Alan Thong

Robotic Radical Prostatectomy in Overweight and Obese Patients: Oncological and Validated-Functional Outcomes

OBJECTIVES To determine the impact of body mass index (BMI) on perioperative functional and oncological outcomes in patients undergoing robotic laparoscopic radical prostatectomy (RLRP) when stratified by BMI. METHODS Data were collected prospectively for 945 consecutive patients undergoing RLRP. Patients were evaluated with the UCLA-PCI-SF36v2 validated-quality-of-life questionnaire preoperatively and postoperatively to 24 months. Patients were stratified by BMI as normal weight (BMI < 25 kg/m(2)), overweight (BMI = 25 to < 30 kg/m(2)) and obese (BMI > or = 30 kg/m(2)) for outcomes analysis. RESULTS Preoperatively, obese men had a significantly greater percentage of medical comorbidities (P < .01) as well as a baseline erectile dysfunction (lower mean baseline Sexual Health Inventory for Men score [P = .01] and UCLA-PCI-SF36v2 sexual function domain scores [P = .01]). Mean operative time was significantly longer in obese patients when compared with normal and overweight men (234 minutes vs 217 minutes vs 214 minutes; P = .0003). Although overall complication rates were comparable between groups, a greater incidence of case abortion caused by pneumoperitoneal pressure with excessive airway pressures was noted in obese men. Urinary continence and potency outcomes were significantly lower for obese men at both 12 and 24 months (all P < .05). CONCLUSIONS In this series, obese men experienced a longer operative time, particularly during the initial robotic experience. As such, surgeons early in their RLRP learning curve should proceed cautiously with surgery in these technically more difficult patients or reserve such cases until the learning curve has been surmounted. These details, including inferior urinary and sexual outcomes, should be discussed with obese patients during preoperative counseling.

Long-term deterioration of joint evaluation scores

We investigated the long-term changes in the Harris Hip and Knee Society scores (HSS and KSS) to determine whether they result from overall functional decline rather than actual changes in the condition of the prosthesis. The HHS for 106 total hip arthroplasties with a minimum follow-up of ten years, no medical complications after operation and no evidence of radiological loosening, and the KSS for 264 total knee arthroplasties with a minimum follow-up of 12 years and no medical complications after operation or signs of radiographical loosening were evaluated. There were statistically significant drops in the functional scoring components of the joint evaluation systems despite no loosening of the prostheses or other significant medical complications. The HHS declined at an average of 0.67 points per year from between three and ten years after operation (p < 0.0001). Contributing to this were deterioration in gait and limp (p < 0.0004), the use of support aids (p < 0.0001), the distance walked (p < 0.0001) and the ability to climb stairs (p < 0.0455). The functional component of the KSS declined significantly at an average 0.88 points per year betwen the third and 12th years (p < 0.0001). There were significant declines in every component of the functional score including the distance walked (p < 0.0001), the ability to climb stairs (p < 0.0001) and the use of support aids (p < 0.0001). The knee score component of the KSS did not decline significantly (p < 0.9750). The combination of functional and pain scores within the HHS system leads to an inaccurate decline in the entire score. The decline of HHS and Knee Society functional scores in total joint arthroplasties, in the absence of implant-related problems, suggests that deterioration in the functional capacity of ageing patients is an important factor in longitudinal studies using these scoring systems.

Intra-operative findings in varus osteoarthritis of the knee: AN ANALYSIS OF PRE-OPERATIVE ALIGNMENT IN POTENTIAL CANDIDATES FOR UNICOMPARTMENTAL ARTHROPLASTY

Interest in unicompartmental knee arthroplasty (UKA) for the treatment of medial compartment osteoarthritis has increased in recent years with apparent improvement in the long-term results. This is a result of improved surgical technique, patient selection, and implant design. In an effort further to improve patient selection we analysed the relationship between the pre-operative alignment of the knee and the anatomical findings at the time of surgery. We compared these findings with the indications for UKA. From 4021 total knee arthroplasties we compared intra-operative observations with the pre-operative clinical data in order to identify knees with isolated, medial, compartment changes, which would have been ideal candidates for UKA. We found that only 247 of the knees (6.1%) met anatomical qualifications for isolated, medial, unicompartmental osteoarthritis, and of these, only 168 (4.3%) met clinical standards ideal for UKA. Preoperative alignment showed a significant relationship with patterns of disease. Logistic regression revealed a relationship between pre-operative alignment and intraoperative findings resembling a Gaussian distribution. Patients with a pre-operative varus alignment of 7 degrees were slightly more likely to be selected for UKA. But the further the anatomical alignment in either direction varies from 7 degrees of varus, the more unlikely it is for the knee to exhibit a disease pattern of isolated, medial, unicompartmental osteoarthritis.

Robotic Laparoscopic Radical Prostatectomy for Biopsy Gleason 8 to 10 : Prediction of Favorable Pathologic Outcome with Preoperative Parameters

PURPOSE We sought to evaluate the pathologic results and postoperative outcomes for men undergoing robot-assisted laparoscopic radical prostatectomy (RLRP) for biopsy Gleason score (GS) 8 to 10 disease. Stratification of these patients according to preoperative variables was also performed in an attempt to predict organ-confined cancer. PATIENTS AND METHODS A prospective RLRP database identified all patients with preoperative biopsy GS 8 to 10. Variables, including prostate-specific antigen (PSA), percent positive biopsy cores (%PBC), maximal percentage of cancer in biopsy core (%MCB), clinical stage, pathologic stage, pathologic GS, surgical margins status, lymph node status, time to biochemical recurrence, and recurrence rate, were evaluated. Preoperative variables were treated as continuous and categorical using PSA, %PBC and %MCB cutoffs of 10 ng/mL, 50%, and 30%, respectively. RESULTS Between February 2003 and September 2007, a total of 1225 RLRPs were performed at the University of Chicago Medical Center. Seventy-two (5.9%) patients had preoperative biopsy GS 8 to 10. Two patients received neoadjuvant hormonal therapy and were excluded. Among 70 patients evaluated, 33 (47%) had organconfined (pT(2)N0) disease. Forty (60.6%) patients had pathologic downgrading to GS <or=7. Overall positive surgical margin (PSM) rate was found to be 24.2%. pT(2)- and pT(3)-PSM rate was 6% and 42.3%, respectively. In multivariate logistic regression analysis, PSA <or=10 ng/mL (P = 0.04) and %MCB <or=30% (P = 0.001) were found to be statistically significant predictors of pT(2)N0 disease. CONCLUSION Preoperative biopsy GS 8 to 10 predicts a significant likelihood of finding non-organ-confined prostate cancer on the final pathology report. Preoperative PSA <or=10 ng/mL and %MCB <or=30% may be used to predict favorable pathologic outcome for these patients during surgical counseling.

Unexpected Long-term Improvements in Urinary and Erectile Function in a Large Cohort of Men with Self-reported Outcomes Following Radical Prostatectomy

BACKGROUND It is generally assumed that if a man does not regain urinary continence or erectile function within 12 mo of radical prostatectomy (RP), then the chance of subsequent recovery is low. OBJECTIVE To determine the probability of achieving good urinary function (UF) or erectile function (EF) up to 48 mo postoperatively in men who reported poor UF or EF at 12 mo after RP. DESIGN, SETTING, AND PARTICIPANTS We identified 3187 patients who underwent RP from 2007 through 2013 at a tertiary institution and had extended multidisciplinary follow-up with patient-reported UF and EF scores at ≥12 mo. INTERVENTION Open or minimally invasive RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary outcome was good UF as defined by a urinary score ≥17 (range: 0-21) or good EF as defined by a modified International Index of Erectile Function-6 score ≥22 (range: 1-30). The probability of functional recovery beyond 12 mo was determined by Kaplan-Meier analyses. RESULTS AND LIMITATIONS Among patients incontinent at 12 mo, the probability of achieving good UF at 24, 36, and 48 mo was 30%, 49%, and 59%. In patients experiencing erectile dysfunction at 12 mo, the probability of recovering EF at 24, 36, and 48 mo was 22%, 32%, and 40%. On multivariable analyses, 12-mo functional score and age were associated with recovery, but only score was consistently significant. CONCLUSIONS Men with incontinence or erectile dysfunction at 12 mo have higher than anticipated rates of subsequent functional improvement. Probability of recovery is strongly influenced by score at 12 mo. Further research should address the impact of ongoing multidisciplinary follow-up care on our observed rates of recovery. PATIENT SUMMARY Many prostate cancer patients continue to recover urinary and erectile function after 12 mo. The level of functional recovery by 12 mo is associated with long-term recovery and should be discussed by the physician and patient when deciding on rehabilitative interventions.

A Single Microfocus (5% or Less) of Gleason 6 Prostate Cancer at Biopsy—Can We Predict Adverse Pathological Outcomes?

PURPOSE Patients with Gleason score 6 microfocal prostate cancer, defined as 5% or less in 1 biopsy core, are often considered to have favorable disease. Few studies have addressed clinical parameters that predict pathological upgrading or up staging at radical prostatectomy. MATERIALS AND METHODS From a prospective database of 1,271 consecutive robot assisted laparoscopic prostatectomies performed from 2003 to 2008 patients with Gleason score 6 microfocal prostate cancer were identified. Adverse pathological outcome was defined as any upgrading and/or up staging on prostatectomy pathological findings. Multivariate logistic regression was used to evaluate the ability of patient age, clinical stage, the total number of biopsy cores, preoperative prostate specific antigen, prostate volume and pathological prostate specific antigen density to predict adverse pathological outcomes. RESULTS A total of 192 patients with a median age of 59 years (range 42 to 73) were identified with Gleason score 6 prostate cancer involving 5% or less of 1 biopsy core, including 177 (92%) with clinical T1c disease. Mean +/- SD preoperative prostate specific antigen was 6.0 +/- 3.9 ng/ml (range 0.8 to 35). Overall 42 patients (22%) had adverse pathological outcomes, including upgrading in 35 (18%) and up staging in 16 (8%). Multivariate logistic regression revealed that age more than 65 years and pathological prostate specific antigen density greater than 0.20 ng/ml/gm were predictive of an increased risk of adverse pathological results (p = 0.0081 and 0.0169, respectively). CONCLUSIONS While a microfocus of Gleason score 6 prostate cancer on biopsy is commonly considered low risk disease, there was a greater than 1/5 risk of pathological upgrading and/or up staging. Patients with Gleason score 6 microfocal prostate cancer should be counseled that they may harbor more aggressive disease, especially when pretreatment clinical risk factors are present, such as advanced age or high clinical prostate specific antigen density.

Preclinical trial of a new dual mTOR inhibitor, MLN0128, using renal cell carcinoma tumorgrafts

mTOR is a rational target in renal cell carcinoma (RCC) because of its role in disease progression. However, the effects of temsirolimus, the only first‐generation mTOR inhibitor approved by the FDA for first‐line treatment of metastatic RCC, on tumor reduction and progression‐free survival are minimal. Second‐generation mTOR inhibitors have not been evaluated on RCC. We compared the effects of temsirolimus and MLN0128, a potent second‐generation mTOR inhibitor, on RCC growth and metastasis using a realistic patient‐derived tissue slice graft (TSG) model. TSGs were derived from three fresh primary RCC specimens by subrenal implantation of precision‐cut tissue slices into immunodeficient mice that were randomized and treated with MLN0128, temsirolimus, or placebo. MLN0128 consistently suppressed primary RCC growth, monitored by magnetic resonance imaging (MRI), in three TSG cohorts for up to 2 months. Temsirolimus, in contrast, only transiently inhibited the growth of TSGs in one of two cohorts before resistance developed. In addition, MLN0128 reduced liver metastases, determined by human‐specific quantitative polymerase chain reaction, in two TSG cohorts, whereas temsirolimus failed to have any significant impact. Moreover, MLN0128 decreased levels of key components of the two mTOR subpathways including TORC1 targets 4EBP1, p‐S6K1, HIF1α and MTA1 and the TORC2 target c‐Myc, consistent with dual inhibition. Our results demonstrated that MLN0128 is superior to temsirolimus in inhibiting primary RCC growth as well as metastases, lending strong support for further clinical development of dual mTOR inhibitors for RCC treatment.

Multi-institutional external validation of seminal vesicle invasion nomograms: head-to-head comparison of Gallina nomogram versus 2007 Partin tables.

PURPOSE The Partin tables represent one of the most widely used prostate cancer staging tools for seminal vesicle invasion (SVI) prediction. Recently, Gallina et al. reported a novel staging tool for the prediction of SVI that further incorporated the use of the percentage of positive biopsy cores. We performed an external validation of the Gallina et al. nomogram and the 2007 Partin tables in a large, multi-institutional North American cohort of men treated with robotic-assisted radical prostatectomy. METHODS AND MATERIALS Clinical and pathologic data were prospectively gathered from 2,606 patients treated with robotic-assisted radical prostatectomy at one of four North American robotic referral centers between 2002 and 2007. Discrimination was quantified with the area under the receiver operating characteristics curve. The calibration compared the predicted and observed SVI rates throughout the entire range of predictions. RESULTS At robotic-assisted radical prostatectomy, SVI was recorded in 4.2% of patients. The discriminant properties of the Gallina et al. nomogram resulted in 81% accuracy compared with 78% for the 2007 Partin tables. The Gallina et al. nomogram overestimated the true rate of SVI. Conversely, the Partin tables underestimated the true rate of SVI. CONCLUSION The Gallina et al. nomogram offers greater accuracy (81%) than the 2007 Partin tables (78%). However, both tools are associated with calibration limitations that need to be acknowledged and considered before their implementation into clinical practice.

Comparative Effectiveness of Targeted Prostate Biopsy Using Magnetic Resonance Imaging Ultrasound Fusion Software and Visual Targeting: a Prospective Study

PURPOSE We compared the diagnostic outcomes of magnetic resonance-ultrasound fusion and visually targeted biopsy for targeting regions of interest on prostate multiparametric magnetic resonance imaging. MATERIALS AND METHODS Patients presenting for prostate biopsy with regions of interest on multiparametric magnetic resonance imaging underwent magnetic resonance imaging targeted biopsy. For each region of interest 2 visually targeted cores were obtained, followed by 2 cores using a magnetic resonance-ultrasound fusion device. Our primary end point was the difference in the detection of high grade (Gleason 7 or greater) and any grade cancer between visually targeted and magnetic resonance-ultrasound fusion, investigated using McNemars method. Secondary end points were the difference in detection rate by biopsy location using a logistic regression model and the difference in median cancer length using the Wilcoxon signed rank test. RESULTS We identified 396 regions of interest in 286 men. The difference in the detection of high grade cancer between magnetic resonance-ultrasound fusion biopsy and visually targeted biopsy was -1.4% (95% CI -6.4 to 3.6, p=0.6) and for any grade cancer the difference was 3.5% (95% CI -1.9 to 8.9, p=0.2). Median cancer length detected by magnetic resonance-ultrasound fusion and visually targeted biopsy was 5.5 vs 5.8 mm, respectively (p=0.8). Magnetic resonance-ultrasound fusion biopsy detected 15% more cancers in the transition zone (p=0.046) and visually targeted biopsy detected 11% more high grade cancer at the prostate base (p=0.005). Only 52% of all high grade cancers were detected by both techniques. CONCLUSIONS We found no evidence of a significant difference in the detection of high grade or any grade cancer between visually targeted and magnetic resonance-ultrasound fusion biopsy. However, the performance of each technique varied in specific biopsy locations and the outcomes of both techniques were complementary. Combining visually targeted biopsy and magnetic resonance-ultrasound fusion biopsy may optimize the detection of prostate cancer.

Patient-derived tissue slice grafts accurately depict response of high-risk primary prostate cancer to androgen deprivation therapy

BackgroundEffective eradication of high-risk primary prostate cancer (HRPCa) could significantly decrease mortality from prostate cancer. However, the discovery of curative therapies for HRPCa is hampered by the lack of authentic preclinical models.MethodsWe improved upon tumorgraft models that have been shown to predict drug response in other cancer types by implanting thin, precision-cut slices of HRPCa under the renal capsule of immunodeficient mice. Tissue slice grafts (TSGs) from 6 cases of HRPCa were established in mice. Following androgen deprivation by castration, TSGs were recovered and the presence and phenotype of cancer cells were evaluated.ResultsHigh-grade cancer in TSGs generated from HRPCa displayed characteristic Gleason patterns and biomarker expression. Response to androgen deprivation therapy (ADT) was as in humans, with some cases exhibiting complete pathologic regression and others showing resistance to castration. As in humans, ADT decreased cell proliferation and prostate-specific antigen expression in TSGs. Adverse pathological features of parent HRPCa were associated with lack of regression of cancer in corresponding TSGs after ADT. Castration-resistant cancer cells remaining in TSGs showed upregulated expression of androgen receptor target genes, as occurs in castration-resistant prostate cancer (CRPC) in humans. Finally, a rare subset of castration-resistant cancer cells in TSGs underwent epithelial-mesenchymal transition, a process also observed in CRPC in humans.ConclusionsOur study demonstrates the feasibility of generating TSGs from multiple patients and of generating a relatively large number of TSGs from the same HRPCa specimen with similar cell composition and histology among control and experimental samples in an in vivo setting. The authentic response of TSGs to ADT, which has been extensively characterized in humans, suggests that TSGs can serve as a surrogate model for clinical trials to achieve rapid and less expensive screening of therapeutics for HRPCa and primary CRPC.