Matthew Kaag

Tumor size is associated with malignant potential in renal cell carcinoma cases.

PURPOSE We evaluated our experience with renal cortical tumors to determine whether tumor size is associated with malignant histology and/or nuclear grade. MATERIALS AND METHODS We identified 2,675 patients treated surgically at our institution for renal cell carcinoma or a benign tumor between 1989 and 2007. Histological subtype and tumor size were obtained from our kidney cancer database and logistic regression analysis was performed. RESULTS Of the 2,675 tumors 311 (12%) were benign and 2,364 (88%) were renal cell carcinoma. The OR for the association of malignancy with tumor size was 1.16 (95% CI 1.11-1.22, p <0.001), indicating that each 1 cm increase in tumor size was associated with a 16% increase in the odds of malignancy. The incidence of benign tumors decreased from 38% for tumors less than 1 cm to 7% for tumors 7 cm or greater. In patients with clear cell renal cell carcinoma each 1 cm increase in tumor size increased the odds of high grade disease (Fuhrman grade 3-4) compared with low grade disease (Fuhrman grade 1-2) by 25% (OR 1.25, 95% CI 1.21-1.30, p <0.001). In this subset the incidence of high grade lesions increased from 0% for tumors less than 1 cm to 59% for tumors greater than 7 cm. CONCLUSIONS Our results confirm previous observations suggesting that the risks of malignancy and high grade tumors increase with tumor size. Patients with small renal masses are at low risk for harboring a high grade clear cell malignancy, which may be useful during initial consultation.

Contemporary Use of Partial Nephrectomy at a Tertiary Care Center in the United States

PURPOSE The use of partial nephrectomy for renal cortical tumors appears unacceptably low in the United States according to population based data. We examined the use of partial nephrectomy at our tertiary care facility in the contemporary era. MATERIALS AND METHODS Using our prospectively maintained nephrectomy database we identified 1,533 patients who were treated for a sporadic and localized renal cortical tumor between 2000 and 2007. Patients with bilateral disease or solitary kidneys were excluded from study and elective operation required an estimated glomerular filtration rate of 45 ml per minute per 1.73 m(2) or greater. Predictors of partial nephrectomy were evaluated using logistic regression models. RESULTS Overall 854 (56%) and 679 patients (44%) were treated with partial and radical nephrectomy, respectively. In the 820 patients treated electively for a tumor 4 cm or less the frequency of partial nephrectomy steadily increased from 69% in 2000 to 89% in 2007. In the 365 patients treated electively for a 4 to 7 cm tumor the frequency of partial nephrectomy also steadily increased from 20% in 2000 to 60% in 2007. On multivariate analysis male gender (p = 0.025), later surgery year (p <0.001), younger patient age (p = 0.005), smaller tumor (p <0.001) and open surgery (p <0.001) were significant predictors of partial nephrectomy. American Society of Anesthesiologists score, race and body mass index were not significantly associated with treatment type. CONCLUSIONS The use of partial nephrectomy is increasing and it is now performed in approximately 90% of patients with T1a tumors at our institution. For reasons that remain unclear certain groups of patients are less likely to be treated with partial nephrectomy.

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.

Metastatic Renal Cell Carcinoma Risk According to Tumor Size

PURPOSE Recent evidence suggests significantly discordant findings regarding tumor size and the metastasis risk in renal cell carcinoma cases. We present our experience with renal cell carcinoma. We evaluated the association between tumor size and the metastasis risk in a large patient cohort. MATERIALS AND METHODS Using our prospectively maintained nephrectomy database we identified 2,691 patients who were treated surgically for a sporadic renal cortical tumor between 1989 and 2008. Associations between tumor size and synchronous metastasis at presentation (M1 renal cell carcinoma) were evaluated with logistic regression models. Metastasis-free survival after surgery was estimated using the Kaplan-Meier method in 2,367 patients who did not present with M1 renal cell carcinoma and were followed postoperatively. RESULTS Of the 2,691 patients 162 presented with metastatic renal cell carcinoma. Only 1 of 781 patients with a tumor less than 3 cm had M1 renal cell carcinoma at presentation and tumor size was significantly associated with metastasis at presentation (for each 1 cm increase OR 1.25, p <0.001). Of the 2,367 patients who did not present with metastasis metastatic disease developed in 171 during a median 2.8-year followup. In this group only 1 of the 720 patients with renal cell carcinoma less than 3 cm showed de novo metastasis during followup. Metastasis-free survival was significantly associated with tumor size (for each 1 cm increase HR 1.24, p <0.001). CONCLUSIONS In our experience tumor size is significantly associated with synchronous and asynchronous metastases after nephrectomy. Our results suggest that the risk of metastatic disease is negligible in patients with tumors less than 3 cm.

Clinical Outcome in a Contemporary Series of Restaged Patients with Clinical T1 Bladder Cancer

OBJECTIVES To evaluate the indications for early and deferred cystectomy and to report the impact of this tailored approach on survival. DESIGN, SETTING, AND PARTICIPANTS We retrospectively studied 523 patients seen at our institution who were initially diagnosed with T1 disease between 1990 and 2007. MEASUREMENTS Variables analyzed included age, gender, multifocality, multifocal T1 disease, carcinoma in situ, grade, recurrence rate, and restaging status. End points were overall and disease-specific survival. RESULTS AND LIMITATIONS A restaging transurethral resection (TUR) was performed in 523 patients. Of the patients who underwent restaging, 106 (20%) were upstaged to muscle-invasive disease and 417 patients were considered true clinical T1 (cT1); 84 of the latter group underwent immediate cystectomy. The median follow-up for survivors was 4.3 yr. The cumulative incidence of disease-specific death at 5 yr was 8% (95% confidence interval [CI], 5-13%), 10% (95% CI, 5-17%), and 44% (95% CI, 35-56%) for those restaged with lower than T1, T1, and T2 disease, respectively. Immediate cystectomy was more likely in patients with cT1 disease at restaging than in those with disease lower than cT1, but there were no other obvious differences in clinical characteristics between those with and without immediate cystectomy. Survival was not statistically different for patients who underwent an immediate cystectomy versus those who were maintained on surveillance with deferred cystectomy if deemed appropriate. Of 333 patients who did not undergo immediate cystectomy, 59 had a deferred cystectomy, and the likelihood of deferred cystectomy was greater in those with T1 disease on restaging TUR (hazard ratio: 2.40; 95% CI, 1.43-4.01; p=0.001). CONCLUSIONS Restaging TUR should be performed in patients diagnosed with cT1 bladder cancer to improve staging accuracy. Patients with T1 disease on restaging are at higher risk of progression and should be considered for early cystectomy.

The Effect of Tumor Location on Prognosis in Patients Treated with Radical Nephroureterectomy at Memorial Sloan-Kettering Cancer Center

BACKGROUND The prognostic impact of primary tumor location on outcomes for patients with upper-tract urothelial carcinoma (UTUC) is still contentious. OBJECTIVE To test the association between tumor location and disease recurrence and cancer-specific survival (CSS) in patients treated with radical nephroureterectomy (RNU) for UTUC. DESIGN, SETTING, AND PARTICIPANTS Prospectively collected data were retrospectively reviewed from 324 consecutive patients treated with RNU between 1995 and 2008 at a single tertiary referral center. Patients who had previous radical cystectomy, preoperative chemotherapy, previous contralateral UTUC, or metastatic disease at presentation were excluded. This left 253 patients for analysis. Tumor location was categorized as renal pelvis or ureter based on the location of the dominant tumor. Recurrences in the bladder only, in nonbladder sites, and in any site were analyzed. INTERVENTION All patients were treated with RNU. MEASUREMENTS Recurrence-free survival and CSS probabilities were estimated using Kaplan-Meier and Cox regression analyses. RESULTS AND LIMITATIONS Median follow-up for survivors was 48 mo. The 5-yr recurrence-free probability (including bladder recurrence) and CSS estimates were 32% and 78%, respectively. On multivariable analysis, pathologic stage was the only predictor for disease recurrence (p=0.01). Tumor location was not an independent predictor for recurrence (hazard ratio: 1.19; p=0.3), and there was no difference in the probability of disease recurrence between ureteral and renal pelvic tumors (p=0.18). On survival analysis, we also found no differences between ureteral and renal pelvic tumors on probability of CSS (p=0.2). On multivariate analysis, pathologic stage (p<0.0001) and nodal status (p=0.01) were associated with worse CSS. This study is limited by its retrospective nature. CONCLUSIONS Our study did not show any differences in recurrence and CSS rates between patients with ureteral and renal pelvic tumors treated with RNU.

Combining imaging and ureteroscopy variables in a preoperative multivariable model for prediction of muscle‐invasive and non‐organ confined disease in patients with upper tract urothelial carcinoma

Study Type – Diagnostic (exploratory cohort)

Endothelial Membrane Remodeling Is Obligate for Anti-Angiogenic Radiosensitization during Tumor Radiosurgery

Background While there is significant interest in combining anti-angiogenesis therapy with conventional anti-cancer treatment, clinical trials have as of yet yielded limited therapeutic gain, mainly because mechanisms of anti-angiogenic therapy remain to a large extent unknown. Currently, anti-angiogenic tumor therapy is conceptualized to either “normalize” dysfunctional tumor vasculature, or to prevent recruitment of circulating endothelial precursors into the tumor. An alternative biology, restricted to delivery of anti-angiogenics immediately prior to single dose radiotherapy (radiosurgery), is provided in the present study. Methodology/Principal Findings Genetic data indicate an acute wave of ceramide-mediated endothelial apoptosis, initiated by acid sphingomyelinase (ASMase), regulates tumor stem cell response to single dose radiotherapy, obligatory for tumor cure. Here we show VEGF prevented radiation-induced ASMase activation in cultured endothelium, occurring within minutes after radiation exposure, consequently repressing apoptosis, an event reversible with exogenous C16-ceramide. Anti-VEGFR2 acts conversely, enhancing ceramide generation and apoptosis. In vivo, MCA/129 fibrosarcoma tumors were implanted in asmase+/+ mice or asmase−/− littermates and irradiated in the presence or absence of anti-VEGFR2 DC101 or anti-VEGF G6-31 antibodies. These anti-angiogenic agents, only if delivered immediately prior to single dose radiotherapy, de-repressed radiation-induced ASMase activation, synergistically increasing the endothelial apoptotic component of tumor response and tumor cure. Anti-angiogenic radiosensitization was abrogated in tumors implanted in asmase−/− mice that provide apoptosis-resistant vasculature, or in wild-type littermates pre-treated with anti-ceramide antibody, indicating that ceramide is necessary for this effect. Conclusions/Significance These studies show that angiogenic factors fail to suppress apoptosis if ceramide remains elevated while anti-angiogenic therapies fail without ceramide elevation, defining a ceramide rheostat that determines outcome of single dose radiotherapy. Understanding the temporal sequencing of anti-angiogenic drugs and radiation enables optimized radiosensitization and design of innovative radiosurgery clinical trials.

Comparison Between Laparoscopic and Open Radical Nephroureterectomy in a Contemporary Group of Patients: Are Recurrence and Disease-Specific Survival Associated with Surgical Technique?

BACKGROUND Open radical nephroureterectomy (ORN) is the current standard of care for upper tract urothelial carcinoma (UTUC), but laparoscopic radical nephroureterectomy (LRN) is emerging as a minimally invasive alternative. Questions remain regarding the oncologic safety of LRN and its relative equivalence to ORN. OBJECTIVE Our aim was to compare recurrence-free and disease-specific survival between ORN and LRN. DESIGN, SETTING, AND PARTICIPANTS We retrospectively analyzed data from 324 consecutive patients treated with radical nephroureterectomy (RN) between 1995 and 2008 at a major cancer center. Patients with previous invasive bladder cancer or contralateral UTUC were excluded. Descriptive data are provided for 112 patients who underwent ORN from 1995 to 2001 (pre-LRN era). Comparative analyses were restricted to patients who underwent ORN (n=109) or LRN (n=53) from 2002 to 2008. Median follow-up for patients without disease recurrence was 23 mo. INTERVENTION All patients underwent RN. MEASUREMENTS Recurrence was categorized as bladder-only recurrence or any recurrence (bladder, contralateral kidney, operative site, regional lymph nodes, or distant metastasis). Recurrence-free probabilities were estimated using Kaplan-Meier methods. A multivariable Cox model was used to evaluate the association between surgical approach and disease recurrence. The probability of disease-specific death was estimated using the cumulative incidence function. RESULTS AND LIMITATIONS Clinical and pathologic characteristics were similar for all patients. The recurrence-free probabilities were similar between ORN and LRN (2-yr estimates: 38% and 42%, respectively; p=0.9 by log-rank test). On multivariable analysis, the surgical approach was not significantly associated with disease recurrence (hazard ratio [HR]: 0.88 for LRN vs ORN; 95% confidence interval [CI], 0.57-1.38; p=0.6). There was no significant difference in bladder-only recurrence (HR: 0.78 for LRN vs ORN; 95% CI, 0.46-1.34; p=0.4) or disease-specific mortality (p=0.9). This study is limited by its retrospective nature. CONCLUSIONS Based on the results of this retrospective study, no evidence indicates that oncologic control is compromised for patients treated with LRN in comparison with ORN.

Chronic Kidney Disease Before and After Partial Nephrectomy

PURPOSE We performed a multi-institutional retrospective cohort study to evaluate baseline renal function of patients who underwent partial nephrectomy for renal tumors, and determined rates of progression to higher stages of chronic kidney disease. MATERIALS AND METHODS The Modification of Diet in Renal Disease study equation was used to estimate glomerular filtration rate. Preoperative and postoperative serum creatinine values were obtained from patients who underwent partial nephrectomy at 6 institutions with a normal contralateral kidney, and had baseline chronic kidney disease stage I (estimated glomerular filtration rate greater than 90 ml/minute/1.73 m(2)), II (estimated glomerular filtration rate 60 to 89 ml/minute/1.73 m(2)) or III (estimated glomerular filtration rate 30 to 59 ml/minute/1.73 m(2)). The end point was change in chronic kidney disease stage at long-term followup (3 to 18 months). Multivariate logistic and Cox regression models tested the association of newly acquired chronic kidney disease stage III or greater with pertinent demographic, tumor and surgical factors. RESULTS For 1,228 patients with followup creatinine data at least 3 months after partial nephrectomy median baseline glomerular filtration rate was 74 ml/minute/1.73 m(2). At baseline 19%, 59% and 22% of patients had chronic kidney disease stage I, II and III, respectively. At long-term followup for patients with baseline chronic kidney disease stage I or II median postoperative glomerular filtration rate was 67 ml/minute/1.73 m(2) with 29% having progression to chronic kidney disease stage III or greater. Increasing age, female gender, increasing tumor size, clamping of the renal artery and vein, and lower preoperative estimated glomerular filtration rate were independently associated with newly acquired chronic kidney disease stage III or greater. The presence of comorbid conditions such as coronary artery disease, diabetes mellitus or hypertension did not independently predict an increased risk of higher chronic kidney disease stage. CONCLUSIONS Chronic kidney disease stage III or greater will develop postoperatively in approximately a third of patients with an estimated glomerular filtration rate greater than 60 ml/minute/1.73 m(2), and this progression is associated with definable demographic, tumor and surgical factors.