Transplanting old organs promotes senescence in young recipients.

In clinical organ transplantation, donor and recipient ages may differ substantially. Old donor organs accumulate senescent cells that have the capacity to induce senescence in naïve cells. We hypothesized that the engraftment of old organs may induce senescence in younger recipients, promoting age-related pathologies. When performing isogeneic cardiac transplants between age-mismatched C57BL/6 old donor (18 months) mice and young and middle-aged C57BL/6 (3- or 12- month-old) recipients , we observed augmented frequencies of senescent cells in draining lymph nodes, adipose tissue, livers, and hindlimb muscles 30 days after transplantation. These observations went along with compromised physical performance and impaired spatial learning and memory abilities. Systemic levels of the senescence-associated secretory phenotype factors, including mitochondrial DNA (mt-DNA), were elevated in recipients. Of mechanistic relevance, injections of mt-DNA phenocopied effects of age-mismatched organ transplantation on accelerating aging. Single treatment of old donor animals with senolytics prior to transplantation attenuated mt-DNA release and improved physical capacities in young recipients. Collectively, we show that transplanting older organs induces senescence in transplant recipients, resulting in compromised physical and cognitive capacities. Depleting senescent cells with senolytics, in turn, represents a promising approach to improve outcomes of older organs.

Pattern of Expression of MicroRNA in Patients with Radiation-Induced Bladder Injury.

INTRODUCTION: Bladder cancer (BC) is sensitive to radiation treatment and a subset of patients experience radiation-induced injuries including shrinkage of bladder due to bladder fibrosis. METHODS: This study is a retrospective cohort study. Three Japanese BC patients were randomly selected. Using a microRNA (miRNA) array, comparing their samples with or without radiation-induced injuries, we have checked the clustering of miRNA expression. RESULTS: Hsa-miR-130a, hsa-miR-200c, hsa-miR-141, and hsa-miR-96 were found to be highly expressed (>50 times) in patients with fibrotic bladder shrinkage (FBS) compared to those with intact bladder (IB) function. In patients with FBS, hsa-miR-6835, hsa-miR-4675, hsa-miR-371a, and hsa-miR-6885 were detected to have lesser than half expression to IB patients. We have analyzed the significance of these genes in relation to overall survival of 409 BC patients retrieved from the Cancer Genome Atlas data set. All available cutoff values between the lower and upper quartiles of expression are used for the selected genes, and false discovery rate using the Benjamini-Hochberg method is computed to correct for multiple hypothesis testing. We have run combined survival analysis of the mean expression of these four miRNAs highly expressed in FBS patients. 175 patients with high expression had a longer median survival of 98.47 months than 23.73 months in 233 patients with low expression (hazard ratio [HR]: 0.53; 0.39-0.72, log-rank p value: 7.3e-0.5). Combination analysis of all 8 genes including hsa-miR-6835, hsa-miR-4675, hsa-miR-371a, and hsa-miR-6885 showed the same HR for OS. Target scanning for these miRNAs matched specific cytokines known as an early biomarker to develop radiation-induced fibrosis. CONCLUSIONS: BC patients with fibrotic radiation injury have specific miRNA expression profile targeting profibrotic cytokines and these miRNAs possibly render to favorable survival.

Sex as a biological variable: Mechanistic insights and clinical relevance in solid organ transplantation.

Biological sex affects immunity broadly, with recognized effects on the incidence and severity of autoimmune diseases, infections, and malignancies. Consequences of sex on alloimmunity and outcomes in solid organ transplantation are less well defined. Clinical studies have shown that donor and recipient sex independently impact transplant outcomes, which are further modified by aging. Potential mechanisms have thus far not been detailed and may include hormonal, genetic, and epigenetic components. Here, we summarize relevant findings in immunity in addition to studies in clinical and experimental organ transplantation detailing the effects of biological sex on alloimmunity. Understanding both clinical impact and mechanisms is expected to provide critical insights on the complexity of alloimmune responses, with the potential to fine-tune treatment and allocation while providing a rationale to include both sexes in transplant research.

Nephron-sparing ureteroscopic surgery vs. radical nephroureterectomy: comparable survival-outcomes in upper tract urothelial carcinoma.

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.

Taurodeoxycholic acid and valine reverse obesity-associated augmented alloimmune responses and prolong allograft survival.

Obesity initiates a chronic inflammatory network linked to perioperative complications and increased acute rejection rates in organ transplantation. Bariatric surgery is the most effective treatment of obesity recommended for morbidly obese transplant recipients. Here, we delineated the effects of obesity and bariatric surgery on alloimmunity and transplant outcomes in diet-induced obese (DIO) mice. Allograft survival was significantly shorter in DIO-mice. When performing sleeve gastrectomies (SGx) prior to transplantation, we found attenuated T cell-derived alloimmune responses resulting in prolonged allograft survival. Administering taurodeoxycholic acid (TDCA) and valine, metabolites depleted in DIO-mice and restored through SGx, prolonged graft survival in DIO-mice comparable with SGx an dampened Th1 and Th17 alloimmune responses while Treg frequencies and CD4+ T cell-derived IL-10 production were augmented. Moreover, in recipient animals treated with TDCA/valine, levels of donor-specific antibodies had been reduced. Mechanistically, TDCA/valine restrained inflammatory M1-macrophage polarization through TGR5 that compromised cAMP signaling and inhibited macrophage-derived T cell activation. Consistently, administering a TGR5 agonist to DIO-mice prolonged allograft survival. Overall, we provide novel insights into obesity-induced inflammation and its impact on alloimmunity. Furthermore, we introduce TDCA/valine as a noninvasive alternative treatment for obese transplant patients.

Preserving and rejuvenating old organs for transplantation: novel treatments including the potential of senolytics.

PURPOSE OF REVIEW: Older donors have the potential to close the gap between demand and supply in solid organs transplantation. Utilizing older organs, at the same time, has been associated with worse short- and long-term outcomes. Here, we introduce potential mechanisms on how treatments during machine perfusion (MP) may safely improve the utilization of older organs. RECENT FINDINGS: Consequences of ischemia reperfusion injury (IRI), a process of acute, sterile inflammation leading to organ injury are more prominent in older organs. Of relevance, organ age and IRI seem to act synergistically, leading to an increase of damage associated molecular patterns that trigger innate and adaptive immune responses. While cold storage has traditionally been considered the standard of care in organ preservation, accumulating data support that both hypothermic and normothermic MP improve organ quality, particularly in older organs. Furthermore, MP provides the opportunity to assess the quality of organs while adding therapeutic agents. Experimental data have already demonstrated the potential of applying treatments during MP. New experimental show that the depletion of senescent cells that accumulate in old organs improves organ quality and transplant outcomes. SUMMARY: As the importance of expanding the donor pool is increasing, MP and novel treatments bear the potential to assess and regenerate older organs, narrowing the gap between demand and supply.

Distinct effect of body mass index by sex as a prognostic factor in localized renal cell carcinoma treated with nephrectomy ~ data from a multi-institutional study in Japan ~.

BACKGROUND: We assessed the prognostic value of body mass index (BMI) in Asian patients with localized RCC who underwent nephrectomy. METHODS: A total of 665 patients who underwent nephrectomy for localized RCC were enrolled in the present study and divided into the two BMI groups: i.e., BMI < 25 in 463 (69.6%) and BMI > 25 in 202 (30.4%) patients. RESULTS: In total, there were 482 (72.5%) males and 183 (27.5%) females. Five-year cancer-specific survival (CSS) rates were significantly higher in increased BMI than the lower BMI group (97.1 and 92.5%: P = 0.007). When stratified by sex, significantly longer CSS in higher BMI was confirmed in males (5-year CSS of 92.7% in BMI < 25 and 98.1% in BMI > 25, p = 0.005), while there was no difference in CSS between BMI groups for female patients. Multivariable analysis exhibited that higher BMI was an independent predictor for favorable CSS in male (cox model: p = 0.041, Fine & Gray regression model: p = 0.014), but not in the female. Subgroup analysis for CSS revealed that favorable CSS with higher BMI was observed in patient subgroups of age < 65 (p = 0.019), clear cell histology (p = 0.018), and tumor size > 4 cm, p = 0.020) as well as male (p = 0.020). CONCLUSION: Our findings collected from the multi-institutional Japanese dataset demonstrated longer survival in patients with higher BMI than lower BMI for non-metastatic RCC treated with nephrectomy. Intriguingly, this finding was restricted to males, but not to females.

Risk stratification for the prediction of overall survival could assist treatment decision-making at diagnosis of castration-resistant prostate cancer: a multicentre collaborative study in Japan.

OBJECTIVES: To assess whether a new risk stratification system according to predictors for overall survival (OS) at the diagnosis of metastatic castration-resistant prostate cancer (mCRPC) could determine treatment outcomes and assist in treatment decision-making. PATIENTS AND METHODS: Two independent clinical cohorts of patients, treated with androgen signalling inhibitors (ASIs: abiraterone and enzalutamide) or docetaxel as a first-line treatment for mCRPC, were used in this study: a derivation cohort (196 patients with mCRPC) and an external validation cohort (211 patients with mCRPC). RESULTS: Three independent predictors for OS, including duration of initial androgen deprivation therapy <12 months before mCRPC diagnosis, alkaline phosphatase level >350 U/dL and haemoglobin level <11 g/dL at the diagnosis of mCRPC, were defined as risk factors. Patients with zero, one and multiple risk factors were assigned to a favourable-, intermediate- and poor-risk group, respectively. The median OS values in each risk group were well separated in the derivation cohort (P < 0.001) as well as in the validation cohort (P < 0.001). Of a total of 407 patients with mCRPC, 84 were assigned to the poor-risk group with the median OS of 12 months. In this group, a trend towards longer OS favouring docetaxel compared to ASIs as the first-line treatment (medians of 17 and 12 months, respectively) was observed. CONCLUSION: The new risk group stratification system could predict patient survival at the diagnosis of mCRPC. Given the convenience of these risk definitions, physicians may be encouraged to consider these risk groups in daily practice.

Adjuvant chemotherapy improves overall survival in patients with localized upper tract urothelial carcinoma harboring pathologic vascular invasion: a propensity score-matched analysis of multi-institutional cohort.

OBJECTIVE: Whether adjuvant chemotherapy (AC) for patients with upper tract urothelial carcinoma (UTUC) offers survival benefit is still controversial. To explore the impact of AC on overall survival (OS) of cN0M0 UTUC patients, we conducted a propensity score-matched analysis using the regression model, including pathologic features such as lymphatic and vascular invasion. METHODS: A multi-institutional cohort of 413 UTUC patient record was used. Propensity score matching was performed to reduce bias by potential confounding factors for survival, including pathologic features from the specimen of radical nephroureterectomy (RNU), RESULTS: Ninety-eight patients were identified as pair-matched groups (49 patients in RNU and 49 patients in RNU + AC). Kaplan-Meier curves demonstrated that a 5-year OS rate of 72.7% for patients treated with RNU + AC was significantly higher than 51.6% for those treated with RNU (p = 0.0156). On multivariate analysis, pathologic vascular invasion (HR 3.41, 95% CI 1.24-10.66, p = 0.0166) and administration of AC (HR 0.45, 95% CI 0.19-0.98, p = 0.0438) still remained as the significant predictors for OS. In patients with pathologic vascular invasion (51 of 98 patients), a significantly longer OS in RNU + AC groups was observed (median OS of 30 and 70 months in RNU and RNU + AC groups, respectively: p = 0.0432), whereas there was no significant difference in the OS between RNU (median OS: not reached) and RNU + AC (median OS: not reached) groups in patients without the invasion (p = 0.4549). CONCLUSION: The result indicates a significant benefit for OS by the administration of AC, and pathologic vascular invasion in the specimen of RNU could help the patient selection to better predict the effect of AC.

The CANLPH Score, an Integrative Model of Systemic Inflammation and Nutrition Status (SINS), Predicts Clinical Outcomes After Surgery in Renal Cell Carcinoma: Data From a Multicenter Cohort in Japan.

BACKGROUND: A myriad of studies have demonstrated the clinical association of systemic inflammatory and nutrition status (SINS) including C-reactive protein/albumin ratio (CAR), the neutrophil/lymphocyte ratio (NLR), and the platelet/hemoglobin ratio (PHR). This study aimed to investigate the predictive value of the score integrating these variables (CANLPH) in patients with renal cell carcinoma (RCC). METHODS: Using cohort data from a multi-institutional study, 757 of 1109 patients were retrospectively analyzed. The optimal cutoff value for outcome prediction of continuous variables in CAR, NLR, and PHR was determined and the CANLPH score was then calculated as the sum score of 0 or 1 by the cutoff value in each ratio. RESULTS: The median follow-up time was 76 months for the patients who survived (n = 585) and 31 months for those who died (n = 172). The Youden Index offered an optimal cutoff of 1.5 for CAR and 2.8 for NLR, and a higher value from the cutoff was assigned as a score of 1. The cutoff value of the PHR was defined as 2.1 for males and 2.3 for females. The patients were assigned a CANLPH score of 0 (47.2%), 1 (31.3%), 2 (13.1%), or 3 (8.5%). In the multivariate analysis, the CANLPH score served as an independent predictor of cancer-specific mortality in both localized and metastatic RCC. CONCLUSION: The score was well-correlated with clinical outcome for the RCC patients. Because this score can be concisely measured at the point of diagnosis, physicians may be encouraged to incorporate this model into the treatment for RCC.

Preoperative Measurement of the Modified Glasgow Prognostic Score Predicts Patient Survival in Non-Metastatic Renal Cell Carcinoma Prior to Nephrectomy.

PURPOSE: The modified Glasgow Prognostic Score (mGPS) by measurement of serum C-reactive protein and albumin levels has been shown to provide prognostic value in various cancer types. The purpose of this study was to evaluate whether preoperative assessment of the mGPS predicts patient survival outcome in renal cell carcinoma (RCC). MATERIALS AND METHODS: Clinicopathological and follow-up data in 219 RCC patients, all of whom underwent curative or non-curative nephrectomy, were collected. Overall survival (OS) and cancer-specific survival (CSS) after nephrectomy were evaluated, and univariate and multivariate analyses were conducted to assess the predictive value of the variables, including the mGPS. RESULTS: During the median follow-up of 57 months, 53 patients (24.2%) were deceased within 22 months of the median OS. The 5-year OS rate from nephrectomy was 85.9 and 18.8% in non-metastatic (n = 195) and metastatic (n = 24) patients, respectively. Increasing mGPS was associated with shorter OS in non-metastatic patients (2-year OS rate of 98.2% in mGPS0, 73.3% in mGPS1, and 44.4% in mGPS2; hazard ratio [HR] 9.96, 95% confidence interval [CI] 4.88-20.13, p < 0.001), whereas no significant difference in OS according to the mGPS was seen in metastatic patients (HR 2.01, 95% CI 0.79-5.16, p = 0.137). On multivariate analysis, the mGPS remained as an independent predictor for OS (HR 5.24, 95% CI 1.39-19.77, p = 0.015) and CSS (HR 4.69, 95% CI 1.13-20.96, p = 0.034) in non-metastatic RCC patients. CONCLUSIONS: The mGPS appeared to be a reliable, preoperatively defined predictive marker with widely standardized protocol in non-metastatic RCC, and should therefore be considered in treatment decision making for RCC patients.

[Idiopathic Lumbar Hernia: A Case Report].

A 68-year-old woman, complained of an indolent lump about 60 × 70 mm in size in the left lower back. We conducted a computed tomography scan, which exhibited a hernia of Gerota'sfascia-commonly called superior lumbar hernia. In the right lateral position, the hernia contents were observed to attenuate, hence only closure of the hernial orifice was conducted by using Kugel patch, without removal of the hernia sack. Six months after the surgery, she has had no relapse of the hernia. Superior lumbar hernia, which occurs in an anatomically brittle region in the lower back, is a rare and potentially serious disease. The urologic surgeon should bear in mind this rarely seen entity.

[A CASE OF ADVANCED BLADDER NEUROENDOCRINE CARCINOMA (SMALL CELL CARCINOMA) SIGNIFICANTLY IMPROVED BY LOW DOSE OF ORAL TEGAFUR-URACIL].

A 81-old-woman underwent a transurethral resection of bladder tumor (TURBT) at a nearby hospital in April 2011. The diagnosis was invasive urothelial carcinoma, G3 with a component of bladder small cell carcinoma, T1 or more. She was recommended to visit our hospital for combined modality therapy of bladder cancer, but she refused the treatment for over one year. In May 2012, she came to our hospital with the chief complaint of pain at urination. Cystoscopy revealed non-papillary sessile tumor in the top of the bladder, and CT scan demonstrated the presence of the right obturator lymph nodes swollen up to 1.2 cm in size. The second TURBT was performed and the diagnosis was bladder small cell carcinoma (pT3N2M0) according to urothelial cancer guidelines of the Japanese Urological Association (JUA). Because she strongly refused hospitalization anymore, we started daily oral intake of low dose Tegafur-Uracil (100 mg) for the treatment. After one month, the serum Neuron-Specific Enolase (NSE; tumor maker of small cell cancer) level was elevated to 27.6 ng/ml and the right obturator lymph node was enlarged up to 1.9 cm. Therefore, the Trgafur-Uracil dose was increased to 200 mg daily. After then, the serum NSE level was decreased to 15.5 ng/ml following reduction in size of the obturator lymph nodes with partial response in December 2013. After two years of follow-up period, her regular urine test showed normal findings, and no apparent recurrence was detected on urinary bladder with MRI and Cystoscopy. This is a case of advanced bladder small cell carcinoma significantly improved by oral administration of Tegafur-Uracil 200 mg/day for over 2 years.

Tissue Distribution of Cisplatin by Intra-arterial Infusion Route in Comparison to Systemic Route: Implication to Therapy for Node-positive Bladder Cancer.

BACKGROUND/AIM: In clinical practice, platinum-based systemic chemotherapy works to shrink pelvic lymph nodes. Intra-arterial (IA) bolus infusion may result in more favorable results than systemic chemotherapy. In the present study, we investigated the distribution of cisplatin administrated by IA infusion in varying organs, specifically focusing on the node tissue, in comparison with the intravenous (IV) route. MATERIALS AND METHODS: Under anesthesia, cisplatin 0.42 mg/body was administrated by IA or IV infusion in rats to mimic a balloon-occluded arterial infusion model used in clinical practice. The kidney, bladder, lymphatic tissue, and peripheral blood were extracted to analyze the amount of cisplatin by inductively coupled plasma-mass spectrometry. RESULTS: Concertation of cisplatin by IA infusion was higher than that by the IV route in the peripheral blood and kidney. IA infusion led to a significantly high concentration of cisplatin in the bladder compared to IV infusion (1.3±0.452 vs. 0.2 ppb/mg ± 0.055, p=0.050). Furthermore, the IA method led to an extremely high concentration of cisplatin in the lymphatic tissue compared to the IV method (0.1±0.036 vs. 13.3±5.36, p=0.048). CONCLUSION: High cisplatin accumulation in the lymphatic tissue and bladder by IA administration may have a potential role for treating patients with node-positive bladder cancer.

Optimal Time Point for Evaluation of Response to Pembrolizumab Treatment in Japanese Patients With Metastatic Urothelial Carcinoma.

BACKGROUND/AIM: The duration of pembrolizumab use in actual daily practice might be shorter than that in clinical trials because termination of pembrolizumab therapy is at the discretion of the physician. We retrospectively reviewed the response to pembrolizumab in Japanese patients with metastatic urothelial carcinoma (mUC) in relation to the time to response (TTR). PATIENTS AND METHODS: The records of 165 patients treated with pembrolizumab for mUC were retrospectively analyzed. Response was evaluated at 2, 4, 6 and 8 months. TTR along with time to best response were analyzed. Phase II-III clinical trials were also reviewed to compare the TTR and time to best overall response. RESULTS: The median patient age was 70 years. The objective response rate in the total cohort was 27.1% (42 out of 155 patients). Median TTR was 2.4 months and the time to best response was 3.1 months. Radiological evaluation at each time point significantly predicted overall survival (OS). Considering the evaluation of response at 2, 4, 6 and 8 months, the response at later time points tended to predict OS better. Multivariate analysis showed that the evaluation of response at 8 months (hazard ratio=1.91, 95% confidence interval=1.16-3.16 months; p<0.01) and best response during the treatment (hazard ratio=1.69, 95% confidence interval=1.17-2.44; p<0.01) independently predicted improved OS. CONCLUSION: Given that response when evaluated at a later point during pembrolizumab treatment more favorably reflected improved survival than when assessed earlier, physicians may be encouraged to wait until at least the termination of pembrolizumab treatment to determine the best response.

Aging Affects the Role of Myeloid-Derived Suppressor Cells in Alloimmunity.

Myeloid-derived suppressor cells (MDSC) are defined as a group of myeloid cells with potent immunoregulatory functions that have been shown to be involved in a variety of immune-related diseases including infections, autoimmune disorders, and cancer. In organ transplantation, MDSC promote tolerance by modifying adaptive immune responses. With aging, however, substantial changes occur that affect immune functions and impact alloimmunity. Since the vast majority of transplant patients are elderly, age-specific modifications of MDSC are of relevance. Furthermore, understanding age-associated changes in MDSC may lead to improved therapeutic strategies. Here, we provide a comprehensive update on the effects of aging on MDSC and discuss potential consequences on alloimmunity.

Primary Graft Dysfunction: The Role of Aging in Lung Ischemia-Reperfusion Injury.

Transplant centers around the world have been using extended criteria donors to remedy the ongoing demand for lung transplantation. With a rapidly aging population, older donors are increasingly considered. Donor age, at the same time has been linked to higher rates of lung ischemia reperfusion injury (IRI). This process of acute, sterile inflammation occurring upon reperfusion is a key driver of primary graft dysfunction (PGD) leading to inferior short- and long-term survival. Understanding and improving the condition of older lungs is thus critical to optimize outcomes. Notably, ex vivo lung perfusion (EVLP) seems to have the potential of reconditioning ischemic lungs through ex-vivo perfusing and ventilation. Here, we aim to delineate mechanisms driving lung IRI and review both experimental and clinical data on the effects of aging in augmenting the consequences of IRI and PGD in lung transplantation.

Unplanned hemodialysis initiation and low geriatric nutritional risk index scores are associated with end-stage renal disease outcomes.

Patients with end-stage renal disease (ESRD) have a low nutritional status and a high mortality risk. The geriatric nutritional risk index (GNRI) is a predictive marker of malnutrition. However, the association between unplanned hemodialysis (HD) and GNRI with mortality remains unclear. In total, 162 patients underwent HD at our hospital. They were divided into two groups: those with unplanned initiation with a central venous catheter (CVC; n = 62) and those with planned initiation with prepared vascular access (n = 100). There were no significant differences in sex, age, malignant tumor, hypertension, and vascular disease, while there were significant differences in the times from the first visit to HD initiation (zero vs. six times, p < 0.001) and days between the first visit and HD initiation (5 vs. 175 days, p < 0.001). The CVC insertion group had significantly lower GNRI scores at initiation (85.7 vs. 99.0, p < 0.001). The adjusted hazard ratios were 4.002 and 3.018 for the GNRI scores and frequency, respectively. The 3-year survival rate was significantly lower in the CVC + low GNRI group (p < 0.0001). The GNRI after 1 month was significantly inferior in the CVC insertion group. Inadequate general management due to late referral to the nephrology department is a risk factor for patients with ESRD.

Prognostic value of the fluctuation in the neutrophil-lymphocyte ratio at 6 weeks of pembrolizumab treatment is specific to the clinical response in metastatic urothelial carcinoma.

PURPOSE: Most patients with metastatic urothelial carcinoma experience no objective response to pembrolizumab and have poor overall survival (OS). Here, we investigated the prognostic value of fluctuation in the neutrophil-lymphocyte ratio (NLR) at 6 weeks of pembrolizumab treatment, focusing on its association with the achievement of objective response. MATERIALS AND METHODS: The clinical records of 177 metastatic urothelial carcinoma patients treated with pembrolizumab were retrospectively analyzed. RESULTS: The median age was 72 years, and the median OS was 14 months. The objective response rate in the total cohort was 26.5% (47 of 177 patients). Multivariable analysis showed that objective response achievement (hazard ratio 0.3 [95% confidence interval 0.15-0.59], P < 0.001) and decline in NLR from that at baseline at 6 weeks of treatment (0.54 [0.34-0.88], P = 0.013) were independent prognostic factors for improved OS. For 47 (26.5%) patients who achieved an objective response, OS was similar regardless of NLR fluctuation at 6 weeks of treatment (P = 0.723). Intriguingly, of the 130 (73.5%) patients with no objective response, those who showed a decreased NLR at 6 weeks of pembrolizumab treatment (57 patients) from that at baseline had significantly longer OS than those with elevated NLR (73 patients) (14 vs. 6 months, P = 0.007). CONCLUSIONS: The fluctuation in NLR from that at baseline at 6 weeks of pembrolizumab treatment may be useful for patients without an objective response. This could potentially aid decision-making for post pembrolizumab therapies.