Hyung L. Kim

Using protein expressions to predict survival in clear cell renal carcinoma.

Purpose: An accurate system for predicting survival for patients with solid tumors will allow for better patient selection for both established and novel therapies. We propose a staging system for clear cell variants of renal cell carcinoma (RCC) that includes molecular predictors and standard clinical predictors such as tumor-node-metastasis (TNM) stage, histological grade, and performance status (PS). Experimental Design: A custom tissue array was constructed using clear cell RCC from 318 patients, representing all stages of localized and metastatic RCC, and immunohistochemically stained for molecular markers Ki67, p53, gelsolin, CA9, CA12, PTEN, EpCAM, and vimentin. We present a strategy for evaluating individual candidate markers for prognostic information and integrating informative markers into a multivariate prognostic system. Results: The overall median follow-up and the median follow-up for surviving patients were 28 and 55 months, respectively. A prognostic model based primarily on molecular markers included metastasis status, p53, CA9, gelsolin, and vimentin as predictors and had high discriminatory power: its statistically validated concordance index (C-index) was found to be 0.75. A prognostic model based on a combination of clinical and molecular predictors included metastasis status, T stage, Eastern Cooperative Oncology Group PS, p53, CA9, and vimentin as predictors and had a C-index of 0.79, which was significantly higher (P < 0.05) than that of prognostic models based on grade alone (C = 0.65), TNM stage alone (C = 0.73), or the University of California Los Angeles integrated staging system (C = 0.76). Conclusions: Protein expressions obtained using widely available technology can complement standard clinical predictors such as TNM stage, histological grade, and PS.

The Learning Curve of Robot-Assisted Radical Cystectomy: Results from the International Robotic Cystectomy Consortium

BACKGROUND Robot-assisted radical cystectomy (RARC) has evolved as a minimally invasive alternative to open radical cystectomy for patients with invasive bladder cancer. OBJECTIVE We sought to define the learning curve for RARC by evaluating results from a multicenter, contemporary, consecutive series of patients who underwent this procedure. DESIGN, SETTING, AND PARTICIPANTS Utilizing the International Robotic Cystectomy Consortium database, a prospectively maintained and institutional review board-approved database, we identified 496 patients who underwent RARC by 21 surgeons at 14 institutions from 2003 to 2009. MEASUREMENTS Cut-off points for operative time, lymph node yield (LNY), estimated blood loss (EBL), and margin positivity were identified. Using specifically designed statistical mixed models, we were able to inversely predict the number of patients required for an institution to reach the predetermined cut-off points. RESULTS AND LIMITATIONS Mean operative time was 386 min, mean EBL was 408 ml, and mean LNY was 18. Overall, 34 of 482 patients (7%) had a positive surgical margin (PSM). Using statistical models, it was estimated that 21 patients were required for operative time to reach 6.5h and 8, 20, and 30 patients were required to reach an LNY of 12, 16, and 20, respectively. For all patients, PSM rates of <5% were achieved after 30 patients. For patients with pathologic stage higher than T2, PSM rates of <15% were achieved after 24 patients. CONCLUSIONS RARC is a challenging procedure but is a technique that is reproducible throughout multiple centers. This report helps to define the learning curve for RARC and demonstrates an acceptable level of proficiency by the 30th case for proxy measures of RARC quality.

Effect of preoperative biofeedback/pelvic floor training on continence in men undergoing radical prostatectomy.

OBJECTIVES To determine whether preoperative biofeedback training improves urinary continence overall or the rate of return of continence in men undergoing radical prostatectomy. METHODS One hundred men scheduled to undergo radical prostatectomy were randomized to receive graded pelvic muscle exercise training with biofeedback 2 to 4 weeks before surgery or to a control group performing pelvic muscle exercises without biofeedback. The biofeedback group was instructed to continue exercises four times per day until surgery and to resume exercises when the urethral catheter was removed following surgery. The control group received written and brief verbal instructions in pelvic muscle exercises before surgery and again after catheter removal. Urinary continence was assessed by personal or phone interviews. RESULTS Six months following surgery, the continence rates, as defined by the use of one pad or less per day, were 94% (44 of 47) and 96% (48 of 50) in the biofeedback and control groups, respectively (P = 0.596). Also, the rate of return as determined at time points 1, 2, 3, and 4 months after surgery was not significantly different between the two groups. CONCLUSIONS Preoperative biofeedback training did not improve the outcome of pelvic muscle exercises on overall continence or the rate of return of urinary control in men undergoing radical prostatectomy.

Surgical Margin Status After Robot Assisted Radical Cystectomy: Results From the International Robotic Cystectomy Consortium

PURPOSE Positive surgical margins at radical cystectomy confer a poor prognosis. We evaluated the incidence and predictors of positive surgical margins in patients who underwent robot assisted radical cystectomy for bladder cancer. MATERIALS AND METHODS Using the International Robotic Cystectomy Consortium database we identified 513 patients who underwent robot assisted radical cystectomy, as done by a total of 22 surgeons at 15 institutions from 2003 to 2009. After stratification by age group, gender, pathological T stage, nodal status, sequential case number and institutional volume logistic regression was used to correlate variables with the likelihood of a positive surgical margin. RESULTS Of the 513 patients 35 (6.8%) had a positive surgical margin. Increasing 10-year age group, lymph node positivity and higher pathological T stage were significantly associated with an increased likelihood of a positive margin (p = 0.010, <0.001 and p <0.001, respectively). Gender, sequential case number and institutional volume were not significantly associated with margin positivity. The rate of margin positive disease at cystectomy was 1.5% for pT2 or less, 8.8% for pT3 and 39% for pT4 disease. CONCLUSIONS Positive surgical margin rates at robot assisted radical cystectomy for advanced bladder cancer were similar to those in open cystectomy series in a large, multi-institutional, prospective cohort. Sequential case number, a surrogate for the learning curve and institutional volume were not significantly associated with positive margins at robot assisted radical cystectomy.

RENAL nephrometry score predicts surgical outcomes of laparoscopic partial nephrectomy

Study Type – Therapy (case series)

Prospective Clinical Trial of Preoperative Sunitinib in Patients With Renal Cell Carcinoma

PURPOSE Sunitinib is an approved treatment for metastatic renal cell carcinoma. We performed a prospective clinical trial to evaluate the safety and clinical response to sunitinib administered before nephrectomy in patients with localized or metastatic clear cell renal cell carcinoma. MATERIALS AND METHODS Patients with biopsy proven clear cell renal cell carcinoma were enrolled in the study and treated with 37.5 mg sunitinib malate daily for 3 months before nephrectomy. The primary end point was safety. RESULTS In an 18-month period 20 patients were enrolled. The most common toxicities were gastrointestinal symptoms and hematological effects. Grade 3 toxicity developed in 6 patients (30%). No surgical complications were attributable to sunitinib treatment. Of the 20 patients 17 (85%) experienced reduced tumor diameter (mean change -11.8%, range -27% to 11%) and cross-sectional area (mean change -27.9%, range -43% to 23%). Enhancement on contrast enhanced computerized tomography decreased in 15 patients (mean HU change -22%, range -74% to 29%). After tumor reduction 8 patients with cT1b disease underwent laparoscopic partial nephrectomy. Surgical parameters, such as blood loss, transfusion rate, operative time and complications, were similar to those in patients who underwent surgery during the study period and were not enrolled in the trial. CONCLUSIONS Preoperative treatment with sunitinib is safe. Sunitinib decreased the size of primary renal cell carcinoma in 17 of 20 patients. Future trials can be considered to evaluate neoadjuvant sunitinib to maximize nephron sparing and decrease the recurrence of high risk, localized renal cell carcinoma.

Large oncosomes mediate intercellular transfer of functional microRNA.

Prostate cancer cells release atypically large extracellular vesicles (EVs), termed large oncosomes, which may play a role in the tumor microenvironment by transporting bioactive molecules across tissue spaces and through the blood stream. In this study, we applied a novel method for selective isolation of large oncosomes applicable to human platelet-poor plasma, where the presence of caveolin-1-positive large oncosomes identified patients with metastatic disease. This procedure was also used to validate results of a miRNA array performed on heterogeneous populations of EVs isolated from tumorigenic RWPE-2 prostate cells and from isogenic non-tumorigenic RWPE-1 cells. The results showed that distinct classes of miRNAs are expressed at higher levels in EVs derived from the tumorigenic cells in comparison to their non-tumorigenic counterpart. Large oncosomes enhanced migration of cancer-associated fibroblasts (CAFs), an effect that was increased by miR-1227, a miRNA abundant in large oncosomes produced by RWPE-2 cells. Our findings suggest that large oncosomes in the circulation report metastatic disease in patients with prostate cancer, and that this class of EV harbors functional molecules that may play a role in conditioning the tumor microenvironment.

Lymphadenectomy at the time of robot‐assisted radical cystectomy: results from the International Robotic Cystectomy Consortium

What’s known on the subject? and What does the study add?

Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines

Background:Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor and rapamycin analogue that is approved for treating advanced renal cell carcinoma (RCC). It is being actively evaluated in clinical trials for melanoma. The mTOR inhibitors are also immunosuppressants and are used clinically to prevent rejection following solid-organ transplant. Novel immunotherapies are being actively developed for immunoresponsive tumours, such as RCC and melanoma.Methods:Immune-modulating effects of temsirolimus were characterised when used in combination with cancer vaccines targeting RCC (RENCA) and melanoma (B16). Cancer vaccines were recombinant tumour-specific proteins (CA9 or gp100), and recombinant heat shock protein (HSP; hsp110) served as the immune adjuvant.Results:In murine models, temsirolimus enhanced the anti-tumour activity of cancer vaccines used to treat established RENCA and B16 tumours. A tumour prevention model established that the enhanced anti-tumour activity associated with temsirolimus was immune mediated. In mice treated with an HSP-based anti-tumour vaccine, temsirolimus-treated CD8 T cells had greater interferon-γ and cytotoxic T-cell responses when compared with mice treated with vaccine alone. Temsirolimus also enhanced the formation of CD8 memory cells following administration of HSP-based cancer vaccine.Conclusion:These results provide a rationale for combining mTOR inhibitor with immunotherapy when treating immunoresponsive tumours.

Percutaneous Biopsy of Renal Cell Carcinoma Underestimates Nuclear Grade

OBJECTIVES To assess the accuracy of renal biopsy for predicting the final nuclear grade and histologic subtype. Small renal masses can be safely observed in select patients who are poor surgical candidates. Renal biopsy may help identify patients who are candidates for observation. METHODS A total of 81 patients (29 female, 52 male) underwent percutaneous biopsy of their renal mass with ultrasound or computed tomography guidance. Percutaneous 18-gauge biopsy cores were obtained, and all patients subsequently underwent radical nephrectomy or partial nephrectomy. Preoperative biopsy results were compared with postoperative specimens. RESULTS The mean tumor size was 5.3 cm (range, 1-17). Overall, biopsy correctly identified 71 of 81 (88%) histologic subtypes. The preoperative biopsy correctly identified 62 of 64 (97%) clear cell renal carcinomas, 9 of 10 (90%) papillary carcinomas, 0 of 3 (0%) chromophobe carcinomas, and 1 of 2 (50%) oncocytomas. The final pathologies for 2 nondiagnostic biopsies were clear cell renal carcinoma and inflammatory pseudotumor. For 67 tumors, the pathologists assigned a nuclear grade for both the biopsy and the final specimen. The biopsy correctly identified 29 of 67 (43%) final nuclear grades. The biopsy underestimated the nuclear grade in 37 of 67 (55%) cases. In 7 of 67 (10%) cases, the biopsy nuclear grade increased by 2 when compared with the final grade. The biopsy rarely overestimated the nuclear grade; 1 case (1%) that was assigned a grade 2 on biopsy was assigned a grade 1 after nephrectomy. CONCLUSIONS Core biopsies for renal masses underestimate nuclear grade in most cases; however, histologic subtype is more reliably assessed, particularly for clear cell renal tumors.