Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial.

BACKGROUND: The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ. METHODS: KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS: Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred. INTERPRETATION: Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial. FUNDING: Merck Sharp & Dohme.

Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study.

BACKGROUND: Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0-2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS: Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0-40·7). 39 (41%; 95% CI 30·7-51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related. INTERPRETATION: Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population. FUNDING: Merck Sharp & Dohme.

Predictors of Recurrence, and Progression-Free and Overall Survival following Open versus Robotic Radical Cystectomy: Analysis from the RAZOR Trial with a 3-Year Followup.

PURPOSE: The RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for 3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival. MATERIALS AND METHODS: We analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis. RESULTS: Estimated progression-free survival at 36 months was 68.4% (95% CI 60.1-75.3) and 65.4% (95% CI 56.8-72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5-80.5) and 68.5% (95% CI 59.8-75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome. CONCLUSIONS: This analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.

Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.

BACKGROUND: Radical cystectomy is the surgical standard for invasive bladder cancer. Robot-assisted cystectomy has been proposed to provide similar oncological outcomes with lower morbidity. We aimed to compare progression-free survival in patients with bladder cancer treated with open cystectomy and robot-assisted cystectomy. METHODS: The RAZOR study is a randomised, open-label, non-inferiority, phase 3 trial done in 15 medical centres in the USA. Eligible participants (aged ≥18 years) had biopsy-proven clinical stage T1-T4, N0-N1, M0 bladder cancer or refractory carcinoma in situ. Individuals who had previously had open abdominal or pelvic surgery, or who had any pre-existing health conditions that would preclude safe initiation or maintenance of pneumoperitoneum were excluded. Patients were centrally assigned (1:1) via a web-based system, with block randomisation by institution, stratified by type of urinary diversion, clinical T stage, and Eastern Cooperative Oncology Group performance status, to receive robot-assisted radical cystectomy or open radical cystectomy with extracorporeal urinary diversion. Treatment allocation was only masked from pathologists. The primary endpoint was 2-year progression-free survival, with non-inferiority established if the lower bound of the one-sided 97·5% CI for the treatment difference (robotic cystectomy minus open cystectomy) was greater than -15 percentage points. The primary analysis was done in the per-protocol population. Safety was assessed in the same population. This trial is registered with ClinicalTrials.gov, number NCT01157676. FINDINGS: Between July 1, 2011, and Nov 18, 2014, 350 participants were randomly assigned to treatment. The intended treatment was robotic cystectomy in 176 patients and open cystectomy in 174 patients. 17 (10%) of 176 patients in the robotic cystectomy group did not have surgery and nine (5%) patients had a different surgery to that they were assigned. 21 (12%) of 174 patients in the open cystectomy group did not have surgery and one (1%) patient had robotic cystectomy instead of open cystectomy. Thus, 302 patients (150 in the robotic cystectomy group and 152 in the open cystectomy group) were included in the per-protocol analysis set. 2-year progression-free survival was 72·3% (95% CI 64·3 to 78·8) in the robotic cystectomy group and 71·6% (95% CI 63·6 to 78·2) in the open cystectomy group (difference 0·7%, 95% CI -9·6% to 10·9%; pnon-inferiority=0·001), indicating non-inferiority of robotic cystectomy. Adverse events occurred in 101 (67%) of 150 patients in the robotic cystectomy group and 105 (69%) of 152 patients in the open cystectomy group. The most common adverse events were urinary tract infection (53 [35%] in the robotic cystectomy group vs 39 [26%] in the open cystectomy group) and postoperative ileus (33 [22%] in the robotic cystectomy group vs 31 [20%] in the open cystectomy group). INTERPRETATION: In patients with bladder cancer, robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival. Increased adoption of robotic surgery in clinical practice should lead to future randomised trials to assess the true value of this surgical approach in patients with other cancer types. FUNDING: National Institutes of Health National Cancer Institute.

A Description and Safety Overview of Irreversible Electroporation for Prostate Tissue Ablation in Intermediate-Risk Prostate Cancer Patients: Preliminary Results from the PRESERVE Trial.

The PRESERVE study (NCT04972097) aims to evaluate the safety and effectiveness of the NanoKnife System to ablate prostate tissue in patients with intermediate-risk prostate cancer (PCa). The NanoKnife uses irreversible electroporation (IRE) to deliver high-voltage electrical pulses to change the permeability of cell membranes, leading to cell death. A total of 121 subjects with organ-confined PCa ≤ T2c, prostate-specific antigens (PSAs) ≤ 15 ng/mL, and a Gleason score of 3 + 4 or 4 + 3 underwent focal ablation of the index lesion. The primary endpoints included negative in-field biopsy and adverse event incidence, type, and severity through 12 months. At the time of analysis, the trial had completed accrual with preliminary follow-up available. Demographics, disease characteristics, procedural details, PSA responses, and adverse events (AEs) are presented. The median (IQR) age at screening was 67.0 (61.0-72.0) years and Gleason distribution 3 + 4 (80.2%) and 4 + 3 (19.8%). At 6 months, all patients with available data (n = 74) experienced a median (IQR) percent reduction in PSA of 67.6% (52.3-82.2%). Only ten subjects (8.3%) experienced a Grade 3 adverse event; five were procedure-related. No Grade ≥ 4 AEs were reported. This study supports prior findings that IRE prostate ablation with the NanoKnife System can be performed safely. Final results are required to fully assess oncological, functional, and safety outcomes.

Oncolytic adenoviral therapy plus pembrolizumab in BCG-unresponsive non-muscle-invasive bladder cancer: the phase 2 CORE-001 trial.

Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in cancer cells with retinoblastoma pathway alterations, previously tested as monotherapy in bacillus Calmette-Guérin (BCG)-experienced non-muscle-invasive bladder cancer. In this phase 2 study, we assessed the potential synergistic efficacy between intravesical cretostimogene and systemic pembrolizumab in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ (CIS). Thirty-five patients were treated with intravesical cretostimogene with systemic pembrolizumab. Induction cretostimogene was administered weekly for 6 weeks followed by three weekly maintenance infusions at months 3, 6, 9, 12 and 18 in patients maintaining complete response (CR). Patients with persistent CIS/high-grade Ta at the 3-month assessment were eligible for re-induction. Pembrolizumab was administered for up to 24 months. The primary endpoint was CR at 12 months as assessed by cystoscopy, urine cytology, cross-sectional imaging and mandatory bladder mapping biopsies. Secondary endpoints included CR at any time, duration of response, progression-free survival and safety. The CR rate in the intention-to-treat population at 12 months was 57.1% (20 out of 35, 95% confidence interval (CI) 40.7-73.5%), meeting the primary endpoint. A total of 29 out of 35 patients (82.9%, 95% CI 70.4-95.3%) derived a CR at 3 months. With a median follow-up of 26.5 months, the median duration of response has not been reached (95% CI 15.7 to not reached). The CR rate at 24 months was 51.4% (18 out of 35) (95% CI 34.9-68.0%). No patient progressed to muscle-invasive bladder cancer in this trial. Adverse events attributed to cretostimogene were low grade, self-limiting and predominantly limited to bladder-related symptoms. A total of 5 out of 35 patients (14.3%) developed grade 3 treatment-related adverse effects. There was no evidence of overlapping or synergistic toxicities. Combination intravesical cretostimogene and systemic pembrolizumab demonstrated enduring efficacy. With a toxicity profile similar to its monotherapy components, this combination may shift the benefit-to-risk ratio for patients with BCG-unresponsive CIS. ClinicalTrials.gov Identifier: NCT04387461 .

Intermedin is overexpressed in hepatocellular carcinoma and regulates cell proliferation and survival.

Angiogenesis is one of the hallmarks of tumor growth and metastasis. Identification of tumor angiogenic factors has been a critical component in understanding cancer biology and treatment. Intermedin (IMD) has been reported to promote angiogenesis in a rat ischemic model and human umbilical vascular endothelial cells. Our study sought to determine the role of IMD in human hepatocellular carcinoma tumor progression. High IMD mRNA expression levels were observed in human hepatocellular carcinoma tumors, even in early stage disease, by real-time RT-PCR. Immunohistochemical analysis of hepatocellular carcinoma clinical samples demonstrated that the tumor regions were significantly more immunoreactive for IMD than adjacent benign liver. Inhibition of IMD expression using RNA interference reduced cell proliferation in SK-Hep-1 and SNU-398 cells. Blockage of IMD signaling using either an antagonist peptide or a neutralizing antibody inhibited growth in a dose-dependent manner with concomitant induction of apoptosis, causing cleavage of caspase-8 and downregulation of Gli1 and Bcl2. Conversely, addition of IMD active peptide increased the phosphorylation level of extracellular signal-regulated kinase. Thus, IMD might play an important role in cell proliferation and survival of hepatocellular carcinoma. Our data suggests that IMD is a potential biomarker and therapeutic target for hepatocellular carcinoma.

Comparison of Perioperative Outcomes for Radical Nephrectomy Based on Surgical Approach for Masses Greater Than 10 cm.

Introduction and Objective: Robot-assisted radical nephrectomy (RRN) is increasingly utilized as an alternative to laparoscopic radical nephrectomy (LRN), but there are concerns over costs and objective benefit. In the setting of very large renal masses (>10 cm), comparison between techniques is limited and it is unclear whether a robotic approach confers any perioperative benefit over LRN or open radical nephrectomy (ORN). In this study, perioperative outcomes of RRN, LRN, and ORN for very large renal masses are compared. Methods: Using the National Cancer Database, patients were identified who underwent radical nephrectomy for kidney tumors >10 cm diagnosed from 2010 to 2015. Patients were analyzed according to surgical approach. Perioperative outcomes, including conversion to open, length of stay, readmission rates, positive surgical margins, and 30- and 90-day mortality were compared among cohorts. Results: A total of 9288 patients met inclusion criteria (RRN = 842, LRN = 2326, ORN = 6120). Compared with ORN, recipients of RRN or LRN had similar rates of 30-day readmission and 30- and 90-day mortality. Length of hospital stay was significantly shorter in RRN (-1.73 days ±0.19; p < 0.0001) and LRN (-1.40 days ±0.12; p < 0.0001) compared with ORN. LRN had a higher rate of conversion to open compared with RRN (odds ratio 1.48; 95% confidence interval 1.10-1.98; p = 0.0087). Conversion to open from RRN or LRN added 1.3 additional days of inpatient stay. Over the study period, RRN use increased from 4.1% to 14.8%, LRN from 20.9% to 25.6%, whereas ORN use decreased from 75% to 59.6%. Conclusions: Minimally invasive approaches are increasingly utilized in very large renal masses. RRN has lower rates of conversion to open but produces comparable perioperative outcomes to LRN. Minimally invasive approaches have a shorter length of inpatient stay but otherwise report similar surgical margin status, readmission rates, and mortality rates compared with ORN.

Management of Advanced Prostate Cancer in Clinical Practice: Real-World Answers to Challenging Dilemmas.

Advanced prostate cancer is a continuum of states distinguished by the presence or absence of metastasis and sensitivity or resistance to androgen deprivation therapy (ADT). Therapeutic options for this disease continue to rapidly evolve, making it a challenge to apply results of clinical trial data to daily patient management. One question relevant to providers is whether molecular biomarkers predictive of response or resistance to therapies are available to guide clinical treatment decisions. Other salient topics include the timing of therapy initiation in patients with biochemical recurrence, treatment approach in low-volume versus high-volume metastatic castrate-sensitive prostate cancer, types of agents available beyond ADT, and timing of their use in men with nonmetastatic castrate-resistant prostate cancer as well as whether sequencing of therapies in metastatic castrate-resistant prostate cancer matters. Additionally, familiarity with emerging treatment strategies is important. This review addresses the gray areas and challenging questions in advanced prostate cancer management that frequently arise in clinical practice.

Tissue microarray analysis of 560 patients with colorectal adenocarcinoma: high expression of HuR predicts poor survival.

The purpose of this study is to characterize the expression of HuR in colorectal carcinoma and determine its correlation with clinical outcome. Differential expression of HuR has been suggested to be of prognostic significance in carcinomas of the ovaries, stomach, and breast. HuR regulates the expression of a variety of proteins critical to carcinogenesis via the pathways of cell-cycle progress, invasion, and metastasis. Increasing evidence suggests that angiogenic pathways are involved. A tissue microarray consisting of tumors from 560 patients with colorectal adenocarcinoma was analyzed for HuR protein expression using a quantitative, automated immunofluorescent microscopy system (AQUA). Clinical data corresponding to each examined specimen collected through an institutional review board (IRB)-approved protocol were analyzed using chi-squared test, Cox regression, and Kaplan-Meier analysis. Median follow-up was 54 months. Along with tumor stage and overall tumor-node-metastasis (TNM) stage, HuR expression was found to be an independent predictor of survival. In patients in the highest quartile of total HuR expression, survival was 22.8 months less than those in the lower quartiles (40.6 versus 63.4 months, p = 0.04). Furthermore, HuR levels correlate positively with expression of vascular endothelial growth factor (VEGF) and CD31, a marker for vascular endothelium. We conclude that expression of high levels of HuR correlates with features of advanced disease and portends poorer survival in patients with colorectal adenocarcinoma. These results further suggest that HuR exerts its tumorigenic effects through VEGF-mediated angiogenesis and may be a novel therapeutic target in colorectal cancer.

Downregulation of survivin is associated with reductions in TNF receptors' mRNA and protein and alterations in nuclear factor kappa B signaling in urothelial cancer cells.

Because survivin is selectively expressed in and associated with an unfavorable prognosis in transitional cell carcinoma of the bladder (TCC), we treated T-24 cells with survivin siRNA. Survivin siRNA treatment caused a profound decrease of survivin protein that was associated with decreased cell growth, a specific G2/M arrest and increased cytochrome c release. Microarray analysis of apoptosis genes showed that levels of 14/114 gene products were decreased after 72 hours treatment with survivin siRNA, including survivin, three TNF receptors, Akt, c-Abl, caspases and their related genes and Bcl-2 and NF-kappaB signaling related genes. TNFR1, pro-caspase-2 and Akt protein levels were decreased after survivin siRNA treatment for 48 and 72 hours. Downregulation of survivin causes changes in mitosis and apoptosis, which may be related to changes in TNF receptors and NF-kappaB signaling.

Molecular markers and mortality in prostate cancer.

OBJECTIVE: To evaluate prognosis in prostate cancer by assessing the independent effect of selected molecular factors (e.g. markers of cell-cycle regulation), in addition to the effect of traditional clinical factors (e.g. anatomical stage, histological grade), in predicting long-term mortality among men newly diagnosed with prostate cancer. PATIENTS AND METHODS: In a community-based population of 64 545 USA veterans aged >/= 50 years and receiving ambulatory care during 1989-90 at nine Veterans Affairs (VA) medical centres in New England, 1274 had incident prostate cancer during 1991-95. We obtained the medical records and diagnostic tissue for these men, and then extracted demographic data and clinical information, and conducted immunohistochemical assays of molecular markers in biopsy tissue, as potential prognostic factors. In this interim analysis, data on 250 patients were analysed; the main outcome was overall mortality to 31 December 2003, providing 8-13 years of follow-up. RESULTS: In 228 (91%) patients with available medical record and laboratory data, the median age was 72 years and the median prostate-specific antigen level was 10.4 ng/mL. In adjusted (multivariate) analyses that included traditional prognostic factors, bcl-2 staining (hazard ratio 2.14, 95% confidence interval 1.27-3.58, P = 0.004) and high microvessel density (1.76, 1.19-2.60; P = 0.005) had an independent effect on the outcome. CONCLUSIONS: Bcl-2 and microvessel density are independent predictors of subsequent death among men with prostate cancer and might have a clinical role in assisting in deciding on treatment.

When Anti-Aging Studies Meet Cancer Chemoprevention: Can Anti-Aging Agent Kill Two Birds with One Blow?

Recent evidence has strongly supported that the rate of aging is controlled, at least to some extent, by evolutionarily conserved nutrient sensing pathways (e.g. the insulin/IGF-1-signaling, mTOR, AMPK, and sirtuins) from worms to humans. These pathways are also commonly involved in carcinogenesis and cancer metabolism. Agents (e.g. metformin, resveratrol, and Rhodiola) that target these nutrient sensing pathways often have both anti-aging and anti-cancer efficacy. These agents not only reprogram energy metabolism of malignant cells, but also target normal postmitotic cells by suppressing their conversion into senescent cells, which confers systematic metabolism benefits. These agents are fundamentally different from chemotherapy (e.g. paclitaxel and doxorubicin) or radiation therapy that causes molecular damage (e.g. DNA and protein damages) and thereby no selection resistance may be expected. By reviewing molecular mechanisms of action, epidemiological evidence, experimental data in tumor models, and early clinical study results, this review provides information supporting the promising use of agents with both anti-aging and anti-cancer efficacy for cancer chemoprevention.

Hereditary kidney cancer.

Significant advances have been made in the understanding of the genetic basis of familial renal neoplasia. Identification of key genes in the pathogenesis of various hereditary renal cancer syndromes has provided opportunities to screen family members at risk and to explore the significance of these genetic abnormalities in the development and genesis of much more common sporadic counterparts. As researchers continue to delineate critical carcinogenic pathways and accumulate expansive knowledge on oncogenic mechanisms driving cancer initiation and progression at the cellular and molecular levels, this information will be integrated and translated into effective diagnostic and therapeutic strategies that will dictate clinical management of all renal cancers.

Robotic-assisted prostatectomy and open radical retropubic prostatectomy for locally-advanced prostate cancer: multi-institution comparison of oncologic outcomes.

PURPOSE: Robotic-assisted laparoscopic prostatectomy (RALP) offers reportedly comparable oncologic outcomes for localized disease compared with open radical retropubic prostatectomy (ORRP). However, the oncologic efficacy of RALP in locally-advanced prostate cancer (PCa) is less clear. We report and compare our experience with RALP and ORRP in men with locally advanced PCa. METHODS: Patients with locally advanced PCa (stage T3 or greater) were identified in both robotic and open cohorts. Clinicopathologic features including age, clinical stage, prostate-specific antigen, surgical margins, and Gleason score were reviewed. We further examined the incidence of positive surgical margins, the effect of the surgical learning curve on margins, and the need for adjuvant therapy. RESULTS: From 1997 to 2010, 1,011 patients underwent RALP and 415 patients were identified who underwent radical retropubic prostatectomy (RRP) across four institutions. 140 patients in the RALP group and 95 in the RRP group had locally advanced PCa on final pathology. The overall robotic positive margin rate 47.1% compared with 51.4% in the RRP group. A trend towards a lower positive margin rate was seen after 300 cases in the RALP group, with 66.7% positive margin rate in the first 300 cases compared with 41.8% in the latter 700 cases. In addition, a lower incidence of biochemical recurrence was also noted in the latter cases (30.6% vs. 9.5%). CONCLUSIONS: Up to 2 out of 3 men undergoing RALP for locally-advanced PCa had positive margins during our initial experience. However, with increasing surgeon experience the overall positive margin rate decreased significantly and was comparable to the positive margin rate for patients with locally advanced disease undergoing ORRP over four academic institutions. We also noted a lower incidence of biochemical recurrence with increasing RALP experience, suggesting better oncologic outcomes with higher volume. Given this data, RALP has comparable oncologic outcomes compared to ORRP, especially with higher volume surgeons.

Laparoscopic repair of inguinal cystocele using cystoscopic light test.

OBJECTIVE: To describe how the cystoscopic light test aids in the repair of inguinal bladder herniation. METHODS: After the diagnosis of a bladder herniation into the right inguinal canal using intravenous pyelography, laparoscopic repair was planned. A cystoscope was manipulated into the defect while turning off the laparoscopic light intra-abdominally. The light of the cystoscope could be identified through the cystocele, and the neck of the hernia was easily recognized. Once the bladder was reduced, the cystoscope was replaced, and reduction of the herniation was confirmed. RESULTS: We were able to successfully reduce the bladder herniation without recurrence at 24 months of follow-up. CONCLUSION: The cystoscopic light test represents a useful tool in the recognition of an inguinal bladder herniation, before, during, and after the definitive repair of the defect.

Poliomyelitis in MuLV-infected ICR-SCID mice after injection of basement membrane matrix contaminated with lactate dehydrogenase-elevating virus.

The arterivirus lactate dehydrogenase-elevating virus (LDV) causes life-long viremia in mice. Although LDV infection generally does not cause disease, infected mice that are homozygous for the Fv1(n) allele are prone to develop poliomyelitis when immunosuppressed, a condition known as age-dependent poliomyelitis. The development of age-dependent poliomyelitis requires coinfection with endogenous murine leukemia virus. Even though LDV is a common contaminant of transplantable tumors, clinical signs of poliomyelitis after inadvertent exposure to LDV have not been described in recent literature. In addition, LDV-induced poliomyelitis has not been reported in SCID or ICR mice. Here we describe the occurrence of poliomyelitis in ICR-SCID mice resulting from injection of LDV-contaminated basement membrane matrix. After exposure to LDV, a subset of mice presented with clinical signs including paresis, which was associated with atrophy of the hindlimb musculature, and tachypnea; in addition, some mice died suddenly with or without premonitory signs. Mice presenting within the first 6 mo after infection had regions of spongiosis, neuronal necrosis and astrocytosis of the ventral spinal cord, and less commonly, brainstem. Axonal degeneration of ventral roots prevailed in more chronically infected mice. LDV was identified by RT-PCR in 12 of 15 mice with typical neuropathology; positive antiLDV immunolabeling was identified in all PCR-positive animals (n = 7) tested. Three of 8 mice with neuropathology but no clinical signs were LDV negative by RT-PCR. RT-PCR yielded murine leukemia virus in spinal cords of all mice tested, regardless of clinical presentation or neuropathology.

Impact of biochemical recurrence in prostate cancer among US veterans.

BACKGROUND: Among men treated for prostate cancer, increasing prostate-specific antigen (PSA) is known as biochemical failure or biochemical recurrence (BCR). The impact of BCR on subsequent mortality is uncertain, however, especially given competing causes of death. METHODS: To describe patterns of BCR and subsequent mortality, we conducted an observational study in a community-based, "high-comorbidity" setting of 623 US veterans diagnosed as having prostate cancer from 1991 to 1995 and receiving radical prostatectomy or radiation therapy. The main outcome measures were BCR, defined as a PSA level of 0.4 ng/mL or higher (treated with surgery) or "PSA nadir+2 ng/mL" (treated with radiation therapy), and prostate cancer mortality, determined through 2006. RESULTS: With 5-, 10-, and 15-year follow-up periods, respectively (for all results shown herein), the cumulative incidence of BCR after prostatectomy (n=225) was 34%, 37%, and 37%; prostate cancer mortality among men who failed treatment (n=81) was 3%, 11%, and 21%. Among men receiving radiation therapy (n=398), the cumulative incidence of BCR was 35%, 46%, and 48%; prostate cancer mortality among those who failed treatment (n=161) was 11%, 20%, and 42%. Overall, BCR was associated with an increased risk of death from prostate cancer in the study population, but the individual probability of this outcome was relatively low. CONCLUSIONS: Biochemical recurrence is associated with increased prostate cancer mortality, yet when BCR occurs only a minority of men subsequently die of their disease. The phrase "most men die with prostate cancer, not of it" applies to elderly veterans, even after failure of primary treatment. New strategies for defining and managing treatment failure in prostate cancer are needed.