Jons W. van Hattum

Objectives: To evaluate the effect of metformin on non‐muscle‐invasive bladder cancer (NMIBC) marker lesions. Patients and methods: A phase II, open‐label, multicentre, marker lesion trial using oral metformin in patients with primary or recurrent, multiple, low‐grade Ta‐T1 NMIBC was conducted. After transurethral resection for histological confirmation, leaving one tumour as a marker lesion, 11 patients were treated with oral metformin up to 3000 mg per day for 3 months. Reported outcomes included response of the marker lesion, safety of metformin, quality of life and pharmacological and immunohistochemical examinations of the mechanism of action of metformin. Results: One complete response and one partial response were observed. In the other nine patients, the marker lesion remained, while five of these patients also developed new Ta low‐grade lesions. Diarrhoea grade ≤ 2 was the most common adverse event (AE), observed in nine out of 11 patients. No serious AEs related to study treatment occurred. Metformin concentrations in the urine were significantly higher than metformin levels in the blood. Immunohistochemical analysis before and after treatment showed no difference in expression of markers associated with the mechanism of metformin. Conclusion: We did not find conclusive evidence for the hypothesis of an antitumour effect of metformin in bladder cancer.

Purpose: Urothelial bladder cancer (UCB) care requires frequent follow-up cystoscopy and surgery. Confocal laser endomicroscopy (CLE) is a probe-based optical technique that can provide real-time microscopic evaluation with the potential for outpatient grading of UCB. This study aims to investigate the diagnostic accuracy and interobserver variability for the grading of UCB with CLE during flexible cystoscopy (fCLE). Methods: Participants scheduled for transurethral resection of papillary bladder tumors were prospectively included for intra-operative fCLE. Exclusion criteria were flat lesions, fluorescein allergy or pregnancy. Two independent observers evaluated fCLE, classifying tumors as low- or high-grade urothelial carcinoma (LGUC/HGUC) or benign. Interobserver agreement was calculated with Cohens kappa (κ) and diagnostic accuracy with 2 × 2 tables. Histopathology was the reference test. Results: Histopathology of 34 lesions revealed 14 HGUC, 14 LGUC and 6 benign tumors. Diagnostic yield for fCLE was 80–85% with a κ of 0.75. Respectively, sensitivity, specificity, NPV and PPV were: for benign tumors 0–20%, 96–100%, unmeasureable-50% and 87%, for LGUC 57–64%, 41–58%, 44–53% and 54–69% and for HGUC 38–57%, 56–68%, 38–57% and 56–68%, with an interobserver agreement of κ 0.61. Conclusion: fCLE is currently insufficient to grade UCB.

Temporary elevation of tumor temperature, also known as hyperthermia, is a safe and well-tolerated treatment modality. The efficacy of hyperthermia can be improved by efficient thermosensitizers, and various candidate drugs, including inhibitors of the heat stress response, have been explored in vitro and in animal models, but clinically relevant thermosensitizers are lacking. Here, we employ unbiased in silico approaches to uncover new mechanisms and compounds that could be leveraged to increase the thermosensitivity of cancer cells. We then focus on elesclomol, a well-performing compound, which amplifies cell killing by hyperthermia by 5- to 20-fold in cell lines and outperforms clinically applied chemotherapy when combined with hyperthermia in vitro. Surprisingly, our findings suggest that the thermosensitizing effects of elesclomol are independent of its previously reported modes of action but depend on copper shuttling. Importantly, we show that, like elesclomol, multiple other copper shuttlers can thermosensitize, suggesting that disturbing copper homeostasis could be a general strategy for improving the efficacy of hyperthermia.

BACKGROUND: Effective oral treatment options for urothelial bladder cancer (BC) are lacking. Metformin, the most frequently used oral drug in type II diabetes mellitus, has putative anticancer properties and could, therefore, influence BC incidence and treatment outcomes. We systematically reviewed the current literature regarding the effect of metformin on BC incidence and oncological outcomes in non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). METHODS: This review was conducted according to the PRISMA guidelines. Literature was gathered through a systematic search in PubMed/Medline, EMBASE and the Cochrane library. Risk of bias was determined using the Cochrane risk-of-bias tool for randomized trials and the Newcastle-Ottawa Scale for non-randomized trials. Hazard ratios (HRs) were extracted and pooled in a random-effects meta-analysis. RESULTS: We reviewed 13 studies, including 3,315,320 patients, considering the risk of developing BC after metformin exposure and 9 studies, including 4,006 patients, on oncological outcomes of patients with BC. Metformin did not affect BC incidence (HR 0.97, 95% CI 0.87 –1.09) or oncological outcomes for NMIBC but did show a reduced risk of recurrence (HR 0.52, 95% CI 0.32 –0.84), cancer-specific mortality (HR 0.58, 95% CI 0.43 –0.78) and overall mortality (HR 0.66, 95% CI 0.47 –0.92) in MIBC. CONCLUSIONS: The role of metformin in the prevention and treatment of BC in patients remains unclear. Although a beneficial effect of metformin on treatment outcomes of certain stages of BC may exist, a definitive conclusion cannot be drawn. Prospective clinical trials are needed to assess the efficacy of metformin for BC treatment.

Despite current treatment strategies, the 5-year overall survival of muscle-invasive bladder cancer (MIBC) is approximately 50%. Historically, radical cystectomy (RC) with neoadjuvant chemotherapy has been the first-choice treatment for this patient group. Recently, several studies have reported encouraging results of using immune checkpoint inhibitors (ICI) prior to RC. However, in recent years, bladder-sparing alternatives such as CRT have gained popularity. The effect of radiotherapy on the tumor microenvironment is an important rationale for combining CRT with ICI therapy. Worldwide, twelve immunochemoradiotherapy (iCRT) trials are ongoing. Each study employs a different chemotherapy and radiotherapy regimen and varies the timing of ICI administration concurrent to radiotherapy, adjuvant, or both. Five studies have presented (preliminary) results showing promising safety and short-term survival data. The first peer-reviewed publications are expected in the near future. The preclinical evidence and preliminary patient data demonstrate the potential of iCRT bladder-sparing treatment for bladder cancer.

INTRODUCTION: This study evaluates the introduction of an electronic pH meter to measure the urinary pH in patients with uric acid (UA) urolithiasis and assess patient’s perspective. MATERIAL AND METHODS: Patients known with UA urolithiasis were included in this single center, non-randomized, prospective feasibility study, IDEAL stage 2a. Their experience with urolithiasis and satisfaction with the method of urinary pH monitoring prior to inclusion was evaluated. All patients received an electronic pH meter and standardized instructions. After a period of 6-12 weeks their experience and satisfaction with this pH meter and new regimen was assessed. Patient satisfaction was scored on a Likert scale 1-5. RESULTS: Eighteen patients were included. Median age was 63 years and median BMI was 30 kg/m2. The cohort consisted of 67% men and 33% women. In their medical history, 55% had unilateral stones, whereas 45% had bilateral stones. The median eGFR was 58 ml/min/1.73 m2. Eighty-nine percent took medication to alkalize their urine, median 3.5 years. Fifteen patients used paper reagent strips and three used an electronic pH meter to assess urinary pH prior to this study. Satisfaction with the method of urinary pH measurement at inclusion was reasonable (median score 3; IQR 1-4). Satisfaction with the new electronic pH meter was good (median score 4; IQR 3-5), as was the overall satisfaction (median score 4; IQR 3-5). The new electronic pH meter was slightly easier to use (median 3.5; IQR 1.75-5), as easy in maintenance (median 3; IQR 2-4) and significantly easier to read (median 5; IQR 4-5). The new electronic pH meter was better (median score 4; IQR 2.75-5) than their previous method. CONCLUSION: The introduction of a standardized approach of urinary pH monitoring for UA urolithiasis patients with an electronic pH meter leads to an easier interpretable outcome and higher patient satisfaction.

Background: Non-muscle-invasive bladder cancer (NMIBC) is the most common neoplasm of the urinary tract and requires life-long invasive surveillance to detect disease recurrence. Currently, there are no effective oral therapies that delay disease recurrence or progression. We recently demonstrated that in mice, metformin accumulates unchanged in the urine. Urothelial cells are exposed to metformin concentrations ~ 240-fold higher than in serum. This was effective in the treatment of mouse bladder cancer models. Methods: We describe the protocol of a multi-centre, open-label, phase II clinical trial of metformin in up to 49 evaluable patients with intermediate-risk NMIBC with the aim to determine the overall response to administration of oral metformin for 3 months on a marker tumour deliberately left following transurethral resection of multiple, papillary NMIBC tumours. All patients will receive metformin orally at doses up to 3000 mg per day. Metformin treatment will start within 2 weeks following transurethral resection of all tumours except one marker lesion. After 3 months of metformin treatment, the effect of metformin on the marker lesion is evaluated by cystoscopy and biopsy under anaesthesia. Residual tumour, if present at this evaluation, will be resected. In case of complete disappearance of the marker lesion, the former tumour area will be biopsied. The primary outcome is the complete response rate of the marker lesion, as determined by decentralised scoring of pre- and post-treatment cystoscopy images by expert independent urologists. Secondary outcomes are the partial response rate, overall safety of metformin and the duration of the time to recurrence. Discussion: Preclinical studies show the potential role of oral metformin treatment in the management of NMIBC. It could offer an alternative to current adjuvant intravesical treatment. If positive, the reported results of this study could warrant further phase III trials to compare the efficacy of metformin against current treatments of intravesical installations with chemotherapy or Bacillus Calmette-Guérin (BCG). Trial registration: This trial is registered in ClinicalTrials.gov under NCT03379909.