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  1. Gakis G, Fahmy O
    Bladder Cancer, 2016 Jul 27;2(3):293-300.
    PMID: 27500197
    Introduction: Although there is evidence that hexaminolevulinate (HAL)-based transurethral bladder tumor resection (TURBT) improves the detection of Ta-T1 non-muscle-invasive bladder cancer (NMIBC) as well as carcinoma in situ there is uncertainty about its beneficial effects on progression. Material and Methods: A systematic literature search was conducted according to the PRISMA statement to identify studies reporting on HAL- vs. white-light (WL-) based TUR-BT in non-muscle invasive bladder cancer between 2000 and 2016. A two-stage selection process was utilized to determine eligible studies. Of a total of 294 studies, 5 (4 randomized and one retrospective) were considered for final analysis. The primary objective was the rate of progression. Results: The median follow-up for patients treated with HAL- and WL-TURBT was 27.6 (1-55.1) and 28.9 (1-53) months, respectively. Of a total of 1301 patients, 644 underwent HAL- and 657 WL-based TURBT. Progression was reported in 44 of 644 patients (6.8%) with HAL- and 70 of 657 patients (10.7%) with WL-TURBT, respectively (median odds ratio: 1.64, 1.10-2.45 for HAL vs. WL; p = 0.01). Data on progression-free survival was reported in a single study with a trend towards improved survival for patients treated with HAL-TURBT (p = 0.05). Conclusions: In this meta-analysis the rate of progression was significantly lower in patients treated with HAL- vs. WL-based TURBT. These results support the initiation of randomized trials on HAL with progression as primary endpoint.
  2. Fahmy O, Khairul-Asri MG, Stenzl A, Gakis G
    Med Hypotheses, 2016 Jul;92:57-8.
    PMID: 27241256 DOI: 10.1016/j.mehy.2016.04.037
    Although intravesical instillation of Bacille-Calmette-Guerin (BCG) immunotherapy was approved many decades ago as a first line therapy for intermediate to high-risk non-muscle invasive bladder cancer, its long-term efficacy is still arguable as a proportion of up to 30-40% of patients will develop recurrence or progression of their disease. Based on currently available data on the clinical application of checkpoint inhibitors in solid tumors, the mucosa-associated lymphoid tissue seems to be a main target for anti-CTLA-4 antibodies. In this manuscript we hypothesize that the combination of anti-CTLA-4 therapy with BCG might enhance the immune activity in the bladder submucosal tissue, and subsequently, improve oncological outcomes of NMIBC.
  3. Fahmy O, Asri K, Schwentner C, Stenzl A, Gakis G
    J Surg Oncol, 2015 Sep;112(4):427-9.
    PMID: 26265262 DOI: 10.1002/jso.24007
    To investigate the current status and feasibility of robotic neobladder diversion after robotic assisted radical cystectomy. A Medline search was conducted resulting in identification of 423 articles. After exclusion of ineligible studies, 3 case series and 5 case reports were considered with a total number of reported cases of 203. Although robotic intracorporeal neobladder reconstruction is in its starting phase, initial perioperative results seem to be comparable to open series. However, randomized studies are needed to confirm non-inferiority.
  4. Schubert T, Rausch S, Fahmy O, Gakis G, Stenzl A
    Ther Adv Urol, 2017 Nov;9(11):251-260.
    PMID: 29662543 DOI: 10.1177/1756287217720401
    Background: For over 100 years white-light cystoscopy has remained the gold-standard technique for the detection of bladder cancer (BCa). Some limitations in the detection of flat lesions (CIS), the differentiation between inflammation and malignancy, the inaccurate determination of the tumor margin status as well as the tumor depth, have led to a variety of technological improvements. The aim of this review is to evaluate the impact of these improvements in the diagnosis of BCa and their effectiveness in clinical practice.

    Methods: A systematic literature search was conducted according to the PRISMA statement to identify studies reporting on imaging modalities in the diagnosis of NMIBC between 2000 and 2017. A two-stage selection process was utilized to determine eligible studies. A total of 74 studies were considered for final analysis.

    Results: Optical imaging technologies have emerged as an adjunct to white-light cystoscopy and can be classified according to their scope as macroscopic, microscopic and molecular. Macroscopic techniques including photodynamic diagnosis (PDD), narrow-band imaging (NBI) and the Storz Professional Image Enhancement System (IMAGE1 S, formerly known as SPIES) are similar to white-light cystoscopy, but are superior in the detection of bladder tumors by means of contrast enhancement. Especially the detection rate of very mute lesions in the bladder mucosa (CIS) could be significantly increased by the use of these methods. Microscopic imaging techniques like confocal laser endomicroscopy and optical coherence tomography permit a real-time high-resolution assessment of the bladder mucosa at a cellular and sub-cellular level with spatial resolutions similar to histology, enabling the surgeon to perform an 'optical biopsy'. Molecular techniques are based on the combination of optical imaging technologies with fluorescence labeling of cancer-specific molecular agents like antibodies. This labeling is intended to favor an optical distinction between benign and malignant tissue.

    Conclusions: Optical improvements of the standard white-light cystoscopy have proven their benefit in the detection of BCa and have found their way into clinical practice. Especially the combination of macroscopic and microscopic techniques may improve diagnostic accuracy. Nevertheless, HAL-PDD guided cystoscopy is the only approach approved for routine use in the diagnosis of BCa by most urological associations in the EU and USA to date.

  5. Fahmy O, Khairul-Asri MG, Stenzl A, Gakis G
    Clin. Exp. Metastasis, 2016 10;33(7):629-35.
    PMID: 27380916 DOI: 10.1007/s10585-016-9807-9
    For many decades, no significant improvements could be achieved to prolong the survival in metastatic bladder cancer. Recently, systemic immunotherapy with checkpoint inhibitors (anti-PD-L1/anti-CTLA-4) has been introduced as a novel treatment modality for patients with metastatic bladder cancer. We conducted a systematic review according to the PRISMA statement for data published on the clinical efficacy of checkpoint inhibitors in metastatic bladder cancer. Clinical efficacy of anti PD-L1 therapy was investigated in prospective trials in a total of 155 patients. Patients with positive expression for PD-L1 tended towards better overall response rates (ORR) compared to those with negative expression (34/76 vs 10/73, 45 vs 14 %; p = 0.21). Among patients with PD-L1 positive tumors, those with non-visceral metastases exhibited significantly higher ORR compared to those with visceral metastases (82 vs 28 %; p = 0.001). For anti-CTLA4 therapy, there were no data retrievable on clinical efficacy. Although data on clinical efficacy of checkpoint inhibitors in metastatic bladder cancer are currently limited, the efficacy of these drugs might depend mainly on the metastatic volume and immune system integrity. Patients with PD-L1 positive tumors and non-visceral metastases seem to derive the highest benefit from therapy.
  6. Fahmy O, Schubert T, Khairul-Asri MG, Stenzl A, Gakis G
    Int J Urol, 2017 04;24(4):320-323.
    PMID: 28208217 DOI: 10.1111/iju.13307
    The surgical treatment of a long proximal ureteral stricture is a challenging situation for reconstructive surgeons. Despite the underlying morbidities, ileal interposition and autotransplantation are the options available to treat complex cases of long segment ureteral stricture. Buccal mucosa has shown excellent results in urethroplasty. However, its use in ureteral reconstruction is infrequent. We report on a 64-year-old female patient with multiple comorbidities and prior abdominal surgeries for Crohn's disease who underwent a successful total substitution of a long segment of the proximal ureter using buccal mucosa. Regular postoperative isotope scans showed improvement in renal function. Based on the pleasant outcome of this case and review of the literature, buccal mucosa might be a viable option with low morbidity in selected cases.
  7. Fahmy O, Kochergin M, Asimakopoulos AD, Gakis G
    Semin Oncol, 2023;50(3-5):102-104.
    PMID: 37718162 DOI: 10.1053/j.seminoncol.2023.09.001
    For many decades, extended pelvic lymph node dissection has been an integral part during radical cystectomy for patients with muscle invasive bladder cancer. This practice was based on large retrospective meta-analyses suggesting an oncologic benefit to an extended dissection. This mini review and meta-analysis includes the two available randomized trials in the current literature. Therefore, it can be considered as the strongest level of evidence regarding the prognostic benefit of an extended pelvic lymphadenectomy. Based on current randomized data, standard pelvic lymph node dissection up to the level of iliac bifurcation is sufficient, and extension of the dissection above this level does not provide any additional oncologic benefit.
  8. Kochergin M, Fahmy O, Asimakopoulos AD, Gakis G
    Curr Opin Urol, 2023 Jul 01;33(4):288-293.
    PMID: 37158221 DOI: 10.1097/MOU.0000000000001101
    PURPOSE OF REVIEW: Primary urethral carcinoma (PUC) is a rare urologic tumor. There is limited evidence on this entity. This review summarizes the existing evidence on lymph node dissection (LND) in patients with PUC.

    RECENT FINDINGS: We performed a systematic search of the PubMed, EMBASE, and Web of Science databases to evaluate the impact of inguinal and pelvic LND on the oncological outcomes of PUC and to identify indications for this procedure.

    RESULTS: Three studies met the inclusion criteria. The cancer detection rate in clinically nonpalpable inguinal lymph node (cN0) was 9% in men and 25% in women. In clinically palpable lymph node (cN+), the malignancy rate was 84% and 50% in men and women, respectively. Overall cancer detection rate in pelvic lymph nodes in patients with cN0 was 29%. Based on tumor stage, the detection rate was 11% in cT1-2 N0 and 37% in cT3-4 N0. Nodal disease was associated with higher recurrence and worse survival. Pelvic LND seems to improve overall survival for patients with LND regardless of the location or stage of lymph nodes. Inguinal LND improved overall survival only in patients with palpable lymph nodes. Inguinal LND had no survival benefit in patients with nonpalpable lymph nodes.

    SUMMARY: The available, albeit scarce, data suggest that inguinal LND derives the highest benefit in women and in patients with palpable inguinal nodes, whereas the benefit of pelvic LND seems to be more pronounced across all stages of invasive PUC. Prospective studies are urgently needed to further address the prognostic benefit of locoregional LND in PUC.

  9. Fahmy O, El-Fayoumi AR, Gakis G, Amend B, Khairul-Asri MG, Stenzl A, et al.
    Cent European J Urol, 2015;68(4):466-70.
    PMID: 26855804 DOI: 10.5173/ceju.2015.627
    Laparoscopic pyeloplasty is considered a standard treatment for ureteropelvic junction obstruction (UPJO). However, the presence of another pathology makes it a more challenging operation and guides the surgeon towards open conversion. In this study, we present our experience in difficult pyeloplasty cases managed by laparoscopy.
  10. Fahmy O, Khairul-Asri MG, Schwentner C, Schubert T, Stenzl A, Zahran MH, et al.
    Eur Urol, 2016 08;70(2):293-8.
    PMID: 26776935 DOI: 10.1016/j.eururo.2015.12.047
    CONTEXT: Although urethral covering during hypospadias repair minimizes the incidence of fistula, wide variation in results among surgeons has been reported.

    OBJECTIVE: To investigate what type of flap used during Snodgrass or fistula repair reduces the incidence of fistula occurrence.

    EVIDENCE ACQUISITION: We systematically reviewed published results for urethral covering during Snodgrass and fistula repair procedures. An initial online search detected 1740 reports. After exclusion of ineligible studies at two stages, we included all patients with clear data on the covering technique used (dartos fascia [DF] vs tunica vaginalis flap [TVF]) and the incidence of postoperative fistula.

    EVIDENCE SYNTHESIS: A total of 51 reports were identified involving 4550 patients, including 33 series on DF use, 11 series on TVF use, and seven retrospective comparative studies. For distal hypospadias, double-layer DF had the lowest rate of fistula incidence when compared to single-layer DF (5/855 [0.6%] vs 156/3077 [5.1%]; p=0.004) and TVF (5/244, 2.0%), while the incidence was highest for single-layer DF among proximal hypospadias cases (9/102, 8.8%). Among repeat cases, fistula incidence was significantly lower for TVF (3/47, 6.4%) than for DF (26/140, 18.6%; p=0.020). Among patients with fistula after primary repair, the incidence of recurrence was 12.2% (11/90) after DF and 5.1% (5/97) after TVF (p=0.39). The absence of a minimum follow-up time and the lack of information regarding skin complications and rates of urethral stricture are limitations of this study.

    CONCLUSION: A double DF during tubularized incised plate urethroplasty should be considered for all patients with distal hypospadias. In proximal, repeat, and fistula repair cases, TVF should be the first choice. On the basis of these findings, we propose an evidence-based algorithm for surgeons who are still in their learning phase or want to improve their results.

    PATIENT SUMMARY: We systematically reviewed the impact of urethral covering in reducing fistula formation after hypospadias repair. We propose an algorithm that might help to maximize success rates for tubularized incised plate urethroplasty.

  11. Renninger M, Fahmy O, Schubert T, Schmid MA, Hassan F, Stenzl A, et al.
    World J Urol, 2020 Feb;38(2):397-406.
    PMID: 31030231 DOI: 10.1007/s00345-019-02780-0
    PURPOSE: To investigate whether hexaminolevulinate-based (HAL) bladder tumor resection (TURBT) impacts on outcomes of patients with primary non-muscle-invasive bladder cancer (NMIBC) who were eventually treated with radical cystectomy (RC).

    METHODS: A total of 131 consecutive patients exhibiting NMIBC at primary diagnosis were retrospectively investigated whether they had undergone any HAL-guided TURBT prior to RC. Uni- and multivariable analyses were used to evaluate the impact of HAL-TURBT on cancer-specific (CSS) and overall survival (OS). The median follow-up was 38 months (IQR 13-56).

    RESULTS: Of the 131 patients, 69 (52.7%) were managed with HAL- and 62 (47.3%) with white light (WL)-TURBT only prior to RC. HAL-TURBT was associated with a higher number of TURBTs prior to RC (p = 0.002) and administration of intravesical chemotherapy (p = 0.043). A trend towards a higher rate of tumor-associated immune cell infiltrates in RC specimens (p = 0.07) and a lower utilization rate of post-operative systemic chemotherapy (p = 0.10) was noted for patients who were treated with HAL-TURBT. The 5-year CSS/OS was 90.9%/74.5% for the HAL-group and 73.8%/55.8% for the WL-group (p = 0.042/0.038). In multivariable analysis, lymph node tumor involvement (p = 0.007), positive surgical margins (p = 0.001) and performance of WL-TURBT only (p = 0.040) were independent predictors for cancer-specific death.

    CONCLUSIONS: The present data suggest that the resection of NMIBC under HAL exerts a beneficial impact on outcomes of patients who will need to undergo RC during their course of disease. This finding may be due to improved risk stratification as the resection under HAL may allow more patients to be treated timely and adequately.

  12. Fahmy O, Khairul-Asri MG, Schubert T, Renninger M, Malek R, Kübler H, et al.
    Urol Oncol, 2018 02;36(2):43-53.
    PMID: 29102254 DOI: 10.1016/j.urolonc.2017.10.002
    OBJECTIVE: This study aimed to comprehensively analyze the oncological long-term outcomes of trimodal therapy (TMT) and radical cystectomy (RC) for the treatment of muscle-invasive bladder cancer (BC) with or without neoadjuvant chemotherapy (NAC).

    PATIENTS AND METHODS: A systematic search was conducted according to the PRISMA guidelines for studies reporting on outcomes after TMT and RC. A total of 57 studies including 30,293 patients were included. The 10-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) rates for TMT and RC were assessed.

    RESULTS: The mean 10-year OS was 30.9% for TMT and 35.1% for RC (P = 0.32). The mean 10-year DSS was 50.9% for TMT and 57.8% for RC (P = 0.26). NAC was administered before therapy to 453 (13.3%) of 3,402 patients treated with TMT and 812 (3.0%) of 27,867 patients treated with RC (P<0.001). Complete response (CR) was achieved in 1,545 (75.3%) of 2,051 evaluable patients treated with TMT. A 5-year OS, DSS, and RFS after CR were 66.9%, 78.3%, and 52.5%, respectively. Downstaging after transurethral bladder tumor resection or NAC to stage ≤pT1 at RC was reported in 2,416 (29.1%) of 8,311 patients. NAC significantly increased the rate of pT0 from 20.2% to 34.3% (P = 0.007) in cT2 and from 3.8% to 23.9% (P<0.001) in cT3-4. A 5-year OS, DSS, and RFS in downstaged patients (≤pT1) at RC were 75.7%, 88.3%, and 75.8%, respectively.

    CONCLUSION: In this analysis, the survival outcomes of patients after TMT and RC for MIBC were comparable. Patients who experienced downstaging after NAC and RC exhibited improved survival compared to patients treated with RC only. Best survival outcomes after TMT are associated with CR to this approach.

  13. Fahmy O, Khairul-Asri MG, Schubert T, Renninger M, Kübler H, Stenzl A, et al.
    Urol Oncol, 2018 02;36(2):54-59.
    PMID: 29196179 DOI: 10.1016/j.urolonc.2017.11.007
    PURPOSE: Currently, identified factors for urethral recurrence (UR) are based on individual reporting which has displayed controversy. In addition, risk of UR is one of the limiting factors to offer neobladder diversion during radical cystectomy (RC). We aim to systematically evaluate the incidence and risk factors of UR post-RC and its effect on survival.

    MATERIALS AND METHODS: A systematic online search was conducted according to PRISMA statement for publications reporting on UR after RC. From initial 802 results, 14 articles including 6169 patients were included finally after exclusion of ineligible studies.

    RESULTS: The incidence rate of UR was 4.4% (1.3%-13.7%). It was significantly lower with neobladder diversion (odds ratio = 0.44, 95% CI: 0.24-0.79, P = 0.006). Muscle invasion (hazard ratio = 1.18, 95% CI: 0.86-1.62, P = 0.31), carcinoma in situ (hazard ratio 0.97, 95% CI: 0.64-1.47, P = 0.88), prostatic stromal involvement (hazard ratio = 2.26, 95% CI: 0.01-627.75, P = 0.78), and prostatic urethral involvement (hazard ratio = 2.04, 95% CI: 0.20-20.80, P = 0.55) have no significant effect on UR. Men displayed tendency toward higher incidence of UR (odds ratio = 2.21, 95% CI: 0.96-5.06, P = 0.06). Absence of recurrence displayed tendency toward better disease specific survival, yet not significant (hazard ratio = 0.84, 95% CI: 0.66-1.08, P = 0.17). These results are limited by the retrospective nature of the included studies.

    CONCLUSION: Muscle invasion, carcinoma in situ and prostatic stromal or urethral involvement at time of RC have no significant effect on UR. Orthotopic neobladder is associated with a significant lower risk of UR after RC.

  14. Fahmy O, Khairul-Asri MG, Hadi SHSM, Gakis G, Stenzl A
    Urol Int, 2017;99(3):249-256.
    PMID: 28675891 DOI: 10.1159/000478789
    BACKGROUND: The role of radical prostatectomy (RP) is still controversial for locally advanced prostate cancer (PC). Radiotherapy (RT) and hormonal therapy (HT) are usually used as a primary treatment.

    MATERIAL AND METHODS: A systematic online search was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis statement. Eligible publications reporting the overall survival (OS) and/or disease-specific survival (DSS) were included. A total of 14 studies, including 17,869 patients, were considered for analysis. The impact of therapeutic modalities on survival was assessed, with a risk of bias assessment according to the Newcastle Ottawa Scale.

    RESULTS: For RP, RT, and HT, the mean 10-year OS was 70.7% (95% CI 61.3-80.2), 65.8% (95% CI 48.1-83.3), and 22.6% (95% CI 4.9-40.3; p = 0.001), respectively. The corresponding 10-year DSS was 84.1% (95% CI 75.1-93.2), 89.4% (95% CI 70.1-108.6), and 50.4% (95% CI 31.2-69.6; p = 0.0127), respectively. Among all treatment combinations, RP displayed significant improvement in OS when included in the treatment (Z = 4.01; p < 0.001). Adjuvant RT significantly improved DSS (Z = 2.7; p = 0.007). Combination of RT and HT favored better OS in comparison to monotherapy with RT or HT (Z = 3.61; p < 0.001).

    CONCLUSION: Improved outcomes in advanced PC were detected for RP plus adjuvant RT vs. RP alone and RT plus adjuvant HT vs. RT alone with comparable survival results between both regimens. RP with adjuvant RT may present the modality of choice when HT is contraindicated.

  15. Fahmy O, Khairul-Asri MG, Schubert T, Renninger M, Stenzl A, Gakis G
    J Urol, 2017 02;197(2):385-390.
    PMID: 27569436 DOI: 10.1016/j.juro.2016.08.088
    PURPOSE: There is controversy in the literature about the oncologic significance of incidental prostate cancer detected at radical cystoprostatectomy for bladder cancer.

    MATERIALS AND METHODS: An online search was done for studies reporting incidental prostate cancer in cystoprostatectomy specimens. After following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines we identified a total of 34 reports containing 13,140 patients who underwent radical cystoprostatectomy for bladder cancer with no previous history of prostate cancer. A cumulative analysis was performed on the available data regarding prevalence, clinicopathological features and oncologic outcomes. RevMan, version 5.3 was used for data meta-analysis.

    RESULTS: Of the 13,140 patients incidental prostate cancer was detected in 3,335 (24.4%). Incidental prostate cancer was significantly associated with greater age (Z = 3.81, p = 0.0001, d = 0.27, 95% CI -0.14-0.68), lymphovascular invasion of bladder cancer (Z = 2.07, p = 0.04, r = 0.14, 95% CI 0.09-0.18) and lower 5-year overall survival (Z = 2.2, p = 0.03). Among patients with clinically significant and insignificant prostate cancer those with clinically significant prostate cancer significantly more frequently showed a positive finding on digital rectal examination (Z = 3.12, p = 0.002, r = 0.10, 95% CI 0-0.19) and lower 5-year overall survival (Z = 2.49, p = 0.01) whereas no effect of age was observed (p = 0.15). Of 1,320 patients monitored for biochemical recurrence prostate specific antigen recurrence, defined as prostate specific antigen greater than 0.02 ng/ml, developed in 25 (1.9%) at between 3 and 102 months.

    CONCLUSIONS: This meta-analysis suggests that incidental prostate cancer detected during histopathological examination of radical cystoprostatectomy specimens might be linked with adverse characteristics and outcomes in patients with invasive bladder cancer.

  16. Kochergin M, Fahmy O, Esken L, Goetze T, Xylinas E, Stief CG, et al.
    Bladder Cancer, 2022;8(3):315-327.
    PMID: 38993684 DOI: 10.3233/BLC-201534
    BACKGROUND: Radical cystectomy (RC) is the standard of care in patients with muscle-invasive bladder cancer. The impact of perioperative red blood cell (RBC) transfusion on oncological outcomes after RC is not clearly established as the existing publications show conflicting results.

    OBJECTIVES: The aim of this systematic review and meta-analysis was to investigate the prognostic role of perioperative RBC transfusion on oncological outcomes after RC.

    METHODS: Systematic online search on PubMed was conducted, based on PRISMA criteria for publications reporting on RBC transfusion during RC. Publications with the following criteria were included: (I) reported data on perioperative blood transfusion; (II) Reported Hazard ratio (HR) and 95% -confidence interval (CI) for the impact of transfusion on survival outcomes. Primary outcome was the impact of perioperative RBC transfusion on recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). Risk of bias assessment was performed using Newcastle-Ottawa Scale. Statistical analysis was performed using Revman 5.4 software.

    RESULTS: From 27 primarily identified publications, 19 eligible articles including 22897 patients were selected. Perioperative RBC transfusion showed no impact on RFS (Z = 1.34; p = 0,18) and significant negative impact on CSS (Z = 2.67; p = 0.008) and OS (Z = 3.22; p = 0.001). Intraoperative RBC transfusion showed no impact on RFS (Z = 0.58; p = 0.56) and CSS (Z = 1.06; p = 0.29) and OS (Z = 1.47; p = 0.14).Postoperative RBC transfusion showed non-significant trend towards improved RFS (Z = 1.89; p = 0.06) and no impact on CSS (Z = 1.56; p = 0.12) and OS (Z = 0.53 p = 0.60).

    CONCLUSION: In this meta-analysis, we found perioperative blood transfusion to be a significant predictor only for worse CSS and OS but not for RFS. This effect may be determined by differences in tumor stages and patient comorbidities for which this meta-analysis cannot control due to lack of respective raw data.

  17. Asimakopoulos AD, Kochergin M, Colalillo G, Fahmy O, Hassan F, Renninger M, et al.
    Bladder Cancer, 2023;9(3):237-251.
    PMID: 38993180 DOI: 10.3233/BLC-230043
    BACKGROUND: With the exception of the FDA-approved valrubicin and pembrolizumab, there are no standard second-line treaments for BCG-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC).

    OBJECTIVES: To provide a systematic review of the novel intravesically administered therapeutic agents for the salvage treatment of BCG-unresponsive NMIBC.

    METHODS: Online search of the PubMed, EMBASE and Web of Science databases was performed. The endpoints of this review were to evaluate the efficacy of the agents in terms of complete response rates (CR) and durability of CR, overall survival, recurrence-free survival and cancer-specific survival and to report on their toxicity profile. A search on Clinicaltrials.gov was performed to identify ongoing clinical trials.

    RESULTS: 14 studies were included in this review. The critical clinical need for the development of an effective, safe and durable intravesical drug for the salvage treatment of high-risk NMIBC seems to be met mainly by intravesical gene therapy; in fact, data support the FDA-approved nadofaragene firadenovec as a potentially important therapeutic advancement in this context. Promising results are also being obtained by the combination of N-803/BCG and by innovative drug delivery systems.

    CONCLUSIONS: Considering the plethora of novel intravesical treatments that have completed phase II evaluation, one can reasonably expect that clinicians will soon have at their disposal new agents and treatment options for BCG-unresponsive NMIBC. In the near future, it will be up to the urologist to identify, for each specific patient, the right agent to use, based on safety, results and cost-effectiveness.

  18. Patel V, Collazo Lorduy A, Stern A, Fahmy O, Pinotti R, Galsky MD, et al.
    Bladder Cancer, 2017 Apr 27;3(2):121-132.
    PMID: 28516157 DOI: 10.3233/BLC-170108
    Background: Cisplatin-based combination chemotherapy is standard treatment for metastatic urothelial carcinoma; however, the vast majority of patients experience disease progression. As systemic therapy alone is rarely curative for the treatment of metastatic urothelial cancer, not only are new therapies needed but also refinement of general treatment principles. Herein, we conducted a systematic review and meta-analysis to explore the role of metastasectomy in metastatic urothelial carcinoma. Methods: We conducted a systematic review of the literature regarding local treatment for metastatic urothelial carcinoma. An online electronic search of the PubMed/MEDLINE and EMBASE databases was performed to identify peer-reviewed articles. All procedures were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Information was then extracted including number of patients, gender, the site of the primary urothelial tumor, site of metastasis, chemotherapy before or after metastasectomy, overall survival (OS), and disease specific survival (DSS) after metastasectomy. A meta-analysis was performed with those studies with sufficient survival data to obtain pooled overall survival. The article quality was assessed using the Cochrane Handbook "risk of bias" tool. Results: Seventeen out of 3963 articles were eligible for review between 1990-2015, including a total of 412 patients. The mean time to recurrence after metastasectomy was 14.25 months. The overall survival from time of metastasectomy ranged from 2 to 60 months. Pooled analyses of studies reported survival data revealed an improved overall survival for patients treated with metastasectomy compared with non-surgical treatment of metastatic lesions (HR 0.63; 95% CI, 0.49-0.81). All, except for three studies, were retrospective and non-randomized, leading to a high risk of bias associated with patient selection, patient attrition, and reporting. Such high potential of selection bias may lead to higher OS than expected. Additionally, treatment and outcome details reported across studies was highly variable. Conclusions: Limited conclusions can be drawn from the available literature exploring the role of metastasectomy in the management of metastatic urothelial cancer due to lack of uniform reporting elements and multiple sources of bias particularly related to a lack of prospective randomized trials. As a subset of patients treated with metastasectomy achieve durable disease control, this approach may be considered for select patients.
  19. Schubert T, Renninger M, Schmid MA, Hassan FN, Sokolakis I, Fahmy O, et al.
    Urol Oncol, 2020 01;38(1):4.e7-4.e15.
    PMID: 31537484 DOI: 10.1016/j.urolonc.2019.08.013
    OBJECTIVES: To assess whether the presence and location of tumor-associated immune cell infiltrates (TAIC) on histological slides obtained from cystectomy specimens impacts on oncological outcomes of patients with bladder cancer (BC).

    MATERIAL AND METHODS: A total of 320 consecutive patients staged with cM0 bladder cancer underwent radical cystectomy (RC) between 2004 and 2013. The presence of TAIC (either located peritumorally [PIC] and/or intratumorally [IIC]) on histological slides was retrospectively assessed and correlated with outcomes. Kaplan-Meier analyses were used to estimate the impact of TAIC on recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS). Multivariable Cox-regression analysis was carried out to evaluate risk factors of recurrence. The median follow-up was 37 months (IQR: 10-55).

    RESULTS: Of the 320 patients, 42 (13.1%) exhibited IIC, 141 (44.1%) PIC and 137 (42.8%) no TAIC in the cystectomy specimens. Absence of TAIC was associated with higher ECOG performance status (P = 0.042), histologically advanced tumor stage (≥pT3a; P < 0.001), lymph node tumor involvement (pN+; P = 0.022), positive soft tissue surgical margins (P = 0.006), lymphovascular invasion (P < 0.001), and elevated serum C-reactive protein levels (P < 0.001). The rate of never smokers was significantly higher in the IIC-group (64.3%) compared to the PIC-group (39.7%, P = 0.007) and those without TAIC (35.8%, P = 0.001). The 3-year RFS/CSS/OS was 73.9%/88.5%/76.7% for patients with IIC, 69.4%/85.2%/70.1% for PIC and 47.6%/68.5%/56.1% for patients without TAIC (P < 0.001/<0.001/0.001 for TAIC vs. no TAIC). In multivariable analysis, adjusted for all significant parameters of univariable analysis, histologically advanced tumor stage (P = 0.003), node-positive disease (P = 0.002), and the absence of TAIC (P = 0.035) were independent prognosticators for recurrence.

    CONCLUSIONS: In this analysis, the presence and location of TAIC in cystectomy specimens was a strong prognosticator for RFS after RC. This finding suggests that the capability of immune cells to migrate into the tumor at the time of RC is prognostically important in invasive bladder cancer.

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