A narrative review of management of muscle-invasive bladder cancer perioperative period: will continuous and combined treatment be the new trend?

Background and Objective: With the emergence of immunotherapy and targeted therapies, there are more options for the perioperative period management of muscle-invasive bladder cancer (MIBC), and various types of clinical studies are emerging, leading to the need to explore ways to choose the optimal treatment modality. This review aims to synthesize past and present treatment modalities and to explore future trends in the perioperative period cares of MIBC for the benefit of clinical practitioners. Methods: A non-systematic, literature search was conducted between March 5, 2023 and November 30, 2023 on PubMed using "perioperative period", "MIBC", "chemotherapy", "radiotherapy", "immunotherapy", "targeted treatment" and "combination" as keywords, along with a search for ongoing clinical studies that were related to the perioperative period of MIBC on classic.clinicaltrials.gov, some latest conference abstracts were also included as references. Key Content and Findings: The trend towards benefit from adjuvant chemotherapy in perioperative chemotherapy is gradually being recognized. Neoadjuvant immunotherapy, including single-agent immunization, like programmed cell death protein 1 (PD-1) inhibitors, programmed cell death 1 ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, and double-immunization, has been confirmed by several clinical studies to be beneficial to clinical remission rates, and the combination regimen is superior to single-agent therapy. Targeted therapies such as antibody-drug conjugate (ADC) are entering MIBC perioperative studies. Multiple sequential and combination clinical studies are gradually disclosing preliminary data on efficacy and safety. Conclusions: Immunotherapy would become an essential perioperative treatment for MIBC, and continuous and integrated perioperative management may become the MIBC treatment mode of the future. ADC medicines will also be a hot research focus in the coming years.

Identifying Optimal Candidates for Trimodality Therapy among Nonmetastatic Muscle-Invasive Bladder Cancer Patients.

(1) Background: This research aims to identify candidates for trimodality therapy (TMT) or radical cystectomy (RC) by using a predictive model. (2) Methods: Patients with nonmetastatic muscle-invasive bladder cancer (MIBC) in the Surveillance, Epidemiology, and End Results (SEER) database were enrolled. The clinical data of 2174 eligible patients were extracted and separated into RC and TMT groups. To control for confounding bias, propensity score matching (PSM) was carried out. A nomogram was established via multivariable logistic regression. The area under the receiver operating characteristic curve (AUC) and calibration curves were used to assess the nomogram's prediction capacity. Decision curve analysis (DCA) was carried out to determine the nomogram's clinical applicability. (3) Results: After being processed with PSM, the OS of the RC group was significantly longer compared with the TMT group (p < 0.001). This remarkable capacity for discrimination was exhibited in the training (AUC: 0.717) and validation (AUC: 0.774) sets. The calibration curves suggested acceptable uniformity. Excellent clinical utility was shown in the DCA curve. The RC and RC-Beneficial group survived significantly longer than the RC and TMT-Beneficial group (p < 0.001) or the TMT group (p < 0.001). However, no significant difference was found between the RC and TMT-Beneficial group and the TMT group (p = 0.321). (4) Conclusions: A predictive model with excellent discrimination and clinical application value was established to identify the optimal patients for TMT among nonmetastatic MIBC patients.

Dermatophagoides Pteronyssinus 1 (DerP1) May Trigger NLRP3-Mediated Corneal Epithelial Cell Pyroptosis by Elevating Interleukin-33 Expression Levels.

PURPOSE: To characterize the in vivo effects of Dermatophagoides pteronyssinus 1 (DerP1) in mice and determine the underlying NLRP3 inflammasome-mediated pyroptosis signaling mechanisms in the human corneal epithelial cells (HCECs). METHODS: DerP1 was used to induce allergic conjunctivitis in C57 mice. HCECs were sensitized with DerP1 in vitro to mimic their condition observed in allergic conjunctivitis in vivo. Transmission electron microscopy was used to evaluate pyroptosis in the HCECs, enzyme-linked immunosorbent assays to assess interleukin (IL)-33, IL-1ß and IL-4 levels, flow cytometry to detect the proportion of Th2 cells, MTT assays to assess cell metabolic activity, immunofluorescence to evaluate the effects of DerP1 on functional HCEC phenotypes, and Western blot assays to detect the expression of NOD-like receptor family pyrin domain-containing 3 (NLRP3), gasdermin D (GSDMD), N-terminal fragment of GSDMD (GSDMD-N), pro-caspase-1, cleaved caspase-1, IL-1ß, and IL-33. IL-33 expression in the HCECs was knocked down via lentivirus transfection. RESULTS: In vivo, DerP1 promotes pyroptosis, production of Th2 inflammatory cytokines and IL-33, and NLRP3 activation in mouse corneas. In vitro, pyroptotic bodies were found in the HCECs after sensitization with DerP1. Various concentrations of DerP1 increased the expression levels of NLRP3, GSDMD, GSDMD-N, pro-caspase-1, cleaved caspase-1, and IL-1ß in the HCECs, with the largest increase observed after exposure to 20 µM DerP1. In vitro, recombinant human IL-33 mediated the expression of pyroptotic biomarkers in the HCECs, whereas IL-33 silencing diminished 20 µM DerP1-induced increase in their expression levels. CONCLUSIONS: DerP1 induces pyroptosis and allergic conjunctivitis, the expression of Th2 inflammatory cytokines, NLRP3 activation, and IL-33 in mouse corneas in our model. These effects would attribute to its activating NLRP3-GSDMD signaling pathway axis via enhancing IL-33 expression in HCECs.

A Prognostic Nomogram Based on Log Odds of Positive Lymph Nodes to Predict Overall Survival for Non-Metastatic Bladder Cancer Patients after Radical Cystectomy.

(1) Purpose: The purpose of this study was to evaluate the prognostic capacity of the pathological N status (pN), lymph node ratio (LNR), and the log odds of positive lymph nodes (LODDS), and to build a prognostic nomogram to predict overall survival (OS) for bladder cancer patients treated by radical cystectomy. (2) Methods: The clinical and pathological characteristics of 10,938 patients with bladder cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2017. The predictive capacity was assessed by univariate and multivariate Cox regression analyses, the area under the receiver operating characteristic curve (AUC), and C-index. Calibration curves, decision curve analysis (DCA), and risk-grouping were utilized to evaluate the predictive accuracy and discriminative ability of the nomogram. (3) Results: LODDS was an independent risk factor for bladder cancer (all p < 0.001) and demonstrated the highest values of C-index and AUC. The values of AUCs in the training cohort were 0.747, 0.743, and 0.735 for predicting 1-, 3-, and 5-year OS, respectively. Calibration curves and DCA curves suggested the excellent clinical application value of our nomogram. (4) Conclusions: LODDS is a better predictive indicator for bladder cancer patients compared to pN and LNR. The LODDS-incorporated nomogram has excellent accuracy and promising clinical application value for non-metastatic bladder cancer after radical cystectomy.