A review of urinary bladder microbiome in patients with bladder cancer and its implications in bladder pathogenesis.

PURPOSE: The recent discovery of the urinary microbiome has led to an emerging field of investigation about the potential role of microorganisms in the pathogenesis of urinary bladder cancer. Few preliminary data have been reported so far implicating urobiome as causative and prognostic factor of bladder tumorigenesis. In the present study, a review of the current evidence is presented about microbiome composition among patients with bladder cancer and healthy individuals as well as possible implications of microbiome on urothelial carcinoma of the bladder. METHODS: A literature review was conducted using PubMed/MEDLINE, Scopus, and the Cochrane library until December 2023. Search algorithm was constructed using the following terms and their associated Mesh terms and Boolean operators: "urinary microbiome" and "urinary microbiota". Studies written in English language, identifying, and comparing urinary microbiome among bladder cancer patients and healthy control group were included in the review. RESULTS: A total of 2,356 reports were identified. From this total 16 articles complied with the inclusion criteria were selected for analysis. These articles represent a total of about 486 bladder cancer patients. CONCLUSION: Recent studies revealed the colonization of the urinary tract and the bladder by micro-organisms using both enhanced culture- and molecular-based techniques for microbial characterization. However, several limitations exist in the literature decreasing the reliability of the current reports. As a result, urinary microbiome consist an ambitious era in bladder cancer research with an increasing number of evidence about its potential pathogenetic, prognostic and therapeutic role.

Validity and reliability of the Greek version of the neurogenic bladder symptom score (NBSS) questionnaire in a sample of Greek patients with multiple sclerosis.

BACKGROUND AND OBJECTIVES: There is no data regarding validity and reliability of the Greek version of Neurogenic Bladder Symptom Score (NBSS) questionnaire. In this study we investigated these parameters using a sample of Greek patients with multiple sclerosis (MS). MATERIALS AND METHODS: Patients with different types and severity of multiple sclerosis were recruited from a single center in Greece prospectively. All patients completed the MusiQoL and NBSS questionnaires at baseline and 20 days later, without receiving any new treatment. Construct validity, internal consistency and test-retest reliability were tested. Internal consistency was investigated using Cronbach's alpha coefficient, while test-retest reliability using Intraclass Correlation Coefficient (ICC). Construct validity was assessed by comparing NBSS quality of life question 24 with MusiQoL questionnaire. RESULTS: A total of 91 patients were evaluated. The dimensions of NBSS exhibited high internal consistency, both for overall questionnaire score (Cronbach's alpha coefficient of 0.91) and for every subdomain separately (Cronbach's alpha coefficient of 0.95 for incontinence, 0.88 for storage symptoms and 0.74 for consequences). Test-retest reliability was satisfactory both for overall score [ICC of 0.85, (0.35-0.94), p < 0.001] and for every subdomain separately (ICC of 0.90 for incontinence, 0.83 for storage symptoms and 0.90 for consequences). Pearson's correlation coefficient of question number 24 of the NBSS questionnaire regarding quality of life with the MusiQoL questionnaire revealed a moderate correlation [r = 0.64, (0.48-0.80), p < 0.0001]. CONCLUSIONS: The Greek version of NBSS appears to be a valid and reliable instrument for assessing neurogenic bladder symptoms in Greek population suffering from multiple sclerosis.

Fragility index of urological literature regarding medical expulsive treatment.

INTRODUCTION: The role of medical expulsive treatment (MET) is controversial. Fragility index is an additional metric to assess randomized controlled trials (RCTs) outcome validity and indicates how many patients would be required to convert a trial from being statistically significant, to not significant. The larger is the FI, the better the trial's data. The aim of this study is to assess FI of RCTs regarding MET for ureteral stones. MATERIALS AND METHODS: A systematic literature search was performed. RCTs, reporting stone expulsion as a dichotomous outcome, showing statistical significance were eligible. FI (the number of patients needed to change from a non-event to event group, to lose statistical significance) and Fragility quotient (FI divided by total sample size), were calculated while Pearson's correlation and Mann-Whitney U test were used as appropriate. RESULTS: Thirty-six RCTs were eligible, with median FI = 3.5 and fragility quotient = 0.042, median sample size = 81, median journal impact factor = 1.73 and median reported p value = 0.008. In 33.3% of the studies, number of patients lost during follow-up was larger than FI, while in 13.89% of the studies, FI was 0, indicating use of inappropriate statistical method. Pearson's correlation showed significant positive association between FI and sample size (r = 0.981), number of events (r = 0.982) and impact factor (r = 0.731), while no association was found with p value or publication year. CONCLUSIONS: In this analysis, a calculated FI of 3.5 indicates that findings from RCTs on MET for ureteral stones are fragile and should be interpreted in combination with clinical thinking and expertise.

Reed Miller Nesbit: Broadening the Horizon of Genitourinary Surgery.

Nesbit has made his name synonymous with transurethral prostate resection and attained eminence by popularizing his technique, although his lifetime achievements and contributions reach many aspects of genitourinary surgery and pediatric urology. We believe our history article will bring memories back to more senior urologists, allow the youngsters to recall a true innovator and versatile surgeon, and appeal to a broad audience such as the readership of Surgical Innovation Journal.

Proteome-based classification of Nonmuscle Invasive Bladder Cancer.

DNA/RNA-based classification of bladder cancer (BC) supports the existence of multiple molecular subtypes, while investigations at the protein level are scarce. Here, we aimed to investigate if Nonmuscle Invasive Bladder Cancer (NMIBC) can be stratified to biologically meaningful groups based on the proteome. Tissue specimens from 117 patients at primary diagnosis (98 with NMIBC and 19 with MIBC), were processed for high-resolution proteomics analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The proteomics output was subjected to unsupervised consensus clustering, principal component analysis (PCA) and investigation of subtype-specific features, pathways, and gene sets. NMIBC patients were optimally stratified to three NMIBC proteomic subtypes (NPS), differing in size, clinicopathologic and molecular backgrounds: NPS1 (mostly high stage/grade/risk samples) was the smallest in size (17/98) and overexpressed proteins reflective of an immune/inflammatory phenotype, involved in cell proliferation, unfolded protein response and DNA damage response, whereas NPS2 (mixed stage/grade/risk composition) presented with an infiltrated/mesenchymal profile. NPS3 was rich in luminal/differentiation markers, in line with its pathological composition (mostly low stage/grade/risk samples). PCA revealed a close proximity of NPS1 and conversely, remoteness of NPS3 to the proteome of MIBC. Proteins distinguishing these two extreme subtypes were also found to consistently differ at the mRNA levels between high and low-risk subtypes of the UROMOL and LUND cohorts. Collectively, our study identifies three proteomic NMIBC subtypes and following a cross-omics validation in two independent cohorts, shortlists molecular features meriting further investigation for their biomarker or potentially therapeutic value.

Open radical prostatectomy after transurethral resection: perioperative, functional, oncologic outcomes.

INTRODUCTION: To demonstrate any differences in the perioperative, functional and oncologic outcomes after radical retropubic prostatectomy (RRP) among those patients having previously performed transurethral resection of prostate (TURP) and those not. MATERIALS AND METHODS: A total of 35 patients were diagnosed with prostate cancer (T1a and T1b) after TURP, underwent RRP and completed a 1 year follow up (group A). They were matched with a cohort of another 35 men (group B) in terms of age, body mass index (BMI), prostatic specific antigen (PSA), Gleason score, prostate volume (before surgery), pathological stage and neurovascular bundle-sparing technique. That was a retrospective study completed between September 2011 and March 2014. RESULTS: Not a significant difference was demonstrated among the two groups of patients concerning the functional and oncologic results. On the other hand, previous prostate surgery made the operation procedure more demanding. Besides, operative time and blood loss (though not translated in transfusion rates) were higher among patients in group A. Besides, catheter removal in group A patients was performed later than their counterparts of group B. CONCLUSIONS: RRP after TURP is a relatively safe procedure and in the hands of experienced surgeons, a previously performed TURP, does not seem to compromise oncologic outcomes of the operation. Continence is preserved, though erectile function seems to be compromised compared with patients undergoing RRP without prior TURP. Moreover, defining the prostate and bladder neck margins can be challenging and the surgeon has to be aware of the difficulties that might confront.

Current therapeutic options targeting bone metastasis in metastatic castration resistant prostate cancer.

Prostate cancer is a major public health problem worldwide, still remaining the most common cancer among elder males in both Europe and USA, being responsible for approximately 30,000 deaths in USA in 2014. Nowadays, after decades of basic research, novel treatment options have emerged focusing on men suffering from metastatic castration-resistant prostate cancer improving overall survival. It is also estimated that more than 90% of such patients develop bone metastasis, resulting in a significant increase in morbidity and mortality. The purpose of this review was to discuss the treatment options targeting bone metastasis in castration-resistant prostate cancer patients by examining the available literature focusing primarily in the role of zoledronic acid, denosumab and radium 223.

Emerging therapies targeting castration-resistant prostate cancer.

PURPOSE: Building on decades of research, the past few years have yielded a near expo-nential increase in treatment modalities for patients with metastatic prostate cancer. Individually, these improvements in overall survival may appear modest, however, nearly all of them have a distinct mechanism of action and the possibility of synergistic effects have yet to be established. The promise of a durable impact on the mortality from metastatic prostate cancer will likely stem from further elucidation of molecular pathways involved in prostate cancer, as well as defining the optimal sequence of treatment for patients with metastatic prostate cancer.

PSMA-based therapeutics for prostate cancer.

INTRODUCTION: The prostate cancer (PCa) consists the most frequently diagnosed malignancy of urogenital system in males. Traditionally, treatment of localized PCa was based on surgery or radiotherapy while hormonotherapy was used in more advanced stages. However, the implementation of radiolabels has revolutionized the landscape of prostate cancer. Specifically, prostate-specific membrane antigen (PSMA) has been investigated in different aspects of PCa therapeutic era. AREAS COVERED: A literature review is presented about the implications of PSMA radiolabels on prostate cancer treatment. PSMA tracers were initially used as an imaging technique. Afterwards, PSMA labeled with isotopes presenting cytotoxic abilities, such as lutetium-117 and actinium-225, while reports exist about the use of radioligand immunotherapy. Meanwhile, ongoing trials examine the development of novel radionuclides as well as the evolution of the PSMA-targeted ligands. EXPERT OPINION: Currently, PSMA radioligand treatment of prostate cancer is approved in the metastatic stage of the disease. Meanwhile, a variety of trials exist about its possible role in less advanced stages. However, plenty of parameters should be addressed before these implementations, such as PSMA dosage, dosimetry issues, and its safety profile. A future well-designed study with proper patient selection is mandatory to further explore PSMA radioligand theranostics perspectives.

Incidental prostate cancer in patients who underwent radical cystectomy for high risk non muscle invasive bladder cancer: Is it clinically significant?

INTRODUCTION AND OBJECTIVE: Non muscle invasive, high-risk, bladder cancer is an entity which is usually treated with radical cystectomy. Incidental prostate cancer refers to prostate cancer detected in radical cystectomy specimens in patients with no signs of the disease. Objective of this study is to report the prevalence, characteristics, and clinical significance of incidental prostate cancer in non-muscle invasive bladder cancer patients treated with radical cystectomy in our department. MATERIAL AND METHODS: We retrospectively reviewed data from 41 patients who underwent radical cystectomy for non-muscle invasive, high risk, bladder cancer during the years 2016-2020 in our department. Prostate cancer was described as clinically significant when there were positive surgical margins, extraprostatic extension, Gleason score >6, or tumor volume ⩾0.5 cm3. Two groups of patients were formed according to the presence or absence of clinically significant prostate cancer. RESULTS: Incidental prostate cancer in the cystectomy specimens was detected in 21 of the 35 patients investigated. Clinically significant prostate cancer was detected in five patients. Positive surgical margins and extraprostatic extension were present in one patient, respectively. Gleason score was more than six in four of the five patients and PCa tumor volume was above 0.5 cm3 in three patients. Two patients with clinically significant prostate cancer were diagnosed with biochemical recurrence during their follow up. CONCLUSIONS: In non-muscle invasive, high-risk patients undergoing radical cystectomy, clinically significant incidental PCa is an important issue as it may affect prognosis, quality of life, metastasis free survival, and overall survival.

Collision kidney tumor with clear cell renal cell carcinoma and papillary type 1 renal cell carcinoma. A case report and review of the literature.

INTRODUCTION: The most common renal neoplasms include clear cell, papillary, and chromophobe renal cell carcinomas. The simultaneous occurrence of different histological types of adjacent neoplasms in the same organ is known as a collision tumor. Collision kidney tumors have already been described but only in rare cases. CASE DESCRIPTION: In this case report we present a 68-year-old man with chronic kidney insufficiency under dialysis who underwent an open right nephrectomy in our department with the histological diagnosis of a collision kidney tumor consisting of clear cell and papillary type 1 renal cell carcinoma. CONCLUSION: To the best of our knowledge, our case of a collision kidney tumor consisting of clear cell RCC and papillary type 1 RCC, is unique in literature.

Clinical impact of ERG and PTEN status in prostate cancer patients underwent radical prostatectomy.

OBJECTIVES: Phosphate and tensin homolog gene (PTEN) acts as a regulator of PI3-KAkt molecular pathway. ETS Related gene (ERG), an oncogene located in chromosome 21q22.2, is involved in prostate cancer (PCa) by serine 2 (TMPRSS2), a protein encoded by TMPRSS2 gene. The aim of this study is to evaluate the clinical impact of PTEN loss and ERG rearrangement in terms of oncologic results in patients diagnosed with localized PCa who underwent radical prostatectomy. MATERIALS AND METHODS: Prospective data were collected from a total of 74 patients who underwent open radical retropubic prostatectomy for localized PCa and immunohistochemical study was performed in tissue samples. The primary antibodies for anti-ERG antibody as well as anti-PTEN antibody were obtained from DAKO. ERG was considered positive if at least 20% of the evaluated cells were stained at least with medium intensity. PTEN protein loss was considered when the intensity of cytoplasmic and nuclear staining was mild or entirely negative across > 10% of tumor cells. RESULTS: Homogenous loss of PTEN was associated with higher clinical International Society of Urological Pathology (ISUP) grade (p = 0.018) while no statistical significant association was present regarding the presence of ERG rearrangement with either ISUPc or ISUPp. After a median follow up of 34 months, 24 patients developed biochemical recurrence. No statistical significant correlation of ERG status with biochemical recurrence was noted while PTEN was associated with biochemical recurrence development in a statistical significant way. Lastly the combination of PTEN loss with ERG rearrangement presence was detected more often in higher ISUPc and ISUPp as well as biochemical recurrence development, although in a non statistical significant way. CONCLUSIONS: Homogenous and heterogenous PTEN loss was associated with biochemical recurrence. No association of ERG and biochemical recurrence was noted. The combination of PTEN loss and ERG rearrangement presented a trend for higher ISUPc and ISUPp as well as biochemical recurrence but not in a statistical significant way.

Outcomes of radical cystectomy in pT4 bladder cancer frail patients: Α high-volume single center study.

Objectives: This study aims to evaluate the effect of frailty in patients undergoing radical cystectomy (RC) for locally advanced bladder cancer. Methods: In this retrospective, single center study we evaluated 51 patients with pT4 bladder cancer treated with radical cystectomy between 2016-2020. Patient frailty was assessed with the Clinical Frailty Scale (CFS). Furthermore, six separate parameters (early mortality index within 30 days after surgery, death after one year, length of stay, respiratory complications, readmission index, total hospital charges) were also evaluated. The patients were categorized on three groups (Group 1, 2, 3) based on the CFS. Results: A total of 51 pT4 RC patients were included in the study. Mean age was 75.6 years. Early mortality rate at 30 days after surgery was low all the groups. One year mortality rate was higher in Group 2 (22%) and 3 (69%). The length of stay and the number of patients with respiratory complications were also higher in the frailer groups. 30 days readmission rate was 22% in Group 2 and 38% in Group 3. Conclusions: Preoperative frailty is associated with worse postoperative results after RC. CFS is an objective tool for patient risk stratification and can predict postoperative complications and mortality.

Current and emerging gonadotropin-releasing hormone (GnRH) antagonists for the treatment of prostate cancer.

Introduction:Androgen deprivation therapy (ADT) is currently the backbone treatment of metastatic prostate cancer and is also used in combination with external beam radiotherapy (EBRT). Castration may be achieved either by bilateral orchiectomy or by administration of LHRH agonists or GnRH antagonists.Areas covered: In this article, the authors assess the current and emerging role of GnRH antagonists for the treatment of prostate cancer focusing on oncological results and safety (i.e. cardiovascular risk). In addition, updated data regarding the first orally administered GnRH antagonist, relugolix, is presented.Expert opinion: Studies demonstrate that GnRH antagonists are at least equal with LHRH agonists in terms of testosterone suppression and PSA progression free survival with a major advantage being rapid testosterone suppression. Thus, the optimal group of patients included symptomatic metastatic prostate cancer patients especially if cardiovascular comorbidities or LUTS are also present. Emerging data regarding benefit of the use of GnRH antagonists in patients with concomitant cardiovascular disease are of great interest. Relugolix has emerged as the first orally administered GnRH antagonist able to achieve and maintain testosterone castration levels and it is associated with a profound reduction of major cardiovascular events.

Relugolix: A new kid on the block among gonadotrophin-releasing hormone antagonists.

Androgen-deprivation therapy (ADT) is the cornerstone of metastatic prostate cancer treatment. ADT can be achieved through surgical castration, or it may be induced either by gonadotrophin-releasing hormone (GnRH) agonists or GnRH antagonists. GnRH antagonists provide a more rapid castration alongside with a safer profile regarding adverse events. Degarelix is the sole GnRH antagonist used in clinical practice. Injection site reactions are the commonest adverse events related to the use of degarelix. Relugolix, a novel molecule, represents the first orally administered United States Food and Drug Administration approved GnRH antagonist, with clinical efficacy equal to that of the established ADT regimens. The main advantages of relugolix are the avoidance of the injection site reactions of GnRH antagonists such as degarelix alongside its patient-friendly oral administration. The aim of the present review article is to present novel data regarding the role of relugolix as ADT for the treatment of prostate cancer. Abbreviations: ADT: androgen-deprivation therapy; FDA: United States Food and Drug Administration.

Clinical impact of combined PTEN and ERG rearrangements in localized prostate cancer.

To the Editor, Prostate cancer (PCa) is nowadays the second most common malignancy diagnosed among men and is responsible for one of the leading causes of cancer mortality. Clinically localized disease may present with a wide variety of clinical behavior including tumors of low clinical significance as well as highly aggressive ones. Among patients treated with either radical prostatectomy or radiotherapy there is a risk of biochemical failure (BF). As a result, it is of outmost interest to develop new markers predicting the risk of BF development.

Novel treatments in BCG failure. Where do we stand today? / Nuevos tratamientos en fallo a BCG. ¿Dónde estamos?

OBJECTIVES: Most patients at first diagnosis of bladder cancer (BC) present with non muscle invasive disease (NMIBC). BCG intravesical therapy after transurethral resection of the bladder tumor is the gold standard in intermediate and high risk NMIBC patients. However, it is estimated that approximately 50% of these patients will present with BCG failure which increases their risk for progression to muscle invasive disease. Currently, the best option for these patients is radical cystectomy. Thus, it is of great interest to pursue new, therapeutic options for BCG failure patients to avoid the necessity of radical cystectomy. We hereby review novel treatment modalities for BCG failure patients. METHODS: This is a narrative review. Keywords for the search were BCG failure, BCG unresponsive, BCG refractory, BCG relapsing and BCG intolerance. Evidence was identified through a search for publications with a ''BCG unresponsive'' tag through 2020. Studies were selected if they contained clinical data on BCG unresponsive therapeutics with near-term availability. Clinical trial landscape evaluation for emerging therapies was performed by searching ClinicalTrials.gov for recruiting/ open interventional trials in 2020. RESULTS: Novel treatment modalities for BCG failure include intravesical chemotherapy, BCG re-challenge or combination of BCG with IFN-α2ß, valrubicin, radiotherapy, electromotive drug administration, vicinium, chemohyperthermia, photodynamic therapy, gene therapy, vaccine therapy and immunotherapy. For patients in whom BCG has once failed a repeat course of BCG or BCG plus interferon appears to be a reasonable practice. Likewise, single agent gemcitabine may be considered a treatment modality. However, after 2 or more BCG failures, especially in patients with earlier relapses or cancer persistence, single agent intravesical chemotherapy with valrubicin, gemcitabine or docetaxel appears to be less active than doublet/triplet intravesical chemotherapy or mitomycin chemothermotherapy. Gene therapy or conjugated antibodies may play a role upon further relapse. Single agent pembrolizumab is unlikely to be used as first line, but may be useful, along with multiple new immunotherapeutics, as part of a multimodal approach towards BCG unresponsive disease. CONCLUSIONS: Results from ongoing trials will provide us useful information about many of the existing regimens and probably new drugs will soon be available for this group of patients.

OBJETIVOS: La mayoría de pacientes al primer diagnóstico de cáncer de vejiga se presentan como canceres no musculo-invasivos. El tratamiento con BCG intravesical después de resección transuretral de vejiga es el tratamiento de elección en los pacientes de riesgo intermedio y alto. Aunque, se estima que aproximadamente el 50% de estos pacientes presentaran un fallo a BCG, que incrementa su riesgo de progresión a enfermedad musculo-invasiva. Actualmente, la mejor opción para estos pacientes es la cistectomía radical. Por tanto, es de alto interés la investigación de nuevos tratamientos para pacientes con fallo a BCG para evita rla cistectomía radical. Hemos revisado las nuevas modalidades de tratamiento en pacientes con fallo a BCG.MÉTODOS: Es una revisión narrativa. Las palabras clave para la búsqueda fueron BCG failure, BCG unresponsive, BCG refractory, BCG relapsing y BCG intolerance. La evidencia se identifico a través de una búsqueda para las publicaciones con BCG un responsive hasta 2020. Los estudios fueron seleccionados si contenían datos clínicos con tratamiento para BCG unresponsive. La evaluación de ensayos clínicos para terapias emergentes se realizó a través de clinicaltrials.gov para ensayos abierto o en recrutamiento, intervencionales en 2020. RESULTADOS: Las nuevas modalidades de tratamiento para el fallo de la BCG incluyen quimioterapia intravesical, reemplace de BCG o combinación de BCG con INF-α2ß, valrubicina, radioterapia, administración electromotiva del tratamiento (EMDA), vicinium, quimiohipertermia, terapia fotodinámica, terapia genética, terapia por vacunas e immunoterapia. Para pacientes en que la BCG ha fallado una vez, el reemplace de BCG o BCG junto interferón parece ser una opción razonable. De la misma forma, gemcitabina sola puede ser utilizada como modalidad de tratamiento. Aunque, después de 2 o mas fallos a BCG, especialmente en pacientes con fallos precoces o persistencia de cáncer, el tratamiento único intravesical con quimioterapia de valrubicina, gemcitabina o docetaxel parece ser menos activa que los dobletes/tripletes de quimioterapia intravesical o mitomicina quimiotermoterapia. La terapiagénica o anticuerpo conjugados parece que juegan un papel en futuras recurrencias. La administración de pembolizumabúnicamente, es poco probable que se utilice como primera línea, pero parece ser útil, junto con los nuevos immunoterápicos como parte de un tratamiento multimodal para la enfermedad refractaria a BCG. CONCLUSIONES: Los resultados de los ensayos clínicos en funcionamiento nos dará información útil de muchos de los regímenes existentes y probablemente nuevas drogas que pronto estarán preparadas para usar en este grupo de pacientes.