Hiroki Ishihara

Time to progression after first-line tyrosine kinase inhibitor predicts survival in patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy

OBJECTIVES The effect of response to first-line tyrosine kinase inhibitor (TKI) therapy on second-line survival in patients with metastatic renal cell carcinoma who receive second-line molecular-targeted therapy (mTT) after first-line failure remains unclear. MATERIALS AND METHODS Sixty patients who developed disease progression after first-line TKI, without prior cytokine therapy, were enrolled. According to the median first-line time to progression (1L-TTP), patients were divided into 2 groups (i.e., short vs. long). Second-line progression-free survival (2L-PFS) and second-line overall survival (2L-OS) were defined as the time from second-line mTT initiation. Survival was calculated with the Kaplan-Meier method and compared using the log-rank test between patients with short and long 1L-PFS. Predictors for survivals were identified using Cox proportional hazards regression models. RESULTS The median 1L-TTP was 8.84 months. Thirty patients (50.0%) with short 1L-TTP (<8.84mo) had significantly shorter 2L-PFS and 2L-OS compared to patients with long 1L-TTP (2L-PFS: 4.96 vs. 10.2mo, P = 0.0002; 2L-OS: 9.6 vs. 28.0mo, P = 0.0036). Multivariable analyses for 2L-PFS and 2L-OS showed that 1L-TTP was an independent predictor both as a categorical classification (cutoff: 8.84mo) and as a continuous variable (both P<0.05). The median follow-up duration was 13.1 months (interquartile range: 6.56-24.7). CONCLUSIONS Patients who achieve a long-term response after first-line TKI therapy could have a favorable prognosis with second-line mTT.

Effect of Systemic Inflammation on Survival in Patients With Metastatic Renal Cell Carcinoma Receiving Second-line Molecular-targeted Therapy

Background The role of systemic inflammatory markers, including C‐reactive protein (CRP), the neutrophil/lymphocyte ratio (NLR), and the platelet/lymphocyte ratio (PLR), in predicting survival for patients with metastatic renal cell carcinoma receiving second‐line molecular‐targeted therapy (mTT) after first‐line tyrosine kinase inhibitor failure remains unclear. Thus, we investigated the relationship between systemic inflammation and survival in such patients. Patients and Methods Sixty‐three patients were evaluated. Progression‐free survival (PFS) and overall survival (OS) after second‐line mTT initiation were evaluated according to the inflammatory marker levels. In addition, the prognostic factors for survival were examined. Results The receiver operating characteristic curves for CRP, NLR, and PLR had areas under the curve of 0.779, 0.619, and 0.655, respectively; no significant differences were noted. The corresponding cutoff values were 0.48, 2.53, and 183. Patients with higher CRP (n = 40), NLR (n = 32), and PLR (n = 22) levels had significantly lower PFS and OS than those with lower CRP, NLR, and PLR levels. Multivariate analyses showed that CRP was the sole independent predictor for PFS and OS. Conclusion Systemic inflammation is associated with survival after second‐line mTT. In particular, CRP was a strong independent predictive biomarker of prognosis. Micro‐Abstract We evaluated the relationship between systematic inflammatory markers (C‐reactive protein, neutrophil/lymphocyte ratio, and platelet/lymphocyte ratio) and survival in a cohort of 63 patients with metastatic renal cell carcinoma receiving second‐line molecular‐targeted therapy after first‐line tyrosine kinase inhibitor failure. Each marker was associated with progression‐free and overall survival. In particular, C‐reactive protein was a strong independent predictive biomarker of prognosis.

Evaluation of Preoperative Aspartate Transaminase/Alanine Transaminase Ratio as an Independent Predictive Biomarker in Patients With Metastatic Renal Cell Carcinoma Undergoing Cytoreductive Nephrectomy: A Propensity Score Matching Study

Micro‐Abstract We evaluated the aspartate transaminase/alanine transaminase (De Ritis) ratio as a predictive biomarker for metastatic renal cell carcinoma patients undergoing cytoreductive nephrectomy, using propensity score matching. The ratio was an independent predictor for cancer‐specific and overall survival after cytoreductive nephrectomy. This novel biomarker can be used to predict the prognosis of metastatic renal cell carcinoma patients before cytoreductive nephrectomy. Background: The usefulness of the aspartate transaminase (AST)/alanine transaminase (ALT) ratio (De Ritis ratio) as a predictive biomarker for patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy (CN) remains unclear. Patients and Methods: The data from 118 patients were retrospectively evaluated. The endpoints were cancer‐specific survival (CSS) and overall survival (OS) after CN. We compared these according to the AST/ALT ratio before and after 1:1 propensity score matching. The independent predictors for CSS and OS were also analyzed. Results: The area under the receiver operating characteristic curve was 0.603. The maximum Youden index indicated that the cutoff value for the AST/ALT ratio was 1.24. Before matching, a high AST/ALT ratio was significantly associated with inferior CSS and OS (P < .05 for all). After matching, 34 patients each were allocated to the high and low AST/ALT ratio groups. In the matched cohort, CSS and OS tended to be lower in the high AST/ALT ratio group, although the results were not statistically significant (median CSS, 18.4 months vs. not reached, P = .121; OS, 18.4 months vs. not reached, P = .0957). Furthermore, multivariate analyses revealed that the AST/ALT ratio was an independent predictor for CSS and OS (CSS hazard ratio, 2.17, P = .0472; OS hazard ratio, 2.30, P = .0258). Conclusion: The preoperative AST/ALT ratio can be an effective predictive biomarker for CSS and OS in patients with mRCC.

Preoperative controlling nutritional status (CONUT) score as a novel predictive biomarker of survival in patients with localized urothelial carcinoma of the upper urinary tract treated with radical nephroureterectomy

OBJECTIVE The purpose of this study was to investigate the correlation between the controlling nutritional status (CONUT) score and survival of patients with localized urothelial carcinoma of the upper urinary tract treated with radical nephroureterectomy (RNU). METHODS AND MATERIALS We retrospectively enrolled 107 patients. CONUT score was calculated based on the serum albumin concentration, lymphocyte count, and total cholesterol concentration. Patients were classified into 2 groups based on CONUT score. Relapse-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) after RNU were compared between the 2 groups, and predictors of survival were analyzed using Cox proportional hazards regression models. RESULTS For CONUT score, the area under the curve was 0.588 and the optimal cutoff value was 3. Twenty-four patients (22.4%) had high CONUT scores. The patients with high CONUT scores had significantly shorter 5-year RFS, CSS, and OS than did those with low CONUT scores (RFS: 50.1% vs. 66.0%; CSS: 28.1% vs. 71.7%; OS: 26.4% vs. 66.8%; all P<0.05). Results of the multivariable analysis, after adjustment for factors such as pT stage, pN stage, tumor grade, presence of lymphovascular invasion, and C-reactive protein level, revealed that CONUT score was an independent predictor of CSS (hazard ratio [HR] = 5.44, P = 0.0016) and OS (HR = 2.90, P = 0.0214) and showed marginal significance for predicting RFS (HR = 2.26, P = 0.0581). CONCLUSIONS Preoperative CONUT score helps predict survival in patients with localized urothelial carcinoma of the upper urinary tract treated with RNU.

The magnitude of best tumor shrinkage during second-line targeted therapy affects progression-free survival but not overall survival in patients with metastatic renal cell carcinoma

OBJECTIVE The present study aimed to evaluate the influence of the magnitude of best tumor shrinkage during second-line targeted therapy after first-line tyrosine kinase inhibitor failure on metastatic renal cell carcinoma prognosis. METHODS Fifty-two patients were enrolled. The magnitude of tumor shrinkage was assessed according to the Response Evaluation Criteria in Solid Tumors v. 1.1, and evaluated as a continuous variable and by categorical classification: good responders (greater than or equal to -30%), mild responders (-0.1 to -29.9%), poor responders (0 to +19.9%) and non-responders (greater than or equal to +20% or new lesions). Overall survival and progression-free survival after second-line therapy initiation were evaluated according to the categorical classification. Factors predicting overall survival and progression-free survival were also examined. RESULTS The mean magnitude of tumor shrinkage was -1.29%, and there were 9, 21, 11 and 11 good responders, mild responders, poor responders and non-responders, respectively. The overall survival and progression-free survival significantly improved as the magnitude of tumor shrinkage increased according to the categorical classification (overall survival: not reached, 27.8, 18.2 and 4.67 months; progression-free survival: 13.4, 8.19, 5.18 and 1.84 months, respectively; P< 0.0001 for both). For overall survival, the magnitude of tomor shrinkage was not demonstrated as an independent indicator in the multivariate analysis (P= 0.0872 for the categorical classification, P= 0.133 for the continuous variable) whereas for second-line progression-free survival, the magnitude of tumor shrinkage according to both the categorical classification and continuous variable was found to be an independent factor in the multivariate analysis (P< 0.0001 for both). CONCLUSIONS The magnitude of tumor shrinkage is an independent predictive factor for progression-free survival, and may represent a surrogate marker for overall survival.

Evaluation of renal function change during first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma

Sunitinib and sorafenib therapy for metastatic renal cell carcinoma can induce the renal dysfunction. Thus, renal function should be carefully monitored, especially during sunitinib therapy, because the impact of sunitinib on renal dysfunction was stronger.

Evaluation of relative dose intensity during the early phase of first-line sunitinib treatment using a 2-week-on/1-week-off regimen for metastatic renal cell carcinoma

Sunitinib treatment with a 2-week-on/1-week-off schedule (Schedule 2/1) is a common alternative regimen with high relative dose intensity (RDI) and superior tolerability for patients with metastatic renal cell carcinoma (mRCC). The prognostic impact of RDI is reported only in 4-week-on/2-week-off or mixed regimens. Herein, we evaluated the prognostic impact of RDI during early-phase sunitinib treatment using Schedule 2/1. Seventy-four patients who received first-line sunitinib treatment using Schedule 2/1 were evaluated. Endpoints were progression-free survival (PFS) and overall survival (OS). We assessed RDI within the initial two cycles (2c-RDI), and its prognostic impact. Predictive factors for 2c-RDI deterioration were also evaluated. The cut-off value of 2c-RDI was set at 65%. Based on this cut-off, 31 patients (42.0%) were classified into the low 2c-RDI group (< 65%). PFS and OS were significantly shorter in the low-2c-RDI patients, compared with the high 2c-RDI patients (median PFS: 6.15 vs. 18.4 months, p = 0.0005; OS 11.0 vs. 39.3 months, p = 0.0002). Furthermore, multivariate analyses showed that the development of dose-limiting toxicities (DLTs) within the initial two cycles, as well as low initial dose, were independent factors for low 2c-RDI (DLTs: OR 18.6, 95% CI 3.27–105.30, p = 0.0010; initial dose: OR 9.26, 95% CI 1.42–60.40, p = 0.020). The most common adverse event was thrombocytopenia (any grade: 24.3%; grade ≥ 3: 8.1%). More than 65% of 2c-RDI should be maintained for optimal therapeutic effect of sunitinib treatment using Schedule 2/1. To achieve the appropriate 2c-RDI, careful follow-up for patient tolerability is needed to avoid early DLT development.

Evaluation of Microvascular Inflammation in ABO-incompatible Kidney Transplantation.

Background In ABO-incompatible kidney transplantation, the diagnostic criteria for antibody-mediated rejection remain controversial because C4d deposition is commonly observed. Thus, we investigated microvascular inflammation (MVI score ≥ 2) within 1 year as a predictor of graft outcome. Methods A total of 148 recipients without preformed or de novo donor-specific anti-HLA antibody were stratified based on MVI score less than 2 (n = 117) and MVI score of 2 or greater (n = 31). Results We found that 5-year graft survival was significantly lower (P = 0.0129) in patients with MVI (89.8%) than in patients without MVI (97.0%). Graft function, as characterized by serum estimated glomerular filtration rate, was also significantly worse for patients with MVI than it was for patients without MVI, between 3 months and 10 years after transplantation (P = 0.048). Multivariate analysis indicated that HLA class II mismatch (P = 0.0085) was an independent marker of MVI. Conclusions Microvascular inflammation score of 2 or greater is significantly associated with poor graft outcome after ABO-incompatible kidney transplantation. We suggest that MVI score of 2 or greater in ABOi transplantation be used as a basis to diagnose antibody-mediated rejection.

Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder Following Kidney Transplantation: A Multi-Institution Study in Japan Over 30 years

ally, ESRD-related RCC is less aggressive, with papillary RCC being the most common histological subtype (48–75%) (6). In their work, Nakai et al. proposed the use of TKI treatment for RCC in hemodialysis patients, comparing the outcomes between 13 patients who received TKI treatment (six of them as first-line therapy) and a control group of 15 patients treated with surgery only. They found that the TKI group was associated with increased blood pressure that required more intensive interventions on hypertension and dry weight (1). The experience of our center suggests that in dialysis patients with RCC, a first-line treatment using TKI might disregard some aspects: the minor severity of the ESRD-related RCC, the documented effectiveness and satisfactory outcome of the surgical approach, and in particular, the more complex long-term management and follow-up of TKItreated patients, potentially eligible for renal transplantation. We believe that this kind of strategy should be reserved exclusively as a second-line therapy for patients with metastatic cancer and those excluded from a kidney transplant waiting list. Our clinical practice, together with the results of Nakai and colleagues, improve the probability for these patients to access the active kidney transplant waiting list. Conversely, the likelihood of becoming good candidates to receive a kidney transplant appears to be reduced in the patients only treated with TKI therapy, due to the necessity of a stricter management of the adverse events, mainly hypertension and dry weight adjustment. To confirm this vision, recent evidence showed that laparoscopic radical nephrectomy appears to be safe and feasible for non-metastatic RCC patients under hemodialysis treatment, and following tumor removal, the patients can be considered as eligible for renal transplant, after an observation waiting period to ensure nonrecurrence (7).

Evaluation of tumor burden after sequential molecular-targeted therapy in patients with metastatic renal cell carcinoma

Background To evaluate the effect of tumor burden on survival in patients with metastatic renal cell carcinoma who are administered sequential molecular-targeted therapy. Methods A total of 68 patients were recruited. Baseline tumor burden at the time of second-line therapy initiation was calculated according to the Response Evaluation Criteria in Solid Tumors v. 1.1. Patients were divided into two subgroups according to the median tumor burden: greater than the median as the high group, lower than the median as the low group. Progression-free survival and overall survival after second-line therapy were analyzed. The effect of tumor burden changes on survival during sequential targeted therapy were also evaluated. Results Median second-line tumor burden was 57.7 cm. The patients with high tumor burden had significantly poorer progression-free survival and overall survival, compared to those with low tumor burden (median progression-free survival = 4.36 vs. 8.19 months, P = 0.0119; overall survival = 9.6 vs. 23.5 months, P = 0.0107). For progression-free survival, multivariate analyses revealed that second-line objective response was an independent predictor (P < 0.0001), but second-line tumor burden was not (P = 0.0826). For overall survival, second-line tumor burden and objective response were independent predictors (P = 0.0300 and <0.0001, respectively). Moreover, there was a positive correlation between first- and second-line tumor burden (r2 = 0.460, P < 0.0001), although tumor burden changes between first- and second-line therapies did not affect survival (median progression-free survival, P = 0.812; overall survival, P = 0.415). Conclusions Second-line tumor burden was an independent predictor of overall survival among patients with metastatic renal cell carcinoma after second-line therapy.