BACKGROUND: The tumoricidal complex alpha1-oleate targets bladder cancer cells, triggering rapid, apoptosis-like tumor cell death. Clinical effects of alpha1-oleate were recently observed in patients with non-muscle invasive bladder cancer (NMIBC), using a randomized, placebo-controlled study protocol. AIMS: To investigate if there are dose-dependent effects of alpha1-oleate. MATERIALS AND METHODS: Here, patients with NMIBC were treated by intravesical instillation of increasing concentrations of alpha1-oleate (1.7, 8.5, or 17 mM) and the treatment response was defined relative to a placebo group. RESULTS: Strong, dose-dependent anti-tumor effects were detected in alpha1-oleate treated patients for a combination of molecular and clinical indicators; a complete or partial response was detected in 88% of tumors treated with 8.5 mM compared to 47% of tumors treated with 1.7 mM of alpha1-oleate. Uptake of alpha1-oleate by the tumor triggered rapid shedding of tumor cells into the urine and cell death by an apoptosis-like mechanism. RNA sequencing of tissue biopsies confirmed the activation of apoptotic cell death and strong inhibition of cancer gene networks, including bladder cancer related genes. Drug-related side effects were not recorded, except for local irritation at the site of instillation. DISCUSSION AND CONCLUSIONS: These dose-dependent anti-tumor effects of alpha1-oleate are promising and support the potential of alpha1-oleate treatment in patients with NMIBC.

• Keywords
• alpha1‐oleate complex, cell shedding, cellular uptake, gene expression, non‐muscle invasive bladder cancer,
• MeSH
• Administration, Intravesical MeSH
• Apoptosis drug effects   MeSH
• Oleic Acid * therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Urinary Bladder Neoplasms * drug therapy   pathology   genetics   MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Oleic Acid * MeSH
• Antineoplastic Agents MeSH

Background: The efficacy of intravesical chemotherapy maintenance for patients with non-muscle invasive bladder cancer (NMIBC) is inferior compared to intravesical bacillus Calmette-Guerin (BCG). How intravesical chemohyperthermia (CHT) compares with BCG is under investigation. Objective: To compare the oncological outcomes and safety profile between intravesical CHT and BCG treatment for intermediate- and high-risk NMIBC. Methods: We performed a systematic review and meta-analysis of clinical studies comparing CHT with BCG for intermediate- and high-risk NMIBC patients. A comprehensive literature search on OVID MEDLINE, EMBASE, and Cochrane Library was conducted. Risk of bias was assessed by the Cochrane RoB tool and ROBINS-I. Certainty of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Results: A total of 2,375 articles were identified and five studies were finally included. Among them, four randomised trials comprising 327 patients (CHT group: 156 patients; BCG group: 171 patients) were included in the meta-analysis. There were no significant differences in the 24-36 months recurrence rates (CHT: 29.5%, BCG: 37.4%; RR: 0.83, 95% CI 0.61-1.13; moderate certainty of evidence) and the 24-36 months progression rates (CHT: 4.4%, BCG: 7.6%, RR = 0.62, 95% CI 0.26-1.49; low certainty of evidence). There were also no significant differences in grade 1-2 adverse events (CHT group: 59.9%, BCG group 54.5%; RR = 1.10, 95% CI 0.93-1.30; moderate certainty of evidence) and grade 3 or above adverse events (CHT group: 23.2%, BCG group 22.5%; RR = 0.99, 95% CI 0.69-1.43; low certainty of evidence). Conclusions: Intravesical CHT had equivalent oncological outcomes and similar safety profile when compared to BCG maintenance therapy for patients with intermediate- and high-risk NMIBC. CHT is a possible alternative treatment in the times of BCG shortage.

• Keywords
• BCG–Bacillus Calmette-Guérin vaccine, TURBT (trans-urethral resection of bladder tumour), bladder cancer, chemohyperthermia, meta-analysis,
• Publication type
• Journal Article MeSH
• Systematic Review MeSH

The protein-lipid complex alpha1-oleate, derived from HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells), is identified as a molecular entity with significant therapeutic potential. Structural characterization of the complex and results of a successful placebo-controlled clinical trial are presented.

• Keywords
• Novel cancer therapy, bladder cancer, low toxicity, peptide-oleate complex, protein folding,
• Publication type
• Journal Article MeSH

Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.

• MeSH
• Apoptosis drug effects   MeSH
• Endocytosis drug effects   MeSH
• Protein Conformation MeSH
• Oleic Acids chemistry   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Urinary Bladder Neoplasms drug therapy   genetics   pathology   MeSH
• Peptides chemistry   pharmacology   therapeutic use   MeSH
• Placebos MeSH
• Proton Magnetic Resonance Spectroscopy MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Amino Acid Sequence MeSH
• Endpoint Determination MeSH
• Thermodynamics MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Oleic Acids MeSH
• Peptides MeSH
• Placebos MeSH

BACKGROUND: Bacillus Calmette-Guérin (BCG) immunotherapy, the standard adjuvant intravesical therapy for some intermediate and most high-risk non-muscle invasive bladder cancers (NMIBCs), suffers from a heterogenous response rate. Molecular markers to help guide responses are scarce and currently not used in the clinical setting. METHODS: To identify novel biomarkers and pathways involved in response to BCG immunotherapy, we performed a genome-wide DNA methylation analysis of NMIBCs before BCG therapy. Genome-wide DNA methylation profiles of DNA isolated from tumors of 26 BCG responders and 27 failures were obtained using the Infinium MethylationEPIC BeadChip. RESULTS: Distinct DNA methylation patterns were found by genome-wide analysis in the two groups. Differentially methylated CpG sites were predominantly located in gene promoters and gene bodies associated with bacterial invasion of epithelial cells, chemokine signaling, endocytosis, and focal adhesion. In total, 40 genomic regions with a significant difference in methylation between responders and failures were detected. The differential methylation state of six of these regions, localized in the promoters of the genes GPR158, KLF8, C12orf42, WDR44, FLT1, and CHST11, were internally validated by bisulfite-sequencing. GPR158 promoter hypermethylation was the best predictor of BCG failure with an AUC of 0.809 (p-value < 0.001). CONCLUSIONS: Tumors from BCG responders and BCG failures harbor distinct DNA methylation profiles. Differentially methylated DNA regions were detected in genes related to pathways involved in bacterial invasion of cells or focal adhesion. We identified candidate DNA methylation biomarkers that may help to predict patient prognosis after external validation in larger, well-designed cohorts.

• Keywords
• BCG refractory, Bacillus Calmette-Guérin, DNA methylation marker, Illumina MethylationEPIC BeadChip, bladder cancer, high-risk bladder cancer, urothelial cancer,
• MeSH
• Adjuvants, Immunologic therapeutic use   MeSH
• BCG Vaccine therapeutic use   MeSH
• Genome-Wide Association Study MeSH
• CpG Islands MeSH
• Heterochromatin MeSH
• Immunotherapy MeSH
• Middle Aged MeSH
• Humans MeSH
• DNA Methylation * MeSH
• Biomarkers, Tumor genetics   MeSH
• Urinary Bladder Neoplasms drug therapy   genetics   pathology   MeSH
• Promoter Regions, Genetic MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adjuvants, Immunologic MeSH
• BCG Vaccine MeSH
• Heterochromatin MeSH
• Biomarkers, Tumor MeSH

BACKGROUND: Epidemiologic studies that investigated alcohol consumption in relation to the risk of bladder cancer (BCa) have demonstrated inconsistent results. We conducted a systematic review and meta-analysis of the literature to investigate the association of alcohol including different types of alcoholic beverages consumption with the risk of BCa. MATERIALS AND METHODS: A systematic search of Web of Science, Medline/PubMed and Cochrane library was performed in May 2018. Studies were considered eligible if they assessed the risk of BCa due to alcohol consumption (moderate or heavy dose) and different types of alcoholic beverages (moderate or heavy dose) in multivariable analysis in the general population (all genders, males or females) or compared with a control group of individuals without BCa. STUDY DESIGN: observational cohorts or case-control. RESULTS: Sixteen studies were included in this meta-analysis. Moderate and heavy alcohol consumption did not increase the risk of BCa in the entire population. Sub-group and sensitivity analyses revealed that heavy alcohol consumption increased significantly the risk of BCa in the Japanese population, RR 1.31 (95% CI 1.08-1.58, P < 0.01) in the multivariable analysis, and in males RR of 1.50 (95% CI 1.18-1.92, P < 0.01), with no significant statistical heterogeneity. Moreover, heavy consumption of spirits drinks increased the risk of BCa in males, RR 1.42 (95% CI 1.15-1.75, P < 0.01). CONCLUSION: In this meta-analysis, moderate and heavy alcohol consumption did not increase the risk of bladder cancer significantly. However, heavy consumption of alcohol might increase the risk of BCa in males and in some specific populations.

• Keywords
• Alcohol consumption, Bladder cancer, Cancer risk,
• MeSH
• Risk Assessment MeSH
• Humans MeSH
• Urinary Bladder Neoplasms epidemiology   etiology   MeSH
• Alcohol Drinking adverse effects   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Systematic Review MeSH

Many changes have been made during these last years and concepts for understanding bladder cancer have evolved. We make an update with the latest findings of the WHO (World Health Organistaion) 2016, ICCR (International Collaboration on Cancer Reporting) and other official organisms and try to show the latest developments. In this document we provide new consensus guidelines and insights. We kept this document short and concise providing consensus guidelines to clinicians for the best patient care, it should be easy to understand for a non pathologists. We focussed on several burning issues, such as the anatomical and histological understanding of the bladder wall, the prognostic significance of grading and the most challenging problems in staging, we underline our needs from the clinicians such as clinical information, we further discuss the histological subtypes of bladder cancer, which is an extremely important issue in the light of molecular classifications and give prognostic insights. Furthermore, we discuss the ICCR worldwide consensus reporting, urinary cytology with the Paris system and several issues such as frozen section specimen.

• Keywords
• Grade, Histology, Pathology, Stage,
• MeSH
• Consensus MeSH
• Humans MeSH
• Urinary Bladder Neoplasms pathology   MeSH
• Practice Guidelines as Topic MeSH
• Societies, Medical MeSH
• Neoplasm Staging MeSH
• Neoplasm Grading MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The aim of the present review was to assess the prognostic impact of lymphovascular invasion (LVI) in transurethral resection (TUR) of bladder cancer (BCa) specimens on clinical outcomes. A systematic review and meta-analysis of the available literature from the past 10 years was performed using MEDLINE, EMBASE and Cochrane library in August 2017. The protocol for this systematic review was registered on PROSPERO (Central Registration Depository: CRD42018084876) and is available in full on the University of York website. Overall, 33 studies (including 6194 patients) evaluating the presence of LVI at TUR were retrieved. LVI was detected in 17.3% of TUR specimens. In 19 studies, including 2941 patients with ≤cT1 stage only, LVI was detected in 15% of specimens. In patients with ≤cT1 stage, LVI at TUR of the bladder tumour (TURBT) was a significant prognostic factor for disease recurrence (pooled hazard ratio [HR] 1.97, 95% CI: 1.47-2.62) and progression (pooled HR 2.95, 95% CI: 2.11-4.13), without heterogeneity (I2 = 0.0%, P = 0.84 and I2 = 0.0%, P = 0.93, respectively). For patients with cT1-2 disease, LVI was significantly associated with upstaging at time of radical cystectomy (pooled odds ratio 2.39, 95% CI: 1.45-3.96), with heterogeneity among studies (I2 = 53.6%, P = 0.044). LVI at TURBT is a robust prognostic factor of disease recurrence and progression in non-muscle invasive BCa. Furthermore, LVI has a strong impact on upstaging in patients with organ-confined disease. The assessment of LVI should be standardized, reported, and considered for inclusion in the TNM classification system, helping clinicians in decision-making and patient counselling.

• Keywords
• #BladderCancer, #blcsm, lymphovascular invasion, meta-analysis, progression, recurrence, transurethral resection, upstaging,
• MeSH
• Blood Vessels pathology   MeSH
• Cystectomy MeSH
• Neoplasm Invasiveness MeSH
• Humans MeSH
• Neoplasm Recurrence, Local pathology   MeSH
• Lymphatic Vessels pathology   MeSH
• Urinary Bladder Neoplasms pathology   surgery   MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Neoplasm Staging MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Systematic Review MeSH

OBJECTIVES: With the advent of novel genomic and transcriptomic technologies, new urinary biomarkers have been identified and tested for bladder cancer (BCa) surveillance. To summarize the current status of urinary biomarkers for the detection of recurrence and/or progression in the follow-up of non-muscle invasive BCa patients, and to assess the value of urinary biomarkers in predicting response to intravesical Bacillus Calmette-Guerin (BCG) therapy. METHODS AND MATERIALS: A medline/pubmed© literature search was performed. The performance of commercially available and investigational biomarkers has been reviewed. End points were cancer detection (recurrence), cancer progression, and response to BCG therapy. RESULTS: The performance requirements for biomarkers are variable according to the clinical scenario. The clinical role of urinary biomarkers in the follow-up of non-muscle invasive BCa patients remains undefined. The FDA-approved tests provide unsatisfactory sensitivity and specificity levels and their use is limited. Fluorescence in situ hybridization (FISH) has been shown to be useful in specific scenarios, mostly as a reflex test and in the setting of equivocal urinary cytology. FISH and immunocytology could conceivably be used to assess BCG response. Recently developed biomarkers have shown promising results; upcoming large trials will test their utility in specific clinical scenarios in a manner similar to a phased drug development strategy. CONCLUSIONS: Current commercially available urinary biomarker-based tests are not sufficiently validated to be widely used in clinical practice. Several novel biomarkers are currently under investigation. Prospective multicenter analyses will be needed to establish their clinical relevance and value.

• Keywords
• Follow-up, Non-muscle invasive bladder cancer, Recurrence, Surveillance, Test, Urinary biomarker,
• MeSH
• BCG Vaccine administration & dosage   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local diagnosis   urine   MeSH
• Biomarkers, Tumor urine   MeSH
• Urinary Bladder Neoplasms drug therapy   urine   MeSH
• Aftercare methods   MeSH
• Sensitivity and Specificity MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• BCG Vaccine MeSH
• Biomarkers, Tumor MeSH

PURPOSE: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis to adequately stage and treat the patient. Persistent disease after TUR is not uncommon and is why re-TUR is recommended in T1G3 patients. When there is T1 tumor in the re-TUR specimen, very high risks of progression (82%) have been reported. We analyze the risks of recurrence, progression to muscle-invasive disease and cancer-specific mortality (CSM) according to tumor stage at re-TUR in T1G3 patients treated with BCG. METHODS: In our retrospective cohort of 2451 T1G3 patients, 934 patients (38.1%) underwent re-TUR. 667 patients had residual disease (71.4%): Ta in 378 (40.5%), T1 in 289 (30.9%) patients. Times to recurrence, progression and CSM in the three groups were estimated using cumulative incidence functions and compared using the Cox regression model. RESULTS: During a median follow-up of 5.2 years, 512 patients recurred. The recurrence rate was significantly higher in patients with a T1 at re-TUR (P < 0.001). Progression rates differed according to the pathology at re-TUR, 25.3% in T1, 14.6% in Ta and 14.2% in case of no residual tumor (P < 0.001). Similar trends were seen in both patients with and without muscle in the original TUR specimen. CONCLUSIONS: Patients with T1G3 tumors and no residual disease or Ta at re-TUR have better recurrence, progression and CSM rates than previously reported, with a CSM rate of 13.1 and a 25.3% progression rate in re-TUR T1 disease.

• Keywords
• Non-muscle invasive bladder cancer, Progression, Re-transurethral resection of the bladder, Recurrence,
• MeSH
• Adjuvants, Immunologic therapeutic use   MeSH
• Administration, Intravesical MeSH
• BCG Vaccine therapeutic use   MeSH
• Cystectomy methods   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local mortality   MeSH
• Urinary Bladder Neoplasms * mortality   pathology   therapy   MeSH
• Follow-Up Studies MeSH
• Cause of Death MeSH
• Disease Progression MeSH
• Proportional Hazards Models MeSH
• Reoperation MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adjuvants, Immunologic MeSH
• BCG Vaccine MeSH