up-regulated in many human cancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC).Immunohistochemical analysis using antibodies against pAkt, PTEN, p27, and pS6 was performed on a tissue microarray constructed from paraffin-embedded specimens from 375 patients treated by nephrectomy for RCC. The expression was associated with pathological parameters and survival.The mTOR pathway was more significantly altered in clear-cell RCC, high-grade tumors, and tumors with poor prognostic features. PS6 and PTEN showed the strongest associations with pathological parameters. Survival tree analysis regarding expression of cytoplasmic pAkt, nuclear pAkt, PTEN, cytoplasmic p27, and pS6 identified staining percentages of 40%, 10%, 75%, 7%, and 70%, respectively, as ideal cutoff values for stratification, with corresponding P-values of .03, .001, .02, .005, and <.0001, respectively. Interestingly, high nuclear pAkt expression was associated with a favorable prognosis, whereas high cytoplasmic pAkt expression was associated with a poor prognosis. In multivariate Cox regression analysis, ECOG PS, T classification, N classification, M classification, cytoplasmic Akt, nuclear pAkt, PTEN, and pS6 were independent prognostic factors of DSS.Components of the mTOR pathway are significantly associated with pathological features and survival. Not all RCC tumor types seem to be equally amenable to mTOR targeted therapy. PTEN, pAkt, p27, and pS6 may serve as surrogate parameters for patient selection and predicting prognosis. Patients with a highly activated mTOR pathway should benefit most from this therapy. External validation of our results is recommended.
View details for DOI 10.1002/cncr.22677
View details for Web of Science ID 000246679100013
View details for PubMedID 17440983
- The role of molecular markers in the staging of renal cell carcinoma BJU INTERNATIONAL 2007; 99 (5): 1208-1211
Prognostic relevance of capsular involvement and collecting system invasion in stage I and II renal cell carcinoma
2007; 99 (4): 821-824
To define the prognostic relevance of capsular involvement (invasion with no penetration) and collecting-system invasion in patients with stage I (pT1N0M0) and stage II (pT2N0M0) renal cell carcinoma (RCC), by evaluating the outcome of patients treated with nephrectomy.In all, 519 patients from a kidney cancer database treated with nephrectomy for stage I and II RCC between 1985 and 2005 were assessed retrospectively. The primary endpoint was recurrence-free survival time. The prognostic relevance of capsular involvement and collecting-system invasion were examined using univariate and multivariate survival analysis.Capsular involvement and collecting-system invasion were evident in 112 (21.6%) and 39 (7.5%) patients, respectively. Capsular involvement was associated with higher Fuhrman grades and larger tumours. The incidence of collecting-system invasion was higher in patients with microvascular invasion. The median follow-up was 49 months. In univariate analysis, patients with capsular involvement and collecting-system invasion had a worse prognosis than patients without (P = 0.007 and <0.001, respectively). In multivariate analysis, capsular involvement (hazard ratio 1.84, P = 0.036) and collecting-system invasion (3.78, P < 0.001) were independent prognostic factors of recurrence-free survival. Interestingly, there was no survival difference between patients with capsular involvement in stage I/II and patients with invasion of perinephric tissue (pT3aN0M0).These findings suggest that capsular involvement and collecting-system invasion are poor prognostic findings in stage I and II RCC. They should both be considered when planning the follow-up. A revised pT3a stage including patients with capsular involvement could improve its prognostic validity.
View details for DOI 10.1111/j.1464=410X.2006.06729x
View details for Web of Science ID 000244977500025
View details for PubMedID 17244281
Is the testis a chemo-privileged site? Is there a blood-testis barrier?
Reviews in urology
2007; 9 (1): 28-32
The incidence of testicular cancer, primarily seminoma, has been increasing in many countries, including the United States. The testis is often the site of residual cancer after adequate treatment with systemic chemotherapy. The blood-testis barrier is commonly cited as the explanation for residual tumor within the gonad after chemotherapy and as the indication for delayed orchiectomy. Conversely, complete eradication of viable tumor from the primary site is common and argues against the testis as a "tumor sanctuary." Residual tumor is also demonstrated within metastatic foci, and the disparity between the histopathologic response of the primary tumor and metastatic sites may be best explained by tumor heterogeneity and multiple tumor clones. Regardless of the scientific and academic arguments, delayed radical orchiectomy remains an important part of treatment for patients undergoing primary chemotherapy.
View details for PubMedID 17396169
Renca/carbonic anhydrase-IC: A murine model of a carbonic anhydrase-IX-expressing renal cell carcinoma
2006; 68 (5): 1132-1138
Carbonic anhydrase-IX (CA-IX) is a cell surface tumor-associated antigen expressed by most clear cell renal cell carcinomas (RCCs). The specificity and the prognostic value of CA-IX provide impetus to create a mouse model of CA-IX-expressing RCC for testing CA-IX-targeted therapies against RCC.A retrovirus encoding the human CA-IX gene was used to transduce the murine RCC line, RENCA. In vivo growth kinetics and CA-IX expression were compared between RENCA and RENCA/CA-IX using heterotopic, metastatic, and orthotopic models.Transduction of RENCA created the RENCA/CA-IX line with nearly 100% CA-IX surface expression. In the heterotopic model, subcutaneous injection of 500,000 and 50,000 cells led to tumor formation at 2 to 2.5 weeks after injection, with similar growth kinetics between the two cell lines at either cell number. In the pulmonary metastatic model, a similar number of metastases was noted after inoculation of RENCA and RENCA/CA-IX. In the orthotopic model, autopsy revealed a CA-IX-expressing renal tumor, as well as CA-IX-expressing metastases to the lungs, liver, contralateral kidney, intestines, and lymph nodes. In all the above models, the RENCA/CA-IX tumors retained expression of CA-IX, as demonstrated by immunohistochemistry staining.RENCA/CA-IX is the first tumor model that manifests in immunocompetent Balb/c mice and stably expresses a defined kidney cancer-associated antigen. It maintains antigen expression, forms metastases, and produces reliable tumor growth kinetics equivalent to that of its parental cell line.
View details for DOI 10.1016/j.urology.2006.08.1073
View details for Web of Science ID 000242592500059
View details for PubMedID 17095063
- Determining the prognosis of patients with renal cell carcinoma: is it time for a re-evaluation? NATURE CLINICAL PRACTICE UROLOGY 2006; 3 (10): 510-511
- The sensitivity of testosterone immunoassays and their role in monitoring antiandrogen therapy UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS 2006; 24 (4): 277-278
Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer
CLINICAL CANCER RESEARCH
2006; 12 (13): 4018-4026
Phytochemicals in plants may have cancer preventive benefits through antioxidation and via gene-nutrient interactions. We sought to determine the effects of pomegranate juice (a major source of antioxidants) consumption on prostate-specific antigen (PSA) progression in men with a rising PSA following primary therapy.A phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy was conducted. Eligible patients had a detectable PSA > 0.2 and < 5 ng/mL and Gleason score < or = 7. Patients were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Clinical end points included safety and effect on serum PSA, serum-induced proliferation and apoptosis of LNCaP cells, serum lipid peroxidation, and serum nitric oxide levels.The study was fully accrued after efficacy criteria were met. There were no serious adverse events reported and the treatment was well tolerated. Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months posttreatment (P < 0.001). In vitro assays comparing pretreatment and posttreatment patient serum on the growth of LNCaP showed a 12% decrease in cell proliferation and a 17% increase in apoptosis (P = 0.0048 and 0.0004, respectively), a 23% increase in serum nitric oxide (P = 0.0085), and significant (P < 0.02) reductions in oxidative state and sensitivity to oxidation of serum lipids after versus before pomegranate juice consumption.We report the first clinical trial of pomegranate juice in patients with prostate cancer. The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study.
View details for DOI 10.1158/1078-0432.CCR-05-2290
View details for Web of Science ID 000238930500023
View details for PubMedID 16818701
Implants of noninvasive papillary urothelial carcinoma in peritoneum and ileocolonic neobladder: Support for "seed and soil" hypothesis of bladder recurrence
2006; 67 (4): 746-750
To explore the underlying mechanism of tumor regrowth in cases of noninvasive urothelial carcinoma that recur in unusual anatomic locations.The pathology files of our institution and the consult service of one of us were searched for cases of noninvasive nonmetastatic urothelial carcinoma with involvement of unusual anatomic sites. Cases in which the mode of spread included direct spread to the adjacent tissue and lymphovascular metastases were excluded. Medical history, including presenting symptoms, and follow-up data were obtained.Two cases of noninvasive urothelial carcinoma were identified. One had presented as an implant in the peritoneal investment of the bladder dome and the other as multiple implants growing on the benign surface of the colonic mucosa of an orthotopic neobladder distant from the anastomosis site. Both cases had initially presented as noninvasive papillary urothelial carcinoma of the renal pelvis. Although the urinary bladder was free of neoplastic changes at nephroureterectomy, both patients also developed several papillary tumors within the bladder shortly after the removal of the kidney.After clinicopathologic correlation, the mode of tumor spread in these cases was best explained by the "seeding/implantation" theory. The urothelial tumor cells in each of these cases demonstrated the ability to implant themselves not only in the urothelium of the bladder but also in the colonic mucosa of a constructed neobladder and on the peritoneal surface.
View details for DOI 10.1016/j.urology.2005.10.023
View details for Web of Science ID 000237054800025
View details for PubMedID 16566991
Prevention of bladder cancer: A review
2006; 49 (2): 226-234
Bladder cancer represents an ideal tumor model to test and apply cancer prevention strategies. In addition to reviewing the epidemiology of transitional cell carcinoma (TCC), we review the current status and the future directions of bladder cancer prevention.A literature review of peer-reviewed articles which address bladder cancer prevention was performed.Pre-clinical and limited clinical data suggest that bladder cancer is responsive to efforts to delay or prevent its development in at-risk patients, and in reducing the risk of recurrence in patients with established disease. Many epidemiologic studies, however, investigating natural products, such as vitamins and herbal compounds, lack conclusive evidence of their chemopreventive effects.While many agents hold promise in the prevention of bladder cancer, none currently can be recommended as proven chemoprevention strategies. Improving the accuracy of patient risk assessment and identification of surrogate endpoint biomarkers are crucial to the testing of these strategies. Efficient study design will ensure rapid and substantial advances in the chemoprevention of bladder cancer.
View details for DOI 10.1016/j.eururo.2005.12.011
View details for Web of Science ID 000235511100007
View details for PubMedID 16413099
Significance of gene expression analysis of renal cell carcinoma
EXPERT REVIEW OF ANTICANCER THERAPY
2006; 6 (2): 293-299
Renal cell carcinoma (RCC) describes a family of epithelial tumors arising from within the kidney. Each subtype of RCC presents a unique clinical picture with varied tumor biology, patient prognosis and response to treatment. Gene expression profiling offers the ability to analyze thousands of candidate genes in high-throughput arrays and has led to a greater knowledge of the molecular genetics of RCC. This powerful technology can identify RCC subtypes, recapitulating and refining the current histological classifications. Gene expression data also promise to advance current staging systems and improve prognostic information for patients and clinicians. Understanding the genetic signature of RCC tumors will allow for sophisticated application of systemic and targeted therapies, improving patient response and minimizing unnecessary exposure of patients to treatment toxicities. This article reviews the significance of gene expression analysis in the understanding of tumor biology and RCC treatment.
View details for DOI 10.1586/14737184.108.40.2063
View details for Web of Science ID 000240922500019
View details for PubMedID 16445381
Secondary hormonal therapy for advanced prostate cancer
JOURNAL OF UROLOGY
2006; 175 (1): 27-34
Androgen ablation remains the cornerstone of management for advanced prostate cancer. Therapeutic options in patients with progressive disease following androgen deprivation include antiandrogen withdrawal, secondary hormonal agents and chemotherapy. Multiple secondary hormonal agents have clinical activity and the sequential use of these agents may lead to prolonged periods of clinical response. We provide a state-of-the-art review of the various agents currently used for secondary hormonal manipulation and discusses their role in the systemic treatment of patients with prostate cancer.A comprehensive review of the peer reviewed literature was performed on the topic of secondary hormonal therapies, including oral antiandrogens, adrenal androgen inhibitors, corticosteroids, estrogenic compounds, gonadotropin-releasing hormone antagonists and alternative hormonal therapies for advanced prostate cancer.Secondary hormonal therapies can provide a safe and effective treatment option in patients with AIPC. The use of steroids and adrenolytics, such as ketoconazole and aminoglutethimide, has resulted in symptomatic improvement and a greater than 50% prostate specific antigen decrease in a substantial percent of patients with AIPC. A similar clinical benefit has been demonstrated with estrogen based therapies. Furthermore, these therapies have demonstrated a decrease in metastatic disease burden. Other novel hormonal therapies are currently under investigation and they may also show promise as secondary hormonal therapies. Finally, guidelines from the United States Food and Drug Administration Prostate Cancer Endpoints Workshop were reviewed in the context of developing new agents.Secondary hormonal therapy serves as an excellent therapeutic option in patients with AIPC in whom primary hormonal therapy has failed. Practicing urologists should familiarize themselves with these oral medications, their indications and their potential side effects.
View details for DOI 10.1016/S0022-5347(05)00034-0
View details for Web of Science ID 000234001100007
View details for PubMedID 16406864
- Open surgical management of renal cell carcinoma in the era of minimally invasive kidney surgery BJU INTERNATIONAL 2005; 96 (9): 1268-1274
Role of molecular markers in the diagnosis and therapy of renal cell carcinoma.
2005; 66 (5): 1-9
Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of renal cell carcinoma (RCC) have paved the way for developments that may enhance early diagnosis, better predict prognosis, and improve survival. Reliable predictive factors are essential for the stratification of patients into clinically meaningful categories that can be used to provide patients with counseling regarding prognosis, select treatment modalities, and determine eligibility for clinical trials. The TNM (tumor, nodes, metastasis) staging system is currently the most extensively used staging system for RCC, but it has undergone systematic revisions as a result of emerging data. Comprehensive integrated staging systems that combine important clinical and pathological variables have been created in an attempt to improve prognostication. Although staging has improved with the development of integrated systems, the incorporation of molecular tumor markers are expected to revolutionize the staging of RCC. This article reviews the important molecular markers in RCC to date and discusses their role in the diagnosis, prognostication, and therapy of patients with RCC.
View details for PubMedID 16194700
- Role of molecular markers in the diagnosis and therapy of renal cell carcinoma UROLOGY 2005; 66 (5A): 1-9
- Adjuvant therapy of renal cell carcinoma: patient selection and therapeutic options BJU INTERNATIONAL 2005; 96 (4): 483-488
- Predicting response to interleukin-2 therapy among patients with renal cell carcinoma JOURNAL OF IMMUNOTHERAPY 2005; 28 (5): 427-429
Carbonic anhydrase IX and the future of molecular markers in renal cell carcinoma
2005; 96 (3): 281-285
The use of carbonic anhydrase IX as a promising molecular marker in RCC is described by authors from Los Angeles, who discuss the promise that molecular markers hold to improve diagnosis, staging, treatment, surveillance and survival of patients with RCC. There is a whole range of new treatments being introduced in the management of metastatic renal cancer. The use of VEGF-targeted therapy has particular importance, especially as it has a strong genetically linked rationale for its potential success in this area. Authors from the USA show that substantial clinical activity has been reported in initial clinical trials. In prostate cancer, drugs targeting microtubules, such as taxanes, have already been introduced clinically, and their success has received widespread attention. A new group of drugs, the epothilones, have similar but not identical binding properties to microtubules, and authors from the USA describe how they have shown activity in hormone-refractory prostate cancer, and are moving to phase III testing.
View details for DOI 10.1111/j.1464-410X.2005.05615.x
View details for Web of Science ID 000230726000011
View details for PubMedID 16042714
Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system
JOURNAL OF UROLOGY
2005; 174 (2): 466-472
We created an evidence based postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma (RCC) based on a risk group stratification system.559 patients undergoing surgery for localized and ocally advanced RCC were stratified into low risk (LR), intermediate risk (IR) and high risk (HR) groups based on the University of California-Los Angeles Integrated Staging System (UISS). Tumor recurrences were identified and categorized according to time and location.Patients with localized disease had a lower 5-year recurrence rate than patients with locally advanced (nodal) disease (27.6% vs 64%, p <0.0001). Patients in the LR, IR, and HR groups following nephrectomy demonstrated 5-year recurrence-free rates of 90.4%, 61.8%, and 41.9%, respectively (p <0.0001), and median times to recurrence of 28.9, 17.8 and 9.5 months, respectively (p <0.0001). Chest and abdomen recurrences comprised of 75% and 37.5%, 77.4% and 58.1%, and 45.2% and 67.7% of recurrences in the LR, IR and HR groups, respectively. In patients with node positive disease, chest and abdomen comprised of 58.8% and 76.5% of recurrences, respectively. Patients undergoing partial nephrectomy did not demonstrate a greater rate of local or distant recurrence compared with patients undergoing radical nephrectomy.Significant differences in incidence and time to recurrence following surgical resection for RCC mandates unique surveillance protocols for patients in each of the UISS risk groups. LR group patients should be followed for at least 5 years, whereas IR and HR group patients require longer surveillance. HR group patients require more stringent abdominal surveillance, whereas LR group patients should emphasize the chest. Patients with nodal disease also require stringent followup. Patients undergoing partial nephrectomy for localized disease can be followed according to the same UISS risk group based protocol.
View details for DOI 10.1097/01.ju.0000165572.38887.da
View details for Web of Science ID 000230604300016
View details for PubMedID 16006866
Novel approaches in the therapy of metastatic renal cell carcinoma
WORLD JOURNAL OF UROLOGY
2005; 23 (3): 202-212
Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.
View details for DOI 10.1007/s00345-004-0466-0
View details for Web of Science ID 000230806900010
View details for PubMedID 15812574
Renal cell carcinoma 2005: New frontiers in staging, prognostication and targeted molecular therapy
JOURNAL OF UROLOGY
2005; 173 (6): 1853-1862
Renal cell carcinoma (RCC) has traditionally been staged using a purely anatomical staging system. Although current staging systems provide good prognostic information, data published in the last few years has led to significant controversies as to whether further revisions are needed and whether improvements can be made with the introduction of new, more accurate and predictive prognostic factors not currently included in traditional staging systems. This review highlights such controversies and provides an update on current staging modalities, prognostic factors and targeted molecular therapy for RCC.A comprehensive review of the peer reviewed literature was performed on the topic of current staging modalities, validated prognostic factors, predictive nomograms, molecular markers and targeted molecular therapy for RCC.A staging system for malignant disease such as RCC uses various characteristics of tumors to stratify patients into clinically meaningful categories, which can be used to provide patients with counseling regarding prognosis, select treatment modalities and determine eligibility for clinical trials. The TNM staging system is currently the most extensively used one. However, it has undergone recent systematic revision due to rapidly emerging data from longer patient followup. The identification of various histological and symptomatic factors has led groups at many centers to develop more comprehensive staging systems that integrate these factors and include patients with metastatic and local disease. While integrated staging systems have improved RCC staging, the recent discovery of molecular tumor markers is expected to revolutionize RCC staging in the future and lead to the development of new therapies based on molecular targeting.Staging systems for RCC serve as a valuable prognostic tool. Several new patient and tumor characteristics have been reported to be important prognostic factors and they have been integrated into current staging systems. In addition, the field of RCC is rapidly undergoing a revolution led by molecular markers and targeted therapies. With this information urologists will be updated with the most current and comprehensive staging strategies, and be provided with a glimpse of the molecular and patient specific staging and treatment paradigms that will in our opinion transform the future management of this malignancy.
View details for DOI 10.1097/01.ju.0000165693.68449.c3
View details for Web of Science ID 000229051700006
View details for PubMedID 15879764
Surveillance following radical or partial nephrectomy for renal cell carcinoma.
Current urology reports
2005; 6 (1): 7-18
Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease and up to 50% treated for localized disease have a recurrence. Although the prognosis generally is poor in these patients, some may respond to immunotherapy and a subset of patients who develop solitary metastases can achieve long-term survival. Therefore, the timely identification of recurrences following surgical extirpation is imperative in the treatment of patients.
View details for PubMedID 15610692
Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75
JOURNAL OF COMPARATIVE NEUROLOGY
1999; 404 (1): 1-20
The neurotrophin receptor p75 is a low-affinity receptor that binds neurotrophins. To investigate the role of p75 in the survival and function of central neurons, p75 null-mutant and wild type litter mate mice were tested on behavioral tasks. Null mutants showed significant performance deficits on water maze, inhibitory avoidance, motor activity, and habituation tasks that may be attributed to cognitive dysfunction or may represent a global sensorimotor impairment. The p75 null-mutant and wild type litter mate mice were assessed for central cholinergic deficit by using quantitative stereology to estimate the total neuronal number in basal forebrain and striatum and for subpopulations expressing the high-affinity tyrosine receptor kinase A (trkA) neurotrophin receptor and choline acetyltransferase (ChAT). In the adult brain, cholinergic neurons of the basal forebrain receive target-derived trophic support, whereas cholinergic striatal neurons do not. Adult p75 null-mutant mice had significant reduction of basal forebrain volume by 25% and had a corresponding significant loss of 37% of total basal forebrain neurons. The basal forebrain population of ChAT-positive neurons in p75-deficient mice declined significantly by 27%, whereas the trkA-positive population did not change significantly. There was no significant change in striatal volume or in striatal neuronal number either in total or by cholinergic subpopulation. These results demonstrate vulnerability to the lack of p75 in adult central neurons that are neurotrophin dependent. In addition, the loss of noncholinergic central neurons in mice lacking p75 suggests a role for p75 in cell survival by an as yet undetermined mechanism. Possible direct and indirect effects of p75 loss on neuronal survival are discussed.
View details for Web of Science ID 000077748200001
View details for PubMedID 9886021
- Basal forebrain neuronal loss in mice lacking neurotrophin receptor p75 SCIENCE 1997; 277 (5327): 837-838