TL-532, a novel specific Toll-like receptor 3 agonist rationally designed for targeting cancers: discovery process and biological characterization.

Toll-like receptor 3 (TLR3) is an innate immune receptor that recognizes double-stranded RNA (dsRNA) and induces inflammation in immune and normal cells to initiate anti-microbial responses. TLR3 acts also as a death receptor only in cancer cells but not in their normal counterparts, making it an attractive target for cancer therapies. To date, all of the TLR3-activating dsRNAs used at preclinical or clinical stages have major drawbacks such as structural heterogeneity, toxicity, and lack of specificity and/or efficacy. We conducted the discovery process of a new family of TLR3 agonists that are chemically manufactured on solid-phase support and perfectly defined in terms of sequence and size. A stepwise discovery process was performed leading to the identification of TL-532, a 70 base pair dsRNA that is potent without transfection reagent and is highly specific for TLR3 without activating other innate nucleic sensors such as RIG-I/MDA5, TLR7, TLR8, and TLR9. TL-532 induces inflammation in murine RAW264.7 myeloid macrophages, in human NCI-H292 lung cancer cells, and it promotes immunogenic apoptosis in tumor cells in vitro and ex vivo without toxicity towards normal primary cells. In conclusion, we identified a novel TLR3 agonist called TL-532 that has promising anticancer properties.

Prognostic Implications of Treatment Delays for Patients with Non-muscle-invasive Bladder Cancer.

BACKGROUND: Delay in treatment is a prognostic factor in muscle-invasive bladder cancer. OBJECTIVE: To evaluate clinical outcomes associated with delays in diagnosis and treatment for patients with non-muscle invasive bladder cancer (NMIBC). DESIGN, SETTING, AND PARTICIPANTS: In this retrospective study we analyzed data for patients treated at our center between November 2008 and December 2016 for intermediate risk (IR) or high risk (HR) NMIBC with an additional intravesical treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time delays from diagnosis to first transurethral resection (TT-TUR), from resection to restaging resection (TT-reTUR), and from the last resection to first instillation (TT-INST) of bacillus Calmette-Guérin (BCG) or mitomycin C (MMC) were documented. To identify the interval of time from which recurrence rates significantly increased, we used nonparametric series regression. Recurrence-free survival (RFS) and progression-free survival for patients in each time delay category were compared using the Kaplan-Meier method. Factors associated with tumor recurrence were analyzed in a multivariable model. RESULTS AND LIMITATIONS: A total of 434 patients were included, of whom 168 (38.7%) had IR and 266 (61.3%) had HR NMIBC. Among the patients, 34.6% had reTUR, 63.6% received BCG, and 36.4% received MMC. The median TT-TUR, TT-reTUR, and TT-INST was 4.0 wk, 6.5 wk, and 7.0 wk, respectively. At 40 mo the rate of recurrence was 28.4% and the rate of progression was 7.3%. Nonparametric analysis revealed that each week in delay increased the risk of recurrence, starting from week 6 for TT-TUR for IR and HR cases, and starting from week 7 for TT-INST for IR cases. RFS was significantly lower with TT-TUR > 6 wk among patients in the IR (p < 0.001) and HR (p = 0.04) groups, and with TT-INST >7 wk for patients in the IR group (p = 0.001). TT-reTUR >7 wk had a significant negative impact on progression (p < 0.017). Multivariable analysis revealed that for IR and HR cases, multifocality (p = 0.02 and p = 0.007) and TT-TUR >6 wk (p = 0.001 and p = 0.03) were independent predictors of recurrence, while TT-INST >7 wk predicted recurrence (p = 0.04) for IR NMIBC. CONCLUSIONS: Our results suggest that delays of >6 wk to first TUR in IR and HR NMIBC, and >7 wk to first instillation in IR cases are associated with increases in the risk of recurrence. TT-reTUR of >7 wk is also associated with higher risk of progression. PATIENT SUMMARY: We evaluated the impact of treatment delays on outcomes for patients with intermediate- and high-risk bladder cancer not invading the bladder wall muscle. We found that delays from diagnosis to first bladder resection, from first resection to repeat resection, and from last resection to bladder instillation treatment increase the rates of cancer recurrence and progression. The medical team should avoid delays in treatment, even for low-grade bladder cancer.

Lymphatic embolization for the management of symptomatic pelvic lymphocele after radical prostatectomy with lymph node dissection: Report of two cases.

INTRODUCTION: Pelvic lymphocele is the most common complication of pelvic lymph node dissection after radical prostatectomy. Management of symptomatic pelvic lymphocele begins with percutaneous drainage, followed by sclerotherapy or surgical marsupialization and more recently, lymphatic embolization. In this article, we show the feasibility and results of two lymphatic embolization after prostatectomy with lymph node dissection. CASE PRESENTATION: We decided to perform lymphatic embolization in two patients with persistent symptomatic pelvic lymphocele, after percutaneous drainage. This was done through inguinal lymph node puncture using Lipiodol and N-butyl cyanoacrylate glue injection. Drainage removal was done on the day after the procedure and clinical recovery was maintained at follow-up visits, 3 and 4 months later, in both patients. Computed tomography at 6 and 10 weeks after embolization showed the disappearance of the lymphocele. CONCLUSION: Our two case reports support the promising results of lymphatic embolization in this pathology.

Recurrence Rate and Cost Consequence of the Shortage of Bacillus Calmette-Guérin Connaught Strain for Bladder Cancer Patients.

BACKGROUND: Between 2013 and 2016, global production of bacillus Calmette-Guérin (BCG) was dramatically reduced due to the collapse of the factory producing BCG Connaught. OBJECTIVE: To evaluate the clinical and economic impact of BCG shortage on a cohort of non-muscle-invasive bladder cancer (NMIBC) patients treated during the period of restricted supply. DESIGN, SETTING AND PARTICIPANTS: This retrospective, before and after, cost-consequence study included patients with intermediate- and high-risk NMIBC. Those resected between November 2011 and September 2013 (control group) were compared with those resected between October 2013 and December 2016 (study group). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the rate of tumor recurrence from 30 d after transurethral resection to the end of follow-up at 24 mo; the secondary endpoints included the average cost of primary treatment, average cost of treatment of recurrence, and excess cost due to BCG shortage per patient. RESULTS AND LIMITATIONS: A total of 402 patients were included: 191 in the control group and 211 in the study group. The rate of recurrence at 24 mo was significantly higher in the study group than in the control group (46.9% vs 16.2%; relative risk: 0.7, 95% confidence interval [0.60; 0.82]; p < 0.001). The increased cost due to the decrease in BCG production was estimated to be €783 per patient with a new diagnosis of NMIBC during the period of restricted supply. This is a retrospective analysis at the level of our unit. A more precise evaluation would require a study of a larger cohort of patients. CONCLUSIONS: The shortage of BCG between October 2013 and December 2016 had a significant medical and economic impact; there was an increased rate of bladder cancer recurrence, and the total cost of care for intermediate- and high-risk NMIBC was higher. PATIENT SUMMARY: In this report, we analyzed the medical and economic impact of bacillus Calmette-Guérin (BCG) shortage that occurred between 2013 and 2016. We found a significant increase of bladder cancer recurrence and progression, and an increase in the number of patients who had to be treated by cystectomy. BCG shortage also had a significant impact on the total cost. Since there are no alternatives to BCG for high-risk non-muscle-invasive bladder cancer patients, BCG production has to be maintained by any means.