HIVEC as an alternative option in non-muscle-invasive bladder cancer: Experiences from a high-volume center.

BACKGROUND: High risk non-muscle invasive bladder cancer (NMIBC) is usually treated with intravesical BCG-therapy. In case of BCG failure radical cystectomy (RC) is the treatment of choice. Nevertheless, many patients are unfit for or unwilling to undergo RC. Hyperthermic intravesical chemotherapy (HIVEC) is a promising bladder sparing therapy in such cases. It was the purpose of the study to evaluate the efficacy of HIVEC in patients with BCG failure as well as in BCG naïve patients in case of BCG shortage or given contra-indications for BCG. METHODS: We analyzed the first 60 patients who received hyperthermic intravesical chemotherapy (HIVEC) at our department. The therapy regimen consisted of an induction course of 6 weekly sessions, followed by a maintenance course with 6 monthly sessions. Fluorescence cystoscopy with urine cytology and bladder mapping was performed after completion of induction and maintenance therapy at 3 and 12 months. About 68.6 % had received a recurrence after or during BCG treatment, 55% of the subjects were BCG-unresponsive NMIBC according to EAU guidelines. RESULTS: The median follow up was 12 months with 12 cycles of HIVEC therapy being administered on average, representing completion of induction and maintenance therapy with 6 cycles each. The 1- and 2-year recurrence-free-survival (RFS) was 67% and 40% respectively. Only one out of 60 patients developed progression to muscle invasion with progression-free-survival (PFS) of 98% at 2 years. No statistical differences were found in RFS for patients failure to BCG compared to patients that were BCG-naïve (BCG unresponsive vs. BCG-naïve) and patients that carried carcinoma in situ (CIS) compared to patients without CIS (CIS vs. no CIS). CONCLUSION: Chemohyperthermia using HIVEC results in high recurrence-free survival and a 2-year progression-free survival rate of 98% with a bladder preservation rate of almost 80%. Comparing our data, HIVEC shows better oncological results together with better tolerability and safety making HIVEC a good alternative for patients who refuse radical cystectomy or who are ineligible for radical cystectomy.

Cost-effectiveness analysis of different treatment modalities in BCG-unresponsive NMIBC.

OBJECTIVE: Radical cystectomy (RC) is the standard of care (SOC) in BCG-unresponsive NMIBC and is associated with a significant health-related quality-of-life burden. Recently, promising results have been published on Gemcitabine/Docetaxel, Pembrolizumab, and Hyperthermic Intravesical Chemotherapy (HIVEC) as salvage therapy options trying to increase the rate of bladder preservation. Here, we performed a Cost-Effectiveness-Analysis of those treatment modalities. PATIENTS AND METHODS: We developed a Markov model from a payer's perspective drawing on clinical data of single-arm trials testing intravesical gemcitabine/docetaxel and pembrolizumab in BCG-unresponsive NMIBC, as well as clinical data from patients receiving hyperthermic intravesical chemotherapy HIVEC (n = 29) as intravesical salvage chemotherapy at our uro-oncological centre in Cologne. Costs were simulated utilising a non-commercial diagnosis-related groups grouper, utilities were derived from comparable cost-effectiveness studies. We used a Monte Carlo simulation to identify the optimal treatment, comparing the incremental cost effectiveness ratios (ICERs) at a willingness-to-pay threshold of €50 000 (euro)/quality-adjusted life year (QALY). RESULTS: Over a horizon of 10 years, gemcitabine/docetaxel, HIVEC, and pembrolizumab were associated with costs of €48 353, €64 438, and €204 580, as well as a gain of QALYs of 6.16, 6.48, and 6.00, resulting in an ICER of €26 482, €42 567, and €184 533 respectively, in comparison to RC with total costs of €21 871 and a gain of QALYs of 5.01. Monte Carlo simulation identified HIVEC as the treatment of choice under assumption of a WTP of <€50 000. CONCLUSION: Considering a WTP of <€50 000/QALY, gemcitabine/docetaxel and HIVEC are highly cost-effective therapeutic options in BCG-refractory NMIBC, while RC remains the cheapest option. At its current price, pembrolizumab would only be cost-effective assuming a price reduction of at least 70%.

[Is there an indication for local treatment in metastasised hormone-sensitive prostate cancer?] / Gibt es eine Indikation zur Lokaltherapie des mHSPC?

In case of newly diagnosed metastasised hormone-sensitive prostate cancer, there are two indications for local treatment: to reduce or avoid local symptoms thus improving quality of life and prolonging survival in a subset of patients. Local treatment must be seen in a multimodal treatment approach and is not a replacement of systemic treatment. In the following review, we highlight the current literature for the different local treatment options, radiotherapy and radical prostatectomy, and try to give indications for which option should be offered to which patient.

Cystic Pelvic Masses in Men: A Presentation of Uncommon Cases and a Literature Review.

Unclear cystic masses in the pelvis in male patients are a rare situation and could be of benign or malignant origin. The underlying diseases demand for specific diagnostic and therapeutic approaches. We present a case series of 3 male patients with different clinical symptoms (perineal pain, urinary retention and a large scrotal cyst) related to cystic lesions in the pelvic region. On all patients initial histopathological workup was unclear. All patients underwent surgery with complete resection of the tumor which revealed a broad spectrum of histopathological findings: unusual form of cystic adenocarcinoma of the prostate, malignant transformation of a dysontogenetic cyst, and finally a very rare diagnosis of a malignant tumor of the Cowper gland. This case series and literature review provide clues for a possible diagnostic and therapeutic approach in the case of unclear pelvic cystic masses and could support urologists during the therapy selection in the future.

[Emergencies in cancer therapy: surgical indications under systemic therapy]. / Notfälle in der medikamentösen Tumortherapie ­ Operative Indikationen unter Systemtherapie.

Emergency surgery due to side-effects of cancer therapy in patients with metastatic disease of the genitourinary tract is rare. Nevertheless, there are a number of emergencies that require rapid intervention and should be recognized by every uro-oncologist. The following review will work out important side-effects requiring surgical treatment, highlighting the main symptoms and the initial management.

Prediction of Significant Prostate Cancer in Equivocal Magnetic Resonance Imaging Lesions: A High-volume International Multicenter Study.

BACKGROUND: Decision of performing prostate biopsy in men with Prostate Imaging Reporting and Data System (PI-RADS) 3 findings in prostate magnetic resonance imaging (MRI) is challenging as they have a low but still relevant risk of harboring significant prostate cancer (sPC). OBJECTIVE: To identify clinical predictors of sPC in men with PI-RADS 3 lesions in prostate MRI and to analyze the hypothetical effect of incorporating prostate-specific antigen density (PSAD) into biopsy decision. DESIGN, SETTING, AND PARTICIPANTS: We analyzed a retrospective multinational cohort from ten academic centers comprising 1476 men who underwent a combined prostate biopsy (MRI targeted plus systematic biopsy) between February 2012 and April 2021 due to a PI-RADS 3 lesion in prostate MRI. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the detection of sPC (ISUP ≥2) in a combined biopsy. Predictors were identified by a regression analysis. Descriptive statistics were applied to evaluate the hypothetical effect of involving PSAD into biopsy decision. RESULTS AND LIMITATIONS: Of all patients, 273/1476 (18.5%) were diagnosed with sPC. MRI-targeted biopsy diagnosed fewer sPC cases than combined strategy: 183/1476 (12.4%) versus 273/1476 (18.5%), p < 0.01. Age (odds ratio [OR] 1.10 [95% confidence interval {CI}: 1.05-1.15], p < 0.001), prior negative biopsy (OR 0.46 [0.24-0.89], p = 0.022), and PSAD (p < 0.001) were found to be independent predictors of sPC. Applying a PSAD cutoff of 0.15, 817/1398 (58.4%) biopsies would have been avoided at the cost of missing sPC in 91 (6.5%) men. Limitations were the retrospective design, heterogeneity of the study cohort due to the long inclusion period, and no central revision of MRI. CONCLUSIONS: Age, previous biopsy status, and PSAD were found to be independent predictors of sPC in men with equivocal prostate MRI. Implementation of PSAD into biopsy decision can avoid unnecessary biopsies. Clinical parameters such as PSAD need validation in a prospective setting. PATIENT SUMMARY: In this study, we looked for clinical predictors of significant prostate cancer in men with Prostate Imaging Reporting and Data System 3 lesions in prostate magnetic resonance imaging. We identified age, previous biopsy status, and especially prostate-specific antigen density as independent predictors.

Cytoreductive radical prostatectomy: who benefits from the surgical approach?

PURPOSE OF REVIEW: Local treatment in oligometastatic prostate cancer patients is associated with improved survival. Nevertheless, in term of surgery, cytoreductive radical prostatectomy has no level of evidence 1 and is an individual treatment approach. We reviewed the recent literature to highlight parameters for selecting patients for a surgical approach. RECENT FINDINGS: Retrospective data on oncologic outcome for cytoreductive prostatectomy are confirmed. We identified several parameters that help to select patients for surgery. Patients with a favorable prostate-specific antigen (PSA) decline after androgen deprivation therapy (ADT) have excellent oncologic long-term control. Circulating tumor cells (CTC's) are frequently analyzed in more advanced prostate cancer. In case of C-reactive protein (CRP) at least a longer interval to develop castration resistant prostate cancer (CRPC) is shown in case of low CTC count at time of surgery. Nutrition status analyzed as the hemoglobin, albumin, lymphocyte, and platelet (HALP)-score is of significant value in demonstrating an effect of CRP. SUMMARY: From retrospective findings we have several clinical and basic science parameters to select patients for CRP. PSA at the time of surgery is the most frequently analyzed one, whereas CTC and HALP-score are promising tools to select patients that need to be validated.

Importance of magnetic resonance imaging and prostate-specific membrane antigen PET-CT in patients treated with salvage radical prostatectomy for radiorecurrent prostate cancer.

BACKGROUND: Accurate staging and identification of optimal candidates for local salvage therapy, such as salvage radical prostatectomy (SRP), is necessary to ensure optimal care in patients with radiorecurrent prostate cancer (PCa). We aimed to analyze performance of magnetic resonance imaging (MRI) and prostate-specific membrane antigen (PSMA)-positron emission tomography (PET)/computed tomography (CT) for predicting pathologic nonorgan confined disease (pT3) and lymph node involvement (pN+) in patients treated with SRP for radiorecurrent PCa. METHODS: We retrospectively reviewed the institutional database to identify patients who underwent MRI or 68 Ga-PSMA-PET/CT before SRP for radiorecurrent PCa. The diagnostic estimates of MRI and PSMA-PET/CT for pT3 and pN+, were calculated. RESULTS: We identified 113 patients with radiorecurrent PCa who underwent preoperative MRI followed by SRP; 53 had preoperative 68 Ga-PSMA-PET/CT. For the detection of pT3 disease, the overall accuracy of MRI was 70% (95% confidence interval [CI] 61-78), sensitivity 40% (95% CI 26-55) and specificity 94% (95% CI 85-98); PSMA-PET/CT had slightly higher accuracy of 77% (95% CI 64-88), and higher sensitivity of 90% (95% CI 68-99), but lower specificity of 70% (95% CI 51-84). For pN+ disease, MRI had poor sensitivity of 14% (95% CI 3-36), specificity of 50 (95% CI 39-61) and total accuracy of 43% (95% CI 34-53); PSMA-PET/CT had an accuracy of 85% (95% CI 72-93), sensitivity of 27% (95% CI 6-61), and specificity of 100% (95% CI 92-100). CONCLUSION: In patients with radiorecurrent PCa, both, MRI, and 68 Ga-PSMA PET/CT are valuable tools for the pre-SRP staging and should be integrated into the standard workup. For lymph node metastases, 68 Ga-PSMA PET/CT is a strong rule-in test with nearly perfect specificity; in contrast MRI had a low accuracy for lymph node metastases.

Prediction of Response to Cisplatin-Based Neoadjuvant Chemotherapy of Muscle-Invasive Bladder Cancer Patients by Molecular Subtyping including KRT and FGFR Target Gene Assessment.

Patients with muscle-invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NAC) have improved prognosis. Molecular subtypes of bladder cancer differ markedly regarding sensitivity to cisplatin-based chemotherapy and harbor FGFR treatment targets to various content. The objective of the present study was to evaluate whether preoperative assessment of molecular subtype as well as FGFR target gene expression is predictive for therapeutic outcome­rate of ypT0 status­to justify subsequent prospective validation within the "BladderBRIDGister". Formalin-fixed paraffin-embedded (FFPE) tissue specimens from transurethral bladder tumor resections (TUR) prior to neoadjuvant chemotherapy and corresponding radical cystectomy samples after chemotherapy of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, Relative gene expression of subtyping markers (e.g., KRT5, KRT20) and target genes (FGFR1, FGFR3) was analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, Kruskal−Wallis, Mann−Whitney and sensitivity/specificity tests were performed by JMP 9.0.0 (SAS software). The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being node-negative during radical cystectomy after 1 to 4 cycles of NAC. When comparing pretreatment with post-treatment samples, the median expression of KRT20 dropped most significantly from DCT 37.38 to 30.65, which compares with a 128-fold decrease. The reduction in gene expression was modest for other luminal marker genes (GATA3 6.8-fold, ERBB2 6.3-fold). In contrast, FGFR1 mRNA expression increased from 33.28 to 35.88 (~6.8-fold increase). Spearman correlation revealed positive association of pretreatment KRT20 mRNA levels with achieving pCR (r = 0.3072: p = 0.0684), whereas pretreatment FGFR1 mRNA was associated with resistance to chemotherapy (r = −0.6418: p < 0.0001). Hierarchical clustering identified luminal tumors of high KRT20 mRNA expression being associated with high pCR rate (10/16; 63%), while the double-negative subgroup with high FGFR1 expression did not respond with pCR (0/9; 0%). Molecular subtyping distinguishes patients with high probability of response from tumors as resistant to neoadjuvant chemotherapy. Targeting FGFR1 in less-differentiated bladder cancer subgroups may sensitize tumors for adopted treatments or subsequent chemotherapy.

Bryostatin-1 Attenuates Ischemia-Elicited Neutrophil Transmigration and Ameliorates Graft Injury after Kidney Transplantation.

Ischemia reperfusion injury (IRI) is a form of sterile inflammation whose severity determines short- and long-term graft fates in kidney transplantation. Neutrophils are now recognized as a key cell type mediating early graft injury, which activates further innate immune responses and intensifies acquired immunity and alloimmunity. Since the macrolide Bryostatin-1 has been shown to block neutrophil transmigration, we aimed to determine whether these findings could be translated to the field of kidney transplantation. To study the effects of Bryostatin-1 on ischemia-elicited neutrophil transmigration, an in vitro model of hypoxia and normoxia was equipped with human endothelial cells and neutrophils. To translate these findings, a porcine renal autotransplantation model with eight hours of reperfusion was used to study neutrophil infiltration in vivo. Graft-specific treatment using Bryostatin-1 (100 nM) was applied during static cold storage. Bryostatin-1 dose-dependently blocked neutrophil activation and transmigration over ischemically challenged endothelial cell monolayers. When applied to porcine renal autografts, Bryostatin-1 reduced neutrophil graft infiltration, attenuated histological and ultrastructural damage, and improved renal function. Our novel findings demonstrate that Bryostatin-1 is a promising pharmacological candidate for graft-specific treatment in kidney transplantation, as it provides protection by blocking neutrophil infiltration and attenuating functional graft injury.