Grading urothelial carcinoma with probe-based confocal laser endomicroscopy during flexible cystoscopy.

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.

Perturbation of Copper Homeostasis Sensitizes Cancer Cells to Elevated Temperature.

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.

Study protocol of a phase II clinical trial of oral metformin for the intravesical treatment of non-muscle invasive bladder cancer.

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.

The Effect of Metformin on Bladder Cancer Incidence and Outcomes: A Systematic Review and Meta-Analysis.

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.

Phase 1 Study of Chemoradiotherapy Combined with Nivolumab ± Ipilimumab for the Curative Treatment of Muscle-invasive Bladder Cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes. OBJECTIVE: To determine the safety of iCRT for MIBC. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 × 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort. INTERVENTION: Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS). RESULTS AND LIMITATIONS: In the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade ≥3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis. CONCLUSIONS: In this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity. PATIENT SUMMARY: We tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combining immune checkpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials.

Introduction of a Standardized Approach of Electronic Urinary pH Monitoring to Assist Alkalization Therapy: A Uric Acid Urolithiasis Patient's Perspective.

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. Materials and Methods: Patients known with UA urolithiasis were included in this single-center, nonrandomized, prospective feasibility study, IDEAL stage 2a. Their experience with urolithiasis and satisfaction with the method of urinary pH monitoring before 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 body mass index 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 estimated glomerular filtration rate was 58 mL/minute/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 before this study. Satisfaction with the method of urinary pH measurement at inclusion was reasonable (median score 3; interquartile range [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.

Bladder-Sparing Chemoradiotherapy Combined with Immune Checkpoint Inhibition for Locally Advanced Urothelial Bladder Cancer-A Review.

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.

Method of alkalization and monitoring of urinary pH for prevention of recurrent uric acid urolithiasis: a systematic review.

Uric acid (UA) urolithiasis comprises around 5-10% of all stones and can frequently recur. Due to the fact that UA stones form in acidic urine with a pH <5.5, these patients require special attention compared to other stone patients. The international guidelines suggest treatment and metaphylaxis by urinary alkalization. The objective of this review is to critically asses the available evidence concerning the method and efficacy of this treatment modality. A systematic review on the methods of metaphylactic therapy using oral alkalization of UA urolithiasis was conducted by two authors. Evidence was sought using a predefined search strategy in seven different databases. The provided evidence was critically evaluated using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane collaboration tool for assessing the risk of bias. Twelve manuscripts were included of which one was a randomised trial. They focussed on ways to alkalize urine and its effect on stone recurrence. Because of their methodology and heterogeneity, the evidence is presented in a narrative review. There were differences in medication used for alkalizing urine, ways of monitoring urine pH and evaluating its efficacy. The reported outcomes also differed between studies. There is currently a lack of clear evidence for the method of alkalization of urine and the method of pH measurement. Besides this, for an established treatment modality, there is lack of long term results for the alkalization therapy. In conclusion, urine alkalization is an established treatment modality for the metaphylaxis of UA urolithiasis despite the lack of evidence from high quality studies on the methods of alkalization and its treatment efficacy. The studies published on this topic are scarce and contain notable risks of bias which should be kept in mind when interpreting the stated results.

Developing a core set of patient-reported outcomes in pancreatic cancer: A Delphi survey.

BACKGROUND: Patient-reported outcomes (PROs) are amongst the most relevant outcome measures in pancreatic cancer care and research. However, it is unknown which out of the numerous PROs are most important to patients and health care professionals (HCPs) in this setting. The aim of this study was to identify a core set of PROs to be incorporated in a nationwide prospective multidisciplinary pancreatic cancer registry. PATIENTS AND METHODS: We performed a two-round Delphi survey among 150 patients diagnosed with pancreatic or periampullary cancer (treated either with curative intent or in palliative setting) and 78 HCPs (surgeons, medical oncologists, gastroenterologists, radiotherapists, nurses, and dietitians) in The Netherlands. In round 1, participants were invited to rate the importance of 53 PROs, which were extracted from 17 different PRO measures and grouped into global domains, on a 1-9 Likert scale. PROs rated as very important (score 7-9) by the majority (≥ 80%) of curative and/or palliative patients as well as HCPs were considered sufficiently important to be incorporated in the core set. PROs not fulfilling these criteria in round 1 were presented again to the participants in round 2 along with individual and group feedback. RESULTS: A total of 97 patients (94%) in curative-intent setting, 38 patients (81%) in palliative setting and 73 HCPs (94%) completed both rounds 1 and 2. After the first round, 7 PROs were included in the core set: general quality of life, general health, physical ability, satisfaction with caregivers, satisfaction with services and care organisation, coping and defecation. After the second round, 10 additional PROs were added: appetite, ability to work/do usual activities, medication use, weight changes, fatigue, negative feelings, positive feelings, fear of recurrence, relationship with partner/family, and pancreatic enzyme replacement therapy use. CONCLUSION: This study provides a core set of PROs selected by patients and HCPs, which may be incorporated in pancreatic cancer care and research. Validation outside the Dutch context is recommended for generalisation and use in international studies.