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BACKGROUND: Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA). METHODS: A multi-omics analysis on 389 BLCA and 35 adjacent normal tissues from a cohort of OMPU-NCC Consortium Japan was retrospectively performed by integrating the whole-exome and RNA-sequence dataset and clinicopathological record. A median follow-up duration of all BLCA cohort was 31 months. RESULTS: FGFR3 alterations (aFGFR3), including recurrent mutations and fusions, accounted for 44% of non-muscle invasive bladder cancer (NMIBC) and 15% of muscle-invasive bladder cancer (MIBC). Within MIBC, the consensus subtypes LumP was significantly more prevalent in aFGFR3, whereas the Ba/Sq subtype exhibited similarity between intact FGFR3 (iFGFR3) and aFGFR3 cases. We revealed that basal markers were significantly increased in MIBC/aFGFR3 compared to MIBC/iFGFR3. Transcriptome analysis highlighted TIM3 as the most upregulated immune-related gene in iFGFR3, with differential immune cell compositions observed between iFGFR3 and aFGFR3. Using EcoTyper, TME heterogeneity was discerned even within aFGFR cases, suggesting potential variations in the response to checkpoint inhibitors (CPIs). Among 72 patients treated with CPIs, the objective response rate (ORR) was comparable between iFGFR3 and aFGFR3 (20% vs 31%; p = 0.467). Strikingly, a significantly higher ORR was noted in LumP/aFGFR3 compared to LumP/iFGFR3 (50% vs 5%; p = 0.022). This trend was validated using data from the IMvigor210 trial. Additionally, several immune-related genes, including IDO1, CCL24, IL1RL1, LGALS4, and NCAM (CD56) were upregulated in LumP/iFGFR3 compared to LumP/aFGFR3 cases. CONCLUSIONS: Differential pathways influenced by aFGFR3 were observed between NMIBC and MIBC, highlighting the upregulation of both luminal and basal markers in MIBC/aFGFR3. Heterogeneous TME was identified within MIBC/aFGFR3, leading to differential outcomes for CPIs. Specifically, a favorable ORR in LumP/aFGFR3 and a poor ORR in LumP/iFGFR3 were observed. We propose TIM3 as a potential target for iFGFR3 (ORR: 20%) and several immune checkpoint genes, including IDO1 and CCL24, for LumP/iFGFR3 (ORR: 5%), indicating promising avenues for precision immunotherapy for BLCA.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias de la Vejiga Urinaria , Humanos , Pronóstico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Biomarcadores de Tumor/genética , Estudios Retrospectivos , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Microambiente Tumoral , Receptor 2 Celular del Virus de la Hepatitis A , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Emerging evidence suggests that the presence of tertiary lymphoid structures (TLS) and neutrophil-lymphocyte ratio (NLR) in peripheral blood is associated with the treatment response to checkpoint inhibitors (CPIs), whereas there is limited knowledge regarding whether these factors reciprocally impact the treatment outcomes of CPIs in metastatic urothelial carcinoma (mUC). Herein, we investigated treatment outcomes of platinum-refractory mUC patients (50 cases with whole-exome and transcriptome sequencing) treated with pembrolizumab. The pathological review identified 24% of cases of TLS in the specimens. There was no significant difference in the NLR between the TLS- and TLS+ groups (p = 0.153). In the lower NLR group, both overall survival and progression-free survival were significantly longer in patients with TLS than in those without TLS, whereas the favorable outcomes associated with TLS were not observed in patients in the higher NLR group. We explored transcriptomic differences in UC with TLS. The TLS was comparably observed between luminal (20%) and basal (25%) tumor subtypes (p = 0.736). Exploring putative immune-checkpoint genes revealed that ICOSLG (B7-H2) was significantly increased in tumors with lower NLR. KRT expression levels exhibited higher basal cell markers (KRT5 and KRT17) in the higher NLR group and lower differentiated cell markers (KRT8 and KRT18) in patients with TLS. In conclusion, the improved outcomes of pembrolizumab treatment in mUC are restricted to patients with lower NLR. Our findings begin to elucidate a distinct molecular pattern for the presence of TLS according to the NLR in peripheral blood.
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Carcinoma de Células Transicionales , Estructuras Linfoides Terciarias , Neoplasias de la Vejiga Urinaria , Humanos , Neutrófilos , Linfocitos , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: It is well known that patients with objective response to pembrolizumab have a durable duration of response leading to favorable survival outcomes. We investigated the possibility of predicting the objective response with concise indicators obtained from daily clinical practice. Methods In our multi-institutional cohort, 220 platinum-refractory metastatic urothelial carcinomas (mUC) treated with pembrolizumab for at least six weeks with complete information of objective response were investigated. Results The median follow-up was 7.3 months, and 119 patients deceased during the follow-up. A multivariate logistic regression analysis exhibited two independent variables predicting the objective response, including the neutrophil-lymphocyte ratio (NLR) change at six weeks of treatment and liver metastasis. We proposed a risk group using these two indicators. Patients with no predictive indicators / one of those were assigned to favorable (42%) / intermittent (47%) risk groups. Patients with both indicators were assigned to poor risk (11%). Notably, the objective response rate was well delineated in 41%, 25%, and 0% for favorable, intermediate, and poor risk groups, respectively (p<0.001). Distinct overall survival (OS) between the risk groups was also confirmed with the median OS of 14.1, 11.7, and 4.2 months in favorable, intermediate, and poor risk groups, respectively. CONCLUSIONS: At the six weeks of the pembrolizumab treatment, our risk model predicts the objective response rate precisely. Notably, those classified as 'poor risk'-marked by liver metastasis and a heightened NLR-should be considered for alternative therapy with a different mode of action, highlighting a critical decision point in treatment optimization.
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PURPOSE: This study investigates the utility of ureteroscopic surgery (URS) as an alternative to radical nephroureterectomy (RNU) in managing upper tract urothelial carcinoma (UTUC), with a focus on survival outcomes and re-evaluation of current the European Association of Urology guidelines criteria. METHODS: We conducted a retrospective, multi-institutional review of 143 UTUC patients treated with URS (n = 35) or RNU (n = 108). Clinicopathological factors were analyzed, and survival outcomes were assessed using Kaplan-Meier analysis and Cox proportional-hazards models. RESULTS: The median follow-up period was 27 months. Overall survival (OS) and radiographic progression-free survival (rPFS) were comparable between the URS and RNU groups (OS: HR 2.42, 95% CI 0.63-9.28, P = 0.0579; rPFS: HR 1.82, 95% CI 0.60-5.47, P = 0.1641). URS conferred superior renal function preservation. In patients characterized by factors such as radiographically invisible lesions, negative cytology, pTa stage, low-grade tumors, and multiple lesions, the OS outcomes with URS were comparable to those with RNU as follows: radiographically invisible lesions (P = 0.5768), negative cytology (P = 0.7626), pTa stage (P = 0.6694), low-grade tumors (P = 0.9870), and multiple lesions (P = 0.8586). CONCLUSION: URS offers survival outcomes similar to RNU, along with better renal function preservation, especially in low-risk UTUC patients. These findings underscore the urgency of re-evaluating the current EAU guidelines and encourage further research into determining the ideal patient selection for URS in UTUC treatment.
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Carcinoma de Células Transicionales , Neoplasias Ureterales , Neoplasias de la Vejiga Urinaria , Humanos , Nefroureterectomía , Neoplasias de la Vejiga Urinaria/cirugía , Carcinoma de Células Transicionales/patología , Ureteroscopía , Estudios Retrospectivos , Neoplasias Ureterales/patología , Nefronas/cirugía , Nefronas/patologíaRESUMEN
BACKGROUND: Immune checkpoint inhibitors can cause various immune-related adverse events (irAEs). This study aimed to evaluate the association between the incidence of irAEs and oncological outcomes of metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab as first-line therapy. PATIENTS AND METHODS: We retrospectively analyzed data from 69 patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy between September 2018 and September 2021 at 4 institutions. Cox regression analyses were performed to investigate the important factors affecting overall survival (OS) in patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy. RESULTS: During observation with a median follow-up of 9.1 months, the median OS was not reached, while the median progression-free survival was 6.0 months. Patients with irAEs had significantly prolonged OS and progression-free survival than those without irAEs (p = .012 and .002, respectively). Multivariate analysis showed that 3 independent factors, including C-reactive protein (CRP), irAEs, and performance status (PS), were significantly associated with OS (p = .04, .02, and .01, respectively). The patients were subsequently divided into 3 groups as follows: group 1, 20 patients with all 3 independent OS predictors; group 2, 18 patients with irAE predictors alone or 2 positive independent OS predictors (irAEs + CRP or irAEs + PS); group 3, 31 patients with 3 negative independent S predictors. OS varied significantly among the 3 groups (p = .004). CONCLUSION: The appearance of irAEs could predict OS in patients with mRCC treated with nivolumab plus ipilimumab as the first-line therapy.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Nivolumab , Ipilimumab/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Estudios Retrospectivos , PronósticoRESUMEN
Background and Purpose: Pembrolizumab has now become a standard of care in metastatic urothelial carcinoma (mUC), although the treatment effect of the drug substantially differs among individuals. Emerging evidence suggests that radiotherapy exerts a synergistic effect with PD-1 blockade. We sought to elucidate the survival outcomes in patients who underwent palliative radiation with the pembrolizumab treatment. Methods: We retrospectively investigated our multi-institutional dataset of 235 platinum-refractory mUC patients treated with pembrolizumab as second-line treatment, collected from January 2018 and October 2021. Propensity score matching was performed to reduce biases by potential confounding factors for overall survival (OS). Results: With a median follow-up of 6.8 months, the median OS from the initiation of pembrolizumab was 13 months in 235 patients. Palliative radiation was performed in 71 (30.2%) patients for whom the median radiation dose and fraction were 30 Gy and 10 fractions, respectively. Irradiated sites were bone in 24 (33.8%), lymph node in 17 (23.9%), lung in 3 (4.2%), brain in 8 (11.3%), and other sites in 19 (26.8%). OS from the initiation of pembrolizumab was significantly longer in patients who underwent concurrent palliative radiation with pembrolizumab (39 patients: median OS: 21 months) than in both patients with palliative radiation before pembrolizumab (32 patients: median OS: 9 months) (p = 0.001) and those without palliative radiation throughout the follow-up (164 patients: median OS: 13 months) (p = 0.019). After the propensity-score matching by putative confounding factors, longer OS in patients treated with concurrent palliative radiation with pembrolizumab (n = 36) was still observed compared to patients without the concurrent palliative radiation (n = 36) in the pair matched cohort (median OS of 29 and 13 months, respectively, p = 0.033). Conclusions: Our findings suggest that the concurrent administration of palliative radiation with pembrolizumab offers a favorable effect on OS in platinum-refractory mUC patients.
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BACKGROUND: There is little evidence of abiraterone acetate (AA) plus prednisone for patients with non-metastatic castration-resistant prostate cancer (nmCRPC). In this study, we conducted a comparative analysis of real-world survival outcomes between AA plus prednisone and enzalutamide (Enz) in patients with nmCRPC, utilizing our consortium dataset. MATERIALS AND METHODS: The clinical records of 133 nmCRPC patients treated with first-line Enz or AA plus prednisone were analyzed. The primary endpoints of the study were overall survival (OS) and cancer-specific survival (CSS). Cumulative incidence function (CIF) using Fine and Gray models was also utilized to assess non-cancer-caused death considering the competing risk of cancer-caused death. RESULTS: During a median follow-up of 36 months, 34 patients (25.6%) had deceased, with a median OS of 99 months in the entire cohort. There were no significant differences in comorbidities between the Enz and AA groups. Time to PSA progression (TTPP: HR 0.81, 95% CI 0.51-1.30, P = 0.375) and CSS (HR 1.32, 95% CI 0.55-3.44, P = 0.5141) were comparable between the two groups. However, intriguingly, there was a trend towards shorter OS in patients treated with AA plus prednisone compared to Enz (HR 0.57, 95% CI 0.29-1.12, P = 0.0978, median of 99 and 69 months in Enz and AA groups, respectively). CIF analysis revealed that nmCRPC patients treated with AA plus prednisone were more likely to result in non-cancer-caused death than those treated with Enz (HR 5.22, 95% CI 1.88-14.50, P = 0.0014). CONCLUSIONS: Our real-world survival analysis suggests that while AA plus prednisone may demonstrate comparable treatment efficacy to Enz in the context of nmCRPC, there may be an increased risk of non-cancer-caused death. Physicians should take into consideration this information when making treatment decisions for patients with nmCRPC.
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Acetato de Abiraterona , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Acetato de Abiraterona/uso terapéutico , Prednisona/uso terapéutico , Feniltiohidantoína/uso terapéutico , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Serum C-reactive protein (CRP) is known to be a biomarker for systemic inflammatory reactions. In the present study, we sought to measure the predictive value of serum CRP level for metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab and nivolumab using our real-world clinical dataset including non-clear cell RCC (nccRCC). The clinical record of patients who underwent the first-line ipilimumab plus nivolumab treatment for mRCC including ccRCC and nccRCC from 2018 to 2021 was retrospectively analyzed. All patients were diagnosed with either intermediate or poor-risk group defined by IMCD (international metastatic RCC database consortium). In total, 74 patients were involved. The median age was 68 years and 24 (32.4%) patients deceased during the follow-up. Forty-five (61%) and 29 (39%) patients were classified into intermediate and poor-risk groups. The one-year overall survival (OS) rate and objective response rate were 65% and 41% for all 74 mRCC patients, respectively. The receiver operating characteristic curve identified 1.0 mg/dL of serum CRP level as an ideal cut-off for predicting overall survival (OS). Serum CRP > 1.0 mg/dL and nccRCC were the independent predictors for OS in 74 mRCC patients. OS for patients with CRP > 1 mg/dL was significantly shorter than those with CRP < 1 mg/dL in both ccRCC (58 patient: p = 0.009) and nccRCC (16 patients: p = 0.008). The present study indicated that serum CRP level is a prognostic indicator for OS in both ccRCC and nccRCC patients treated with the first-line ipilimumab plus nivolumab treatment.