Soluble Immune Checkpoint Molecules as Predictors of Efficacy in Immuno-Oncology Combination Therapy in Advanced Renal Cell Carcinoma.

Immuno-oncology (IO) combination therapy is the first-line treatment for advanced renal cell carcinoma (RCC). However, biomarkers for predicting the response to IO combination therapy are lacking. Here, we investigated the association between the expression of soluble immune checkpoint molecules and the therapeutic efficacy of IO combination therapy in advanced RCC. The expression of soluble programmed cell death-1 (sPD-1), soluble programmed cell death ligand-1 (sPD-L1), soluble PD-L2 (sPD-L2), and lymphocyte activation gene-3 (sLAG-3) was assessed in plasma samples from 42 patients with advanced RCC who received first-line IO combination therapy. All IMDC risk classifications were represented among the patients, including 14.3, 57.1, and 28.6% with favorable, intermediate, and poor risk, respectively. Univariate analysis revealed that prior nephrectomy, sPD-L2 levels, and sLAG-3 levels were significant factors affecting progression-free survival (PFS), whereas multivariate analyses suggested that sPD-L2 and sLAG-3 levels were independent prognostic factors for PFS. In a univariate analysis of the overall survival, prior nephrectomy and sPD-L2 levels were significant factors; no significant differences were observed in the multivariate analysis. No significant correlation was observed between the sPD-L2 and sLAG-3 levels and PD-L2 and LAG-3 expression via immunohistochemistry. In conclusion, sPD-L2 and sLAG-3 expression may serve as a potential biomarker for predicting IO combination therapy efficacy.

TAS0313 plus Pembrolizumab for Post-Chemotherapy Immune Checkpoint Inhibitor-Naïve Locally Advanced or Metastatic Urothelial Carcinoma.

We evaluated the efficacy and safety of TAS0313, a multi-epitope long peptide vaccine, plus pembrolizumab in post-chemotherapy immune checkpoint inhibitor-naïve patients with locally advanced/metastatic urothelial carcinoma (la/mUC). TAS0313 9 mg was administered subcutaneously followed by pembrolizumab 200 mg on Day 1, and as monotherapy on Day 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Biomarkers of response were assessed. In 36 patients enrolled, the ORR was 33.3% (complete response: 7 patients; partial response: 5 patients). Median PFS was 5.0 months; 6- and 12-month progression-free rates were 46.4% and 36.5%, respectively. Median OS was not reached; 6-, 12-, and 24-month OS rates were 83.3%, 72.2%, and 55.1%, respectively. In post hoc analysis, patients with a tumor infiltrating CD8+ lymphocyte (CD8+ TIL) count ≥99 and/or programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥50 and lymphocyte count >1,380 cells/µL had higher ORRs and prolonged PFS versus patients with a CD8+ TIL count <99, PD-L1 CPS <50, and lymphocyte count ≤1,380 cells/µL. Thirty-four (94.4%) patients receiving combination therapy experienced treatment-related adverse events (AE), with pyrexia (n = 15, 41.7%), injection-site reactions (n = 15, 41.7%), injection-site induration (n = 6, 16.7%), and malaise (n = 6, 16.7%) the most common. No grade ≥3 treatment-related AEs occurred in ≥10% of patients. TAS0313 plus pembrolizumab combination therapy showed promising efficacy and manageable safety in la/mUC. Clinical Trial Registration: JapicCTI-183824.

GnRH antagonist monotherapy versus a GnRH agonist plus bicalutamide for advanced hormone-sensitive prostate cancer; KYUCOG-1401.

OBJECTIVES: To compare the effectiveness and safety of gonadotropin-releasing hormone (GnRH) antagonist monotherapy to combined androgen blockade (CAB) with a GnRH agonist and bicalutamide in patients with advanced hormone-sensitive prostate cancer (HSPC). METHODS: The study was conducted as KYUCOG-1401 trial (UMIN000014243) and enrolled 200 patients who were randomly assigned to either group A (GnRH antagonist monotherapy followed by the addition of bicalutamide) or group B (CAB by a GnRH agonist and bicalutamide). The primary endpoint was PSA progression-free survival. The secondary endpoints were the time to CAB treatment failure, radiographic progression-free survival, overall survival, changes in serum parameters, including PSA, hormones, and bone and lipid metabolic markers, and adverse events. RESULTS: PSA progression-free survival was significantly longer in group B (hazard ratio [HR], 95% confidence interval [CI]; 1.40, 1.01-1.95, p = 0.041). The time to CAB treatment failure was slightly longer in group A (HR, 95% CI; 0.80, 0.59-1.08, p = 0.146). No significant differences were observed in radiographic progression-free survival or overall survival. The percentage of patients with serum testosterone that did not reach the castration level was higher at 60 weeks (p = 0.046) in group A. No significant differences were noted in the serum levels of bone metabolic or lipid markers between the two groups. An injection site reaction was more frequent in group A. CONCLUSIONS: The present results support the potential of CAB using a GnRH agonist and bicalutamide as a more effective treatment for advanced HSPC than GnRH antagonist monotherapy.

Investigation of Effect Predictors of Desmopressin in Nocturia Patients With Nocturnal Polyuria.

BACKGROUND/AIM: Effect predictors of desmopressin for nocturia associated with nocturnal polyuria are understudied. Herein, we investigated the effects of desmopressin on sleep and patient quality of life. We defined cases in which administration of desmopressin led to hours of undisturbed sleep (HUS) ≥3 hours as "marked response cases" and examined predictive factors of desmopressin treatment response. PATIENTS AND METHODS: Our study included 129 patients who were administered desmopressin 50 µg for nocturia associated with nocturnal polyuria at our hospital. Efficacy and safety of desmopressin were examined using bladder diaries, International Prostate Symptom Score, Overactive Bladder Symptom Score, Athens Insomnia Scale, Patient Global Impression of Improvement (PGI-I) score, physical examinations, blood tests, and body composition analyzers, and the predictors of desmopressin efficacy were investigated. RESULTS: Significant improvements in all endpoints were observed from the early stage onward after desmopressin treatment compared with before treatment. After treatment, HUS was significantly longer in patients with good PGI-I scores, which indicated patient satisfaction. Variation in nocturnal micturition frequency did not affect the improvement in patient satisfaction. Examination of cases defined as "marked response cases" showed that the mean night-time urine volume was an independent predictor of treatment response. CONCLUSION: Desmopressin can improve patients' quality of life and sleep by extending HUS. This suggests that desmopressin may be effective in patients with high mean night-time urine volumes based on their bladder diary.

Sarcopenia and the Therapeutic Effects of Androgen Receptor-axis-targeted Therapies in Patients With Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Sarcopenia is a syndrome characterized by the progressive and generalized loss of skeletal muscle mass and has been reported to be a poor prognostic factor for taxane-treated castration-resistant prostate cancer (CRPC). However, whether sarcopenia affects androgen receptor axis-targeted therapies (ARATs) remains unknown. In the present study, we investigated the association between sarcopenia in CRPC and treatment outcomes of ARATs. PATIENTS AND METHODS: From January 2015 to September 2022, 127 patients who received ARATs as 1st-line treatment for CRPC at our two hospitals were included in the study. We retrospectively evaluated sarcopenia using computed tomography images and investigated whether sarcopenia affects the progression-free survival (PFS) and overall survival (OS) of patients with CRPC treated with ARATs. RESULTS: Out of 127 patients, 99 were diagnosed with sarcopenia. The PFS of the sarcopenic group administered ARATs was significantly better than that of the non-sarcopenic group. Furthermore, in the multivariate analysis of PFS, sarcopenia was an independent favourable prognostic factor. However, there was no significant difference in the OS between the sarcopenic and non-sarcopenia groups. CONCLUSION: ARATs could more effectively treat patients with CRPC and sarcopenia than patients with CRPC without sarcopenia. Sarcopenia may positively influence the therapeutic effects of ARATs.

Prognostic Value of Absolute Lymphocyte Count in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab Plus Ipilimumab.

Nivolumab and ipilimumab (NIVO + IPI) is standard therapy for patients with advanced renal cell carcinoma (RCC). Absolute lymphocyte count (ALC) is a valuable prognostic factor in patients with various cancers treated with immune checkpoint inhibitors. Herein, we determined the prognostic value of pretreatment ALC in advanced RCC patients treated with NIVO + IPI as first-line therapy. Data from 46 advanced RCC patients treated with NIVO + IPI between September 2018 and August 2022 were retrospectively reviewed and analyzed. Median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with low than high ALC (PFS: p = 0.0095; OS: p = 0.0182). Multivariate analysis suggested that prior nephrectomy [hazard ratio (HR) = 3.854, 95% confidence interval (CI) = 1.433-10.359, p = 0.0075] and pretreatment ALC (HR = 2.513, 95% CI = 1.119-5.648, p = 0.0257) were independent factors for PFS. Our new prognostic ALNx model based on ALC and prior nephrectomy suggested that the poor-risk group was a predictor of significantly worse PFS (p < 0.0001) and OS (p = 0.0016). Collectively, the developed ALNx model may be a novel predictor of response in advanced RCC patients treated with NIVO + IPI.

Determining the optimal initial dose for Japanese patients with nocturnal polyuria using an initial dose of desmopressin 50 µg.

OBJECTIVE: There is no consistent opinion on the optimal initial dose of desmopressin for patients with nocturnal polyuria. Over a period of 12 weeks, we investigated the safety and efficacy of an initial dose of 50 µg of desmopressin for elderly men. METHODS: Eighty patients (mean age: 78.8 years) were started on an initial dose of 50 µg of desmopressin for nocturia associated with nocturnal polyuria. Safety and efficacy were evaluated after 1, 4, and 12 weeks using a frequency-volume chart, Athens Insomnia Scale, Patient Global Impression of Improvement scale, physical examination, blood tests, and a body composition analyzer. RESULTS: Along with reduction in the frequency and volume of night-time urination, improvements in hours of undisturbed sleep, nocturnal polyuria index, and International Prostate Symptom Score, and Overactive Bladder Symptom Scores on quality of life measures were also observed. Hyponatremia was observed in 15 patients (18.7%). However, only 5.0% of patients had hyponatremia after the dose was reduced to 25 µg, and the continuation rate at 12 weeks was high at 87.5%. Age and other physical factors, such as body mass index, body water content, body fat mass, and muscle mass were not significant predictors of adverse events. CONCLUSIONS: Our study suggests that an initial dose of 50 µg is more effective than a uniformly minimum dose based on factors such as age and physique. Furthermore, a high continuation rate can be achieved by appropriately reducing the dose, if adverse events occur.

Discontinuation of pembrolizumab for advanced urothelial carcinoma without disease progression: Nationwide cohort study.

Pembrolizumab, an anti-programmed death 1 monoclonal antibody, has revolutionized the treatment of metastatic urothelial carcinoma. However, the optimal treatment duration for treatment responders has not been established. To address this, we retrospectively assess the treatment outcomes and duration of pembrolizumab for patients whose best response was complete response (CR) or partial response (PR) in a Japanese nationwide cohort of platinum-refractory metastatic urothelial carcinoma. Of 203 patients whose best response was CR or PR, 83 patients discontinued pembrolizumab before progression. The median pembrolizumab treatment duration was 6.9 months. The 2-year relapse-free survival (RFS), treatment-free survival, and OS rates after discontinuation were 49.0%, 57.4%, and 74.5%, respectively. CR, higher hemoglobin levels, and a better Eastern Cooperative Oncology Group performance status at the time of discontinuation were associated with significantly better RFS. Pembrolizumab was re-administered to 12 patients. Pembrolizumab re-challenge resulted in CR, PR, stable disease, and progressive disease in six, three, two, and one patient, respectively. Propensity score-matched landmark analysis revealed no significant OS difference between patients who continued or discontinued pembrolizumab at 6, 12, and 18 months (p = 0.91, 0.99, and 0.25, respectively). Our findings demonstrated that patients with objective responses had favorable survival outcomes and suggested that pembrolizumab could be discontinued safely in this population. This study should drive further efforts to optimize the treatment duration for pembrolizumab responders.

Sarcopenia and excess visceral fat accumulation negatively affect early urinary function after I-125 low-dose-rate brachytherapy for localized prostate cancer.

OBJECTIVES: To evaluate the effects of sarcopenia and excess visceral fat accumulation on early urinary function after I-125 low-dose-rate brachytherapy for prostate cancer. METHODS: We retrospectively reviewed consecutive patients who underwent brachytherapy for prostate cancer. Pre-treatment computed tomography was used to measure skeletal muscle index at the L3 level to assess sarcopenia and visceral fat area at the umbilical level. The International Prostate Symptom Score and the University of California Los Angeles Prostate Cancer Index were used to assess quality of life during the 24 months after brachytherapy. Logistic regression analysis was used to examine whether sarcopenia and excess visceral fat accumulation had clinically significant effects on post-treatment quality of life. RESULTS: Among 246 patients, 92 (37.4%) were stratified into the sarcopenia group and 141 (57.3%) into the excess visceral fat accumulation group. The sarcopenia group had significantly lower University of California Los Angeles Prostate Cancer Index urinary function than the non-sarcopenia group 24 months post-brachytherapy. The excess visceral fat accumulation group had significantly poorer International Prostate Symptom Score total, storage, and voiding scores than the non-excess accumulation group 12 months post-brachytherapy. In the multivariate analysis, sarcopenia had a clinically significant adverse effect on the University of California Los Angeles Prostate Cancer Index urinary function at 12 months. Excess visceral fat accumulation had a clinically significant adverse effect on the International Prostate Symptom Score voiding and storage scores at 12 months. CONCLUSIONS: Sarcopenia and excess visceral fat accumulation negatively affect urinary function early after I-125 low-dose-rate brachytherapy for prostate cancer.

Improved Survival of Real-world Japanese Patients With Advanced Renal Cell Carcinoma Treated With Immuno-oncology Combination Therapy.

BACKGROUND/AIM: Immuno-oncology (IO) combination therapy has become the standard of treatment for advanced renal cell carcinoma (RCC). In this retrospective study, we compared the efficacy of first-line molecular targeted therapy (MTT), administered as monotherapy, and IO combination therapy using real-world data of Japanese patients. PATIENTS AND METHODS: The clinical information of 202 patients with RCC who received MTT (n=144) or IO combination therapy (n=58) at the Kurume University Hospital from May 2008 to May 2022 was collected and retrospectively analyzed. The Cox proportional hazards model was used for univariate and multivariate analyses, with hazard ratios (HRs) and 95% confidence intervals (CIs) calculated. RESULTS: The patients treated with IO combination therapy had a prolonged progression-free survival (PFS) compared with those treated with MTT (p=0.0038). IO combination therapy was significantly associated with a better PFS in patients with intermediate (p=0.0072) and poor risk (p=0.0411) but not in those with favorable risk (p=0.5434). Furthermore, overall survival with IO combination therapy was significantly better in patients at poor risk (p=0.0335). Multivariate analyses suggested that prior nephrectomy (HR=1.501, 95%CI=1.048-2.150, p=0.0268) and first-line therapy (HR=1.962, 95%CI=1.288-2.986, p=0.0017) were independent prognostic factors for PFS. CONCLUSION: IO combination therapy significantly improved the PFS of patients with advanced RCC, especially those with intermediate- and poor-risk disease. Further investigations focusing on the improvement of survival are warranted.

Immune responses of patients without cancer recurrence after a cancer vaccine over a long term.

The present study aimed to clarify the humoral and cellular immune responses of patients with cancer who experienced no recurrence over a long term after receiving a cancer vaccine. The immune kinetics were investigated in response to a personalized peptide vaccination (PPV) among 44 Japanese patients without an active tumor at entry to the vaccination: Lung adenocarcinoma (n=11); colon (n=18); and breast cancer (n=15) (9, 10, 12, 8 and 5 patients with stage I, II, III and IV recurrences, respectively). The patients' immunoglobulin G (IgG) and cytotoxic T lymphocyte (CTL) activities were measured using a multiplexed Luminex assay and an interferon-γ release assay, respectively. There were no severe adverse events related to the PPV other than a grade III injection site reaction. A potent boost in IgG or CTL at the end of the 1st vaccination cycle was observed in 77% of the patients (n=84). The IgG levels were sustained throughout the follow-up period, whereas the CTL levels declined and were transient. A total of 37 of the 44 patients (84%) had no recurrence, with a median follow-up of 67.6 months (interquartile range, 45.6-82.8 months). Overall, the PPV induced long-term humoral immunity with transient cellular immunity in the majority of patients with cancer without an active tumor at their entry to the PPV.

Radiotherapy plus androgen deprivation therapy for prostate-specific antigen persistence in lymph node-positive prostate cancer.

The treatment for lymph node involvement (LNI) after radical prostatectomy (RP) has not been established. This study aimed to reveal the outcomes of various management strategies among patients with LNI after RP. Retrospectively, 561 patients with LNI after pelvic lymph node dissection (PLND) with RP treated between 2006 and 2019 at 33 institutions participating in the Japanese Urological Oncology Group were investigated. Metastasis-free survival (MFS) was the primary outcome. Patients were stratified by prostate-specific antigen (PSA) persistence after RP. Cox regression models were used to analyze the relationships between clinicopathological characteristics and survival. Survival analyses were conducted using the Kaplan-Meier method and log-rank test with or without propensity score matching. Prognoses, including MFS and overall survival, were prominently inferior among patients with persistent PSA compared with those without persistent PSA. In multivariate analysis, androgen deprivation therapy (ADT) plus radiotherapy (RT) was associated with better MFS than ADT alone among patients with persistent PSA (hazard ratio = 0.37; 95% confidence interval = 0.15-0.93; p = 0.034). Similarly, MFS and overall survival were significantly better for ADT plus RT than for ADT alone among patients with persistent PSA after propensity score matching. This study indicated that PSA persistence in LNI prostate cancer increased the risk of poor prognoses, and intensive treatment featuring the addition of RT to ADT might improve survival.

Impact of Gleason score of the tumor at the positive surgical margin as a prognostic factor.

Although numerous studies have reported that a positive surgical margin (PSM) is the most important predictive factor for biochemical recurrence (BCR) of prostate cancer (PCa), only a small number of studies have evaluated the predictive value of the Gleason score (GS) of the tumor at the margin in radical prostatectomy (RP). The present study aimed to investigate the preoperative factors that predict PSM and the significant predictive factors for BCR in cases with PSM. In addition, it was examined whether documenting the GS of the tumor at the margin in pathological reports is useful as a predictive factor for BCR. Data of 241 patients with PCa who underwent RP at Kurume University Hospital (Kurume, Japan) between January 2007 and December 2011 were retrospectively reviewed. The median follow-up period was 72 months and 122 patients had at least one PSM. The time to BCR was significantly shorter in patients with PSM than in those with a negative surgical margin. Multivariate analysis demonstrated that >10 ng/ml prostate-specific antigen at diagnosis (P=0.024) and >25% positive core at biopsy (P=0.041) were independent prognostic preoperative factors for PSM. The GS of the tumor at the margin was equal, lower and higher than those of the main tumor in 74 (60.7%), 16 (13.1%) and 32 (26.2%) RPs, respectively. The BCR rates were 35.7, 55.1 and 82.1% in patients whose GS of the tumor at the margin was 6, 7 and 8-10, respectively (P=0.0017). The GS of the tumor at the PSM (P=0.038) and anatomic location of the PSM (P=0.04) were identified as independent prognostic preoperative factors for BCR, whereas the GS of the main tumor and margin length were not. These results suggest that documenting the GS at the margin in pathological reports is useful as a predictive factor for BCR.

Survival outcomes of non-definitive therapy for muscle-invasive bladder cancer.

To analyze the risks and survival outcomes of non-definitive therapy (nDT) for muscle-invasive bladder cancer (MIBC), which may provide useful information for future treatment selection, the present study analyzed 124 patients who were diagnosed with MIBC (cT2-4aN1-2M0) and treated at Kurume University Hospital (Kurume, Japan) with definitive therapy (DT; including radical cystectomy and trimodal therapy) or nDT [transurethral resection of bladder tumor (TURBT) monotherapy or TURBT plus chemotherapy]. Differences in survival outcomes between the two groups were estimated using the Kaplan-Meier method and analyzed using the log-rank test. Cox proportional hazards regression models were used for multivariate analysis of each survival outcome. Of the 124 patients, 45% were treated with nDT, and among these, 50% were treated with TURBT monotherapy and 50% were treated with TURBT plus chemotherapy. Of the patients who chose definitive treatment, 69% were treated with radical cystectomy. The median age in the nDT group was 77 years, which was significantly higher than that in the DT group. Additionally, the proportion of patients with poor performance status, high Charlson comorbidity index and high neutrophil-lymphocyte ratio values was significantly higher in the nDT group. nDT was associated with significantly reduced overall survival, cancer-specific survival and progression-free survival rates, and was a poor prognostic factor for all survival outcomes compared with DT. In conclusion, nDT was associated with a high cancer-related mortality risk. The most appropriate treatment method should be discussed with the patients after providing them with sufficient information on the risks and benefits of each treatment method.

Immune-related adverse events are clinical biomarkers to predict favorable outcomes in advanced renal cell carcinoma treated with nivolumab plus ipilimumab.

BACKGROUND: Immune checkpoint inhibitors cause various immune-related adverse events. The present study examined the association between the incidence of immune-related adverse events and survival outcomes in patients treated with nivolumab plus ipilimumab for patients with advanced renal cell carcinoma. In addition, we compared the effect of adverse event profiles on survival for patients receiving nivolumab plus ipilimumab. METHODS: A total of 35 patients with advanced renal cell carcinoma who were treated with nivolumab plus ipilimumab from August 2018 to August 2021 were retrospectively reviewed and analyzed. Cox proportional hazards models were used for univariate and multivariate analyses, and hazard ratio and 95% confidence intervals were calculated. RESULTS: Of the 35 patients, 22 (62.9%) experienced immune-related adverse events. The median progression-free survival (P = 0.0012) and overall survival (P = 0.0147) were significantly longer in patients with immune-related adverse events than in those without immune-related adverse events. Multivariate analysis showed that the incidence of immune-related adverse events was an independent factor for progression-free survival (hazard ratio = 4.940, 95% confidence interval: 1.558-15.664, P = 0.0067). Skin reaction was a positive predictive immune-related adverse events for progression-free survival (hazard ratio = 9.322, 95% confidence interval: 1.954-44.475, P = 0.0051). CONCLUSION: Patients with advanced renal cell carcinoma with immune-related adverse events had superior clinical outcomes of nivolumab plus ipilimumab treatment than those without immune-related adverse events. Skin immune-related adverse events may be effective biomarkers in patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab.

[EFFICACY AND SAFETY OF INITIAL DESMOPRESSIN DOSE OF 50 µg IN ELDERLY MALE PATIENTS WITH NOCTURNAL POLYURIA].

(Introduction) Low-dose desmopressin is now available for the treatment of nocturia associated with nocturnal polyuria in men, and its usefulness in a dose-dependent manner has been reported. Since side effects such as hyponatremia have reported frequently, the initial dose has been set at 25 µg in many cases considering age and other factors. In the present study, we investigated the efficacy and safety of an initial dose of 50 µg in elderly patients. (Subjects and methods) At Chikugo city hospital, 45 patients were started on desmopressin at an initial dose of 50 µg for nocturia with nocturnal polyuria. Efficacy and safety after one and four weeks were evaluated based on bladder (micturition) diary. The investigated parameters included frequency of nocturnal urination, nocturnal polyuria index, time to first nocturnal void, first nocturnal urine volume, nocturnal urine volume, International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), and Athens Insomnia Scale. Physical examinations were also carried out, along with blood tests. (Results) The mean age of the patients was 78.3 years, which was higher than that reported in prior studies. After one week of treatment, there was a significant decrease in the frequency of nocturnal urination and nocturnal urine volume, as well as a prolongation of the time to first nocturnal void, improvement in nocturnal polyuria index, and improvement in IPSS, IPSS-QOL, OABSS, and Athens Insomnia Scale. In terms of safety, adverse events were observed in eight patients (17.8%), and hyponatremia was observed in seven patients (15.6%), which was comparable to the findings of prior reports. (Conclusion) Good therapeutic results were obtained in elderly patients at an initial desmopressin dose of 50 µg, indicating that the drug could be safely administered to elderly patients with regular follow-ups and appropriate withdrawal and dose reductions.

Efficacy and safety of pembrolizumab for older patients with chemoresistant urothelial carcinoma assessed using propensity score matching.

BACKGROUND: We used real-world and large-scale data to assess the clinical efficacy and safety of pembrolizumab in older patients with advanced urothelial carcinoma (UC). METHODS: A total of 608 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. All patients were histologically diagnosed with pure UC. Using propensity score matching (PSM) (ECOG performance status, site of metastasis, hemoglobin level and neutrophil-to-lymphocyte ratio, 1:1 matching), the overall survival (OS) and adverse events (AEs) of patients <75 and ≥75 years old were compared. RESULTS: The median follow-up (IQR) period was 16.1 (9.9-20.5) months. After PSM, there were 215 patients each in the aged <75 years and aged ≥75-year-old groups. The median OS of all patients was estimated to be 10.4 months (95% confidence interval [CI] = 8.8-12.1). After PSM, the median OS was 7.8 months (95% CI = 5.2-10.4) in the <75-year-old group and 10.4 months (95% CI = 7.3-13.5) in the ≥75-year-old group (P = 0.186). Any-grade AEs were more frequently reported in the ≥75-year-old group in comparison to the age <75-year-old group (55.3% vs. 41.9%, P = 0.007), whereas there was no significant difference between the two groups in the incidence of grade ≥3 AEs (10.2% vs. 12.6%, P = 0.544). The objective response rate, defined as complete remission or a partial response, was 22.8% in the <75-year-old group and 25.1% in the ≥75-year-old group (P = 0.651). CONCLUSIONS: The present study demonstrates that age does not affect the efficacy and safety of pembrolizumab treatment for advanced chemoresistant UC. Pembrolizumab treatment should not be avoided based on chronological age; however, close monitoring for the development of treatment-related AE should be considered for older patients.

Pre-pembrolizumab neutrophil-to-lymphocyte ratio (NLR) predicts the efficacy of second-line pembrolizumab treatment in urothelial cancer regardless of the pre-chemo NLR.

Neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with prognosis of urothelial cancer (UC) patients receiving systemic chemotherapy or immunotherapy. However, it has not been elucidated how preceding first-line chemotherapy affects NLR and subsequent second-line pembrolizumab treatment. This multicenter study analyzed 458 patients with metastatic UC who received first-line chemotherapy and second-line pembrolizumab with regard to pre-chemotherapy and pre-pembrolizumab NLR in association with the efficacy of chemotherapy and pembrolizumab treatment. NLR was increased in 47% while decreased in 53% of patients before and after first-line chemotherapy. High pre-chemotherapy NLR (≥ 3) was significantly associated with unfavorable overall (OS, P = 0.0001) and progression-free (P < 0.0001) survivals after first-line chemotherapy. However, pre-chemotherapy NLR showed only modest influence on radiological response and survival after second-line pembrolizumab treatment, whereas pre-pembrolizumab NLR showed higher association. NLR decrease was associated with partial response or greater objective response by first-line chemotherapy, while NLR increase was associated with higher patient age. In conclusion, immediate pre-chemotherapy and pre-pembrolizumab NLR was significantly associated with efficacy of the following treatment, respectively. However, even patients with high pre-chemotherapy NLR achieved favorable OS if they had their NLR reduced by chemotherapy, whereas those with high pre-chemotherapy NLR yielded unfavorable OS if they had their NLR remained high after chemotherapy, suggesting that chemotherapy may have differential effect on the efficacy of subsequent pembrolizumab treatment in UC patients.

Absolute lymphocyte count is an independent predictor of survival in patients with metastatic renal cell carcinoma treated with nivolumab.

OBJECTIVE: Programmed cell death-1 antibody therapy has demonstrated improved progression-free survival and overall survival in patients with metastatic renal cell carcinoma. However, there are limited studies on biomarkers that can predict the efficacy of immune checkpoint inhibitors. We examined the influence of peripheral inflammatory biomarkers on the clinical outcomes of patients with metastatic renal cell carcinoma treated with nivolumab. METHODS: Data of 38 patients with metastatic renal cell carcinoma, who were treated with nivolumab monotherapy after receiving at least one molecular targeted therapy from November 2016 to February 2021, were retrospectively reviewed and analyzed. RESULTS: Median progression-free survival and overall survival were significantly shorter in patients with low absolute lymphocyte count (<1300/µl) versus those with high absolute lymphocyte count (progression-free survival: P = 0.0102; overall survival: P = 0.0026). Median overall survival was shorter in patients with high neutrophil-lymphocyte ratio (≥3.0) versus those with low neutrophil-lymphocyte ratio (P = 0.0344). Multivariate analysis showed that absolute lymphocyte count was an independent factor for progression-free survival (hazard ratio = 2.332, 95% confidence interval = 1.012-5.375, P = 0.0468) and overall survival (hazard ratio = 4.153, 95% confidence interval = 1.108-15.570, P = 0.0347). Increased absolute lymphocyte count, 1 month after nivolumab initiation, was a positive predictive factor for progression-free survival (hazard ratio = 0.419, 95% confidence interval = 0.189-0.926, P = 0.0317) and overall survival (hazard ratio = 0.285, 95% confidence interval = 0.091-0.890, P = 0.0308). CONCLUSION: Our study indicates that peripheral absolute lymphocyte count, before nivolumab initiation, is a predictor of poor response in metastatic renal cell carcinoma. Additionally, increased absolute lymphocyte count, 1 month post-nivolumab initiation, can be a predictor of the effects of nivolumab.

Synchronous primary triple urogenital malignant tumors of kidney, prostate and bladder.

Synchronous occurrence of triple primary cancers of urinary tract is quite rare and represents a difficult treatment challenge. Here, we report a case of a 78-year-old man with synchronous renal cell carcinoma, urothelial carcinoma of urinary bladder and adenocarcinoma of prostate within a short period. To the best of our knowledge, this is the 20th reported of triple primary cancers of urinary tract and the first synchronous case with bone metastasis in the literature.