Safety, Tolerability, and Preliminary Efficacy of TAR-200 in Patients with Muscle-invasive Bladder Cancer Who Refused or Were Unfit for Curative-intent Therapy : A Phase 1 Study

Half of patients with muscle-invasive bladder cancer worldwide may not receive curative-intent therapy. Elderly or frail patients are most affected by this unmet need. TAR-200 is a novel, intravesical drug delivery system that provides sustained, local release of gemcitabine into the bladder over a 21-day dosing cycle. The phase 1 TAR-200-103 study evaluated the safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who either refused or were unfit for curative-intent therapy.Materials and Eligible patients had cT2-cT3bN0M0 urothelial carcinoma of the bladder. TAR-200 was inserted for 4 consecutive 21-day cycles over 84 days. The primary end points were safety and tolerability at 84 days. Secondary end points included rates of clinical complete response and partial response as determined by cystoscopy, biopsy, and imaging; duration of response; and overall survival. Median age of the 35 enrolled patients was 84 years, and most were male (24/35, 68.6%). Treatment-emergent adverse events related to TAR-200 occurred in 15 patients. Two patients experienced treatment-emergent adverse events leading to removal of TAR-200. At 3 months, complete response and partial response rates were 31.4% (11/35) and 8.6% (3/35), respectively, yielding an overall response rate of 40.0% (14/35; 95% CI 23.9-57.9). Median overall survival and duration of response were 27.3 months (95% CI 10.1-not estimable) and 14 months (95% CI 10.6-22.7), respectively. Progression-free rate at 12 months was 70.5%. TAR-200 was generally safe, well tolerated, and had beneficial preliminary efficacy in this elderly and frail cohort with limited treatment options

The conundrum of recurrent low-grade tumours: to treat or to observe?

Item does not contain fulltextPURPOSE OF REVIEW: To describe the importance of risk stratification and the role of more conservative management like office fulguration, office laser ablation and active surveillance in recurrent low-grade Ta tumours. RECENT FINDINGS: Updated models have been designed for risk stratification of intermediate-risk tumours. Conservative forms of management like office fulguration or laser ablation and even active surveillance seem well tolerated; however, randomized, controlled trials are lacking. In patients who have been tumour free for 5 years, late recurrences have been described. SUMMARY: Recurrent low-grade Ta tumours are classified in the intermediate risk group, which is a heterogeneous group. Therefore, risk stratification should be done by updated models or patients should be stratified in a risk group sub-classification. Recurrent low-grade Ta patients have a favourable prognosis and consequently are prone to overtreatment. Office fulguration or laser ablation or even active surveillance could be implemented in strictly selected patients. For active surveillance, Miyake et al. proposed a helpful flowchart with criteria for patient selection and for intervention. Follow up using cystoscopy and cytology is essential, but an optimal scheme has not been identified. As late recurrences are not infrequent and recurrent low-grade Ta patients can even die from bladder cancer, long term follow-up should be performed yearly, by cystoscopy and cytology

Inducible expression of catalytically active type 1 serine/threonine protein phosphatase in a human carcinoma cell line

Abstract Background One of the major cellular serine/threonine protein phosphatases is protein phosphatase type 1 (PP1). Studies employing many eukaryotic systems all point to a crucial role for PP1 activity in controlling cell cycle progression. One physiological substrate for PP1 appears to be the product of the retinoblastoma susceptibility gene (pRB), a demonstrated tumor suppressor. The growth suppressive activity of pRB is regulated by its phosphorylation state. Of critical importance is the question of the in vivo effect of PP1 activity on pRB and growth regulation. As a first step towards addressing this question, we developed an inducible PP1 expression system to investigate the regulation of PP1 activity. Results We have established a cell line for inducing protein expression of the type 1, alpha-isotype, serine/threonine protein phosphatase (PP1α). A plasmid encoding a fusion protein of the catalytic subunit of PP1α with a 6-histidine peptide (6His) and a peptide from hemagluttinin (HA) was transfected into the UMUC3 transitional cell carcinoma cell line, previously transfected with the reverse tetracycline transactivator plasmid pUHD172-1neo. A stable cell line designated LLWO2F was established by selection with hygromycin B. 6His-HA-PP1α protein appeared in cell lysates within two hours following addition of doxycycline to the culture medium. This protein localizes to the nucleus as does endogenous PP1α, and was shown to associate with PNUTS, a PP1-nuclear targeting subunit. Like endogenous PP1α, immunocomplexed 6His-HA-PP1α is active toward phosphorylase a and the product of the retinoblastoma susceptibility gene, pRB. When forcibly overexpressing 6His-HA-PP1α, there is a concomitant decrease in endogenous PP1α levels. Conclusions These data suggest the existence of an autoregulatory mechanism by which PP1α protein levels and activity remain relatively constant. RT-PCR analyses of isolated polysome fractions support the notion that this putative autoregulatory mechanism is exerted, at least in part, at the translational level. Implications of these findings for the study of PP1α function in vivo are discussed.</p