Prognostic indicators for upper tract urothelial carcinoma after radical nephroureterectomy: the impact of lymphovascular invasion.

UNLABELLED: What's known on the subject? and What does the study add? In an array of urological and non-urological malignancies, lymphovascular invasion (LVI) is a pathological feature known to be associated with adverse outcomes for recurrence and survival. For some cancers, LVI has therefore been incorporated into American Joint Committee on Cancer TNM staging algorithms. This study presents an analysis of the impact of LVI in upper urinary tract urothelial carcinoma (UTUC) treated at our institution over a 20-year period. In addition to known associations with features of aggressive disease and overall survival, we were able to show that LVI-positive status upsets the TNM staging for UTUC. Namely, patients with superficial stage and LVI-positive disease have overall survival outcomes similar to those of patients with muscle-invasive LVI-negative carcinoma. Such evidence may support the addition of LVI to future TNM staging algorithms for UTUC. OBJECTIVE: To assess the impact of lymphovascular invasion (LVI) on the prognosis of patients with upper urinary tract urothelial cell carcinoma (UTUC) treated with radical nephroureterectomy (RNU). PATIENTS AND METHODS: The Columbia University Medical Center Urologic Oncology database was queried and 211 patients undergoing RNU for UTUC between 1990 and 2010 were identified. These cases were retrospectively reviewed, and the prognostic significance of relevant clinical and pathological variables was analysed using log-rank tests and Cox proportional hazards regression models. Actuarial survival curves were calculated using the Kaplan-Meier method. RESULTS: LVI was observed in 68 patients (32.2%). The proportion of LVI increased with advancing stage, high grade, positive margin status, concomitant carcinoma in situ, and lymph node metastases. The 5- and 10-year overall survival rates were 74.7% and 53.1% in the absence of LVI, and 35.7% and 28.6% in the presence of LVI, respectively. In multivariate analysis, age, race and LVI were independent predictors of overall survival. CONCLUSIONS: The presence of LVI on pathological review of RNU specimens was associated with worse overall survival in patients with UTUC. LVI status should be included in the pathological report for RNU specimens to help guide postoperative therapeutic options. With confirmation from large international studies, inclusion of LVI in the tumour-node-metastasis staging system for UTUC should be considered.

Maximizing intravesical therapy options: is there an advantage to the administration of perioperative mitomycin C prior to an induction course of BCG?

INTRODUCTION: This study sought to evaluate cancer-specific outcomes among patients who received perioperative mitomycin C (MMC) prior to induction BCG versus those who received induction BCG alone. MATERIALS AND METHODS: Between January 2000 and August 2010, 260 patients were identified who underwent a course of induction BCG with or without concomitant perioperative MMC. Specifically, patients who received 40 mg MMC following transurethral resection of all visible tumor followed by an induction course of BCG were compared to a similar cohort of patients who received induction BCG alone. The primary endpoints were overall and recurrence-free survival (RFS). RESULTS: A total of 212 patients were identified who received induction BCG alone, and 48 who received perioperative MMC with induction BCG. The aggregate patient cohort was comprised of those with non-muscle invasive disease (NMI), and there was no difference between groupings with respect to common demographic and pathologic variables. Over a median follow up of 34.5 months, there was no difference in overall survival between cohorts. RFS was superior among patients who received combined therapy (5 year survival: 37.5% versus 56.3%, p = 0.023). Nevertheless, the regimen of intravesical therapy did not reach significance as an independent predictor (HR 0.61, p = 0.055, CI 0.36-1.01). CONCLUSION: Although the combination therapy group demonstrated a significant RFS advantage, the intravesical therapy regimen did not independently modulate this benefit. Further investigation is warranted to determine if immediate MMC prior to a course of induction BCG confers a benefit to RFS. Nevertheless, this pilot investigation sets an important precedent on the management of NMI bladder cancer, nonwithstanding the absence of contemporary large scale, randomized trials.

Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication.

Oncolytic herpes simplex virus-1 (oHSV) vectors selectively replicate in tumor cells, where they kill through oncolysis while sparing normal cells. One of the drawbacks of oHSV vectors is their limited replication and spread to neighboring cancer cells. Here, we report the outcome of a high-throughput chemical library screen to identify small-molecule compounds that augment the replication of oHSV G47Delta. Of the 2,640-screened bioactives, 6 compounds were identified and subsequently validated for enhanced G47Delta replication. Two of these compounds, dipyridamole and dilazep, interfered with nucleotide metabolism by potently and directly inhibiting the equilibrative nucleoside transporter-1 (ENT1). Replicative amplification promoted by dipyridamole and dilazep were dependent on HSV mutations in ICP6, the large subunit of ribonucleotide reductase. Our results indicate that ENT1 antagonists augment oHSV replication in tumor cells by increasing cellular ribonucleoside activity.