Christopher J. Kane

Impact of Obesity on Biochemical Control After Radical Prostatectomy for Clinically Localized Prostate Cancer: A Report by the Shared Equal Access Regional Cancer Hospital Database Study Group

PURPOSE Given the limited information regarding the impact of obesity on treatment outcomes for prostate cancer, we sought to examine the relationship between body mass index (BMI) and cancer control after radical prostatectomy (RP). PATIENTS AND METHODS We compared clinicopathologic and biochemical outcome information across BMI groups from 1,106 men treated with RP between 1988 and 2002. Multivariate analysis was used to determine if BMI significantly predicted adverse pathology or biochemical recurrence. RESULTS Obesity was related to year of surgery (P <.001) and race (P <.001), with black men having the highest obesity rates. Obese patients had higher biopsy and pathologic grade tumors (P <.001). On multivariate analysis, BMI > or = 35 kg/m(2) was associated with a trend for higher rates of positive surgical margins (P =.008). Overweight patients (BMI, 25 to 30 kg/m(2)) had a significantly decreased risk of seminal vesicle invasion (P =.039). After controlling for all preoperative clinical variables including year of surgery, BMI > or = 35 kg/m(2) significantly predicted biochemical failure after RP (P =.002). After controlling for surgical margin status, BMI > or = 35 kg/m(2) remained a significant predictor of biochemical failure (P =.012). There was a trend for BMI > or = 35 kg/m(2) to be associated with higher failure rates than BMI between 30 and 35 kg/m(2) (P =.053). CONCLUSION The percentage of obese men undergoing RP in our data set doubled in the last 10 years. Obesity was associated with higher-grade tumors, a trend toward increased risk of positive surgical margins, and higher biochemical failure rates among men treated with RP. A BMI > or = 35 kg/m(2) was associated with a higher risk of failure than a BMI between 30 and 35 kg/m(2).

Active surveillance for the management of prostate cancer in a contemporary cohort

Active surveillance followed by selective treatment for men who have evidence of disease progression may be an option for select patients with early‐stage prostate cancer. In this article, the authors report their experience in a contemporary cohort of men with prostate cancer who were managed with active surveillance.

Renal cell cancer stage migration: analysis of the National Cancer Data Base.

Evidence exists to suggest a pattern of increasing early diagnosis of renal cell carcinoma (RCC). The aim of the study was to analyze patterns of disease presentation and outcome of RCC by AJCC stage using data from the National Cancer Data Base (NCDB) over a 12‐year period.

Prostate Size and Risk of High-Grade, Advanced Prostate Cancer and Biochemical Progression After Radical Prostatectomy: A Search Database Study

PURPOSE Prostate growth and differentiation are under androgenic control, and prior studies suggested that tumors that develop in hypogonadal men are more aggressive. We examined whether prostate weight was associated with tumor grade, advanced disease, or risk of biochemical progression after radical prostatectomy (RP). PATIENTS AND METHODS We evaluated the association of prostate weight with pathologic tumor grade, positive surgical margins, extracapsular disease, and seminal vesicle invasion using logistic regression and with biochemical progression using Cox proportional hazards regression among 1,602 men treated with RP between 1988 and 2003 at five equal-access medical centers, which composed the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. RESULTS In outcome prediction models including multiple predictor variables, it was found that the predictor variable of prostate weight was significantly inversely associated with the outcomes of high-grade disease, positive surgical margins, extracapsular extension (all P < or = .004), and biochemical progression (comparing prostate weight < 20 v > or = 100 g: relative risk = 8.43; 95% CI, 2.9 to 24.0; P < .001). Similar associations were seen between preoperative transrectal ultrasound-measured prostate volume and high-grade disease, positive surgical margins, extracapsular extension (all P < or = .005), seminal vesicle invasion (P = .07), and biochemical progression (P = .06). CONCLUSION Men with smaller prostates had more high-grade cancers and more advanced disease and were at greater risk of progression after RP. These results suggest that prostate size may be an important prognostic variable that should be evaluated for use pre- and postoperatively to predict biochemical progression.

Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial

BACKGROUND Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. METHODS In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. FINDINGS Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. INTERPRETATION Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. FUNDING US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.

Impact of body weight on urinary electrolytes in urinary stone formers

OBJECTIVES Obesity increases the risk of developing chronic medical conditions such as diabetes mellitus, hypertension, and coronary artery disease. We performed a retrospective review of a large data base on urinary stones to determine if differences are found in urine and serum chemistries among obese and nonobese stone-forming patients. The effect of body weight on stone recurrence among urinary stone formers was also determined. METHODS A national data base containing serum biochemical profiles, 24-hour urine specimens, and standardized questionnaires was retrospectively evaluated from 5942 consecutive patients with urinary stone disease. Stone-forming patients were classified by body weight: nonobese men, less than 100 kg and nonobese women, less than 85 kg; intermediate men, 100 to 120 kg and intermediate women, 85 to 100 kg; and obese men, more than 120 kg and obese women, more than 100 kg. RESULTS Obese stone formers comprised 6.8% (n = 404) of the patient population. The mean weight in the nonobese and obese groups was 81 kg versus 134 kg, respectively, for men and 64 kg versus 112 kg, respectively, for women. Obese patients represented 3.8% of the male and 12.6% of the female population. Obese patients had increased urinary excretion of sodium, calcium, magnesium, citrate, sulfate, phosphate, oxalate, uric acid, and cystine; obesity was associated with increased urinary volumes and urine osmolality compared with the nonobese patients. Obese men had increased concentration of urinary sodium, oxalate, uric acid, sulfate, and phosphate when corrected for urinary volume. Obese women had increased concentrations of sodium, uric acid, sulfate, phosphate, and cystine. The mean number of stone episodes in nonobese versus obese men was similar (3.55 and 3.56), whereas mean stone episodes were 2.93 and 3.38 (P = 0.045) for nonobese versus obese women. CONCLUSIONS Among known stone formers, obesity is associated with unique changes in both serum and urinary chemistries. These changes are associated with an increased incidence of urinary stone episodes in obese women but not in obese men.

Obesity, Serum Prostate Specific Antigen and Prostate Size: Implications for Prostate Cancer Detection

PURPOSE Obesity has been associated with lower serum testosterone, theoretically resulting in decreased PSA production. Obesity has also been associated with prostatic enlargement, making the detection of existent cancer more difficult. Together these findings would result in an apparent protective effect of obesity on prostate cancer risk due to technical detection issues unrelated to cancer biology. We examined the association between BMI, and PSA and prostate weight in a cohort of men undergoing RP. MATERIALS AND METHODS We evaluated the association of BMI with prostate weight and PSA using linear regression, adjusting for patient age at RP, year of RP, race, and pathological stage and grade in 1,414 men treated with RP between 1988 and 2004 at the 5 equal access medical centers that comprise the Shared Equal Access Regional Cancer Hospital Database. RESULTS On multivariate analysis increasing BMI was associated with increasing prostate weight but only in men younger than 63 years and not in men 63 years or older (p-trend <0.001 and 0.44, respectively). In men younger than 63 years mean multivariate adjusted prostate weight +/- SE in those with a BMI of less than 25 vs 30 to 34.9 kg/m was 33.8 +/- 1.4 vs 41.4 +/- 1.6 gm. There was no significant association between BMI and preoperative PSA (p-trend = 0.70). CONCLUSIONS In a cohort of men undergoing RP obesity was associated with larger prostate size but only in younger men. There was no association between BMI and PSA. Assuming equal PSA, the degree of prostatic enlargement observed in younger obese men in this study would be expected to result in a modest decrease in the odds of detecting prostate cancer in a contemporary series of PSA screened men due to the decreased sensitivity of cancer detection related to larger prostate size. Obesity may appear protective for prostate cancer in younger men due to technical issues unrelated to cancer biology.

URETERAL STENTING AFTER URETEROSCOPY FOR DISTAL URETERAL CALCULI: A MULTI-INSTITUTIONAL PROSPECTIVE RANDOMIZED CONTROLLED STUDY ASSESSING PAIN, OUTCOMES AND COMPLICATIONS

PURPOSE We compare postoperative pain, stone-free rates and complications after ureteroscopic treatment of distal ureteral calculi with or without the use of ureteral stents. MATERIALS AND METHODS A total of 113 patients with distal ureteral calculi amenable to ureteroscopic treatment were prospectively randomized into stented (53) and unstented (60) groups. Stones were managed with semirigid ureteroscopes with or without distal ureteral dilation and/or intracorporeal lithotripsy. Preoperative and postoperative pain questionnaires were obtained from each patient. Patients with stents had them removed 3 to 10 days postoperatively. Radiographic followup was performed postoperatively to assess stone-free rates and evidence of obstruction. RESULTS Six patients randomized to the unstented group were withdrawn from the study after significant intraoperative ureteral trauma was recognized, including 3 ureteral perforations, that required ureteral stent placement, leaving 53 with stents and 54 without for analysis. Patients with stents had statistically significantly more postoperative flank pain (p = 0.005), bladder pain (p <0.001), urinary symptoms (p = 0.002), overall pain (p <0.001) and total narcotic use (p <0.001) compared to the unstented group. Intraoperative ureteral dilation or intracorporeal lithotripsy did not statistically significantly affect postoperative pain or narcotic use in either group (p >0.05 in all cases). Overall mean stone size in our study was 6.6 mm. There were 4 (7.4%) patients without stents who required postoperative readmission to the hospital secondary to flank pain. All patients (85%) who underwent imaging postoperatively were without evidence of obstruction or ureteral stricture on followup imaging (mean followup plus or minus standard deviation 1.8 +/- 1.5 months), and the stone-free rate was 99.1%. CONCLUSIONS Uncomplicated ureteroscopy for distal ureteral calculi with or without intraoperative ureteral dilation can safely be performed without placement of a ureteral stent. Patients without stents had significantly less pain, fewer urinary symptoms and decreased narcotic use postoperatively.

Immunosuppressive plasma cells impede T cell-dependent immunogenic chemotherapy

Cancer-associated genetic alterations induce expression of tumour antigens that can activate CD8+ cytotoxic T cells (CTLs), but the microenvironment of established tumours promotes immune tolerance through poorly understood mechanisms. Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers. Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms. Our previous studies revealed that B cells recruited by the chemokine CXCL13 into prostate cancer tumours promote the progression of castrate-resistant prostate cancer by producing lymphotoxin, which activates an IκB kinase α (IKKα)-BMI1 module in prostate cancer stem cells. Because castrate-resistant prostate cancer is refractory to most therapies, we examined B cell involvement in the acquisition of chemotherapy resistance. Here we focus on oxaliplatin, an immunogenic chemotherapeutic agent that is effective in aggressive prostate cancer. We show that mouse B cells modulate the response to low-dose oxaliplatin, which promotes tumour-directed CTL activation by inducing immunogenic cell death. Three different mouse prostate cancer models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGFβ receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.

Prospective Comparison of Computerized Tomography and Excretory Urography in the Initial Evaluation of Asymptomatic Microhematuria

PURPOSE The ideal imaging study for evaluation of the upper urinary tract in patients with microhematuria has been debated. We prospectively compared the diagnostic yield of computerized tomography (CT) to excretory urography (IVP) in the initial evaluation of asymptomatic microhematuria. MATERIALS AND METHODS Between December 1998 and June 2001, 115 patients presenting with asymptomatic microhematuria underwent CT and IVP before cystoscopy. Helical CT images with 5 mm. adrenal and kidney slices with and without contrast material were followed by delayed 5 mm. ureteral contrast images through the bladder base. Each CT and IVP was examined by a radiologist who was blinded to the result of the other imaging study. Diagnostic yields of the imaging techniques were compared using the test of 2 proportions and chi-square analysis. RESULTS Radiographic abnormalities were noted on CT or IVP in 38 patients. Sensitivity was 100% for CT and 60.5% for IVP, and specificity 97.4% for CT and 90.9% for IVP. CT accuracy was 98.3% compared to IVP accuracy which was 80.9% (p <0.001). A total of 40 nonurological diagnoses were made by CT, including 3 abdominal aortic aneurysms and 1 iliac artery aneurysm. No additional diagnoses were made by IVP. Fewer additional radiographic studies were recommended after CT than after IVP. CONCLUSIONS The use of CT in the initial evaluation of asymptomatic microhematuria results in better diagnostic yield. In addition, more nonurological diagnoses can be made and less additional radiography is needed to confirm a diagnosis.