[Radical cystectomy in the geriatric population. Tools for screening postoperative complications]. / Cystectomie radicale chez les patients gériatriques. Outils de dépistage des complications postopératoires.

Radical cystectomy is the gold standard for the treatment of muscle-invasive bladder cancer. Advanced age is only a relative criterion when selecting patients eligible for radical cystectomy, and to reduce post-operative complications, the management of an elderly patient requires a multidisciplinary approach. The role of the geriatrician is therefore essential, in collaboration with the urologist, to ensure appropriate follow-up. A series of preoperative screening tests should be used to identify frailer patients who are at high risk of developing complications, so that appropriate follow-up can be carried out.

La cystectomie radicale est le traitement de choix du cancer de la vessie musculo-invasif. L'âge avancé ne représente qu'un critère relatif lors de la sélection des patients éligibles à une cystectomie radicale. Afin de réduire les complications postopératoires, la prise en charge d'un patient âgé nécessite une approche multidisciplinaire. Le rôle du gériatre est donc essentiel, en collaboration avec l'urologue, afin d'assurer un suivi approprié. Une série de tests de dépistage préopératoires identifie les patients plus fragiles, présentant un risque accru de complications, et permet de réaliser un suivi adapté.

[Bladder cancer : a comprehensive follow-up for an efficient and personalized care]. / Cancer de la vessie : un suivi personnalisé pour une prise en charge efficiente.

Bladder cancer is a common cancer in the Swiss population. The heterogeneous nature of the disease requires long-term oncological monitoring, as well as metabolic and functional follow-up. Patients' quality of life must also be considered during follow-up.

Le cancer de la vessie est fréquent dans la population suisse. Son évolution étant hétérogène, cela nécessite une surveillance oncologique sur le long terme, mais également un suivi sur les plans métabolique et fonctionnel. La qualité de vie des patients doit aussi être considérée pendant le suivi.

[A Swiss Urological Society register of cystectomies to improve surgical quality]. / Un registre des cystectomies de la Société suisse d'urologie pour une meilleure qualité chirurgicale.

In the era of highly specialised medicine, the Swiss Urological Society has set up a national register from January 2019 that will prospectively record all data relating to cystectomies. Doctors will be able to use this information to compare their activities at national level, refine surgical techniques and optimise the perioperative management of cystectomy patients. This article presents the register and provides an initial assessment of cystectomy surgery activity in Switzerland over the first four years of its set up.

Dans l'ère de la médecine hautement spécialisée, la Société suisse d'urologie a mis au point dès janvier 2019 un registre national permettant de répertorier prospectivement l'ensemble des données relatives aux cystectomies. Les médecins profitent de ces renseignements pour comparer leur activité au niveau national, affiner les techniques chirurgicales et optimiser la prise en charge périopératoire des patients opérés d'une cystectomie. Cet article est consacré à la présentation du registre et offre un bilan initial de l'activité chirurgicale de cystectomie en Suisse au cours des quatre premières années de sa mise en place.

Impact of Enhanced Recovery after Surgery® Protocol Compliance on Length of Stay, Bowel Recovery and Complications after Radical Cystectomy.

BACKGROUND: Despite existing standardized surgical techniques and the development of new perioperative care protocols, radical cystectomy (RC) morbidity remains a serious challenge for urologists. Postoperative ileus (POI) is one of the most common postoperative complications, often leading to a longer length of stay (LOS). The aim of our study was to assess the impact of compliance to the Enhanced Recovery After Surgery (ERAS®) protocol on bowel recovery, 30-day complications and LOS after RC for bladder cancer (BC). METHODS: Data from consecutive patients undergoing RC for BC within an ERAS® dedicated protocol were analyzed. Exclusion criteria were urinary diversion other than ileal conduit and palliative RC. Patients were divided into two groups according to their compliance (A: low-compliance and B: high-compliance). ERAS® compliance was extracted from the ERAS® Interactive Audit System (EIAS) database. Postoperative complications were prospectively recorded by a dedicated study nurse 30 days after RC. POI was defined as the placement of a nasogastric tube. Logistic regression analysis was used to identify predictors of 30-day complications and POI. RESULTS: After considering the exclusion criteria, 108 patients were included for the final analysis. The median global compliance to the ERAS® protocol was 61%. A total of 78 (72%) patients had a compliance <65% (group A), while the remaining 30 (28%) had a compliance >65% (group B). No significant differences were found among the two groups regarding the 30-day complication rate (86% in group A versus 73% in group B, p = 0.82) and LOS (14 days in group A versus 15 days in group B, p = 0.82). The time to stool was significantly shorter in group B (4 days versus 6 days, p = 0.02), and the time to tolerate solid food was slightly faster in group B but not significant (8 versus 7 days, p = 0.23). The POI rate was significantly lower in patients with a higher ERAS® compliance (20% versus 46%, p = 0.01). A multivariate analysis showed that ERAS® compliance was not significantly associated with 30-day total complications. However, a lower compliance to the ERAS® protocol and age > 75 years were significant independent predictors of POI. CONCLUSIONS: Our study provides further evidence to support the beneficial effect of the ERAS® protocol in patients undergoing RC, particularly in terms of facilitating a faster recovery of bowel function and preventing POI. Future research should focus on investigating novel approaches and interventions to improve compliance with the ERAS® protocol. This may involve patient education, multidisciplinary teamwork, and continuous quality improvement initiatives.

Respiratory Complications after Cystectomy with Urinary Diversion: Avoidable Complications or Ineluctable Destiny?

Background: Cystectomy with urinary diversion (CUD) is a highly morbid surgery. Despite implementing an enhanced recovery after surgery (ERAS®) protocol, postoperative respiratory complications (PRC) within 30 days after surgery remain frequent. This study aims to identify patients at higher risk of developing PRC after CUD. Methods: We conducted a retrospective analysis of 242 patients who underwent CUD at Lausanne University Hospital from 2012 to 2022, adhering to ERAS® guidelines. Data on postoperative complications, including pneumonia, respiratory failure, pulmonary embolism, lobar atelectasis, and pleural effusion, were analyzed. Chi-square and Mann-Whitney U tests compared patients with and without PRC. A multivariable Cox model identified independent prognostic factors. Results: PRC occurred in 41 patients (17%). Those with PRC experienced longer hospital stays and higher 30-day mortality rates. Poor ERAS® compliance was a significant risk factor. Multivariable analysis showed pneumonia was associated with postoperative ileus, while pulmonary embolism correlated with infectious and cardiovascular complications. Conclusions: PRC result in extended hospitalization and decreased survival. Rigorous adherence to ERAS® protocols, including early mobilization, respiratory physiotherapy, and avoiding nasogastric tubes, is essential for preventing PRC.

UROPOT: study protocol for a randomized, double-blind phase I/II trial for metabolism-based potentiation of antimicrobial prophylaxis in the urological tract.

BACKGROUND: Urinary tract catheters, including Double-J or ureteral stents, are prone to bacterial colonization forming biofilms and leading to asymptomatic bacteriuria. In the context of asymptomatic bacteriuria, endourological procedures causing mucosa-inducing lesions can lead to severe infections. Antibiotic prophylaxis is warranted, yet its efficacy is limited by biofilm formation on stents. Biofilms promote antibiotic tolerance, the capacity of genetically susceptible bacteria to survive a normally lethal dose of antimicrobial therapy. The UROPOT study evaluates the effectiveness of a first-in-type metabolism-based aminoglycoside potentiation for (i) preventing infectious complications of asymptomatic bacteriuria during mucosa lesion-inducing endourological procedures and (ii) assessing its anti-tolerance efficacy. METHODS: The UROPOT trial is a phase I/II single-center (Lausanne University Hospital (CHUV), Switzerland) randomized double-blinded trial. Over 2 years, patients with asymptomatic Escherichia coli and/or Klebsiella pneumoniae bacteriuria, undergoing endourological procedures, will be randomly allocated to one of three treatment arms (1:1:1 randomization ratio, 30 patients per group) to evaluate the efficacy of mannitol-potentiated low-dose amikacin compared to established standard treatments (ceftriaxone or amikacin standard dose). Patients will be recruited at the CHUV Urology Outpatient Clinic. The primary outcome is the comparative incidence of postoperative urinary tract infections (assessed at 48 h) between the investigational amikacin/mannitol therapy and standard (ceftriaxone or amikacin) antibiotic prophylaxis, defined by specific systemic symptoms and/or positive blood and/or urine culture. Secondary outcomes include assessing microbiological eradication through anti-biofilm activity, sustained microbiological eradication, and mannitol and antibiotics pharmacokinetics in blood and urine. Safety outcomes will evaluate the incidence of adverse events following amikacin/mannitol therapy and postoperative surgical complications at postoperative day 14. DISCUSSION: UROPOT tests a novel antimicrobial strategy based on "metabolic potentiation" for prophylaxis enabling aminoglycoside dose reduction and targeting biofilm activity. The anti-biofilm effect may prove beneficial, particularly in patients who have a permanent stent in situ needing recurrent endourological manipulations strategies in preventing infections and achieving sustained microbiological eradication in pre-stented patients. TRIAL REGISTRATION: The protocol is approved by the local ethics committee (CER-VD, 2023-01369, protocole 2.0) and the Swiss Agency for Therapeutic Products (Swissmedic, 701,676) and is registered on the NIH's ClinicalTrials.gov (trial registration number: NCT05761405). Registered on March 07, 2023.

Intravesical Ty21a treatment of non-muscle invasive bladder cancer induces immune responses that correlate with safety and may be associated to therapy potential.

BACKGROUND: Standard of care treatment of non-muscle invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette Guérin (BCG) is associated with side effects, disease recurrence/progression and supply shortages. We recently showed in a phase I trial (NCT03421236) that intravesical instillation in patients with NMIBC with the maximal tolerated dose of Ty21a/Vivotif, the oral vaccine against typhoid fever, might have a better safety profile. In the present report, we assessed the immunogenicity of intravesical Ty21a in patients of the clinical trial that had received the maximal tolerated dose and compared it with data obtained in patients that had received standard BCG. METHODS: Urinary cytokines and immune cells of patients with NMIBC treated with intravesical instillations of Ty21a (n=13, groups A and F in NCT03421236) or with standard BCG in a concomitant observational study (n=12, UROV1) were determined by Luminex and flow cytometry, respectively. Serum anti-lipopolysaccharide Typhi antibodies and circulating Ty21a-specific T-cell responses were also determined in the Ty21a patients. Multiple comparisons of different paired variables were performed with a mixed-effect analysis, followed by Sidak post-test. Single comparisons were performed with a paired or an unpaired Student's t-test. RESULTS: As compared with BCG, Ty21a induced lower levels of inflammatory urinary cytokines, which correlated to the milder adverse events (AEs) observed in Ty21a patients. However, both Ty21a and BCG induced a Th1 tumor environment. Peripheral Ty21a-specific T-cell responses and/or antibodies were observed in most Ty21a patients, pointing the bladder as an efficient local immune inductive site. Besides, Ty21a-mediated stimulation of unconventional Vδ2 T cells was also observed, which turned out more efficient than BCG. Finally, few Ty21a instillations were sufficient for increasing urinary infiltration of dendritic cells and T cells, which were previously associated with therapeutic efficacy in the orthotopic mouse model of NMIBC. CONCLUSIONS: Ty21a immunotherapy of patient with NMIBC is promising with fewer inflammatory cytokines and mild AE, but induction of immune responses with possible antitumor potentials. Future phase II clinical trials are necessary to explore possible efficacy of intravesical Ty21a.

Intravesical Ty21a Treatment of Non-muscle-invasive Bladder Cancer Shows a Good Safety Profile.

Standard-of-care immunotherapy for non-muscle-invasive bladder cancer (NMIBC) with intravesical Bacillus Calmettte-Guérin (BCG) is associated with adverse events (AEs), disease recurrence/progression, and supply shortages. Preclinical data have shown that intravesical instillation of Ty21a/Vivotif, the oral vaccine against typhoid fever, may be an effective and safer alternative to BCG. We assessed the safety of intravesical Ty21a in NMIBC. For ethical reasons, patients with low- or intermediate-risk NMIBC not requiring BCG immunotherapy were enrolled. To determine the maximum tolerated dose, escalating doses of Ty21a/Vivotif were intravesically instilled in three patients once a week for 4 wk in phase 1a. In phase 1b, ten patients received the selected dose (1 × 108 CFU) once a week for 6 wk, as for standard BCG therapy. At this dose, all patients completed their treatment. Most patients experienced minor systemic AEs, while half reported mild local bladder AEs. AEs only occurred after one or two instillations for 40% of the patients. Ty21a bacteria were only recovered in three out of 72 urinary samples at 1 wk after instillation. Intravesical Ty21a might be well tolerated with no cumulative side effects, no fever >39 °C, and lower risk of bacterial persistence than with BCG. Ty21a treatment thus warrants clinical trials to explore its safety and antitumor efficacy in high-risk NMIBC. This trial is registered on ClinicalTrials.gov as NCT03421236. Patient summary: We examined the safety of a new intra-bladder immunotherapy for non-muscle-invasive bladder cancer as an alternative to the standard BCG treatment. Our data show that the Ty21a vaccine might be well tolerated. Further studies are needed to determine the safety and antitumor efficacy of this treatment.

Double Positive CD4+CD8+ T Cells Are Enriched in Urological Cancers and Favor T Helper-2 Polarization.

The immune system plays a central role in cancer development, showing both anti-tumor and pro-tumor activities depending on the immune cell subsets and the disease context. While CD8 T cells are associated with a favorable outcome in most cancers, only T helper type 1 (Th1) CD4 T cells play a protective role, in contrast to Th2 CD4 T cells. Double positive (DP) CD4+CD8+ T cells remain understudied, although they were already described in human cancers, with conflicting data regarding their role. Here, we quantified and phenotypically/functionally characterized DP T cells in blood from urological cancer patients. We analyzed blood leukocytes of 24 healthy donors (HD) and 114 patients with urological cancers, including bladder (n = 54), prostate (n = 31), and kidney (n = 29) cancer patients using 10-color flow cytometry. As compared to HD, levels of circulating DP T cells were elevated in all urological cancer patients, which could be attributed to increased frequencies of both CD4highCD8low and CD4+CD8high DP T-cell subsets. Of note, most CD4highCD8low DP T cells show a CD8αα phenotype, whereas CD4+CD8high cells express both CD8α and CD8ß subunits. Functional properties were investigated using ex-vivo generated DP T-cell clones. DP T cells from patients were skewed toward an effector memory phenotype, along with enhanced Th2 cytokine production. Interestingly, both CD8αα and CD8αß DP T cells were able to trigger Th2 polarization of naïve CD4 T cells, while restraining Th1 induction. Thus, these data highlight a previously unrecognized immunoregulatory mechanism involving DP CD4+CD8+ T cells in urological cancers.

ILC2-modulated T cell-to-MDSC balance is associated with bladder cancer recurrence.

Non-muscle-invasive bladder cancer (NMIBC) is a highly recurrent tumor despite intravesical immunotherapy instillation with the bacillus Calmette-Guérin (BCG) vaccine. In a prospective longitudinal study, we took advantage of BCG instillations, which increase local immune infiltration, to characterize immune cell populations in the urine of patients with NMIBC as a surrogate for the bladder tumor microenvironment. We observed an infiltration of neutrophils, T cells, monocytic myeloid-derived suppressor cells (M-MDSCs), and group 2 innate lymphoid cells (ILC2). Notably, patients with a T cell-to-MDSC ratio of less than 1 showed dramatically lower recurrence-free survival than did patients with a ratio of greater than 1. Analysis of early and later time points indicated that this patient dichotomy existed prior to BCG treatment. ILC2 frequency was associated with detectable IL-13 in the urine and correlated with the level of recruited M-MDSCs, which highly expressed IL-13 receptor α1. In vitro, ILC2 were increased and potently expressed IL-13 in the presence of BCG or tumor cells. IL-13 induced the preferential recruitment and suppressive function of monocytes. Thus, the T cell-to-MDSC balance, associated with a skewing toward type 2 immunity, may predict bladder tumor recurrence and influence the mortality of patients with muscle-invasive cancer. Moreover, these results underline the ILC2/IL-13 axis as a targetable pathway to curtail the M-MDSC compartment and improve bladder cancer treatment.

Immunoregulation of Dendritic Cell Subsets by Inhibitory Receptors in Urothelial Cancer.

Blockade of inhibitory receptors (IRs) overexpressed by T cells can activate antitumor immune responses, resulting in the most promising therapeutic approaches, particularly in bladder cancer, currently able to extend patient survival. Thanks to their ability to cross-present antigens to T cells, dendritic cells (DCs) are an immune cell population that plays a central role in the generation of effective antitumor T-cell responses. While IR function and expression have been investigated in T cells, very few data are available for DCs. Therefore, we analyzed whether DCs express IRs that can decrease their functions. To this end, we investigated several IRs (PD-1, CTLA-4, BTLA, TIM-3, and CD160) in circulating CD1c+ DCs, CD141+ DCs, and plasmacytoid DCs from healthy donors and patients with urothelial cancer (UCa). Different DC subsets expressed BTLA and TIM-3 but not other IRs. More importantly, BTLA and TIM-3 were significantly upregulated in DCs from blood of UCa patients. Locally, bladder tumor-infiltrating DCs also overexpressed BTLA and TIM-3 compared to DCs from paired nontumoral tissue. Finally, in vitro functional experiments showed that ligand-mediated engagement of BTLA and TIM-3 receptors significantly reduced the secretion of effector cytokines by DC subpopulations. Our findings demonstrate that UCa induces local and systemic overexpression of BTLA and TIM-3 by DCs that may result in their functional inhibition, highlighting these receptors as potential targets for UCa treatment. PATIENT SUMMARY: We investigated the expression and function of a panel of inhibitory receptors in dendritic cells (DCs), an immune cell subpopulation critical in initiation of protective immune responses, among patients with urothelial carcinoma. We found high expression of BTLA and TIM-3 by blood and tumor DCs, which could potentially mediate decreased DC function. The results suggest that BTLA and TIM-3 might be new targets for urothelial carcinoma treatment.

Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth.