Purpose: IDO1 induces immune suppression in T cells through L-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer.Patients and Methods: The study consisted of a 3 þ 3 doseescalation stage (n ¼ 66) and a tumor-specific expansion stage (n ¼ 92). Navoximod was given orally every 12 hours continuously for 21 consecutive days of each cycle with the exception of cycle 1, where navoximod administration started on day À1 to characterize pharmacokinetics. Atezolizumab was administered by intravenous infusion 1,200 mg every 3 weeks on day 1 of each cycle.Results: Patients (n ¼ 157) received navoximod at 6 dose levels (50-1,000 mg) in combination with atezolizu-mab. The maximum administered dose was 1,000 mg twice daily; the MTD was not reached. Navoximod demonstrated a linear pharmacokinetic profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, head and neck squamous cell carcinoma, cervical, neural sheath, nonsmall cell lung cancer, triple-negative breast cancer, renal cell carcinoma, urothelial bladder cancer): 6 (9%) doseescalation patients achieved partial response, and 10 (11%) expansion patients achieved partial response or complete response.Conclusions: The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Although activity was observed, there was no clear evidence of benefit from adding navoximod to atezolizumab.

What’s known on the subject? and What does the study add? The suprapubic catheter (SPC) is a useful and widely used tool in urological practice. However, complications can arise from its insertion or ongoing care. Currently there are no guidelines relating to SPC usage. This study has reviewed the available clinical evidence relating to SPC usage. Where this is lacking, expert opinion has been sought. Guidelines are suggested to help maximise safety and ensure best practice in relation to SPC usage. OBJECTIVE To report the British Association of Urological Surgeons’ guidelines on the indications for, safe insertion of, and subsequent care for suprapubic catheters. METHODS A comprehensive literature search was conducted to identify the evidence base. This was reviewed by a guideline development group (GDG), who then drew up the recommendations. Where there was no supporting evidence expert opinion of the GDG and a wider body of consultees was used. RESULTS Suprapubic catheterisation is widely used, and generally considered a safe procedure. There is however a small risk of serious complications. Whilst the evidence base is small, the GDG has produced a consensus statement on SPC use with the aim of minimising risks and establishing best practice (Table 1). It should be of relevance to all those involved in the insertion and care of suprapubic catheters. Given the paucity of evidence, areas for future research and development are also highlighted. This review has been commissioned and approved by BAUS and the Section of Female, Neurological and Urodynamic Urology. Summary of recommendations for suprapubic catheters (SPCs) practice General considerations• Clinicians who are involved in the management of patients with long‐term catheters should consider in each case whether an SPC would offer advantages to the patient over the use of a urethral catheter• Patients in whom an SPC is felt to be appropriate should have access to an efficient and expert service for SPC insertion• Patients who are undergoing SPC placement either as an isolated or as a combined procedure should undergo an appropriate consent procedure with best practice including the provision of both verbal and written informationThe suprapubic catheterization procedure• If appropriate expertise for SPC insertion is not available at a particular time, suprapubic aspiration of urine using a needle of up to 21 gauge can be used as a means of temporarily relieving the patient’s symptoms (LE3)• A general or regional anaesthetic should be used if the bladder cannot be comfortably filled with at least 300 mL of fluid and in spinal cord injury patients with an injury level of T6 or above (LE3)• The use of antibiotic prophylaxis is recommended for patients where the urine is likely to be colonized with bacteria despite there being a lack of published data addressing this issue (LE3)• The different catheter insertion techniques and kits have not been compared in adequate clinical trials; the choice of technique is therefore a matter of individual preference. All...

Objective To compare the long‐term outcomes of a tension‐free vaginal tape (TVT; Gynecare™, Somerville, NJ, USA), autologous fascial sling (AFS) and xenograft sling (porcine dermis, Pelvicol™; Bard, Murray Hill, NJ, USA) in the management of female stress urinary incontinence (SUI). Patients and Methods A multicentre randomised controlled trial carried out in four UK centres from 2001 to 2006 involving 201 women requiring primary surgery for SUI. The women were randomly assigned to receive TVT, AFS or Pelvicol. The primary outcome was surgical success defined as ‘women reporting being completely ‘dry’ or ‘improved’ at the time of follow‐up’. The secondary outcomes included ‘completely dry’ rates, changes in the Bristol Female Lower Urinary Tract Symptoms (BFLUTS) and EuroQoL EQ‐5D questionnaire scores. Results In all, 162 (80.6%) women were available for follow‐up with a median (range) duration of 10 (6.6–12.6) years. ‘Success’ rates for TVT, AFS and Pelvicol were 73%, 75.4% and 58%, respectively. Comparing the 1‐ and 10‐year ‘success’ rates, there was deterioration from 93% to 73% (P < 0.05) in the TVT arm and 90% to 75.4% (P < 0.05) in the AFS arm; ‘dry’ rates were 31.7%, 50.8% and 15.7%, respectively. Overall, the ‘dry’ rates favoured AFS when compared with Pelvicol (P < 0.001) and TVT (P = 0.036). The re‐operation rate for persistent SUI was 3.2% (two patients) in the TVT arm, 13.1% (five) in the Pelvicol arm, while none of the patients in the AFS arm required further intervention. Conclusions Our study indicates there is not enough evidence to suggest a difference in long‐term success rates between AFS and TVT. However, there is some evidence that ‘dry’ rates for AFS may be more durable than TVT.

Developed as an oral anticancer drug to treat estrogen receptor-positive breast cancer, GDC-0810 was shown to be a potent inhibitor of organic anion-transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) from an in vitro assay. A clinical study was conducted to assess the drug-drug interaction potential between GDC-0810 and pravastatin, which is a relatively selective and sensitive OATP1B1/1B3 substrate. Fifteen healthy female subjects of non-childbearing potential were enrolled in the study. On day 1 in period 1, a single 10-mg dose of pravastatin was administered to all subjects. Following a 4-day washout period, 600 mg of GDC-0810 was administered once daily on days 5 through 8 in period 2 to achieve steady-state concentrations. On day 7, a single dose of 10-mg pravastatin was coadministered with the 600-mg GDC-0810 dose. Concentrations of pravastatin (periods 1 and 2) and GDC-0810 (period 2 only) were quantified in blood samples and subsequently used to calculate the pharmacokinetics (PK) parameters. The pravastatin mean maximal concentration and area under the curve values were approximately 20% and 41% higher, respectively, following pravastatin coadministration with GDC-0810 compared to pravastatin alone. Based on the magnitude of change in this drug-drug interaction study, dose adjustments for pravastatin (and other OATP1B1/1B3 substrates) were not considered necessary when administered with GDC-0810. Retrospectively, the endogenous biomarkers of OATP1B1/1B3, coproporphyrin I and III, were also measured and showed changes comparable to those of pravastatin, indicating their utility in detecting weak inhibition of OATP1B1/1B3 in the clinical setting.

OBJECTIVES To evaluate the efficacy and complications of botulinum A toxin (Dysport, Ipsen Ltd, Slough, UK) 500 U in refractory idiopathic detrusor overactivity (IDO). PATIENTS AND METHODS In a prospective study of 25 patients with refractory IDO, the baseline evaluation included an assessment of symptoms, a 7‐day voiding diary, 24‐h pad test, record of symptoms on a visual analogue scale (VAS) (0–10), the Kings Health Questionnaire (KHQ) and urodynamics. Dysport 500 U was administered at 20 sites in the bladder, sparing the trigone. Patients were followed at 6 weeks and 3, 6 and 9 months; the urodynamic assessment was repeated at 3 months. RESULTS Fifteen (63%) patients reported being continent from 1 week after treatment; at 3 months, six (32%) (P = 0.01) patients were still dry, remaining so at 6 months (P = 0.025). Weekly leakage episodes decreased from 5.5 to 1.8 (P = 0.044) at 6 weeks and this was sustained, at 2.7 episodes (P = 0.012), at 9 months. The mean VAS score (0–10) decreased from 8.3 to 5.0 (P = 0.001) at 1 week, to 5.0 at 6 weeks (P = 0.001) and 3 months (P = 0.03) and to 6.1 (P = 0.013) at 6 months. On the KHQ there was a significant improvement in the severity measures domain (P = 0.021) and incontinence impact domain (P = 0.015) up to 9 months. The volume at first desire to void increased from 177 to 251 mL (P = 0.04) at 3 months. At 6 weeks and 3 months, 35% of patients required catheterization, as did 22% at 6 months, but only one at 9 months. CONCLUSIONS Intradetrusor Dysport 500 U was associated with significant subjective and objective improvements in refractory IDO. The present patients initially had a significant increase in voiding dysfunction that resolved by 9 months.