Nora Ruel

Identification of a 4-microRNA signature for clear cell renal cell carcinoma metastasis and prognosis.

Renal cell carcinoma (RCC) metastasis portends a poor prognosis and cannot be reliably predicted. Early determination of the metastatic potential of RCC may help guide proper treatment. We analyzed microRNA (miRNA) expression in clear cell RCC (ccRCC) for the purpose of developing a miRNA expression signature to determine the risk of metastasis and prognosis. We used the microarray technology to profile miRNA expression of 78 benign kidney and ccRCC samples. Using 28 localized and metastatic ccRCC specimens as the training cohort and the univariate logistic regression and risk score methods, we developed a miRNA signature model in which the expression levels of miR-10b, miR-139-5p, miR-130b and miR-199b-5p were used to determine the status of ccRCC metastasis. We validated the signature in an independent 40-sample testing cohort of different stages of primary ccRCCs using the microarray data. Within the testing cohort patients who had at least 5 years follow-up if no metastasis developed, the signature showed a high sensitivity and specificity. The risk status was proven to be associated with the cancer-specific survival. Using the most stably expressed miRNA among benign and tumorous kidney tissue as the internal reference for normalization, we successfully converted his signature to be a quantitative PCR (qPCR)-based assay, which showed the same high sensitivity and specificity. The 4-miRNA is associated with ccRCC metastasis and prognosis. The signature is ready for and will benefit from further large clinical cohort validation and has the potential for clinical application.

Standardized Analysis of Frequency and Severity of Complications After Robot-assisted Radical Cystectomy

BACKGROUND Comprehensive and standardized reporting of adverse events after robot-assisted radical cystectomy (RARC) and urinary diversion for bladder cancer is necessary to evaluate the magnitude of morbidity for this complex operation. OBJECTIVE To accurately identify and assess postoperative morbidity after RARC using a standardized reporting system. DESIGN, SETTING, AND PARTICIPANTS A total of 241 consecutive patients underwent RARC, extended pelvic lymph node dissection, and urinary diversion between 2003 and 2011. In all, 196 patients consented to a prospective database, and they are the subject of this report. Continent diversions were performed in 68% of cases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS All complications within 90 d of surgery were defined and categorized by a five-grade and 10-domain modification of the Clavien system. Univariable and multivariable logistic regression analyses were used to identify predictors of complications. Grade 1-2 complications were categorized as minor, and grade 3-5 complications were categorized as major. All blood transfusions were recorded as grade ≥2. RESULTS AND LIMITATIONS Eighty percent of patients (156 of 196 patients) experienced a complication of any grade ≤90 d after surgery. A total of 475 adverse events (113 major) were recorded, with 365 adverse events (77%) occurring ≤30 d after surgery. Sixty-eight patients (35%) experienced a major complication within the first 90 d. Other than blood transfusions given (86 patients [43.9%]), infectious, gastrointestinal, and procedural complications were the most common, at 16.2%, 14.1%, and 10.3%, respectively. Age, comorbidity, preoperative hematocrit, estimated blood loss, and length of surgery were predictive of a complication of any grade, while comorbidity, preoperative hematocrit, and orthotopic diversion were predictive of major complications. The 90-d mortality rate was 4.1%. The main limitation is lack of a control group. CONCLUSIONS Analysis of postoperative morbidity following RARC demonstrates a considerable complication rate, though the rate is comparable to contemporary open series that followed similar reporting guidelines. This finding reinforces the need for complete and standardized reporting when evaluating surgical techniques and comparing published series.

Radioiodinated versus Radiometal-Labeled Anti–Carcinoembryonic Antigen Single-Chain Fv-Fc Antibody Fragments: Optimal Pharmacokinetics for Therapy

Antibody fragments with optimized pharmacokinetic profiles hold potential for detection and therapy of tumor malignancies. We studied the behavior of three anti-carcinoembryonic antigen (CEA) single-chain Fv-Fc (scFv-Fc) variants (I253A, H310A, and H310A/H435Q; Kabat numbering system) that exhibited differential serum persistence. Biodistribution studies done on CEA-positive tumor xenografted mice revealed that the 111In-labeled I253A fragment with the slowest clearance kinetics (T1/2beta, 27.7 h) achieved the highest tumor uptake (44.6% ID/g at 24 h), whereas the radiometal-labeled H310A/H435Q fragment with the most rapid elimination (T1/2beta, 7.05 h) reached a maximum of 28.0% ID/g at 12 h postinjection. The H310A protein was characterized by both intermediate serum half-life and tumor uptake. The 111In-based biodistribution studies showed that all three fragments were eliminated primarily through the liver, and hepatic radiometal activity correlated with the rate of fragment clearance. The 111In-labeled H310A/H435Q protein exhibited the highest liver uptake (23.5% ID/g at 24 h). Metabolism of the 125I-labeled scFv-Fc proteins resulted in low normal organ activity. Finally, the 125I/111In biodistribution data allowed for dose estimations, which suggest the 131I-labeled scFv-Fc H310A/H435Q as a promising candidate for radioimmunotherapy.

Early and Late Complications of Robot-Assisted Radical Cystectomy: A Standardized Analysis by Urinary Diversion Type

PURPOSE Minimally invasive surgical treatment for bladder cancer has gained popularity but standardized data on complications are lacking. Urinary diversion type contributes to complications and to our knowledge diversion types after minimally invasive cystectomy have not yet been compared. We evaluated perioperative complications stratified by urinary diversion type in patients treated with robot-assisted radical cystectomy. MATERIALS AND METHODS We analyzed the records of 209 consecutive patients who underwent robot-assisted radical cystectomy at our institution from 2003 to 2012 with respect to perioperative complications, including severity, time period (early and late) and diversion type. All complications were reviewed by academic urologists. Urinary diversion was also done. As outcome measurements and statistical analysis, univariate and multivariate logistic regression models were used to determine predictors of various complications. RESULTS The American Society of Anesthesiologists(®) (ASA) score was 3 or greater in 80% of patients and continent diversion was performed in 68%. Median followup was 35 months. Within 90 days 77.5% of patients experienced any complication and 32% experienced a major complication. The 90-day mortality rate was 5.3%. Most complications were gastrointestinal, infectious and hematological. On multivariate analysis patients with ileal conduit diversion had a decreased likelihood of complications compared to patients with Indiana pouch and orthotopic bladder substitute diversion despite the selection of a more comorbid population for conduit diversion. Continent diversion was associated with a higher likelihood of urinary tract infection. Our results are comparable to those of previously reported open and minimally invasive cystectomy series. CONCLUSIONS Open or minimally invasive cystectomy is a complex, morbid procedure. Urinary diversion is a significant contributor to complications, as is patient comorbidity. Although patients with an ileal conduit had more comorbidities, they experienced fewer complications than those with an orthotopic bladder substitute or Indiana pouch diversion.

Robotic Extended Pelvic Lymphadenectomy for Intermediate- and High-Risk Prostate Cancer

BACKGROUND Accurate staging of prostate cancer is enhanced by a thorough evaluation of the pelvic lymph nodes. Limited data are available regarding robotic extended pelvic lymphadenectomy (PLA) in this setting. OBJECTIVE Analyze our experience performing robotic extended PLA. DESIGN, SETTING, AND PARTICIPANTS A total of 143 consecutive men with intermediate- or high-risk clinically localized adenocarcinoma of the prostate underwent robotic extended PLA and radical prostatectomy between September 2010 and November 2011 by a single surgeon. SURGICAL PROCEDURE Lymph node packets were sent separately from bilateral common, external, and internal iliacs, obturators, node of Cloquet, and anterior prostatic fat. MEASUREMENTS Descriptive statistics were used to summarize lymph node yields and positive nodes. Clinical variables were examined in logistic regression models to predict lymph node positivity. RESULTS AND LIMITATIONS Median lymph node yield was 20 (range: 9-65, interquartile range: 15-25). Eighteen patients (13%) were found to have metastatic prostate cancer in the lymph nodes. The mean number of positive nodes found was 2.9 (range: 1-11). In 14 of 18 node-positive patients (78%), the extent of nodal invasion was outside the boundaries of a limited PLA. For four patients with positive nodes (22%), prostate biopsy predicted unilateral disease but PLA revealed contralateral positive lymph nodes. A total of 82% of patients experienced no complications, and most Clavien grade 1-2 complications consisted of anastomotic leakage, urinary retention, ileus, and lymphocele. Only 4% of patients experienced a grade 3 complication. Under multivariate regression analysis, prostate-specific antigen (PSA), clinical stage, and maximum biopsy core tumor volume were identified as significant predictors of finding positive pelvic lymph nodes (area under the curve: 91%). The main limitations include short follow-up and lack of randomization. CONCLUSIONS Robotic extended bilateral PLA for prostate cancer up to the common iliac bifurcation increases nodal yield and positive nodal rate and can be performed safely. PSA, clinical stage, and maximum biopsy core volume are predictors for lymph node invasion. Long-term follow-up is needed to evaluate for therapeutic benefit.

Standardized comparison of robot-assisted limited and extended pelvic lymphadenectomy for prostate cancer

Extended pelvic lymphadenectomy is the present standard of care according to European Association of Urology guidelines. Extended dissection improves staging, removes more metastatic lymph nodes, and potentially has therapeutic benefits. Previous reports have examined the morbidity of extended dissection compared with a more limited dissection in the open and laparoscopic setting. While some have suggested an increased complication rate with extended node dissection, others have not. This represents the first study focused on comparing the complications associated with the extent of node dissection using the modified Clavien system and Martin criteria in the literature on robot‐assisted surgery. In a single surgeon series, we found no statistically significant differences in complications. With careful anatomic dissection, robot‐assisted extended lymph node dissection can be performed safely and effectively, although operating time and length of hospital of stay are slightly increased.

Pooled Analysis of Clinical Outcomes with Neoadjuvant Cisplatin and Gemcitabine Chemotherapy for Muscle Invasive Bladder Cancer

PURPOSE Neoadjuvant chemotherapy for muscle invasive bladder cancer has been shown to confer a survival advantage in phase III studies. Although cisplatin and gemcitabine are often used in this setting, a comprehensive evaluation of this regimen is lacking. In this review we summarize the efficacy of neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer based on currently published studies. MATERIALS AND METHODS A systematic literature review was conducted in April 2012 searching MEDLINE® databases. Articles were selected if they included patients with muscle invasive bladder cancer, evaluated the combination of cisplatin and gemcitabine as neoadjuvant treatment, and reported pathological data after cystectomy. Cisplatin and gemcitabine dosing regimens and clinical data were further summarized using weighted averages. RESULTS Seven studies encompassing 164 patients were published between 2007 and 2012. The majority of patients (79%) received cisplatin and gemcitabine on a 21-day cycle. A weighted average of 19.2 lymph nodes was obtained at cystectomy, and 29.7% of patients were found to have pN1 disease. Pathological down staging to pT0 and less than pT2 occurred in 42 (25.6%) and 67 (46.5%) patients, respectively. CONCLUSIONS Neoadjuvant cisplatin and gemcitabine yield appreciable pathological response rates in patients with muscle invasive bladder cancer. Since pathological response has been implicated as a potential surrogate for survival in muscle invasive bladder cancer, these data suggest that neoadjuvant cisplatin and gemcitabine may warrant further prospective assessment.

Functional Outcomes and Complications in Patients With Bladder Cancer Undergoing Robotic-assisted Radical Cystectomy With Extracorporeal Indiana Pouch Continent Cutaneous Urinary Diversion

OBJECTIVE To evaluate the functional outcomes and complications for patients with bladder cancer undergoing robotic-assisted laparoscopic radical cystectomy with Indiana pouch continent cutaneous urinary diversion. METHODS From February 2004 to March 2010, 34 patients underwent robotic-assisted laparoscopic radical cystectomy with Indiana pouch continent cutaneous urinary diversion reconstruction. After surgery, the complications were identified, categorized, and graded using an established 5-grade modification of the original Clavien grading system, and continence was assessed. Descriptive statistics were used in evaluating the outcomes. Fischers exact test was used in the comparison of early and late Clavien grade III complications. RESULTS Overall, 175 (123 early and 52 late) complications after surgery were reported in 32 (94%) of 34 patients. Within 90 days of surgery, 31 (91%) of 34 patients experienced ≥ 1 early complication. Of 34 patients, 15 (44%) reported ≥ 1 late complications (>90 days). Most (85% and 69%, respectively) early and late complications were graded as minor (grade II or less). Fewer patients with early complications required an additional intervention (grade III) compared with patients with late complications (14% vs 31%; P = .116). The most common complication in both intervals was infection, reported in 22% and 37% of patients with early and late complications, respectively. The continence data for 31 patients at a mean follow-up of 20.1 months (median 12.0) showed that all but 1 patient (97%) had daytime and nighttime continence. CONCLUSION Patients undergoing robotic-assisted laparoscopic radical cystectomy with Indiana pouch continent cutaneous urinary diversion reconstruction have comparable complication rates and functional outcomes compared with patients in the open series.

Analysis of regional lymph nodes in periprostatic fat following robot-assisted radical prostatectomy

Study Type – Therapy (case series)

A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma.

This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. A total of 28 patients with newly diagnosed or relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with 4 or less prior therapies were eligible for this open-label phase II study. Oral vorinostat 200 mg was administered twice daily on days 1–14 along with 375 mg/m2 of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. Primary end point was objective response rate, with secondary end points of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months for previously treated patients, and not reached for untreated patients. The regimen was well tolerated over long treatment periods with the most common grade 3/4 adverse events being asymptomatic thrombosis, neutropenia, thrombocytopenia, lymphopenia, and fatigue. The vorinostat/rituximab combination exhibits activity in indolent B-cell non-Hodgkin lymphoma with an acceptable safety profile and durable responses. Re-treatment was effective in 2 of 3 relapsing responders. This phase II clinical trial was registered at clinicaltrials.gov identifier: 00720876.