Oncological outcomes of prophylactic urethrectomy at the time of radical cystectomy for bladder cancer: A nationwide multi-institutional study.

OBJECTIVES: To determine the effects of prophylactic urethrectomy (PU) on oncological and perioperative outcomes in patients with bladder cancer (BC) undergoing radical cystectomy (RC). METHODS: This retrospective study analyzed data on 1976 evaluable patients with BC who underwent RC. Patients were drawn from 36 institutions within the Japanese Urological Oncology Group. Oncological outcomes were compared using restricted mean survival times (RMSTs) based on inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves for non-urinary tract recurrence-free survival (NUTRFS), cancer-specific survival (CSS), and overall survival (OS). Interaction terms within IPTW-adjusted Cox regression models were examined to assess the heterogeneity of treatment effect based on the risk of urethral recurrence (UR). The association between PU, estimated blood loss (EBL), and the incidence of severe postoperative surgical complications (SPSCs) (Clavien-Dindo grade 3 or higher) was analyzed. RESULTS: Of 1976 patients, 1448 (73.3%) received PU. IPTW adjustment was used to balance baseline characteristics between the treatment groups. Within the 107-month window of patient monitoring, PU showed no survival benefits (NUTRFS difference: 0.2 months [95% confidence interval: -6.8 to 7.3]; CSS, 1.2 [-4.9 to 7.3]; OS, 0 [-6.5 to 6.5]). No significant interactions were observed with factors associated with UR, and PU was associated with unfavorable perioperative outcomes (EBL, 1179 mL vs. 983 mL; SPSC, 14.6% vs. 7.0%). CONCLUSIONS: This study showed that (1) PU was not associated with survival in patients with BC undergoing RC, regardless of UR-associated factors, and (2) PU was associated with unfavorable perioperative outcomes.

Current issues and management consensus of advanced prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference-JAPAN 2023.

OBJECTIVE: To evaluate and compare the voting results of Japanese urologists with the global panel at the Advanced Prostate Cancer Consensus Conference (APCCC) 2022. METHODS: Among the 198 questions discussed at the APCCC 2022, the APCCC-JAPAN 2023 focused on 14 key questions related to the management of advanced prostate cancer with insufficient high-level evidence based on their relevance to the Japanese cohort. A panel of six prostate cancer experts addressed these 14 questions and presented the latest evidence to Japanese urologists who voted on-site using a web-based system. The results were compared with those of APCCC 2022. RESULTS: This study found significant differences in the voting results between Japanese urologists and the global panel regarding several crucial issues related to advanced prostate cancer management. These differences were those observed in treatment preferences, monitoring strategies, and treatment choices in specific clinical scenarios. These findings highlight the need for a nuanced approach tailored to the unique challenges with considerations of the Japanese healthcare environment. CONCLUSIONS: APCCC-JAPAN 2023 provides valuable insights into the current clinical issues surrounding the management of advanced prostate cancer in Japan. The partial divergence in the consensus between Japanese urologists and the global panel underscores the importance of a context-specific approach. The results of this study provide practical guidance for physicians facing complex challenges and should be used to inform decision-making in the management of advanced prostate cancer.

Extracellular vesicles as novel uro-oncology biomarkers: insights toward clinical applications.

PURPOSE OF REVIEW: We discussed the challenges associated with the clinical application of extracellular vesicles and summarized their potential impact on oncological clinical practice in urology. RECENT FINDINGS: Despite extensive research on extracellular vesicles, their clinical applications remain limited; this is likely to be because of small study cohorts, a lack of large-scale analyses, and the impact of variable extraction and storage methods on analysis outcomes. However, promising results have emerged from clinical trials targeting urinary extracellular vesicles in prostate cancer using ExoDx Prostate Test. The ExoDx Prostate Test has demonstrated its efficacy in diagnosing prostate cancer in previous studies and is the only FDA-approved kit for this purpose. Moreover, recent trials have investigated the use of the ExoDx Prostate Test to determine the optimal timing for biopsies in prostate cancer patients undergoing active surveillance. SUMMARY: We summarized recent studies on the potential of extracellular vesicles in the management of urological cancers. Particularly, the diagnosis of prostate cancer using the ExoDx Prostate Test has yielded positive results in several clinical trials. Additionally, while there are other studies suggesting its efficacy, most of these are based on retrospective analyses. These findings warrant further large-scale studies to optimize extracellular vesicle-based diagnostic and monitoring strategies. Although further research is required, extracellular vesicles would be attractive for early detection and surveillance.

Perioperative renal function change and oncological outcomes of radical nephroureterectomy in patients with upper tract urothelial carcinoma: A multicenter retrospective study.

BACKGROUND: The effect of radical nephroureterectomy (RNUx) on postoperative renal function in patients diagnosed with upper tract urothelial carcinoma (UTUC) has not been thoroughly explored. METHODS: We conducted a retrospective analysis including 785 patients who underwent RNUx for UTUC. We assessed the preoperative and postoperative estimated glomerular filtration rates (eGFRs) and factors related to the decline in eGFR. Additionally, we examined the effect of comorbidities (diabetes or hypertension) on the postoperative eGFR at 1 year. Cox proportional hazard models were employed to investigate the clinical effect of RNUx on oncological outcomes, including non-urothelial tract recurrence-free survival (NUTRFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: The median preoperative and postoperative eGFR levels were 54.7 and 40.6 ml/min/1.73 m2 respectively. The proportions of patients with preoperative and postoperative eGFR ≥60 mL/min/1.73 m2 were 35.9% and 5.1%, respectively. The median decline in the eGFR after surgery was 26.8%. Patients with preoperative eGFR <60 ml/min/1.73 m2 demonstrated significantly lower odds of a postoperative decline in eGFR of 25% or more. The effect of comorbidities on postoperative eGFR at 1 year was significant (P = 0.048). The 3-year NUTRFS, CSS, and OS rates were 72.9%, 85.2%, and 81.5%, respectively. Preoperative chronic kidney disease was an independent factor associated with inferior NUTRFS, CSS, and OS. CONCLUSION: Different degrees of impairment of renal function occur among UTUC patients. Only 5.1% of patients retain a postoperative eGFR ≥60 ml/min/1.73 m2. Preoperative renal impairment was linked to reduced odds of postoperative eGFR decrease and associated with survival. In addition, the presence of comorbidities had a significant effect on the decline in eGFR. These findings emphasize the importance of developing evidence-based perioperative treatment strategies for UTUC patients with impaired renal function.

Effectiveness and safety of granulocyte colony-stimulating factor priming regimen for acute myeloid leukemia: A systematic review and meta-analysis of the Clinical Practice Guideline for the use of G-CSF 2022 from the Japan Society of Clinical Oncology.

BACKGROUND: The outcomes of relapsed or refractory acute myeloid leukemia (AML) remain poor. Although the concomitant use of granulocyte colony-stimulating factor (G-CSF) and anti-chemotherapeutic agents has been investigated to improve the antileukemic effect on AML, its usefulness remains controversial. This study aimed to investigate the effects of G-CSF priming as a remission induction therapy or salvage chemotherapy. METHODS: We performed a thorough literature search for studies related to the priming effect of G-CSF using PubMed, Ichushi-Web, and the Cochrane Library. A qualitative analysis of the pooled data was performed, and risk ratios (RRs) with confidence intervals (CIs) were calculated and summarized. RESULTS: Two reviewers independently extracted and accessed the 278 records identified during the initial screening, and 62 full-text articles were assessed for eligibility in second screening. Eleven studies were included in the qualitative analysis and 10 in the meta-analysis. A systematic review revealed that priming with G-CSF did not correlate with an improvement in response rate and overall survival (OS). The result of the meta-analysis revealed the tendency for lower relapse rate in the G-CSF priming groups without inter-study heterogeneity [RR, 0.91 (95% CI 0.82-1.01), p = 0.08; I2 = 4%, p = 0.35]. In specific populations, including patients with intermediate cytogenetic risk and those receiving high-dose cytarabine, the G-CSF priming regimen prolonged OS. CONCLUSIONS: G-CSF priming in combination with intensive remission induction treatment is not universally effective in patients with AML. Further studies are required to identify the patient cohort for which G-CSF priming is recommended.

Exploring animal protein sources against prevent age-related short-term memory decline in mice: Dietary fish (Alaska Pollock) protein exhibits superior protective effects.

Dietary factors, particularly proteins, have been extensively explored to combat cognitive impairment. We have previously reported that dietary fish (Alaska Pollock) protein (APP) is more effective than casein (CAS) or fish oil in maintaining short-term memory in senescence-accelerated mice prone 10 (SAMP10). To examine the specificity of the protective effect of APP intakes against short-term memory decline, we assessed the impact of various dietary animal proteins, including APP, CAS, chicken breast protein (CP), and whey protein (WP), against age-related cognitive function in SAMP10 mice. After feeding the experimental diets for 5 months, memory was assessed using the Y-maze. The APP group exhibited a significant increase in spontaneous alternation behavior as an indicator of working memory when group compared with groups fed with other protein source. Additionally, the APP group displayed significantly higher neurofilament heavy chain positivity than the CAS and CP groups, as evidenced immunohistochemical analysis. Gut microbiota analysis indicated that dietary APP significantly enhanced the relative abundance of Lactobacillus, which positively correlated with spontaneous alternation behavior. Collectively, these findings suggest that dietary APP is more effective than CAS, CP, or WP in preventing age-related short-term memory decline and morphological abnormalities in the hippocampal axons of SAMP10 mice. Moreover, APP-mediated improvements in cognitive deficits may be associated with changes in microbiota diversity. PRACTICAL APPLICATION: This research suggests that dietary fish protein from Alaska Pollock may be more efficient in prevention short-term memory decline in mice, compared to other animal proteins. This finding has practical implications for nutritional optimization, developing the new health food products, and elucidating the relationship between the impact of specific proteins on gut microbiota and prevention of age-related cognitive decline.

C-Reactive Protein-Albumin Ratio Predicts Objective Response to Enfortumab Vedotin in Metastatic Urothelial Carcinoma.

BACKGROUND: Enfortumab vedotin (EV), an antibody-drug conjugate that targets Nectin-4, is used for patients with metastatic urothelial carcinoma who have experienced progression on platinum-based chemotherapy and checkpoint inhibitors. Despite the widespread use of the drug, evidence remains scarce regarding clinical indicators that can predict the response to EV treatment. OBJECTIVE: We aimed to explore the predictive value of clinical indicators derived from peripheral blood tests for treatment responses to EV. METHODS: We utilized records of 109 patients with metastatic urothelial carcinoma treated by EV from our multi-institutional dataset. Receiver operating characteristic curve analyses for predicting objective responses including several indicators from blood examinations, such as C-reactive protein-albumin ratio (CAR), hemoglobin, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and lactate dehydrogenase, were performed. The optimal cutoff points were determined by the Youden index. Logistic regression analyses for achieving objective responses to EV treatment were performed among these indicators. RESULTS: The median age of the cohort was 74 years, and the median follow-up duration was 10 months for the entire group. Median overall survival and progression-free survival from the initiation of EV were 12 and 6 months, respectively. The objective response rate and disease control rate were 48% and 70%, respectively. The receiver operating characteristic curve analysis aimed at predicting the achievement of an objective response to EV showed that the concordant index for the CAR was 0.774, significantly surpassing other indicators such as hemoglobin level, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and serum lactate dehydrogenase. The Youden index identified an optimal cutoff value of 1 for CAR (mg/L for C-reactive protein and g/dL for serum albumin level) in predicting the objective response to EV treatment. Using the cutoff value for the CAR, the cohort was divided into 32 patients (29%) with lower CAR and 77 patients (71%) with higher CAR. The objective response rate was observed to be 84% in the lower CAR group and 32% in the higher CAR group (p < 0.0001). A logistic regression analysis revealed that an Eastern Cooperative Oncology Group Performance Status ≥1 (p = 0.04) and a CAR ≥1 (p < 0.001) were identified as independent predictors for the objective response to EV. CONCLUSIONS: The evaluation of the CAR from a concise blood examination at the initiation of EV could effectively predict the treatment response to EV in patients with metastatic urothelial carcinoma after the progression of platinum-based chemotherapy and checkpoint inhibitors.

Enfortumab vedotin, an antibody-drug conjugate that targets Nectin-4, is currently used for patients with metastatic urothelial carcinoma who no longer respond to checkpoint inhibitors. In the present report, we investigated which clinical indicators can predict achieving an objective response to enfortumab vedotin at the initiation of treatment. Among the blood-based putative indicators, the C-reactive protein-albumin ratio showed the highest value for predicting the treatment response to enfortumab vedotin. As the C-reactive protein-albumin ratio can be easily assessed from blood tests, physicians can consider evaluating it at the start of the EV treatment.

Therapeutic use of granulocyte colony-stimulating factor (G-CSF) in patients with febrile neutropenia: a comprehensive systematic review for clinical practice guidelines for the use of G-CSF 2022 from the Japan Society of Clinical Oncology.

BACKGROUND: Febrile neutropenia represents a critical oncologic emergency, and its management is pivotal in cancer therapy. In several guidelines, the use of granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapy-induced febrile neutropenia is not routinely recommended except in high-risk cases. The Japan Society of Clinical Oncology has updated its clinical practice guidelines for the use of G-CSF, incorporating a systematic review to address this clinical question. METHODS: The systematic review was conducted by performing a comprehensive literature search across PubMed, the Cochrane Library, and Ichushi-Web, focusing on publications from January 1990 to December 2019. Selected studies included randomized controlled trials (RCTs), non-RCTs, and cohort and case-control studies. Evaluated outcomes included overall survival, infection-related mortality, hospitalization duration, quality of life, and pain. RESULTS: The initial search yielded 332 records. Following two rounds of screening, two records were selected for both qualitative and quantitative synthesis including meta-analysis. Regarding infection-related mortality, the event to case ratio was 5:134 (3.73%) in the G-CSF group versus 6:129 (4.65%) in the non-G-CSF group, resulting in a relative risk of 0.83 (95% confidence interval, 0.27-2.58; p = 0.54), which was not statistically significant. Only median values for hospitalization duration were available from the two RCTs, precluding a meta-analysis. For overall survival, quality of life, and pain, no suitable studies were found for analysis, rendering their assessment unfeasible. CONCLUSION: A weak recommendation is made that G-CSF treatment not be administered to patients with febrile neutropenia during cancer chemotherapy. G-CSF treatment can be considered for patients at high risk.

Effects of oral administration of nonselective Trk inhibitor on bladder overactivity in rodent models of prostatic inflammation.

BACKGROUND: Our research focused on the assessment of the impact of systemic inhibition of Trk receptors, which bind to nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), on bladder hypersensitivity in two distinct rodent models of prostatic inflammation (PI). METHODS: Male Sprague-Dawley rats were divided into three groups (n = 6 each): the control group (no PI, vehicle administration), the untreated group (PI, vehicle administration), and the treated group (PI, nonselective Trk inhibitor, GNF 5837, administration). PI in rats was induced by a intraprostatic injection of 5% formalin. Posttreatment, we carried out conscious cystometry and a range of histological and molecular analyses. Moreover, the study additionally evaluated the effects of a nonselective Trk inhibitor on bladder overactivity in a mouse model of PI, which was induced by prostate epithelium-specific conditional deletion of E-cadherin. RESULTS: The rat model of PI showed upregulations of NGF and BDNF in both bladder and prostate tissues in association with bladder overactivity and inflammation in the ventral lobes of the prostate. GNF 5837 treatment effectively mitigated these PI-induced changes, along with reductions in TrkA, TrkB, TrkC, and TRPV1 mRNA expressions in L6-S1 dorsal root ganglia. Also, in the mouse PI model, GNF 5837 treatment similarly improved bladder overactivity. CONCLUSIONS: The findings of our study suggest that Trk receptor inhibition, which reduced bladder hypersensitivity and inflammatory responses in the prostate, along with a decrease in overexpression of Trk and TRPV1 receptors in sensory pathways, could be an effective treatment strategy for male lower urinary tract symptoms associated with PI and bladder overactivity.

Effectiveness and safety of enzalutamide and apalutamide in the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC): a multicenter retrospective study.

OBJECTIVE: Phase III clinical trials demonstrated the efficacy of enzalutamide and apalutamide in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and PSA doubling time ≤10 months. Although these drugs have been shown to vary in their adverse event (AE) profiles, the differences in their efficacy profiles remain to be evaluated. Therefore, this retrospective study was conducted to evaluate the efficacy of these drugs in patients with nmCRPC. METHODS: This study evaluated 191 patients with nmCRPC treated with enzalutamide (n = 137) or apalutamide (n = 54) in the first-line setting at Jikei University Hospital or its affiliated hospitals between May 2014 and November 2022. Endpoints were defined as oncological outcomes (i.e., PSA response, PFS, PSA-PFS, MFS, CSS, and OS) and AEs. RESULTS: No significant differences were noted in patient backgrounds between the two groups. Patients exhibiting a maximum PSA response of >50% and >90% accounted for 74.5% and 48.9% of patients in the enzalutamide group, and 75.9% and 42.6% of patients in the apalutamide group, respectively, with no significant difference between the groups. The median PSA-PFS was 10 months in the enzalutamide group but not in the apalutamide group, with no significant difference between the groups (P = 0.48). No significant differences were observed in MFS, CSS, or OS between the groups. Patients reporting AEs of all grades and grade 3 or higher accounted for 56.2% and 4.3% of those in the enzalutamide group and 57.4% and 7.4% of those in the apalutamide group, respectively. The most common AE was fatigue (26.3%) in the enzalutamide group and skin rash (27.8%) in the apalutamide group. CONCLUSION: In this retrospective study of their efficacy and safety, enzalutamide and apalutamide were shown to exhibit comparable oncological outcomes but quite different AE profiles, suggesting that their differential use may be warranted based on these findings.

Effect of a variant histology on the oncological outcomes of Japanese patients with upper tract urothelial carcinomas after radical nephroureterectomy: a multicenter retrospective study.

Background: An earlier systematic review and meta-analysis found that patients with a certain histological variant of upper tract urothelial carcinoma (UTUC) exhibited more advanced disease and poorer survival than those with pure UTUC. A difference in the clinicopathological UTUC characteristics of Caucasian and Japanese patients has been reported, but few studies have investigated the clinical impact of the variant histology in Japanese UTUC patients. Methods: We retrospectively enrolled 824 Japanese patients with pTa-4N0-1M0 UTUCs who underwent radical nephroureterectomy without neoadjuvant chemotherapy. Subsequently, we explored the effects of the variant histology on disease aggressiveness and the oncological outcomes. We used Cox's proportional hazards models to identify significant predictors of oncological outcomes, specifically intravesical recurrence-free survival (IVRFS), recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: Of the 824 UTUC patients, 32 (3.9%) exhibited a variant histology that correlated significantly with a higher pathological T stage and lymphovascular invasion (LVI). Univariate analysis revealed that the variant histology was an independent risk factor for suboptimal RFS, CSS, and OS. However, significance was lost on multivariate analyses. Conclusions: The variant histology does not add to the prognostic information imparted by the pathological findings after radical nephroureterectomy, particularly in Japanese UTUC patients.

Extracellular vesicles and prostate cancer management: a narrative review.

Background and Objective: Prostate cancer (PCa) is the second most common male cancer in the United States. Although new drugs have recently been approved, clinical challenges remain, notably the precise detection and prognostic implications of drug-resistant PCa. Extracellular vesicles (EVs), nanoscale lipid membrane vesicles, are actively secreted into the extracellular milieu by a variety of cell types. Over the past decade, interest in EVs has grown, and emerging evidence suggests that EVs play pivotal roles in cancer biology. In this review, we would like to summarize recent reports on EVs in PCa and discuss the potential clinical applications. Methods: We performed a non-systematic literature review using the PubMed database to identify articles specifically related to EVs and PCa management. Key Content and Findings: EVs contain pathogenic components, such as proteins, DNA fragments, mRNA, non-coding RNA, and lipids, all of which can trigger intercellular signaling within tumor microenvironments. Thereby, EVs exert significant effects on several stages of cancer progression, influencing the immune system, angiogenesis, and the establishment of pre-metastatic niches. Furthermore, as EVs are encapsulated, their contents are stable in bodily fluids, and thus EVs have recently attracted attention as a novel kind of liquid biopsy. Conclusions: We have summarized recent research on how EVs may aid PCa management. To date, we have discovered only the tip of the iceberg. We anticipate that further research will yield innovative therapeutic modalities, thereby aiding all PCa patients.

Radiographic Progression Without Corresponding Prostate-specific Antigen Progression in Patients with Metastatic Castration-sensitive Prostate Cancer Receiving Apalutamide: Secondary Analysis of the TITAN Trial.

BACKGROUND AND OBJECTIVE: In prostate cancer treated with androgen deprivation therapy (ADT), the initial sign of treatment resistance is often prostate-specific antigen (PSA) progression, followed by radiographic progression. However, the association between these two forms of progression remains unclear, especially in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with androgen receptor pathway inhibitors. We sought to evaluate the association between radiographic progression, PSA progression, and outcomes of apalutamide therapy in mCSPC. METHODS: We analyzed individual participant-level data for patients randomized within the TITAN trial who experienced radiographic progression during follow-up (N = 326). This study investigated radiographic progression without simultaneous or preceding PSA progression, as defined by the Prostate Cancer Working Group 2 (discordant progression), and explored the association of such progression with radiographic progression-free survival. KEY FINDINGS AND LIMITATIONS: Among the patients who developed radiographic progression, 115 (35.3%) had been treated with apalutamide plus ADT (the apalutamide group) and 211 (64.7%) with placebo plus ADT (the placebo group). Discordant progression occurred in 52.2% of patients (60 of 115) in the apalutamide group and 27.5% (58 of 211) in the placebo group (p < 0.001). A multivariable logistic regression analysis showed that discordant progression was associated with apalutamide treatment. We found evidence of an association between discordant progression and shorter radiographic progression-free survival. CONCLUSIONS AND CLINICAL IMPLICATIONS: This study found that nearly half of the patients with mCSPC treated with apalutamide who experienced radiographic progression developed it without corresponding PSA progression, suggesting that heavy reliance on PSA monitoring may be inadequate for assessing disease activity in this context. PATIENT SUMMARY: In patients who have metastatic castration-sensitive prostate cancer (mCSPC) and are being treated with apalutamide, radiographic images may show cancer progression even if prostate-specific antigen tests indicate no change. This highlights the importance of regular imaging when using apalutamide to manage mCSPC.

Association Between Serum Magnesium Levels and Outcomes of Atezolizumab in Patients With Metastatic Urothelial Carcinoma.

BACKGROUND/AIM: Evidence suggests that serum magnesium levels are associated with outcomes of immune checkpoint inhibitors (ICIs). However, this association remains under-explored in patients with metastatic urothelial carcinoma (UC) treated with ICIs. PATIENTS AND METHODS: This prognostic study used individual participant-level data from 1,281 patients with locally advanced or metastatic UC treated with atezolizumab (N=855) or chemotherapy (N=426) who participated in the IMvigor210 and the IMvigor211 trials. Multivariable Cox proportional hazards regression and Fine-Gray subdistribution hazards regression models were used to examine the association of baseline serum magnesium levels with overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs). RESULTS: No evidence of an association was found between baseline serum magnesium levels and PFS or OS in patients treated with atezolizumab [PFS, hazard ratio (HR)=1.03, 95% confidence interval (CI)=0.78-1.35; OS, HR=1.13, 95%CI=0.84-1.51] or chemotherapy (PFS, HR=0.93, 95%CI=0.62-1.40; OS, HR=0.91, 95%CI=0.59-1.40). We also found no evidence of association with irAEs (subdistribution HR=1.29, 95%CI=0.81-2.07) in patients receiving atezolizumab. CONCLUSION: This study found no evidence of an association between baseline serum magnesium levels and treatment outcomes or irAEs in patients with metastatic UC receiving atezolizumab. Contrary to previous research suggesting a role for magnesium in cancer therapy, these results indicate that serum magnesium levels may not serve as a biomarker to predict outcomes in these patients.

First-line immunotherapy of metastatic renal cell carcinoma: an updated network meta-analysis including triplet therapy.

OBJECTIVE: To compare the differential efficacy of first-line immune checkpoint inhibitor (ICI)-based combined therapies among patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), as recently, the efficacy of triplet therapy comprising nivolumab plus ipilimumab plus cabozantinib has been published. PATIENTS AND METHODS: Three databases were searched in December 2022 for randomised controlled trials (RCTs) analysing oncological outcomes in patients with mRCC treated with first-line ICI-based combined therapies. We performed network meta-analysis (NMA) to compare the outcomes, including progression-free survival (PFS) and objective response rates (ORRs), in patients with intermediate- and poor-risk mRCC; we also assessed treatment-related adverse events. RESULTS: Overall, seven RCTs were included in the meta-analyses and NMAs. Treatment ranking analysis revealed that pembrolizumab + lenvatinib (99%) had the highest likelihood of improved PFS, followed by nivolumab + cabozantinib (79%), and nivolumab + ipilimumab + cabozantinib (77%). Notably, compared to nivolumab + cabozantinib, adding ipilimumab to nivolumab + cabozantinib did not improve PFS (hazard ratio 1.02, 95% confidence interval 0.72-1.43). Regarding ORRs, treatment ranking analysis also revealed that pembrolizumab + lenvatinib had the highest likelihood of providing better ORRs (99.7%). The likelihoods of improved PFS and ORRs of pembrolizumab + lenvatinib were true in both International Metastatic RCC Database Consortium (IMDC) risk groups. CONCLUSIONS: Our analyses confirmed the robust efficacy of pembrolizumab + lenvatinib as first-line treatment for patients with intermediate or poor IMDC risk mRCC. Triplet therapy did not result in superior efficacy. Considering both toxicity and the lack of mature overall survival data, triplet therapy should only be considered in selected patients.

Fourth national Japanese antimicrobial susceptibility pattern surveillance program: Bacterial isolates from patients with complicated urinary tract infections.

INTRODUCTION: Antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using the national surveillance data, comprising 793 bacterial strains from eight clinically relevant species. MATERIALS AND METHODS: Data were collected for the fourth national surveillance project from July 2020 to December 2021 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was supervised with the cooperation of 43 medical institutions throughout Japan. RESULTS: Fluoroquinolone required a minimum inhibitory concentration (MIC) of 2-64 mg/L to inhibit the 330 tested Escherichia coli strains. The proportion of levofloxacin-resistant E. coli strains increased from 28.6% in 2008 to 29.6% in 2011, 38.5% in 2015, and 44.5% in 2021. The proportion of levofloxacin-resistant strains of Pseudomonas aeruginosa also increased from previous survey results, showing a continuing downward trend. Conversely, the proportion of levofloxacin-resistant strains of Enterococcus faecalis decreased relative to previous reports. Neither multidrug-resistant P. aeruginosa nor carbapenem-resistant Enterobacteriaceae were detected. For methicillin-resistant Staphylococcus aureus (MRSA), the proportion of vancomycin-susceptible strains (MIC of 2 µg/mL) decreased from 14.7% to 7.7%. DISCUSSION: Bacterial strains that produced extended-spectrum ß-lactamase included E. coli (82/330 strains, 24.8%), Klebsiella pneumoniae (11/68 strains, 16.2%), and Proteus mirabilis (4/26 strains, 15.4%). As compared to previous surveillance reports, these strains showed an increase in proportion over the years.

Comparison of the efficacy of enfortumab vedotin between patients with metastatic urothelial carcinoma who were treated with avelumab or pembrolizumab: real-world data from a multi-institutional study in Japan.

OBJECTIVES: Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for metastatic urothelial carcinoma (UC) refractory to prior treatment with immune checkpoint inhibitors (ICIs). However, the difference in efficacy of EV after each ICIs and prognostic factors are not well known. We aimed to compare the efficacy of EV in patients with metastatic UC who were treated with avelumab or pembrolizumab and to identify the prognostic factors. METHODS: The records of 100 patients with advanced metastatic UC who received EV after the administration of either avelumab or pembrolizumab were retrospectively collected from five academic hospitals in Japan. RESULTS: The median follow-up period was 6.7 months. The median overall survival (OS) and progression-free survival (PFS) in the EV after avelumab/pembrolizumab group were not reached/14.7 months (p = 0.17) and 10.4/5.2 months (p = 0.039), respectively. The objective response rates (ORR) were 66.6% and 46.8% in EV after avelumab and EV after pembrolizumab groups, respectively (p = 0.14). Multivariate analysis identified histological variants, liver metastasis, low serum albumin levels, and high serum CRP level as significant poor prognostic factors. The median OS and PFS of cachexia patients with both low serum albumin levels and high serum CRP levels were 6.0 months and 0.93 months, respectively. CONCLUSION: PFS was superior in patients treated with EV after avelumab to EV after pembrolizumab. However, OS showed no significant difference between the two groups. Because the prognosis of patients with cachexia is extremely poor, the initiation of EV should be discussed in these patients.